Sande's HIV - AIDS Medicine (PDFDrive)

Chapter |1|
The global epidemiology of HIV/AIDS

Irum Zaidi, Kevin M. De Cock
global epidemic and shows great genetic diversity with nine

OVERVIEW OF THE GLOBAL EPIDEMIC subtypes (A–D, F–H, J, and K) and at least 48 circulating
recombinant forms. HIV-1 groups N, O, and P are rare
There have been tremendous changes in the global HIV and essentially restricted to persons from Central Africa.
epidemic since the 1990s with declines in incident infec- The single most common subtype of HIV-1 is subtype C,
tions, increased coverage of antiretroviral therapy, stabili- which affects nearly 17 million people in southern Africa,
zation or declines in HIV prevalence, reduction of mother- parts of East Africa, and Asia [2]. The number of HIV-2 in-
to-child transmission, and reduction in AIDS-related fections globally is small and seems to be decreasing; most
deaths. Many of these advances resulted from the dramatic are associated with West Africa.
increase in HIV program investments in low- and middle-
income countries, which grew from US$1.4 billion in
2001 to US$15.9 billion in 2009. These resources
have supported HIV treatment for over 6 million people MEASUREMENT OF DISEASE
worldwide [1].
Nonetheless, even with the recent stabilization of the Methods for measuring HIV incidence and prevalence
global epidemic, HIV/AIDS has had devastating impact continue to evolve to more accurately measure disease bur-
on lives worldwide and especially in sub-Saharan Africa. den [3]. The progression of the disease, late manifestation
There were an estimated 33.3 million (31.4–35.3 million) of symptoms, HIV testing behaviors, and antiretroviral
people globally living with HIV at the end of 2009, a num- therapy all challenge our ability to use epidemiologic
ber that may continue to increase as incident cases continue and laboratory methods to measure HIV incidence and
to accrue and deaths to fall secondary to antiretroviral ther- prevalence [4, 5].
apy. A decrease in new HIV infections has occurred, from Surveillance methods have drastically improved within
an estimated 3.1 million (2.9–3.4 million) in 2001 to the past decade. In low- and middle-income countries,
2.6 million (2.3–2.8 million) in 2009 [1]. sentinel surveillance among pregnant women attending
There is genetic, epidemiologic, and behavioral heteroge- antenatal clinics has been the cornerstone of efforts to esti-
neity in the global HIV epidemic, with different regions dis- mate HIV prevalence in the general population. Pregnant
proportionately impacted by the virus. Generalized spread women are by definition sexually active, give insight into
has occurred in sub-Saharan Africa while HIV/AIDS else- prevalence trends in the general population, and are easy
where has largely been restricted to key vulnerable popula- to survey since they access health services [6]. The coverage
tions (men who have sex with men, injecting drug users, and quality of this surveillance approach has improved to
and sex workers and their clients) [1]. provide more representative data [7].
Phylogenetically, two types of HIV are recognized, HIV-1 Countries with generalized HIV epidemics, meaning that
and HIV-2; within HIV-1 there are four groups, group M, HIV transmission is sustained in the general population
group N, group O, and group P and within HIV-2, eight outside of core groups, have in addition been conducting
groups. HIV-1 group M is the predominant cause of the periodic national household surveys to estimate national
3
Section | 1 | Epidemiology and biology of HIV infection
HIV prevalence and collect behavioral information related with men, and special studies can address diverse issues
to HIV acquisition and transmission. Arbitrarily, an HIV such as access to and adherence to therapy or the spectrum
prevalence greater than 1% has sometimes been assumed of disease in people living with HIV.
to indicate generalized spread, although this assumption Case reporting requires use of a standard case definition
is unreliable. Several high-burden countries have now con- which is a surveillance tool, and not intended for clinical
ducted more than one household survey, usually at approx- management of patients. For clinical purposes, staging sys-
imately 5-year intervals, to monitor trends and measure tems can help assist clinicians define where individual
impact of HIV programs. These national surveys are used patients lie on the spectrum of HIV-associated immunode-
to adjust prevalence levels from sentinel site surveillance ficiency and disease. Different case definitions have been
in pregnant women to more accurately reflect those of used over time as understanding of HIV/AIDS and surveil-
the general population. Common experience has been that lance practices evolved, and taking account of local re-
in relation to nationally representative household surveys, sources for investigation and reporting of cases.
sentinel site surveillance based on pregnant women att- The revised 2006 case definitions and staging system pro-
ending antenatal clinics has tended to overestimate HIV posed by WHO provide standardized definitions for global
prevalence. This realization was key to UNAIDS and the use to improve patient management, patient monitoring,
World Health Organization (WHO) lowering global HIV and surveillance [9, 10]. Four clinical stages and four
estimates considerably in late 2007 [3]. immunological stages were established (Table 1.1a and
Countries with low-level or concentrated epidemics con- 1.1b), reflecting the known decline in clinical status and
duct biological and behavioral surveys among high-risk CD4 cells with the progression of HIV disease. The surveil-
populations, which include injection drug users, men lance definitions for HIV/AIDS were also revised to include
who have sex with men, and male and female sex workers. three categories: HIV infection, advanced HIV disease,
New methods for accessing higher-risk populations that are and AIDS (Box 1.1). Although a standard case definition
often hard to reach continue to be validated [8]. Recently, for primary (acute) HIV infection is not established, iden-
countries with generalized epidemics have also been con- tifying and reporting cases of primary infection may be im-
ducting biological and behavioral surveys among higher- portant because these represent very recent infections.
risk populations that are disproportionately affected even Symptomatic primary HIV infection presents one to four
in generalized epidemics. An important epidemiologic weeks after HIV acquisition and may include any of the
exercise has been estimating the respective population following symptoms:
sizes of these high-risk groups, allowing estimates of their • Lymphadenopathy;
total numbers of HIV infections and contributions to • Pharyngitis;
overall HIV infection incidence, which is useful for alloca- • Maculopapular rash;
tion of resources for prevention of different modes of • Orogenital or oesophageal ulcers;
transmission. • Menigoencephalitis;
In high-income, industrialized countries such as the • Lymphopenia (including low CD4); and
United States and countries in Europe, which have concen- • Opportunistic infections.
trated epidemics, individual AIDS case reporting was for
These clinical conditions should not be confused with
a long time the basis for monitoring epidemiologic
clinical staging criteria. Primary HIV infection can be
trends. Because of the long incubation period between
diagnosed by recent HIV antibody development or by
HIV infection and disease, AIDS case surveillance reflects
identifying HIV products (HIV-RNA or HIV-DNA and/or
patterns of HIV transmission that were prevalent several
ultrasensitive HIV p24 antigen with a negative HIV
years earlier. With the advent of antiretroviral therapy the
antibody test).
predictable progression to AIDS was interrupted, thus se-
verely limiting the ability of AIDS data to give insight into
HIV transmission patterns. As a result, the importance of
HIV infection case reporting was considerably enhanced.
Today, high-income countries with robust surveillance sys- Table 1.1a WHO clinical staging of established
tems track both HIV and AIDS case reports, but both give HIV infection
incomplete information.
HIV case reports reflect HIV incidence imperfectly be- HIV-ASSOCIATED WHO CLINICAL
cause they require HIV-infected persons to be tested and SYMPTOMS STAGE
reported. AIDS case rates are affected by previous HIV inci-
Asymptomatic 1
dence but also by the effectiveness of HIV diagnosis, access
to antiretroviral therapy, and response to treatment. For as Mild symptoms 2
complete as possible an understanding of the HIV/AIDS ep-
idemic, in addition to case reporting there is also a need for Advanced symptoms 3
surveys and special studies. Surveys include behavioral and
Severe symptoms 4
biologic studies in special groups such as men who have sex
4
Chapter |1| The global epidemiology of HIV/AIDS
Table 1.1b WHO immunological classification for established HIV infection
HIV-ASSOCIATED AGE-RELATED CD4 VALUES

IMMUNODEFICIENCY
< 11 mo 12–35 mo 36–59 mo 5 yrs

(%) (%) (%) (per mm3)
None/not significant > 35 > 30 > 25 > 500
Mild 30–35 25–30 20–25 350–499
Advanced 25–30 20–25 15–20 200–349
Severe < 25 < 20 < 15 < 200 or < 15%
Box 1.1 WHO case definition for HIV infection for reporting for adults and children
1. Adults, and children 18 months and older: 2. Immunologic criteria for diagnosis of advanced HIV in
Diagnosis of HIV infection is made with: adults and children 5 years, with documented HIV
Positive HIV antibody testing (rapid or laboratory- infection:
based EIA). This is usually confirmed by a second HIV CD4 count less than 350/mm3 in an HIV-infected adult or
antibody test (rapid or laboratory-based EIA) relying on child.
different antigens or on different operating 3. Immunologic criteria for diagnosis of advanced HIV in
characteristics. a child <5 years of age with documented HIV
And/or infection:
Positive virological test for HIV or its components %CD4 < 30 in those 11 months of age;
(HIV-RNA or HIV-DNA or ultrasensitive HIV p 24 antigen) %CD4 < 25 in those aged 12–35 months; and
confirmed by a second virological test obtained from a %CD4 < 20 in those aged 36–59 months.
separate determination. 1
2. Children younger than 18 months: Where access to virological testing in children less than
Diagnosis of HIV infection is made with: 18 months is limited, confirmation of HIV infection can be
Positive virological test for HIV or its components obtained from repeat testing on the same specimen where
(HIV-RNA or HIV-DNA or ultrasensitive HIV p 24 antigen) laboratory quality assurance, including specimen handling is
confirmed by a second virological test obtained from a guaranteed.
2
separate determination taken more than 4 weeks after AIDS in adults and children is defined as clinical diagnosis
birth [1]. (presumptive or definitive ) of any one stage 4 condition (as
Positive antibody testing is not recommended for defined in annex 1); OR immunological criteria in adults and
definitive or confirmatory diagnosis of HIV infection in children > 5 years with documented HIV infection first-ever
children until 18 months of age. documented CD4 count less than 200/mm3 or %CD4 <15; or
WHO criteria for diagnosis of advanced HIV in a child < 5 years with documented HIV infection first-ever
(including AIDS [2]) for reporting for adults and documented CD4 of %CD4 < 25 in those infants 11
children months of age; %CD4 < 20 in those aged 12–35 months, or
1. Clinical criteria for diagnosis of advanced HIV in %CD4 < 15 in those aged 35–59 months.
adults and children with documented HIV Note: AIDS case reporting is no longer required if HIV
infection: infection or advanced HIV infection is reported.
Presumptive or definitive diagnosis of any one stage 3 or
stage 4 condition.
Countries with established national HIV case surveil-

lance systems (mostly Western countries) use back- HIV TRANSMISSION
calculation methods or direct calculation to determine
HIV prevalence and incidence [4, 11]. Other countries rely HIV is transmitted from person to person through hetero-
on epidemic models based on data from surveillance of key sexual and male-to-male sexual intercourse; through expo-
populations to estimate HIV prevalence and incidence and sure to infected blood or blood products; and from mother
monitor trends [12]. to child, including through breastfeeding. Surveillance
5
plays an important role in quantifying the proportional Injection drug use and exposure to
contribution of different modes of transmission to the contaminated blood
overall epidemic in any country, allowing rational resource
allocation for prevention, treatment, and care to different There are an estimated 15.9 million (11–21 million) injec-
groups. tors worldwide, and injection drug use is an increasing phe-
nomenon globally that is extending into regions where it
was previously not seen. Eastern Europe has the highest
Sexual transmission rates of injection drug use (Fig. 1.1), which is coupled with
Most HIV infections are transmitted sexually, with hete- high rates of HIV among this population. Overall, there are
rosexual transmission being the dominant mode of trans- an estimated 3 million HIV-positive drug injectors world-
mission globally. As with all modes of transmission, wide with the majority residing in China, Russia, and the
infectiousness is determined by viral load: the higher the United States [18].
viral load, the more likely that transmission will occur. Although HIV infection from exposure to contaminated
Other sexually transmitted infections, especially ulcerative blood and blood products was recognized early on as an
conditions including HSV-2 infection, increase viral shed- important mode of transmission, transfusion safety initia-
ding in genital fluids and transmissibility [13]. Male cir- tives have essentially eliminated or very greatly reduced the
cumcision is partially protective (approximately 50–60% risk of acquiring HIV infection from contaminated blood.
efficacy) against heterosexual acquisition of HIV [14]. Although the risk of HIV transmission through needlestick
Although there is no definitive evidence that male circum- injury is well understood (0.003 risk of transmission
cision protects against male-to-female transmission, indi- for uncomplicated needlesticks from an infected source),
rect benefit to women will ultimately result from reduced the relative contribution of such nosocomial events to over-
HIV prevalence in men. The risk of HIV infection increases all numbers of HIV infections in high-burden settings has
with the number of sex partners, and because of their high been difficult to quantify [19].
viral load, persons recently infected may contribute dispro-
portionately to spread [15]. The highest rates of HIV infec-
tion are found in persons with the greatest rate of partner
change such as sex workers. There is debate about the epi- REGIONAL REVIEW
demiologic impact of concurrent versus sequential partner-
ships, the former suggested as establishing more efficient
Sub-Saharan Africa
transmission networks. In the generalized epidemics of
southern and eastern Africa, a substantial proportion of Although two-thirds of all HIV-infected persons reside in
heterosexually transmitted infections occur in stable or sub-Saharan Africa, this most heavily affected part of the
long-term sero-discordant couples. world has seen substantial epidemiologic changes over
High rates of HIV infection are found among men who the past 10 years, with a decrease in new HIV infections
have sex with men almost everywhere they have been stud- and deaths and stabilizing or declining HIV prevalence.
ied. Recognition that male-to-male sex occurs in virtually Sub-Saharan Africa illustrates better than any other region
all countries, including in sub-Saharan Africa, is relatively the social, economic, demographic, and medical impact of
recent, as is the documentation of high rates of HIV infec- HIV/AIDS which accounted for the unprecedented global
tion in men who have sex with men in societies suffering health response.
generalized HIV epidemics [16]. Striking heterogeneity characterizes the sub-Saharan
African epidemic, with the highest rates of infection in
southern African countries, followed by countries in East,
Mother-to-child transmission
West, and Central Africa (Fig. 1.2). Twenty-five percent of
HIV can be transmitted from mother to child in utero, all persons living with HIV in sub-Saharan Africa reside in
around delivery, or after birth during breastfeeding. South Africa. Although rates of infection are extremely high
Prophylaxis or treatment with antiretroviral drugs has in neighboring countries, their small populations mean that
drastically reduced the vertical transmission rate, which absolute numbers of infected persons are limited. Nigeria,
without intervention ranges from about 15% in non- which has a much lower HIV prevalence than countries in
breastfeeding women to 45% for those breastfeeding up southern Africa, accounts for 15% of Africans living with
to 24 months [17]. HIV, and countries of East Africa for one quarter [1].
The great majority of HIV-infected women reside in sub- Heterosexual transmission accounts for most of the HIV
Saharan Africa where the overall HIV prevalence in women transmission in sub-Saharan Africa and women contribute
aged 15–24 was estimated at 3.4%; in 2009 there were an approximately 60% of all HIV infections. Serial age and sex-
estimated 370,000 children newly infected with HIV, with specific prevalence shows women are infected at younger
the majority of these infections occurring in sub-Saharan ages than men, presumably a reflection of older men with
Africa. HIV having sex with younger women. A relatively recent
6
No reports of injecting drug use identified

Injecting drug use reported but no estimate of prevalence
1%
0.5% – < 1%
0.25% – < 0.5%
> 0% – < 0.25%
Figure 1.1 Global prevalence of injection drug use.

Reprinted from the Lancet. Mathers BM, Degenhardt L, Phillips B, et al. Global epidemiology of injecting drug use and HIV among people who inject
drugs: a systematic review. Lancet 2010; 375:1014–1028. Copyright Elsevier 2010.
No data
< 0.1%
0.1% – < 0.5%
0.5% – < 1%
1% – < 5%
5% – < 15%
> 15% – < 20%
Figure 1.2 Global prevalence of HIV, 2009.

From UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2010. With permission of UNAIDS=ONUSIDA 2010.
7
recognition is that sub-Saharan Africa also has an epidemic West

of HIV among men who have sex with men and that many
West Africa has considerable virologic diversity, with all
of such men also have sexual relations with women. Most
subtypes and circulating recombinant forms found in this
studies have shown higher HIV prevalence among men
sub-region [2]. Nigeria has the largest HIV epidemic in the
who have sex with men than among exclusively heterosex-
sub-region, with an estimated adult prevalence of 3.6% and
ual males, in the range of approximately 12–30% [16].
3.3 million persons living with HIV. Others countries with
Although approximately 70% of AIDS-related deaths
higher prevalence are Côte d’Ivoire, Ghana, and Togo,
worldwide occur in sub-Saharan Africa, AIDS-related
countries that have been closely linked by trade and move-
mortality on the continent has declined with scale-up of
ment of people. Most countries have either stabilizing or
antitretroviral therapy [1].
decreasing HIV epidemics, although Sierra Leone (1.1%
in 2001 to 1.6% in 2009) and Gambia have shown increas-
South ing adult HIV prevalence (0.6 to 2.0% in Gambia).
HIV incidence estimates indicate slowing epidemics in
Countries in southern Africa have the highest rates of HIV
many countries in the sub-region, with Côte d’Ivoire,
in the world with the largest number of people living with
Guinea-Bissau, and Ghana showing the greatest reduction
HIV in South Africa, an estimated 5.6 million. Lack of male
in incident infections. With the reduction of incidence (and
circumcision, high rates of HSV-2, intergenerational sex,
prevalence) in Guinea-Bissau and other countries with
and high rates of partner change consequent upon large-
HIV-2, the overall prevalence of HIV-2 is also decreasing
scale migration for work all likely contributed to generating
to less than one million infections worldwide [2]. Data
and sustaining these severe epidemics. Swaziland has
from Côte d’Ivoire also illustrate a reduction in behaviors
the highest adult HIV prevalence (25.9%) in the world.
related to HIV transmission among men and women with
Botswana and Lesotho also have extremely high prevalence
decreasing HIV prevalence, including among young
(24.8%, 23.6%), while HIV prevalence in Angola (2%)
women 15–24 years attending antenatal clinics [21].
is very low compared to other countries within the sub-
The lower prevalence of HIV infection in West Africa than
region [1]. The prolonged civil war in Angola seems to have
in other sub-regions is likely to be due in part to high rates
had a protective effect against HIV by limiting travel and in-
of male circumcision [23].
teractions with other countries in the region with higher
HIV prevalence [20].
Incidence estimates suggest decreasing numbers of new Central
infections since 2001 in almost all countries in southern
Africa, with Botswana, Namibia, Swaziland, and Zimbabwe Cameroon and the Democratic Republic of Congo (DRC)
experiencing the greatest relative declines. Additionally, in have the greatest HIV-1 genetic diversity in the world,
Malawi, Namibia, Zambia, and Zimbabwe, measurement with nearly all subtypes and CRF in these countries. HIV
of sexual behaviors shows declines in the percent of people prevalence in this sub-region is stabilizing, with some
who had had sex by the age of 15–19 years, who had more countries experiencing a decrease in incident infections.
than one partner in the past year, and who had more than Cameroon has the greatest number of persons infected
one partner in the past and did not use condoms [21]. HIV (610,000), with an overall adult HIV prevalence of
prevalence is higher among young women than young men 5.3%. The Republic of Congo shows the lowest adult
in most of the countries in the sub-region. HIV prevalence, 3.4%. Incidence estimates in the region
show decreasing new infections in the Central African Re-
public, Congo, and Gabon [1]. Data from surveillance in
East antenatal clinics in the DRC also illustrate declining prev-
The HIV epidemic in East Africa shows sign of slowing and alence among antenatal clinic attendees from 2004 to
stabilization. Although adult HIV prevalence rates are 2009 [24].
lower in the sub-region than in southern Africa, ranging
from 2.9% in Rwanda to 6.3% in Kenya, the actual number
Europe
of people living with HIV is high given the large popula-
tions in East African countries [1]. Overall there may have There were an estimated 2.2 million people living with HIV
been changes in HIV risk behaviors and likely reduced HIV in WHO’s European Region whose countries have HIV and
incidence in countries such as Ethiopia, Kenya, and Tanza- AIDS case reporting systems of varying completeness. A to-
nia, but patterns of change are diverse [21]. In Uganda, for tal of 53,427 cases of HIV were diagnosed and reported
example, there is concern that gains in HIV prevention from 49 of the 53 countries in the WHO European Region
achieved early on in the epidemic are being reversed [22]. in 2009 (case surveillance data were not available from
While antenatal HIV prevalence has declined in Kenya in Austria, Monaco, Russia, and Turkey). There were a total
the early part of this century, the trend in antenatal HIV of 6,568 AIDS cases reported in 2009 (Austria, Sweden,
prevalence in Uganda has been upwards [22]. Monaco, Russia, and Turkey did not report) and 1,776
8
cases diagnosed with AIDS were reported to have died, al- has doubled since 2001, with most infections among drug
most half the AIDS-related deaths reported in 2008 [25]. injectors. HIV prevalence among high-risk populations in
The three sub-regions within Europe have differing epi- Moscow show elevated prevalence among injection drug
demics, with Eastern Europe experiencing increasing HIV users (15.6%), men who have sex with men (8.3%),
incidence related to injection drug use; HIV epidemics in and female sex workers (4.5%) [1]. With an estimated
the central and western sub-regions seem to be stable with 1.8 million injection drug users in Russia, the HIV epidemic
HIV infection rates remaining similar over the past five among this population is increasing and an important pub-
years. lic health challenge since HIV-infected drug injectors can
drive secondary transmission to sex partners and children
as a result of mother-to-child transmission [18].
West
In 2009, 24,703 cases of HIV infection were newly diag-
nosed from 21 of 23 countries in the sub-region, a rate Central
of 6.7 per 100,000. Seventy-two percent of cases diagnosed A total of 1,612 cases of HIV were diagnosed in 2009 (all 14
were among males and 10% of cases were in persons 15–24 countries reporting); a rate of 1.4 per 100,000. The majority
years old. Nearly half (40%) of the cases diagnosed with of cases diagnosed were among males (80%) and 19% of
HIV in 2009 resulted from heterosexual transmission, the cases were in persons between 15 and 24 years of
many of which were in persons originating from sub- age. Of the cases reported with risk factor information
Saharan Africa. The remaining cases diagnosed were among (63%), one-third identified male-to-male sex as the mode
men who have sex with men (37%), among whom rates of transmission, which represents a doubling since 2004.
have consistently increased since 2004, and 4% were Heterosexual transmission remained relatively stable since
among injecting drug users in whom rates have been 2004 (24% of cases) while injection drug use increased
steadily declining. Less than 1% of cases were the result 157% since 2004 (8% of cases), though the absolute num-
of perinatal transmission, transfusions, or nosocomial in- ber of injection drug use cases remain small. A total of 404
fections. A total of 4,361 AIDS cases were diagnosed in AIDS cases were diagnosed in 2009 from 14 of the 15 coun-
2009 from 20 of 23 countries in the western sub-region, tries in the central sub-region, with an overall AIDS rate of
with an overall AIDS rate of 1.1 per 100,000 [25]. 0.3 per 100,000.
East North America

In 2009, 27,112 HIV cases were diagnosed and reported
from 14 of the 15 countries in the eastern sub-region
United States
(Russia did not report, and the reported data therefore rep- With an estimated 1.1 million people living with HIV, the
resent a serious underestimate of the sub-region’s epi- United States is the most heavily affected country in the
demic). Fewer than half the cases (41%) were among industrialized world [26, 27]. In the 40 states that have
females and 14% among 15–24 year olds. Although 46% stable HIV reporting systems, the rate of HIV diagnoses
of cases diagnosed in 2009 identified heterosexual trans- was 17.4 per 100,000 in 2009 [27]. AIDS reporting from
mission as the mode of transmission, this may be an under- all 50 states shows an AIDS diagnosis rate of 11.2 per
estimate because of unrecognized or unreported sexual 100,000 in 2009. In 2008, the death rate of persons
transmission from partners who inject drugs, such as in with HIV (the cause of death may or may not have been
Georgia and Azerbaijan [25]. HIV-related) was 7.0 per 100,000 population, a rate that
Overall, heterosexual transmission has increased since has been stable since 2006. Deaths in persons reported
2004 along with the overall rate of new HIV reports in the with AIDS were 5.3 per 100,000, a 7% annual decrease
sub-region (11.3 per 100,000 in 2004 and 18.9 in 2009). from 2006.
Injection drug use accounted for 39% of reported cases while The overall rate of HIV diagnoses seems to have stabi-
perinatal transmission and transmission among men who lized since 2006 with an estimated 42,000 diagnoses per
have sex with men accounted for less than 3% of the cases; year. Males account for 76% of HIV diagnoses, with a rate
perinatal transmission has doubled in the past two years, of 32.7 per 100,000, constant since 2006, while the rate of
and male-to-male transmission has also increased although diagnoses among women has slightly decreased to 9.8 per
the reported numbers remain relatively small. In 2009, a total 100,000 in 2009. There has been an increase in HIV diag-
of 1803 AIDS cases were diagnosed from 13 of the 14 coun- noses among younger age groups (15–19 and 20–24
tries, with an overall AIDS rate of 1.3 per 100,000. Underre- years) as well as in the older age group of 55–59 years.
porting from countries in this sub-region is substantial and HIV diagnoses among children less than 13 years due to
data presented are an underestimate [25]. perinatal transmission continued to decrease, with an
Recent results from epidemic modeling suggest that the estimated 131 children diagnosed in 2009, maintaining
HIV epidemic in Russia (1% HIV prevalence in 2009) the precipitous decline in mother-to-child transmission of
9
HIV infections, their rate (7.2 per 100,000) was about nine
Table 1.2 Diagnoses of HIV Infection among adults
times lower than that in African Americans; the lowest over-
and adolescents, 2009—40 states and 5 US dependent
all rate of reported HIV infections was in Asians (6.4 per
areas
100,000) (Table 1.2). In 2008, 33% of people diagnosed
with HIV also received an AIDS diagnosis within one year,
No. %
indicating HIV is being diagnosed relatively late.
Transmission category
Male-to-male sexual category 24,312 56.4 Canada
Injection drug use 4,172 9.7 The HIV epidemic seems to be stable in Canada, with
approximately 65,000 people estimated to be living with
Male-to-male sexual contact 1,157 2.7 HIV. The majority of new infections are among men
and IDU who have sex with men and heterosexuals from HIV en-
Heterosexual contacta 13,257 31.0 demic countries. The indigenous Aboriginal population
is disproportionately affected [28].
b
Other 75 0.2
Race/ethnicity
Latin America and the Caribbean
American Indian/Alaska Native 91 0.04
Caribbean
Asian 293 1.2
There are an estimated 240,000 people living with HIV in
Black/African American 10,135 42.0 the Caribbean region. With an estimated prevalence of
HIV infection of 1%, the Caribbean is the second highest
Hispanic/Latinoc 4,692 19.4 burdened region in the world. Overall, more women
(53%) are estimated to be living with HIV than men,
Native Hawaiian/Other Pacific 22 0.1
Islander but this is greatly influenced by the epidemic in Haiti
where 61% of infections are among women. The Bahamas
White 8,613 35.7 has the highest estimated adult HIV prevalence in the re-
gion, 3.1%, although there has been a decrease in HIV
Multiple races 287 1.2 prevalence among 15- to 24-year-old pregnant women
Source: Centers of Disease Control and Prevention. HIV
in the past 10 years [1, 21]. Other countries in the region
Surveillance Report, 2009; vol 21. http://www.cdc.gov/hiv/topics/ have less than 2% prevalence. Most countries in the Carib-
surveillance/resources/reports. Published February 2011. Accessed bean have concentrated epidemics with elevated HIV
April 9, 2011. prevalence in key populations including sex workers and
Note: Data include persons with a diagnosis of HIV infection men who have sex with men [29]. Haiti stands out as
regardless of stage of disease at diagnosis. All displayed data have
an exception, having been affected earliest and demon-
been statistically adjusted to account for reporting delays and
missing risk-factor Information, but not for incomplete reporting.
strating a predominantly heterosexual epidemic. AIDS-
a
Heterosexual contact with a person known to have, or to be at related deaths have decreased in the sub-region since
high risk for, HIV infection. 2001 by 37%, with an estimated 12,000 AIDS-related
b
Includes hemophilia, blood transfusion, perinatal exposure, and deaths in 2009 [1].
risk factor not reported or not identified.
c
Hispanics/Latinos can be of any race.
Central and South America

There are an estimated 1.4 million people living with HIV
HIV since the 1990s. Male-to-male sex accounted for in Latin America, slightly higher than in 2001, with an es-
over half of the new cases diagnosed in 2009 followed timated adult HIV prevalence of 0.5%. However, there has
by heterosexual contact (31%) and injection drug use been a reduction in new infections since 2001, down to
(Table 1.2). 92,000 new infections in 2009. Belize has the highest adult
Over half of HIV diagnoses in 2009 were among African HIV prevalence (2.3%), with most countries having a
Americans, with a rate of 66.6 per 100,000, the highest rate prevalence below 1%. Over half of HIV-infected persons re-
across all racial and ethnic groups. The second most highly side in three countries: Brazil, Argentina, and Columbia.
affected group by race or ethnicity were Hispanics and La- In most of the countries in the sub-region HIV prevalence
tinos who accounted for 17% of infections with a rate of is slightly higher among young males than young females,
22.8 per 100,000. Although whites accounted for 28% of with the exception of Belize and Guyana. Similar to the
10
Caribbean and North America, the epidemic is concen- adults living with HIV), which was lower than the 1.2%
trated among high-risk populations. adult prevalence in 2001. AIDS-related deaths decreased
HIV seroprevalence surveys in capital cities show ele- by almost half in 2009 to 3100 deaths among adults and
vated prevalence specifically among men who have sex children. In contrast HIV prevalence has increased in Indo-
with men and female sex workers. Georgetown, Guyana, nesia where there are now 300,000 adults living with HIV
has the highest HIV prevalence among female sex workers for a prevalence of 0.2%. Although the majority of infec-
(16.6%), followed by San Salvador (4.1%). Prevalence tions are among high-risk groups, there are geographic dif-
among men who have sex with men is also higher than ferences and in the general population of Tanah Papau the
in the general population; in recent surveys their preva- prevalence was 2.4% [31]. Indonesia, like many other
lence ranged from 20.3% in Santiago, Chile, to 4.2% in countries in the sub-region, has a high HIV prevalence
Nicaragua [1]. among injection drug users in the capital city (52.4% in
More data are also available on population size esti- 2007), as do Thailand (38.7%, 2009), Myanmar (36.3%,
mates for high-risk groups. For example, in El Salvador 2008), Cambodia (24.4%, 2007), and Pakistan and Nepal
there are an estimated 12,500 men who have sex with (21%) [1].
men (3.4% of men) and 7000 female sex workers (1.4%
of women)[30]. Triangulating the population size esti-
mates for high-risk groups with their HIV prevalence esti- East Asia
mates provides valuable insights into the risks and
There are an estimated 770,000 persons living with HIV in
prevention needs of male and female partners and clients
the five countries of East Asia, with 96% of the infections in
of sex workers.
China, which represents an adult HIV prevalence of 0.1%,
the highest in the sub-region. Although females only ac-
count for 32% of infections the proportion has been in-
Asia creasing since 2001, along with the overall increasing
Overall an estimated 4.9 million people are living with HIV prevalence in China. The rate of new infections seems to
in the Asia region, for an estimated stable HIV prevalence in be stabilizing, with an estimated 48,000 new infections
adults of 0.4%. HIV incidence in Asia appears to have de- in 2009. Modes of transmission have been changing over
creased slightly from 2001 to 360,000 new infections annu- the years, with most recent estimates showing a small in-
ally, with an estimated 300,000 total AIDS-related deaths crease in the proportion of men who have sex with men
in 2009. Overall more men are infected with HIV (66% infected. Given the vast size of China, there are important
of all infections) in this region, although HIV infections geographic variations, with six provinces carrying over 70%
among women seem to be increasing. Thailand has the of the disease burden (Yunnan, Guangxi, Henan, Sichuan,
highest adult prevalence in the region, estimated at 1.3%, Xinjiang, and Guangdong) [32]. Estimated AIDS-related
indicating about 520,000 persons living with HIV, lower deaths were 26,000 in 2009, suggesting a stabilization of
than the 1.7% prevalence estimated for 2001. India ac- mortality in recent years.
counts for almost half of all HIV infections in the region,
with 2.4 million persons living with HIV, which represents
an adult HIV prevalence of 0.3%. HIV infection in the region Central Asia and Middle East
is primarily concentrated among high-risk groups including In 2009 there were an estimated 60,000 people living with
injection drug users, sex workers and their clients, and men HIV in the Central Asia sub-region, with HIV prevalence
who have sex with men, although there is great variation re- apparently increasing among certain populations, espe-
gionally in the contribution to the epidemic from specific cially injection drug users [33]. Adult HIV prevalence in
risk groups [1]. 2009 was highest in Kyrgyzstan at 0.3% and lowest in
Uzbekistan and Kazakhstan at 0.1%. There are an esti-
mated 247,500 injection drug users in Central Asia, with
South and Southeast Asia HIV prevalence ranging from 17.6% in Dushanbe to 2.9%
HIV epidemics in this region of Asia are mainly among in- in Astana [18].
jection drug users, female sex workers, and their clients. Al- The HIV epidemic in the Middle East (including coun-
though HIV prevalence estimates remain low, the increase tries in North Africa) remains the lowest burdened in the
in the estimated numbers or persons living with HIV sug- world, concentrated among certain risk groups, primarily
gests there may be emerging, concentrated epidemics in injection drug users and men who have sex with men
countries like Bangladesh, Nepal, Pakistan, and the Philip- [34]. Sudan has the highest prevalence in the sub-region,
pines. Other countries, such as Cambodia, Myanmar, and with an estimated 260,000 people living with HIV, which
Thailand exhibit decreasing HIV prevalence. In 2009, Cam- accounts for over half of the estimated 460,000 in the entire
bodia had an estimated 0.5% adult HIV prevalence (56,000 sub-region [1].
11
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13
Chapter |2|
The origins and diversification of HIV
Michael Worobey, Guan-Zhu Han
virus (SIV). The genealogical patterns that emerge from

INTRODUCTION phylogenies provide not only an invaluable historical
record but also a window through which we can glimpse
Human immunodeficiency virus (HIV) is not one but sev- the medically relevant evolutionary and epidemiological
eral related viruses that have crossed into the human pop- processes that generated the patterns. Gene trees also offer
ulation on multiple occasions from non-human primate a framework for systematizing the extensive genetic diver-
reservoir species in Africa. Only one such lineage, the sity of HIV and related viruses into a coherent classification
“main” group of HIV type 1 (HIV-1 group M), has reached scheme. With any organism’s classification, however, there
pandemic proportions; it accounts for more than 99% of is a danger of becoming fixated on pattern rather than pro-
the more than 40 million HIV infections and has a global cess, and HIV is no exception. Some of the potential pitfalls
distribution. The other HIVs, though relatively minor, hold of doing so are discussed below.
important clues about the nature of the origins and diver- AIDS was first recognized in the USA in the early 1980s
sification of this important group. This chapter will begin [1], and the discovery of HIV followed soon after [2]. It is
with a broad scope, surveying the primate lentivirus radi- now clear, however, that HIV emerged decades earlier,
ation and placing the various HIV groups within it. It will from naturally infected primates on another continent
then focus specifically on the genesis of HIV-1 group M, [3]. Figure 2.1 illustrates the relationships between the
summarizing when, where, and how this most important different variants of HIV and related viruses that have been
HIV variant originated, diversified, and spread around discovered in a large number of African monkeys and
the world. An important goal of this chapter will be to apes. To date, over 40 species of non-human primates
bring into sharp relief the biological meaning and medical have shown evidence of infection by SIV [4], every one
relevance of the various levels of HIV genetic diversity of which is restricted in range to sub-Saharan Africa. Since
commonly recognized (“types,” “groups,” “subtypes,” the primate lentiviruses form a single, distinct clade on the
and so on). Understanding what such classifications do mammalian lentivirus phylogeny, and given that no pri-
and do not represent is critical to any rational approach mates outside of Africa appear to be infected, SIV evidently
to exploiting knowledge about viral evolution in order had its origin in an African monkey at some point suffi-
to combat HIV/AIDS. ciently deep in time to account for its spread throughout
most of the continent, and into most of the (catarrhine)
primate species there.
Unlike HIV, natural SIV infections generally cause little
THE DEEP ROOTS OF HIV illness in their hosts and most are thought to be non-
pathogenic. The low pathogenicity has been well docu-
Phylogenetic trees, reconstructed using the remarkably rich mented in African green monkeys and sooty mangabeys.
historical information stamped into the genomes of these However, a recent breakthrough demonstrated that wild
viruses, have emerged as the pre-eminent tools for recon- chimpanzees naturally infected with SIV do develop hall-
structing the history of HIV and simian immunodeficiency marks of AIDS-like illness; SIV infection, as with HIV-1
15
HIV-1,SIVgor, and SIVcpz
SIVgor
P.t.s. P
O N
P.t.t.
SIVdrl
Bioko
SIVdrl
SIVmnd-2
M
SIVrcm
SIVsab
SIVver
SIVgrv
SIVtan
SIVmus-2 SIVmnd-1
SIVprg Bioko
SIVgsn SIVIst SIVsun
SIVmus-1 SIVwrc
SIVmon SIVreg SIVbcm SIVolc

Bioko C E Bioko
U
G
SIVtal B
A SIVcol
D
SIVsyk SIVdeb
HIV-2 and SIVsmm
SIVden
Figure 2.1 Maximum likelihood phylogenetic tree of SIV and HIV partial pol protein sequences. The sequences were downloaded
from the Los Alamos National Laboratories HIV database (http://www.hiv.lanl.gov). The phylogenetic tree was reconstructed under
the Jones-Taylor-Thornton (JTT) model of amino acid substitution with gamma distributed with invariant sites. SIVcpz strains
recovered from Pan troglodytes troglodytes (P.t.t.) and SIVgor strains from Gorilla gorilla are lightly shaded, while those from
P. t. schweinfurthii (P.t.s.) are darkly shaded. The SIV strains isolated from Bioko island are lightly shaded. The abbreviations and
species names are as follows: SIVdrl, drill; SIVmnd-1 and SIVmnd-2, mandrill; SIVrcm, red-capped mangabey; SIVsab, green monkey;
SIVgrv, grivet; SIVtan, tantalus monkey; SIVver, vervet monkey; SIVmus-1 and SIVmus-2, mustached guenon; SIVgsn, greater spot-
nosed monkey; SIVmon, mona monkey; SIVreg, red-eared guenon; SIVtal, talapoin; SIVsyk, Sykes’s monkey; SIVdeb, De Brazza’s
monkey; SIVden, Dent’s mona; SIVbcm, black colobus monkey; SIVcol, colobus monkey; SIVolc, olive colobus; SIVwrc, western red
colobus; SIVlst, L’Hoest’s monkey; SIVsun, sun-tailed monkey; SIVprg, Preuss’s guenon; SIVsmm, sooty mangabey; SIVcpz, common
chimpanzee; SIVgor, gorrilla.
and HIV-2 infection, is associated with progressive CD4 cell co-diverged with their primate hosts, as the animals split
loss, lymphatic tissue destruction, and premature death [5]. into new species from their common ancestors. However,
Pan troglodytes schweinfurthii infected with SIV in Gombe the pattern of closely related hosts having closely related
National Park in Tanzania have a markedly higher death viruses might be explained not by co-divergence but by
rate than non-infected animals [5]. cross-species transmission events occurring preferentially
The precise nature of the time scale of SIV evolution is still between closely related hosts [6]. For example, detailed
open to question. Initially, comparisons of primate and phylogenetic analysis shows that recent cross-species trans-
virus phylogenies led to suggestions that some SIVs have mission events, instead of ancient co-divergence, likely
16
Chapter |2| The origins and diversification of HIV
underlie the fact that three closely related hominoid pri- that HIV lineages intermingle on the tree with SIV lineages.
mates (human, chimpanzees, and gorillas) harbor closely HIV-1 groups N and M are both more closely related to some
related lentiviruses [7]. Studies of genes involved in innate of the SIVcpz viruses on the tree than they are to HIV-1 group
immunity, such as APOBEC3G [8], suggest just the sort O, whose lineage branched off the main trunk at an earlier
of mechanism that could generate such a pattern of corre- point. In other words, HIV-1 group M shared a most recent
spondence even if the viruses and their hosts did not common ancestor with a chimpanzee virus, not with HIV-1
co-diverge. group O. HIV-1 groups P and O are most closely related
Hence, even at this advanced stage of the investigation of to SIVgor [7, 14]. Likewise, HIV-2 group E is the “sister”
one of the most medically important pathogens, until re- group to one SIVsmm strain, and HIV-2 group A is the sister
cently there has been little agreement on whether its pro- group of another. If there had been only a single transmis-
genitors have been circulating in African primates for sion from each reservoir species to humans, we would expect
millions or just thousands of years. A recent study, how- the human viruses to fall into single clusters (or monophy-
ever, revealed evidence for several SIV lineages endemic letic clades, in the jargon of phylogenetics)—one for HIV-1
to Bioko Island, Equatorial Guinea. This island was isolated and one for HIV-2. This is not the case.
from Africa as sea level rose 10,000 to 12,000 years ago. No- Recombination, whereby genes from separate strains are
tably, each of Bioko’s four SIV lineages is most closely recombined into a new, chimeric viral genome within a du-
lated to a virus circulating in hosts of the same genus on ally infected host, complicates these phylogenetic infer-
the African mainland rather than to the SIVs of other Bioko ences somewhat. For example, HIV-1 group N (or its SIV
species (Fig. 2.1). This phylogeographic approach estab- precursor), though closely related to HIV-1 group M in
lished that SIV is ancient—at least 32,000 years old [9]. the pol region (Fig. 2.1), apparently arose from a recombi-
The discovery of an endogenous lentivirus in the genome nation event [15]: some of its genome is much more dis-
of the gray mouse lemur (Microcebus murinus) also suggests tantly related to group M [16]. Such complications aside,
a time scale of millions of years for primate lentiviruses the HIV lineages depicted in Fig. 2.1 are thought to have
[10]. On the other hand, molecular clock methods cali- arisen from an independent cross-species transmission,
brated by using modern sequences make it hard to conceive and hence each of these groups is thought to be more
of dates older than a few thousand years for the SIV MRCA closely related to either SIVcpz or SIVsmm than to the other
[11, 12]. Extrapolations from the rapid short-term evolu- groups in its type.
tionary rates observed in lentiviruses [13] suggest that, So, while the different types of HIV denote the different
for SIV lineages that diverged more than even a few thou- primate reservoirs that have served as sources of human in-
sand years ago, the molecular evidence of shared ancestry fection, the various groups within each type represent puta-
ought to have become overwritten by a succession of nucle- tive independent introductions from primate to human.
otide substitutions. Clearly, more work is still needed to Within HIV-1, at least four such events are inferred, giving
resolve this conundrum, including developing new models rise to HIV-1 groups M, O [17], N [15], and P [14]. Within
of sequence evolution that incorporate the idiosyncrasies of HIV-2, eight independent transmissions are indicated, cor-
RNA virus evolution. Nevertheless, it is now very clear that responding to HIV-2 groups A through H [3, 18]. Earlier
SIV is no newcomer; these viruses have almost certainly been studies of HIV-2 used the term subtype for these lineages,
circulating for tens of thousands of years at least, raising the but this usage has given way to the use of the term group
obvious question: what changed within the past hundred in order to bring HIV-2 nomenclature in line with the more
years that allowed multiple SIV lineages to successfully widely cited (if slightly less logical) HIV-1 conventions
establish themselves in the human population? [18]. The goal of the change was to emphasize the biolog-
ical parallel between the different lineages of HIV-1 and
HIV-2 that arose via unique zoonotic origins. In this sense,
HIV nomenclature reflects rather well the evolutionary
HIV/SIV NOMENCLATURE processes driving observed patterns of genetic diversity.
The term subtype, in turn, is used within HIV-1 group M.
Of the dozens of species with naturally occurring SIV, just Each of the branches in the M group in Fig. 2.1 represents
three, the common chimpanzee (Pan troglodytes), the gorilla one of the recognized subtypes (A to D, F to H, J, K). Dif-
(Gorilla gorilla), and the sooty mangabey (Cercocebus atys), ferent subtypes dominate in different regions. For example,
are the putative reservoirs of HIV. HIV type 1 (HIV-1) is subtype B accounts for most infections in Europe and the
the designation given to forms of the human virus linked Americas, subtype C predominates in southern African
to SIV from P. troglodytes (SIVcpz) and G. gorilla (SIVgor), countries like South Africa, as well as in India, and subtype
while HIV type 2 (HIV-2) denotes human viruses related D is common in east Africa. The unfortunate fact that sub-
to the sooty mangabey virus (SIVsmm). Inspection of the types are nested within groups, rather than types, in this nam-
SIV/HIV phylogenetic tree shows that, within both SIVcpz/ ing scheme, owes to the fact that the use of the term
SIVgor and SIVsmm, more than one cross-species transmis- predates the discovery of HIV-1 group O, at which point
sion event has occurred (Fig. 2.1). The key observation here is the new designation of group had to be wedged between
17
type and subtype. The system of naming HIVs and SIVs has detected elsewhere. Although HIV-2 accounts for relatively
thus evolved over time as the full diversity of natural SIV few infections compared with HIV-1, many more cross-
infections in African primates was revealed, and as new, species transmissions involving this virus have been
distinct lineages of HIV have been discovered. detected, with eight groups (A–H) currently recognized.
As hinted above, recombination plays a large role in the Only two of these, groups A and B, appear to have estab-
evolution of both SIV and HIV [19]. The existence of clear lished themselves as endemic human infections. In all
recombinants, with genomes that are mosaics of distinct the other cases, the “group” is in fact composed of a single
lineages, has led to the introduction of a formal system patient infected with an HIV-2 variant that is sufficiently ge-
for recognizing them [20]. These circulating recombinant netically divergent from the others that it was likely ac-
forms (CRFs) represent virus populations that have diversi- quired independently. Some or all of these may represent
fied from a single, ancestral strain generated by recombina- evolutionary “dead ends [24].” In some cases, the human
tion between two or more of the recognized M group virus bears a surprisingly close resemblance to SIVsmm,
subtypes [20]. The “missing” subtypes, E and I, have been infecting free-living or pet sooty mangabeys from the same
re-classified as CRFs after detailed analysis of their genomes local area [24, 25], strong evidence of repeated indepen-
revealed that they had recombinant origins [20]. Some dent cross-species transmission.
CRFs are the dominant HIV-1 group M strain in some The geographical origins of HIV-1 have taken longer to
locales (e.g. CRF01 in Thailand, CRF02 in Nigeria). piece together, but it now seems clear that all four HIV-1
There is also abundant evidence of recombination groups, as well as SIVgor, form a monophyletic cluster
among the SIVs of different primate species, and even be- with SIVcpz from P. troglodytes troglodytes, the “central”
tween HIV-1 groups M and O [21]. Most notably, the pro- chimpanzee, whose range encompasses southern Cam-
genitor of HIV-1, SIVcpz, turns out to be a recombinant eroon, Central African Republic, Equatorial Guinea,
between the SIVs of red-capped mangabeys and greater Gabon, and the Republic of Congo (Congo-Brazzaville)
spot-nosed monkeys, two prey species of the chimpanzee [3, 16, 26, 27]. Although both the central chimpanzee
[22]. All strains of HIV-1 are thus ultimately recombinant and the “eastern” subspecies, P. t. schweinfurthii, are natu-
in origin, their genomes a mosaic of two monkey viruses, rally infected with SIVcpz, the viruses recovered from the
trafficked through an ape intermediary. two chimpanzee lineages form distinct clades on the SIV
In summary, the primate lentivirus phylogenetic tree and phylogenetic tree (Fig. 2.1), indicating that they have been
the system of HIV nomenclature reflect some key evolu- evolving in isolation for a considerable time.
tionary insights. First, SIVs are naturally found in a variety While two instances of cross-species transmission from
of sub-Saharan African primates and this region is hence chimpanzees to humans (HIV-1 groups M and N) are un-
the cradle of HIV. Second, despite the many primates equivocally phylogenetically linked to the SIVcpz of the
infected, and frequent opportunities for human exposure, P. t. troglodytes chimpanzee, HIV-1 groups O and P fall
as far as is known SIV has only crossed successfully into within the radiation of SIVcpz strains but are mostly closed
humans from chimpanzees, gorillas, and sooty mangabeys, to SIVgor of G. gorilla (Fig. 2.1). It remains unclear whether
but has crossed multiple times from each, a curious pattern gorillas were the immediate source of either or both of
for which no definitive explanation has been proposed. HIV-1 groups O and P. No known variant of HIV-1 has
Finally, the virus that first appeared on the medical world’s emerged from the eastern chimpanzee (dark shading in
radar in high-risk populations in the USA made an extraor- Fig. 2.1). HIV-1 groups N, O, and P are all endemic to Came-
dinary journey there: from African monkeys, then to the roon, within the range of P. t. troglodytes, and none have
apes that preyed upon them, then onto human beings in spread substantially beyond this presumptive region of ori-
central Africa and beyond. gin. Group O exhibits about 0.4% prevalence in Cameroon
[28], group N is exceedingly rare, with less than 10 infected
individuals identified to date [29], and group P infections are
WHERE DID HIV ENTER THE also extremely rare, accounting for only 0.06% of HIV infec-
tions [30]. Despite the relative rarity of groups N and O, their
HUMAN POPULATION? pathogenic profile appears indistinguishable from group M’s
[28], an indication that pathogenic potential and epidemic be-
Using the geographic distributions of the primate species havior of AIDS viruses are not necessarily coupled [18]. Since
that have spawned HIV variants it has been possible to in- group P was identified only recently, little is known on its
fer, with remarkable precision, the specific areas in Africa pathogenic profile.
where the various HIV-1 and HIV-2 groups originated. Given the very different properties of the four groups, M,
HIV-2 was the first to give up its secrets, and by the early O, N, and P, in terms of rate of spread through human host
1990s it was clear that different groups of HIV-2 were inde- populations, it is tempting to speculate that their pathogenic
pendently derived from SIVsmm, the SIV variant endemic properties may owe more to their common genetic heritage,
in the sooty mangabey monkeys of West Africa [23]. as close relatives descended from SIVcpz, than to conver-
HIV-2 is endemic to the same region, and is only rarely gent evolutionary trajectories once they entered humans.
18
The discovery of the first rare variant of HIV-2 known to changes at the same site—a particular concern with fast-
cause immunosuppression lends support to this notion evolving organisms, (2) to calibrate the “molecular clock,”
[18], but future studies will be required to further clarify and (3) to account adequately for the inherent “sloppiness”
the ground rules of the evolution of HIV pathogenicity. of the clock and any potential methodological biases. For-
The geographical source of the main group of HIV-1 has tunately, we can calibrate the clock simply by watching HIV
been somewhat obscured by its global spread, but the avail- evolve in real time: samples collected over a span of several
able evidence links it to the same region. Group M falls years will reveal the rate at which substitutions accrue, with
soundly among the diverse viruses of the P. t. troglodytes early sampled sequences tending to have short branches
chimpanzees—powerful evidence that it emerged from (less change) and late-sampled sequences tending to have
within their range [16]. By screening non-invasively col- longer branch lengths (more change). As for dealing with
lected fecal samples from the region, Beatrice Hahn and col- the noisy phylogenetic signal, it is important to consider
leagues have identified several closely related SIVcpz strains appropriate confidence intervals around estimated diver-
from wild-living Cameroonian chimpanzees, viruses that gence dates. A recent study of HIV-1 group O, for example,
are remarkably similar to group M, and which form a estimated that its most recent common ancestor existed in
well-supported cluster with it on phylogenetic trees. These 1920, but with a wide confidence interval (1890–1940)
analyses pinpoint the probable source of the viruses that [33]. The estimate for group M is 1912 (1884–1924) [32],
gave rise to the HIV-1 group M pandemic as being chimpan- while those for HIV-2 groups A and B are 1940 (1924–
zees in southeastern Cameroon [31]. From there, the virus 1956) and 1945 (1931–1959), respectively [34]. And
likely made its way, perhaps diffusing along the Sangha although the specter of unaccounted-for recombination
River and then down the Congo River, to Kinshasa [32]. biasing such estimates looms over such analyses [35], there
While the fuse was evidently lit in rural southeastern is surprisingly little indication that it systematically affects
Cameroon, the truly explosive growth of the pandemic divergence date inferences in one direction or the other [33].
was likely linked to its arrival in the region’s largest city. Inferences from more or less contemporary sequences,
though, are not the only source of information about his-
torical landmarks in HIV evolution. Arguably the most im-
WHEN DID HIV ENTER THE portant HIV-1 sequence published to date is that of ZR59,
recovered from an archival blood sample taken from an
HUMAN POPULATION? adult male in 1959 in what is now the Democratic Republic
of the Congo (DRC) [36]. Recently we recovered viral se-
It has been said that RNA viruses represent a “moving tar- quences (DRC60) from a Bouin’s-fixed paraffin-embedded
get,” and the point is well taken. HIV has been measured lymph node biopsy specimen obtained in 1960 from an
directly and found to have an error rate as high as 10 4 mu- adult female in Kinshasa (DRC) [32]. While ZR59 is basal
tations per site and two to three recombination events per to subtype D, DRC60 is closet to the ancestral node of sub-
genome per replication cycle. The high error rate of its re- type A/A1. The genetic distance between ZR59 and DRC60
verse transcriptase, plus its high replication rate, mean that showed not only that the main group of HIV-1 was already
mutations rapidly arise and accumulate, making HIV one circulating in the human population at this early date but
of the fastest evolving organisms in nature. also, more importantly, that this group of viruses must have
Generally, the longer the time span since two HIV se- been circulating for some considerable time before this
quences diverged from a common ancestor, the greater point. Relaxed molecular clock analyses with DRC60 and
the number of nucleotide differences we expect when we ZR59 date the MRCA of the M group to near the beginning
compare their homologous gene sequences. Although dif- of the twentieth century, right around the same time that
ferent regions of the genome evolve at different rates [33], sizeable cities first appeared in the region [32]. It seems
and a strict “molecular clock” is often rejected with HIV likely that the rise of cities, plus the roads, railways, and
molecular data sets [13], this observation means that illu- steamboats that linked their inhabitants into large national
minating inferences about the timing of HIV evolution can and regional social fabrics, played a crucial role in allowing
often be culled from alignments of gene sequences. nascent HIVs to establish themselves in human popula-
Estimates of the time to the most recent common ances- tions at this time.
tor of each of the four most prevalent HIV groups have been
inferred using phylogenetic trees and maximum likelihood
and/or Bayesian statistical methods [13, 33, 34]. Behind HIV/AIDS: COLLATERAL DAMAGE
the sophisticated mathematical models used for such infer-
ences lies a simple concept: if viral nucleotide sequences FROM UNSAFE MEDICAL PRACTICES?
diverge from each other by, say, 1% per year after they split
from a common ancestor, then a pair of sequences that The phylogenetic position of ZR59 and DRC60 sequences
differ by, say, 30% must have diverged about 30 years are, on their own, enough to argue convincingly against the
ago. The tricks with HIV are (1) to correct for multiple controversial theory that HIV-1 group M had its origins in
19
experimental polio vaccines allegedly prepared using SIV- infection, and those favoring the subsequent spread of a vi-
contaminated chimpanzee tissue, then administered across rus that has become established. A plethora of “dirty nee-
central Africa in the late 1950s [37]. Perhaps more than any dles” may have helped spread HIV-2 groups A, B and
other modern human disease, AIDS has inspired impas- HIV-1 groups M and O in Africa in the 1950s and later,
sioned debate about the circumstances surrounding its or- but the establishment of each—the transmission of the
igins and spread, and the “Oral Polio Vaccine/AIDS” (OPV/ ancestral SIV into the first human host, and the initial
AIDS) hypothesis has been one of the most controversial human-to-human transmission of each nascent HIV—
explanations. While the idea was worthy of careful consid- appears to have occurred earlier. Iatrogenic infection is
eration since—at least in later incarnations—it correctly not currently the dominant mode of HIV transmission in
implicated chimpanzees as the source of HIV-1 group sub-Saharan Africa [43, 44], and may never have been,
M, several lines of evidence have argued strongly against but this is not to say that it is not a serious concern. Even
it. First there is the “disconnect” between the inferred if it accounts for only 5% of HIV incidence there, then
M group divergence date (around the turn of the 20th there are presumably more medically infected HIV-positive
century) and the earliest use of the experimental vaccines Africans than there are HIV-positive Americans in the entire
(1957), a discrepancy in timing that, as explained in the US epidemic. Such is the magnitude of the HIV/AIDS
next section, cannot be resolved by invoking a separate epidemic in the hardest hit region.
introduction for each subtype [38]. There is also the
geographical evidence discussed above: all forms of HIV-
1, including the M group, evidently evolved from a P. t. trog- THE MEANING OF GENETIC DIVERSITY
lodytes SIVcpz-like ancestor. The chimpanzees implicated in
the OPV/AIDS theory were collected from the Democratic WITHIN HIV-1 GROUP M
Republic of the Congo. Such P. t. schweinfurthii chimpan-
zees, including ones collected near Kisangani, where the Given the attention paid to them, it is of clear medical im-
polio vaccine work was centered, are infected by a distant portance to understand the nature of the HIV-1 group M
cousin of HIV-1 group M [27, 39], one that is not a plausi- subtypes. Recognizing certain lineages as “subtypes” has
ble M group precursor. certainly aided the tracking of epidemiologically important
The fact that SIVcpz is a recombinant of two monkey SIVs lineages across the globe [20]. But parsing the huge amount
is also very telling since it puts the lie to the woolly notion of genetic diversity within the main group of HIV-1 into
that non-natural circumstances such as mass vaccinations subtypes has also imbued them with an undeserved status.
are somehow required for the successful transmission of Are they well-defined biological entities with intrinsic,
SIV from one species to the next [37]. In fact, the non- medically meaningful properties? Is it a sound idea, for ex-
human primate SIVs tell a very different story, one where ample, to pursue subtype-specific vaccines against different
transmission between species is a common, perhaps even portions of global HIV-1 M variation (as opposed to
dominant, evolutionary process. Recombination events broader or narrower phylogenetic criteria)? Answering such
imply a history of cross-species transfers among not only fundamental questions requires careful differentiation be-
chimpanzees, red-capped mangabeys, and greater spot- tween pattern and process.
nosed monkeys [22] but also others, including green mon- Figure 2.2 shows a phylogenetic tree encompassing the
keys (C. sabeus). Cross-species transmission must also have global diversity of group M strains. Below the tree are
introduced at least one of the two distinct mandrill SIVs two schematic phylogenies showing the phylogenetic pat-
(Fig. 2.1) [40]. Moreover, several species, including patas tern observed when only sequences from outside of the
monkeys, yellow baboons, and chacma baboons, have ac- group M epicenter are analyzed (left), versus the pattern
quired SIV from local African green monkeys with which obtained when sequences from the putative source popula-
they interact [41]. Despite claims to the contrary [37, 42], tion are added (right). The labels indicate recognized sub-
the phylogenetics of SIV and HIV indicate that primate type/CRF designations. The crucial point here is that the
lentiviruses have the capacity to cross species boundaries subtypes within group M are artifacts of “founder” effects
and establish new epidemics naturally. And the discovery and biased sampling [38, 45]. The “subtypiness” of group
that SIV in chimpanzees is pathogenic [5] is as clear a dem- M, with distinct clades separated by long internal branches
onstration as one could ask for that neither vaccines nor in- reflective of independent evolutionary history, only arises
jections are necessary to generate pathogenic lentiviruses. on phylogenies reconstructed with sequences sampled out-
It follows from this observation, and from the pre-1950 side of the central African source of the pandemic. When
divergence dates for all the epidemic forms of HIV, that the samples from the source population are included, the gaps
rapid growth of unsterile injections in Africa beginning in between the subtypes fill in and largely disappear (lower
the 1950s was not the key to the establishment of HIV, as right schematic). So do the subtypes [38].
has been proposed [42]. When considering the emergence The “source” population is represented in Figure 2.2
of HIV, it is helpful to decompose the process into factors by HIV sequences sampled in the Democratic Republic of
promoting the establishment of HIV as a human-to-human the Congo (DRC), the country with the most extensive
20
F
CRF01
Common CRF04
ancestor
ca. 1912
J G
H
Figure 2.2 A maximum likelihood phylogenetic tree of HIV-1 group M (top) plus schematic representations of the M group subtypes
(below). The phylogeny is courtesy of Andrew Rambaut and is based on partial env gene (V2–V5) sequences collected both within
the Democratic Republic of the Congo (light branches) [38, 46] and outside the DRC (dark branches) (http://www.hiv.lanl.gov).
The branches radiating from the center are drawn to scale. The ancestor of each subtype/CRF is marked with a circle. Several
DRC strains fall basal to these points, and the much more extensive diversity of group M lineages encountered in the DRC indicates
that this region has experienced a long, continuous epidemic.
M-group genetic diversity described to date [46] and the by global diversity. Describing such basal lineages as mem-
longest evidence of the presence of the virus [36]. It is bers of these subtypes misses the point. The subtypes only
the best sampled central African country [46], but whether have meaning outside of this epicenter region, and these
its M group diversity is uniquely rich remains to be seen. basal lineages already existed before the “birth” of the sub-
M-group genetic diversity on the other side of the Congo type (i.e. before some strain was exported out of the source
River, in Brazzaville (Republic of Congo), is also extensive region and began a chain of infections elsewhere, in relative
[47]. Although the sampling in the Congo–Brazzaville isolation). The lack of a clear distinction between strains in
study was far less intensive, the same pattern emerges from this part of the group M phylogeny underscores the lack
the phylogenies: there is a preponderance of unclassifiable of intrinsic biological properties uniting members of a
strains and strains that fell basal to the subtypes as defined subtype (Fig. 2.3).
21
Figure 2.3 The processes underlying the phylogenetic patterns observed in HIV-1 group M. Time/divergence increases down the
vertical axis; number of infected hosts is represented on the horizontal axis; arrows depict recombination. Several successful
lineages (smaller triangles) trace their ancestry back to the source population (large triangle). This source population derives from
a single infected host (apex), and has been evolving as a continuous epidemic; hence the lack of clear subtypes [29]. In addition
to nucleotide substitution, recombination occurs regularly within all the populations (arrows) [26], but will be most conspicuous
within the source with its full range of diversity, and between contemporary, divergent strains (bottom arrow). Early, complex
recombinants reflect the special legacy of recombination in the ancestral zone where the most divergent strains have always
co-circulated and recombined. Small triangles correspond both to subtypes and circulating recombinants forms (e.g. CRF02 in
Nigeria). In each instance, a founder effect has occurred such that one strain has been exported outside the geographical range of
the source population and has initiated an epidemic elsewhere.
(Adapted from Worobey M, The occurrence and impact of viral recombination, DPhil thesis, 2001: University of Oxford, UK.)
by SIV and HIV. A more difficult challenge still confronts

CONCLUSION us: fully discerning the medically relevant aspects of past,
current, and future HIV genetic diversity and then translat-
Although it is clear that it would be naı̈ve to treat subtypes as ing such knowledge into successful therapeutic and preven-
“immunotypes,” rational vaccine design (to highlight one tive control measures. With many existing and potential
important medical example) demands much more detailed medical approaches, there is an urgent need to come to
information about the precise relationship between HIV ge- grips not only with the remarkable diversity of currently
netic diversity and human biology. How many future HIV circulating strains of HIV but also with the relentless
vaccines will be required to protect people in an HIV-diverse onslaught of new genetic variation that will be generated
country like the DRC? One? Ten? Or is the notion of an ef- by these viruses in future months, years, and decades.
fective, protective vaccine perhaps doomed to failure? We On the other hand, and on a more positive note, many of
simply cannot say at the moment. In light of the fact that the most effective or promising interventions in our current
wild-type HIV-infected individuals are eventually unable arsenal, including widespread antiretroviral therapy, counsel-
to protect against even the most local level of phylogenetic ing and testing, pre-exposure prophylaxis, circumcision, part-
diversity—the swarm of strains that replicate within their ner reduction efforts, microbical gels, and condom use, are
own bodies—we cannot currently rule out this sobering ones that do not depend on a deep understanding of HIV ge-
possibility. Without such fundamental knowledge about netic diversity. Indeed, many or all of these approaches can be
the consequences of HIV genetic variation, it is difficult expected to work about equally well across the entire range of
to make informed decisions about how best to allocate HIV variation. It is conceivable that ardent prevention efforts
research dollars among the different methods of control. based on these approaches will lead to the effective extirpa-
The rapid evolution of HIV has left behind a record of the tion of HIV in many areas long before we have worked out
virus’s past, and reconstructing the circumstances of its or- HIV’s evolutionary enigmas or developed clever vaccines that
igins and emergence has been a major triumph, one that can surmount the challenges posed by the virus’s genetic
has yielded key insights into the public health risks posed diversity.
22
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24
Chapter |3|
Molecular biology of HIV: implications
for new therapies
Warner C. Greene, B. Matija Peterlin, Matthew H. Stremlau
Sharply curbing the expanding global HIV epidemic BMS 488043 is a promising second-generation attach-
requires more effective approaches to decrease the horizon- ment inhibitor that blocks the insertion of this CD4 residue
tal and vertical spread of this pathogenic retrovirus coupled into this pocket of gp120. Protein-based approaches to
with the broader use of existing and likely new antiretrovi- interrupting the gp120–CD4 interaction are also being de-
ral therapies. These interventions must be deployable in the veloped. Numerous studies have identified a handful of
developing world, where HIV is hitting the hardest. Under- monoclonal antibodies against HIV-1 that neutralize pri-
standing the dynamic interplay of HIV with its host at the mary isolates of HIV-1 in vitro and prevent infection in
molecular and cellular levels forms the foundation for suc- non-human primate models [2–4]. Although these anti-
cess in this endeavor. In the following sections, we review bodies clearly prevent infection in animal models, very
our current understanding of the HIV life cycle, highlight- high doses of the antibodies are required for clinical effects
ing promising future points of attack. in HIV-infected patients. Other protein-based therapies in-
clude PRO 542, a tetravalent fusion protein containing the
D1 and D2 domains of human CD4 and the heavy- and
light-chain constant regions of human IgG2 [5, 6]. Phase
I and II clinical trials revealed modest decreases in viral load
HIV ENTRY in patients with advanced disease [7]. Another candidate is
ibalizumab (formerly TNX-355), a humanized anti-CD4
The 9-kilobase HIV RNA encodes nine genes, yielding 15 IgG4 monoclonal antibody that specifically reacts with a
distinct proteins. Compared to other retroviruses, HIV is conformational epitope in the D2 domain of CD4 induced
genetically complex. Investigations over the past several by gp120 binding. This antibody blocks subsequent Env
years yielded informative insights into the function of each engagement of the HIV chemokine co-receptors [8]. The
of HIV’s individual gene products, many of which could antibody showed beneficial activity relative to optimized
form potential targets for new therapies (Fig. 3.1). To pro- background therapy in patients and has advanced to phase
ductively infect a cellular target, HIV must introduce its II clinical trials [9].
genetic material into the cytoplasm of this cell. HIV entry The second phase of HIV entry involves the engage-
requires the initial binding or attachment of the HIV enve- ment of the HIV co-receptors. The initial binding of tri-
lope protein to (Env) CD4 receptors on the surface of target meric gp120 to CD4 induces a conformational change
cells. The rational development of inhibitors of HIV attach- in the envelope that promotes binding of the virion to
ment has been propelled by structural studies unraveling a specific subset of chemokine co-receptors. These recep-
the “lock and key” assembly of trimeric gp120 Env spikes tors contain seven membrane-spanning domains and
present on virions with CD4 receptors residing on the normally help hematopoietic cells to migrate down spe-
surface of the target cells [1]. The insertion of a key phenyl- cific chemokine gradients to sites of inflammation.
alanine residue in the outer portion of the CD4 protein into Although these receptors signal through G proteins [10],
a recessed pocket in gp120 produces a very high-affinity such signaling is not required for HIV infection. Twelve
interaction of these two proteins. different chemokine receptors function as HIV co-receptors
25
Ltr Vif Vpu Env Nef

Long Terminal Repeat Viral Infectivity Factor (p23) Viral Protein U gp160 Envelope Protein Negative Effector (p24)
• Contains control regions • Overcomes the post-entry • Promotes CD4 • Cleaved in endoplasmic • Promotes down-
that bind host transcription restricting activity of the degradation reticulum to gp120 (SU) regulation of
factors (NF-κB, NFAT, host cytidine deaminases, • Overcomes and gp41 (TM) by furin surface CD4 and
Sp1, TBP) APOBEC3G and 3F inhibitory effects of MHC I expression
• gp120 mediates CD4
tetherin (BST-2)
• Required for the initiation and chemokine receptor • Blocks apoptosis
to promote virion
of transcription binding, while gp41 • Enhances virion
release
• Contains sequences giving rise mediates fusion infectivity
to trans-acting RNA response • Contains RNA response • Alters state of
element (TAR) that binds Tat element (RRE) that cellular activation
binds Rev
• Progression to
disease slowed
significantly in
absence of Nef
5′ U3 R U5 U3 R U5 3′
Gag Pol Vpr Rev Tat

Pr55 gag Polymerase Viral Protein R (p15) Regulator of Viral Transcriptional
• Polyprotein processed • Encodes a variety • Promotes G2 Gene Expression (p19) Activator (p14)
by PR of viral enzymes, cell cycle arrest • Binds RRE • Binds TAR
• MA, Matrix (p17) including PR (p10), • Facilitates HIV • Inhibits viral RNA • In presence of host
Undergoes myristylation that RT and RNAse H infection of splicing and promotes cyclin T1 and CDK9,
helps target Gag polyprotein (p66/51), and IN (p32) macrophages nuclear export of enhances RNA
to lipid rafts; implicated in all processed by PR incompletely spliced Pol II elongation
nuclear import of HIV pre- viral RNAs on the viral DNA
integration complex (PIC) template
• CA, Capsid (p24)
Binds cyclophilin A
• NC, Nucleocapsid (p7)
Zn finger; RNA binding protein
• p6
Interacts with Vpr; contains
late domain (PTAP) that binds
TSG101 and participates in
terminal steps of virion budding
Figure 3.1 An overview of the organization of the 9-kb genome of the HIV provirus and a summary of the functions of its nine
genes encoding 15 different proteins.
in cultured cells, but only two, CCR5 and CXCR4, are nor- pharmaceutical development of small molecules that pre-
mally used in vivo [10]. CCR5 binds macrophage-tropic, vent HIV interaction with CCR5. Within only 7 years after
non-syncytium-inducing (R5-tropic) viruses, which are as- the discovery of HIV co-receptors, several small-molecule
sociated with mucosal and intravenous transmission of antagonists of CCR5 entered clinical use. Maraviroc (Sel-
HIV infection. CXCR4 binds T-cell-tropic, syncytium- zentry) is a low-molecular-weight CCR5 antagonist used
inducing (X4-tropic) viruses, which generally emerge only for treatment of HIV-infected persons harboring
during the later stages of disease [11]. Utilization of CXCR4 R5 viruses resistant to conventional drugs [14]. Treat-
is associated with accelerated disease progression but only ment of therapy-naı̈ve patients with Maraviroc is still
occurs in about half of patients infected with HIV. being analyzed in clinical trials. TAK-220, another low-
A naturally occurring deletion of 32 base pairs in the molecular-weight compound, targets a pocket between
CCR5 gene [12, 13] is present in approximately 13% of in- the transmembrane helicies of CCR5, thereby altering the
dividuals of northern European descent. This mutation conformation of the receptor, and has advanced to phase
gives rise to a truncated form of the CCR5 receptor that I clinical trials [15]. Protein-based CCR5 inhibitors include
never reaches the cell surface. Emphasizing the key role PRO 140, a humanized mouse antibody that recognizes an
of CCR5 in horizontal transmission, individuals homozy- epitope at the CCR5 N-terminus, which has entered phase
gous for this CCR5 D32mutation (1–2% of the Caucasian II clinical trials [16]. Interest has also focused on using
population) are almost completely resistant to HIV in- modified versions of the chemokine RANTES, a natural li-
fection [12, 13]. This “experiment of nature” propelled gand for CCR5, to block HIV infection. A key unanswered
26
Chapter |3| Molecular biology of HIV: implications for new therapies
concern is whether blockade of CCR5 will promote an dendritic cell has matured and migrated to regional lymph
earlier switch to CXCR4 co-receptor utilization by HIV. nodes, where it engages T cells [24]. Indeed, these virus-
As noted, such a switch could lead to more rapid clinical laden vesicles may selectively accumulate at the immuno-
deterioration since many more CD4 T cells express CXCR4 logical synapse formed between dendritic cells and CD4
than CCR5. T cells. Thus, dendritic cells expressing DC-SIGN or related
Both CD4 and chemokine co-receptors for HIV are found C-type lectin receptors may act as “Trojan horses,” facilitat-
disproportionately within lipid signaling rafts located ing the spread of HIV from mucosal surfaces to lymphatic
within the cell membrane [17]. These cholesterol- and organs in the absence of productive infection of the
sphingolipid-enriched microdomains likely provide a bet- dendritic cell itself.
ter environment for membrane fusion possibly because Recent studies describe an innate recognition pathway
HIV virions bud from such lipid rafts and acquire similar for HIV-1 in dendritic cells [25]. HIV-1 does not replicate
lipids [18]. Removing cholesterol from virions, producer in dendritic cells; however, this block can be overcome
cells, or target cells greatly decreases the infectivity of HIV by the accessory protein Vpx from simian immunodefi-
[19]. Studies are under way exploring whether cholesterol- ciency virus (SIVmac). When this block is bypassed, HIV-1
depleting compounds might be efficacious as topically replaces dendritic cell activation and the production of
applied microbicides to inhibit HIV transmission at muco- type I interferons. HIV-1-mediated activation of dendritic
sal surfaces. The development of effective microbicides cells induced virus-specific IFN-g-producing T cells and
would form an exceptionally valuable approach in efforts caused proliferation of CD4 T cells. Activating the HIV-1
to prevent HIV transmission. Approximately 50 microbi- sensor in dendritic cells could potentially improve the
cide candidates are in different stages of development in effectiveness of current vaccine candidates.
the microbicide pipeline. Thus far, mostly non-specific
microbicides, such as surfactants and polyanions, have
completed phase III clinical testing, and none has demon-
strated clear statistical evidence of protection [20]. Tenofo- EARLY CYTOPLASMIC EVENTS
vir, a nucleotide analogue reverse transcriptase inhibitor, is
the most advanced clinical candidate. A 1% vaginal gel for- HIV-1 contains an internal viral RNA–protein complex
mulation of tenofovir reduced HIV acquisition by nearly surrounded by a protein shell, termed the capsid core
40% overall in the recently completed CAPRISA phase II [26]. Upon viral fusion, the capsid core is released into
trial in South African women [21]. the cytoplasm of the target cell. Although the ensuing
The third phase of HIV entry is virion fusion. The binding stages are poorly understood, the capsid core is thought
of surface gp120, CD4, and the chemokine co-receptors gen- to undergo a controlled disassembly reaction. This pro-
erates a sharp conformational change in gp41, the second cess appears to involve phosphorylation of the matrix
HIV envelope protein [22]. Assembled as a trimer on the protein by a mitogen-activated protein (MAP) kinase
virion membrane, this coiled-coil protein springs open, [27] and additional actions of cyclophilin A [28] and
projecting three peptide fusion domains that “harpoon” the viral proteins Nef [29] and Vif [30]. Optimal stability
the lipid bilayer of the target cell. The gp41 trimers then of the capsid core appears to be critical for successful in-
fold back on themselves, forming a hairpin structure. The fection of the host cell. Mutations that alter the stability
recently approved T20 fusion inhibitor, enfuvirtide, prevents of the core, by rendering the particle either too stable
the formation of the hairpin structure essential for successful or unstable, impair infection [31]. Thus, small molecules
fusion. The fusion reaction leads to intracytoplasmic inser- that perturb the structure and/or disassembly process
tion of the HIV viral core [22]. may have therapeutic benefit. One recently identified
HIV virions also enter cells by endocytosis. However, this candidate, PF-3450074 (PF74), appears to trigger prema-
form of entry does not lead to productive viral infection ture uncoating of the capsid core, leading to an inability
likely because the internalized virions are inactivated to successfully complete subsequent steps in the viral life
within acidified endosomes. However, a special form of en- cycle [32].
docytosis associated with facilitated infection of CD4 T After the viral core is uncoated, the viral reverse transcrip-
cells has been described in dendritic cells. These cells nor- tion complex is liberated and begins the conversion of viral
mally process and present antigens to immune cells, and RNA into double-stranded DNA [33]. This complex in-
many dendritic cells express a specialized attachment re- cludes the diploid viral RNA genome, tRNALys primer, re-
ceptor termed DC-SIGN [23] or closely related C-type lectin verse transcriptase, integrase, matrix, nucleocapsid, viral
receptors. DC-SIGN binds HIV gp120 with high affinity but protein R (Vpr), and various host proteins. It docks with ac-
does not trigger the conformational changes in env required tin microfilaments [34]. This interaction, mediated by the
for fusion. Rather, virions bound to DC-SIGN may be inter- phosphorylated matrix, is required for the commencement
nalized into a vesicular compartment that does not lead of efficient reverse transcription. A variety of nucleoside
to viral inactivation. These vesicles containing viable HIV (AZT, ddI, ddC, and 3TC), nucleotide (tenofovir), and
virions are transported back to the cell surface after the non-nucleoside (nevirapine) inhibitors of the HIV reverse
27
transcriptase are widely used in the clinic. Indeed, targeting of the PIC with one or more components of the nuclear
of the viral reverse transcriptase represents one of the most pore complex. The multiple nuclear targeting signals within
successful strategies for impairing HIV growth. Effective re- the PIC, which could involve yet-to-be-identified cellular
verse transcription yields the HIV preintegration complex factors, may also function in a cooperative manner or play
(PIC), composed of double-stranded viral cDNA, integrase, larger roles individually in different target cells. For exam-
matrix, Vpr, reverse transcriptase, and the high mobility ple, while Vpr is not needed for HIV infection of nondivid-
group DNA-binding protein HMGI(Y) [35]. The PIC may ing, resting T cells [49], it markedly enhances viral infection
move toward the nucleus by sliding down microtubules in nondividing macrophages [50]. The finding that both
[36, 37]. Adenovirus and herpes simplex virus 1 similarly matrix [51] and Vpr [48] shuttle between the nucleus
dock to microtubules and use the microtubule-associated and cytoplasm likely ensures their availability for incorpo-
dynein molecular motor for cytoplasmic transport. This ration into new virions.
finding suggests that many viruses utilize these cytoskeletal Host factors involved in nuclear import of the PIC also
structures for directional movement. Overexpression of remain to be identified. One report implicated importin
FEZ1, a regulator of cytoskeletal transport, blocks both 7, one of a family of nuclear import receptors responsible
HIV-1 and murine leukemia virus infection at a step after for the uptake of ribosomal proteins and histones [52].
reverse transcription [38]. Thus, overexpressed FEZ1 might Another report suggested Nup98, a component of the
disrupt normal virus trafficking. nuclear pore complex, could be required for HIV-1 infec-
At least two host proteins associate with the PIC and are im- tion [53]. More recent work suggests small host RNAs, such
portant for its function. One is BAF-1 (barrier to autointegra- as specific tRNAs, bind to the PIC and facilitate its entry
tion factor-1), a small DNA-binding protein [39]. Removal of into the nucleus [54]. However, the roles of these factors
BAF-1 promotes the suicidal pathway of autointegration, have yet to be conclusively demonstrated.
which occurs when the 3’-ends of the reverse transcript attack
sites within the viral DNA. The other host protein is LAP2a,
a laminin-assocated component of the nuclear envelope,
which promotes productive PIC integration [40]. INTEGRATION
Once inside the nucleus, the viral PIC establishes a func-

tional provirus (Fig. 3.2). Effective integration of the
CROSSING THE NUCLEAR PORE double-stranded viral DNA into the host chromosome is
mediated by the HIV integrase, which binds the ends of the
Unlike most animal retroviruses, HIV can infect non- viral DNA [35]. The host proteins HMGI(Y) and barrier to
dividing cells, such as terminally differentiated macro- autointegration (BAF) are required for efficient integration,
phages [41]. This requires an ability of the viral PIC to although their precise functions remain unknown [55].
cross intact nuclear membranes. With a Stokes radius of ap- Integrase removes nucleotides from viral ends, producing a
proximately 28 nm, resembling the size of a ribosome two-base recess and thereby correcting the ragged ends gener-
[42], the PIC is about twice as large as the maximal diam- ated by the terminal transferase activity of reverse transcrip-
eter of the central aqueous channel of the nuclear pore. tase [35]. It also catalyzes the subsequent joining reaction
It seems likely that the 3-mm contour length of viral DNA that establishes the HIV provirus within the chromosome.
must undergo significant compaction, and the import Recent studies indicate that HIV integration preferentially
process must involve considerable molecular gymnastics. occurs in actively transcribed genes [56].
One of the more controversial areas of HIV research in- The search for integrase inhibitors has been slow.
volves the identification of key viral proteins that mediate Only one integrase inhibitor, raltegravir (Isentress 1),
the nuclear import of the PIC. Integrase [43], matrix [44], is approved for clinical use [57]. Raltegravir, as well as
and Vpr [45] have each been implicated (Fig. 3.2). Because similar compounds, selectively blocks DNA strand trans-
plus-strand synthesis is discontinuous in reverse transcrip- fer activity and is therefore referred to as integrase strand
tion, a triple helical DNA domain or “DNA flap” that may transfer inhibitors (INSTIs). Resistance to raltegravir de-
bind a host protein containing a nuclear targeting signal is velops rapidly: a single mutation is sufficient to confer
produced [46]. Matrix encodes a canonical nuclear localiza- resistance [58].
tion signal that is recognized by the importins-a and -b, One host factor required for HIV-1 integration is LEDGF/
which are key components in the classical nuclear import p75 (lens epithelium-derived growth factor), a nuclear
pathway. However, recent studies questioned the contribu- transcriptional co-activator [59]. LEDGF/p75 binds tightly
tions of the nuclear import signal in integrase as well as the to HIV-1 integrase and appears to act as a chromatin-
DNA flap to the nuclear uptake of the PIC [47]. The HIV associated receptor for preintegration complexes [60, 61].
Vpr gene product [48] contains at least three noncanonical In cells devoid of endogenous LEDGF/p75 protein, both
nuclear targeting signals. Vpr may bypass the importin the levels of HIV-1 integration and their genomic distribu-
system altogether, perhaps mediating the direct docking tion are significantly perturbed [62, 63].
28
Cytoplasm Nucleus
HIV-1 Matrix (MA)
Vpr
Capsid (CA) gp120
Integrase (IN) Envelope

protein
Nucleocapsid trimer
Integration
(NC) gp41 LTR
RNA genome
Reverse
Protease HIV
transcriptase (RT)
Nef provirus
LTR
Envelope Nuclear
protein import
CD4 receptor LEDGF/p75
Chemokine NHEJ
coreceptor Microtubules Recombination
LTR LTR
Preintegration LTR
complex Nuclear
Lipid raft pore complex
Microtubule
Fusion trafficking
Tat Nef (?)

Cyclophilin A Preintegration complex
Uncoating RT
cDNA
flap IN
MA
Vpr
Figure 3.2 Schematic description of early events occurring after HIV infection of a susceptible target cell, interactions among gp120,
CD4, and chemokine receptors (CCR5 or CXCR4) lead to gp41-mediated fusion followed by virion uncoating, reverse transcription of
the RNA genome, nuclear import of the viral preintegration complex, and integration of the double-stranded viral cDNA into the host
chromosome, thus establishing the HIV provirus.
Another host factor that seems to mediate the association double-strand break detected within a cell is sufficient to
of the preintegration complex with chromatin after nuclear induce G1 cell-cycle arrest. The ability of the free ends of
entry is emerin, a component of the inner nuclear mem- the viral DNA to mimic such double-strand chromosomal
brane [64]. The association of emerin with the PIC is me- breaks may contribute to the direct cytopathic effects
diated by BAF, and both proteins appear to cooperate to observed with HIV.
promote HIV integration into chromatin.
Not all PICs that enter the nucleus result in a functional
provirus. The ends of the viral DNA may be joined to form a
2-LTR (long terminal repeat) circle or the viral genome may TRANSCRIPTIONAL EVENTS
undergo homologous recombination yielding a single LTR
circle. Finally, the viral DNA may autointegrate into itself, Integration can lead to latent or transcriptionally active
producing a rearranged circular structure. Although some forms of viral infection [67]. The chromosomal environ-
circular forms may direct the synthesis of the transcrip- ment at the site of viral integration likely helps shape the
tional transactivator Tat and Nef, none produces infectious provirus’s transcriptional activity [68]. For example, provi-
virus [65]. The nonhomologous end-joining system may ral integration into repressed heterochromatin might favor
form 2-LTR circles to protect the cell [66]. This system the generation of latent proviruses (Fig. 3.3). In addition,
is responsible for rapid repair of double-strand breaks, the transcriptional status of HIV-1 is tightly coupled to the
which minimizes the number of free DNA ends within activation state of the cell. In resting T cells, nucleosomes
the cell, thereby preventing an apoptotic response. A single adjacent to the HIV promoter (e.g., Nuc 1) bear the
29
characteristic marks of silent heterochromatin, such as ly-

Potential mechanisms of post-integration HIV latency
sine 9 trimethylated histone 3, heterochromatin protein 1,
Area of detail
and low levels of histone acetylation [69]. Furthermore,
the 5’ LTR of HIV can bind negative regulators of transcrip-
tion, such as p50 homodimers (inactive form of nuclear
LTR
LTR factor kB, NF-kB) or the C-promoter binding factor 1
[70]. Both of these factors recruit histone deacetylases that
act on Nuc1. Silencing is reinforced by methylation of two
CpG islands and the subsequent binding of Methyl-CpG
Ac Me Me
binding domain protein 2 (MDB2) [71, 72]. Finally, latency
can be enhanced by post-transcriptional mechanisms, such
HDAC-1 as impaired HIV mRNA nuclear export and the expression of
MBD2 host micro-RNAs.
p50 p50 Because antiretroviral therapy can control, but not cure
HIV infection, recent efforts have focused on the possibility
CBF-1
that latent viruses can be reactivated and then purged by
pharmacological manipulations. Three types of agents,
Integration into heterochromatin where transcription is repressed by histone all aimed at reactivating latent viruses, have been tested:
deacetylation, DNA methylation and recruitment of methyl-binding T cell activators, inhibitors of histone-modifying enzymes,
repressors like MBD2 and inhibitors of DNA methylation [73]. Clinical trials
CTD
have assessed T cell activators such as IL-2, IL-7, and anti-
RNAPII bodies specific to the T cell receptor CD3 subunit. Although
LTR these therapies transiently reduced the latent virus reser-
TAR voir, patients generally experienced rapid viral rebound
upon antiretroviral therapy cessation [74, 75]. In other
studies, valproic acid, a weak inhibitor of histone deacety-
Short HIV transcripts + lase activity, showed some ability to decrease the pool
Ineffective RNAPII elongation of latently infected resting CD4 T cells; however, these
in the absence of Tat effects have not been confirmed [76, 77]. In vivo studies
have shown induction of transcriptionally repressed latent
viruses using a combination of activators (e.g. the NF-kB
Transcriptional activation of HIV-1 gene expression inducer prostratin) in combination with inhibitors of his-
tone deacetylation (e.g. valproic acid and suberoylanilide
NFAT
hydroxamic acid) and DNA methylation (e.g., 5-aza-2’-
NF-κB Sp1 deoxycytidine) [71, 74, 78]. The combination of drugs
P P aimed at purging latent reservoirs of virus may also activate
P
CTD endogenous retroelements. Thus, the benefits of reactivat-

P P
P P
RNAPII ing latent proviruses must be weighed against the risk of ret-
rotransposition-induced insertional mutagenesis.
κB Sp1
In the host genome, the 5’ LTR functions like other
Enhancer-binding CDK9
proteins eukaryotic transcriptional units. It contains downstream
Tat Cyclin T1 and upstream promoter elements, which include the initi-
p-TEFb complex
AWI/SNF ator (Inr), TATA-box (T), and three Sp1 sites [79]. These
regions help position the RNA polymerase II (RNAPII) at
Chromatin p300
remodeling the site of initiation of transcription and assemble the pre-
Kat5 Set7/9
initiation complexes. Transcription begins, but the poly-
merase fails to elongate efficiently along the viral genome
(Fig. 3.3). In the process, short nonpolyadenylated tran-
Tat and cyclin T1 binding to TAR activates CDK9, leading to phosphorylation
scripts are synthesized, which are stable and persist in
of the C-terminal domain (CTD) of RNA PII and effective elongation
cells due to the formation of an RNA stem loop called
the transactivation response (TAR) element [80]. Slightly
Figure 3.3 A summary of two different mechanisms
potentially underlying post-integration HIV latency contrasted upstream of the promoter is the transcriptional enhancer,
with the central role of Tat in promoting productive infection in which HIV-1 binds NF-kB, nuclear factor of activated
of target cells. T cells (NFAT), and Ets family members [81]. NF-kB and
NFAT relocalize to the nucleus after cellular activation.
NF-kB is liberated from its cytoplasmic inhibitor, IkB, by
30
stimulus-coupled phosphorylation, polyubiquitylation, with Tat. These enzymes acetylate Tat at lysines 50 and 51,
and proteasomal degradation of the inhibitor [82]. NFAT promoting the disassociation of Tat from the TAR RNA and
is dephosphorylated by calcineurin (a reaction inhibited leading to the start of transcriptional elongation [94–96].
by cyclosporin A) and, after its nuclear import, assembles
with AP1 to form the fully active transcriptional complex
[83]. NF-kB, which is composed of p50 and p65 (RelA) sub-
units, increases both the rates of initiation and elongation of EXPRESSION OF VIRAL GENES
viral transcription [84]. Since NF-kB is activated after several
antigen-specific and cytokine-mediated events, it can stimu- Transcription of the viral genome results in more than a
late transcription of silent proviruses primarily through the dozen different HIV-specific transcripts [97]. Some are pro-
recruitment of histone acetyltransferases that remodel Nuc1 cessed cotranscriptionally and, in the absence of inhibitory
Tat is responsible for markedly increasing the rate of viral RNA sequences (IRS), transported rapidly into the cyto-
gene expression. With cyclin T1 (CycT1), it binds TAR and plasm [98]. These multiply spliced transcripts encode
recruits the cellular cyclin-dependent kinase 9 (Cdk9) to Nef, Tat, and Rev, the “early” expressed genes of HIV. Other
the HIV LTR (Fig. 3.3) [85]. In the positive transcription singly spliced or unspliced viral transcripts remain in the
elongation factor b (P-TEFb) complex, Cdk9 phosphory- nucleus and are relatively stable. These viral transcripts en-
lates the C-terminal domain of RNAPII, which marks the code the structural, enzymatic, and accessory proteins and
transition from initiation to elongation of eukaryotic trans- represent viral genomic RNAs needed for the assembly of
cription [86]. Other targets of P-TEFb include negative fully infectious virions.
transcription elongation factors (N-TEF), such as the Incomplete splicing likely results from suboptimal splice
DRB-sensitivity inducing (DSIF) and negative elongation donor and acceptor sites in viral transcripts. In addition,
(NELF) factors [86]. P-TEFb can be found in two distinct the regulator of virion gene expression, Rev, may inhibit
complexes, a small P-TEFb that contains only cdk9 and splicing by its interaction with alternate splicing factor/
cyclin T, and a large P-TEFb that also contains 7SK small splicing factor 2 (ASF/SF2) [99] and its associated p32
nuclear RNA and HEXIM1 (hexamethylene bisacetamide- protein [100].
induced protein 1). Transport of the incompletely spliced viral transcripts to
In the absence of Tat, the HIV LTR functions as a very poor the cytoplasm depends on an adequate supply of Rev [98].
promoter because it so effectively binds these negative trans- Rev is a small shuttling protein that binds a complex RNA
cription factors in vivo. An arginine-rich motif (ARM) stem loop termed the Rev response element (RRE), which
within Tat binds to the 5´ bulge region in TAR. A shorter is located in the env gene. Rev binds first with high affinity
ARM in cyclin T1, which is also called the Tat-TAR recogni- to a small region of the RRE termed the stem loop IIB
tion motif (TRM), engages the central loop of TAR [85]. (Fig. 3.4) [101]. This binding leads to the multimerization
These regions form a high-affinity RNA-binding unit that of Rev on the remainder of the RRE. In addition to a nuclear
is required for Tat transactivation. In the presence of the localization signal, Rev contains a leucine-rich nuclear
complex between Tat and P-TEFb, the RNAPII becomes a export sequence (NES) [98]. Of note, the study of Rev
highly efficient elongating complex. Tat also recruits the was the catalyst for the identification of such NESs in many
SWI/SNF chromatin remodeling complex to the HIV pro- cellular proteins and of the complex formed between
moter [87–89] to relieve the elongation block imposed CRM-1/exportin-1 and this sequence [98].
by repressive nucleosomes. Rev functions by binding directly to CRM-1, the main nu-
Because murine CycT1 contains a cysteine at position clear export receptor for host ribosomal and small nuclear
261, the complex between Tat and murine P-TEFb binds RNAs [102]. In addition to CRM-1, Rev also uses several
TAR weakly [90]. Thus, Tat transactivation is severely other co-factors for RNA export. These factors include
compromised in murine cells. Cdk9 also must be autophos- Rab/hRIP [103], RanBP1 [104], Sam68 [105], and heteroge-
phorylated on several serines and threonines near its neous nuclear ribonucleoprotein A1 (hnRNP A1). Ran is a
C-terminus for productive interactions among Tat, P-TEFb, small guanine nucleotide–binding protein that switches be-
and TAR [91]. Additionally, basal levels of P-TEFb may tween GTP- and GDP-bound states. RanGDP is found pre-
be low in resting cells or only weakly active due to the dominantly in the cytoplasm because RanGAP is expressed
interaction between P-TEFb and 7SK RNA [92]. in this cellular compartment. Conversely, the Ran nucleo-
Post-translational modifications of Tat, such as phos- tide exchange factor RCC1, which charges Ran with GTP,
phorylation, methylation, and acetylation, modify its func- is expressed predominantly in the nucleus. The inverse
tion and allow it to specifically interact with a wide array of nucleocytoplasmic gradients of RanGTP and RanGDP pro-
cellular partners. For example, the lysine methyltransferase duced by the subcellular localization of these enzymes likely
Set7/9 associates with the HIV promoter and monomethy- plays a major role in determining the directional transport
lates lysine 51, a highly conserved residue located in of proteins into and out of the nucleus. Outbound cargo is
the RNA-binding domain of Tat [93]. Several histone- only effectively loaded onto the CRM-1/exportin-1 in the
modifiying enzymes, such as p300/CBP, also associate presence of RanGTP. However, when the complex reaches
31
Rev Tat AP-2

adaptors
Nef CD4
receptor
Importin β
Nef
Lysosome
Rab7/β-COP
CRM-1 Inhibition
of apoptosis CD4 down-
Ran GTP
↓ASK-1 regulation
RRE ( ↑PI3-K
↓p53
)
AAA Coated pit
Full-length genomic RNA
AAA ↑ RanGDP
Gag-Pol
env mRNA Virion
Rev
assembly
CRM-1 Env
DNA Vpr
Vpr-induced
nuclear
Endosomes
herniation
MHC I
Golgi ↑Nef
Contributes to
G2 cell cycle arrest
Figure 3.4 A summary of late events in the HIV-infected cell, culminating in the assembly of new infectious virions. Highlighted
are the roles of various viral proteins in optimizing the intracellular environment for viral replication including, down-regulation of
CD4 and MHC I and inhibition of apoptosis by Nef, and the induction of G2 cell-cycle arrest by Vpr. A key action of the HIV Rev
protein in promoting nuclear export of incompletely spliced viral transcripts that encode the structural and enzymatic proteins
as well as the viral genome of new virions is also illustrated.
the cytoplasm, GTP is hydrolyzed to GDP and the bound translation [107]. Translation of the Gag–Pol polyprotein re-
cargo is released. The opposite relationship regulates the nu- quires a ribosomal frameshift before the Gag stop codon and
clear import by importins-a and -b, where nuclear RanGTP presumably host proteins to complete protein synthesis;
stimulates cargo release [98]. however, the identities of these factors remain unknown.
For HIV infection to spread, a balance between splicing
and transport of incompletely spliced viral mRNA species
must be achieved. If splicing is too efficient, then only
the multiply spliced transcripts appear in the cytoplasm. REPLICATING NEW VIRUSES
Although required, these regulatory proteins are insuffi-
cient to support full viral replication. However, if splicing In contrast to Tat and Rev, which act directly on viral RNA
is markedly impaired, adequate synthesis of Tat, Rev, structures, Nef reshapes the environment of the infected
and Nef will not occur. In many non-primate cells, HIV cell to optimize viral replication (Fig. 3.4) [10]. The ab-
transcripts may be overly spliced, thus producing a block sence of Nef in infected monkeys and humans is associated
to viral replication in these hosts [106]. with much slower clinical progression to AIDS [108, 109].
The HIV-1 RNA transcript contains a long 5’-untranslated This increase in virulence caused by Nef appears to be asso-
region (UTR) leader. Consequently, the start codons for Gag ciated with its ability to affect signaling cascades, including
translation are often preceded by nonproductive start and the activation of T cell antigen receptor [110], and to de-
stop codons. This situation suggests that HIV-1 might con- crease the expression of CD4 on the cell surface [111,
tain an internal ribosome entry site (IRES) to initiate 112]. Nef also promotes the production and release of
32
more infectious virions [113, 114]. Effects of Nef on the visibility of infected cells to CD8 cytotoxic T cells.
PI3-K signaling cascade—which involves the guanine nu- For rerouting MHC 1 to the lysosomes for degradation,
cleotide exchange factor Vav, the small GTPases Cdc42 Nef recruits the clatherin adaptor AP-1 and subsequently
and Rac1, and p21-activated kinase PAK—cause profound b-COP, to the cytoplasmic tail of MHC 1 [122–124]. How-
cytoskeletal rearrangments and alter downstream effector ever, Nef does not decrease the expression of HLA-C [125],
functions [115]. Indeed, Nef and viral structural proteins so that natural killer cells cannot recognize and kill the
colocalize in lipid rafts [114, 116]. Two other HIV proteins infected cells.
assist Nef in down-regulating expression of CD4 [117]. Nef also inhibits apoptosis. It binds to and inhibits the
Trimeric gp120 binds CD4 in the endoplasmic reticulum, intermediate apoptosis signal regulating kinase-1 (ASK-1)
slowing its export to the plasma membrane [118], and [126] that functions in the Fas and TNFR death signaling
Vpu binds the cytoplasmic tail of CD4, promoting recruit- pathways and stimulates the phosphorylation of Bad lead-
ment of TrCP and Skp1p (Fig. 3.5). These events target CD4 ing to its sequestration by 14-3-3 proteins (Fig. 3.4) [127].
for ubiquitylation and proteasomal degradation before it Nef also binds and inhibits p53 [128]. Via these different
reaches the cell surface [119]. mechanisms, Nef prolongs the life of the infected cell,
Nef reduces immunological response to HIV infec- thereby optimizing viral replication.
tions directly and indirectly. In T cells, Nef activates the ex- Other viral proteins also participate in the modification of
pression of FasL (CD95L), which induces apoptosis in the environment in infected cells. Rev-dependent expression
bystander cells that express Fas [120], thereby killing cyto- of Vpr induces the arrest of proliferating infected cells at
toxic T cells that could eliminate HIV-1-infected cells. It the G2/M phase of the cell cycle [129]. Since the viral LTR
reduces the expression of MHC I determinants on the cell is more active during G2, this arrest likely enhances viral
surface [121] (Fig. 3.4) and so decreases the immunological gene expression [130]. These cell-cycle arresting properties
Ub
Virion
budding Envelope
Ub
Ub
Endophilin Lipid raft
brane
a mem
Plasm
Myristylation AIP-1 Alix

VPS ESCRT
4A,B Disassembly
MA
CHMP3
CA
Gag EAP20 CHMP6 CHMP2A,B

TSG101 Ub CHMP4A,B,C CHMP5
Ub EAP30
Ub VPS28 EAP45 CHMP1A,B
NC
VPS37
ESCRT-2 ESCRT-3
ESCRT-1
PTAP
p6
YPxL
Figure 3.5 Late steps in the assembly of new virions and host factors in virion budding. Components of the endosomal sorting
complex for transport (ESCRT) machinery, most notably TSG101, AIP/Alix, and Vps4, play critical roles in the terminal phases of virion
budding. In infected cells, Gag redirects the ESCRT machinery to the plasma membrane and uses it to bud out from the cell.
Ubiquitylation of cargo is usually involved in ESCRT function. Therefore, ubiquitylation of Gag likely facilitates its interaction with
components of the ESCRT-1, ESCRT-2, and ESCRT-3 complexes. Several other host proteins not traditionally classified as part of the
ESCRT machinery may also play a role in budding. For example, the endophilins are a family of proteins that induce
membrane curvature. Endophilins, or similar proteins, may facilitate endocytic vesicle budding of the virus.
33
involve localized defects in the structure of the nuclear the budding of virions into the extracellular space away
lamina that lead to dynamic, DNA-filled herniations that from the cytoplasm. Several other host proteins not tradi-
project from the nuclear envelope into the cytoplasm tionally classified as part of the ESCRT pathway also likely
(Fig. 3.4) [131]. Intermittently, these herniations rupture, play a role in budding. For example, endophilin belongs
causing the mixing of soluble nuclear and cytoplasmic to a family of proteins that induce membrane curvature,
proteins. thereby facilitating endocytic vesicle budding [143].
Although overexpression of the Gag binding domains of
TSG101 and AIP/Alix potently inhibit spreading lentiviral
ASSEMBLY AND BUDDING infection in tissue culture, neither domain is viable as a
therapeutic target. However, small molecules that inter-
OF HIV VIRIONS fere with the p6–TSG101 and p6–AIP/Alix interaction
sites could have therapeutic benefits. As a first step to-
New virions are assembled at the plasma membrane wards this goal, PTAP peptide mimetics that competitively
(Fig. 3.5). Each virion consists of roughly 1,500 Gag and inhibit the p6–TSG101 interaction have been engineered;
100 Gag–Pol polyproteins [132], two copies of the viral however, to be useful therapeutically, they need to be ren-
RNA genome, and Vpr [133]. Several proteins participate dered cell permeable [144].
in the assembly process, including Gag–Pol, and Gag
polyproteins as well as Nef and Env. A human ATP-binding
protein, HP68 (previously identified as an RNase L inhib-
itor), likely acts as a molecular chaperone, facilitating ANTIVIRAL HOST FACTORS
conformational changes in Gag needed for the assembly
of these capsids [134]. The Gag polyproteins are subject
APOBEC3G
to myristylation [135], and thus preferentially associate
with cholesterol- and glycolipid-enriched membrane In primary CD4 T lymphocytes, Vif plays a key but poorly
microdomains, often referred to as membrane rafts [136]. understood role in the assembly of infectious virions. In
Virion budding occurs through these specialized regions the absence of Vif, normal levels of virus are produced,
in the lipid bilayer, yielding virions with cholesterol-rich but these virions are noninfectious, displaying an arrest at
membranes. This lipid composition likely favors release, the level of reverse transcription in the subsequent target
stability, and fusion of virions with the subsequent target cell. Heterokaryon analyses involving the fusion of nonper-
cell [18]. missive (requires Vif for viral growth) and permissive cells
The process of retroviral budding usurps the endosomal (support the growth of Vif-deficient viruses) revealed that
sorting complex required for transport (ESCRT) machin- Vif overcomes the effects of a natural inhibitor of HIV rep-
ery. This complex comprises of approximately 20 proteins lication [145, 146]. This restriction factor was ultimately
that form four complexes and is responsible for sorting identified as APOBEC3G [147] and shown be a member
cargo proteins for delivery to the late endosome compart- of a large family of RNA editing/DNA mutator enzymes
ment or multivesicular bodies [137]. It is now apparent with cytidine deaminase activity. In the absence of Vif ex-
that HIV-1 makes specific contacts with the ESCRT ma- pression, APOBEC3G is incorporated into virus particles
chinery through two regions within the p6 region of in the producer cell [148, 149]. When these virions infect
Gag. These short peptide sequences are called late do- the next target cells, APOBEC3G deaminates dC in the sin-
mains and serve to recruit the cellular proteins TSG101 gle-stranded minus strand viral DNA producing dU at these
(through PTAP motifs) and AIP-1/ALIX (through YPxL sites [150]. These viral DNAs are either degraded by the
motifs) [138, 139]. Ubiquitylation of cargo is usually in- combined action of uracil N-glycosylase and apurinic-
volved in ESCRT function, and the p6 protein also appears apyrimidinic endoculease or plus strand DNA is synthe-
to be modified by ubiquitylation. The product of the tu- sized producing dG!dA hypermutations and likely the
mor suppressor gene 101 or TSG101 binds the PTAP motif introduction of multiple stop codons in normally open
of p6 Gag and also recognizes ubiquitin through its ubi- reading frames. Vif circumvents these antiviral activities of
quitin enzyme 2 (UEV) domain [140, 141]. The TSG101 APOBEC3G by targeting the antiviral enzyme for both accel-
protein normally associates with other cellular proteins erated degradation in proteasomes and decreased synthesis
in the vacuolar protein-sorting pathway to form the (Fig. 3.6) [148, 151, 152]. In terms of the accelerated deg-
ESCRT-1 complex that selects cargo for incorporation into radation, Vif both binds to APOBEC3G and a specifc E3
the multivesicular body (MVB) [142]. The MVB is pro- ligase complex that mediates polyubiquitylation of APO-
duced when surface patches on late endosomes bud away BEC3G, marking it for proteasomal degradation [153].
from the cytoplasm and fuse with lysosomes, releasing These combined effects lead to the depletion of intracellular
their contents for degradation within this organelle. In APOBEC3G in the virus-producing cell; thus, the enzyme is
the case of HIV, TSG101 appears to be “hijacked” for not available for virion incorporation.
34
Budding
virus stuck
Infectious virus
SCF-Iike EloB Cul5 Rbx

complex EloC E2
Vif
tetherin Ub
(BST-2) APOBEC3G
Vif
Ub Budding
Vpu
265 Ub
Proteasome Ub
n APOBEC3G
HMM complex Vif
Vif Lethal
Lysosome hypermutation
AAAA APOBEC3G
TRIM5α
Disruption of
normal uncoating
Figure 3.6 Host restriction factors block HIV-1 at various stages in its life cycle. TRIM5a targets the incoming viral capsid and disrupts
the normal uncoating process. APOBEC3G, as well as other members of the APOBEC3 family, are incorporated into budding virions in
the absence of Vif. Once in the target cell, APOBEC3 enzymes deaminate cytosine residues in the single-stranded minus-strand viral
DNA, leading to lethal hypermutation. Vif overcomes the APOBEC3G block by both promoting polyubiquitylation and proteasome-
mediated degradation of this enzyme and by partially blocking APOBEC3G translation. In the absence of Vpu, tetherin/BST-2 prevents
the budding of HIV virions. Vpu antagonizes tetherin by promoting its degradation by the proteasome and lysosome.
The assembly of Vif with APOBEC3G and Vif-induced motif 5a protein, or TRIM5a [156]. TRIM5a derives its
degradation of the antiretroviral enzyme provide an in- name from its tripartite motif that includes a zinc-binding
triguing new target for antiviral drug development. The ring finger, a B box domain that also binds zinc, and a
goal is to identify small molecules that would interfere coiled-coil region (SPRY domain). TRIM5a also contains
with APOBEC3G degradation. The result would be to pre- a C-terminal B30.2/SPRY domain hypothesized to mediate
serve the intracellular levels of the enzyme, making it protein–protein interactions. When levels of rhesus
available for incorporation into the virion and poised to TRIM5a are decreased by RNA interference, HIV replication
unleash its potent DNA-mutating effects during the next in these cells is greatly increased. In contrast to the inhibi-
round of reverse transcription. To this end, cell-based tory effects of rhesus TRIM5a, human TRIM5a only mod-
screens in which APOBEC3G is fused to a fluorescent pro- estly impairs HIV replication.
tein and expressed in the presence of Vif have been devised The mechanism by which TRIM5a exerts its antiviral ef-
[154, 155]. Although several compounds that display fect is not fully understood. TRIM5a targets intact or par-
antiviral activity were identified by these screens, none tially uncoated incoming viral cores [157–159]. It has
has entered clinical trials. been suggested that TRIM5a blocks HIV-1 infection by
causing the cells to undergo rapid disassembly [160, 161]
and/or by recruiting cellular proteasomal degradation ma-
TRIM5a
chinery [162–165]. Interestingly, in some primate species
HIV fails to replicate in most nonhuman primate cells (e.g., owl monkey), the C-terminal B30.2/SPRY domain
(chimpanzee and gibbon ape cells are notable exceptions). has been replaced by cyclophilin A [166]. This “TRIM-
HIV entry occurs normally in these “nonpermissive” pri- Cyp” fusion protein potently inhibits HIV-1 infection. In-
mate cells, but encounters a block prior to reverse transcrip- deed, fusion of cyclophilin A to the C-termini of several
tion. The host restriction factor responsible for this block nonrestriction TRIM proteins also generated functional
in nonhuman primate cells was identified as the tripartite HIV-1 restriction factors.
35
With a greater understanding of how rhesus TRIM5a mechanisms underlying viral cytopathicity. Such cell death
acts, it may be possible to develop small molecules that is not only limited to infected targets but also involves
enhance the ability of human TRIM5a to associate with uninfected bystander cells [174]. Murine cells do not
and restrict HIV-1. A single amino acid substitution support efficient assembly and/or release of Gag [175].
greatly enhances the antiviral potency of human TRIM5a Currently, this defect represents a major impediment to
[167]. The binding of a small molecule could induce a the successful development of a rodent model of AIDS.
conformational change that transforms human TRIM5a Proposed mechanisms for HIV killing of T cells include
into a potent restriction factor. However, this poses a sub- the formation of giant cell syncytia through the interactions
stantial challenge because most drugs are designed to dis- of gp120 with CD4 and chemokine receptors [176]; the ac-
rupt an interaction or interfere with an enzymatic activity cumulation of unintegrated linear forms of viral DNA; the
rather than elicit a gain-of-function interaction between proapoptotic effects of the Tat [177], Nef [178], and Vpr
two binding partners. [179] proteins; and the adverse effects conferred by the
metabolic burden that HIV replication [180] places on
the infected cell. Of note, expression of Nef alone as a trans-
Tetherin gene in mice recapitulates many of the clinical features of
The most recently identified host restriction factor, tetherin AIDS, including immunodeficiency and loss of CD4-
(BST-2), inhibits viral replication by “tethering” mature vi- infected cells [181].
rions on infected cell surfaces and preventing their release Although CD4 T cells undergo a dramatic cytopathic
[168, 169]. HIV-1 escapes the tetherin block through the response during infection, more than 95% of these cells
actions of its accessory protein Vpu. The mechanism by are not productively infected. The mechanism of cell
which Vpu antagonizes tetherin are not well understood; death in these bystander cells has eluded HIV researchers
however, Vpu seems to sequester tetherin from the site for many years. A recent study now shows that death of
of budding, reduce its surface expression, and promote these bystander cells involves abortive HIV infection
its proteasomal degradation [170–172]. Tetherin is induc- [182]. Drugs that block HIV entry or the early steps of re-
ible by IFN-a, and high levels can suppress viral replication verse transcription prevent CD4 T cell death, while inhib-
even in the presence of Vpu [173]. Therefore, enhancing itors of later events in the viral life cycle do not. Abortive
tetherin expression by treatment with IFN-a represents a infection appears to lead to the accumulation of incom-
possible therapeutic approach. However, IFN-a treatment plete reverse transcripts [182]. These cytoplasmic nucleic
also has harmful consequences, such as contributing to acids activate a host defense program that elicits a coor-
the high levels of immune activation that drive progression dinated apoptotic and inflammatory response that ulti-
toward AIDS. A more direct approach (e.g., identifying mately leads to cell death.
small molecules that interfere with the tetherin–Vpu inter- Technical advances in recent years have vastly ex-
action) may ultimately prove most useful as a therapeutic panded our view of viral–host protein interactions.
strategy. Genome-wide screens using libraries of small interfering
RNA molecules have identified hundreds of new host
cell factors required for HIV-1 replication. Three recent
screens, which evaluated more than 20,000 genes, iden-
SUMMARY AND PERSPECTIVE tified a total of 842 genes that reduce HIV-1 infection
when knocked-down by RNA interference [183–185].
The global AIDS pandemic continues to expand. Advances The lack of overlap between the three screens surprised
in antiretroviral therapies have slowed its advance in the in- many researchers in the HIV field. Therefore, caution
dustrialized world but due to limited availability have must be used in interpreting the results. In addition to
had less impact in the developing world. Because of its high in vitro screens, molecular genetics are using genome-
rate of mutation, HIV is able to refine and optimize its wide association studies to identify an even greater num-
interactions with various host proteins and pathways, ber of host factors. These studies involve large cohorts of
thereby promoting its growth and spread. The virus ensures HIV-infected individuals to identify human genetic dif-
that the host cell survives until the viral replicative cycle is ferences that influence viral load and progression toward
completed. Possibly even more damaging, HIV establishes AIDS [186]. Although the role and relevance of these
stable latent forms that support the chronic nature of infec- host factors to HIV-1 infection need to be confirmed,
tion. Eradication of the virus appears unlikely until effec- their identification vastly expands the number of poten-
tive methods for purging these latent viral reservoirs are tial targets for antiretroviral therapy.
developed. Finally, future therapies will likely target viral proteins
Basic science will clearly play a leading role in future other than its enzymes, namely reverse transcriptase, prote-
attempts to solve the mysteries of viral latency and replica- ase, and integrase. Although only under preclinical evalua-
tion. A small-animal model that recapitulates the patho- tion, small chemicals capable of interfering with Tat
genic mechanisms of HIV is sorely needed to study the transactivation [187] and Rev-dependent nuclear export
36
of viral transcripts are under study [188]. As a proof of prin-

ciple, dominant-negative mutants of Tat, Rev, and Gag pro- ACKNOWLEDGMENTS
teins block viral replication [189]. By increasing the
number of antiviral compounds available that target dif-
We thank Gary Howard and Stephen Ordway for editorial
ferent steps in the viral replicative cycle and by ensuring
support, Robin Givens and Sue Cammack for administra-
that these drugs can be deployed in developing countries,
tive support, and the National Institutes of Health (R01
we should be positioned better both to extend survival
AI45234, R01 CA86814, P01 HD40543), the UCSF Califor-
and to improve the quality of life for infected individuals
nia AIDS Research Center (CC02-SF-002), and the J. David
and to inhibit the spread of AIDS.
Gladstone Institutes for funding support.
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43
Chapter |4|
The immune response to HIV
Clive M. Gray, Pamela Gumbi, Lycias Zembe, Mopo Radebe, Bruce Walker
of acute viral infections (such as influenza, rotavirus, or

INTRODUCTION respiratory syncytial virus) as well as acute viral infections
followed by latent infection (herpes simplex virus or
Most people in the world live in poverty-stricken con- Epstein–Barr virus). This will allow a foundation for dis-
ditions where they are continuously confronted with a cussing why successful immune mechanisms are not func-
plethora of pathogenic organisms—some successfully re- tional in the majority of HIV-1-infected individuals. Much
pelled, some resulting in clinically overt disease, and others knowledge on the first immune events during acute HIV-1
resulting in persistent latent infection. The human immune infection has also accumulated, providing additional clues
system has evolved to combat these genetically diverse or- to the arms of immunity that are triggered upon first en-
ganisms, including viruses, bacteria, and protozoa, through counter with the virus. The field has been shaped by the hy-
genetically governed responses involving multiple recep- pothesis that the initial immune response to HIV infection
tors and ligands. Even with clinically overt or persistent is translatable to what would be expected or required from
infections, most people with an intact immune system a vaccine. We will discuss clues as to what may constitute
ultimately survive most infections. a protective immune response from disease progression
In marked contrast stands HIV infection. The spread of in a small proportion of people who are HIV-1 infected,
HIV-1 worldwide represents one of the great challenges but can spontaneously contain viral replication to only
to confront host immunity, since the key target is the a few RNA copies. Finally, we will discuss some of the fail-
CD4 T cell lymphocyte, infection and depletion of which ures and partial successes of recent vaccine trials, which
severely undermines effective immune responses. As a re- have provided insight into the requirements for potential
sult, most people who become infected and remain protective immune mechanisms.
untreated will ultimately succumb to one or more of the
large variety of infectious organisms that humans are con-
fronted with on a daily basis. By 2010, there was an esti- GENERAL PRINCIPLES OF AN
mated 2.4–2.9 million people becoming newly infected
with HIV, with 1.8 million dying of AIDS-related causes ANTIVIRAL IMMUNE RESPONSE
(http://www.unaids.org, 2011 Global Report).
The ultimate solution to the HIV epidemic relies on the The degree to which pathogenic organisms establish pro-
development of an effective vaccine that can be delivered to ductive infections is determined in part by the integrity
those at risk. The ability to achieve this elusive goal will be of epithelial and mucosal cells: skin, respiratory tract,
facilitated by a comprehensive understanding of the key alimentary tract, urogenital tract, and conjunctiva. These
immune responses that contribute to protection from in- regions serve as physical barriers between the exterior
fection, or protection from disease progression in those and internal environment and any abrasions or lesions
who become infected. In this chapter, we will review the will allow potential pathogenic organisms into either the
current state of knowledge of what is needed for an AIDS blood or lymphatic circulation. Once these physical bar-
vaccine, first by comparison to effective immune clearance riers have been transcended, there are two major categories
45
of host immune responses, namely innate and acquired immune response. In general terms, if the anatomical
immunity. arrangement of lymphoid tissue disintegrates due to pa-
The innate immune response represents the first line of thology, the impact will result in disrupted antigen presen-
defense, and serves to rapidly attenuate the impact of most tation and loss of both B and T cell priming and the
infectious organisms. From an evolutionary perspective, inability to provide protective immunity.
innate immunity shares properties with lower vertebrate Movement of T cells from one lymphoid region to
mechanisms of engulfment and phagocytosis and the re- another allows both CD4 and CD8 T cells to encounter
sponse consists of specialized cells, such as macrophages, processed antigen in the paracortical region of the lymph
natural killer cells, dendritic cells, and polymorphonuclear node. After engaging and processing antigen in the periph-
leukocytes. Infectious organisms that survive the innate im- eral tissue, dendritic cells will migrate to lymph nodes,
mune response, or residues from such a response, are dealt where there is selection of reactive T cells through TcR en-
with by the specific acquired immune response. gagement with viral peptides situated in the binding groove
Acquired immunity has three central tenets: specificity, of the human leukocyte antigen molecules on the surface of
recognition of protein structures via the interaction of re- the antigen presenting cells. This process results in multiple
ceptors and ligands; diversity, variations in specificity, clones of expanded T cells, leading to diversity.
where multiple receptors interact with different protein The MHC in humans is known as the human leukocyte
structures; and memory, where different T and B cells that antigen (HLA) system and is one of the most polymorphic
have been primed to antigens can be recalled at a subse- proteins in the human population. The uniqueness of indi-
quent point in time with a more rapid response. viduals is partly defined by HLA, where each person has a
What governs specificity and diversity of the adaptive im- defined HLA type consisting of pairs of inherited genes.
mune response is the genetic make-up of the host, where As the sole function of class I and II HLA is to present pro-
genes encoding for the major histocompatibility complex cessed pathogen-derived peptides, or epitopes, to circulat-
(MHC), T cell receptors (TcR), and immunoglobulins ing T cells, possible aberrant T cell function and recognition
(B cell receptors) dictate how and which regions of the of self, as in autoimmunity, will thus involve the HLA. HLA
pathogen are encountered by the immune system. The class I molecules are co-dominantly expressed on antigen
molecules encoded by these genes are central to specificity, presenting cells, and they play an important role in regulat-
diversity, and memory and constitute the internal coming the fitness of the immune system through a process of
position of each individual and is collectively known as selecting and presenting immunogenic peptides to CD8
“self.” An acquired immune response that results in the suc- T cells by TcR recognition (Fig. 4.1A). HLA alleles are
cessful clearance of an invading organism can be under- X-linked and inherited in pairs (heterozygous), and it is
stood by the exquisite difference in recognition between noteworthy that in HIV infection, individuals who are ho-
“self” and “non-self.” The ultimate outcome of this process mozygous for one or more alleles (inheriting the same HLA
is preservation and survival of the species. allele from both parents) progress more rapidly to AIDS
than heterozygotes [1]. Additionally, HLA-B is more poly-
morphic than HLA-A and HLA-C and the influence of HLA-
ACQUIRED IMMUNITY TO VIRAL B is known to have the strongest impact in HIV set point,
which is strongly predictive of the rate of progression [2]
INFECTIONS when compared to HLA-A and HLA-C molecules [3, 4].
The manner by which epitopes are processed and bound
The immune system consists of parallel blood and lym- by the HLA molecule is highly specific and governed by cer-
phatic circulations, ensuring that different cells participating tain rules associated with the binding motif structures of
in an immune response can migrate back and forth between each HLA and in the correct orientation will be recognized
non-lymphoid tissue and the different secondary lymphoid by activated CD8 cytotoxic T lymphocytes (Fig. 4.1A).
structures (such as the spleen and lymph nodes). Bone mar- Sequence changes can occur at anchor positions of targeted
row is the primary lymphoid organ, where the precursors to epitopes and reduce or interfere with peptide binding to the
all mature immunocompetent cells are derived as pluripo- restricting HLA class I molecule. Moreover, amino acid
tential progenitor cells. B and T cells develop into mature changes within or immediately adjacent to CD8 T cell epi-
immunocompetent cells in the bone marrow and thymus, topes can impede intracellular antigen processing or directly
respectively. T cells that leave the thymus are “naı̈ve” and modify the structural interaction between the epitope of
have yet to encounter invading pathogens. HLA class I complex and the TcR of the corresponding
Lymph nodes are crucial for providing the correct mic- CD8 T cells. The ability of viruses to acquire sequence mu-
roenvironment and anatomical structures required for tations resulting in the loss of recognition by HIV-1-specific
initiating an immune response. The micro-anatomical CD8 T cells poses a major hurdle for current vaccine efforts.
arrangement of the lymph node enables T cells to en- HLA class II molecules have a more restricted distribu-
counter processed viral proteins presented by specialized tion and are expressed only on specific cell types and on
antigen presenting cells, which initiates the adaptive T cells after activation. Classically, CD4 T cells provide
46
Chapter |4| The immune response to HIV
Activated CD8+
cytotoxic
T lymphocyte
TcR
Kill
Virus
HLA I
CD8
Tissue cells
Viral protein
"Self" protein
Figure 4.1A Cells infected by viruses or intracellular bacteria are detected and destroyed by CD8 cytotoxic T lymphocytes.
CD8 cytotoxic T lymphocytes are activated in the secondary lymphoid organs and migrate to sites of inflammation where they
scan cell surfaces with their T cell receptors (TcR) for recognition of foreign peptide antigens displayed on cell surface HLA class I
molecules. HLA class I receptors are constitutively expressed on the surface of all cells except erythrocytes. CD8 cytotoxic T
lymphocytes destroy target cells by releasing granzymes and perforin and cell-degrading molecules (with permission from
Immunopaedia, http://www.immunopaedia.org).
“help” to the immune response by liberating a series of cy- A balance exists between pro- and anti-inflammatory
tokines important for coordinating cellular activity and in- immune responses imparted by these CD4 subsets for main-
ducing activated B cells to become antibody-secreting taining the integrity and homeostatic balance of cells in the
plasma cells (Fig. 4.1B). First identified in murine models, host. Recently, T helper follicular cells that are involved in
the multitudinous number of cytokines have been orga- the development of antibody-producing plasma cells in the
nized into a network model of Th1, Th2, Treg, and Th17 germinal centers of lymphoid tissue have been described [6].
cells. A Th1-type response consists of CD4 T cells liberating How do these cells fit together in healthy humans? CD8
a profile of cytokines that direct T cell immunity and in- T cells make up the smaller proportion of CD3 T cells and
volves IL-1, IL-2, IL-6, IL-12, IL-15, TNF-a, and IFN-g, for are involved in protecting the host from invading patho-
example. A Th-2-type response consists of CD4 T cells lib- gens. These cells function by killing virally infected cells,
erating a profile of cytokines that directs humoral immune which are marked by the surface expression of HLA class
responses and is involved in switching on B cell immunity. I molecules that present virus-derived epitopes that are typ-
These cytokines include, among others, IL-4, IL-5, and IL- ically 8-11 amino acids in length (as described above,
10. A Th17-type response consists of an IL-17A, IL-17F, Fig. 4.1A). These CD8 T cells function with the help of
and IL-22 profile and is involved in conferring protection CD4 T helper cells. The killing potential of CD8 T cells is
against bacteria, fungi, and mycobacteria [5] and to play through either perforin/granzyme or Fas–Fas-L interactions
a role in mucosal defense in the gut. Tregs are and erupted and effete infected cells are engulfed and
CD4þCD25hiFoxP3þ and have been shown to down- processed by dendritic cells; virally derived epitopes are
regulate the activation and proliferation of T cells [5]. presented via cross-presentation [7] by class II HLA
47
Plasma cell
Activated
B lymphocyte
T cell zone
B cell
activation
signal
CD
4
Secondary
HL
A II
lymphoid organ
TC
R
Antibodies
CD4 helper
T lymphocyte
Figure 4.1B CD4 helper T lymphocytes stimulate B lymphocytes presenting peptide antigens associated with HLA class II receptors in
the T cell zone of secondary lymphoid organs. The CD4 helper T lymphocyte provides activation signals to the B lymphocyte
to proliferate and differentiate into antibody-secreting plasma cells. Memory B lymphocytes are also generated for long-term
immunity (with permission from Immunopaedia, http://www.immunopaedia.org).
molecules and drive CD4 T cell responses. Typically most being recognized as a disease of the mucosal immune
(99%) expanded viral antigen-specific T cell effector clones system [8], where vaginal and rectal mucosa are the pre-
induced in the acute phase of infection will die through dominant sites of HIV entry and the gut-associated lym-
apoptosis as the immune response wanes, leaving a small phoid tissue (GALT) is the site of initial HIV replication.
residual population of T effector memory cells that mi- During the early phase of simian immunodeficiency virus
grate to non-lymphoid tissues or T central memory (TCM) (SIV) and HIV infection, there is a rapid and widespread
cells that recirculate through the lymphatic system and massive depletion of activated mucosal CD4 T cells at
blood circulation and can be rapidly reactivated upon sec- mucosal sites and this occurs before significant depletion
ondary exposure to viral antigens. in blood and lymph nodes [9]. Recent evidence confirms
that the level of CD4 T cell depletion is far higher than at
first anticipated, with 60–80% of memory CD4 T cells de-
IMMUNE RESPONSE TO HIV-1 pleted during early infection. Thus, within the first few
weeks of HIV infection, the virus targets the mucosal im-
INFECTION mune system and dramatically depletes the CD4 T cells
at this site. It has also been shown that HIV targeting of ac-
The course of immunological events from the time of trans- tivated CD4 T cells in mucosal tissues persists throughout
mission can be divided into acute, early, and chronic infection, and not just in acute infection as previously
phases of infection. The greatest challenges HIV presents thought. Mucosal tissues are likely to be a major source
to the immune system include the selective infection of of viral replication, persistence, and continual CD4 T cell
CD4 T lymphocytes and the extensive viral genetic vari- loss in HIV-infected individuals. Reduced CD4 T cell fre-
ability due to mutations. quencies during chronic HIV infection have also been
Is HIV a disease of the mucosal immune system? A num- shown in other mucosal sites such as rectal mucosa [10],
ber of studies have highlighted the importance of the male genital tract [11], female genital tract [9], and lung
mucosa in HIV pathogenesis and it is now increasingly mucosa [12].
48
Genital epidermaI Genital T cell B cell zone

HIV layer Iymph zone
node
CD4 helper
T lymphocyte
IL-1
Squamous IL-6
epithelial TNF-α
cell layer
Activated epidermal
Langerhans cell
T cell migration
and virus
dissemination
Figure 4.2 Epidermal Langerhans cells are a subset of dendritic cells found in the squamous epithelium of the female vagina and
male inner foreskin and are the first immune cells to contact HIV during heterosexual contact. They express surface CD207 (langerin)
that capture virus by binding to gp120 and induces internalization and degradation of virus. Activated cells migrate to draining
lymph nodes for antigen presentation to CD4 T lymphocytes, which can also become infected by surface-bound virus. Langerhans
cells also express CD4 and CCR5 and can become infected. Activated Langerhans cells produce pro-inflammatory cytokines IL-1,
IL-6, and TNF-a that can cause fever in acute infection (with permission from Immunopaedia, http://www.immunopaedia.org).
Figure 4.2 shows some of the local factors in the mucosal prognostic of disease outcome, where high levels of viremia
microenvironment that may facilitate HIV replication in are associated with a more rapid course of infection leading
mucosal tissues independently from blood: (i) the local- to AIDS. It is noteworthy that seroconversion (4), by the
ized cytokine milieu; (ii) differing inflammatory signals; detection of anti-Gag binding antibodies, occurs after peak
and (iii) the presence of different immune cell types in viremia and that detection of neutralizing antibodies occurs
these distinct compartments. These factors highlight muco- only after approximately 3 months post transmission.
sal sites as critically important in the context of not only un- In addition to virus-specific CD8 T cells, CD4 T cells
derstanding HIV pathogenesis but also in terms of being appear to be critical for immune control. Animal models
able to possibly dampen or correct the imbalance of proof chronic viral infections established that virus-specific
inflammatory signals in potential therapeutic or preventive CD4 T cells play an essential role in maintenance of effec-
modalities. tive immunity (reviewed in Day and Walker [16]), and the
During acute HIV infection, there appears to be a hierarchy immune response to HIV appears to follow these same
of systemic immune responses that occur. Figure 4.3 shows a requirements. The detection of enhanced proliferation of
composite schema of the known sequence of immunological anti-HIV-specific CD4 T cells in individuals who maintain
responses that occur during infection. After viral transmis- long-term control of HIV replication [17] and in patients
sion (1), where there appears to be a selection of single strain treated for acute infection with potent antiretroviral ther-
variants at the mucosa [13], there is dissemination (2) of the apy [17–19] suggest that the function of these cells is cen-
virus to the lymphoid tissue [14] during the acute phase of tral to influencing viral set point and for controlling virus.
infection. Within days after viral transmission, viremia peaks As discussed, a large number of CD4 T cells are infected
and the downward slope is thought to be a result of a robust in the gut and that the bulk of the CD4 T cell pool resides
cellular immune response leading to initial control (3) of within lymphoid tissue around the gastrointestinal tract.
virus [15]. Natural history studies have shown that viral set Direct killing of CCR5 CD4 T cells within the gut
point is achieved within 6 months of infection and is [20, 21] and memory CD4 cells in multiple tissues [22]
49
Chronic infection
Acute infection (asymptomatic) AIDS
3 Control
CD4 T lymphocytes
Neutralizing
Dissemination 2 antibodies
CD8 T lymphocytes
4 Seroconversion
Binding
antibodies
Transmission 1
Time from infection (months to years)
Figure 4.3 A typical immune response to untreated HIV infection shows a rapid increase in viremia in the acute phase, which
declines to a set point. A decline in CD4 T cells coincides with the increase in viral load. HIV-specific CD8 cytotoxic T lymphocyte
responses reduce the viral load and an increase in CD4 T cells is observed. HIV-specific binding antibodies appear after the
reduction of viremia, but antibodies are detectable by ELISA only later in acute infection. During chronic infection, CD4 T cells
decline slowly and viral load remains stable. Neutralizing antibodies begin to appear around 3 months post infection. Continued
HIV replication and immune evasion exhausts the immune system, leading to opportunistic infection and AIDS in most infected people,
albeit with varying lengths of time (with permission from Immunopaedia, http://www.immunopaedia.org).
by HIV has been postulated as the main mechanism for monkeys during acute SIV infection led to delayed emer-
CD4 T cell depletion during SIV infection in monkeys, gence of neutralizing antibodies and no change in early
and extrapolations to HIV-induced depletion of CD4 T cells viral kinetics [25]. Additionally, passive transfer of neu-
within the human gut have also been made [23]. Figure 4.4 tralizing antibodies in monkeys can protect against intra-
shows the potential scenario of microbial translocation venous and mucosal challenge of SIV [26]. Thus it is
from the gut lumen. Studies of HIV/AIDS pathogenesis clear that neutralizing antibodies are important for pre-
have long-focused on the role of CD4 T-cell depletion as vention of viral infection, but perhaps less clear once
a key marker of disease progression [24]. The pathogenesis HIV-1 infection has become established. Recent compre-
of HIV infection is now characterized by CD4 T cell immu- hensive longitudinal studies of autologous neutralizing
nodeficiency in the context of generalized immune acti- antibody responses following acute infection indicate a
vation and dysregulation, with massive memory CD4 T significant antiviral effect of these responses, in that the
cell infection and depletion during acute infection. This viral inhibitory capacity is of sufficient magnitude to
is followed by gradual loss of remaining CD4 T cells completely replace circulating neutralization-sensitive vi-
caused by persistent immune hyperactivation. Activation rus with successive populations of neutralization-resistant
of CD4 T cells results in increased target cells for the virus, virus [33].
excessive apoptosis of uninfected T cells, generalized im-
mune dysfunction, and impaired ability to control HIV
replication. WHY THE IMMUNE RESPONSE FAILS
In addition to cellular immune responses that emerge rap-
idly after HIV transmission, active humoral immunity is ap- TO CONTROL HIV
parent by the increased titers of anti-Gag antibodies, which
are used diagnostically to assess seroconversion. Functional From our discussion so far, HIV infection provokes a burst
antibodies are those that can block or neutralize HIV entry of immune activity that results in potent targeted cytotoxic-
into CD4-bearing cells and such neutralizing antibodies T lymphocyte (CTL) responses, CD4 T cell function, and
mainly target the highly variable V3 loop, the CD4 binding the induction of antibodies. These immunological compo-
domain, and the more conserved gp41 transmembrane pro- nents have been found to be central role-players in effective
tein of HIV-1. Although high titers of neutralizing antibodies clearance of many other viral infections, but fail to clear
can completely prevent infection in animal models, the role HIV-1 infection without exception. Why is HIV neither
of these responses in viral containment following infec- eliminated nor effectively contained following infection?
tion in humans remains uncertain. During acute infec- A number of possibilities exist. First, it is important to un-
tion, these responses appear following the initial drop derstand from a virological perspective that HIV-1 estab-
in viremia, and experimental depletion of B cells in lishes persistent infection by infecting CD4-bearing cells
50
Lamina propria
Crypt of Lieberkühn
Macrophage
Microbial
antigens
Microbes
Translocation
Lymphatic vessel
Dendritic cell
Mucins
Antimicrobial
defense molecules
Microvilli Venule
Epithelial Paneth cell

stem cell
T lymphocyte
Goblet cell
Arteriole
Enterocyte
Figure 4.4 Activation of the mucosal immune system due to HIV replication in CD4 T helper lymphocytes in the lamina propria
leads to the production of pro-inflammatory cytokines. This can cause a disruption of gut epithelial cell development, most
notably resulting in villous atrophy and increased gut permeability to microbes and microbial antigens. The consequences of this
are malabsorption of nutrients due to reduced absorptive surface area and further stimulation of mucosal immune cells that
can enhance HIV replication (with permission from Immunopaedia, http://www.immunopaedia.org).
and integrates into the host genome as provirus. Both pri- account for a lack of long-term control of HIV infection
mary and secondary lymphoid tissues are targets for seeding are probably complex. The following are some of the factors
by HIV soon after transmission and the anatomical structures for which there is now experimental evidence suggesting that
within lymph nodes, spleen, and bone marrow are affected they may participate in the ultimate lack of ability to control
by the presence of virus. Consequently, from an immunolog- HIV replication.
ical perspective, the persistence of antigen directly within the
secondary lymphoid structures will influence T and B cell
Escape from neutralizing antibodies
clonality and drive cells into a hyperactivated state. As dis-
cussed earlier, the high rate of HIV mutability, due to the Despite gradual broadening of the neutralizing antibody
error-prone nature of reverse transcriptase, in response to response following acute infection, it does not become suf-
specific B and T cell reactivity, leads to immune escape and ficiently broad to neutralize the next population of virus to
contributes to viral persistence within the host. arise [27, 28], and the neutralizing antibody responses for-
It is also important to understand that almost 30 years af- ever lag behind the evolution of the envelope gene. The rel-
ter AIDS was first identified, the critical immune functions evance of neutralization antibody escape in loss of overall
that control HIV replication remain to be defined. A simplis- control of viremia is open to debate as escape has also been
tic view has been that strong CD8 T cell responses, together observed in HIV-infected individuals who persistently con-
with strong neutralizing antibodies and virus-specific CD4 trol viremia [29, 30].
T cells, would lead to control of viremia. The breadth and
magnitude of CD8 T cell responses do not correlate with
Escape from CD8 T cell control
control of viremia, at least as measured by IFN-g responses.
Although neutralizing antibodies are detectable, there is no Studies in acute HIV infection have shown that mutations
simple relationship between these and viremia. Even virus- in the HIV genome occurs rapidly, resulting in viral escape
specific CD4 T cells, which seem critical for maintenance of from specific CD8 T cell recognition. During the course of
effective cellular and humoral immune responses in animal infection the HIV-1 pathogen encodes numerous poten-
models of chronic infection, can be found in some persons tially immunogenic determinants; yet, CD8 T cells only
with progressive infection. Thus the mechanisms that recognize and respond to a minute fraction of potential
51
viral epitopes. These CD8 T cells responses can be classi- of CD8 T cells that are CD4dim following activation has been
fied as immunodominant, co-dominant, and subdomi- demonstrated, suggesting that infection of this population of
nant, depending on their relative contribution to the CD8 T cells may contribute to loss of CD8 T cell function in
overall magnitude of HIV-1-specific CD8 T cell responses vivo [47, 48].
in a given individual. Data from both human and animal
models indicate that during acute infection, highly effective
Impaired dendritic cell function
HIV-1-specific CD8 T cells are narrowly directed against
selected epitopes and do so in a hierarchal order [31]. This Dendritic cells (DCs) are reported to be among the first
may suggest that the hierarchy of HIV-1-specific CD8 T-cell cells with which HIV-1 interacts and through expression
responses in acute infection may be crucial for the of a diverse array of receptors and signaling molecules,
effectiveness of the immune response in chronic infection DC’s capture and process HIV-1, and present associated an-
[31, 32]. Mutations within targeted epitopes [33, 34] can tigens to T cells. DCs serve as crucial links between innate
also abrogate established CD8 T cell responses, as can and adaptive immune responses through expression of
mutations in flanking residues that impair normal antigen pattern-recognition receptors (PRRs) such as Toll-like re-
processing. Both of these lead to loss of recognition by ceptors (TLRs) and intracellular pathogen sensors, which
established T cell responses. trigger specific signaling pathways that lead to host defense.
There are also recent studies in the SIV model and in a small
human clinical trial suggesting impaired induction of im-
CD8 T cell dysfunction
mune responses in chronic infection, which may be related
Defects in differentiation and maturation of CTL [35–37] to the impaired function of DC during viral infection.
may result in impaired in vivo function, and may relate to These studies [49], in which adoptive transfer of in vitro ma-
lack of CD4 T cells help that is critical for maintenance tured DCs loaded with inactivated virus led to a decrease in
of effective immunity. Most studies to date have defined set point viremia and increase in virus-specific immune re-
CD8 T cell responses based on the ability to secrete sponses, need to be confirmed by additional groups, but
IFN-g, which based on animal model data may be the last suggest that there is impairment in the inductive phase
effector response to be lost by CD8 T cells [38]. While of the immune response.
T cells, in particular CD8 T cells, have the ability to carry
out many functions in response to antigens including
Lymphoid structure degeneration
cytotoxicity, release of IFN-g, TNF-a, and MIP-1b, for exam-
ple, many previous studies on HIV-specific T cell responses After infection, HIV-1 resides within the germinal centers of
focused on measuring one or two functions of these cells. the lymph nodes, spleen, tonsils, and thymus and exists,
The advancement in flow cytometry recently has allowed in the main, as whole virus on the surface of follicular den-
the measurement of multiple T cell functions, including de- dritic cells (FDCs) in the lymph node. As a result, the normal
granulation (CD107a mobilization), cytokines (for exam- function of FDC in presenting antigen may be overridden.
ple IFN-g, IL-2, and TNF-a) and chemokine production Viral transmission is thought to be cell-associated and pro-
(for example, MIP-1b) [39] to determine whether it is the ductive infection most likely takes place in lymphoid struc-
quality of HIV-specific T cell response rather than frequency tures in close proximity to the cervix and rectum, where
or breadth that is the important factor in HIV disease pro- DCs from the newly infected individual migrate from the
gression. Interestingly such studies have found out that cervical region to lymph nodes elsewhere in the body.
non-progression [39] or elite control [40] in HIV infection Complete virus is most likely carried on DCs by dendritic
is associated with maintenance of high levels of polyfunc- cell-specific intercellular adhesion molecule-3-grabbing
tional CD8 T cells. Other studies further dissected poly- non-integrin (DC-SIGN), which aids in transmission to T
functionality and demonstrated that it is the up- cells [50] in the lymph nodes distal to the point of viral
regulation of perforin, a cytolytic enzyme, that is associated transmission. Although there are no clear data relating
with control in HIV infection [41]. Recent data indicate a the dissolution of the lymph node architecture with persis-
functional impairment in the ability of CD8 T cells to pro- tence of virus, and ongoing immune responses, it may be
liferate to viral antigens in persons with progressive disease hypothesized that destruction of the platform used to ini-
that is maintained in persons with non-progressing infec- tiate immune responses leads to an overall failure in T cell
tion [36], and present in the earliest stages of acute infec- priming to new antigens. Evidence from regenerated lym-
tion when viral load is rapidly declining [42]. phoid structures after successful antiretroviral treatment
supports this notion [51].
Impaired CD4 T cell responses
Other concomitant infections
The composition of functionally distinct subsets of virus-
specific CD4 T cells, including IL-2- and IL-2/IFN-g-secreting The extent to which the ability to control HIV may be im-
HIV-1-specific CD4 T cells, may be critical [43–45], as paired by other concomitant infections is a particularly rel-
may cell killing by CD8 T cells [46]. Infection of a subset evant question for those areas where the epidemic is
52
currently most rapidly expanding. In many regions of the cytotoxic T cell activity and chemokine receptor mutations
world, co-infections with Mycobacterium tuberculosis as significant markers associating with their seronegative
(mTB) [52] and other co-viral infections are predominant, status. Less well-associated factors such as chemokine pro-
and the impact of co-infections on host immunity to duction, HLA alleles/haplotypes, helper T cell responses,
HIV is also relatively unknown. Herpes simplex virus type humoral responses, and soluble inhibitory factors have
2 (HSV-2) infection, for example, results in a persistent been described, but less uniformly. Evidence for mucosal
localized inflammatory response in the dermis below the HIV-specific IgA antibodies in HEPS individuals also pro-
healed lesion, consisting of HSV-2-specific CD4 T cells that vide evidence for possible protective roles of local antibody
express CCR5 or CXCR4, which are important HIV co-re- responses—although these studies often have examined
ceptors. [53] Furthermore, HSV-2 suppressive therapy small numbers of individuals [60].
was shown to significantly reduce plasma viral loads and A more recent exploration of defining which immune
reduce genital tract HIV shedding in HIV-infected women factors correlate with protection, or attenuation of disease
co-infected with HSV-2 [54]. in HIV-infected individuals, has been to identify human
Human papilloma virus (HPV) infection of the cervix genes with polymorphic variants that influence the out-
may influence HIV pathogenesis by inducing the produc- come of HIV-1 exposure or infection. Several AIDS-
tion of immune and inflammatory factors that enhance restricting genes (ARG) have been identified within the
HIV expression [55]. A meta-analysis was recently per- human genome that are related to either resistance or accel-
formed on 39 different studies that reported the effect eration of disease (reviewed by O’Brien and Nelson [61]).
of genital tract infections on the detection of HIV shed- Unbiased assessment of genes involved in viral control in
ding in the genital tract [56]. In this meta-analysis, HIV- HIV-infected people, using a whole genome association
1 detection in the genital tract was increased most sub- strategy, have strongly associated specific HLA genes, most
stantially by urethritis and cervicitis. Cervical discharge notably HLA-B*57-01, with viral set point.
or mucopus, gonorrhoea, chlamydial infection, and vul-
vovaginal candidiasis were also significantly associated
with HIV shedding. Alternatively, some studies have
shown that there may be beneficial protective effects of
HIV co-infection with GB virus C (GBV-C) [57], where PROSPECTS FOR VACCINES
protection may result from the induction of different
chemokines that have anti-HIV properties. However, the A vaccine is of paramount importance to develop and im-
mortality rates within cohort studies in populations of plement as a public health option in many regions of the
mine workers in southern Africa who are co-infected with globe where HIV-1 incidence rates are extremely high. If a
mTB and HIV suggest that co-bacterial infections are preventive vaccine can lower the rate of secondary viral
anything but protective [58, 59]. transmission, this will have a significant effect of mitigat-
ing the epidemic. Although successful vaccines have been
implemented for diseases such as smallpox, polio, mea-
sles, and hepatitis B, replicating these designs for HIV-1
may not be appropriate. Persistence of HIV leading to
EVIDENCE FOR CORRELATES OF
chronic infection and the continuous viral evolution in
PROTECTION TO HIV-1 INFECTION the infected host, to evade antibody and CTL responses,
needs to be accounted for. It is known, for example, that
Even though HIV-1 infection establishes persistence and chronic persistence of antigen leads to diminished central
undermines immunity, there are a small number of people memory T cells, and the inability of the immune system to
who are infected but are clinically healthy and can control mount an effective secondary response [62]. Thus a vac-
viremia to extraordinarily low levels: to less than 50 copies/ cine would be required to enhance the pool of central
mL plasma. Additionally, there are also individuals who memory, either in a preventive nature or as a therapeu-
have frequent high-risk sexual encounters and who have tic option. Development of therapeutic vaccines is ex-
a high probability of being exposed to HIV, but remain tremely relevant for the large numbers of HIV-1-infected
uninfected. These two cohorts of individuals may provide individuals, where the aim would be to redirect immunity
clues to which factors of host immunity correlate with under the cover of antiretroviral therapy to effectively
delayed disease or possible protection from infection contain infection.
[57]. Identity of these immune factors is important for There is no doubt that a successful preventive vaccine
providing clues to protective immunity and for devising will need to evoke aspects of innate, cellular, and humoral
successful vaccine strategies. Several cohort studies, includ- immunity. As the major determining factor of disease
ing those of highly exposed persistently seronegative progression in an individual is viremia and the level of in-
(HEPS) sex workers, occupationally exposed healthcare fectiousness is proportional to the magnitude of the viral
workers, and uninfected babies born to HIV-infected load in plasma, genital tract secretions, and breast-milk,
mothers, have reported evidence for systemic and mucosal a vaccine capable of controlling viral replication would
53
potentially lower the rate of disease progression and sec- in the event of a subsequent exposure or infection with
ondary transmission. Typically a phase IIb test-of-concept HIV-1. The aim of an HIV vaccine response would be to
or III efficacy vaccine trial measures the candidate vaccine generate pools of vaccine-specific long-lived central mem-
relative to a placebo control arm. The primary end-point ory CD8 T cells. As discussed above, the persistence of an-
measurement is lower incidence in the vaccine arm, al- tigen upon HIV infection compromises the development of
though it is more likely that a secondary end-point will central memory CD8 T cells, whereas the transient nature of
be levels of viremia at a specific time post infection and vaccine-related antigens would create a more favorable
the time to set point. The recently halted STEP study, which environment for induction of central memory.
was a double-blind phase II test-of-concept trial in 3,000 Other vaccine candidates are either in early clinical trials
HIV seronegative volunteers in North America, the Carib- or in the pipeline of development (http://www.iavi.org,
bean, South America, and Australia receiving three injec- http://www.hvtn.org, http://www.chavi.org, and http://
tions of an adenovirus vector (MRKAd5) containing www.cavd.org). Whatever the eventual mechanisms lead-
subtype B gag/pol/nef genes, failed to show efficacy and ing to successful vaccine immunity, mucosal responses that
made no impact on levels of viremia at 3 months after vac- can neutralize or contain HIV at the point of entry will
cination in those who became infected [63]. Early follow- need to be elicited, to cater for the genetic heterogeneity
up showed that the vaccine arm may have been deleterious of HIV-1 across the globe, and to generate long-term mem-
and hinted at promoting infection, but over longer-term ory. Notwithstanding these challenging scientific issues,
follow-up, the number of infections per study arm became uniform access of a stable vaccine to all individuals at an
non-significant. The one factor associated with infection affordable cost is a social and political challenge that needs
was whether men were circumcised [63], with the uncir- to be addressed in tandem with scientific development.
cumcised male being more susceptible. Whether this has
to do with epidermal Langerhans cells in the foreskin that
can trap virus (Fig. 4.2) is open to question. A companion
trial in South Africa, the Phambili trial, showed a HIV infec- CONCLUSION
tivity pattern similar to that of the STEP study, with the
major difference being that more women than men HIV infection elicits robust cellular and humoral immune
were enrolled and thus the enhanced infectivity in the responses, but the vast majority of persons ultimately fail to
vaccine arm in this trial was not related to circumcision control viremia and progress to AIDS. Although progress
status [64]. In contrast to the failure of the STEP and Pham- has been made in understanding the reasons for ultimate
bili studies to show vaccine efficacy was the modest success lack of control, there are critical gaps in our knowledge that
of the prime boost phase III RV144 trial in Thailand [65]. need to be resolved to facilitate rational vaccine design, and
This trial consisted of priming with a recombinant canary- to guide immunotherapeutic interventions. Among these
pox vector vaccine (ALVAC-HIV vCP1521) plus two are the critical ratios of humoral and cellular immune re-
booster doses of a recombinant glycoprotein 120 subunit sponses, the critical viral antigens to target, the means to in-
(AIDSVAX B/E) in 16,402 HIV-1 seronegative men and duce broadly cross-reactive protective immunity to the
women in Thailand. The recombinant gp120 immunogen multiple strains currently fueling the global epidemics,
alone showed no efficacy in a large earlier trial in Thailand and vaccine vector systems that are able to elicit potent anti-
[66], but when combined with the ALVAC product as a viral immune responses. Great strides have been made re-
boost, showed a 31.2% efficacy using a modified intent- cently in the detection, isolation, and crystallization of
to-treat analysis [65]. broadly neutralizing antibodies [67–70] and the design
Through the combined analyses of the STEP/Phambili of candidate immunogens based on the structures of these
and RV144 trial results, there will hopefully be insight into antibody molecules.
immune responses that are, and are not, important for vac- With a modestly successful vaccine strategy and learning
cine efficacy. However, what clues do we have so far of the from trial failures, as well as major scientific advances in the
kind of immune response that will be required from a vac- structure and function of broadly neutralizing antibodies,
cine? The immune responses detected in monkeys as well there is reason for optimism. Emerging data also suggest
as those detected in HEPS individuals and long-term that HIV may not be infinitely mutable, but that there
non-progressors suggest that an effective HIV vaccine are predictable mutations that occur within given residues
will need to elicit neutralizing antibodies, CD4 T cell when they come under immune selection pressure.
responses, and CTL [52]. As discussed, since the major Whether this knowledge can lead to the refinement of a
route of viral transmission is through mucosal barriers, vaccine strategy that would provide sufficient protection
and that HIV may be regarded as a disease of mucosal im- against circulating viruses remains to be determined. In
munity, it will be crucial to elicit mucosal vaccine-induced the meantime, HIV will remain the most significant infec-
immunity and not only systemic immunity. One feature of tious disease of our generation, and will continue to extract
a vaccine-induced response is the elicitation of long-lived a disproportionate toll on those most marginalized and
memory CD4 and CD8 T cells that can be rapidly recalled disenfranchised in each society.
54
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57
Chapter |5|
Viral and host determinants
of HIV-1 disease progression
Daniëlle van Manen, Angélique B. van ‘t Wout, Hanneke Schuitemaker
macaques by B cell depletion [3–5], albeit not in all studies

INTRODUCTION [6]. Moreover, passive transfer of three broadly neutralizing
antibodies resulted in a delay in viral rebound after cessation
The clinical course of HIV-1 infection can be highly of antiretroviral therapy in acutely HIV-1-infected individuals
variable, with extremes of disease progression within [7]. However, HIV-1 can escape from neutralizing antibodies
12 months after seroconversion or continuous asymptom- and a neutralization-resistant phenotype is associated with
atic infection for more than 20 years. The loss of CD4 T changes in the viral envelope [2, 8–10]. The existence of
cells is one of the hallmarks of HIV-1 infection, which in this escape mechanism was first demonstrated in ma-
the absence of combination antiviral therapy ultimately caques [11] and in a laboratory worker who became acci-
leads to immunodeficiency. The mechanism by which dentally infected with the neutralization-sensitive HIV-1
CD4 T cells are lost is still under debate, but the vital role variant IIIB and in whom a neutralization-resistant IIIB-
of virus-driven chronic immune activation and increased related variant evolved [12]. A major component of the
cell turnover is now well accepted. A high and persistent viral escape mechanism is the increase and repositioning
level of virus replication seems to be the driving force. of glycans, the so-called glycan shield [1, 2]. Glycans are
The high variability in the clinical course of HIV-1 infection strategically positioned and repositioned continuously
is therefore determined by the level of HIV-1 load, which throughout infection, in a way that minimally affects the
itself is determined by the interplay between viral and host interaction of the envelope with the receptor molecules
(genetic) factors. In this chapter, we will discuss these fac- on the cell surface, but maximally hinders the binding of
tors and their effect on HIV-1 load and disease progression neutralizing antibodies [2]. Additionally, elongation of
in the natural course of infection. variable loops in Env has been associated with neutraliza-
tion resistance [9, 10, 13, 14].
Despite the rapid escape of HIV-1, the neutralizing anti-
body response was initially still considered to be important
SPECIFIC (ADAPTIVE) ANTIVIRAL because escape from humoral immunity was thought to co-
IMMUNE RESPONSE incide with a loss of viral fitness [15], which would give rise
to a lower viral load set point and hence an ameliorated dis-
ease course. However, later studies found that escape from
Humoral immune response neutralizing antibodies did not coincide with a reduction
Upon infection with HIV-1, both cellular and humoral in replication fitness [16]. In recent years, interest has
immune responses are mounted against the virus. The increased for broadly neutralizing antibodies. These anti-
humoral immune response initially consists mainly of bind- bodies can neutralize HIV-1 variants from different sub-
ing antibodies. Only after a few weeks to months, neutralizing types and are therefore considered to be directed against
antibodies emerge [1, 2]. The importance of neutralizing anti- conserved epitopes. Based on this it was hypothesized that
bodies in controlling infection was indicated in SIV-infected escape from these broadly neutralizing antibodies would
59
be extremely difficult for the virus and would come at an influence CTL function, by affecting antigen processing
extreme fitness cost. Surprisingly, escape from autologous and presentation [34].
serum with broadly neutralizing antibodies occurred rap-
idly and was also not associated with a loss in viral replica-
tion fitness [10]. This is most likely because escape is not Cellular immune response:
associated with mutations in the epitope itself, but rather helper T lymphocytes
with the above-mentioned changes in the viral envelope,
The functioning of HIV-1-specific CTL depends on the pres-
being an increased number of glycans and an increased
ence of functional CD4 helper T cells. The presence of CD4
length of the variable loops that may occlude the antibody
helper T cells that proliferate and produce both IL-2 and
epitope. In agreement with the rapid escape, the presence
IFN-g in response to HIV-specific peptide pools early in in-
of even broadly neutralizing activity in serum was not
fection are not predictive for prolonged AIDS-free survival
associated with a prolonged asymptomatic course of
[35]. However, during the course of infection, the loss of
infection [17, 18].
these helper T cells, together with the loss of all functional
CD4 T cells, causes a less efficient immune response, thus
allowing opportunistic infections to bypass the immune
Cellular immune response: system, finally resulting in disease progression and AIDS.
cytotoxic T lymphocytes In mouse models it was demonstrated that the presence
HIV-1 specific cellular immune responses, mediated by cy- of CD4 T cells during priming of CTLs is essential for the
totoxic and helper T lymphocytes, emerge very rapidly after maintenance of immunological memory after the acute in-
infection [19–21]. Several observations have suggested that fection phase, whereas their continuous presence was not
HIV-1 specific CD8 cytotoxic T cells (CTLs) contribute to required for CTL expansion [36, 37]. It can thus be envi-
the control of HIV infection. Strong CTL responses are sioned that with the loss of CD4 T cells during HIV-1 infec-
often observed in long-term asymptomatic HIV-1-infected tion no efficient new CD8 T cell memory is generated in
individuals but diminish with progression to AIDS [22]. later phases of the infection.
It cannot be excluded, however, that these preserved
CTL responses are a consequence, rather than a cause,
of prolonged asymptomatic survival. Experimental deple-
CHRONIC IMMUNE ACTIVATION
tion of CD8 T cells in SIV-infected macaques led to the loss
of control of acute infection and to increased viral load in AND CD4 T CELL LOSS
chronic infection [23, 24]. Later studies showed,
however, that CD4 T cells under these conditions started Depletion of CD4 T cells, which is preceded by a loss of
to proliferate, providing the virus with an excellent oppor- proliferative responses to polyclonal stimuli [38] and
tunity to replicate, which may explain the rise in viral recall antigens [39], is one of the major characteristics
load [25]. of HIV-1 infection [40]. The fact that HIV-1 uses CD4 as
Finally, the quality of T cell responses early in infec- a cellular entry receptor together with the observation
tion was not associated with AIDS-free survival [26]. that CD4 T cells are specifically lost in HIV-1 infection
As for neutralizing humoral immunity, this lack of effect led to the logical conclusion that virus-mediated killing
of CTLs may be due to viral escape. Escape mutations in of target cells was the main cause for this cell loss. How-
even a single epitope may lead to loss of immune con- ever, the frequency of infected cells in peripheral blood
trol by CTLs [27]. Viruses with CTL escape mutations in the chronic phase of infection is too low to account
can be rapidly selected and overtake the viral quasispe- for the ongoing depletion of CD4 T cells by viral infec-
cies in as little as 6 weeks after first emergence [28]. tion [41, 42]. Several converging lines of evidence now
The rapid selection of these escape variants is in fact suggest that hyperactivation of the immune system in
the strongest argument that CTLs are effective in vivo. response to chronic HIV-1 infection may be the culprit
The impact of certain CTL escape mutations on viral fit- [43]. Hyperactivation is responsible for an increased na-
ness [29, 30] was also demonstrated by complete rever- ive T cell turnover, leading ultimately to the exhaustion
sal of the escape mutation to the wild-type sequence of the naive T cell compartment, which then cannot com-
upon transmission to a new individual [31]. The selec- pensate for the enhanced death of memory CD4 T cells
tive pressure of CTLs is such that at a population level, into which the activated CD4 T cells mature. Indeed,
the virus strains circulating in a population have adapted the level of immune activation was found to be at least
to the most common human leukocyte antigen (HLA) as good a predictor of disease progression as the level of
types in that population [32, 33]. The complex viral replication [44, 45]. Additional evidence came from
influence of HLA on HIV-1 disease course will be dis- the comparison of SIV infection in sooty mangabeys and
cussed later in the section on host polymorphisms. Mu- African green monkeys on the one hand and in Asian
tations outside CTL epitopes have also been described to macaque species on the other [46]. SIV infection in Asian
60
Chapter |5| Viral and host determinants of HIV-1 disease progression
macaques generally leads to high virus loads, declining

CD4 T cell numbers, and disease within 2 years [47]. Sooty VIRAL FACTORS THAT INFLUENCE
mangabeys and African green monkeys can both be infected VIRAL LOAD: BIOLOGICAL
with SIV and despite overt viral replication these animals
have stable CD4 counts and do not progress to disease
PHENOTYPE
[48, 49]. The stable CD4 counts in the presence of high viral
load is in line with the assumption that virus-mediated kill- HIV-1 can vary with respect to biological properties such as
ing has no large effect on total CD4 T cell numbers. Despite replication rate, cell tropism, co-receptor use, and neutral-
the high viral load, these animals show no evidence of ization sensitivity. The use of different co-receptors by HIV-
hyperactivation of their immune system as observed in 1 is a general phenomenon for viruses from all different
SIV-infected macaques and HIV-1-infected humans [49]. subtypes and circulating recombinant forms (CRFs),
This suggests that although the increased turnover of naive although quantitative differences in the prevalence of
T cells in HIV-1-infected individuals is virus driven, the HIV-1 variants that can use the CXC chemokine receptor
responsiveness is determined by host factors. More recently 4 (CXCR4-using variants) among subtypes exist. Virus
it was demonstrated that the initial immune response variants with different biological properties dominate in
against the virus was similar in both the non-pathogenic different phases of infection. New infections are generally
and pathogenic macaque model. Interestingly, this initial re- established by HIV-1 variants that use CD4 and addition-
sponse was then down-regulated only in the non- ally the CC chemokine receptor 5 (CCR5) as a co-receptor
pathogenic macaque model but not in the pathogenic SIV (R5 variants) [64–68]. Even if both R5 and CXCR4-using
macaque model [50–52]. The underlying mechanism for variants are present in the donor, most often only the R5
the differential regulation of the immune response needs variants are detected in the recipient [65, 66, 69]. With pro-
to be elucidated. It has been suggested that at least two popu- gression of disease, a shift in the viral quasispecies toward
lations of CD4 T cells are important in mediating this im- more rapidly replicating T cell-tropic R5 variants is ob-
mune response: Th17 cells, defined by the secretion of served [64]. In the natural course of approximately half
cytokine IL-17, which are thought to be critical in the de- of HIV-1 subtype B-infected individuals this is associated
fense against bacterial and fungal pathogens, and regulatory with the appearance of CXCR4-using HIV-1 variants prior
T cells (Tregs), expressing FoxP3, which are able to induce to AIDS diagnosis [70]. CXCR4-using variants are associ-
tolerance against self-antigens and prevent autoimmunity. ated with an accelerated CD4 T cell decline and a more
The pro-inflammatory Th17 cells and immunoregulatory rapid disease progression [71, 72]. The accelerated loss of
Tregs have antagonistic effector functions; a shift in this bal- CD4 T cells after appearance of CXCR4-using variants
ance might be critical in the outcome of HIV disease. Indeed, can be explained from the fact that naı̈ve T cells express
the loss of Th17/Treg balance was associated with chronic CXCR4 but not CCR5, while memory cells express both
immune activation and pathogenic SIV infection in non- CXCR4 and CCR5 [73]. This co-receptor expression pattern
human primates [53]. The mechanisms responsible for se- makes naı̈ve T cells a unique target cell population for
lective Th17/Treg imbalance during pathogenic infection CXCR4-using variants. Indeed, clonal virus isolation from
are as yet undefined. naı̈ve T cells resulted in predominantly CXCR4-using vari-
ants, whereas both R5 and CXCR4-using biological virus
clones could be obtained from the memory T cells from
CD4 depletion in the gut the same individuals [74]. It can be envisaged that infection
In both the SIV macaque model and in HIV-1-infected and subsequent virus-mediated killing of naı̈ve T cells by
humans it was demonstrated that already during the phase CXCR4-using virus variants directly interferes with T cell
of primary infection a massive depletion of CD4 T cells ontogeny as the infected and killed naı̈ve T cell will no lon-
occurs in all tissues, including the gut-associated lymphoid ger give rise to a daughter cell population. Considering the
tissues (GALT) where more than 80% of T cells reside potential beneficial effect of an expanded target cell popu-
[54–57]. This depletion of lymphocytes from the GALT oc- lation and the limited number of amino acid substitutions
curs within days and seems to be irreversible [58]. It was in V3 that is sufficient to confer CXCR4-using capability to
shown that HIV-1 infection and depletion in the acute R5 variants, it is puzzling that CXCR4-using variants
phase was not restricted to activated memory cells as also emerge prior to AIDS diagnosis in only a proportion of
a high frequency of infected resting CD4 T cells could be infected individuals [75, 76]. It has been hypothesized that
demonstrated [59, 60]. The unique capacity of HIV-1 to the absence of CXCR4-using variants early in HIV-1 infec-
replicate in non-dividing cells is in agreement with this ob- tion may be due to their higher vulnerability to the host
servation [61]. Recently it has been reported that Th17 cells adaptive immune responses, in particular neutralizing
are preferentially lost from the GI tract. Importantly, this loss antibodies. The fact that these variants appear more fre-
is observed in HIV-1 infection and pathogenic SIV infection quently after the initial decline of CD4 T cells indeed sug-
of rhesus macaques, but not in non-pathogenic SIV infection gests that they may represent a peculiar, congenic form of
of sooty mangabeys [62, 63]. opportunistic infection. The first appearing CXCR4-using
61
variants are more sensitive to neutralizing antibodies di- and they are dispensable for viral replication in some cell
rected against the CD4 binding site than their coexisting types. It is believed that their main function is dedicated
R5 variants [77]. Moreover, a conserved neutralization epi- to mechanisms to escape or manipulate adaptive and in-
tope, designated D19, is invariably cryptic in R5 variants of nate immunity. Here we describe how Vpr, Vpu, Nef, and
different genetic subtypes, but it is consistently exposed in Vif each suppress the antiviral activity of specific host cell
CXCR4-using variants, rendering such variants sensitive to factors.
neutralization by a specific antibody [78].
Nef
Evolution of co-receptor use
In the SIV macaque model it was demonstrated that inoc-
Phylogenetic analyses of HIV-1 envelope sequences have ulation with SIV that lacked the Nef gene resulted in infec-
shown that CXCR4-using variants directly evolve from tion but not disease progression [89]. A cohort of
R5 variants, after which the CXCR4-using and R5 viruses individuals in Sydney infected with HIV-1 from the same
coexist within the same individual [79, 80]. After the first source and classified as long-term non-progressors, all car-
appearance of CXCR4-using variants, both R5 and ried a DNef HIV-1 variant [90], although some have ulti-
CXCR4-using variants continuously evolve away from the mately progressed to AIDS-defining events [91]. Multiple
common ancestor and each other. However, this is only Nef activities are known, which are mostly genetically sep-
evident for the env gene as CXCR4-using and R5 virus popu- arable and make use of distinct elements located through-
lations cannot be distinguished on the basis of gag se- out the Nef molecule. Nef alters the intracellular trafficking
quences due to frequent recombination events outside of important immune molecules, such as class I and II ma-
the env gene [81]. In general, the first CXCR4-using variants jor histocompatibility complex proteins (MHC-I, MHC-II),
can still use CCR5 on primary cells, albeit it far less effi- CD4, and DC-SIGN [92–95]. Down-regulation of MHC-I
ciently [82]. Recent studies have shown that failure of mara- proteins on the surface of the cell by Nef protects HIV-
viroc, a small molecule CCR5 antagonist, is caused by the infected cells from recognition and killing by CTLs, while
presence of R5 variants that can use maraviroc-bound Nef-dependent CD4 removal enables optimal release of in-
CCR5 for entry [83] or by the presence of CXCR4-using fectious virions. More directly, Nef also triggers apoptotic
variants, which upon closer inspection were existent pre- pathways, affecting survival of bystander CD4 T cells [96].
therapy [84, 85]. The continued evolution of CXCR4-using Furthermore, Nef promotes the induction of cellular trans-
and R5 variants is also evident from changes in their biolog- cription factors that can elevate viral replication [97] and
ical properties over time. Early CXCR4-using variants are Nef intersects with the macrophage CD40L signaling path-
more sensitive to the inhibitory effect of co-receptor antag- way to promote infectivity [98]. Recently it has been
onists AMD3100 and T22 than late-stage-obtained CXCR4- reported that Nef can transfer from infected cells into B
using variants [82]. In analogy, late-stage R5 variants from cells, leading to impaired class switching [99]. Thus, Nef
individuals who never developed CXCR4-using variants are supports viral replication via both direct and indirect
less sensitive to inhibition by the natural ligand of CCR5, mechanisms.
RANTES [86]. The co-receptor inhibitor resistance of R5
and CXCR4-using variants is correlated with the immune
status of the host. Although the exact mechanism of resis- Vif
tance remains to be established, the observation is sugges- The HIV-1 protein Vif is essential for viral replication by
tive for selection of HIV-1 variants that use their co-receptor counteracting the effects of apolipoprotein B mRNA editing
with increasing efficiency as the infection progresses. In a enzyme, catalytic polypeptide-like (APOBEC) 3 G and APO-
recent study we have observed that viruses with this late- BEC3F, mediators of one aspect of the innate immunity, a
stage phenotype can be transmitted to a new host after potent cellular defense system against retroviral infection
which evolution continued [87]. So, while R5 variants [100, 101]. APOBEC3F and APOBEC3G are members of
are preferentially transmitted over CXCR4-using variants, the APOBEC superfamily of cytosine deaminases which,
there does not seem to be a preferential transmission phe- in the absence of Vif, are incorporated into the virion. Dur-
notype within R5 variants. The fact that HIV-1 envelope is ing reverse transcription of the viral genome in a new cell,
changing at a population level over calendar time is in line they deaminate cytidine to uracil, inducing lethal G-to-A
with this observation [88]. hypermutation in the viral DNA [102, 103]. Vif can bind
both APOBEC3F and APOBEC3G and redirect it by ubiqui-
tination to degradation in the proteasome, thereby prevent-
Viral accessory genes
ing the viral DNA from mutation [104, 105]. More recently it
The HIV-1 genome encodes for three structural proteins was reported that the expression of truncated or misfolded
(Gag, Pol, and Env), two regulatory proteins (Tat and viral proteins due to APOBEC3G editing enhances the recog-
Rev) and four accessory proteins: Vpr, Vpu, Nef, and Vif. nition of HIV-1-infected cells by CTLs, linking the innate
Initially the function of the accessory genes was not clear and adaptive immune responses [106].
62
Vpr individuals, as uninfected individuals without CCR5 func-

tion (i.e. those homozygous for the 32 base pair deletion in
Monkeys infected with SIV without Vpr function had se-
CCR5) show no overt clinical symptoms.
verely attenuated infections with much lower viral burden
The more recent genome-wide association studies
and no evidence of disease progression [107], confirming
(GWAS) offer a hypothesis-free analysis of the genome to
the role of Vpr in viral pathogenesis. Multiple functions
find novel factors influencing HIV-1 infection and disease
of the viral protein Vpr have been reported. First, Vpr has
course. GWAS are a tool to examine the complete genome
been shown to interact with cellular factors leading to
of different individuals to determine variation between in-
the inhibition of host cell proliferation by a G2 cell cycle
dividuals, mostly at the level of single DNA mutations, the
arrest of infected cells [108], although the virological
so-called single-nucleotide polymorphisms (SNPs). Associ-
role remains unclear. Vpr also has a nuclear localization
ations between these SNPs and HIV-1 susceptibility or HIV-
signal and facilitates nuclear localization of the viral pre-
1 disease course and thus identification of genes essential to
integration complex [109, 110]. By interaction of Vpr
HIV-1 and of gene variants present in healthy individuals
with various transcriptional factors on the LTR promoter,
that affect HIV-1 may ultimately lead to new prevention
the viral protein induces HIV-1 viral gene transcription
strategies and therapies, similar to the development of
[111]. Additionally, Vpr causes cell death by inducing
CCR5 antagonists.
apoptosis [112].
Vpu Human leukocyte antigens

Two distinct functions have been associated with the viral
The HLA genes map to chromosome 6 and form one of the
protein U (Vpu). Vpu down-regulates CD4 cell surface ex-
most polymorphic regions in the human genome. HLA
pression by targeting CD4 for degradation in the endoplas-
class I loci, HLA-A, B, and C all encode for a large number
mic reticulum of infected cells [113]. Vpu is also known to
of different alleles. Each individual expresses two HLA-A,
enhance efficient viral particle release, by antagonizing the
two HLA-B, and two HLA-C alleles on the surface of all their
action of tetherin [114, 115]. Tetherin is a transmembrane
cells. These HLA molecules present viral antigens to CD8
protein that blocks the release of budding HIV-1 virions by
T cells, thereby initiating a cytotoxic T cell response. Due
directly anchoring the viral particle to the surface of the cell.
to the large variation that is created by six different HLA
The retained virions are internalized by endocytosis and
molecules, a large diversity of viral peptides that supports
subsequently degraded.
potent immunity can be presented. Homozygosity for
HLA alleles reduces the repertoire that can be presented
to the immune system, thereby limiting the number of epi-
HOST FACTORS THAT INFLUENCE topes recognized by CTLs. Indeed, homozygosity has been
HIV-1 ACQUISITION AND DISEASE associated with faster disease progression [119, 120]. More-
over, certain class I alleles have been implicated in the var-
PROGRESSION iable clinical course of HIV-1 infection. HLA-B*27 [27] and
B*57 are consistently associated with effective control of
Several host factors that influence the clinical course of HIV-1 and delayed disease progression, albeit that this as-
HIV-1 infection have been identified. Initially, these host sociation is not absolute [29, 30]. HLA-B*5701 has been
genetic factors were discovered in candidate gene studies associated with long-term non-progression in Caucasian
(see Table 5.1), in which gene variants that were already populations [121, 122], while the closely related HLA-
known or suspected to play a role in HIV-1 pathogenesis B*5703 is associated with delayed disease progression
and immune regulation were tested for association with after HIV-1 infection in individuals from African descent
HIV-1 infection and/or disease progression. Examples of [123, 124]. This was confirmed in a GWAS in African Amer-
these are genes that encode proteins necessary for HIV-1 en- icans [125]. Additionally, HLA-B*57 seems to be associated
try in a cell or for efficient replication and propagation of with control of HIV-1 already early in infection as the prev-
the virus. In addition, variations in innate and adaptive alence of this allele was significantly lower in individuals
immune-regulatory genes and in specific viral-restriction with symptomatic acute infection, when compared to a
genes have been studied for association with HIV-1 disease. chronically infected population [126]. HLA-B*27 and
Of these, the HLA genes are discussed in more detail below. HLA-B*57 restricted CTL select for HIV-1 variants that have
The variants that were identified in most of these candidate escape mutations in certain epitopes in more conserved re-
gene studies turned out to have large effects on disease risk, gions that come at a relatively high fitness cost to the virus.
even in small cohorts (see Table 5.1) and most have been This is supported by the observation that escape mutations
reviewed extensively before [116–118]. In the case of in some epitopes that are restricted by HLA-B*57 immedi-
CCR5, this has even resulted in the development of new ately revert to wild-type sequences after transmission to
antiviral strategies to block CCR5 in HIV-1-infected a non-HLA-B*57 individual [31]. Interestingly, HIV-1
63
Section | 1 |
64
Table 5.1 Host factors that influence HIV-1 acquisition and disease progression discovered by candidate gene studies
HOST FACTOR FUNCTION POLYMORPHISM EFFECT ON GENE EFFECT ON HIV EVIDENCE REFERENCES
Chemokine receptors
CCR5 Viral co- 32 bp deletion Truncation, no Protection from HIV-1 infection Strong [148–150]
receptor membrane expression
Epidemiology and biology of HIV infection

Delayed disease progression Strong [148, 151, 152]
m303 Truncation, no Protection from HIV-1 infection Strong [153]

membrane expression
CCR5P1 Increased expression Accelerated disease progression Strong [154]
CCR2 Viral co- V64I Interaction with Delayed disease progression Strong [155–158]
receptor CXCR4
CCR2þCCR5 Viral co- HHE haplotype Increased CCR5 Accelerated disease progression Strong [154, 159]
receptor expression
DARC Trans- -46 C Decreased expression Susceptibility to HIV-1 infection Controversial [160–162]
receptor
Delayed disease progression Controversial [160–164]
CXCR6 Secondary rs2234358 Delayed disease progression Weak [165]

co-receptor
CXCR1 Il 8 receptor Haplotype Ha Delayed disease progression Weak [166]
CX3CR1 Secondary V249I Accelerated or delayed disease Controversial [167–170]

co-receptor progression
T280M Accelerated disease progression Controversial [167–172]
Chemokine ligands
CCL5 CCR5 ligand -403 G/A, -28 G/C, Influences expression Accelerated or delayed disease Controversial [173–177]
In1.1 C haplotype progression
CCL3L1 CCR5 ligand Low copy number Decreased expression Susceptibility to HIV-1 infection Controversial [178–181]
Accelerated disease progression Controversial [179–182]
CXCL12 CXCR4 ligand 3’A Accelerated or delayed disease Controversial [183–186]

progression
Chapter
Interleukins
IL4 Immune -589 Increased expression Increased or decreased CXCR4- Controversial [187, 188]
regulation emergence
Delayed disease progression Controversial [187–189]
|5|
IL10 Immune 5’-A Decreased expression Susceptibility to HIV-1 infection Strong [190]
regulation
Viral and host determinants of HIV-1 disease progression

Accelerated disease progression Strong [190]
Toll-like receptors
TLR4 PAMP 1063A/G High viral load Weak [191]
recognition
TLR7 PAMP Gln11Leu Accelerated disease progression Weak [192]

recognition
TLR9 PAMP 1635A/G Accelerated or delayed disease Controversial [191, 193, 194]
recognition progression
HIV dependency factors

TSG101 Viral budding -183 T/C and 181A/C Accelerated or delayed CD4 T cell Controversial [195, 196]
decline and viral load
HIV restriction factors

TRIM5a Uncoating H43Y Decreased activity Accelerated disease progression Controversial [197–200]
R136Q Decreased activity Protection from HIV-1 infection Controversial [199, 201]
PPIA Uncoating 1604A/G Accelerated CD4 T cell decline Controversial [195, 202, 203]
1650 C/G Accelerated or delayed disease Controversial [195, 202, 203]

progression
APOBEC3G Deamination H186R Accelerated disease progression in Controversial [204, 205]

Africans
C40693T Susceptibility to HIV-1 infection Weak [206]
Continued
65
Section | 1 |
66
Table 5.1 Host factors that influence HIV-1 acquisition and disease progression discovered by candidate gene studies—cont’d
HOST FACTOR FUNCTION POLYMORPHISM EFFECT ON GENE EFFECT ON HIV EVIDENCE REFERENCES
Human leukocyte antigens

All HLA types Ag Homozygosity Decreased recognition Accelerated disease progression Strong [119, 120]
recognition
Epidemiology and biology of HIV infection

HLA-B*27 Ag Protective epitope Delayed disease progression Strong [27]
recognition recognition
HLA-B*57 Ag Protective epitope Delayed disease progression Strong [29, 30, 121, 122, 125,
recognition recognition 126, 128, 207]
HLA-B*35Px Ag Protective epitope Accelerated disease progression Strong [120]

recognition recognition
HLA-C Ag rs9264942 Increased expression Delayed disease progression [128, 129]

recognition
NK receptors, KIR
KIR3DS1 NK activity Increased activity Decreased viral load set point [208]
Protection from HIV-1 infection [209]
KIR3DS1 þ HLA-B NK activity Increased activity Delayed disease progression [210, 211]
Bw4-80I
HLA-B Bw4-80I Protection from HIV-1 infection [212]

and/or HLA-B*57
variants of HLA-B*57-typed individuals with a typical disinfection in long-term non-progressors (LTNPs) and rapid
ease course had additional mutations that compensated for progressors (RP), in the genomics of resistance to immuno-
the fitness cost associated with the mutations in CTL epi- deficiency virus (GRIV) cohort. The non-progression GRIV
topes. These compensatory mutations were not observed GWAS identified mainly associations between the clinical
in HLA-B*57-typed long-term non-progressors [29]. An- course of infection and genetic variation in chromosome
other mechanism for HLA-B*57-related control involves 6 and could confirm both the HCP5 and the ZNRD1 locus
induction of strong CTL responses against the escaped identified by the EURO-CHAVI cohort. The analysis of RP
epitopes [127]. revealed several interesting loci, but these need to be repli-
HLA-B*35Px, a subgroup of HLA-B*35 based on cated in other cohorts. Viral load was also used as a pheno-
peptide-binding properties, is associated with a more be- type in the multinational HIV controllers study. A large
nign disease course after HIV-1 infection [120], for which cohort was divided into HIV-1 controllers, who are able
the underlying mechanism is not fully clear. While it seems to control viral load after infection to levels < 50 copies
that HLA-B is most frequently implicated in the course of of viral RNA/ml plasma, and HIV-1 progressors, those
HIV-1 disease, a GWAS revealed genetic variation in the who failed to ever control viremia. Over 300 SNPs that were
HLA-C gene region to be associated with viral control genome-wide significantly associated with viral load were
and slower progression to AIDS [128, 129], confirming ear- identified and all were located within the MHC gene re-
lier data [130]. The protective allele of this polymorphism gion. Specific amino acids in the HLA-B peptide binding
is associated with high HLA-C cell surface expression, pos- groove (associated with rs2395029 HCP5 SNP), as well
sibly through affecting a 3’UTR miRNA binding site that as an independent HLA-C effect (associated with
can degrade or repress translation of the HLA-C gene rs9264942 HLA-C SNP), were found to be associated with
[129, 131]. the capacity to control HIV-1 [135].
A multi-stage GWAS in US seroconverters compared RP,
moderate progressors, and LTNPs, followed by replication
GENOME-WIDE ASSOCIATION of interesting signals in another cohort [136]. Variation up-
stream of PROX1, a negative regulator of IFN-g expression
STUDIES in T cells, was associated with slower progression to AIDS.
Another GWAS amongst US seroconverters identified a
To date, the disease-associated phenotypes that have been cluster of SNPs in the gene PARD3B to be associated with
used in the search for novel host genetic factors involved in a delayed survival time to AIDS [137]. One of the variants
HIV pathogenesis are largely overlapping and correlated in this cluster could be confirmed in two European cohorts
with each other. The first reported GWAS performed in of rapid progressors.
the EURO-CHAVI cohort used two phenotypes: HIV RNA The majority of GWAS performed have focused on popu-
viral load at set point, with viral load set point defined as lations from European descent. The first published GWAS
the steady-state viral load after the acute phase of the pri- on a non-European population searched for associations
mary HIV-1 infection, or extrapolated time to a CD4 count with viral load at set point in African Americans [125].
< 350 cells/mm3 [128]. In the EURO-CHAVI cohort two Although no loci were genome-wide significantly associ-
loci were genome-wide significantly (p < 5 10-8) associated with viral load at set point, one of the strongest asso-
ated with viral load set point. One of these loci is tagged by ciations was a SNP tagging the HLA-B*5703 allele. This
SNP rs2395029 near the HLA complex 5 gene (HCP5), a confirms the important association between HLA-B*57
gene localized within the MHC class I region. SNP and viral load variation, both in African Americans and
rs2395029 is in nearly absolute linkage disequilibrium in individuals of European ancestry.
(LD) with HLA-B*57, whose protective effect was known In a mother-to-child transmission cohort in Malawi, in
already, as discussed above [121, 122]. The other locus which HIV-uninfected children and HIV-infected infants
is tagged by SNP rs9264942, located 35 kb upstream from HIV-infected mothers are compared, several regions
of HLA-C. were identified to be potentially associated with vertical
This first GWAS additionally identified variants in the transmission of HIV-1. However, these findings still need
zinc ribbon domain-containing protein 1 (ZNRD1) to be further examination and replication [138].
associated with progression to CD4 count < 350 cells/ A linkage analysis in a cohort of SIV-infected macaques
mm3. Dalmasso et al. [132] also used viral load as a disease [139] revealed MHC class I markers and an unknown X
phenotype in their GWAS, but evaluated plasma HIV-RNA chromosomal locus to be associated with progression to
and cellular HIV-DNA levels during primary infection AIDS. The association between the signal on the X chromo-
rather than at set point. Most of the variants strongly asso- some and AIDS progression could be replicated in a cohort
ciated with HIV-RNA and HIV-DNA levels were localized in of HIV-1-infected patients.
the MHC region, including rs2395029 in the HCP5 region. Two studies performed a genetic association analysis of
Limou et al. [133] and Le Clerc et al. [134] looked for in vitro susceptibility to HIV-1 infection in lymphoblastoid
genetic associations with extreme phenotypes in HIV-1 B cell lines from a family cohort (CEPH) [140] and in
67
primary monocyte-derived macrophages [141]. The first the replication cycle of HIV-1 that were studied. Interest-
study identified the LY6 gene family and the SNP in LY6 ingly, several genes that were identified to be involved in
subsequently turned out to be associated with accelerated HIV-1 replication could be grouped in pathways or catego-
disease progression in one of two cohorts of HIV-1-infected ries of genes, such as nuclear import and export, transcrip-
patients. In the second study we observed a strong as- tion factors, components of the NF-kB complex, and
sociation between a SNP intronic of DYRK1A and in vitro kinases. In another approach, a cDNA library representing
HIV-1 replication in monocyte-derived macrophages. 15,000 unique genes was used to find novel factors that
This SNP appeared to be associated with HIV-1 disease when overexpressed could enhance HIV-1 infection
progression in vivo in two independent cohort studies. [147]. The mixed lineage kinase 3 (MLK3) was identified
as one of the strongest enhancers of HIV-1 replication,
confirmed by RNAi gene expression silencing.
GENOME-WIDE siRNA, cDNA
AND GENE-EXPRESSION SCREENS
ON HIV-1 REPLICATION CONCLUSION
Genome-wide scanning of RNA for more than 20,000 hu- As is clear from the above, the clinical course of HIV-1 in-
man proteins has been performed to identify genes re- fection is influenced by many host genetic factors as well as
quired for HIV-1 replication. Three studies used siRNA viral factors. This is logical from the point of view that the
transfection to knock down gene expression [142–144] genome of HIV-1 only encodes a limited number of pro-
and one study used short hairpin RNA transduction for teins, rendering it dependent on cellular proteins for repli-
gene silencing [145]. These four studies identified over cation. On the other hand, HIV-1 needs to protect itself
1,000 proteins that may be required for optimal viral rep- from the host’s innate and adaptive antiviral defense mech-
lication. However, only three genes were identified in all anisms in order to persist. Multiple interactions between vi-
four studies [146]. These were mediator complex subunit ral proteins and host cellular factors have been observed,
6 (MED6), which is involved in transcription of RNA poly- and may be pursued for the design of new antiviral thera-
merase II-dependent genes, mediator complex subunit 7 pies. As described, polymorphisms in several host factors
(MED7), which is required for efficient transcription of have been identified and some variants have now been con-
Sp1, and v-rel reticuloendotheliosis viral oncogene homo- vincingly associated with disease progression in several co-
log A (RELA), which is part of the NF-kB complex. The min- horts. However, it will require meta-analyses to complete
imal overlap in outcome of these studies may be caused by and validate the identification of host genetic factors that
differences in cell types used for analysis and the steps in are associated with disease course.
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Chapter |6|
Acute HIV infection
Anthony D. Kelleher, David A. Cooper
immunological events have already occurred (Fig. 6.1).

INTRODUCTION The so-called window period, despite being apparently
silent on diagnostic tests, is neither immunologically nor vi-
Although HIV infection is a chronic progressive infection, rologically silent. Insight into many of these earliest events
it is well recognized that the initial stages of the infection has been gained from animal models such as SIV infection
are characterized by an acute viral syndrome. Despite this of rhesus macaques as these events are impossible to study
illness often being mild and under-diagnosed, increasing in humans for a range of practical and ethical reasons.
understanding of the links between pathophysiology and Most infections occur at mucosal membranes. After
clinical manifestations has provided insights into the earli- crossing epithelial barriers, the initial cells infected by virus
est interactions between host and virus. The virological and are both dendritic cells and CD4 T cells that populate the
immunological events that immediately follow HIV infec- mucosal tissues of the genitourinary and/or colonic mu-
tion are highly dynamic and there is increasing evidence cosa. Dendritic cells are capable of harboring and trans-
these events impact on long-term outcome of the infection porting the virus to lymphoid tissue with or without
and rates of disease progression. The clinical presentation being productively infected [1]. However, whether infected
of initial infection is variously referred to as acute HIV infec- or just transporting the virus, these cells are capable of
tion, primary infection illness, acute retroviral syndrome, or transferring virus to multiple CD4 T cells as they fulfill their
seroconversion illness. Although there is variation in the normal role of antigen presentation to T cells. This interac-
clinical manifestations, there are distinct characteristics tion simultaneously triggers an immune response consist-
associated with this illness. The diagnosis of acute HIV ing of both T cell (involving activation of both CD4 and
infection is based on a combination of clinical acumen CD8 T cells) and antibody responses while facilitating in-
and characteristic findings on a range of laboratory tests. fection of responding CD4 T cells. This process drives pref-
Although there are theoretical arguments supporting the erential infection and subsequent death of HIV-specific
value of therapeutic intervention at this stage of the disease CD4 T cells, resulting in the early deletion of these critical
its clinical benefit is yet to be definitively demonstrated. cells from the host’s immune response to the virus [2]. After
However, the identification of this condition has the poten- infection of lymphoid tissue there is subsequent, rapid dis-
tial to impact upon both the care of an individual patient semination of the virus to multiple tissues including the
and upon the health of a population by early institution central nervous system.
of interventions limiting spread of the infection.
CD4 T cell responses

PATHOPHYSIOLOGY As with any primary immune response, the adaptive im-
mune response takes time to develop. The virus replicates
By the time a patient presents with clinical manifestations relatively unchecked during this period. Plasma viremia
of acute HIV infection, even in those with negative or inde- is detectable and viral load increases exponentially
terminate serology, a whole series of virological and (Fig. 6.1). At primary infection in SIV-macaque models
77
Viral load 106

(copies/mL)
105
104
103
102
0 1 2 3 4 5 6
A Months after infection
Cells/mm3 1000
750
500
250
0 1 2 3 4 5 6
B Months after infection
%CD8 2.0
T cells
1.5
1.0
0.5
0 1 2 3 4 5 6
C Months after infection
Figure 6.1 Dynamics of virological and immunological events during acute infection and their relationship to diagnostic readouts.
(A) Green lines show the changes in plasma viral load measured in RNA copies/mL of plasma. The solid green line shows a typical
viral load time course and outcome; the dashed green line shows viral load time course with a likely poor long-term outcome,
and the dotted green line shows the time course of the patient likely to have a good prognosis. The blue-gray shaded area
indicates the onset and offset of clinical manifestations. The blue line shows the typical time course of p24 antigen detection.
The magenta line shows the time course of development of HIV antibodies. The horizontal gray box shows the period during which
a typical EIA will be positive. The purple box shows the timing at which a detuned EIA will become positive. (B) Typical time
course of CD4 and CD8 T cell counts in peripheral blood. The blue line is the CD4 T cell count; the yellow line is the CD8 T cell count.
A typical viral load curve is shown for reference (green line). (C) The yellow line shows a representative antigen specific CD8 CTL
response as measured by response to a single immuno-dominant epitope. The horizontal boxes show the typical time course of HIV-
specific CD4 T cell responses and the blue horizontal bar shows the presence of CD4 T cells capable of proliferation and production of
IL-2. The gray box shows time course of cells capable of producing IFN-g.
78
Chapter |6| Acute HIV infection
there is massive infection and depletion of CD4 T cells, infection [18]. The initial response is usually highly focused
particularly those at tissue sites such as lymphoid tissue, on a limited number of high-avidity epitopes. The response
gut, and genitourinary tracts [3, 4]. Similar processes ap- broadens with time. Responses to a range of HIV proteins,
pear to be occurring in humans early in HIV infection including regulatory and accessory proteins such as Tat and
[5, 6]. This depletion in tissues is reflected in a reduction Nef, are present [19, 20].
in CD4 T cell count in peripheral blood. CD8 CTL responses place pressure on the virus. Adap-
In humans, HIV-specific CD4 T cell responses are tive evolution of the virus to these responses occurs early,
detectable early in infection [7, 8]. Initially, these consist allowing selection of immune escape variants capable of
of cells capable of producing both IL-2 and IFN-g and of evading CTL responses within several weeks of infection
proliferating in response to HIV antigens, but these cells [21, 22].
rapidly lose their ability to proliferate and produce IL-2
in the majority of patients (Fig. 6.1 C) [7, 9, 10]. The excep-
tion appears to be in those individuals that control virus
Antibody responses
replication. In the remainder of patients HIV-specific Although antibodies to various HIV proteins, particularly
CD4 T cells are detectable, but consist almost entirely of p24 and envelope proteins, are detectable soon after infec-
cells capable of producing IFN-g without proliferative or tion, most of these antibodies play no clear role in control
IL-2-producing capacity (Fig. 6.1 C). This depletion occurs of infection. The majority of the antibody response is to in-
in both peripheral blood and tissues. ternal proteins. Of the antibodies directed at the envelope
T cells homing to peripheral lymphoid tissue such as the proteins, the overwhelming majority are not neutralizing
gut and genitourinary tracts preferentially express the che- in nature [23]. Neutralizing antibodies, capable of prevent-
mokine receptor CCR5. The preferential depletion of these ing viral entry and therefore new infection, are slow to arise
cells may be due to selective infection and cytolysis due to a and are usually detectable not less than 4–8 weeks after in-
heightened susceptibility to infection by the virus strain as- fection [24]. When neutralizing antibodies do occur they
sociated with transmission [11, 12]. Preferential infection place pressure on the virus. The virus responds to this pres-
of CD4 T cells specifically responding to HIV infection re- sure, rapidly adapting through the generation of escape var-
sults in loss of these cells and almost certainly accounts for iants [25, 26]. New rounds of neutralizing antibodies are
the pathognomic phenomenon of anergy to HIV antigens also delayed in their development.
seen later in HIV infection [2]. Therapy initiated early
can preserve this responsiveness and may limit the deple-
tion from and support the repopulation of these cells at Innate immune responses
mucosal sites [5, 6].
The role of innate immune responses in primary infection
is still not clearly understood. Dendritic cells play a role in
the transport of virus to lymphoid tissue, and can act as a
CD8 T cell responses “Trojan horse,” transmitting captured virus to CD4 T cells,
assisting in the dissemination of infection. However, den-
In contrast to the decrease in CD4 T cell numbers, CD8 T dritic cells play a critical role in the control of infection as
cell numbers rise dramatically during acute infection they are essential for cross-priming and induction of CD8
(Fig. 6.1B). This increase consists almost entirely of acti- CTL responses as well as CD4 T cell responses [1]. While
vated T cells [13]. Many of these activated, proliferating, myeloid dendritic cell numbers are maintained, plasmacy-
and expanding cells are cytotoxic T cells (CTL) specifically toid dendritic cell numbers are depleted during primary in-
targeted to HIV (Fig. 6.1 C) [14, 15]. Their ability to lyse fection [27].
infected targets and prevent infection of new cells is Natural killer (NK) cells are a significant component
thought to limit viral expansion, halting the exponential in- of the innate immune response in the early control of viral
crease in plasma viral load that follows initial infection and infections. NK cells increase in number during acute HIV in-
to at least partially determine the eventual viral set point. fection prior to seroconversion and before significant CD8
While CD8 CTL are detectable, a second set of CD8 T cells T cell responses are evident [28]. However, as viral replica-
capable of suppressing viral replication through secretion of tion increases, NK cell responses become impaired [29].
a range of soluble factors, including MIP1-a, MIP1-b,
RANTES, and an as yet unidentified cytokine called CAF,
is also detectable during acute HIV-infection [16]. Deliber-
ate depletion of CD8 T cells from SIV-infected macaques at Immune and virological outcomes
primary infection results in increases of viral load set point
at resolution of primary infection
and accounts for more rapid disease progression [17].
In peripheral blood, HIV-specific CD8 T cells are among Upon onset of these HIV-specific immune responses viral
the first immune responses detectable, usually during the load declines. CD4 T cell counts partially recover but do
clinical presentation of acute infection. In macaques, not return to normal levels. CD8 T cell numbers drop but
SIV-specific CD8 T cells can be detected within 8 days of remain elevated well above the normal range (Fig. 6.1).
79
These changes maintain a reversed CD4:CD8 T cell ratio, Despite these processes, a range of adaptive mutations
despite partial normalization of CD4 T cell counts. Markers within the transmitted virus may be maintained. Horizon-
of immune activation particularly those expressed on the tal and vertical transmission of both drug resistance muta-
surface of CD8 T cells (e.g. CD38), remain substantially in- tions and immune escape mutations are well documented
creased. Plasma viral load reaches a steady state or set point [38, 39]. However, thereafter, mutations reflecting adapta-
approximately 3–6 months post-infection [30]. This level tion to the new host also occur rapidly with mutations
reflects a balance between the pathogenicity and replica- allowing escape from both CTL and neutralizing antibody
tion fitness of the virus and the effectiveness of the host’s pressure arising rapidly [21, 22, 26]. The virus adapts to the
initial immune response. This level predicts long-term dis- altered pressures placed upon it, with selection of the most
ease outcome (Fig. 6.1) [31]. replication-competent variants occurring rapidly. Variation
can occur in all genes. The reasons for differences in the rate
of variation relate to varying levels of gene plasticity and
differences in the pressures applied.
Virus
Initial infection in the overwhelming majority of cases
occurs with the virus using the CCR5 co-receptor. This che- Co-infection and superinfection
mokine receptor is expressed preferentially on monocytes, As explained above, simultaneous co-infection with several
dendritic cells, and memory CD4 T cells. Viral tropism for quasispecies occur in a significant minority of cases espe-
CCR5 is determined by the amino acid sequence of specific cially in the presence of impaired mucosal barriers. In
regions of Env. The observation of almost exclusive CCR5 addition superinfection with a second virus within the first
co-receptor tropism in viruses isolated early in infection 2 years post initial infection has been reported with increas-
strongly suggests selection of viral strains from within the ing frequency, at least in non-B subtype infections. Super-
transmitting host’s multiple quasispecies by the process infection, in B subtype infections, appears rare or at least
of transmission. uncommon [40–42]; however, in areas where micro-
Furthermore, the virus appears highly homogenous, epidemics of different subtypes intersect, superinfection ap-
shortly after transmission. Two factors may contribute to pears more common [43, 44]. The presence of more than
homogeneity of transmitted strains. The first is the concept one viral quasispecies may be advantageous to the virus,
of a molecular sieve, where the process of transmission se- allowing it to evolve more quickly within a host through
lects for the variants most capable of transmission from recombination events.
among the swarm of quasispecies in the transmitting host.
Certain envelope variants appear to have an advantage dur-
ing the transmission process. The selection of CCR5 tropic
variants is the clearest example. More recently, in subtype C CLINICAL MANIFESTATIONS
virus, variants carrying env sequences with shorter V1–V4
intervals and reduced numbers of glycosylation sites appear The rate of recognition of the clinical manifestations of pri-
to be preferentially transmitted [32]. This molecular sieve is mary infection varies markedly. An acute illness associated
most obvious in heterosexual transmission where the ma- with recent infection with HIV-1 can be identified in the
jority of transmissions are by a single viral quasispecies that majority of individuals with reported rates ranging from
is most often not the dominant quasispecies in the trans- 50 to 90% [45–48]. Initial descriptions described the
mitting host. The restrictions on transmission are less strin- illness as resembling infectious mononucleosis, with the
gent when they occur in men who have sex with men, in the major manifestations being fever, pharyngitis, and adeno-
presence of intercurrent sexually transmitted infections, pathy [45], but further studies have demonstrated that
and in intravenous drug users where a larger proportion using this triad alone to describe the clinical manifestations
of transmissions involve multiple quasispecies [33–35]. is restrictive [48]. Symptoms associated with initial in-
These observations suggest that intact mucosal surfaces fection and subsequent seroconversion can vary from
impose a strong selection pressure on the virus. completely absent through to an acute debilitating illness
Additionally, homogeneity of transmitted strains may be requiring hospitalization. The rate of identification is de-
contributed to by rapid viral adaptation to its new host pendent on high levels of clinical suspicion, experience
post-transmission. Post-transmission, the virus tends to re- with making the diagnosis, the availability of medical re-
vert from mutations that were advantageous in the original sources, and suspicion on the part of the patient. Although
host towards wild type. This process of reversion affects the overwhelming majority of reports of this illness have
both drug resistance and immune escape mutations been in the context of the developed world with subtype
[36, 37]. The rate of reversion inversely correlates with B infections, similar manifestations have been reported
the fitness cost to the virus in its new host with reversion with other viral subtypes in developing world settings. Sim-
of non-advantageous mutations in the new host occurring ilarly, although most reported series also arise from cohorts
very quickly. where the major mode of transmission is sexual, similar
80
prevalence of symptomatic illness and similar clinical man- progression to disease. More rapid CD4 T cell count de-
ifestations have been reported in intravenous drug users clines have been documented in those who present to a
[9, 49]. In adults, clinical manifestations and severity are physician [54]. The presence of candidiasis, neurological
not dependent on age, sex, race, or geographical factors. involvement, or a prolonged illness lasting more than
Although no concurrent studies have been performed, a 14 days is associated with a worse prognosis [48].
study in a US population showed that 49% sought medical Co-infection with other viruses, such as cytomegalovirus
attention for symptoms [50], while up to 44% of African (CMV), or other sexually transmitted infections (STIs),
women took some time off work due to primary infection occurs. These co-infections can make the clinical presen-
symptoms [51]. Although published reports are sparse, tation more complicated [55]. Co-infection with other
similar manifestations are seen in adolescents [52]. viruses such as herpes viruses, hepatitis B or C virus, or
The time from exposure to illness is typically 2–4 weeks other STIs such as chlamydia or syphilis must be consid-
(range: 6–42 days) [45–48], but there are rare, isolated re- ered in the diagnostic work-up.
ports of delayed seroconversion of up to 12 months post- As stated, race, mode of acquisition, or viral subtype does
exposure. The acute illness typically lasts approximately not appear to impact upon the severity of the illness. Pre-
3 weeks and is of rapid onset. In the main, the symptoms existing impaired immune responses, as demonstrated by
are self-limiting. However, up to 20% of cases can require low pre-existing CD4 T cell count, low CD4:CD8 T cell ra-
hospitalization or be associated with the presence of op- tios, or impaired delayed-type hypersensitivity reactions,
portunistic infections like candidiasis, herpes zoster, cryp- are associated with increased risk of a symptomatic illness,
tococcosis, and Pneumocystis jiroveci pneumonia. The as is transmission from an index case with advanced HIV
likelihood of primary infection being complicated by an disease [56, 57].
opportunistic infection is related to the extent of CD4
T cell depression [53].
The main clinical manifestations are fever, pharyngitis,
adenopathy, rash, myalgia or arthralgia, headaches, and fa- DIAGNOSIS
tigue or asthenia. The pharyngitis is non-exudative and the
tonsils are not coated. The rash is classically maculopapu- Clinical suspicion, based upon recognition of the constel-
lar, symmetrical with lesions 0.5–1 cm in diameter affect- lation of clinical signs detailed in the previous section,
ing face and or trunk, but may also affect the hands combined with knowledge of possible exposure to the virus
including the palms. Other manifestations include mouth in the previous 2–8 weeks, plus laboratory confirmation of
ulcers and gastrointestinal upset including diarrhea, ody- recent HIV infection, are the cornerstones of diagnosis. For
nophagia, anorexia, abdominal pain, and vomiting. Head- these reasons, the diagnosis should always be considered in
aches can be associated with retro-orbital pain exacerbated individuals presenting with apparently nonspecific symp-
by movement of the eyes and meningitic or encephalitic toms if they belong to a risk group for HIV infection. The
symptoms and signs. Lymphadenopathy tends to be more differential diagnosis of primary HIV-1 infection includes
common in the cervical region but can affect axillary and other viral infections, particularly with herpes viruses, such
inguinal regions [45–48, 53]. as Epstein–Barr virus (EBV) and CMV, but also includes
The originally described triad of dominant manifesta- other viral illnesses and STIs, particularly syphilis. Usually,
tions—fever, pharyngitis, and lymphadenopathy—occurs the confirmation or exclusion of the diagnosis of acute HIV
in a significant minority of patients. Although fever is the infection in the laboratory is straightforward. Therefore, the
most common manifestation, it occurs in less than three- critical step in the process is the consideration of the diag-
quarters of patients. In the absence of a typical mononucleo- nosis as a possibility.
sis-like presentation, fever is most commonly associated with Early diagnosis has advantages for both the individual
headache, oral ulceration, and/or abdominal pain. In the ab- and the population. It allows institution of therapies in
sence of fever the most common manifestations are pharyn- the context of a relatively intact immune system. Further-
gitis, lethargy, myalgia, rash, headache, and adenopathy [48]. more, effective therapy reduces viral load and therefore vi-
Lymphadenopathy may be slow to resolve, persisting well ral turnover, markedly limiting the rate at which virus
after the resolution of other manifestations. mutants arise, allowing adaptation to either drug pressure
Clinical presentations are reasonably nonspecific and or immune responses. As the severity of the illness has im-
not easily distinguishable from other viral illnesses on plications for long-term outcome, it may influence deci-
clinical grounds alone. However, this constellation of sions regarding timing of institution of therapy. Early
symptoms in those at risk should trigger consideration of initiation of risk-modification counseling limits the poten-
primary infection illness in the differential diagnosis and tial for transmission, particularly as transmission probabil-
should initiate laboratory investigation including HIV ity increases with high viral loads such as those that
serology. characterize primary infection [58–60]. However, the effec-
The severity of the illness appears to impact on long- tiveness of this intervention will depend upon the stage of
term outcome, with greater severity predicting more rapid the epidemic and the extent to which transmission is to
81
casual partners [61]. The identification and early diagnosis testing platforms that can also employ fluids other than
of primary HIV infection is an essential component of the blood, including saliva. In general these rapid tests have
“Test and Treat” strategies that have been proposed as a lower specificity and sensitivity than the standard labo-
mechanism of limiting or in the best-case scenario stalling ratory-based tests. This type of test may have a role in
the epidemic. This strategy relies on very early diagnosis of diagnosis, particularly in the absence of formal labora-
large proportions of all new infections in a population and tory support in resource-poor settings [64]. In addition
the rapid institution of antiretroviral therapy (ART) to these rapid tests may also increase the overall coverage
reduce viral load, thereby reducing or eliminating trans- of HIV testing as a significant minority of people tested
mission of the virus. While modeling of this concept has for HIV never return to receive their test results; how-
provided encouraging results, this strategy requires sub- ever, in low prevalence populations, tests with even high
stantial implementation research to provide evidence for specificity, if used alone, will result in substantial num-
practicality and effectiveness [62]. bers of false-positive results [65].
As is typical of immune responses to infection anti-HIV
IgM antibodies precede the development of IgG anti-
LABORATORY TESTING bodies. However, detection of IgM antibodies alone is
not routinely used in the diagnosis of recent HIV infection
AND DIAGNOSIS because of unacceptable rates of false-positive results.
Antibodies are usually detectable by EIA or Western blot
Although nucleic acid testing is playing a greater role in the within 2 weeks of infection; however, the length of this
diagnosis and management of acute HIV infection, serol- window period varies depending on the diagnostic kit
ogy is still the mainstay of diagnosis. The relative suscepti- used (Fig. 6.1).
bility of nucleic acid testing to false-negative results as a Immunoblotting demonstrates that antibodies develop
result of sequence variation, particularly across different vi- in typical and predictable patterns (Fig. 6.2). This knowl-
ral subtypes, still prevents these tests becoming the main- edge can be used for early identification of likely serocon-
stay of diagnosis. verters triggering other testing to support the diagnosis of
The routine detection of primary infection relies on the early or acute HIV infection. These tests include direct
generation of antibodies to the virus. As these take a finite detection of virus (see below). Antibodies to p24 or Env
period to develop, there is an unavoidable window period are typically the earliest antibodies detectable with virtually
after infection when these tests will be negative, even in the all sera being positive 2 weeks or more after the onset of
presence of established infection (Fig. 6.1). The length of the acute illness. Antibodies to other proteins develop se-
this period is, to some extent, dependent upon the sensitiv- quentially with a fully positive Western blot present by
ity of the test used. In general, those assays where the viral 3 months after infection. However, individuals identified
proteins are derived from viral lysates alone are less sensi- soon after exposure may have negative EIA and negative
tive than those in which lysates are supplemented by re- or indeterminate immunoblot results at the time of their
combinant proteins or peptides. The window period can first blood draw. Definitive serological diagnosis then
be further shortened by detection of virus directly, through depends on tracking responses over time until diagnostic
either protein-based assays for the detection of p24 protein criteria are fulfilled. Laboratories interested in studying
or nucleic acid testing based on the detection of either pro- acute infection have developed algorithms for the rapid
viral DNA or viral RNA (Fig. 6.1). However, even these tests detection and confirmation of these cases (Fig. 6.3).
will be negative for up to 2 weeks following infection [63]. Importantly, highly suppressive ART commenced early in
The sequential development of positive results initially on the course of acute HIV infection can change the pattern
nucleic acid tests and then on various serological tests has of antibody development, resulting in freezing antibody
been used to formally divide the period of primary infec- development at the stage at which therapy was com-
tion into stages called Fiebig stages [63]. menced [66]. This can cause diagnostic difficulties;
Criteria for diagnosis of HIV-1 infection vary from coun- however, upon interruption of therapy and subsequent in-
try to country but the diagnosis in the laboratory of acute creases in viral load, antibody responses develop rapidly to a
HIV infection is dependent upon either an evolving pattern fully positive immunoblot pattern.
of antibody production or a new positive test in the pres-
ence of a documented recent negative test.
Detuned serology and other testing
to detect recent infection
Serology
In the absence of a developing antibody pattern, diagnosis
A range of tests for detecting antibodies that will make the di- of early infection is usually dependent upon the availability
agnosis of HIV infection are available. These include a variety of recently negative serology. However, a range of serolog-
of enzyme immunoassay (EIA)-type technologies and immu- ical techniques that can indicate recent infection are
noblotting. These now include a variety of “point of care” becoming available. These techniques are based on the
82
Figure 6.2 Development of HIV antibodies over time,

following infection. Sequential immunoblots
performed on serum samples from a typical
seroconverter showing characteristic pattern of gp160
antibodies to various HIV proteins at acute infection. gp120
p68
p55
HIV viral proteins (kd)

p53
gp(41–45)
p40
p34
p24
p18
serum control
10
11
12
13
14
1
2
3
4
5
6
7
8
9
2 3 4 5 6 7 14 20 26 27 30 42 54 79
Weeks post onset of illness
Figure 6.3 An example of a “flat” diagnostic

algorithm for rapid identification of true
Primary HIV infection ??
acute infection cases. A barrage of diagnostic
tests is set up in parallel, allowing for faster
turnaround times, but this is a more expensive
strategy and is usually only adopted in reference
laboratories with an interest in primary infection. Western Proviral DNA PCR/
ELISA 1 (x2) ELISA 2 (x2) blot p24 antigen Plasma RNA PCR
observation that both the intensity and the affinity of the detected by detuned EIAs varies from test to test, but in gen-
antibodies increase over time. The best known of these eral these assays detect infections within the past 6 months
techniques is the “detuned” EIA. In these assays, the sensi- (Figs 6.1, 6.4) [64].
tivity of a standard EIA is deliberately compromised However, this assay performs with quite different charac-
through increasing the dilution of the sera tested and reduc- teristics in non-B subtype viruses, limiting its utility outside
ing incubation times. In these compromised EIA, sera the developed world [67]. More recent developments with
from individuals with fully established infection still pro- IgG capture EIAs may have overcome some of these prob-
duce a positive response, but sera from those with recent lems [68, 69]. Other methodologies for detecting recent in-
infection will give a negative response and therefore fection depend on the affinity maturation of antibodies
“detune.” The period over which recent infection can be to particular epitopes or detection of development of p24
83
Figure 6.4 Relative performance of a standard

diagnostic EIA and a detuned EIA. The detuned
Standardized EIA will become positive several months later
optical than the standard highly optimized and sensitive
density Standard Detuned Interpretation diagnostic EIA. In the interval shown by the
Standard EIA EIA double-headed arrow, the diagnosis of a recent
EIA infection can be made by the discrepant results
Recent
Positive Negative between the two tests.
infection
Detuned
EIA Established
Positive Positive infection
Time (days)
antibodies of a particular isotype [70]. However, the perfor- Nucleic acid testing
mance of these tests on non-B subtypes has not been
Detection of proviral DNA by polymerase chain reaction
assessed. Another mechanism of diagnosing early infection
(PCR) techniques is a sensitive and specific way of diagnos-
employs an algorithm that takes into account the character-
ing HIV infection and is a very useful adjunct test in the
istic patterns in development of individual bands and
context of primary infection in those with negative or inde-
intensities of bands upon Western blot. This simple algo-
terminate serology. The test is often positive up to 2 days
rithm appears to have greater specificity for recent infection
prior to the p24 antibody test (Fig. 6.1); however, it works
than detuned testing. The further development of this type
less efficiently in non-subtype B infections. The other major
of test will aid with collection of epidemiologic data on
use of this test is for the early diagnosis of mother-to-child
rates of new infections, rates of disease progression, and
transmission, as maternal antibodies make the use of sero-
early diagnosis for individuals.
logical strategies for neonatal diagnosis problematical. Viral
RNA can be used as an alternative, but care must used when
Detection of virus choosing the correct test as many of the standard viral load
tests used for monitoring of infection and response to ther-
The main role of direct viral detection in the diagnosis of apy have a low but problematical false-positive rate in true
primary infection is in reducing the window period in seronegatives. Therefore, the viral load detected must be
those with negative or indeterminate serological testing. > 5000 copies/mL on two separate occasions before the di-
The ability to directly detect viral components p24 or agnosis can be made with certainty. Used in this way, the test
nucleic acid (plasma RNA or proviral DNA) supports the usually first becomes positive about the same time as the p24
likely diagnosis of HIV infection. antigen. Alternative qualitative RNA detection kits have been
developed for screening of blood donations and can be used
to screen pooled samples. These give positive readouts at
p24 Antigen detection lower RNA levels and therefore reduce the window period
This test employs EIA technology. The test is highly specific further but are not currently approved for use in routine
and, although not sensitive in chronic disease, is character- diagnosis [63]. As with the proviral DNA test, RNA tests
istically transiently positive early in acute infection in those are susceptible to false-negative results in variant strains.
with negative or very early antibody responses. The test is
usually positive 3–6 days prior to a sensitive antibody
Viral load during primary infection
EIA (Fig. 6.1) [63].
Many commercially available tests now combine anti- Following diagnosis, the patient is usually monitored using
body and antigen detection in a single EIA. These kits offer standard surrogate markers of disease progression, viral
significant advantages in screening for positive diagnoses, load, and CD4 T cell count. A low nadir CD4 cell count
especially at primary infection. Subsequent testing will re- and higher viral load at 2–4 months, but not peak viral
veal whether the positive result is driven by the presence of load, is associated with a poorer prognosis [54, 72], while
antigen or antibody. The majority of the latest generation rapid falls in viral load are associated with a better progno-
of p24 antigen tests (“4th generation kits”) perform well sis. Set point viral load is attained between 3 and 6 months
with non-B clade isolates [71]. post-infection [30], and the higher this level, the worse the
84
prognosis. Cervical and semen HIV viral loads mirror short term, longer-term follow-up suggested this effect
plasma viral loads with high levels during primary infec- was diluted with time [79, 80]. Some studies suggest that
tion before a set point is reached [73, 74]. This would con- initiating early, transient therapy during acute HIV infec-
tribute to the reported increase in transmission risk during tion slows the rate of disease progression and delays the
primary HIV infection [59]. need for long-term ART [81, 82]. Combination ART is def-
initely effective in improving both CD4 T cell count and
viral load, compared with untreated historical controls,
Drug resistance testing while those patients are on treatment. However, the
Drug resistance can be determined either phenotypically or long-term advantage of these regimens has not been dem-
genotypically. The determination of drug resistance at pri- onstrated and in general CD4 T cell counts and viral load
mary infection is generally recommended by expert panels return to similar set points as those untreated individuals
and can serve two purposes. First, it can serve as a public upon cessation of therapy [78]. Other therapeutic ap-
health surveillance mechanism providing information re- proaches such as structured treatment interruptions and
garding population rates of transmission of drug-resistant short-course therapy lasting up to 12 months have been
variants. Second, it provides important information for advocated after apparent success in selected individuals.
the individual if therapeutic intervention is being consid- However, randomized clinical trials have demonstrated
ered. Rates of transmitted resistance vary markedly between that structured treatment interruptions are detrimental to
populations [75]. In the absence of drug pressure, some of individuals compared to constant ART and should be
these mutations revert over time, while some, particularly avoided [83]. There are significant amounts of data suggest-
those that are compensated by secondary mutations or ing improvements or maintenance of various functional
those that do not significantly impact on viral fitness, tend HIV-specific immune responses mediated by both CD4
to be maintained. The impact of these transmitted muta- and CD8 T cells; however, the impact of these changes
tions on long-term outcome is still to be determined, but on long-term outcome are unclear at this time [7, 8].
theoretically, they will compromise response to ART. The presumed benefits of early intervention with sup-
Transmitted resistance mutations may behave differently pressive ART include reduction in viral load resulting in re-
from those in an individual stopping therapy where there is duction of transmission and preservation of the immune
often rapid outgrowth of wild-type or reversion variants. system preventing depletion of CD4 T cells. Although there
Mutations may be maintained post-transmission for much has been fairly universal acceptance of initiation of therapy
longer periods than after withdrawal of therapy. While the for those diagnosed during acute infection, attitudes of
M184V 3TC mutation often reverts rapidly and the T215Y physicians are becoming more conservative, driven by
AZT mutation partially reverts to 215 S/C/D, others, partic- the lack of efficacy data and the cumulative toxicities of
ularly the K103N mutation, may be maintained for long ART regimens. Recent data suggest that adverse events, in-
periods of time [76]. cluding gastrointestinal upsets, lipodystrophy, and mood
disorders, are recorded in 51% of individuals treated, with
only 75% achieving good viral load control [84]. The first
randomized clinical trial of combined ART commenced at
MANAGEMENT primary infection (SPARTAC) will provide insight into
whether early treatment of limited duration (3 months or
Once the definitive diagnosis is made, it must be commu- 1 year) in patients with PHI can influence long-term CD4
nicated to the patient in a clear and supportive manner. The T cell decline and disease progression [82]. This trial is com-
patient must fully understand the diagnosis and appreciate plete and the preliminary results were released in late 2011.
the need to adopt safe practices that minimize further Hopefully, this study will give some definitive guidance on
spread of the infection. There is evidence that earlier diag- therapeutic intervention during primary infection.
nosis if linked to effective counseling services can modify
behavior and reduce transmission at a time of high viral
load and therefore the likely probability of transmission
per unsafe event [77]. Therapy of primary infection is sup- CONCLUSION
portive. The initiation of ART during acute infection is sug-
gested by a range of treatment guidelines, but usually only Primary infection is a dynamic process. To a significant
in the context of clinical trial. Although there are theoretical degree, long-term outcomes of the natural history of HIV
reasons to support this approach, there are still no defini- infection are determined by the pathophysiological events
tive data from controlled clinical trials which demonstrate occurring during this period. Identification of patients
that combination antiretroviral chemotherapy has a posi- during acute infection allows for ideal management of
tive effect on long-term clinical outcome [78]. Although the infection from its earliest stages and has the potential
the first randomized trial of zidovudine monotherapy at to significantly impact further spread of the epidemic
primary infection suggested a therapeutic benefit in the through early institution of risk-reduction strategies.
85
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1999;180(2):320–9. et al. Amplified transmission of [84] Schiffer V, Deveau C, Meyer L, et al.
[67] Young CL, Hu DJ, Byers R, et al. HIV-1: comparison of HIV-1 Recent changes in the management
Evaluation of a sensitive/less concentrations in semen and blood of primary HIV-1 infection: results
sensitive testing algorithm using the during acute and chronic infection. from the French PRIMO cohort. HIV
bioMérieux Vironostika-LS assay for AIDS 2007;21(13):1723–30. Med 2004;5(5):326–33.
88
Chapter |7|
Biology of HIV-1 transmission
Julie Overbaugh
HIV-1 can be transmitted from an infected mother to her

INTRODUCTION infant in utero, during delivery, or through breastfeeding
[4, 5]. In the absence of any interventions to reduce trans-
HIV-1 has spread rapidly around the globe, and in some parts mission, approximately one-third of infants born to HIV-1-
of sub-Saharan Africainfects up toone-thirdof adults aged 15– infected mothers will become infected. In breastfeeding
49. Indeed, the effects of HIV-1 have been most devastating in populations, the risk of HIV-1 infection is almost double
the developing world: of the estimated 2.6 million new infec- the risk in non-breastfeeding populations. While it may
tions occurring each year, nearly 70% take place there (http:// seem reasonable to therefore recommend against breast-
www.unaids.org). While there remains continued spread feeding for all HIV-1-infected mothers, this must be bal-
of HIV-1 globally, recent estimates suggest that the number anced with the potential for increased mortality due to
of new infections are decreasing; there were 20% fewer other infectious diseases, which can often occur in regions
infections in 2009 than in 1999 (http://www.unaids.org). where access to clean water is limited. Fortunately, mother-
HIV-1 can be transmitted sexually, from mothers to their to-child transmission of HIV-1 can be lowered consider-
infants, and via contaminated blood. Globally, heterosex- ably by antiviral treatment. In developed countries where
ual transmission accounts for the vast majority of new cases state-of-the-art treatment is available, and HIV-1 infected
of HIV-1 infection, and the epidemic has had similar mothers do not breastfeed, transmission is as low as
impact on men and women, with cases in women on the 1–2%. There is also increasing access to antivirals to pre-
rise [1]. Since sexually infected women who become preg- vent mother-to-child transmission in developing countries,
nant can in turn transmit the virus to their infants (called leading to decreased transmission rates.
vertical transmission), preventing sexual transmission is
viewed as key to slowing the HIV-1 pandemic.
Despite the remarkable spread of HIV, the risk of transmis- FACTORS IN THE INFECTING PARTNER
sion per exposure is low; estimates are on the order of 0.1% THAT DETERMINE THE LIKELIHOOD
per contact for heterosexual transmission. The per-contact
risk is higher (1%) for male-to-male sexual transmission, OF TRANSMISSION
and for blood exposures via contaminated needles (called
parenteral transmission) [2]. These numbers may underesti- Higher virus levels in the infecting host (also called index
mate the risk for persons who have other endogenous or ex- case or source partner) are correlated with infection [2].
ogenous risk factors that increase their susceptibility, as host This is perhaps unsurprising, as one might expect that expo-
factors of the source partner as well as those of the exposed sure to a higher dose of virus would increase the likelihood
individual are known to alter transmission risk. Certain fea- of transmission. In most studies, viral levels have been de-
tures of the virus may also influence its fitness for transmis- fined by measuring systemic HIV-1 RNA in plasma, even
sion. Thus, the per-contact risk should be considered an though plasma may not be the major bodily fluid to which
average estimate that may be much higher (or lower) in the person is exposed to during sexual contact. These find-
certain circumstances, as discussed below [3]. ings could therefore reflect the fact that the levels of virus in
89
blood plasma are correlated with the viral levels in other presumably very similar to the virus that was transmitted,
body fluids, such as genital secretions. Indeed, one recent is genetically more homogeneous than the virus popula-
study provided direct evidence that genital virus levels tion that is present during chronic infection [8]. The viral
predict HIV-1 transmission, and this was true even after ac- sequences present during the early stages of infection are
counting for plasma virus levels [6]. The presence of sexu- often remarkably homogeneous, which suggest that a sin-
ally transmitted diseases (STDs) has been shown to gle virus was transmitted. This transmitted viral sequences,
increase risk of transmission. Many STDs increase genital which can only be inferred from the sequence detected
HIV-1 levels, which could in turn increase risk by increasing weeks later when HIV-1 reaches high enough levels to de-
HIV-1 exposure. tect, has recently been dubbed a founder virus. However,
Virus levels are highest during acute (primary) HIV-1 in- studies in women first suggested that multiple viral se-
fection, before the virus is contained by the host, and this is quences are sometimes transmitted, and this has now been
thought to be the time when a person is most infectious [2]. observed in other populations and linked to the presence of
Viral levels drop after primary infection resolves, and then biological cofactors such as other STDs [8]. Even in cases
slowly and steadily increase over time. Thus, the advanced where the virus is genetically heterogeneous early in infec-
stage of HIV-1 infection, when CD4 counts are low, is also tion, it is generally less diverse than what would be
a time when a person is potentially highly infectious [3]. expected during chronic infection, suggesting that only a
There are several risk factors common to both vertical subset of variants are successfully transmitted. More recent
transmission and sexual transmission, including the levels detailed studies of viruses in both the index case and their
of plasma virus in the index case [2, 4]. In the case of ver- newly infected partner (transmission pairs) near the time of
tical transmission, it has been shown that the levels of ma- HIV-1 acquisition provide direct evidence for this transmis-
ternal breast-milk virus and genital virus correlate with the sion bottleneck [9]. However, in some situations it is pos-
risk of infant infection. Poor breast health in a breastfeed- sible that the limited diversity of transmitted strains
ing mother, particularly mastitis, increases infant risk of indicates that the source partners harbored a virus popula-
infection. tion of limited diversity, perhaps because they transmitted
Premature birth has been associated with increased in- during their primary infection, which is a time of high
fant HIV-1 infection, which could reflect an increased risk infectivity.
of premature birth for infants infected in utero, rather than No matter what the complexity of the viral genotype, the
prematurity leading to a greater chance of HIV-1 infection. viruses present within the first few months after infection
A prolonged duration of ruptured membranes is associated almost invariably require the CCR5 co-receptor for entry
with increased transmission, whereas cesarean-section (these are called R5 viruses) [10]; CCR5 is one of two major
birth is associated with decreased risk. Presumably, these HIV-1 co-receptors (the other being CXCR4), and the co-
associations reflect the fact that during transit through receptor, along with the CD4 receptor, is critical for HIV-
the birth canal, the infant may be exposed to HIV-1 in both 1 entry into cells. The observation that most recently trans-
blood and genital secretions. mitted viruses are R5 viruses suggests that CCR5 variants
are favored for transmission. This apparent selection for
R5 viruses occurs during all routes of transmission, includ-
ing sexual, vertical, and parenteral routes. In support of this
model, it has been shown that individuals who do not
FACTORS IN VIRAL SELECTION express cell surface CCR5 due to a specific genetic poly-
morphism are less susceptible to HIV infection (see also
HIV-1 is highly genetically variable and it continually below).
evolves and adapts in the infected host [7]. HIV-1 seems Despite the fact that transmitted viruses share a common
to undergo a selective bottleneck during transmission be- co-receptor requirement, the viruses transmitted from
cause very few viruses are apparently transmitted from different individuals are quite genetically distinct. This
one host to another. It is possible that this bottleneck is diversity has made vaccine development a daunting
at least partially a result of stochastic events that reflect prospect. Thus, there has been considerable interest in de-
the low frequency at which HIV-1 is transmitted. But it fining common features among transmitted viral strains.
may also indicate that there is selection for particular vari- Signature sequence characteristics have been noted among
ants with certain properties. The major lines of evidence to viruses present early in infection, at least in some popula-
support selective transmission include the observations tions [8], and they may provide insights into which bio-
that (1) the early virus population is often genetically less logical properties of viruses increase their fitness for
diverse than the source-virus population; and (2) viruses transmission. Many studies have attempted to identify bi-
present early in infection tend to infect cells using one ological characteristics that confer the selective advantage
particular co-receptor (CCR5). for transmitted HIV-1 variants, but none have identified
Many studies of the past two decades have shown a clear biological phenotype common to all transmitted
that the virus population early in infection, which is strains that may explain their selection.
90
Chapter |7| Biology of HIV-1 transmission
index case and the uninfected partner may increase the risk
ENDOGENOUS HOST FACTORS of transmission. HLA proteins are acquired on the virus as it
buds from the host cell, and it has been postulated that dis-
cordance of HLA may mark the infectious virus as more
Host genetics immunologically foreign, and thus decrease transmis-
Multiple host genetic polymorphisms have been linked to sion. Genes involved in innate immunity—the killer cell-
HIV-1 susceptibility [11–13]. The mutations that have been immunoglobulin-like receptor (KIR) genes that bind to
identified derive largely from targeted studies focused on HLA proteins and modulate natural killer (NK) cell activ-
genes that code for host factors known to be critical for ity—have also been implicated in HIV-1 susceptibility.
HIV-1 replication. For example, many studies have focused NK cells play a central role in the initial antiviral response.
on allelic variation within co-receptor genes, or genes cod- Both allelic differences and expression differences in KIR
ing for ligands that bind the HIV-1 co-receptors (e.g. CCL5/ have been implicated in HIV susceptibility, although these
RANTES for CCR5 and CXCL12/SDF1 for CXCR4) and findings are somewhat preliminary [11].
thus potentially compete for HIV-1 entry. Therefore, alter- To date, host genes identified as risk factors for HIV-1 ac-
ations in the expression or function of the proteins encoded quisition have primarily been uncovered because these
by these genes could impact HIV-1 replication at the cellu- genes/proteins were known to play a role in HIV-1 biology.
lar level. Overall, studies of host genetic factors have pro- It is possible that a more global genomic approach, which
vided a somewhat complex view of the effects of host would sample a larger number of genes independently of
genetics on HIV-1 transmission, as consistent results have whether they have an established link to HIV-1 replication
not always been found across studies. This may partially or immunity, could yield a much longer list of polymor-
be due to the complexity of the interactions between the phisms involved in HIV-1 susceptibility. Indeed, there is
different alleles, as well as differences in allele frequency considerable interest in these genome-wide approaches
and other factors in the populations examined. Moreover, to studying HIV resistance in individuals who are HIV-1
with many of the mutations it is unclear whether they ac- negative despite being highly exposed to HIV-1 [12]. It is
tually affect protein levels or function, or whether they were thought that examining a large group of highly exposed
detected because they are genetically linked to other muta- HIV-1 negative individuals may reveal other host genes im-
tions in nearby genes, which play a more direct role in portant in HIV-1 susceptibility. However, identifying such
transmission. cohorts is complicated because HIV-1 transmission is a
Some studies have found clear and consistent evidence somewhat rare event that can be influenced by many other
for a direct association between host genetics and HIV-1 factors, making it hard to truly define those who are more
susceptibility. This is the case with CCR5, where an inacti- resistant to infection versus those who are simply beating
vating genetic mutation (D32), which is present in a small the odds.
fraction of Caucasians, has been associated with reduced
susceptibility to HIV-1 infection in high-risk individuals
with the homozygous D32 CCR5 allele. Lymphocytes EXOGENOUS HOST FACTORS
and macrophages from these individuals are not permissive
to replication of R5 viruses, providing biological support STDs, female hormones,
for the observed associations. However, this mutation is
not found in Africans, and therefore is not a modulating
male circumcision
risk factor for the African epidemic. Thus, although the Sexually transmitted diseases are a major risk factor for
D32 CCR5 mutation can have pronounced effects on HIV-1 infection, and both ulcerative and non-ulcerative
HIV-1 susceptibility for an exposed individual, it has had STDs have been shown to increase susceptibility to HIV-1
limited global impact on HIV-1 spread. [2,14]. These include a variety of specific sexually
A variety of other mutations in CCR5, found particularly acquired infections, both viral (e.g. herpes simplex virus
in the promoter region, also appear to affect HIV-1 suscep- type 2, HSV-2) and bacterial (e.g. Neisseria gonorrhoeae
tibility. In addition, single nucleotide polymorphisms and Treponema pallidum). It is likely that these STDs
(SNPs) in several genes that encode chemokines or cyto- enhance susceptibility in part by increasing the number
kines have been linked to HIV-1 susceptibility. In some of activated T lymphocytes, which are targets for HIV-1
cases, a particular haplotype, one that includes several infection, at mucosal surfaces. In addition, some may dis-
SNPs, has been associated with susceptibility. The biologi- rupt mucosal integrity, providing access to T lymphocytes
cal mechanism of action of most of these mutations, alone and other potential target cells in the submucosa.
or in combination, remains to be elucidated. The estimates of the effect of STDs on the risk of HIV-1
Genetic variations in loci encoding molecules that play a infection vary from study to study, but are likely to be in
role in acquired immunity have also been associated with the range of two- to fivefold. Given the high prevalence
HIV-1 transmission risk. Several studies suggest that human of STDs in many parts of the world, the overall impact of
leukocyte antigen (HLA) allele concordance between the STDs on HIV-1 spread is therefore potentially significant.
91
One of the STDs most commonly associated with increased CD4 T lymphocytes are important either in the initial in-
HIV-1 infection is HSV-2, which can be treated with sup- fection event and/or in subsequent dissemination of the vi-
pressive therapies such as daily acyclovir. However, studies rus from the mucosal site of entry. There is local expansion
evaluating the impact of treatment for HSV-2 on HIV-1 of virus that preceded dissemination of SIV to the lymph
acquisition did not show any benefit [15]. This was nodes and periphery, at which point infection is irrevoca-
true whether HSV-2 was treated in the HIV-1-infected bly underway. Dendritic cells (DCs) are thought to play a
partner (to attempt to reduce infectiousness) or in the role, possibly facilitating infection of the CD4 lympho-
HIV-1-exposed partner. cytes, and/or enhancing virus spread [19]. DCs express
Three landmark studies have shown that male CD4 and, depending on their maturation state, may
circumcision reduce the risk of HIV-1 acquisition in express HIV-1 co-receptor(s). Immature DCs express CCR5
men by 60% (e.g [16] http://www.who.int/hiv/topics/ and can be infected by HIV-1 in vitro, whereas mature
malecircumcision/en/index.html). The precise mechanism DCs cannot. More importantly, both immature and ma-
of protection is unknown but there are several plausible bi- ture DCs have been shown to capture HIV-1 and transfer
ological explanations including the fact that the foreskin it to CD4 T lymphocytes in vitro. Thus, one plausible
may contain potential HIV-1 target cells and/or that tears model of HIV-1 transmission is that DCs positioned just
in the foreskin could provide a portal of entry for HIV-1. below the mucosal epithelium capture HIV-1 and facilitate
There is also some evidence that circumcision may help re- its transfer to lymphocytes, where the virus rapidly repli-
duce the risk of other STDs. Thus, the long-term benefit of cates and amplifies. Indeed, in the macaque model studies,
circumcision for men may be even greater given the inter- virus dissemination to the draining lymph node has been
play of STDs and HIV-1 infection, and because the benefit shown to occur within 1 to 2 days after vaginal inoculation,
of circumcision accrues over a lifetime. and DCs have been implicated. During the initial stages of
Unfortunately, there is no evidence to suggest a protective virus amplification, the gut-associated lymphoid tissue is a
effect of male circumcision on transmission from infected major site of virus replication, leading to considerable
men to their female partners, but a long-term reduction of damage due to CD4 lymphocyte cell killing.
HIV prevalence in men may nonetheless benefit women There is uncertainty over whether any of the models of
by reducing their exposure. For women, several studies have HIV-1 transmission reflect reality, which stems from our
shown that the use of hormonal contraceptives increases inability to study the earliest events in HIV-1 infection.
their risk of acquiring the virus. However, the association be- Generally, infection cannot be detected, at least using
tween use of hormonal contraceptives and HIV-1 suscepti- non-invasive methods, for several weeks after the initial
bility has not been observed in all studies, particularly transmission, at which time the virus has become well
those in which there is not frequent monitoring to permit established throughout the host tissues. Thus, the earliest
good estimates of the time of infection. Thus, there is no events that lead to successful HIV-1 transmission have sim-
clear consensus on the extent of risk to women that results ply not been studied. The studies conducted in the ma-
from use of hormonal contraceptives [17]. caque model have employed a very high inoculum, and
viruses that are unlikely to represent those typically trans-
mitted between humans. Thus, it is hard to know how well
EARLY TARGET CELLS AND INITIAL these models mimic HIV-1 transmission. Remarkably, it is
not even clear whether the virus that is transmitted is cell-
VIRUS–HOST DYNAMICS free (extracellular, free virus) or cell-associated. Without
good knowledge of the precise molecular interactions that
At least two molecules are required for HIV-1 entry into govern initial infection, the design of interventions to target
cells: CD4, plus a multiple-membrane-spanning chemo- them is particularly challenging.
kine receptor, such as CCR5 or CXCR4 [7, 10]. Because
CD4 is required for virus binding, the host range of
HIV-1 is largely restricted to CD4 cells, which include
a subset of T lymphocytes (T-helper cells), cells of the SUPERINFECTION
monocyte lineage, and dendritic cells. Each of these cells
is therefore a potential target for initial HIV-1 infection, Re-infection by HIV-1 from another
and there is some evidence to support a role for each in
early infection. However, as much of this information
source partner
derives from either animal or culture model systems, each More and more data have been accumulating to suggest that
of which has limitations, the initial target cell for HIV-1 transmission of HIV-1 occurs in the face of pre-existing HIV-
infection in a new host is not known. 1 infection [20]. The first definitive evidence for superinfec-
Studies using a SIV/macaque model of HIV-1 transmis- tion came from some intensively monitored subjects who
sion showed that CD4 T lymphocytes are among the first were part of various trials or studies. In these cases, one virus
target cells of SIV infection [18]. These findings imply that was detected over several visits, and then a second virus,
92
Chapter |7| Biology of HIV-1 transmission
which differed more than would be expected by de novo var- to prevent their infection is a concept similar to providing
iation, emerged in the virus population. One case presented anti-malarial drugs to individuals in areas with high malaria
particularly compelling evidence for superinfection: after the burden. This prophylaxis approach was first successfully
person had engaged in high-risk behavior on holiday, a sec- used in children exposed to maternal HIV-1. Several recent
ond strain was detected that was characteristic of those circu- studies now support the use of this approach in adults
lating in the region where the subject had vacationed [21]. exposed to HIV-1 through heterosexual contact [22, 23].
However, many of these cases were somewhat unusual be- Importantly, antiviral prophylaxis was shown to provide
cause the subjects had had treatment interruptions, or protection whether it was taken orally as a daily
showed evidence of a less virulent initial virus, in some cases medication or used topically as a vaginal microbicide. Pro-
because it had acquired drug-resistance mutations, presum- tection was linked to adherence in using the medications
ably in a treated source partner prior to transmission. and encouraging adherence will be critical in implementing
Subsequent studies suggested that re-infections are almost these exciting new prevention approaches.
as common as initial infections, and that they occur in the There is also considerable interest in the potential bene-
face of high levels of replication of the first virus [20]. This fits of antiviral treatment of infected individuals in reduc-
suggests that re-infection can occur even when the host ing virus spread. These treatments reduce source virus
already harbors a virus that is highly fit and well established. levels and treatment of infected mothers has been repeat-
Of concern is the fact that re-infections appear to be occur- edly shown to reduce transmission to their infants. Thus,
ring in some cases at a time when immune responses have treatment may not only benefit the infected individual
had adequate time to develop to the first infection, but be- but also can have an effect at the population level. It is cur-
fore immune function is completely compromised later in rently unclear whether provision of drugs to HIV-1-infected
infection. Indeed, several studies have shown that individ- or to HIV-1-uninfected, highly-exposed individuals would
uals who became superinfected had immune responses to provide the most benefit in slowing the global spread of
their first infection similar to responses of individuals HIV-1, and this is a critical consideration given the limited
who were not superinfected. Nonetheless, these responses resources available for antiviral treatment.
did not protect them from a second HIV-1 infection [20]. As a result of the findings of recent clinical trials, we now
These findings suggest that a vaccine will have to elicit have several new effective approaches for preventing HIV
anti-HIV-1 immune responses that are better than those that transmission, including male circumcision and antiviral
are generated to a naturally occurring HIV-1 infection. prophylaxis. Broad implementation of these prevention
tools represents the next significant challenge, as these
methods are seemingly more complex than other known
PREVENTING HIV-1 TRANSMISSION effective methods, such as the use of condoms. Designing
new, targeted approaches to prevent HIV transmission is
A highly effective vaccine would be the best method for sig- also a challenge, given our rather limited understanding
nificantly impacting HIV-1 spread and thus is the Holy of the initial events in HIV-1 transmission. Critical aspects
Grail of HIV-1 prevention efforts. However, vaccine trials of transmission, such as the precise source of the virus and
have met with only modest success [18] and an effective initial target cells for infection, are not known. Thus, a bet-
HIV-1 vaccine is not likely to become available any time ter understanding of the factors that drive transmission of
in the near future. In the meantime, much of HIV-1 preven- HIV-1 may lead to novel approaches that can be added to
tion has focused on educational efforts to reduce risk be- the growing list of effective prevention tools.
haviors and consequent exposure. Increasing attention
has been focused on the potential benefit of antivirals in
preventing HIV-1 spread, including the use of these drugs ACKNOWLEDGMENTS
in both the HIV-1-infected and HIV-1-uninfected partner.
Providing antiretroviral drugs to HIV-1-exposed individuals I thank Jared Baeten and Scott McClelland for their input.
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Chapter |8|
The design of a global HIV vaccine1
Jerome H. Kim, Nelson L. Michael
Since our first knowledge of the HIV-1 epidemic in 1981 it program of HIV prevention, an effective HIV-1 vaccine
is estimated that over 80 million persons have contracted would still have a powerful impact on the epidemic, and
the disease. In 2010 the United Nations Joint Programme modeling has suggested that a vaccine with efficacy as low
on AIDS estimated a total of 33 million people living with as 30% ( antiretroviral introduction) would be cost-effective
HIV infection and 14,000 new infections per day—the and could reduce the epidemic r0 to less than 1 [8].
majority of these infections occurring in resource-constrained
settings where access to appropriate care and treatment is
limited [1]. In sub-Saharan Africa HIV/AIDS is the leading
cause of death and has reduced economic growth, caused HIV BIOLOGY
social disruption, and loss of productivity.
It is possible, however, using available public health
measures to significantly reduce the rates of infection. HIV-1 is a lentivirus, as are simian immunodeficiency virus
In a setting where the predominant route of infection (SIV), feline immunodeficiency virus, visna, equine infec-
was through commercial sex workers, Thailand dramati- tious anemia virus, and bovine immunodeficiency virus.
cally slowed its HIV-1 epidemic by instituting a 100% con- The HIV-1 capsid is surrounded by host cell membrane
dom campaign [2]. However, it has proven difficult to and 20–75 viral envelope spikes (gp120/gp41). The capsid
translate success in Thailand to other countries, as the char- holds two positive strand viral RNA genomes, tRNA, and re-
acteristics of local epidemics, drug use, customs, sexual verse transcriptase. Viral entry occurs after a high-affinity in-
practices, funding, and perhaps viral subtypes have proved teraction between CD4 and the gp120 envelope (Env) spike,
difficult to overcome. causing a conformational change and exposure of a co-
For these reasons, since the discovery of the etiologic receptor binding site (CXCR4 or CCR5 most commonly)
agent of HIV-1 in 1984, development of a vaccine has been [9–11]. Interaction with the co-receptor initiates a further
a high priority. A number of approaches have been tested in set of rapid conformational changes, resulting in apposition
efficacy trials [3–7], and one was recently found to have of the viral and host cell membranes and, ultimately, fusion.
modest efficacy [7]. At the same time, efforts at prevention, Membrane fusion is followed by entry of the capsid protein
care, and treatment have appeared to reduce the global bur- into the cytoplasm, release of the viral RNA and associated
den of infection [1], and efficacy testing of both vaginal reverse transcriptase, reverse transcription, and integration
microbicides and pre-exposure chemoprophylaxis has re- of the viral DNA into the host cell DNA.
cently been shown to prevent infection when used. How- Once HIV-1 infects CD4 T cells, virions are formed at a
ever, as a public health tool, vaccines have the advantage rate of 108–109 per day. Infected CD4 T cells have a half-life
of not requiring action on the part of the individual (except of 1–2 days [12]. HIV-1 does not always result in lytic in-
for vaccination itself). As a part of a comprehensive fection of the host cell. Latently infected, quiescent cells be-
come a reservoir of infection; cell division is accompanied
by bursts of viremia, some cell death, but also incidental
1
The views expressed in this chapter are those of the authors and do not replication of virus integrated in the host DNA by homeo-
reflect the official views of the Departments of the Army or Defense. static proliferation [13, 14] (reviewed in Trono et al. [15)].
97
Section | 2 | Prevention, diagnosis, and treatment of HIV infection
Two features and related implications of HIV biology de-

serve to be highlighted with regard to vaccines. The first, FEATURES OF TRANSMITTED VIRUSES
which will be described more fully later, is ability of the
virus to generate genotypic diversity through its rate of rep-
Within a chronically infected individual HIV-1 exists as a
lication, intrinsic error-prone replication, and frequent
quasispecies, or swarm, with hundreds or thousands of dif-
recombination. Practically this means that the virus rapidly
ferent variants. Diversity is generated through two mecha-
evades or "escapes" from incipient humoral and cellular
nisms. First, the HIV RT is error prone (3 10-5 bases) and
immune responses [16–18]. More broadly, however, it
lacks a proof-reading function. Second, the virus is capable
suggests that it may be necessary to develop multiple
of recombination (7–30 crossovers per genome) during re-
"subtype"-specific vaccines or vaccine(s) capable of tackling
verse transcription. Practically this means that, given the
the issue of subtypes and regional epidemic diversity. The
rate of HIV replication in chronic infection, thousands of
second feature is the speed with which the post-infection
mutant progeny might be generated every day (reviewed
events occur; after a "take" the virus spreads rapidly to re-
in Taylor and Hammer [25)].
gional then systemic lymphatic tissue, most prominently
However, studies suggest that transmitted viruses have
the gut-associated lymphoid tissue (GALT). Taken together
unique features and are not necessarily representative of
with the profound and persistent depletion of the GALT and
the quasispecies in the transmitting individual. That the
the early establishment of latently infected cells, the preven-
most commonly recognized sequences in the quasispecies
tion of acquisition, if it is possible, may need to occur before
are not necessarily the transmitted/founder (T/F) isolate ar-
productive infection is established—in the earliest phases
gues that there is "selection" for certain characteristics.
of virus interaction with the host [17].
It was early found that the vast majority of transmitted
isolates utilized the CCR5 co-receptor. Transmitted Envs
tend to be shorter and less glycosylated than "chronic"
Env [26–29], but this finding has not been universal
PATHOGENESIS OF ACUTE [30]. Several groups have reported that T/F viruses have
HIV-1 INFECTION shorter V1V2 loops, and it was recently found that the T/
F Envs have a greater affinity for a4b7 [31]. T/F strains
may be able to use cells with lower CCR5 or CD4 density
Acute HIV-1 infection, well described in rhesus macaques
[31, 32], and are more susceptible to CCR5 inhibitors.
and less precisely known in humans, is the front line for
In addition several studies have shown that the typical
HIV-1 vaccines. The mechanisms of viral "take" in the vag-
infectious event in genital mucosal transmission involves
inal, urethral, glans, or rectal mucosa will need to be op-
a single T/F virus 80–90% of the time, while intrarectal
posed by humoral or cellular effectors that can prevent
mucosal transmission may involve single T/F 60–80% of
the infection of CD4 targets, eliminate CD4 infected targets
the time [31, 33–35]. In transmission cases the founding
(without becoming infected), or prevent the infection of
viruses often resemble ancestral sequences more than the
secondary CD4 targets. The relative contribution of these
other members of the donor quasispecies [36], suggesting
early infection scenarios and mechanisms in vivo is not
again that there are unique features of transmitting
known, so the study of acute HIV-1 infection and in partic-
viruses that, in the relatively uncommon event of mucosal
ular the impact of vaccine-induced immune responses on
transmission, are associated with productive infection.
these pathogenetic events is critical to successful vaccine
These features of T/F envelopes suggest that there may be
development.
a brief window of opportunity, influenced by stochastic
In the earliest stages of HIV infection, days–weeks after
events not yet defined, where the individual infecting
initial exposure in man, HIV-1 initiates massive infection
virus may be uniquely susceptible to innate or adaptive im-
and depletion of the GALT; home to roughly 70% of
mune effector mechanisms that may limit subsequent
CD4 T cells [19–21]. In SIV vaccine challenge models, pres-
events in pathogenesis that lead to local, then systemic,
ervation of gut T central memory CD4 cells is correlated
infection [37].
with improved survival. Integrin a4b7, which appears to
bind to the V2 loop of HIV-1 Env and to up-regulate virus
production, also directs homing of CD4 T cells to gut and
genital mucosa through its ligand MADCAM-1, which is CHALLENGES TO HIV VACCINE
expressed on mucosal epithelial cells [22, 23]. Interestingly, DEVELOPMENT
the infusion of a rhesus-mouse hybrid monoclonal anti-
body (MAb) prior to high-dose intravenous (IV) challenge
What makes an HIV vaccine different?
results in significant reduction in plasma viremia and latent
virus pools [24]. Whether human vaccines can induce Historically, vaccines have been developed for infections
responses that interfere with a4b7 and whether this will where the natural immune response controls the initial in-
affect acquisition of infection remain unknown. fection and prevents further infection of the host. This does
98
Chapter |8| The design of a global HIV vaccine
not hold for HIV-1. The host immune response does not protection) it may be important to look at the parallels be-
eliminate infection or control progressive disease, and in tween the human and NHP infection models. We consider
fact, participates in its persistence. The host immune re- NHP first because many of the other issues are impacted by
sponse does not prevent superinfection (this is how recom- data from NHP studies, and appreciation of the strengths
binants develop). Practically this means that there is no and weaknesses of the model are critical to this discussion.
proof of concept from natural infection that informs vaccine There are two types of virus: SIV and chimeric SIV-HIV
development; there is no protective (against acquisition) (SHIV). Within SIV there are two different sources of chal-
natural immune response that a vaccine should mimic. An lenge and inserts, SIVmac251 (SIVmac239 is a clone) and
empiric approach to vaccine testing, informed by clues from SIVsmE660. There are three principal challenge models: in-
basic and translational research, would be a traditional re- travenous, intrarectal, and intravaginal. All are powered to
sponse. A positive signal (i.e. protection) would then pro- achieve infection relatively quickly, and not with the fre-
vide: (1) additional direction or clues; (2) potential or quency of infection/challenge seen with human intrarectal
actual correlates of risk/protection [38, 39]; (3) a representa- and intravaginal infection.
tive animal model; and (4) a basis upon which to build fur- Vaccination with recombinant Ad5 (Merck) HIV vaccine
ther informed (but still empirical) testing. followed by simian-human immunodeficiency viruses
Thirty years into the epidemic, the challenges to the iden- (SHIV) intravenous challenge was associated with reduc-
tification and development of HIV vaccine immunogens re- tion in post-infection viral load [41], but did not predict
main profound. Three issues deserve particular attention: the outcome of the Step trial where the challenge was
(1) subtype diversity; (2) animal models; and (3) defining intrarectal. The SHIV used in those studies, SHIV89.6P, tar-
protective immune responses. geted CXCR4þ cells and was therefore not a good mimic
of acute HIV infection in vivo. When the challenge was
SIVmac251, no benefit was seen [42]. Whether IV challenge
Subtype diversity with an X4/R5 tropic virus was an appropriate model for
HIV-1 diversity is one of the greatest challenges to the devel- screening of candidate vaccines underscores the difficulties
opment of an effective vaccine and is manifest virologically faced by NHP studies in the absence of human correlates.
by the intrinsic error rate of reverse transcriptase and fre- Alternatively, SHIV162P3 has been used to demonstrate
quent intragenic recombination and at a population level the efficacy of various subunit HIV Env vaccines [43, 44]
by the diversity of subtypes, recombinant forms, and rapid and to establish potential correlates of protection. These
and continuous evolution within infected hosts. From studies await confirmation in human efficacy testing,
the time of the initial zoonotic transmission events of HIV which will inform vaccine development and confirm the
(early twentieth century), three main groups are recognized: animal model/virus challenge.
M (major), O (outlier), and N (non-major, non-outlier). In humans, the viral quasispecies in an infected person is
A fourth group, designated P, related to a gorilla SIV, has also broad (10–15%) and the T/F virus is usually (except in
been described. There are regionally prominent subtypes acute infection) a minority member of that quasispecies.
that are geographically based and differ from each other In NHP studies, the challenge stocks are more narrow in
by roughly 25–35% (intraperson variation typically is distribution and are based largely upon SIVmac251 or
<10% and intrasubtype diversity is 15–20%)—the nine SIVsmE660 (an alternative SIVdelta670 is not widely used).
current subtypes and 50þ circulating recombinant forms While it is possible to establish challenge conditions where
(CRFs) underscore the complexity of the global epidemic the number of T/F viruses [45, 46] approximates the
[25]. In general, subtype B predominates in North America human condition, the chances of acquiring infection after
and Europe, subtype C in southern Africa and India, subtype a single intrarectal or intravaginal challenge still exceed the
A in East Africa, CRF01_AE in Southeast Asia, and probability seen in humans [45, 46]. Since it has long been
CRF02_AG in West Africa. There are other regions with a established in vaccinology that large challenge inocula can
mixture of subtypes, and some areas, such as East Africa, overcome vaccines of known efficacy, the impact of the
where 50% of strains are unique recombinant forms high per challenge infection rate is unknown.
(URFs), found (thus far) in only a single infected individual. The use of low-dose mucosal SIV challenge has, however,
Also subtype diversity is increasingly recognized in Europe demonstrated acquisition effects similar to that of the Thai
and the USA; an HIV vaccine that targets only a single sub- HIV vaccine trial [47, 48], and refinements to the NHP
type may have limited utility in many parts of the world. model including penile challenge are being developed.
One of the vaccines showing a protective effect in NHP is
the Vaccine Research Center (VRC) DNA/recombinant ad-
Animal models enovirus type 5; it is in phase IIb clinical testing now
Non-human primates (NHP) models of infection and chal- (HVTN505) and the outcome will inform and refine the
lenge have been evolving rapidly in recent years (reviewed NHP model [48]. SHIVs are the only way to test HIV Env
in Genesca et al. [40)]. In the absence of a validated animal vaccines and may be the principal test for new constructs
model (i.e. mirroring what is seen in terms of human utilizing "mosaic" antigens [49, 50]. The use of new SHIV
99
constructs (SHIV SF162P3/4) and pathogenic SHIVs [51] as protecting HEPS against HIV infection in Kenyan
will provide new insights and may extend the utility of CSW [68]. Among EC strong, polyfunctional, and broad
the NHP model in conjunction with advances in human HIV-specific cellular immune responses are associated
HIV vaccine design. with persistent, highly suppressive control of HIV infection
[69, 70]. Similarly, strong cellular immune responses
against SIV associated with post-infection viral load control
Defining protective immune responses are reported with both attenuated SIV vectors and replicat-
Which immune response(s) protects against HIV infection? ing CMV-SIV vaccines [60, 61, 71].
Unfortunately the answer is unknown. Perhaps the recently
completed RV144 trial will provide a correlate of risk that
Correlates from monkey studies
can be incorporated into the testing of future candidates. In
the absence of correlate, empirically derived target immu- One of the advantages of a NHP model that is validated
nogenicity that can be tested in efficacy trials in humans against the human model is that it may be possible to
provides the most systematic (if expensive) approach. It use a laboratory measure of immunogenicity/protection
is known from NHP studies that HIVIG and broadly neu- in monkeys that will reliably predict protection in humans.
tralizing antibody (BNAb) can protect animals from intra- In the absence of a validated model, it is still possible to
vaginal SHIV challenge. Interestingly, an ADCC null glean from NHP studies at least supportive evidence for
mutation of the Fc chain of the b12 BNAb reduces its ability advancing products to human efficacy trials.
to protect against infection, suggesting that neutralization How much antibody is enough? While protection from
works in concert with other humoral effector mechanisms intravenous or high-dose intravaginal SHIV challenge re-
in vivo to achieve an optimal effect [52, 53]. HIV-1-infected quired relatively high levels of NAb, polyclonal HIVþ sera,
persons have recently been the source of a number of or 1b12 [72, 73], lower doses appear to be necessary for
BNAbs [54–56] that neutralize 70–90% of all tested viral prevention of acquisition using a low-dose intravaginal
isolates. These BNAbs have high rates of VH gene mutation challenge [72, 74], but even these levels may exceed that
(12–30%) and abnormally long HCDR3 regions, so seen in human HIV vaccine efficacy trials.
whether BNAbs can be elicited by vaccination is unknown. Using a NAb-sensitive SHIV (SF162P4) it was possible
Also, BNAbs were isolated from persons with chronic pro- to prevent infection via intravaginal challenge using a ho-
gressive infection, implying that these antibodies were a re- mologous protein administered intramuscularly (IM) or
sponse to chronic infection but did not control it [54–56]. IM and intranasally [44]. Protection appeared to correlate
Whether T cell responses, in the absence of antibody can with NAb levels against SHIVSF162P4. Priming with
protect against infection is not known [57]. Depletion of B alphavirus (Venezuelan equine encephalitis) viral vector
cells did not affect NHP control of an intravenous SIV chal- encoding SF162P4 Env and boosting with a gp140DV2
lenge, though depletion of CD8 T cells did [58, 59]. It is an homologous Env (MF59 adjuvant) protected NHP against
assumption that the induction of non-neutralizing (and an intrarectal SHIVSF162P4 challenge. Analogously, pro-
certainly non-broadly neutralizing) antibody may provide tection correlated with NAb to the challenge strain, but
de facto evidence that T cell responses are sufficient to was also correlated with total Env binding antibody and
protect against infection. The premise of vaccines inducing pre-challenge avidity [43]. An HIV-ADA-based, DNA
primarily cellular immune responses (CMI vaccines) was prime and MVA boost also protected NHP against intra-
that, while sterilizing immunity might be achieved by rectal challenge with SHIVSF162P3 (not neutralization
BNAb, CMI vaccines might reduce post-infection viral load sensitive), and acquisition was inversely correlated with
[60–63] after high-dose intravenous (or mucosa) chal- avidity to natural (but not monomeric or trimeric)
lenge. More recent studies have suggested that some ADA [75]. Letvin et al. have also reported that, after
"CMI" vaccines, such as DNA/Ad5, are capable of inducing DNA (SIVmac251) prime and recombinant Ad5 boosting
antibody at the same level as seen in the Thai HIV vaccine (SIVmac251), protection against intrarectal E660 chal-
trial and might still protect against infection by SIVsmE660 lenge was correlated with low levels of NAb to E660 in
in low-dose mucosal challenge [48, 64]. a human PBMC assay and to a lesser degree in pseudovirus
Two other sources of information on what might consti- TZM-bl neutralization assays [48]. CD4 Env-specific
tute protective immune responses are found in special responses were also correlated with protection against
cases: those persons who, despite repetitive exposure acquisition [48]. Whether the same correlations will
remain uninfected (highly exposed persistently seronega- hold in human studies is unknown. A DNA prime/rAd5
tive, HEPS) and those HIV-infected persons whose immune (subtype A, B, C) phase IIb study is currently under
systems appear to nearly completely control viral replica- way, and has recently been changed to evaluate HIV-1
tion (long-term nonprogressors, elite controllers, EC). acquisition (HVTN505).
It appears the HEPS groups manifest some level of HIV- A replicating CMV-SIV vaccine has been shown to sub-
specific cellular response [65–67]. Both cellular (prolifera- stantially reduce post-infection viral load in an SIVmac239
tion) and IgA-mediated HIV neutralization were implicated intrarectal challenge, occasionally to undetectable levels,
100
with CD8 T effector memory (Tem) cells being the immune The Step (HVTN 502) and Phambili (HVTN 503) vaccine
response correlated with viral load, and more recent data trials were the first human efficacy trials to explore whether
suggest that this vaccine may protect against acquisition the Merck recombinant adenovirus type 5 HIV vaccine,
as well in a low-dose intrarectal challenge [60]. which induced strong IFN-g ELISpot CMI responses, could
prevent infection or reduce post-infection viremia. The
Merck vaccine was composed of replication-incompetent
Ad5 (MRKrAd5 HIV-1) expressing HIV-1 clade B gag, pol,
HUMAN HIV VACCINE TRIALS
and nef. The Step study enrolled predominantly high-risk
populations including MSM and high-risk heterosexual
HIV/AIDS was first recognized syndromically in 1981. The women in North and South America and Australia, and
virus was identified in 1984, and the first efficacy tests of heterosexual women and men in the Caribbean [3, 89].
HIV vaccines began in 1998. From a theoretical perspective, The Phambili study enrolled heterosexual men and women
many have ruled out the use of whole inactivated and live in South Africa [5]. HVTN 502 was unexpectedly termi-
attenuated vaccines, though preclinical work continues. nated for futility involving the study primary endpoints,
Historically, the initial focus was upon Env subunit vac- virtually all of which were in MSM. Moreover, in subjects
cines, such as the AIDSVAX B/B’ protein tested in Vax004 with pre-existing Ad5-specific neutralizing antibody titers,
that induced binding and type-specific antibody. This a greater number of HIV-1 infections occurred in vaccine
was followed by live recombinant prime–protein boost than in placebo recipients. The biological basis for this ob-
vaccines that appeared to increase cellular responses and servation remains unclear. Post-hoc multivariate analysis
to provide similar levels of antibody; an example is the further suggested that the greatest increased risk was in
ALVAC-HIV (canarypox) vCP1521 plus AIDSVAX B/E men who had pre-existing Ad5-specific neutralizing anti-
tested in Thailand (RV144). Interest then focused upon bodies and who were uncircumcised [90].
recombinant, replication deficient adenovirus type 5 vac- Though the Step and Phambili trials were stopped for fu-
cines, alone and with a DNA prime (the Merck rAd5 and tility, the trials suggested that the intravenous SHIV NHP
the VRC DNA/rAd5 vaccines), which appeared to induce challenge model (with the SHIVs tested) could be mislead-
greater IFN-g ELISpot positivity than canarypox vectors. ing and inadequate for evaluating T cell vaccines. While the
In this section we will first review the vaccines that have MRKrAd5 vaccine generated more consistent Gag ELISpot
undergone efficacy testing and then proceed to a discussion than canarypox-based regimens, this did not appear to be
of vaccines under development by class. We will conclude sufficient to protect against infection. The SIVmac251
with a brief look at the future landscape of HIV vaccine de- model did predict that the MRKrAd5 vaccine would not
velopment holds. control viral load; it, however, did not predict the observed
effect on acquisition [42]. An important lesson of the
MRKrAd5 vaccine trials is that immunity to vectors should
Human efficacy trials
be evaluated in future clinical studies [91].
Production of subunit Env proteins was centered initially The Thai phase III HIV vaccine trial (RV144) of ALVAC-
on laboratory-grown viruses that are CXCR4-tropic. Both HIV and AIDSVAX gp120 B/E prime–boost showed mod-
gp160 and gp120 proteins were prepared [76–86], and est protection (modified intent to treat, mITT) against
eventually two bivalent vaccines from VaxGen were tested acquisition of HIV infection in a community (low) risk
in phase III trials. AIDSVAX B/B’ contained gp120 from the population in Thailand with a 42-month vaccine efficacy
laboratory-adapted strain MN and the primary isolate of 31.2% [7]. AIDSVAX gp120 B/E had shown no efficacy
GNE8. Vax004 tested AIDSVAX B/B in 5,403 men who have in a previous phase III trial in Thai IDUs [6]. There was
sex with men (MSM) and high-risk women in the USA, no effect on early post-infection HIV-1 RNA viral load
Canada, and Europe. Infection rates among the 3,598 vac- or CD4 count. A combined analysis of previous phase I
cine and 1,805 placebo recipients were similar at 6.7 and and II ALVAC-HIV and gp120 prime–boost studies
7.0%, respectively [4]. Vax003 utilized the AIDSVAX B/E showed a VE of 50% at roughly 12–24 months post vac-
vaccine, consisting of the gp120 Env from the laboratory- cination, a difference that was not statistically significant.
adapted HIVMN and the primary isolate CM244 (desig- Similar to RV144 the results also showed no effect on viral
nated A244). A total of 2,546 Thai injection drug users load [92].
(IDUs) were enrolled into Vax003. Vaccine efficacy was es- While a VE of 31% at 42 months is not sufficient for li-
timated at 0.1% (95% CI, 30.8% to 23.8%) [6]. Further censure, it does provide an important proof-of-principle—
non-prespecified analyses of Vax004 antibody-directed a safe and effective HIV vaccine is possible. Two findings
cell-mediated viral inhibition (ADCVI) showed an inverse that did not achieve statistical significance in the pre-
correlation between ADCVI levels and HIV acquisition. This specified analysis are worthy of emphasis. The first observa-
effect was influenced by Fcg IIa and IIIa polymorphisms tion was that those with the lowest baseline risk (incidence
[87]. More recently, Gilbert et al. reported low levels of neu- 0.23/100 person-years) had a VE of 40%, while those with
tralizing antibody against Tier 2 isolates in Vax 004 [88]. the highest baseline risk (incidence 0.36/100 person-years)
101
had a VE of 3.7%. The second important observation was DNA and viral vectors
that VE appeared to decrease with time; at month 12 of
the study it was 60% and fell to 44% by month 18. If early Live recombinant vaccines are viral vector-based products
VE of 60% could be extended with boosting, it would have including the canarypox (ALVAC), modified vaccinia An-
important implications for vaccine development. kara (MVA), and adenovirus vaccines. These can be used in-
The NIAID Vaccine Research Center has developed a dividually or combined with other vaccines in prime–boost
DNA–rAd5 prime–boost regimen that is currently in phase mode, to elicit cellular and humoral responses.
IIb efficacy testing (HVTN 505) among circumcised MSM The pox viruses (canarypox, fowlpox, vaccinia, and
who are Ad5 seronegative [93–95]. These subtype A/B/C MVA) have been studied alone and paired with a variety
vaccines were tested in three phase IIa trials, IAVI V001, of different Env subunits (gp120, gp140, gp160). In addi-
HVTN 204, and RV172, and found to be safe and immuno- tion to a vaccinia-vectored HIV vaccine, several groups have
genic [96, 97]. Pre-existing Ad5-NAbs did not appear to studied attenuated versions of vaccinia in the form of mod-
affect the frequency or magnitude of T cell responses with ified vaccinia Ankara (MVA) and NYVAC. An MVA contain-
this prime–boost vaccine. ing subtype A inserts was found in phase II trials in Africa to
be non-immunogenic, but subsequent trials using MVAs
containing B, C, and CRF01 inserts showed elicited re-
HIV vaccine concepts sponses dominated by CD4 T cell responses [111–118].
Although strong anti-vector responses have been found,
A partial list of current HIV vaccine trials is provided in it is still possible to boost responses with additional doses
Table 8.1. Part of the difficulty in describing the landscape of MVA [117].
of HIV vaccines has been the use of two or more different DNA priming followed by Env boosting has generated
vaccines within a vaccination protocol. The prime–boost some NAb but no BNAb [119]. Similarly, DNA has been used
concept utilizes a DNA or viral vector prime with a boost to prime MVA and adenovirus vaccines. HIV-1 neutralizing
of peptides/protein or different viral vector. Such an antibody was augmented by priming with gp160 recombi-
approach often avoids the problems inherent to the re- nant vaccinia and boosting with rgp160 in vaccinia-naive
petitive use of viral vectors—vector-specific immune adults. DNA/MVA gave strong IFN-g ELISpot in a study con-
responses that may limit the immunogenicity of the vac- ducted by the Karolinska Institute [120]. Similarly, DNA
cine insert. In this section we will describe vaccines of in- prime with a NYVAC boost induced polyfunctional and
terest, individually and in prime–boost combinations. long-lasting T cell responses [121–123]. DNA/rAd5-induced
Importantly, the prime–boost concept only has utility binding antibody and HIV-specific T cell responses were
where the efficacy gained by two different vaccines is suf- detected in 63% of vaccinees. ELISpot responses for DNA
ficiently large to justify the complications imposed by the prime with low-dose (63%) or high-dose (60%) rAd5 were
use of two products. similar—positive responses were predominantly to Env pep-
tides, followed by Pol or Gag, regardless of the immunization
regimen. The high-dose rAd5 boost had the highest frequency
Subunit vaccines of responders to all three antigens tested (Env, Gag, or Pol),
Since the failure of the AIDSVAX B/B’ and B/E vaccines to while responses were approximately equal for the other
prevent HIV infection in MSM and IDUs, respectively [4, immunization groups for two antigens (20–26%) [97]. These
6], much work has been done to try to improve Env substudies are the basis for the ongoing HVTN 505 trial [93, 96,
unit design to induce broadly neutralizing antibodies. 97, 124].
These approaches fall into three categories: (1) creating
"native" Env trimers, simulating the mature Env trimer
The future
on virus particles [98–100]; (2) improving Env conforma-
tion by deletion of loops (V2) [101, 102], alteration of gly- For the canarypox plus gp120 prime–boost combination, a
cosylation, or epitope masking [101, 103, 104]; (3) series of phase IIb trials is anticipated in Thailand and
presenting of epitopes exposed by ligand CD4 binding South Africa to attempt to extend the durability and mag-
[105]. These approaches are confounded by the poor im- nitude of the protective responses to levels consistent with
munogenicity of conserved epitopes that are shielded by public health value. Studies to determine whether an im-
glycosylation [18, 106], appear only briefly [107], or are munologic correlate of risk (or protection) exists in
sterically or entropically impaired [108, 109]. In general RV144 have been conducted; if that correlate of risk can
these modifications have, as pure subunit vaccines and be validated in humans and NHPs, it may accelerate the de-
also in prime–boost configuration with viral vector or velopment of future HIV vaccine candidates. In addition, as
DNA prime, yielded some NAb against homologous vi- a proof of concept, rapid adaptive design trials focused
ruses or easy-to-neutralize Tier 1 HIV but have not gener- around the pox–protein prime–boost concept could be ex-
ated broadly neutralizing Ab (summarized in Mascola and ecuted in order to more efficiently obtain information
Montefiori [110]). about potential correlates [125].
102
Chapter
Table 8.1 List of phase II–III HIV vaccine trials
START VACCINE CANDIDATE VOLUNTEERS TRIAL SITES CLADE STATUS REFERENCE OR

DATE STRATEGY VACCINES (N) CLINICALTRIALS.GOV
IDENTIFIER
|8|
Phase III
RV 144 October Canarypox vector ALVAC-HIV 16,403 Thailand B/E Ongoing Rerks-Ngarm S, Pitisuttithum P,
2003 prime and protein vCP1521, Nitayaphan S, et al,
The design of a global HIV vaccine

boost AIDSVAXgp Vaccination with ALVAC and
120 B/E AIDSVAX to prevent HIV-1
infection in Thailand, N Engl J
Med 2009; 361:2209–2220.
VAX 003 March Protein AIDSVAX B/E 2,500 Thailand B/E Completed Pitisuttithum P, Gilbert P,
1999 Gurwith M, et al, Randomized,
double-blind, placebo-
controlled efficacy trial of a
bivalent recombinant
glycoprotein 120 HIV-1 vaccine
among injection drug users in
Bangkok, Thailand, J Infect Dis
2006; 194:1661–1671.
VAX 004 June 1998 Protein AIDVAX B/B 5,400 USA, Canada, B Completed Flynn NM, Forthal DN, Harro
Puerto Rico, CD, et al, Placebo-controlled
Netherlands phase 3 trial of a recombinant
glycoprotein 120 vaccine to
prevent HIV-1 infection, J
Infect Dis 2005; 191:654–665.
Phase IIb
Step Study: July 2005 Adenovirus vector MRKrAd5 HIV-1 3,000 USA, Canada, B Suspended Buchbinder SP, Mehrotra DV,
HVTN 502, Gaf/ Pol/Nef Peru, Dominican Duerr A, et al, Efficacy
Merck 023 Republic, Haiti, assessment of a cell-mediated
Puerto Rico, immunity HIV-1 vaccine (the
Australia Step Study): a double-blind,
randomised, placebo-
controlled, test-of-concept
trial, Lancet 2008;
372:1881–1893.
Continued
103
Section | 2 |
104
Table 8.1 List of phase II–III HIV vaccine trials—cont’d

IDENTIFIER
Prevention, diagnosis, and treatment of HIV infection

Phase IIb—cont’d
Phambili February Adenovirus vector MRKrAd5 3,000 South Africa B Suspended NCT00413725
Study: 2007 HIV-1 Gag/
HVTN 502 Pol/Nef
PAVE 100 June 2007 Plasmid DNA VRC-HIVDNA0 — USA — Withdrawn NCT00498056
prime and 16-00-VP, before
adenovirus VRC-HIVADV0 enrollment
vector boost 14-00-VP
Phase IIa
HVTN 205 January Plasmid DNA pGA2/JS7 225 USA, Peru, B Ongoing NCT00820846
2009 prime and DNA, MVA/ South Africa
vaccinia virus HIV62
vector boost
IAVI 010 April 2003 Vaccinia virus DNA, HIVA, 111 Kenya, UK A Completed Peters BS, Jaoko W, Vardas E,
vector with/ MVA, HIVA et al, Studies of a prophylactic
without DNA HIV-1 vaccine candidate based
plasmid primer on modified vaccinia virus
Ankara (MVA) with and
without DNA priming: effects
of dosage and route on safety
and immunogenicity, Vaccine
2007; 25:2120–2127.
Phase II
ANRSVAC September Protein LIPO-5 156 France B Completed NCT00121758
18 2004 (lipopeptides)
TaMoVac June 2010 Plasmid DNA HIVIS, DNA, 120 Tanzania Multiple Due to start Barkari M, personal
01 prime and MVA-CMDR June 2010 communication 2010.
vaccinia virus
vector boost
Chapter
AVEG201 December Comparison of rgp120, HIV-1 296 USA B Completed McElrath MJ, Corey L,
1992 two recombinant SF-2, MN Montefiori D, et al, A phase II
proteins rgp120 study of two HIV type 1
envelope vaccines, comparing
their immunogenicity in
populations at risk for
|8|
acquiring HIV type 1 infection,
AIDS Res Hum Retroviruses
2000; 16:907–919.
The design of a global HIV vaccine

AVEG202, May 1997 Canarypox vector ALVAC-HIV 420 USA B Completed Belshe RB, Stevens C, Gorse
HIVNET prime with/ MN120TMG GJ, et al, Safety and
014 without strain immunogenicity of a
recombinant (vCP205), canarypox-vectored human
gp120 protein rgp120, HIV immunodeficiency virus type 1
boost 1SF-2 vaccine with or without gp120:
a phase 2 study in higher- and
lower-risk volunteers, J Infect
Dis 2001; 183:1343–1352.
HIVNET June 2000 Canarypox vector ALVAC 200 Brazil, Haiti, Peru, B Completed Cleghorn F, Pape JW,
026 prime with/ vCP1452, MN Trinidad and Schechter M, et al, Lessons
without rgp120 Tobago from a multisite international
recombinant trial in the Caribbean and
gp120 protein South America of an HIV-1
boost canarypox vaccine (ALVAC-
HIV vCP1452) with or without
boosting with MN rgp120, J
Acquir Immune Defic Syndr
2007; 46:222–230.
HVTN 203 December Canarypox vector ALVAC 330 USA B Completed Russell ND, Graham BS, Keefer
2000 prime with/ vCP1452, MC, et al, Phase 2 study of an
without AIDSVAX B/B HIV-1 canarypox vaccine
recombinant (vCP1452) alone and in
gp120 protein combination with rgp120:
boost negative results fail to trigger a
phase 3 correlates trial, J
Acquir Immune Defic Syndr
2007; 44:203–212.
Continued
105
Section | 2 |
106
Table 8.1 List of phase II–III HIV vaccine trials—cont’d

IDENTIFIER
Phase II—cont’d
HVTN 204 September Plasmid DNA VRC-HIVDNA0 480 USA B Completed NCT00125970

2005 prime and 16-00-VP,
adenovirus vector VRC-HIVADV0
boost 14-00-VP
HVTN 505 July 2009 Plasmid DNA VRC-HIVDNA0 Estimated USA Multiple Ongoing NCT00865566
prime and 16-00-VP, 1350
adenovirus vector VRC-HIVADV0
boost 14-00-VP
IAVI A002 November Plasmid DNA tgAAC09 84 Zambia, Uganda, C Completed NCT000888446
2005 prime and South Africa
adenovirus vector
boost
IAVI V002 2007 Plasmid DNA VRC-HIVDNA0 300 Kenya, Uganda, Multiple Withdrawn NCT00415649
prime and 16-00-VP Zambia, Rwanda before
adenovirus vector VRC-HIVADV0 enrollment
boost 14-00-VP
Reprinted from The Lancet Infectious Diseases 10, Ross et al, Progress towards development of an HIV vaccine: report of the AIDS Vaccine 2009 Conference; 305–316. Copyright 2010. With
permission from Elsevier.
A number of other vaccine concepts have not yet been sufficiently immunogenic. Data should be available soon on
tested in humans. These include virus-like particles (VLP), alphavirus-based vaccines (Sindbis and Venezuelan equine
live attenuated HIV, or replication competent viral vectors encephalitis). Other concepts such as rare serotype adenovi-
(as opposed to attenuated vectors such as MVA or NYVAC). ruses, and vaccines containing mosaic inserts are planned for
The early adeno-associated virus [126, 127] vectors were not human clinical trials in the near future [49, 50, 128, 129].
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112
Chapter |9|
HIV prevention
Salim S. Abdool Karim
INTRODUCTION PREVENTING SEXUAL

TRANSMISSION (BOX 9.1)
One of the greatest challenges facing the world today is the
control of the human immunodeficiency virus (HIV) epi- Reducing sexual transmission, especially heterosexual
demic. At the end of 2009 an estimated 33.3 million people transmission, of HIV is critical to altering the current epi-
were living with HIV [1]. While intravenous drug use is the demic trajectory in many parts of the world. Prevention
major route of transmission in several countries, sexual of sexual transmission can be achieved through reduction
transmission is the dominant mode of HIV spread globally, in the number of discordant sexual acts and/or reduction
with a concomitant epidemic in infants born to HIV- of the probability of HIV transmission in discordant sexual
infected mothers. Although many regions and countries acts [2].
are showing signs of declining or stabilizing epidemics, There is no risk of sexually acquired HIV infection among
some countries still have unacceptably high HIV prevalence individuals who practice sexual abstinence or lifelong mutual
and incidence rates. In contrast to the first two decades of monogamy. Serial monogamy, where there are multiple se-
the HIV pandemic, today women comprise about half of all quential individual short-lived monogamous partnerships,
adults living with HIV/AIDS globally [1]. In sub-Saharan is associated with an increased risk of HIV, but not to the same
Africa, young women aged 15–24 years are as much as eight extent as the increase in risk of transmission emanating from
times more likely than men to be HIV-infected. multiple concurrent sexual partnerships [3]. Reduction in the
HIV prevention focuses, on the one hand, on reducing number of concurrent sexual partnerships and the use of con-
the likelihood of and vulnerability to infection in those doms are key components of HIV prevention messages,
who are currently uninfected and, on the other hand, on widely promoted as part of “ABCCC” campaigns promoting
reducing the risk of transmission from those who are cur- Abstinence, Be faithful, Condomize, Counseling and testing,
rently infected with HIV. The latter is an important new and Circumcision.
opportunity for enhancing prevention efforts through inte-
gration of prevention programs into the health services
which are scaling up AIDS treatment and the prevention
Abstinence
of mother-to-child transmission (MTCT).
Significant advances in HIV prevention have been Abstinence is a HIV prevention strategy promoted primar-
achieved in the past three decades. This chapter summarizes ily for adolescents and entails either delaying sexual in-
the known existing HIV prevention options and describes the itiation or practicing “secondary abstinence,” which is a
new HIV prevention strategies currently under development. prolonged period without sexual activity amongst those
113
frequency, and number of people with overlapping part-

Box 9.1 Evidence-based HIV prevention nerships strongly influence this association [6–8]. The link
strategies between concurrent relationships and HIV risk is particu-
larly relevant in sexual partnering between younger women
For sexual transmission: and older men [9], which is a major factor in HIV spread in
• Abstinence southern Africa.
• Behavior change programs, including school-based sex
education
• Male and female condom promotion
Condoms
• HIV counseling and testing
• Medical male circumcision Condoms are inexpensive and relatively easy to use and pro-
• STD screening and treatment vide protection against acquisition and transmission of HIV,
• Antiretroviral microbicides for prevention of male-to-
a wide range of other sexually transmitted infections, and
female transmission pregnancy. When used correctly and consistently, the latex
male condom is highly effective in preventing the sexual
• Oral antiretroviral pre-exposure prophylaxis for
prevention of male-to-male transmission transmission of HIV. Although numerous studies conducted
over the past decade have demonstrated the steady increase
• Treatment for prevention
in acceptability and use of male condoms [4, 10], a review of
• Integration of behavioral prevention programs into AIDS
HIV risk studies [11] estimates that only about 20% of ado-
treatment services (prevention for positives)
lescents use male condoms consistently.
For mother-to-child transmission: To be effective as a prevention option and to impact on
• Preventive antiretroviral therapy for the mother in the growth of the epidemic, access to condoms, especially
combination with prophylactic antiretrovirals for the female condoms, needs to be drastically scaled-up. In ad-
baby dition, barriers to condom use need to be addressed; some
• Cesarean delivery of the most common being: the widespread perception
• Breastfeeding alternatives: avoidance of breastfeeding, that condoms reduce sexual pleasure and that suggesting
exclusive breastfeeding or prophylactic antiretrovirals the use of condoms represents self-acknowledgment of
during breastfeeding HIV infection or a lack of trust in the partner [12, 13].
• Contraceptive and reproductive health services. Some studies have found that young people may also as-
sociate condom use with promiscuity and sexually trans-
For blood-borne transmission: mitted infections including HIV/AIDS [14]. In the context
• Harm reduction programs of a marital relationship or stable partnership where
• Blood screening and safety pregnancy is desired, or where subordination of women
• Infection control in healthcare settings limits their ability to negotiate safer sex practices, attempts
• Post-exposure antiretroviral prophylaxis to introduce or promote condom use have had limited
success.
who have previously been sexually active [4]. The impact of

Counseling and testing
abstinence on HIV prevention appears to be limited, with HIV counseling and testing has been shown to be both
short-lived success despite the widespread implementation efficacious in reducing risky sexual behaviors [15] and
of abstinence messages. In settings where the epidemic is cost-effective as a prevention intervention [16]. Knowl-
generalized and probability of infection is high because edge of HIV status is an important gateway for targeted
of high disease burden, postponement of sexual initiation prevention and care efforts. It creates an opportunity for
in women simply delays the age of infection, but does not addressing prevention efforts along a continuum that in-
in itself reduce rates of infection [5]. Regardless, abstinence cludes those uninfected who are at high risk of getting
remains an important component of HIV prevention in infected, those recently infected, those with established
youth, especially targeting delaying sexual debut. infection but asymptomatic, those who have advancing
HIV disease, and those on antiretroviral treatment. How-
ever, large numbers of people, especially in sub-Saharan
Africa, are unaware of their HIV status [17]. A study in
Be faithful
the USA has shown that individuals who are unaware of
Individuals with multiple partners may face an increased their HIV infection are 3.5 times more likely to transmit
HIV risk due to overlapping sexual relationships, although the virus to others than those who know about their infec-
gender and other factors such as overlap duration, sexual tion [18].
114
Chapter |9| HIV prevention
Medical male circumcision simplex type 2 virus infection [23, 24]. Despite the prom-
ising 42% reduction in HIV incidence rates observed in a
Medical male circumcision is a proven HIV prevention randomized controlled trial conducted in Tanzania follow-
option for men [19], reducing the risk of female-to-male ing treatment of sexually transmitted infections [25], other
transmission of HIV by up to 60%. Although this preven- similar studies have failed to replicate these results [26].
tion option took some time to be incorporated in the Notwithstanding the inconsistent findings from these tri-
HIV prevention package, widespread use of medical male als, the significant sexual and reproductive health challenge
circumcision to reduce HIV risk is fast gaining momentum, posed by the high burden of curable sexually transmitted
particularly in sub-Saharan African countries. For example, infections needs to be addressed in any HIV prevention
in Kenya and Botswana, policies to have 80% of 0- to effort.
49-year-old HIV-uninfected males circumcised by 2013
and 2014, respectively, have been approved [20]. It is
estimated by mathematical modeling that widespread im-
Antiretroviral microbicides for
plementation of male circumcision could avert between
2 and 3 million HIV infections in sub-Saharan Africa [21]. prevention of male-to-female
While women do not gain a direct benefit from circumcision transmission
of men, they derive an indirect benefit over time as fewer
The search for a female-controlled prevention option has
men become infected with HIV. Medical male circumcision
been ongoing since 1990 [27]. In 2010, the CAPRISA
of HIV-infected men does not seem to reduce the risk of HIV
004 trial showed that an antiretroviral drug, formulated
acquisition in their female partners. Similarly, medical male
as a topical vaginal gel, prevents male-to-female transmis-
circumcision does not demonstrate protection against HIV
sion of HIV. In this trial, tenofovir gel, used before and after
transmission in men who have sex with men (MSMs).
sex, reduced HIV acquisition by 39% [28].This trial has
contributed to the growing body of randomized control
trial-based evidence for preventing HIV sexual transmission
STD screening and treatment
(Fig. 9.1). It is anticipated that a licensed product will be
An estimated 340 million new cases of curable sexually available by 2014. Although tenofovir gel will not provide
transmitted infections occurred globally in the 15–49 years complete protection against HIV, it still has the potential to
old age group in 1999 [22]. HIV transmission and acquisi- have an enormous public health benefit. In South Africa
tion during heterosexual intercourse is enhanced in the alone, this new prevention technology could avert an esti-
presence of sexually transmitted infections, particularly ul- mated 1.3 million new HIV infections and 800,000 AIDS
cerative infections such as syphilis, chancroid, and herpes deaths over the next 20 years [29].
Figure 9.1 Randomized controlled trial

evidence-based effective strategies for Study Effect size (CI)
preventing sexual transmission of HIV infection.
Treatment as prevention 96% (74;100)

(Africa, Asia, Americas)
Medical male circumcision 54% (38;66)

(Orange Farm, Rakai, South Africa)
PrEP for MSMs 44% (15;63)

(Americas, Thailand, South Africa)
STD treatment 42% (15;63)

(Mwanza)
Microbicide 39% (6;60)

(CAPRISA 004 tenofovir gel)
HIV vaccine 31% (1;51)

(Thai RV144)
0 10 20 30 40 50 60 70 80 90 100
Efficacy (%)
115
Despite the optimism that a licensed vaginal microbicide no protection against HIV infection. Several trials in discor-
will be available soon, widespread implementation of dant couples, women, and injecting drug users are still
microbicides as an HIV prevention option faces several ongoing.
challenges. Firstly, because the microbicides in the most ad- If successful, scale up of PrEP will require integration into
vanced stage of development are mostly antiretroviral existing HIV prevention services, which currently need to
drugs that are also being used for AIDS treatment, there be strengthened, especially in Africa, where the need is
are concerns about the potential for drug resistance devel- greatest. Similar to microbicides, implementation of PrEP
opment. Regular HIV testing will most likely need to ac- will require long-term follow-up and surveillance for mon-
company the implementation of microbicides to itoring adverse events, adherence, drug resistance, impact
minimize the potential of drug resistance development. of drug resistance on later AIDS treatment, and risk com-
Microbicides will also only work if they are widely accepted pensation/behavioral disinhibition. The potential contri-
and used consistently by women. In clinical trial settings bution of PrEP to drug resistance may not be as severe as
high levels of adherence have been achievable. However, originally thought. Mathematical modeling of the impact
the same may not pertain to “real world” settings where of antiretroviral therapy and PrEP combined on HIV trans-
microbicides are likely to be implemented in under- mission and drug resistance has shown that while prevalence
developed public healthcare facilities without adequate at- of drug resistance is anticipated to increase to a median of
tention to adherence support. Strategies for ensuring long- 9% after 10 years of antiretroviral therapy (ART) and PrEP
term adherence to microbicides will be essential if they are rollout, most of the new drug resistance is anticipated to
to succeed as a HIV prevention option. Concerns have been be from ART of HIV-infected patients rather than PrEP[33]
raised about the potential for risk compensation/behav- in HIV-uninfected people.
ioral disinhibition and careful attention will need to be
paid to messaging if microbicides are implemented to en-
sure existing risk reduction behavior messaging is not
undermined.
“Treatment for prevention” strategy
The development of microbicides for rectal use has gath- In addition to using antiretroviral drugs in HIV-uninfected
ered momentum recently but remains several years away. people to prevent transmission of HIV, antiretroviral ther-
In addition to new formulations and delivery devices, apy has been shown to reduce infectiousness of an HIV-
future microbicide development is likely to focus on a infected individual, thereby limiting the risk of onward
combination of antiretroviral drugs and combinations of viral transmission [34]. In the HPTN 052 trial [35], ART
antiretroviral agents with contraceptives. initiated in patients with CD4 counts between 350 and
550 cells/mm3 reduced HIV incidence in their HIV-
uninfected partners by 96% compared to patients where
Oral antiretroviral pre-exposure ART was deferred to the point at which the patient’s CD4
prophylaxis for prevention of count dropped below 250 cells/mm3.
The rationale for this strategy stems from studies of discor-
male-to-male transmission
dant couples that demonstrate a strong relationship between
Oral antiretroviral drugs used as pre-exposure prophylaxis viral load and the probability of HIV transmission [2]. A pro-
(PrEP) have recently been shown to successfully reduce the spective cohort analysis among discordant heterosexual Af-
risk of sexually transmitted HIV. The iPrEX trial showed rican couples showed that HIV transmission was rare in
that Truvada (a combination of tenofovir and emtricita- those on ART. In this study, the majority of HIV transmis-
bine) taken daily reduced HIV acquisition by 44% in sions (70%) occurred when plasma HIV concentrations
men who have sex with men [30]. exceeded 50,000 copies/mL [36].
Since Truvada is already a licensed antiretroviral drug for There are many challenges in implementing this ap-
AIDS treatment, its widespread implementation as HIV proach: the difficulty in identifying HIV-infected people
prevention among men who have sex with men began in who are asymptomatic; the lack of health service capacity
2011. Based on the results of the iPrEX study, the Centers to increase the numbers of patients on treatment (espe-
for Disease Control and Prevention and other US Public cially in Africa, where the HIV burden is greatest); and fi-
Health Service agencies have issued guidance on the use nancial constraints already hampering availability of
of PrEP among MSMs at high risk for HIV acquisition in AIDS treatment to those who need it for therapeutic rea-
the United States as part of a comprehensive set of HIV pre- sons. Various approaches to implementing treatment
vention services [31]. for prevention are being developed and investigated. Sev-
However, oral PrEP has not yet been shown to be effec- eral clinical trials for evaluating the community-level
tive in other at-risk populations. A trial assessing the effi- effectiveness of various strategies for HIV testing and
cacy of Truvada as PrEP in women was prematurely initiation of ART for preventing transmission of HIV are
halted in April 2011 [32] as it was considered futile to concurrently underway. The scale-up of and increasing access
tinue the trial following an interim analysis that showed to HIV counseling and testing and antiretroviral drugs
116
has created a new opportunity for integrating prevention has since been superseded by trials testing combination
and care. According to a mathematical model with ex- antiretrovirals. The most effective therapy is a combination
treme assumptions, the “test and treat” strategy, where of three antiretroviral drugs taken during pregnancy and
all individuals who test HIV-infected are immediately ini- breastfeeding [41].
tiated on ART, irrespective of CD4 count, could lead to a Obstetric practices: Cesarean delivery reduces MTCT by
substantial prevention benefit [37]. 80% compared to vaginal, although it is not a sustainable
option in developing countries with high HIV prevalences
as the health services would be unable to cope with the
additional burden of additional cesarean sections and
Integration of behavioral prevention
sepsis rates following cesarean section may be
programs into AIDS treatment unacceptable.
services (prevention for positives) Breastfeeding: Total avoidance of breastfeeding is the
most effective mechanism for preventing breastfeeding
Differentiated from generalized prevention, which targets
transmission. In some resource-constrained settings the
everyone at risk for HIV as well as those who are HIV-
use of formula feeding to reduce MTCT is precluded due
infected but have not yet undergone HIV testing, positive
to the lack of clean running water. In these instances
prevention focuses on addressing continued high-risk
women should be advised to exclusively breastfeed and
practices for HIV transmission among people who know
abruptly wean their infant or, if they have regular access
they are HIV-infected. Clinic-delivered positive prevention
to antiretroviral drugs, they should exclusively breastfeed
interventions have been most successful when integrated
for the first 6 months and then introduce mix feeding
into routine clinical services. The Clinician-Initiated HIV
until the infant is able to have a safe diet without
Risk Reduction Intervention for HIV-Positive Persons, known
breastmilk [42]. Recent data from the HPTN 046 trial
as the Options Project, is one such example, where prevention
demonstrated that providing infants with daily
was effectively integrated into care services by clinicians [38].
nevirapine for up to 6 months lowered risk of
Two separate meta-analyses of randomized controlled trials
breastfeeding MTCT by more than 50% compared to a
have shown that interventions targeting HIV-infected indi-
placebo by age 6 months [43].
viduals are efficacious in reducing unprotected sex and
acquisition of sexually transmitted diseases [39, 40]. MTCT rates below 1% can be readily attained with effec-
tive implementation of existing MTCT prevention strategies
and MTCT has been virtually eliminated in high-income
countries. In 2009, UNAIDS made a call for the virtual
PREVENTING MOTHER-TO-CHILD elimination of MTCT in low- and middle-income countries
TRANSMISSION (BOX 9.1) by 2015, an accomplishment that can only be possible if
90% of pregnant women are reached with services match-
ing WHO guidelines, HIV incidence is reduced by 50%,
Since the discovery in 1994 that the antiretroviral drug azi-
the need for family planning is met, and breastfeeding is
dothymidine (AZT) could reduce MTCT of HIV from 25.5 to
restricted to 12 months [1].
8.3%, substantial progress has been made in this prevention
area. The number of infants infected by their mothers con-
tinues to decline in most countries and in 2009 an estimated
370,000 children contracted HIV from their mothers, a PREVENTING BLOOD-BORNE
decrease of almost 25% in 5 years [1]. TRANSMISSION (BOX 9.1)
Reduction in unwanted pregnancy in HIV-infected
women is an important component of efforts to reduce
the number of children acquiring HIV. MTCT of HIV oc- Transmission of HIV through exposure to infected blood
curs in the intrauterine period, during labor and delivery, can occur through transfusion of blood and blood prod-
and postnatally through breastfeeding. Prevention strate- ucts, through sharing of needles and syringes among in-
gies for reducing MTCT have been targeted at these jecting drug users and through inadvertent nosocomial
time points and include a combination of antiretroviral transmission (e.g. through needlestick injuries) in health-
drugs, changes in obstetric practices, and alternatives to care settings.
breastfeeding.
Antiretroviral drugs: The simplest and most affordable Harm reduction for injection
regimen for preventing MTCT is HIVNET 012, which uses
drug users
a single dose of nevirapine for the mother and a single
dose of nevirapine for the newborn. However, one of the Globally, there are approximately 15.9 million injecting
biggest concerns with using this regimen has been drug users, 3 million of whom are HIV-infected. Although
nevirapine resistance. The single-dose nevirapine regimen the majority of injecting drug users reside in low- and
117
middle-income countries, especially in Eastern Europe, virtually eliminate the risk of transmitting HIV through
East and Southeast Asia, and Latin America, new epidemics donated blood in high-income countries. The use of
of injecting drug use are also emerging in sub-Saharan the newer-generation p24 antigen assays and polymerase
Africa [44]. Although injection drug use is distinct from sex- chain reaction for detecting viral RNA in blood donors
ual intercourse as a mode of transmission, the two routes who may be in the window period for HIV infection is
are frequently linked epidemiologically. Injection drug a further strategy used to reduce the risk of transfusing
users are often young and sexually active, potentially expos- infected blood. However, there are significant variations
ing their sexual partners, children, and fetuses to the virus. in the extent and quality of blood screening, and recip-
In addition, injection drug use is common in the commer- ients of blood transfusions in some countries remain at
cial sex industry. risk of acquiring HIV.
There is substantial evidence that HIV epidemics among
injecting drug users can be prevented, stabilized, and even
reversed. The WHO, United Nations Office on Drugs and
Crime (UNODC), and UNAIDS recommend the following Universal precautions and nosocomial
nine activities be included in a comprehensive package for transmission
the prevention, treatment and care of HIV among injecting
Healthcare workers exposed to blood and body fluids
drug users:
have a low but measurable risk of occupational infection
(1) Needle and syringe programs; with HIV. In a review of transmission probability esti-
(2) Opioid substitution therapy and other drug mates, infectivity following a needlestick exposure was
dependence treatment; estimated to range from 0 to 2.38% (weighted mean,
(3) HIV testing and counseling; 0.23%) [46]. While international guidelines recommend
(4) Antiretroviral therapy for drug users living with HIV; the use of relatively inexpensive auto-disable syringes as
(5) Prevention and treatment of sexually transmitted the “equipment of choice” for helping prevent HIV trans-
infections; mission in healthcare settings, only 38% of low- and mid-
(6) Condom promotion; dle-income countries were using such syringes in their
(7) Targeted information, education, and national vaccine programs in 2004 [47]. Risk of exposure
communication for injecting drug users and their to blood or other body fluids can be significantly lowered
sexual partners; through healthcare workers’ adherence to “universal pre-
(8) Vaccination, diagnosis, and treatment of viral cautions,” which involves the routine use of gloves and
hepatitis; and other protective gear to prevent occupational exposures,
(9) Prevention, diagnosis, and treatment of tuberculosis safe disposal of sharps, and timely administration of a
[44]. four-week prophylactic course of antiretroviral prophy-
Despite access to HIV prevention services, including laxis following exposure.
harm-reduction programs having increased substantially
in many countries, a systematic review of global, regional,
and national coverage has shown that HIV prevention,
treatment, and care services for people who inject drugs re- Antiretrovirals for post-exposure
mains suboptimal [45]. In 2009 the median coverage of prophylaxis
HIV prevention services for injecting drug users was esti-
Following exposure to HIV, there is a small “window of
mated to be 32% [44].
opportunity” to use ART to prevent systemic infection.
This strategy, known as post-exposure prophylaxis
(PEP), has been shown to prevent both occupational
HIV screening of the blood supply [48] and non-occupational exposure [49]. However, the
effectiveness of PEP in preventing the establishment of
for safe transfusions
HIV infection depends on a number of factors, including
Notable progress has been made worldwide in improv- route and dose of exposure, efficacy of drug(s) used, inter-
ing the safety of national blood supplies. The creation val between exposure and initiation of drug(s), and level
of nationally coordinated blood transfusion services of adherence to the drug [48, 49]. The current consensus is
and introduction of a range of policies and procedures, that combination ART should be initiated as soon as pos-
with a particular focus on HIV screening of donated sible after exposure, and continued for at least four weeks
blood for detecting antibodies to HIV, the reduction of [50]. To minimize the possibility of behavioral disinhibi-
unnecessary transfusions, and development of improved tion among individuals receiving PEP for sexual or drug-
donor screening and deferral techniques have helped to use exposures, it is recommended that PEP provision be
118
accompanied by behavioral counseling following a poten- Combination prevention

tial sexual exposure to HIV [51].
A single HIV prevention intervention is unlikely to be able
to alter the epidemic trajectory as HIV epidemics in com-
munities are complex and comprise a mosaic of different
HIV PREVENTION STRATEGIES risk factors and different routes of transmission. Hence,
UNDER DEVELOPMENT the proposal that a mix of behavioral, biomedical, and
structural HIV prevention actions could alter the course
of the HIV epidemic has arisen. The combination of HIV
Vaccines prevention interventions needed will vary depending on
Although a safe, effective, preventive HIV vaccine would cultural context, the population targeted, and the stage of
provide the best method for controlling the HIV pan- the epidemic. Studies are now being developed to assess
demic, its successful development has, to date, eluded whether the epidemic can be slowed or stopped at a com-
scientists. munity level through high coverage of a combination of
Clinical trials of candidate HIV vaccines have been existing prevention strategies.
underway since 1987 but only a few products have
reached late-stage clinical trial testing. Both the bivalent,
recombinant gp120 vaccine (AIDSVAX) and Merck’s CONCLUSION
adenovirus serotype 5 (Ad5)-based vaccine candidate
(MRKAd5) failed to show protection against HIV. In fact, The most recent estimates from UNAIDS indicate that
the latter trial may have enhanced the risk of HIV infec- approximately 7,100 people become infected with HIV
tion, especially in those with pre-existing immunity to daily and for every person initiated on treatment, two
the adenovirus-5 vector. In 2009, however, results from new infections occur. In the meantime, several countries
the Thai RV144 trial provided the first indication that a have achieved substantial reductions in HIV incidence,
vaccine could prevent HIV infection. This trial tested a in many instances without a clear reason to explain this
prime–boost combination of a canarypox vector vaccine outcome.
(ALVAC HIV) and gp120 protein (AIDSVAX B/E) and Providing treatment for everyone who needs it is at pre-
showed that vaccine recipients had a 31% lower rate sent unsustainable. New approaches for extending treat-
of HIV infection than those receiving the placebo [52]. ment for both its life-saving potential and its prevention
Interestingly, the RV144 trial showed evidence of HIV benefit need to be developed. Substantial progress has been
prevention but no evidence of viral suppression and fur- made in the development of HIV vaccines; results from the
ther studies for better understanding these results are Thai RV144 trial and the identification of new anti-HIV an-
underway. While this trial produced promising results, tibodies with broadly neutralizing potential has injected
the vaccine is not being considered for implementation new enthusiasm into this field which has suffered several
due to its suboptimal efficacy. setbacks in the past. An AIDS vaccine remains an important
There are several other AIDS vaccine candidates in the hope for the control of HIV/AIDS, but its realization is still
clinical pipeline and nearly all are devised to elicit several years away.
cell-mediated immunity, a strategy that has so far proved None of the existing HIV prevention strategies or tech-
disappointing. In 2009, the isolation of two new broadly nologies will, in isolation, be able to solve the AIDS pan-
neutralizing antibodies, PG9 and PG16 [53], capable of tar- demic. Rather, a synergistic combination of effective
geting a wide spectrum of HIV variants, has reinvigorated prevention strategies such as behavior change, HIV testing,
the enthusiasm for broadly neutralizing antibodies and circumcision, and widespread access to male and female
the role they could play in the development of a vaccine condoms will be needed at high levels of coverage. At the
against HIV. Several more broadly neutralizing antibodies same time, AIDS treatment and prevention needs to be in-
have also since been isolated. tegrated, to take advantage of “treatment for prevention”
Vaccine development is severely hampered by the lack of strategies, effective microbicides, or oral PrEP. Combining
any immune correlate that has been shown to prevent viral the recently identified benefits of antiretrovirals either as
infection or clear initial viral infection. The human im- prophylaxis in HIV-uninfected people or as “treatment
mune system generally fails to spontaneously clear HIV infor prevention” in HIV-infected people with interventions
fection and so there is no natural immune process for the like medical male circumcision and condom promotion
vaccine candidates to mimic. It is, however, believed that could create the synergy necessary to turn the tide against
approaches aimed at eliciting both humoral and cell- HIV. With the addition of antiretroviral drugs to the pre-
mediated immunity are most promising to prevent or at vention arsenal, stopping the HIV epidemic is now within
least control retroviral infection. our grasp.
119
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Research, Acceptability, and Fidelity
121
Chapter | 10 |
Laboratory testing for HIV infection
James C. Shepherd, Oliver Laeyendecker, Thomas C. Quinn
of the test kits are shown when possible but do not reflect
INTRODUCTION technician costs, which vary greatly by country and by region.
Significant price reductions for some reagents have been ne-
In the 30 years since HIV infection was first recognized it has gotiated by the World Health Organization (WHO) and the
spurred the development of a number of laboratory tests to aid Clinton Foundation (http://www.clintonfoundation.org) in
in the diagnosis and management of the disease. The use of order to make these tests more affordable.
these tests has become well established in America and Europe
and there are a number of up-to-date reviews of HIV laboratory
testing available for these areas [1]. There is less experience DIAGNOSTIC TESTING
with using laboratory testing in the developing world where
HIV subtypes may be different, host responses to the virus During, or shortly after, the clinical presentation of acute
may vary, and technical and financial resources may be lim- retroviral infection, IgM antibodies to Gag (p17, p24,
ited. Much experience has been gained since 2005 with the ex- p55) and Env (gp41,120,160) first appear [2]. This re-
pansion of testing and treatment programs in sub-Saharan sponse seems similar throughout the world, regardless of
Africa and Asia. In this chapter, laboratory tests for the diagno- HIV subtype or host population [3]. The appearance of
sis and management of HIV infection are described with an the IgM response is followed weeks to months later by
emphasis on those in use or applicable to resource-limited IgG antibodies to Gag and Env epitopes and later still to viral
settings. enzymes and regulatory proteins. The time to first detectable
Initially, tests for the diagnosis of HIV infection, including IgG seroconversion by enzyme immunoassay in most stud-
tests of body fluids other than blood, and tests for incident ies in Europe and America is 2 weeks with a median of 3–4
versus prevalent infections, are described. Next, tests that weeks [2]. Almost all newly HIV-infected individuals will
measure the robustness of the immune system, including have detectable IgG by 6 months.
relatively simple tests for measuring CD4 T cells are de- Currently the most established tests for detecting HIV in-
scribed. Tests that measure the amount of virus present in fection rely on an enzyme-linked immunoabsorbent assay
an individual for diagnosis, prognosis, and monitoring of (ELISA) as an initial screening test (cost US$1–1.50 per
therapy are then presented. Finally, an overview of tests that test). This method involves coating a solid surface such
detect drug resistance mutations in HIV are also described. A as the plastic of a 96 well plate with antigen and using this
brief additional section on two tests (HLA-B5701 testing and as an affinity matrix for IgG present in a serum sample.
HIV tropism testing) has been included. None of these tests First-generation ELISA used crude lysates of HIV as antigen,
are valuable without accurate quality control procedures followed by second- and third-generation tests using
for validating the results being generated. Pricing1 for each increasingly refined recombinant preparations of HIV pro-
teins to coat the plastic. Current fourth-generation tests use
1 a combination of IgG antibody capture by the immobilized
Prices are quoted from UNAIDS, UNICEF, WHO, MSF—sources and
prices of selected drugs and diagnostics for people living with HIV/ recombinant antigen and HIV antigen capture by immobi-
AIDS; http://www.unaids.org/en/inþfocus June 2004. lized antibody simultaneously in the same reaction to
123
increase sensitivity [4]. The consequent reduction in and therefore are not suited to many parts of the world
the “window period,” particularly in developing world where the prevalence of HIV is high.
areas where incident infection is frequent, is important A test that has worked well in resource-poor areas is the
for reducing the number of false-negative results. rapid HIV test. There are several of these approved for use
The mechanics of ELISA lend themselves to high by both the FDA and the WHO. The basic method requires
throughput, rapid testing with automation and thus is spotting of whole blood or serum/plasma on a test strip
the preferred screening test in the developed world. The with HIV antigen prebound (http://www.cdc.gov/hiv/
US FDA and the WHO have validated a number of these rapid_testing). Lateral chromatography of the antibodies
assays for use worldwide (see http://www.fda.gov/cber/ within the test strip and reaction with the immobilized
products/testkits/htm; http://www.who.int/diagnostics_ HIV proteins is revealed colorimetrically in a “pregnancy
laboratory/evaluations/hiv/en). The ELISA has also been test” fashion within minutes. These tests have higher than
evaluated in less developed countries with a variety of 99% sensitivity and specificity when combined with a con-
HIV subtypes and similar results for accuracy have been firmatory test such as Western blot in the developed world
obtained [3, 5]. The cost–benefit analysis of frequency of or a second rapid test in the developing world [6]. The lack
HIV testing will depend on the background risk of the pop- of sample preparation, ease of storage, simple visual read-
ulation and the background incidence in the population out, speed, and cost (US$0.47–1.30) make these tests at-
but in developed countries testing is rarely recommended tractive for use all over the world and they have been
more frequently than annually. evaluated in a number of African countries where their sen-
Despite high specificity, the use of ELISA in populations sitivity and specificity profiles have been comparable with
where the prevalence of disease is low will lead to a high results in Europe and America [5, 7, 8]. A number of algo-
proportion of positive results being false. Thus, the pre- rithms (Fig. 10.1) have been developed for confirmation
ferred testing strategy in the developed world is to confirm of rapid testing results without resorting to ELISA or West-
positive or indeterminate (an intermediate colorimetric re- ern blotting and these have been validated in different
action) results in the ELISA with a second test, Western blot. resource-poor settings [9].
This uses a similar concept to ELISA but the immobilized Other screening strategies for HIV infection have tested
antigens are first separated by size through SDS-PAGE elec- for the presence of antibodies in fluids other than blood.
trophoresis and then bound to a solid medium. Antibody Levels of IgG are much lower in urine than in plasma but a
reactivity to different-sized proteins of HIV can be deter- highly sensitive screening test for urine, similar to ELISA,
mined. The criteria for a Western blot positive test vary has a reported sensitivity of 99% and a specificity of 94%
depending on the manufacturer of the test kit and the fluid and is FDA approved [10]. A positive result should be con-
being tested. In general, sera with antibodies reactive to firmed with a standard serological ELISA. Saliva contains
gp120 and gp160 plus either gp41 or p24 must be present much higher concentrations of IgA and IgG than blood
to confirm a positive ELISA [2]. Western blots require sig- and there is an FDA-approved collection method involv-
nificant time and resources and are costly (US$11 per test), ing soaking a pad in the mouth and then testing the
Figure 10.1 Testing algorithm for use with rapid

Single test Serial Parallel testing. Pos, positive; Neg, negative; Indet,
strategy strategy strategy indeterminate.
Test 1 Test 1 Test 1 & 2
Pos Neg Pos Neg Both Both Discrepant

Pos Neg
Test 2 Test 3
Pos Neg Pos Neg
Pos Neg Pos Indet Neg Pos Neg

result result result result result result result
124
Chapter | 10 | Laboratory testing for HIV infection
adsorbed antibodies in a standard ELISA/Western blot sys- and specific method for detecting incident infection in
tem, which is extremely sensitive and specific [11]. An at-risk populations, but requires surveys in excess of
ELISA test for IgG in cervico-vaginal secretions is available. 50,000 individuals [15]. It has not been tested in re-
The principal benefit of these approaches lies in their con- source-poor areas but may be rapidly adaptable to Eastern
venience for the patient and the lessened risk of needle- Europe or China where PCR technology is already avail-
stick injury to the tester, but their reliance on ELISA for able. For all cross-sectional incidence approaches, sample
screening or confirmation make them less adaptable to sizes in the thousands are needed with an accurate knowl-
the developing world. edge of factors associated with misclassification.
Vertical transmission of HIV presents a particular diagnos- Laboratory diagnosis of HIV-2 is frequently necessary
tic challenge as placentally transfered maternal antibodies depending on geographical area, travel, and exposure his-
can persist in the neonate for as long as 18 months post- tory. Infection with HIV-2 is prevalent in West Africa and
partum [12]. Nucleic acid testing (DNA or RNA) provides in many cases, HIV-1-infected people are also infected with
the most sensitive method for diagnosing HIV in an infant. HIV-2, although it is rare in the rest of the world. The virus
At 4–6 weeks, most infants can be diagnosed using these is less transmissible, replicates more slowly, and causes a
methods. slower rate of T cell decline and there are few standardized
For epidemiological purposes, it is important to measure tests useful for management. The diagnostic testing meth-
the incidence of HIV infection in populations. Recently, odology for HIV-2 is identical to that for HIV-1, except
chronically infected individuals can be differentiated by that the serological tests are specific for antibodies against
biological changes that occur as the immune system re- HIV-2 proteins. Currently there is one commercially avail-
sponds over time to the infection [13]. The evolution of able assay for HIV-2 Western blot testing (HIVBlot 2.2-
the immune response is shown in Figure 10.2. There is a Genelabs) but no viral load test. However, HIV-2 viral load
window period of approximately 3 weeks, where HIV data can be generated by real-time RT-PCR using primers
RNA can be detected but an antibody response to the virus specific for HIV-2 [16]. There are rapid test kits and diag-
is not detectable. During the initial development of the nostic ELISA tests available specifically for HIV-2 and one
humoral response, the strength of binding and concentra- test available for diagnosis of both HIV-1 and HIV-2 simul-
tion of antibody specific for HIV increases with time. taneously [17,18], although 20–30% of HIV-1 ELISA tests
There is also a switching of the class of antibody to the vi- do not detect antibodies to HIV-2 [1].
rus. An epidemiological tool for determining incidence
rates from cross-sectional population sampling exploit
these biologic differences between incident and chroni-
cally infected individuals. Currently the only commer- MONITORING PATIENT HEALTH
cially available assay is the BED-capture EIA (BED-
CEIA), though many groups have developed their own as-
Tests for estimating T lymphocytes
says [14]. Polymerase chain reaction (PCR) of pooled
blood samples for detecting viral RNA positive samples Monitoring of the health of the immune system is accom-
before antibody has developed has been pioneered in plished with estimates of the number of CD4 T cells cir-
North Carolina, USA, and may be the most sensitive culating in a person’s bloodstream. This is the most
Figure 10.2 Biological changes that occur early

in HIV infection. HIV virus in blood increases and
falls to a viral set point (RNA, orange line); [Ab] Ab binding strength RNA anti-p24 IgG3
concentration of antibody specific to HIV Relative +
increases (Ab, light blue line). The binding N I P* POS WB
quantity
strength of antibody specific to HIV antigen
increases and plateaus (Ab binding strength,
dark blue line); switching of antibody isotype
occurs with the temporal appearance of IgG3
specific to HIV (anti-p24 IgG3, green line).
–
0 25 50 75 100 125 150 175 200 225
Days from HIV infection
125
reliable prognostic test available [19] and is the primary CD4 lymphocytes that can then be counted in a hemato-
means of deciding need for anti-viral treatment. Tests of cytometer by light microscopy. The latter uses magnetic
CD8 T cells are valuable for measuring anti-HIV cytolytic beads that are coated with anti-CD4 antibody to purify
activity as a research tool but their number has not been CD4 lymphocytes from whole blood using a magnet.
found to correlate with clinical outcome. A newer test, the PIMA POC CD4 Counter (Clondial
The value of a CD4 determination at any particular time Gmbh), consists of a disposable test cartridge containing
point is approximate, with wide confidence intervals. Thus, dried reagents. All of these “low-tech” methods correlate
the utility of testing is mainly in observing trends. The well with flow cytometry both in Europe and in the devel-
recommended interval of testing is 3–6 months (see oping world [23].
DHHS, WHO guidelines) although some national treat-
ment programs, notably Malawi, have scaled up without
widespread CD4 testing. A result markedly different from
prior results should be repeated. In addition, many factors
Routine laboratory testing
other than HIV-1 influence the CD4 count, including Most of this chapter describes in detail the laboratory test-
diurnal variation, intercurrent illness, corticosteroid use, ing unique to the diagnosis and management of HIV. How-
idiopathic lymphocytopenia, and splenectomy [1]. Of sig- ever, there are a number of routine screening tests that
nificance in some parts of the world, most notably Brazil should be repeated at intervals during the management
and Haiti, is the interaction between HIV-1 and HTLV-1 of HIV infection and these are summarized in Table 10.1
co-infection. In these patients the true level of immunosup- for a North American setting. It should be remembered that
pression is more accurately represented by a CD4 T cell the normal parameters for most of these tests have been de-
value half as high as that actually measured [20]. The veloped in North American and European populations
CD4 T cell fraction of total lymphocytes, expressed as a and will need to be adjusted to local population norms.
CD4 percentage, is sometimes used to account for varia- In addition, the differences in prevalence of opportunistic
tion in the total number of T cells but this has not been pathogens in different parts of the world (TB, HBV vs
found to correlate as accurately with risk for opportunistic HCV, Cryptococcus vs toxoplasmosis, etc.) create different
infection as the absolute count [21]. The total lymphocyte imperatives for screening.
count has been used with some success in resource-poor
areas as a surrogate for T-cell counting, although the sensi-
tivity of this strategy was found to be low in a cohort in
Uganda [22]. MONITORING VIRAL REPLICATION
The standard method in America and Europe for mea-
suring CD4 T cells is by flow cytometry. This requires a
Viral load testing
fresh blood sample and antibody reagents specific for
CD4 and CD8 that are labeled with fluorescent molecules. Assays that detect the virus itself have been developed for
The number of labeled cells present is counted by flow of two purposes—to detect incident infection earlier than pos-
individual cells past a fluorescence detector. This is expen- sible with antibody testing and, more frequently, to mon-
sive, both in equipment and in reagents (US$6–20 per itor antiretroviral therapy (ART). Antigen capture assays
test), and requires frequent calibration of the machine. that detect p24, an early viral antigen, have been evaluated
A variation on standard flow cytometry for CD4 counting for early diagnosis and monitoring of therapy and have
is leukogating. The primary advantage of leukogating is been incorporated into the strategy of antibody/antigen de-
the ability to do the analysis in a single reaction with a tection in the fourth-generation ELISA [4]. As a screening
lowered cost of reagents (<US$4 per test) but still requires tool in developed countries for early infection it has not
an expensive flow cytometer for detection. For medium been as popular as the STARHS technique or more sensitive
throughput applications, a microflow method that is nucleic acid detection methods. Limited evidence has sug-
more portable and uses smaller volumes has been devel- gested that p24 quantification (US$10 per test) may poten-
oped (Guava Technologies). Lower throughput methods tially replace nucleic acid quantification as a measure of
such as FACSCount (Becton-Dickinson) and PointCare viral load [24]. In the developing world the reliance of
(Beckman Coulter) give automated, absolute, or absolute p24 detection on ELISA-type technology has hampered
plus percentage CD4 counts, respectively, making the its widespread use for monitoring of therapy, although it
PointCare machine more useful for pediatric monitoring. has been successfully used to reduce the “window period”
Alternative, low throughput (<10 samples per day) in subtype E infections in a research study [25]. There is ev-
methods that have been developed specifically for re- idence that although the specificity of p24 testing is close to
source-limited laboratories are Cyto-Spheres (Beckman 100% the sensitivity in non-subtype B infections can be
Coulter) (US$4–8 per test) and Dynabeads (Dynal Bio- quite low [26].
tech) (US$3–5 per test). The former uses latex beads Much more widely used are tests that detect and measure
coated with anti-CD4 monoclonal antibody to “rosette” viral nucleic acid in blood and other body fluids. The most
126
Table 10.1 Pocket guide to adult HIV/AIDS treatment, January 2010
TEST COMMENT
HIV serology Sensitivity and specificity standard serology is >99%

False positives: human error
False negatives: usually “window period”
Acute HIV: HIV RNA level >10,000 copies/mL; confirm seroconversion
Rapid tests: confirm positives
CD4 Reproducibility: 95% CI ¼ 30%

False high levels—splenectomy (use CD4%) concurrent HTLV-1
Repeat every 3–6 months
%—CD4 >500 ¼ >29%, 200–500 ¼ 14–28%, <200 ¼ <14%
HIV viral load Reproducibility: 95% CI ¼ 0.3 log10 copies/mL or 50%

Repeat every 3–4 months
Repeat at 2–6 weeks after starting or changing ART, then every 3–4 months
CBC Repeat every 3–6 months; more frequently as indicated

Macrocytosis with AZT and d4T
Chemical profile Include LFT and renal function

Repeat LFT with all Pls and NNRTIs, ETOH, and hepatitis
Repeat renal function with IDV and TDF
Hepatitis screen Anti-HCV, anti-HAV anti-HbsAg (if prior vaccine) or anti-HBcAg

Abnormal LFT: get anti-HCV and HBsAg
Positive anti-HCV: get quantitative HCV
Neg anti-HBs: vaccinate for HBV
Pos HBsAg or anti-HCV: get LFTs
Neg anti-HAV: HAV vaccine routine
Fasting lipid profile Patient at risk

and glucose Baseline for ART; repeat at 3–6 months and then yearly
Toxoplasma IgG 10–15% positive in USA

If negative repeat when symptomatic or when CD4 < 100
PPD Indicated if no history of TB or prior positive PPD

Induration >5 mm is indication for INH 9 months
PAP smear Baseline, at 6 months and then annual; if “inadequate”—repeat; if atypia—refer to

gynecologist
Chest X-ray Indicated with pulmonary sx, positive PPD or history of chest disease; some do baseline
X-ray routinely
Urinary NAAT for gonorrhea “Consider” in sexually active patients

and chlamydia Repeat at 6–12-month intervals depending on risk
HLA-B 5701 test Screening for ABC treatment
Tropism assay If plan to use CCR5 antagonist (MVC)
VDRL Baseline and repeat annually in sexually active patients

Confirm positives with FTA-ABS
Renal screen Urinalysis and creatinine

If 1þ proteinuria or elevated creatinine: quantify urine protein and do renal ultrasound
G6PD level Consider: most susceptible are men of African, Mediterranean, Asian, or Sephardic Jewish
descent. If positive, avoid oxidant drugs dapsone and primaquine; ? sulfonamide
Reprinted with permission of Bartlett JG, Gallant JE. Medical management of HIV infection. Baltimore, MD: Johns Hopkins Medicine Health
Publishing Business Group; 2010; #2010 John G. Bartlett.
127
commonly used of these in the developed world is reverse- viral RNA detection by PCR behaves slightly differently
transcriptase polymerase chain reaction (RT-PCR) of viral to RNA detection by branched-chain DNA methods. The
RNA isolated from plasma (US$20–100 per test). Viral low cut-off for sensitivity is 50 copies/mL with PCR-based
RNA is extracted and transcribed to single-stranded DNA methods and 75 copies/mL with bDNA methods. Often a
and amplified by PCR. There is an ultrasensitive version persistently positive result at the very low range of PCR will
of this test that can reliably measure virus as low as 50 be below detection by bDNA. The clinical significance of
RNA copies/mL in plasma as well as a standard version these differences is unclear as patients with a persistent
with sensitivity to 400 RNA copies/mL. There are tests in but very low level of viremia do not appear to collect
development that can measure virus at levels as low as resistance mutations [29].
20 copies/mL. Sensitivity for diagnosis is excellent but spec- Evidence that the RT-PCR-, bDNA-, and NASBA-based
ificity is significantly lower than serology and therefore measurements are adaptable to non-subtype B HIV-1 is
these tests are not routinely recommended for primary limited but current studies suggest that bDNA-based mea-
screening, except for acute HIV infection [27]. The level surements may be the most reliable with subtypes A
of viral replication is very high during acute HIV infection through G [30]. Of the PCR-based tests, the Roche Amplicor
and can be used for diagnosis of early HIV infection, partic- version 1.5 demonstrated good reproducibility. Neverthe-
ularly if the assay consistently reports an elevated viral load less, the requirements for an antiseptic, dust-free environ-
of at least 100,000 copies/mL. Values below 10,000 copies/ ment, constant electricity, pure water, and significant
mL are to be viewed with suspicion in the diagnosis of acute equipment expenditure make viral nucleic acid detection
HIV [28]. Another proven technology frequently used for one of the hardest tests to introduce into resource-poor
the quantification of HIV viral loads is branched DNA laboratories. For these reasons, as well as cost, most re-
(bDNA). In this method, HIV RNA is captured by one set source-limited treatment programs have chosen to scale-
of immobilized oligonucleotides and detected by a second up without any viral load testing and rely on immunolog-
set. Amplification of the target is achieved by hybridizing ical or clinical signs and symptoms to detect failure of ART.
with a successive set of probes attached to a signaling en- However, monitoring by clinical symptoms and signs or by
zyme. A third and newer viral load testing methodology only immunologic changes has been shown to be inaccu-
is NASBA (nucleic-acid sequence-based amplification). rate in assessing those who are failing treatment [31]. There
The Nuclisens EasyQ (bioMérieux) combined proprietary remains an urgent need for development of viral detection
NASBA with real-time detection using molecular beacons methods that are useful clinically but do not require
in a single step. delicate equipment or distilled water. Detection of viral
The principal use of viral load monitoring is in monitor- DNA is extremely sensitive and DNA is a more stable
ing of therapy. It is well established in Europe and America molecule than RNA, but there are limited data on the
that those individuals with higher viral loads progress to correlation between circulating pro-viral DNA and viral
AIDS more rapidly than those with lower viral loads replication.
[19]. It is also well established in developing world practice
that the most sensitive test for detecting failure of ART is vi-
ral load. Thus, the very first sign that the virus is no longer Monitoring drug resistance
completely susceptible to the antiretroviral drugs adminis-
mutations
tered is a rising viral load rather than a falling CD4 cell
count. Initial therapy should result in a 10-fold decrease The final cornerstone of laboratory monitoring of HIV is
in viral load within 1 week of initiating therapy and a drug resistance testing. The importance of this is growing
100-fold decline by 4 weeks [1]. Successfully treated pa- as the prevalence of HIV strains resistant to ART grows and
tients should have a viral load below the limit of detection the transmission of drug-resistant strains increases. Cur-
by an ultrasensitive test at 3 months. Reasons for declines rent estimates in the USA put the frequency of new infec-
in viral loads less dramatic than these after initiation of ART tions caused by viruses with at least one major drug
may be poor adherence with therapy or viral resistance to resistance mutation at around 10–25% [32]. This figure
drugs. The standard error of viral load measurement is ap- may be reached in the developing world as antiretrovirals
proximately 0.3 log copies/mL so any change in viral load are increasingly used, although levels of adherence have
less than this is not considered significant. been sufficiently high to limit widespread drug resistance
Current practice guidelines (Department of Health and so far. The exception is common NNRTI resistance as a re-
Social Services, USA, http://www.aidsinfo.nih.gov) recom- sult of single-dose nevirapine use for prevention of verti-
mend a baseline viral load followed by regular measure- cal transmission, which is well documented [33]. The
ments every 3 months, regardless of whether the patient indications for resistance testing are growing from the
is on therapy or not. This allows a rapid response to the original FDA-approved indications for rational drug selec-
emergence of resistant virus in individuals already on drug tion in a patient on ART who has had either a less than sat-
therapy, and initiation of therapy in those with a rising viral isfactory response to a new regimen or a rising viral load
load and a falling CD4 count. It has been observed that on an established regimen [33]. It is now recommended
128
by many authorities for patients with new or chronic become invaluable for guiding therapeutic decisions. The
infections prior to selection of their first ART regimen Stanford-IAS website (http://hivdb.stanford.edu) is a valu-
(DHHS, http://www.aidsinfo.nih.gov/guidelines; IAS- able and growing resource for this information.
USA, http://www.iasusa.org). It is proposed by WHO to
monitor treatment of naı̈ve individuals by country and
regional sampling to detect the rate of drug-resistant Tests for treatment selection
viral transmission in different geographical areas of the
developing world and respond accordingly (http://www. Two new tests have been introduced since this chapter was
who.int/hiv/). last written. One, a test of the host genetics, detects the pres-
The cheapest and most commonly used test of resistant ence or absence of Human Lymphocyte Antigen allele (HLA)
mutations is genotypic (US$100–150 per test), as opposed B5701 (Labcorp, $100). A negative test for HLAB5701 has a
to the more time-consuming and laborious phenotypic 100% negative predictive value for abacavir hypersensitiv-
testing (US$800–1000 per test). Genotyping involves am- ity reactions and testing is recommended before initiation
plification of the reverse transcriptase and protease genes of abacavir. HLAB5701 is present in about 10% of Cauca-
by RT-PCR from the circulating swarm of viral RNA and sians but is present in less than 1% of Africans [39].
DNA sequencing of the major products of the amplifica- The other new test detects viral tropism (either CCR5-
tion. Currently there are two FDA-approved assays for tropic, CXCR4-tropic, or dual/mixed), which measures
the genotypic assessment for resistant virus (Trugene by the HIV co-receptor molecule preference on CD4 T cells.
Visible Genetics and ViroSeq by Applied Biosystems)[34, The only current FDA-approved entry inhibitors are
35]. The mutations are reported as amino acid substitu- CCR5 antagonists and the indication for tropism testing
tions at specific numbered codons and the interpretation is in preparation for use of one of these drugs. If CXCR4-
of drug susceptibility is aided by computer algorithms tropic virus is present, then current entry inhibitors are
using rules generated from past data, most of which have contraindicated. The test is expensive (Trofile, Monogram
been generated from sequencing of subtype B [33]. The test Biosciences; $2000), takes several weeks, and has limited
requires a viral load of at least 500 copies/mL and in most the widespread use of entry inhibitors up to now. There
cases unless the selecting drug is present or recently with- is evidence that, despite subtype differences in co-receptor
drawn, the predominant species detected will be wild-type tropism, entry inhibitors may be valuable in resource-
virus, which tends to outgrow mutated virus. Indeed, recent limited settings but their cost and the cost of tropism testing
evidence suggests that transmitted drug-resistant virus may has limited their use.
revert to wild type over time in the absence of drug selection
pressure [36]. The extraction of viral RNA, amplification by
RT-PCR, and sequencing of amplified products and their QUALITY ASSURANCE AND
analysis, requires a laboratory with stable electricity, clean
water, a highly trained staff, a dedicated laboratory man- QUALITY CONTROL
ager, and initial investment in instrumentation of well over
US$100,000. As with all clinically useful tests, QA/QC is crucial. The ac-
The phenotyping assay also involves an initial amplifi- curacy of the results of all the tests described here are
cation of the reverse transcriptase and protease genes, highly dependent upon the level of training of the techni-
which are then cloned into an HIV pseudotyping vector cal staff and the maintenance and calibration of the equip-
that is then grown in the presence of permissive tissue cul- ment. In addition, the reproducibility of testing must be
ture cells and drug. The results are easier to interpret for assured. Thus all labs performing laboratory monitoring
single agents—the virus either grows efficiently in the for HIV diagnosis and management should be part of a
drug’s presence or not, but combinations of drugs in a network where each site can check their results against a
phenotypic assay are still being evaluated [37]. The reli- panel of standards validated at other sites. In addition,
ance on tissue culture imposes the rigors of sterility upon there should be a mechanism whereby “low-tech” tests
a laboratory and this may limit its attractiveness to can be compared with “high-tech” gold standard tests at
resource-limited sites. suitable intervals. Biological standards can be purchased
There is a pressing need for more information on muta- commercially. Standards for testing in the USA are deter-
tions and mutational pathways in HIV-1 subtypes other than mined by the College of American Pathology (http://
B and correlations between codon substitutions and pheno- www.cap.org). The WHO is facilitating the establishment
typic changes in drug susceptibility [38]. As more HIV- of an electronic data monitoring system for QA/QC of
infected people are treated all over the world these data will resource-poor laboratories.
129
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antiretroviral treatment failure in
131
Chapter | 11 |
Overview of antiretroviral therapy
Susa Coffey, Paul A. Volberding
management including the design and timing of initial

INTRODUCTION combination regimens and of secondary or salvage ther-
apy. It will summarize current ARV drugs with respect to
common toxicities, resistance patterns, and drug interac-
Antiretroviral (ARV) therapy (ART) is one of the most dra-
tions, but will defer to other chapters that deal with many
matic examples of successful drug development in the history
of these topics in much more detail.
of medicine. While current ART cannot eradicate HIV infec-
The central goal of HIV therapy is maximal suppression
tion, it can reduce HIV replication to extremely low levels
of viral replication in order to allow immune recovery, and
and allow the restoration of immune function to safe (though
to prevent the selection of drug resistance mutations [1–3].
perhaps not normal) levels in the vast majority of treated per-
Successful ART must durably restore or maintain immune
sons. It thus can make possible the recovery and maintenance
of health in a previously progressive and uniformly fatal syn- competence and the control of infections and malignancies
drome. ART can, furthermore, reduce HIV transmission and that characterize the AIDS syndrome. Beyond that, ART
even prevent initial infection. The obvious benefits of ART re- should enhance and extend the healthy life span of treated
alized in wealthy economies are also seen in resource-limited individuals.
areas in which treatment increasingly is being made available. In the resource-rich world, the availability of newer ARV
Success in ART is not difficult, but does require substan- medications and new classes of ARVs has made it possible
tial resources and the careful application of principles to achieve virologic suppression even in most patients
learned from clinical trials and from treatment program de- infected with HIV resistant to multiple ARV agents or entire
velopment. Drugs that form potent multi-agent regimens drug classes [4–6]. For those patients in whom therapy
must be continuously available and affordable. Laboratory does not fully suppress viremia, ART can still dramatically
assays must be available to diagnose HIV infection and, ide- slow disease progression [7, 8]. While ART does improve
ally, to stage the illness and monitor treatment response immune function and reduce morbidity and mortality as-
and toxicity. Also important are assays used to detect sociated with HIV (most strikingly in those with lower
ARV resistance both to improve initial response and to ad- CD4 counts), control of HIV viremia unfortunately may
just regimens that have lost effectiveness. Effective ART also not result in complete normalization of immune function
requires access to healthcare providers—physicians and or complete reversal of the inflammatory state associated
others—sufficiently trained to diagnose infection, to select with HIV; this is an area of active study [9–11].
appropriate drug combinations and to initiate them at the
appropriate stage in HIV disease, and to identify treatment THE NATURAL HISTORY OF
failure. Providers must be expert in educating patients in
medication adherence and in managing ARV toxicity and HIV INFECTION
drug interactions. They must also be able to adjust regi-
mens to maintain viral suppression despite drug resistance. Untreated HIV infection results in persisting and relatively
This chapter will provide a brief review of the biology constant levels of viremia and a progressive immune attri-
of HIV therapy and the essential questions of ARV tion reflected most obviously, but only in part, by a decline
133
in the numbers of circulating CD4 T lymphocytes [12, 13]. Early targets in the HIV life cycle
The rate of CD4 cell loss varies widely among infected indi-
viduals but averages 60–80 cells/mm3 annually [14, 15]. After the viral surface glycoprotein gp120 and the cell sur-
Constitutional symptoms and serious infections and malig- face protein CD4 interact in attachment [29], the CD4
nancies arise with immune attrition, particularly when the changes its conformation to allow the engagement into this
peripheral CD4 count falls below 200 cells/mm3. Many with complex of a second cell surface protein, the co-receptor,
initial, or acute, primary HIV infection have a 1- to 2-week whose natural function is to act as a chemokine receptor,
clinical illness [16, 17]. Following recovery from any symp- either CCR5 or CXCR4 [30, 31]. The CD4–gp120–chemo-
toms of this acute phase of HIV infection, most are asymp- kine receptor complex in turn activates the viral gp41,
tomatic until much later in the disease course [18]. With which uncoils, inserts a fusion protein into the cell surface
progressing disease, some experience constitutional signs membrane, recoils while tethered to the cell, and approxi-
and symptoms—chronic or recurring fevers, malaise, weight mates the viral and cell membranes, resulting in their fusion
loss, or other evidence of chronic inflammation. Advanced [32]. The CCR5 chemokine co-receptor is the target of one
HIV disease, also termed AIDS, when the CD4 count is ARV class, the CCR5 antagonist. It is the first class directed
below 200/mm3, is punctuated by opportunistic infections at a human target. The currently available agent is maraviroc;
and malignancies that range from treatable inconveniences others are in development. The tethered uncoiled gp41 is the
to rapidly fatal and irreversible acute illnesses. While the risk target of the fusion inhibitor enfuvirtide. These “early” acting
of AIDS-related conditions increases sharply with declining drugs can actually prevent cellular HIV infection, in contrast
CD4 counts, some illnesses associated with HIV and AIDS to other available ARV drugs.
may occur at high CD4 levels (e.g. tuberculosis, non-
Hodgkin lymphoma). Additionally, a number of so-called Middle targets in the HIV life cycle
“non-AIDS” complications, such as “non-AIDS” malignan-
cies, and cardiovascular, liver, kidney, and neurocognitive dis- Following membrane fusion, the viral core enters and
ease, may occur at relatively high CD4 counts [11, 19–25]. A uncoats in the target cell cytoplasm where the viral genes
number of these complications appear to be associated with encoded on the single-strand HIV RNA genome are reverse
persistent immune activation and inflammation present in transcribed into a dual-strand DNA copy [33]. The enzyme
untreated persons with HIV infection, even at high CD4 that facilitates this, reverse transcriptase, is the target of
counts, and are incompletely reversed by ART [26, 27]. Some many ARV drugs, some structural analogs of normal nucle-
researchers have suggested that HIV infection results in osides or nucleotides [34, 35]. Other drugs that block this
what may be considered an acceleration of the normal aging enzyme, the non-nucleosides, bind to the enzyme’s active
process [26, 27]. While some individuals progress from site, but have a chemical structure that does not resemble
initial infection to death in as little as 12 months, most nucleosides [36, 37]. Reverse transcriptase inhibitors of
are relatively stable for a number of years. A very small num- both types only act following cellular infection by HIV.
ber of HIV-infected individuals maintain control of HIV By convention, the nucleosides (or nucleotides)—like re-
without medications and may survive many years with no verse transcriptase drugs—are called the NRTIs while the
apparent ill health [28]. non-nucleoside agents are called the NNRTIs.
HIV disease is staged by the CD4 count, with numbers After reverse transcription, the dual-stranded HIV DNA
above 500/mm3 considered in the normal range, while virus is incorporated into the host cell’s DNA via a process
those below 200/mm3 [3] indicate advanced disease or mediated by the viral enzyme integrase. Integrase inhibi-
AIDS. As the risk of specific opportunistic diseases corre- tors target this enzyme [38]. Raltegravir is the first available
lates closely with the CD4 count, this test is of particular integrase inhibitor; others are in development.
value in patient management. By contrast, levels of HIV vi-
remia are less predictive of disease stage, but may correlate
Late targets in the HIV life cycle
with the rate of disease progression, and may indicate
treatment failure. As the new HIV virion forms inside the cell and then buds
into the extracellular environment, trimming of the struc-
tural or gag-related proteins by HIV protease is necessary
for full infectivity. HIV protease inhibitors (PIs) target that
THE HIV LIFE CYCLE enzyme. Most PIs typically are used in combination with
low-dose ritonavir. Ritonavir is itself a PI, but in current
Reviewed in detail elsewhere, a brief summary of the HIV practice is used only as a pharmacokinetic enhancer of
life cycle focused on targets of existing drugs can help in the co-administered PI, to increase plasma levels of that
considering ARV regimen design. These targets will be con- PI and allow added potency and convenience [39]. The
sidered early, middle, or late in the life cycle, corresponding co-administration of low-dose ritonavir is commonly
to currently approved ARV drugs blocking cell entry, reverse called “boosting.” A ritonavir-boosted PI is counted as a
transcription, integration, or HIV protease processing. single drug as the ritonavir dosage is sub-therapeutic.
134
Chapter | 11 | Overview of antiretroviral therapy
Potential drug targets in the late life cycle events include gag by prior toxicity or drug resistance. Preferred combinations
protein maturation [40] and vif [41], a viral gene that ap- are co-formulations of two drugs in a single pill, with
pears to act by inhibiting innate cellular antiretroviral either lamivudine or emtricitabine as one of the agents.
factors. Co-formulation increases convenience and potentially im-
proves medication adherence [46]. NRTIs as a class may
cause lipoatrophy and lactic acidosis, though the risk of
COMPONENTS OF ARV REGIMENS these varies widely with specific NRTIs.
Achieving treatment goals through suppressing HIV replica- Lamivudine (3TC) and emtricitabine (FTC)
tion to the lowest possible levels requires the simultaneous
use of multiple ARV drugs. Most initial ARV regimens consist Lamivudine and emtricitabine are closely related NRTIs
of a dual NRTI “backbone” and a third or “cornerstone” drug and can be used interchangeably. One or the other typically
[2, 3]. Typically, the “cornerstone” drug is an NNRTI, a PI is included in a dual NRTI backbone. They are very well tol-
(usually boosted by low-dose ritonavir), or an integrase in- erated, though emtricitabine may cause patchy hyper-
hibitor. Alternative approaches, e.g. regimens composed pigmentation, particularly in dark-skinned individuals.
of three NRTIs, a PI and an NNRTI without NRTIs, or A single mutation, M184V, confers high-level HIV resis-
boosted-PI monotherapy, have been attempted but gener- tance to 3TC and FTC. Both NRTIs are also active against
ally have been less potent [42–44]. These are not currently hepatitis B virus (HBV) but in persons with HBV co-infec-
a preferred option for most patients, though additional stud- tion, should not be used without other HBV-active drugs
ies are underway. Each drug in a typical triple-drug combi- because HBV resistance commonly develops [47].
nation must be considered on its own in terms of
potency, convenience, and toxicity, but the entire regimen Dual NRTI backbones: co-formulations
must be similarly considered. Designing an optimum regi-
men must be individualized for each patient. These factors Tenofovir (TDF) plus emtricitabine (FTC)
are discussed in greater detail later in this chapter.
This is a potent and convenient one pill, once daily back-
Summarizing each ARV drug and all possible regimens
bone, and is recommended by US [2, 3] and European
of choice is beyond the scope of this review, although
guidelines [48] as the preferred NRTI combination for
Tables 11.1 and 11.2 offer a brief overview of commonly
most patients. It also is co-formulated with efavirenz as a
used agents and regimens. Excellent summaries of current
three-drug combination tablet. Tenofovir usually is well
ART information are included in guidelines published by
tolerated in short-term use but has been associated with renal
national and international organizations. In the United
toxicity; renal function should be monitored [49]. Questions
States, both the DHHS [3] and the IAS-USA [2] guidelines
of potential bone toxicity are under investigation [50, 51].
are frequently updated. The DHHS guidelines are an espe-
Tenofovir has interactions, especially with atazanavir (whose
cially extensive information resource for many aspects of
levels decrease) and didanosine (whose levels increase).
drug potency, toxicity, and interactions. The IAS-USA also
When used with didanosine, increases in CD4 counts may
publishes updated guidelines of ARV resistance testing [45],
be dampened; this combination should be avoided [52].
which are extremely useful for planning treatment. Other
Both tenofovir and emtricitabine are active against hepatitis
chapters in this book address HIV biology and important
B virus, and in persons with HIV–HBV co-infection this com-
ARV treatment issues including drug toxicity, drug resistance,
bination is recommended as part of the anti-HIV regimen in
adherence, and drug interactions. These chapters should be
to co-treat HBV infection (although emtricitabine is not ap-
consulted for this crucial information.
proved for this indication).
The HIV resistance pattern of tenofovir includes a K65R
mutation that can lead to cross-resistance with some
AN OVERVIEW OF COMMON other drugs in this class. This mutation is rare if either a thy-
COMPONENTS OF ARV REGIMENS midine analog, or a potent “cornerstone” drug is co-
administered [53]. Thymidine analog mutations (TAMs)
may decrease the potency of tenofovir.
Initial ARV regimens typically comprise a dual NRTI “back-
bone” and a third or “cornerstone” drug [2, 3].
Abacavir (ABC) plus lamivudine (3TC)
This one pill, once daily co-formulation, also has had ex-
NRTIs
tensive clinical application [54]. Abacavir is a potent
Of all possible two-drug NRTI combinations, several are non-thymidine NRTI with no significant drug interactions.
commonly prescribed, while others are to be avoided It is well tolerated in long-term use but may cause an
and yet others can be useful in specific situations affected occasionally severe hypersensitivity reaction in early use
135
Section | 2 |
136
Table 11.1 Antiretroviral drugs in common use
DRUG CLASS GENERIC COMMON DOSE IN COMMON DOSING IN ADULTS COMMENTS

DRUG NAME ABBREVIATION FORMULATION
Nucleoside/nucleotide Potential class adverse effects: lipoatrophy (especially D4T, ZDV), lactic acidosis
reverse transcriptase Dosage must be adjusted in persons with renal impairment (abacavir is an exception)
inhibitor (NRTI)

Lamivudine 3TC 150-, 300-mg tabs 300 mg once daily or May be used interchangeably
(also available in two fixed dose 150 mg b.i.d. with FTC; a recommended agent
combinations, one with ZDV, one for NRTI backbones.
with ABC and one with both ABC Well tolerated.
and ZDV in resource-limited Low genetic barrier to resistance.
settings (RLS), available in various Active against hepatitis B (HBV)
generic co-formulations) but resistance quickly develops if
used as HBV monotherapy. In
persons with HIV/HBV
co-infection, should be used
along with TDF or another HBV
therapy, and as part of fully
suppressive anti-HIV ART
regimen. HBV may flare if
discontinued
Emtricitabine FTC 200-mg caps 200 mg once daily May be used interchangeably
(also available in two fixed dose with 3TC; a recommended agent
combinations, one with TDF, and for NRTI backbones.
one with both TDF and EFV) Low genetic barrier to resistance.
Well tolerated.
May cause hyperpigmentation,
especially in dark-skinned
persons.
Active against HBV—see 3TC
for cautions
Tenofovir TDF 150-, 200-, 250-, 300-mg tabs 300 mg once daily A recommended agent for NRTI
Also oral powder (also available in backbones (with FTC or 3TC).
three fixed dose combinations, one May cause renal toxicity.
with FTC, one with both FTC and Active against hepatitis B, and
EFV, and one with both FTC and hepatitis B may flare if
RPV) discontinued.
Combination of TDF þ ddI may
impair CD4 recovery; may have
reduced potency
Chapter | 11 |
Abacavir ABC 300-mg tabs 300 mg b.i.d. or 600 mg Can cause rash; also systemic
(also available in two fixed dose once daily hypersensitivity reaction in
combinations, one with 3TC, and persons at risk (HLA B5701
one with both 3TC and ZDV) positive) that can be fatal if drug
not stopped or if it is reinitiated
after initial reaction. Screen for
HLA B5701 before treatment.
May increase risk of myocardial

infarction.
May be less potent than TDF in
persons with pretreatment HIV
RNA >100,000 copies/mL
Zidovudine ZDV, AZT 100-mg caps, 300-mg tabs 300 mg b.i.d. Common adverse effects:
(also available in two fixed dose anemia, macrocytosis, fatigue,
combinations; one with 3TC, nausea, lipoatrophy.
another with both 3TC and ABC; in Must be used b.i.d.
RLS, available in various generic co- Should not be used with d4T
formulations)
Stavudine d4T 15-, 20-, 30-, 40-mg caps 40 mg b.i.d. if >60 kg; Common adverse effects:
(in RLS, available in various 30 mg b.i.d. if <60 kg peripheral neuropathy,
generic co-formulations) lipoatrophy, lactic acidosis,
pancreatitis; more common when
used with ddI.
Should not be used with ZDV
Didanosine ddI 125-, 200-, 250-, 400-mg 400 mg once daily if Taken ½ hour before or 2 hours
enteric-coated caps >60 kg; after a meal.
(in RLS, available in various 250 mg once daily if See caution with d4T. Reduce
genetic formulations) <60 kg or if used with TDF dose when used with tenofovir.
May increase risk of myocardial
infarction.
Inferior efficacy in several ART
combinations.
Combination of TDF þ ddI may
impair CD4 recovery
Non-nucleoside Adverse effects: rash (usually transient but may be severe, including Stevens–Johnson syndrome)
reverse transcriptase Many drug–drug interactions.
inhibitor (NNRTI) Low genetic barrier to resistance (especially EFV, NVP, RPV), extensive cross-resistance
Continued
137
Section | 2 |
138
Table 11.1 Antiretroviral drugs in common use—cont’d

Efavirenz EFV 50-, 200-mg caps; 600-mg tabs 600 mg once daily Low genetic barrier to resistance.
(also available in a fixed dose Common adverse effects: vivid
combination, with FTC and TDF) dreams, sleep disturbance,

dizziness, mood perturbation,
usually transient; hyperlipidemia.
Can cause teratogenicity.
Take on empty stomach, usually
at bedtime
Nevirapine NVP Immediate release (IR): 200-mg 200 mg once daily for first Low genetic barrier to resistance.
tabs 14 days, then 200 mg Can cause hepatotoxicity,
(in RLS, available in various generic b.i.d. (IR) or 400 mg once especially in those with higher
co-formulations) daily (XR) pretreatment HIV CD4 counts
Extended release (XR): 400-mg tabs (>250 cells/mm3 in women,
>400 cells/mm3 in men) or
chronic liver disease; occasionally
fatal
Etravirine ETR 100-, 200-mg tabs 200 mg b.i.d. Usually used in advanced lines of
therapy. Effective against some
HIV strains with NNRTI resistance;
resistance testing should
guide use
Rilpivirine RPV 25-mg tabs 25 mg once daily Low genetic barrier to resistance.
(also available in a fixed dose For use in initial therapy.
combination, with FTC and TDF) Compared with EFV: higher rate
of virologic failure in patients with
baseline HIV RNA >100,000
copies/mL; more resistance in
those with virologic failure;
fewer adverse effects
Protease inhibitor (PI) Potential class adverse effects: dyslipidemia, fat distribution abnormalities, hyperglycemia, nausea, diarrhea, hepatotoxicity,
possible cardiovascular risk.
Many drug–drug interactions.
High genetic barrier to resistance (RTV-boosted PIs)
RTV boosting: low-dose ritonavir can be co-administered with most PIs as a pharmacokinetic “booster”; some PIs require ritonavir boosting,
and interactions with some other drugs may require that ritonavir be used
Chapter | 11 |
Atazanavir ATV 100-, 150-, 200, 300–mg caps • 300 mg once daily Usually well tolerated; little lipid
with RTV 100 mg or GI effect. Causes elevated
once daily. indirect bilirubin levels.
• 400 mg once daily Must be boosted by ritonavir
(without RTV) when used with tenofovir.
Gastric acid lowering medications
(especially proton pump
inhibitors) interfere with

absorption
Darunavir DRV 75-, 150-, 400-, 600-mg tabs • 600 mg b.i.d. with Usually potent in HIV moderately
RTV 100 mg b.i.d. resistant to other drugs in PI class.
• If no DRV resistance May cause rash
mutations, 800 mg
once daily with
ritonavir 100 mg
once daily
Fosamprenavir FPV, f-APV 700-mg tabs • 1400 mg once daily May cause rash, GI disorders,
with RTV 200 mg hyperlipidemia
once daily.
• 700 mg b.i.d. with
100 mg RTV b.i.d.
• 1400 mg b.i.d.
(without RTV)
Indinavir IDV 100-, 200-, 333-, • 800 mg b.i.d. with Adverse effects common:
400-mg caps RTV 100–200 mg hyperbilirubinemia, retinoid-like
b.i.d. effects, renal stones, GI disorders,
metabolic abnormalities. Should
be taken with extra hydration
Lopinavir/ LPV/rtv 200-mg LPV/50-mg RTV tabs, • 400/100 mg b.i.d. Can cause GI disorders,
ritonavir 100-mg LPV/25-mg RTV tabs • If treatment naı̈ve, hyperlipidemia, cardiac
may give 800/ conduction abnormalities.
200 mg once daily. Increase to 500/125 mg b.i.d. if
combined with EFV or NVP
Nelfinavir NFV 250-, 625-mg tabs • 1250 mg b.i.d. Diarrhea is common.

Less potent than RTV-boosted PIs
Continued
139
Section | 2 |
140
Table 11.1 Antiretroviral drugs in common use—cont’d

Ritonavir RTV 100-mg tabs or caps • 100–200 mg once Used as pharmacokinetic booster
daily—b.i.d. as boost for several other PIs; not used as
for other PI (dosage sole PI (because GI disorders,

depends on the hyperlipidemia are common).
specific PI) Many drug–drug interactions
Saquinavir SQV 500-mg tabs, 200-mg caps • 1000 mg b.i.d. with May cause GI disorders,
RTV 100 mg b.i.d. hyperlipidemias, cardiac
conduction abnormalities
Tipranavir TPV 250-mg caps • 500 mg once daily Approved only in salvage therapy.
with 200 mg RTV Must be ritonavir boosted. Can
cause hepatotoxicity, GI
disorders, hyperlipidemia, rash.
Not for use in patients with
moderate/severe hepatic
insufficiency
Integrase inhibitor Raltegravir RAL 400-mg tabs • 400 mg b.i.d. Low genetic barrier to resistance.
Few recognized adverse effects or
drug–drug interactions (rifampin
is an exception).
Limited data in combination with
NRTIs other than TDF/FTC
CCR5 antagonist Maraviroc MVC 150-, 300-mg tabs • Dosage depends on Only effective in patients with
co-administered exclusive CCR5 tropism; must test
ARVs and other tropism before giving maraviroc.
medications Limited data in combination with
NRTIs other than ZDV and 3TC.
MVC levels may be affected by
co-administered medications
Fusion inhibitor Enfuvirtide T-20 Vial of 108 mg lyophilized powder • 90 mg s.q. b.i.d. Commonly causes injection site
reconstituted with 1.1 mL reactions
sterile water
Table 11.2 Common antiretroviral regimens using FDC backbones for initial therapy
REGIMEN ADVANTAGES DISADVANTAGES OF THE REGIMENa
NRTI backbone: TDFþFTC NRTI considerations
[TDFþFTC]þEFV All once daily in one combination pill. Two drugs with low resistance barrier.
Extensive data demonstrating efficacy. Avoid EFV in first trimester of pregnancy or in women who
Per US guidelines, a recommended may become pregnant
regimen for initial therapy
[TDFþFTC]þNVP Low pill burden (2 pills). Two drugs with low resistance barrier
NVP effective in preventing HIV
transmission in pregnant women.
Can be once daily (with NVP XR
formulation)
[TDFþFTC]þRPV All once daily in one combination pill Two drugs with low resistance barrier.
Low incidence of adverse effects Compared with [TDFþFTC]þEFV, higher rate of virologic
failure in those with baseline HIV RNA >100,000 copies/mL;
more resistance in those with virologic failure.
Little information available on interactions with other
drugs
[TDFþFTC]þATV/rtv All once daily, low pill burden (3 pills).

Per US guidelines, a recommended
[TDFþFTC]þDRV/rtv Can be once daily if no DRV-associated

resistance mutations.
[TDFþFTC]þLPV/rtv Can be once daily More pills and greater risk of adverse effects than in
recommended combinations
[TDFþFTC]þSQV/rtv No once daily option.

More pills and greater risk of adverse effects than in
[TDFþFTC]þFPV/rtv Can be once daily in More pills and greater risk of adverse effects than in
initial therapy recommended combinations
[TDFþFTC]þIDV/rtv No once daily option.

Likely has greater toxicity than other regimens
[TDFþFTC]þNFV No once daily option.

[TDFþFTC]þRAL Well tolerated. Two drugs with low resistance barrier; RAL is b.i.d.
Few drug–drug interactions.
[TDFþFTC]þMVC MVC effective only against CCR5 tropic virus; tropism

testing must be done before starting MVC.
Limited experience with this combination.
MVC is b.i.d.
Continued
141
Table 11.2 Common antiretroviral regimens using FDC backbones for initial therapy—cont’d
NRTI backbone: ABCþ3TC ABCþ3TC (compared to TDFþFTC) may have higher rates
of early virologic failure in patients with baseline viral load
>100,000 copies/mL
[ABCþ3TC]þEFV All once daily, low pill burden (2 pills). Two drugs with low resistance barrier.
Substantial data show efficacy Both ABC and EFV can cause rash.
Avoid EFV in first trimester of pregnancy or in women who
may become pregnant
[ABCþ3TC]þNVP Low pill burden (3 pills). Two drugs with low resistance barrier.
Can be once daily (with NVP XR Both ABC and NVP can cause rash
formulation)
[ABCþ3TC]þATV/rtv All once daily, low pill burden (3 pills)
[ABCþ3TC]þATV All once daily; avoids RTV. Lower genetic barrier to resistance than ATV/rtv
Low pill burden (3 pills)
[ABCþ3TC]þLPV/rtv Can be once daily if no See Table 11.1 for LPV/rtv considerations.
LPV/rtv resistance More pills; greater risk of adverse effects than in
recommended combinations, especially with once daily
dosing
[ABCþ3TC]þSQV/rtv No once daily option.

[ABCþ3TC]þFPV/rtv Can be once daily in Both ABC and FPV can cause rash.
initial therapy More pills and greater risk of adverse effects than in
[ABCþ3TC]þDRV/rtv Can be once daily if no Both ABC and DRV can cause rash
DRV resistance
[ABCþ3TC]þIDV/rtv No once daily option.

[ABCþ3TC]þNFV No once daily option.

[ABCþ3TC]þRAL Few drug–drug interactions. Limited clinical experience with this combination.
Low pill burden (3 pills) RAL is b.i.d.
Two drugs with low resistance barrier
[ABCþ3TC]þMVC MVC effective only against CCR5 tropic virus; tropism

MVC is b.i.d.
Limited experience with this combination
NRTI backbone: ZDVþ3TC ZDV may have greater toxicity than TDF or ABC, may have
lower CD4 increases than TDF/FTC or ABC/3TC.
ZDV is b.i.d.
AZT/3TC is the preferred NRTI backbone in
pregnant women
142
Table 11.2 Common antiretroviral regimens using FDC backbones for initial therapy—cont’d
[ZDVþ3TC]þEFV Two drugs with low resistance barrier.

ZDVþ3TC is b.i.d., EFV is once daily.
Avoid EFV in first trimester of pregnancy or in women who
may become pregnant
[ZDVþ3TC]þNVP All b.i.d. Two drugs with low resistance barrier.

A preferred regimen for preventing No once daily option
mother-to-child transmission in
pregnant women
[ZDVþ3TC]þATV/rtv ZDVþ3TC is b.i.d.
[ZDVþ3TC]þDRV/rtv ZDVþ3TC is b.i.d.
[ZDVþ3TC]þLPV/rtv A preferred regimen for preventing No once daily option.

mother-to-child transmission in More pills and greater risk of adverse effects than in
pregnant women recommended combinations
[ZDVþ3TC]þSQV/rtv No once daily option.

[ZDVþ3TC]þFPV/rtv No once daily option.

[ZDVþ3TC]þIDV/rtv No once daily option.

[ZDVþ3TC]þNFV Effective in preventing mother-to-child No once daily option.

transmission in pregnant women More pills and greater risk of adverse effects than in
[ZDVþ3TC]þRAL All b.i.d.

Few drug–drug interactions
[ZDVþ3TC]þMVC All b.i.d. MVC effective only against CCR5 tropic virus; tropism
No once daily option
[ZDVþ3TCþABC] Low pill burden—one pill b.i.d. Less potent than regimens with NNRTI or PI component
a
See Table 11.1 for disadvantages of individual ARVs.
Many combinations for initial ART can be constructed using available agents. Each has potential advantages and disadvantages, and the selection of
ARV regimens should be individualized. Combinations that have a high degree of efficacy, safety, tolerability, and convenience include those listed
above, all of which are recommended by current US and European guidelines (note that alternative combinations may be indicated for the
individual patient).
characterized by fever, rash, malaise, and, in extreme cases abacavir, and those testing positive should not be given
where the drug is continued or reintroduced, circulatory abacavir [3, 56]. Abacavir has been associated with adverse
collapse and death [55]. Hypersensitivity to abacavir is cardiovascular effects in some studies but not others; the
closely associated with HLA B*5701, and genetic screening possibility of cardiovascular toxicity remains under investi-
for this allele should be done before treatment with gation [57, 58]. In patients with high pre-treatment HIV
143
viral loads (>100,000 copies/mL) one study found that reg- tenofovir increases the risk of toxicity due to didanosine
imens containing abacavir–lamivudine were not as effective (dose adjustment of didanosine is required); additionally,
in suppressing HIV viremia as those with tenofovir–emtrici- various ART regimens that contain this NRTI backbone
tabine; this result has not been found consistently [59]. As have had elevated rates of virologic failure, and (in patients
mentioned above, lamivudine should not be used in per- with virologic suppression) poor CD4 increases [52, 63].
sons with HBV infection without other HBV-active drugs be-
cause HBV resistance commonly develops. Drug resistance
patterns with abacavir are similar to tenofovir with a K65R Cornerstone agents
mutation, but also seen is the L74V mutation. TAMs may
decrease the potency of abacavir.
Non-nucleoside RTIs
All NNRTIs may cause rash (occasionally severe, including
Stevens–Johnson syndrome), and have interactions with
Zidovudine (ZDV) plus lamivudine (3TC) many other medications, including other ARVs. Efavirenz
This combination was the first to be co-formulated and has and nevirapine have low genetic barriers to resistance,
had extensive use. It must be used twice daily. Zidovudine and single mutations can convey cross-class resistance.
can cause anemia, sometimes of severe grade. It also may
cause nausea, fatigue, facial and peripheral fat loss (lipo- Efavirenz (EFV)
atrophy), and other symptomatic adverse effects. Because
Efavirenz is a potent, once daily NNRTI and is the preferred
of toxicity concerns, zidovudine is not recommended in
“third agent” in many initial ARV triple-drug regimens [2,
the resource-rich world unless other options are not possible;
3, 48]. It is available in a co-formulation with tenofovir and
however, it still is commonly used in resource-constrained
emtricitabine. Short-term toxicity is usually temporary and
areas. For treatment of pregnant women, though, zidovu-
typically does not require treatment interruption. Most
dine remains the preferred NRTI, as it has been extensively
common early adverse effects are central nervous system
studied in the prevention of perinatal HIV transmission
(CNS) symptoms, including vivid dreams and neuropsy-
[60]. This combination has minimal interactions with other
chiatric symptoms. Efavirenz usually is well tolerated in
ARV drugs. Zidovudine’s resistance barrier is fairly broad. As
the long term. The resistance pattern of efavirenz overlaps
mentioned above, lamivudine should not be used in persons
that of other drugs in this class. Even single mutations, es-
with HBV without other HBV-active drugs because HBV re-
pecially K103N and Y181 C or I, commonly lead to high-
sistance commonly develops.
level resistance to nevirapine, and additional NNRTI resis-
tance mutations accumulate with time spent on a failing
Comments on other NRTIs regimen. The long serum half-life of efavirenz, on the other
hand, may allow durable activity and limited resistance se-
Stavudine (d4T) lection even with compromised adherence [64]. Impor-
tantly, because of reports of neural tube defects in infants
This thymidine analog was used extensively in the past but
of women exposed to efavirenz during early pregnancy, efa-
long-term toxicities sharply limit its use. It is strongly asso-
virenz is contraindicated in the first trimester of pregnancy
ciated with peripheral lipoatrophy, peripheral neuropathy,
and should be avoided if possible in women who may be-
and lactic acidosis. The risk of these toxicities is com-
come pregnant while taking the drug [60]. If efavirenz is
pounded when stavudine is used with didanosine, and this
used, women should be fully informed about the need
combination is contraindicated. In the resource-rich world,
for effective contraception.
stavudine is not recommended unless other ARVs cannot
be used [2, 3]. Stavudine has been widely used in generic
formulations in resource-constrained settings due to low Nevirapine (NVP)
cost, but there, too, toxicities may be severe, and WHO Nevirapine is similar in many respects to efavirenz, but may
guidelines recommend the use of alternative NRTIs, if be somewhat less potent. The original formulation typi-
possible [61]. cally is dosed twice daily; an extended release tablet for
once-daily dosing is also available. Its short-term toxicity
includes rash (potentially severe) [65] but not the CNS side
Didanosine (ddI) effects of efavirenz. Nevirapine, however, may cause an un-
Didanosine is a NRTI used once daily in an enteric-coated common but occasionally severe or even fatal hepatic hy-
formulation. It may have significant adverse effects in persensitivity reaction in the early weeks of treatment. In
longer-term use, and is not currently recommended if other some studies, this has been more common in women
NRTIs are available. Toxicities include peripheral neuropa- and in those with higher CD4 counts at nevirapine initia-
thy, pancreatitis, lipoatrophy, and lactic acidosis, especially tion (women with CD4 >250 cells/mm3, men with CD4
if used with stavudine; this combination is contraindicated, >400 cells/mm3) [66], and nevirapine should not be
particularly in pregnant women [3, 62]. Combination with started in these individuals unless expected benefits
144
outweigh risks. Nevirapine resistance overlaps that of efa- Darunavir (DRV)

virenz. Nevirapine is extensively used worldwide in co- Darunavir must be given with ritonavir boosting. Daruna-
formulated regimens, and also is widely used during preg- vir–ritonavir is used in both initial and salvage regimens,
nancy, where it reduces risk of HIV transmission to the and is active against HIV with moderate resistance to other
infant. PI agents. It may be given once daily in persons whose HIV
has no resistance to darunavir (twice daily in others). In re-
Other NNRTIs source-rich areas, it is a recommended PI for initial ART [2,
3, 48]. It is relatively well tolerated but may cause GI distur-
Etravirine (ETR) bance and hyperlipidemia [70].
Etravirine is a newer NNRTI that is active against certain
strains of HIV with resistance to efavirenz or nevirapine (re-
sistance testing should be done to guide appropriate use). Other PIs
Rilpivirine (RPV) Lopinavir (LPV)/ritonavir (RTV)
In 2011, rilpivirine was licensed for use in initial ARV regi- This co-formulated PI (the only one in this class) can be
mens in adults. It is dosed once daily. It appears to be less used once or twice daily in initial therapy. It is potent
effective than efavirenz in achieving virologic suppression but is associated with moderate GI complaints and can in-
in patients with high pretreatment HIV RNA (>100,000 crease adverse lipid profiles [69–72]. It has been associated
copies/mL), but is associated with fewer adverse effects [67]. with an increased risk of cardiovascular events [57]. It is po-
Other NNRTIs are in development. tent and has a broad resistance barrier and may be used in
initial therapy or in appropriate salvage regimens. It is the
recommended PI for use in pregnant women [60].
Protease inhibitors (PIs) Other PIs are in less common current use than those dis-
Most PIs may be pharmacologically enhanced with the co- cussed above, but each can have a place in individualized
administration of low-dose ritonavir, and some PIs require ARV regimens.
such boosting to achieve therapeutic levels. Ritonavir- Fosamprenavir (FPV) may be administered with or with-
boosted PIs generally are the preferred PIs for most pa- out ritonavir boosting. In initial therapy, boosted fosam-
tients. Ritonavir boosting typically adds both potency prenavir may be given once or twice daily [73].
and convenience, enabling less frequent administration Saquinavir (SQV) in its current formulation is given
and fewer pills per dose, but it may add adverse effects or twice daily and must be used with low-dose ritonavir
drug–drug interactions. As a class, PIs have been associated [72]. It is relatively well tolerated and may be used in initial
with both short-term and persisting gastrointestinal (GI) therapy or in appropriate salvage regimens.
distress, as well as metabolic disorders such as hyperlipid- Nelfinavir (NFV) is unique among the PIs in that it may
emia and insulin resistance. The incidence of these varies not be ritonavir boosted and is thus used alone. It is less
with the particular PI. PIs interact with many other medica- potent than boosted PIs [74]. This, and the fact that it com-
tions, including other ARVs, usually via inhibition of he- monly causes diarrhea, has limited its use except in ritona-
patic cytochrome p450 isoenzymes. Ritonavir-boosted vir-intolerant patients and during pregnancy, where it is
PIs have a broad genetic resistance barrier. Each has a char- considered quite safe [60].
acteristic set of induced mutations, described more fully in Indinavir (IDV) is rarely used because of toxicities. It can
the chapter on ARV drug resistance. cause hyperglycemia and renal disease [75]. More common
side effects include renal stones due to precipitated excreted
Atazanavir (ATZ) drug and retinoid-like cutaneous reactions [76]. Boosted
indinavir must be used twice daily, and unboosted indina-
Atazanavir is administered once daily, typically in initial vir must be used every 8 hours.
therapy, and may be used with or without ritonavir. Rito- Tipranavir (TPV) is used to treat appropriate strains of PI-
navir boosting improves drug levels without substantially resistant HIV. It must be co-administered with a relatively
increased toxicity [68]. In resource-rich areas, atazanavir– high dosage of ritonavir, and may cause more GI and liver
ritonavir is a recommended PI for initial ART [2, 3, 48]. toxicity than other PIs. It must be refrigerated.
It usually is well tolerated, and has fewer GI and lipid effects
than other PIs [69]. It commonly causes indirect hyperbi-
lirubinemia and sometimes icterus or jaundice. While this
is not a true hepatotoxicity, it may concern patients, and
Integrase inhibitors
they should be appropriately informed. Unboosted ataza- Raltegravir (RAL) is the only currently available integrase
navir should not be used with tenofovir, as its levels are re- inhibitor. It is potent against susceptible HIV strains, and
duced by that NRTI, and absorption may be reduced by the has few recognized adverse effects [77]. It may be used in
concurrent use of medications that suppress gastric acid [3]. initial therapy or in salvage regimens. Raltegravir must be
145
given twice daily [78]. It has a relatively low barrier to her wishes for once- or twice-daily treatment, and other
resistance. health conditions (e.g. hepatitis B, which may require co-
Other integrase inhibitors are in development. treatment, or hyperlipidemia, which may be worsened by
certain ARVs). The possibility of pregnancy should be con-
sidered in all women of reproductive age (e.g. to avoid efa-
CCR5 antagonists virenz). Also, the patient’s concern for specific side effects
Maraviroc (MVC) is the available agent in this class. It is ac- should be elicited. For example, some patients are less will-
tive only against HIV that uses the CCR5 co-receptor exclu- ing to tolerate the neuropsychiatric side effects associated
sively, and testing for co-receptor tropism must be done in with efavirenz while others may not tolerate diarrhea, even
order to determine whether treatment with this agent is ap- if mild, which can complicate some PIs. All possible drug
propriate. It must be given twice daily, and its dosage must interactions, both within the ARV regimen and with any
be adjusted according to co-administered medicines. It ini- other prescribed or non-prescribed drugs, must also be con-
tially was used primarily as a component of salvage therapy sidered and, when possible, avoided. Ideally, all ARV agents
but has been studied in initial therapy [79, 80]. Maraviroc in a regimen can be used simultaneously without restric-
has been less widely used in clinical practice than other tions on food or fluid intake.
classes. It has few recognized adverse effects, but long-term
safety data are lacking. Resistance to maraviroc has been de-
scribed but is not well characterized. Virologic nonresponse Pretreatment assessment
to maraviroc typically is due to the presence of the CXCR4 Testing for presence of pre-existing genetic ARV resistance
co-receptor. mutations should ideally be done before ART, and results
Other coreceptor antagonists are in development. should be considered in the design of the ARV regimen. If
abacavir is being considered, screening for HLA B*5701
Fusion inhibitors should be done (abacavir is contraindicated if positive for
this allele); if maraviroc is considered, tropism testing must
Enfuvirtide (ENF, T-20) is given subcutaneously twice daily be done (maraviroc is contraindicated if CXCR4 is present);
and commonly causes bothersome reactions at the injec- if integrase inhibitor resistance is possible, specific testing for
tion site. It is active against HIV with resistance to the other integrase resistance mutations should be obtained.
classes of ARVs and has been used in salvage regimens [81, Chronic health problems that may be exacerbated during
82]. Since newer classes of oral ARVs have become available ARV therapy such as hyperlipidemia or hyperglycemia
to treat ARV-resistant HIV, the need for enfuvirtide has should be diagnosed and appropriately managed. Also, a
declined. thorough medication history is required as ARV drugs
may lead to adverse interactions (e.g. acid blocking medi-
cations decrease the absorption of atazanavir). The drug
CLINICAL APPLICATION OF ART history should include non-prescription and illicit agents,
and herbal remedies. Underlying factors that might affect
Successful management of HIV infection requires the pre- drug absorption or metabolism should be assessed at base-
scription of a potent ARV drug combination at an appropri- line, especially renal and hepatic function. Guidelines
ate point in the disease course. This regimen must be taken for ARV use in the setting of chronic kidney disease are
correctly and continuously for many years (lifelong), to sup- available [83].
press this chronic and non-curable infection. The design of
an ARV regimen is relatively straightforward with initial ther-
apy (unless there is baseline resistance), but may become Optimal timing of initial ARV therapy
much more complex if treatment fails and drug resistance ARV therapy of very recently acquired HIV infection is of
develops, or the patient develops unexpected or severe side uncertain benefit, and the appropriate subject of ongoing
effects or drug interactions. clinical trials [84, 85]. Chronic HIV infection—generally
defined as beginning about 12 months after exposure—
should be treated well before the onset of opportunistic in-
ARV regimen design
fections or malignancies. In asymptomatic individuals,
The choice of a specific ARV regimen is an absolutely crucial treatment is guided by CD4 T lymphocyte counts and, to
one, because a good choice, individualized for that person’s a lesser degree, plasma viral loads.
needs and concerns, can result in disease recovery and du- The optimal CD4 threshold at which to start ART in asymp-
rable benefit (Table 11.2). Amongst potential regimens that tomatic persons is not clearly known, but based on recent
have appropriate potency (e.g. chosen with resistance test studies, US and international guidelines generally have
and CD4 and viral load results in mind), the choice for moved toward earlier treatment. While immunologic and
the specific patient should consider factors such as his/ clinical recovery is expected even when ARV use is delayed
146
until late disease stages, immune restoration may be less ro- response and assess prescription adherence. At the same time,
bust in those cases and life expectancy may be significantly side effects can be discussed as they contribute to longer-term
shorter [5, 6, 9–11, 20, 21, 86]. As a strategy, earlier treatment non-adherence and may be reduced by regimen alteration or
is based on an increasing understanding of the ongoing dam- symptomatic treatment. Laboratory testing shortly after ARV
age caused by HIV across the spectrum of CD4 counts, and of initiation is also useful for detecting drug toxicity. Early ad-
the long-term consequences of untreated HIV, including verse effects of ARV drugs include hepatotoxicity, dyslipide-
chronic immune activation and inflammation, and coincides mias, hyperbilirubinemia, and anemia. The frequency of
with the availability of safer and more convenient ARV op- toxicity monitoring should be driven by the specific agents
tions [87]. An additional possible benefit of earlier ART is used and individual patient considerations, and, of course,
reduction in HIV transmission to others [88–90]. any interval clinical signs or symptoms.
US and European guidelines strongly recommend ARV The goal of initial ART, reducing plasma viral load below
initiation if the CD4 count is <350 cells/mm3, with the assay detection limits, is commonly achieved within 12
urgency of ART increasing as the CD4 declines further weeks, but may require 24 weeks of treatment, especially
[2, 3, 48]. US guidelines also recommend ART in those with if the pre-treatment baseline viral load was extremely high
CD4 counts 350–500 cells/mm3 [2, 3]. In persons with high [96]. Non-adherence should be suspected if the plasma vi-
CD4 counts (e.g. >500 cells/mm3), ART initiation is of ral load fails to fall quickly, or if it plateaus above detection
unproven benefit but is the subject of investigation [3, 18, levels. Prolonged viremia in the face of ARV exposure will
91]. Current US DHHS guidelines state that 50% of their ex- result in drug resistance selection, limiting the possibility of
perts favor ART initiation in those with CD4 >500 cells/ successful ART.
mm3 [3]. Some experts advocate treating all infected persons The frequency of clinical and laboratory monitoring in
as soon as they are diagnosed, for possible individual as well patients with undetectable plasma HIV titers is variable.
as public health benefits [92, 93]. ART is strongly recom- Many practitioners ask patients to be seen every 3 to 4
mended in certain groups of patients regardless of CD4 months if all is going well. With very stable patients, this
count, such as pregnant women, those with hepatitis B interval can gradually be extended, but usually to no longer
when the hepatitis requires treatment, and those with than every 6 months. Each visit should address potential
HIV-associated nephropathy. In resource-limited settings, drug toxicity and problems specific to HIV disease. Medica-
the WHO recommends ART when the CD4 count is 350 tion adherence should be assessed and reinforced at each
cells/mm3 or clinical stage 3 or 4 disease is present [61]. visit, as should safe HIV transmission risk behaviors.
In advanced-stage HIV disease, opportunistic infections In resource-constrained settings, laboratory tests may not
(OIs) or cancers may require immediate management, be- be available, and clinical recovery is used to guide treat-
fore ART. Optimal timing of ART initiation in persons with ment decisions, with or without CD4 counts. HIV viral load
an OI is not precisely known, but data available thus far testing, although more expensive, is fundamentally impor-
suggest that for most OIs (including tuberculosis), starting tant in identifying virologic failure, and lack of access to
ART soon after the start of treatment of the OI improves sur- this testing increases the risk that treatment failure will
vival, though the incidence of immune reconstitution in- not be detected until high levels of ARV resistance have
flammatory reactions may be higher (an exception may been selected. Appropriate laboratory tests should be done
be CNS infections such as cryptococcal meningitis, in if toxicity is suspected.
which appropriate infection-specific treatment should be
well established before ART initiation) [13, 94, 95]. Pa-
tients may have other conditions that affect the timing or
choice of ARVs, e.g. pregnancy or hepatitis B infection. VIROLOGIC FAILURE
Patients should be fully informed before ARV medica-
tions are first prescribed. Patient counseling should include Current ARV regimens are sufficiently potent to suppress vi-
information on potential drug side effects, the importance remia in almost all patients (although low-level viremia
of excellent and continuous medication adherence, and the (<200 copies/mm) may be present, and does not necessar-
need for ongoing safe behaviors to prevent HIV transmis- ily signify virologic failure) [3]. If virologic suppression
sion. The patient initiating ART should have access to does not happen, possible causes should be examined.
sources knowledgeable in ARV use should questions or The most common reason for failure of initial ART is poor
concerns arise. medication adherence [46, 97]. Non-adherence can be in-
termittent or nearly continuous. It can involve the entire
regimen or only selected agents. Non-adherence can be
seen with the first doses prescribed or can occur at any later
Monitoring ART
point, even after prolonged periods of excellent adherence.
There are no definitive standards for laboratory monitoring It may reflect a lack of appropriate baseline counseling, the
of ARV therapy. Most would check the viral load within sev- onset of drug side effects, or interval substance or alcohol
eral weeks of treatment initiation to assess initial virologic misuse. It also may represent “treatment fatigue.”
147
Another possible cause of ART failure is preexisting HIV Serious side effects that require permanent avoidance of
resistance—either because the patient was infected at base- the offending drug include hypersensitivity reactions to
line with HIV already harboring drug resistance or because abacavir and idiosyncratic nevirapine hepatotoxicity. On
he/she had developed resistance on a prior ARV regimen the other hand, in most cases the early CNS side effects
(including ARVs given to prevent perinatal HIV transmis- with efavirenz or rashes with efavirenz or nevirapine are
sion). The risk of treatment failure due to resistance can temporary and the drugs can be continued. In some cases
be reduced with baseline resistance testing, if available. Al- additional medications can be used to control adverse ef-
ternatively, there may be inadequate ARV exposure due to fects. For example, zidovudine-associated anemia can be re-
malabsorption or drug interactions. The former is rare, versed at least partially by recombinant erythropoietin and
but drug interactions are common and should be avoided hyperlipidemias can be controlled, although often only
by a careful baseline drug history, again including non- partially, with diet, exercise, or statins. In these cases, the
prescription products. Of non-ARV drugs, interactions ARV causing the side effect can either be replaced with
threatening ARV response are most common with gastric one not having the toxicity or can be continued, along with
acid blockers, especially the potent proton pump inhibitors additional medication to treat the adverse effect. Toxicity
and with antituberculosis therapy, where rifamycin interac- that is chronic and potentially irreversible includes stavu-
tions with protease inhibitors are common [3]. dine-associated peripheral lipoatrophy or neuropathy.
Regardless of the cause, ARV drug resistance often accom- With these, the offending ARV should be replaced with
panies virologic failure, and certain mutations in each of an appropriate alternative.
the ARV classes cause extensive cross-resistance within It is important to consider the impact of “minor” but
the class. Resistance testing should be performed in every chronic treatment side effects. Over time, these can lead
case of insufficient suppression or rebound, if possible. Vi- to non-adherence. Patients should be asked specifically
rologic failure of the first or even second regimen should about the impact of bothersome low-level gastrointestinal,
prompt an immediate reattempt to again suppress viremia CNS, or other toxicity. If present, changing to other drugs
below detection limits. As dictated by circumstances, this should be considered.
may involve adherence support or a change of one or more
drugs to reduce side effects or to correct for resistance mu-
tations. Resuppression in early failure typically is straight-
TOPICS IN “LATE” SALVAGE
forward if non-adherence is the cause and can be
corrected. Virologic failure with multiple resistance muta- ARV THERAPY
tions is much more difficult to reverse.
Each case of “late failure” is unique in terms of prior drugs
used, toxicity experienced, and drug resistance patterns seen,
Specific management approaches so broad generalizations are inescapable (and thus of lim-
in virologic failure ited practical value) in suggesting management strategies.
Given the availability of agents in new ARV classes and ad-
Non-adherence to prescribed regimen ditional ARVs in older classes, it is possible to achieve viro-
A crucial question is whether the patient stopped all medi- logic suppression in the great majority of patients with ARV-
cations or stopped only selected drugs. Also key are whether resistant virus; thus in nearly all cases a new drug regimen
non-adherence was intermittent or continuous, and whether should be designed for maximal suppression. If viral sup-
it was triggered by side effects or inconvenience. Finally and pression is not possible with available ARVs, continued
critically, it must be determined whether non-adherence therapy is usually preferred to full discontinuation.
resulted in resistance selection. Absent intolerance or resis-
tance, the ARV regimen originally prescribed can be contin-
ued if adherence can be re-established, and if significant Adding a new drug to a “failing”
resistance mutations have not yet been selected. In all cases,
regimen
the need for rigorous adherence should be stressed along
with practical advice on how this can be achieved. In patients with ongoing viremia and resistance to multiple
drugs, adding a single new ARV, whether of a new and non-
cross-resistant class (as with an integrase inhibitor or CCR5
Toxicity to selected drugs antagonist), or with less cross-resistance, like the PI daruna-
ARV side effects range in severity from minor inconve- vir, is of limited value. Unless a new ARV can be used with
niences to life-threatening (see Chapter 14 for an expanded at least one, or preferably two, other active agents, its intro-
discussion). Some are transient, others continue over time. duction is rapidly followed by drug resistance selection.
Some can be ameliorated with other medications while Guidelines, therefore, suggest the earlier use of such new
others are not treatable, and an alternative ARV must be agents to improve the likelihood of resuppression of
substituted. viremia with more durable clinical benefits [2, 3].
148
of CD4 count [61]. Clinical and/or CD4 improvements are

ARV TREATMENT APPROACHES IN then followed as evidence of treatment benefit and ART is
RESOURCE-CONSTRAINED SETTINGS continued unless either suggests treatment failure. HIV viral
load testing is of clear utility in identifying and managing
treatment failure, and should be done, if possible, if ART
There is no difference in the goals of ART in resource- failure is suspected. Appropriate laboratory tests should
limited settings, but the access to drugs and monitoring be done if toxicity is suspected.
tests may necessitate very different choices. The availabil- Each element of this discussion is changing rapidly as
ity of ARV regimens in many countries is severely limited more international funding for HIV care is reaching many
by cost issues, often consisting primarily of generic fixed- countries most affected by the HIV epidemic.
dose combinations. Secondary regimens are even more
constrained. In many countries, stavudine continues to
be used even though neuropathy and lipoatrophy are
ARVs as pre-exposure prophylaxis
common and international guidelines recommend
against its use [61]. Important drugs like PIs are too expen- Recent studies have examined the use of ARV medications
sive for common use. Initial regimens often are NNRTI in HIV-uninfected individuals to prevent HIV infection
based and PIs may not be available for salvage. Treatment through sexual exposure. One study found that pre-
of common co-infections, especially tuberculosis, also exposure prophylaxis (PrEP) using daily oral tenofovir þ
may pose problems in ART because of interactions be- emtricitabine reduced the risk of HIV in high-risk men
tween antimicrobials (particularly rifampicins) and PIs who have sex with men [98] and another showed that teno-
or NNRTIs. fovir vaginal gel, used pericoitally, reduced the rate of HIV
Laboratory tests may also be unavailable in many set- infection in heterosexual women [99]. On the other hand,
tings. CD4 testing is more widely available than HIV viral preliminary results of another clinical trial using daily oral
load testing and resistance tests are generally unavailable. tenofovir þ emtricitabine in HIV-uninfected heterosexual
While clinical criteria can be used to initiate ART, this ap- women did not show evidence of protection [100]. In each
proach may lead to late treatment of many individuals. study, participants were also given other risk-reduction in-
Current WHO Guidelines recommend ARV initiation when terventions, including counseling, condom provision, and
the CD4 falls to or below 350 cells/mm3, and in anyone STD testing and treatment. Additional studies of these and
with advanced HIV disease (WHO stage 3 or 4) regardless other prevention strategies using ARVs are under way.
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153
Chapter | 12 |
Development and transmission
of HIV drug resistance
Mark A. Wainberg, Gerasimos J. Zaharatos
inhibitor (INSTI) and has an intermediate genetic barrier

INTRODUCTION for resistance, since an accumulation of two or more muta-
tions in IN are generally required in order for this com-
HIV-1 drug resistance has emerged as a major problem that pound to lose its antiviral efficacy [18, 19].
limits the effectiveness of antiviral drugs in treatment Furthermore, differences have also been reported in re-
regimens. Many studies have shown that the development gard to the development and evolution of antiretroviral drug
and transmission of drug-resistant HIV-1 is largely a conse- resistance between subtype B HIV-1 and several group M
quence of incompletely suppressive antiretroviral regi- non-B subtypes. Non-B subtypes, e.g. subtype C HIV-1 var-
mens; HIV-1 drug resistance can significantly diminish iants, are known to possess naturally occurring polymor-
the effectiveness and duration of benefit associated with phisms at several RT and PR codons that are implicated in
combination therapy for the treatment of HIV/AIDS [1–6]. drug resistance [20, 21]. In some studies, the presence of
Resistance-conferring mutations in each of the HIV-1 reverse these polymorphisms did not significantly reduce suscepti-
transcriptase (RT), protease (PR), and integrase (IN) genes bility to ARVs in phenotypic resistance assays or limit the
may precede the initiation of therapy due to each of spon- effectiveness of an initial antiretroviral therapy regimen
taneous mutagenesis and the spread of resistant viruses for a period of up to 18 months [20, 22]. However, it has also
by sexual and other means. However, it is also generally been suggested that polymorphisms at resistance positions
believed that multiple drug mutations to any single or may sometimes facilitate selection of novel pathways leading
combination of antiretroviral agents (ARVs) are required to drug resistance, especially with incompletely suppressive
in order to produce clinical resistance to most ARVs and antiretroviral regimens [20]. This, in turn, may have impor-
that these are in fact selected following residual viral rep- tant clinical implications with respect to choice of effective
lication in the presence of incompletely suppressive drug antiretroviral therapy (ART). This warrants increased geno-
regimens [7–9]. typic surveillance on a worldwide basis, as the prevalence
In the case of the protease inhibitors (PIs) [10–12], and of non-B HIV-1 infection is increasing rapidly.
most nucleoside analog reverse transcriptase inhibitors As illustrated in Figures 12.1–12.5, it has been possible to
(NRTIs), the development of progressive high-level pheno- select numerous drug resistance mutations for all licensed
typic drug resistance follows the accumulation of primary ARVs and investigational agents such as some HIV-1 entry in-
resistance-conferring mutations in each of the HIV-1 PR hibitors [5, 6, 23]. In view of the hypervariability of HIV-1 and
and RT genes [13–15]. Non-nucleoside reverse transcrip- the inability of many current antiretroviral combinations
tase inhibitors (NNRTIs) have low genetic barriers for the to completely suppress viral replication, especially in patients
development of drug resistance and, frequently, a single with prior treatment failure, it is essential that new anti-HIV
primary drug resistance mutation to any one NNRTI may drug discovery initiatives focus on the identification of new
be sufficient to confer high-level phenotypic drug resis- therapeutic targets and the development of ARVs with more
tance to this entire class of ARVs [16, 17]. Raltegravir is robust genetic barriers for resistance and a broader spectrum
the only currently approved integrase strand transfer of activity against drug-resistant HIV-1 variants.
155
Figure 12.1 Common NRTI mutations associated

M D K L T K
with HIV drug resistance. The letter designation at
ZDV 41 67 70 210 215 219
the top of a box refers to the amino acid that is
L N R W YF QE
K L M present in the wild-type sequence of RT. The letters
ddI 41 65 67 70 74 184 210 215 219 at the bottom refer to substitutions associated with
R V V
T drug resistance. Sometimes, several different
ddC 41 65 67 69 70 74 184 210 215 219 amino acid changes at the same codon can confer
E
D
V
drug resistance, as for example both Y and F in the
3TC 44 118 184 case of position 215.
D I VI
Y
ABC 41 65 67 70 74 115 184 210 215 219
V F V
d4T 41 67 70 75 210 215 219
TMSA
TDF 41 65 67 70 210 215 219
Thymidine-associated mutaion (TAM)
Note: Tenofovir (TDF) is a nucleotide RT inhibitor (NtRTI)
Figure 12.2 Common NNRTI mutations

L K V V Y Y G
NVP 100 103 106 108 181 188 190
associated with HIV drug resistance. The letter
I N A I CI CLH A designation at the top of a box refers to the amino
K Y P acid that is present in the wild-type sequence of RT.
DLV 103 181 236 The letters at the bottom refer to substitutions
N C L associated with drug resistance. Sometimes,
L K V Y Y G P several different amino acid changes at the same
EFV 100 103 108 181 188 190 225
codon can confer drug resistance, as for example
I N I C L SA H
K Y
both C and I in the case of position 181. The novel
Multi-NNRTI 103 188 NNRTI, etravirine (ETR) can often be used to treat
resistance N L individuals whose viruses contain mutations
associated with resistance to either NVP or EFV.
However, the signature mutation that is apparently
responsible for resistance against both ETR as well
as rilpivirine (RPV), the most recently approved
member of the NNRTI family, is E138K. In all
likelihood, the E138K mutation will have the ability
to also confer cross-resistance to both NVP and
EFV, thereby eliminating the likelihood for the
successful use of NNRTIs in therapy. Accordingly, it
is important that efforts be made to prevent the
E138K mutation from arising and from being
transmitted.
GENERATION OF HIV-1 DRUG among viral strains studied in vitro [27]. Overall mutation
rates for wild-type laboratory strains of HIV-1 have been
RESISTANCE reported to range from 97 10-4 to 200 10-4 per
nucleotide for the HXB2 clonal variant of HIV-1 to as high
Resistance mutations to ARVs may arise spontaneously as a as 800 10-4 per nucleotide for the HIV-1 NY5 strain [24, 27].
result of the error-prone replication of HIV-1 and, in addi- In addition to the low fidelity of DNA synthesis by HIV-1
tion, are selected both in vitro and in vivo by pharmacolog- RT, other interdependent factors that affect rates of HIV
ical pressure [24–26]. The high rate of spontaneous mutagenesis include RT processivity, viral replication
mutation in HIV-1 has been largely attributed to the ab- capacity, viral pool size, and availability of target cells for
sence of a 3’-5’exonuclease proof-reading mechanism. infection [28–31]. It follows that an alteration in any or
Sequence analyses of HIV-1 DNA have detected several a combination of these factors might influence the develop-
types of mutations including base substitutions, additions, ment of HIV drug resistance. There are also data showing
and deletions [24]. The frequency of spontaneous muta- that thymidine analog mutations (TAMs) in RT can signif-
tion for HIV-1 varies considerably as a result of differences icantly increase the likelihood of further mutational HIV-1
156
Chapter | 12 | Development and transmission of HIV drug resistance
L K L V M M I A G V V I L
IDV 10 20 24 32 36 46 54 71 73 77 82 84 90
IRV MR I I I IL V VT SA I AFTS V M
L
RTV 10 20 32 33 36 46 54 71 77 82 84 90
FIRV F VL
G
SQV 10 48 54 71 73 77 82 84 90
IRV V S A
D N
NFV 10 30 36 46 54 71 77 82 84 88 90
FI N DS
I I
APV 10 32 46 47 50 54 73 84 90
FIRV V V LVM
F L
LPV/r 10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90
L VL P AFTS
Multi-PI 10 46 54 82 84 90
resistance
VML
Primary mutation
Secondary mutation
Significance unknown
Figure 12.3 Common PR mutations associated with HIV drug resistance. The letter designation at the top of a box refers to the amino
acid that is present in the wild-type sequence of PR. The letters at the bottom refer to substitutions associated with drug resistance.
Sometimes, several different amino acid changes at the same codon can confer drug resistance, as for example both I and L in the case
of position [46]. Resistance to darunanavir and tipranavir involve multiple combinations of the above mutations, and both these drugs
have a higher genetic barrier for resistance then other members of the PI family of drugs.
Figure 12.4 Mutations in the envelope gene

G I V Q Q N N
associated with resistance to enfuvirtide Enfuvirtide 36 37 38 39 40 42 43
(T20, Fuzeon). D V A R H T D
S M
A
Figure 12.5 Primary mutations in the integrase

Y Q N
gene associated with resistance to raltegravir. The Raltegravir 143 148 155
development of clinically significant resistance to R H H
raltegravir requires the presence of one of the H K
mutations in this Figure together with other C R
secondary mutations that, together with a primary
mutation, will increase the level of resistance while
also causing an increase in viral repliative capacity.
distributions and evolution of drug resistance; further-

more, this can happen in the presence or absence of have been developed to block RT; these are NRTIs that
concomitantly administered NRTIs [32, 33]. act to arrest DNA chain elongation by acting as competitive
inhibitors of RT and NNRTIs that act as non-competitive
antagonists of enzyme activity by binding to the catalytic
site of RT. NRTIs are administered to patients as precursor
INHIBITORS OF REVERSE
compounds that are phosphorylated to their active triphos-
TRANSCRIPTASE phate form by cellular enzymes. These compounds lack
a 3’ hydroxyl group (OH) necessary for elongation of
The RT enzyme is encoded by the HIV pol gene and is re- viral DNA. These analogs can compete effectively with nor-
sponsible for the transcription of double-stranded proviral mal deoxynucleotide triphosphate (dNTP) substrates for
DNA from viral genomic RNA. Two categories of drugs binding to RT and incorporation into viral DNA [34, 35].
157
NNRTI antiviral activity involves the binding of these is inexpensive. In the case of ZDV, increases in IC50 below
non-competitive inhibitors to a hydrophobic pocket close threefold are regarded as non-significant, while 10-to
to the catalytic site of RT [36, 37]. NNRTI inhibition re- 50-fold increases usually represent partial resistance, and
duces the catalytic rate of polymerization without affecting increases above 50-fold denote high-level resistance.
nucleotide binding or nucleotide-induced conformational Patient resistance to nucleoside analogs can often
change [38]. NNRTIs are particularly active at template po- develop independently of the dose of drug that is admin-
sitions at which the RT enzyme naturally pauses. NNRTIs istered. Tissue culture data have shown that HIV-1 resis-
do not seem to influence the competition between tance can be easily demonstrated against each of NRTIs,
dideoxynucleotide triphosphates (ddNTPs) and the natu- NNRTIs, and PIs, by gradually increasing the concentration
rally occurring dNTPs for insertion into the growing of compound in the tissue culture medium [45, 46].
proviral DNA chain [39]. Cell lines are especially useful in this regard, since HIV rep-
Both types of RT inhibitors have been shown to success- lication occurs very efficiently in such hosts. Tissue culture
fully diminish plasma viral burden in HIV-1-infected sub- selection provides an effective pre-clinical means of study-
jects. However, monotherapy with all drugs has led to drug ing HIV mutagenesis, especially since the same resistance-
resistance. Patients who receive combinations of three or conferring mutations that arise in cell culture are usually
more drugs are less likely to develop resistance, since these predictive of those that will appear clinically. Owing to
“cocktails” can suppress viral replication with much greater the high turnover and mutation rate of HIV-1, the retroviral
efficiency than single drugs or two drugs in combination. quasispecies will also include defective virions and singly
Although mutagenesis is less likely to happen in this cir- mutated drug-resistant variants that are present prior
cumstance, it can still occur, and the emergence of drug- to commencement of therapy. Multiply mutated variants
resistant breakthrough viruses has been demonstrated in appear later, because it requires time to accumulate multi-
patients receiving highly active ART [40, 41]. Furthermore, ple mutations within a single viral genome. Therefore, mul-
the persistence of reservoirs of latently infected cells repre- tiply mutated viruses are not commonly found in the
sents another major impediment to currently used antiretroviral pool of untreated patients. An exception to this
HIV chemotherapy [42]. Replication of HIV might resume involves cases of new infection with drug-resistant viruses
once therapy is stopped or interrupted and, therefore, erad- transmitted from extensively treated individuals. Patients
ication of a latent reservoir of 105 cells might take as long as with advanced infection have a higher viral load and a
60 years, a goal that is not practical with currently available broader range of quasispecies than newly infected individ-
drugs and technology [42, 43]. uals. Such patients are often immunosuppressed and may
Resistance to 3TC ((-)-2’, 3’-dideoxy-3’-thiacytidine, also have diminished ability to immunologically control
lamivudine) and emtricitabine (FTC) can develop quickly, viral replication, possibly leading to more rapid develop-
whereas resistance to other NRTIs will commonly appear ment of drug resistance.
only after about 6 months of non-suppressive therapy. Phe- Site-directed mutagenesis has shown that a variety of
notypic resistance is detected by comparing the IC50 RT mutations encode HIV resistance to both NRTIs and
(or drug concentration capable of blocking viral replication NNRTIs. Crystallographic and biochemical data have
by 50%) of pretreatment viral isolates with those obtained demonstrated that mutations conferring resistance to
after therapy. Thus, higher IC50 values obtained after NNRTIs are found in the peptide residues that make con-
months or years of treatment can reflect a loss in viral sus- tact with these compounds within their binding pocket
ceptibility to ARVs. Selective polymerase chain reaction [36, 37].
(PCR) analysis of the RT genome confirms that the number Resistance-encoding mutations to NRTIs are found in
of mutations associated with drug resistance usually in- different regions of the RT enzyme, probably due to the
creases concomitantly with increases in IC50 values. complexities of nucleoside incorporation, which involve
Mutations associated with drug resistance have been several distinct steps. These mutations can decrease RT sus-
reported in response to the use of any single NRTI or ceptibility to nucleoside analogs. A summary of primary RT
NNRTI [44]. However, not all drugs elicit the same muta- mutations has been published [44].
genic response; sensitivity and resistance patterns must It has also been shown that a family of insertion and
be considered on an individual drug basis. For example, deletion mutations between codons 67 and 70 can cause
patients on 3TC monotherapy may develop high-level, i.e. resistance to a variety of NRTIs including ZDV, 3TC, ddI,
1000-fold resistance within weeks, whereas 6 months or ddC, and d4T. Usually, these insertion mutations confer
more are often required in order for sensitivity to ZDV to multidrug resistance (MDR) when present in a ZDV-
drop by 50- to 100-fold. In contrast, HIV may appear to re- resistant background. Another less frequently observed re-
main partially sensitive, even after prolonged monotherapy, sistance mutation, K65R, has been shown to be associated
to several other commonly used nucleoside analogs: ddI with prior treatment with ABC- and tenofovir (TDF)-
(didanosine), d4T (stavudine), and ABC (abacavir). Of the containing regimens and results in reduced antiviral sus-
latter, only ABC is commonly used in Western countries to- ceptibility to both of these agents. Hence, resistance to
day, although the use of d4T, which is often toxic, continues these ARVs can develop via genetic pathways involving
in many developing country settings, mainly because it either the TAMs or K65R as hallmark drug resistance
158
mutations [47]. In recent years, the proportion of geno-

typed clinical samples containing K65R has increased from PROTEASE INHIBITORS
less than 1 to almost 4%, reflecting the increased use of
TDF in first-line treatment regimens in developed countries.
Drug-resistant viruses have been observed in the case of all
Diminished sensitivity to NNRTIs appears quickly both in
PIs developed to date [65–67]. In addition, some strains of
culture selection protocols and in patients [36, 48]. NNRTIs
HIV have displayed cross-resistance to a variety of PIs after
share a common binding site, and mutations that encode
either clinical use or in vitro drug exposure [65–67]. In gen-
NNRTI resistance are located within the binding pocket that
eral, the patterns of mutations observed with PIs are more
makes drug contact [36, 37, 39–46, 48–53]. This explains
complex than those observed with RT antagonists. First, a
the finding that extensive cross-resistance is observed among
greater number of mutations within the PR gene are re-
several approved NNRTIs. A substitution at codon 181
quired for resistance to occur. This is especially true for
(tyrosine to cysteine) (Y181C) is a common mutation that
both darunavir and tipranavir, that almost always require
encodes cross-resistance among many NNRTIs [49, 54,
a greater accumulation of the resistant mutations listed
55]. Replacement of Y181 by a serine or histidine also con-
in Figure 12.3 in order for resistance to occur, than would
ferred HIV resistance to NNRTIs [56]. A mutation at amino
be the case for any other member of the PI family of drugs.
acid 236 (proline to leucine) (P236L), conferring resistance
There is also greater variability, among PIs, in temporal pat-
to a particular class of NNRTIs that include delavirdine, can
terns of appearance of different mutations and the manner
also diminish resistance to nevirapine (NVP) and efavirenz
in which different combinations of mutations can give rise
(EFV), particularly if a Y181C mutation is also present in
to phenotypic resistance. These data suggest that the PR en-
the same virus [57]. Other important substitutions are
zyme can adapt more easily than RT to pressures exerted by
Y188C and Y188H and can also confer NNRTI resistance.
antiviral drugs. At least 40 mutations in PR have been iden-
Another drug resistance mutation, namely K103N (ly-
tified as responsible for resistance to PIs [65–67].
sine to asparagine), is commonly observed and is respon-
Certain of the mutations within the PR gene are more im-
sible for reduced susceptibility to many approved
portant than others and can confer resistance, virtually on
NNRTIs including efavirenz and nevirapine [49, 54, 55].
their own, to at least certain PIs [65–67]. One mutation, in
Substitution of K103N results in alteration of interactions
particular, D30N, is probably unique to nelfinavir (NFV),
between NNRTIs and RT. The K103N mutation shows syn-
a potent HIV PI. However, a variety of other mutations
ergy with Y181C in regard to resistance to NNRTIs, unlike
may confer cross-resistance among multiple drugs within
antagonistic interactions involving Y181C and P236L [55].
the PI family. In addition, wide arrays of secondary mutations
Recently, a mutation at position E138K was shown to en-
that, when combined with primary mutations, can cause in-
code resistance against a newer NNRTI termed etravirine
creased levels of resistance to occur have been observed. On
that has been shown to be effective in second-line thera-
the other hand, the presence of certain of these secondary mu-
peutic regimens [58]. This E138K mutation also seems to
tations on their own may not lead to drug resistance, and, in
be associated with resistance to rilpivirine, a novel NNRTI
this context, some of these amino acid changes should be
that is currently undergoing advanced clinical trials for po-
considered to represent naturally occurring polymorphisms.
tential use in first-line therapy in association with NRTIs.
In addition, it should be noted that resistance to PIs can also
Resistance to NNRTIs is also observed in cell-free enzyme
result from mutations within the substrates of the PR enzyme,
assays [52, 54, 59–61]. Both Y181I and Y188L mediate de-
i.e. the gag and gag-pol precursor proteins of HIV. A variety of
creased sensitivity to NNRTIs without affecting either sub-
studies have now shown that mutations at cleavage sites
strate recognition or catalytic efficiency, supporting the
within these substrates can be responsible for drug resistance,
idea that resistance to NNRTIs is attributable to diminished
both in tissue culture and in treated patients. However, the
ability of these drugs to be bound by RT.
full clinical significance of cleavage site mutations in regard
In recent years, a new member of the NNRTI family, etra-
to PR resistance is not understood.
virine (ETV), has been approved for use in patients with
pre-existing resistance against NVP and EFV. ETV possesses
excellent activity against viruses containing the K103N and
T181C mutations, among others, that are associated with FUSION AND ENTRY INHIBITORS
resistance against first-generation NNRTIs [62, 63]. How-
ever, the activity of ETV may be compromised by other mu- A single fusion inhibitor and a single entry inhibitor have
tations such as E138K, although it remains to be been approved for use in clinical practice. The fusion inhib-
determined whether this mutation will appear to signifi- itor is the polypeptide enfuvirtide (ENF), which is admin-
cant extent in patients who fail ETV-containing ARV regi- istered subcutaneously. The entry inhibitor is maraviroc
mens [64]. Several drug companies are now trying to (MVC), which is orally bioavailable.
develop novel NNRTIs that will hopefully have a higher ge- ENF is a 36 amino acid synthetic peptide that structurally
netic barrier for resistance than either NVP or EFV for use in mimics the heptad repeat 2 (HR2) region of gp41. It also
first-line ARV regimens. Several such compounds are now inhibits the association of HR2 with the heptad repeat
being studied in clinical trials. (HR1) of the same protein. This action impedes the
159
formation of a six-helix bundle that mediates the fusion of sensitivity to some NNRTIs while retaining susceptibility to
the HIV envelope and cell membrane. ENF is generally re- others such as nevirapine and delavirdine, NRTIs, and PIs
served for highly experienced patients who have failed all [83–85]. In contrast, the drug sensitivity of subtype C iso-
other therapies and is used in association with an opti- lates from treatment-naı̈ve patients in Zimbabwe was
mized background ARV regimen [68]. reported to be similar to that of subtype B isolates [84]. Re-
Mutations at positions 36–45 (GIVQQQNNLL) of the cent studies conducted with Ethiopian subtype C clinical
HR1 region are extremely important in the development isolates showed natural resistance to NNRTIs in one case
of resistance. Even a single amino acid substitution can and resistance to ZDV in another, due to natural polymor-
cause a significant reduction in drug susceptibility. As a phisms at positions G190A and K70R, respectively [86].
result, ENF is considered to have a low genetic barrier for Another study reported no differences in drug susceptibility
resistance. The emergence of mutations at amino acids among subtypes A, B, C, and E; subtype D viruses showed
36–45 was detected in 94% (205/218) of viruses from reduced susceptibility due to rapid growth kinetics [87].
patients experiencing virological failure while taking ENF High prevalence (i.e. 94%) of a valine polymorphism
in each of two clinical trials. The most frequent mutations (GTG) at position 106 in RT from subtype C HIV-1 clinical
were at positions 38 (47.7%, 104/218; most often V38A), isolates has also been reported [88]. In tissue culture exper-
43 (30.7%, 58/218; most often N43D), and 36 (26.6%, 58/ iments, selection of subtype C with efavirenz (EFV)
218; most often G36D) [68–70]. was associated with development of high-level (i.e. 100-
MVC is a CCR5 co-receptor inhibitor. It binds to the to 1000-fold) phenotypic resistance to all NNRTIs. This
CCR5 co-receptor of the susceptible host cell. By doing was a consequence of a V106M mutation that arose in place
so, it prevents the HIV-1 gp120 protein from interacting of the V106A substitution that is more commonly
with the CCR5 co-receptor, resulting in blockage of viral seen with subtype B viruses [88]. This V106M mutation
entry. The results of the MOTIVATE trials showed that conferred broad cross-resistance to all currently approved
MVC can be effective in the treatment of advanced HIV dis- NNRTIs and was selected on the basis of differential
ease, when combined with other ARVs, in patients whose codon usage at position 106 in RT, due to redundancy in
viruses were CCR5-tropic. MVC seems not to be effective the genetic code.
against viruses that are tropic for the CXCR4 co-receptor. Genotypic diversity and drug resistance may be particu-
Its use is limited to patients who have a laboratory assay larly relevant in establishing treatment strategies against
that confirms that their virus is CCR5-tropic. Most testing African and Asian strains. First, since many antiviral drugs
for MVC eligibility is now conducted by sequencing of have been designed based on sequences of subtype B RT
the HIV-1 env gene, although a phenotypic test is also and PR enzymes, and drug resistance profiles, if not re-
available for this purpose [71, 72]. sponses, may be different for non-B viral strains. Second,
Resistance to MVC is associated with both a complex drug resistance may develop more rapidly in resource-poor
array of mutations in the V3 loop that do not cause countries where only suboptimal therapeutic regimens are
cross-resistance to ENF as well a pre-existing minority often available. Global phenotypic and genotypic monitor-
populations of CXCR4-tropic viruses that may became pre- ing programs of non-B subtypes is warranted so as not to
dominant after treatment with MVC [73, 74]. jeopardize the outcome of recently introduced antiretrovi-
Resistance to MVC can also be attributed to viruses of dual ral strategies [89].
and/or mixed tropism in regard to CCR5 and CXCR4. It has
also been demonstrated that certain CCR5-tropic variants
may rarely be able to use complexes between MVC and
CCR5 receptors to gain entry into cells. Recently, MVC
TRANSMISSION OF HIV
had also been approved for use in treatment-naı̈ve patients. DRUG RESISTANCE
As stated, highly active ART, including drugs that inhibit

ANTIRETROVIRAL DRUG RESISTANCE the RT and PR enzymes of HIV-1, has resulted in declining
IN NON-B SUBTYPES OF HIV-1 morbidity and mortality [90]. The failure to completely
suppress viral replication allows for the development of
GROUP M genotypic changes in HIV-1 that confer resistance to each
of the major classes of antiretroviral drugs [91–93]. Cumu-
Genotypic divergence of pol gene sequences between differ- lative data now indicate that viruses containing single drug-
ent HIV-1 subtypes is only beginning to be investigated, resistance mutations can be transmitted to approximately
although the RT and PR enzymes are the main targets of 10–15% of newly infected persons in Western countries
ART [75–79]. Group O and HIV-2 viruses carry natural in which ARVs have been available for many years, with
polymorphisms Y181C and Y181I that confer intrinsic re- transmission of dual- and triple-class MDR observed in
sistance to NNRTIs [80–82]. Subtype F isolates, showing 3–5% of cases [94–97].
11% nucleotide sequence variation from subtype B and There is concern that the transmission of MDR viruses in
group M viruses, have also been reported to have reduced primary HIV-1 infection (PHI) may limit future therapeutic
160
options. Treatment failure has been observed in several capacity from a WT variant strain from the isolated source
individuals harboring MDR infections [97–99]. Some re- partner following a treatment interruption. Fitness consid-
ports have shown an impaired fitness of transmitted erations may also have been important in a WT superinfec-
MDR variants compared with wild-type infections acquired tion of an initial MDR infection and cases of subtype B
in PHI [100], and the mutations that were transmitted in superinfection following A/E infections that elicited low-
such patients persisted in the absence of treatment [100]. level viremia [103, 104].
This persistence differs from the rapid outgrowth of WT In newly infected individuals, multi-mutated viruses
viruses in established infections upon treatment interrup- conferring MDR may represent a new determinant of viro-
tion, due to the selective growth advantage and fitness of logical outcome. Persistence of MDR in the absence of
WT variants [100–102]. Taken together, these findings treatment raises serious issues regarding HIV-1 manage-
suggest that archival WT viruses may not exist in MDR ment. For recently infected MDR patients, drug resistance
infections transmitted during PHI. analysis and viral fitness may provide useful information
Several reports have also documented cases of inter- in regard to ultimate therapeutic strategies.
subtype superinfection (A/E and B) in recently infected in- It is interesting to note that the presence of the M184V
jection drug users (IDUs) [103, 104]. Other studies have mutation in reverse transcriptase, associated with high-
failed to confirm superinfection following IDU exposure, level resistance to 3TC, seems to have been associated with
suggesting that superinfection is a relatively rare event the persistence of low viral load. In two PHI cases, re-
[105, 106]. Several subsequent reports demonstrated bounds to a high level of plasma viremia occurred only
superinfection in subtype B infections. In one case, a WT at times when the M184V mutation in RT could no longer
superinfection arose following a primary MDR infection be detected. A third PHI patient maintained low plasma vi-
[107, 108]. remia over 5 years, and his virus also contained the M184V
It is important to assess the virological consequences of mutation throughout this time. In an additional individ-
transmission of drug-resistant variants in primary infec- ual, high viral loads were present at times after primary in-
tion, as well as the time to disappearance of resistant virus fection despite the M184V mutation, but virus could only
in those patients not initially treated. be isolated from this individual in co-culture experiments
Genotypic analysis indicates that a single dominant after loss of the M184V mutation [109]. These data are con-
HIV-1 species can persist for more than 2 years in circulating sistent with previous findings on loss of fitness conferred by
plasma and peripheral blood mononuclear cells (PBMCs), the M184V mutation in reverse transcriptase, alongside
regardless of route of transmission. Resistant and MDR multiple other pleiotropic effects, including diminished
infections can persist for 2–7 years following PHI. processivity, diminished rates of nucleotide excision, and
Superinfection with a second MDR strain in a patient diminished rates of initiation of reverse transcription
originally infected with an MDR strain from an identified [112–114].
source partner has also been described [109]. Despite a Other studies suggest that MDR infections have impaired
rapid decline in plasma viremia suggestive of an effective replicative capacity, leading to more efficient antiviral im-
immune response, this patient was susceptible to a second mune responses [115–118]. A relative absence of genotypic
infection, which occurred concomitantly with a dramatic changes in these viruses over time further supports the con-
rise in viral load. Other subtype B superinfections have also cept of expansion of predominant MDR quasispecies dur-
been described, as well as intersubtype A/E and B superin- ing primary infection. Recombination events can also occur
fections [103, 104, 108, 110, 111]. Most of the superinfec- in this period. It is also important to point out that the rep-
tions described have occurred in the first year following lication fitness of a given virus versus its transmission
initial infection. fitness may represent two very different concepts.
Many have attributed superinfection to co-infection dur- ART, by reducing HIV-1 replication, has been shown not
ing primary infection. Two longitudinal studies involving only to impact significantly on morbidity and mortality but
IDU populations (n ¼ 37 in both studies) indicated that su- also to reduce the spread of HIV-1 [119, 120]. Treatment
perinfection is a rare phenomenon not observed during effectiveness is hampered by the development of drug-
1–12 years of follow-up spanning 215 and 1,072 total years resistant (DR) strains, leading to virological failure [121].
of exposure [107, 108]. However, it is not known whether The transmissibility of DR strains is not fully understood
any patients were recruited within the first year of HIV-1 ex- and may differ from that of wild-type [74] strains for at least
posure in these studies. In the case of the MDR infections two reasons. One is the relative fitness of DR strains com-
cited above, identification of the source partner of infection pared with WT in the absence of therapy. Second is the de-
argues against co-infection [109]. gree to which partially active therapies can reduce viral load
Findings of HIV-1 superinfection are a matter of concern in persons harboring resistant viruses [122, 123]. As a con-
insofar as such results challenge the assumption that im- sequence of widespread use of ART in North America, the
mune responses can protect against reinfection. Of course, transmission of DR strains in recently infected individuals
the impaired viral fitness of the initial MDR infection de- increased from 3.8% in 1996 to 14% in 2000. Such an
scribed above may be a factor in permitting superinfection. increase of primary DR is of public health concern, since
The initial MDR strain showed a 13-fold impaired replicative a clear association between DR and early treatment failure
161
has been reported [97]. However, several groups in Europe of MDR HIV-1 variants, are problematic and can seri-
and Australia have reported a recent stable or decreasing ously limit the number of effective treatment options
trend in DR transmission for RT and/or PI [124, 125], that are available for long-term management of HIV
and have attributed this decline to the widespread use of infection.
suppressive triple ARV regimens since 1996. This presup- Additional strategies, in addition to new drug discov-
poses that transmission of DR variants may have previously ery programs, are urgently required to help curb the de-
been more common due to the widespread use of subopti- velopment of drug-resistant HIV-1. The best approach is
mal therapy or even monotherapy regimes prior to 1996 to use non-toxic drugs in combination to suppress viral
and the likelihood that these suboptimal regimens may replication to as great an extent as is possible. If effective
have been selected for drug resistance mutations with very drugs are not available for reasons of resistance and/or
high frequency [125]. availability, consideration could be given to the mainte-
nance of specific fitness-attenuating drug resistance mu-
tations [127, 128]. The M184V substitution in RT has
CONCLUSION been extensively studied in this regard because of its
ability to impair viral replication capacity while limiting
The accumulation of specific resistance-conferring muta- the development of subsequent drug resistance muta-
tions is associated with the development of phenotypic tions in HIV-1 RT, e.g. TAMs and the Q151M multidrug
resistance to anti-HIV drugs which can significantly di- complex resistance mutation associated with use of AZT
minish the effectiveness and longevity of ART. Cross- and d4T [129, 130]. Of course, restricted evolution of
resistance among drugs of the same class also occurs fre- drug resistance may also result from other alterations
quently and is most problematic with NNRTIs due to of RT function by M184V{112}. One recent study has
their lower genetic barrier for rapid selection of drug re- shown that viruses containing the M184V mutation are
sistance compared to other classes of ARVs. There are detected less frequently than viruses containing other
now also data indicating that cross-resistance amongst mutations associated with drug resistance in newly
NRTIs may be more widespread than initially thought infected hosts [114], perhaps because M184V compro-
[126]. Furthermore, the emergence of new drug resis- mises viral replicative capacity. Further work on these
tance mutations is helping to establish new mutant dis- and other topics is needed to improve our understanding
tributions with additional pathways for developing of HIV drug resistance in the context of clinical relevance,
cross-resistance to ARVs [127]. These new patterns of successful antiviral chemotherapy, and likelihood of trans-
cross-resistance, together with increasing transmission mission of drug-resistant viruses [131].
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167
Chapter | 13 |
Pharmacology of antiretroviral drugs
Concepta Merry, Charles W. Flexner
interventions and may result in the transmission of

INTRODUCTION resistant virus, which is more expensive and difficult
to treat.
The main role of clinical pharmacology is to describe,
There may be no discipline in modern medicine in which quantify, and predict drug concentrations and response
clinical pharmacology is more relevant than in the care of in order to design safe and effective regimens. The applica-
the HIV-infected patient. In the developed world many pa- tion of clinical pharmacology to HIV treatment is intended
tients currently take at least three antiretroviral (ARV) drugs to optimize outcomes for individual patients and to
plus medications for the prophylaxis and treatment of op- prevent the emergence of drug-resistant virus. While an indi-
portunistic infections in addition sometimes to medication vidualized approach to HIV treatment including therapeutic
for co-infections such as hepatitis B or C virus and/or a drug monitoring in selected patients may be the aim of treat-
variety of medications for the management of chronic dis- ment in the developed world and can be supported by clin-
eases such as hypertension and diabetes mellitus. In the ical pharmacology, the combination of a public health
developing world patients also take at least three ARV drugs approach to prescribing and shifting of tasks from highly
plus medications for the prophylaxis and treatment of skilled to less skilled health cadres in the developing world
opportunistic infections in addition sometimes to medica- in reality limits the impact of clinical pharmacology to
tion for co-endemic diseases such as tuberculosis (TB), informing policy and generating recommendations.
malaria, worm infestations or neglected tropical diseases Antiretroviral treatment guidelines are continuously
and/or a variety of medications for the management of updated and improved to reflect new data and novel drugs
chronic diseases such as hypertension and diabetes melli- but the pharmacological principles underlying these guide-
tus [1]. Hence the potential for complex drug–drug interac- lines tend to remain unchanged (http://www.aidsinfo.nih.
tions [2]. Selecting appropriate medications and gov/guidelines; http://www.who.int/hiv/pub/guidelines).
constructing an effective ARV regimen can be difficult in The following sections review the clinical pharmacology
this era of chronic polypharmacy. In addition to contend- of relevance to the optimal prescribing of ARV drugs.
ing with drug resistance, the clinician is faced with drug–
food effects, proper spacing of medications, drug–drug
interactions, overlapping toxicities, and patient adherence ANTIRETROVIRAL DRUGS
with the regimen.
It is essential to ensure optimal dosing for patients, as
high drug concentrations may be associated with more There are currently five classes of drugs available for the
frequent adverse effects and low drug concentrations may treatment of HIV infection:
be associated with the development of treatment failure 1. Nucleoside (NRTI) and nucleotide (NtRTI) reverse
[3, 4]. Sub-therapeutic drug concentrations can promote transcriptase inhibitors;
the emergence of resistant forms of HIV, and thus result 2. Non-nucleoside reverse transcriptase inhibitors
in treatment failure [5]. Development of resistance com- (NNRTI);
promises the response of the patient to future therapeutic 3. Protease inhibitors (PI);
169
only benefit from a smaller number of drugs used in com-

Table 13.1 Licensed antiretroviral drugs
bination. For example:
NRTI and NNRTIa PIa INSTI EI • Emtricitabine (FTC) is an analog of lamivudine

NtRTIa (3TC), and therefore these drugs should not be co-
prescribed;
AZT EFV SQV RAL T-20 • Fosamprenavir is a prodrug of amprenavir;
• Ritonavir is a potent PI with intrinsic ARV activity; it is
d4T NVP RTV MVC poorly tolerated and is now prescribed mainly to boost
3TC DLV IDV the concentrations of other PIs; and
• Resistance to any single ARV may confer cross-
ddC ETR APV resistance to other drugs in the same class, e.g. patients
who develop resistance to nevirapine may also be
ddI FPV
resistant to efavirenz [6].
FTC ATV
ABC NFV
PHARMACOKINETIC DEFINITIONS
TDF TPV
LPV/r Figure 13.1 summarizes the key pharmacokinetic parame-

ters that characterize orally administered drugs. There are
DRV limited data on the correlation between different pharma-
a
cokinetic parameters and clinical outcome for HIV-infected
NRTI, nucleoside reverse transcriptase inhibitor; NtRTI, nucleotide
patients.
reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse
transcriptase inhibitor; PI, protease inhibitor; INSTI. integrase strand • Trough concentration: the concentration of drug in the
transfer inhibitor; EI, entry inhibitor; AZT, zidovudine; EFV, efavirenz; blood immediately before the next dose is
SQV, saquinavir; RAL, raltegravir; T-20, enfuvirtide; d4T, stavudine; administered, although this does not necessarily
NVP, nevirapine; RTV, ritonavir; MVC, maraviroc; 3TC, lamivudine;
represent the lowest concentration during a dosing
DLV, delavirdine; IDV, indinavir; ddC, dideoxycytidine; ETR,
etravirine; APV, amprenavir; ddI, didanosine; FPV, fosamprenavir;
interval.
FTC, emtricitabine; ATV, atazanavir; ABC, abacavir; NFV, nelfinavir; • Minimum concentration (Cmin): the lowest
TDF, tenofovir; TPV, tipranavir; LPV/r, lopinavir/ritonavir co- concentration of drug in the blood following the
formulation; DRV, darunavir. administered dose. The lowest drug concentration
frequently occurs immediately before the next dose is
administered; for these drugs, the minimum
concentration and the trough concentration are
4. Entry inhibitors; and identical. However, some drugs such as nelfinavir
5. Integrase inhibitors. (NFV) have delayed absorption and the drug
There are over 20 different original licensed ARV prepara- concentration falls even lower following the
tions (Table 13.1). There are also a growing number of administered dose until the next dose is absorbed. Low
fixed-dose co-formulations, pediatric formulations, and ge- minimum drug concentrations may be associated with
nerically manufactured drugs. In practice the patient can increased risk of virologic failure for some ARVs [3].
Figure 13.1 A summary of the key

pharmacokinetic parameters that characterize
orally administered drugs.
Cmax= peak
Drug
concentration
Cmin
Area under the curve (AUC) = trough
IC90
Area of potential HIV replication
IC50
Dosing interval
Time
170
Chapter | 13 | Pharmacology of antiretroviral drugs
Low Cmin may also occur due to drug–drug interactions prevalence of genetic polymorphisms that result in
or non-adherence. a slower rate of clearance of NNRTIs such as
• Peak concentration (Cmax): the maximum efavirenz [8, 9].
concentration of drug measured in the blood following
the administered dose. High peak concentrations
correlate with drug toxicity for indinavir and possibly DRUG METABOLISM
ritonavir [3, 7].
• Area under the curve (AUC): measure of the total net
exposure of a patient to a drug over the dosing interval, Intracellular phosphorylation
usually based on plasma concentrations. The NRTIs are prodrugs which are converted by host cellu-
• Steady state: point at which the input mass of drug is lar enzymes in the cytoplasm to an active triphosphate. Oc-
equivalent to the mass eliminated from the body by casionally, there may be competition for intracellular
clearance during any unit of time. For a drug phosphorylation pathways by similar NRTIs; this can result
administered every half-life, this takes approximately in clinically relevant drug interactions. For example, zido-
five half-lives to achieve. vudine (azidothymidine; AZT) has been shown to impair
• Half-life: the length of time it takes for the the intracellular phosphorylation of d4T in vitro; when
concentration of drug in the plasma to fall by 50%. This these two drugs were combined in clinical trials, this com-
is important clinically, as different constituents of a bination was associated with unfavorable outcomes as
triple-drug regimen may have different half-lives. compared to using either drug without the other, or with
Therefore, if the clinician stops all drugs at the same other regimens containing two NRTIs [10].
time, the drug with the shortest half-life is eliminated Tenofovir is also a prodrug that is converted intracellu-
first, followed by the drug with the second shortest larly to the active diphosphate. Since tenofovir starts with
half-life, followed by the drug with the longest half-life. a single phosphate group, the diphosphate of this drug is
This exposes the patient’s virus sequentially to triple analogous to an NRTI triphosphate. Purine nucleoside
therapy, dual therapy, and ultimately monotherapy. phosphorylase (PNP) is an enzyme responsible in part
Drugs such as efavirenz and nevirapine have long for the catabolic metabolism of didanosine (ddI). The ac-
half-lives and may pose a significant risk for the tivity of PNP is inhibited by tenofovir and tenofovir mono-
development of resistance in these circumstances. phosphate, resulting in increased plasma concentrations
Therefore it is prudent to stop the individual of ddI [11]. Use of a reduced dose of enteric coated ddI
components of a triple regimen at different times (250 mg/day), with or without food, produces plasma
depending on the respective half-lives of the ddI concentrations similar to that achieved with standard
constituent drugs: e.g. a patient receiving a ddI dosing of 400 mg/day in the absence of tenofovir
combination of stavudine (d4T), 3TC plus [12]. Hence it is recommended to either avoid the combi-
nevirapine could stop the nevirapine on day 1 and nation of tenofovir plus ddI or to reduce the dose of ddI
continue the d4T plus 3TC for at least 2 weeks to if co-prescribed tenofovir with (http://www.aidsinfo.nih.
provide effective triple therapy as the nevirapine is gov/guidelines).
eliminated from the body. Alternatively a PI could be The combination of d4T with ddI is also no longer
introduced to provide cover during this elimination recommended as it is associated with unacceptably high
phase. The optimal interval between stopping NNRTIs levels of clinical toxicity, especially peripheral neuropathy
and the other ARV drugs in the regimen is not known. and pancreatitis.
This raises logistical issues in resource-limited settings
where patients may receive a generic formulation of
a fixed-dose combination of, for example, d4T plus
3TC plus nevirapine. For such patients, it may be DRUG TRANSPORT PROTEINS
preferable to stop the fixed-dose combination and
continue the patient on either a fixed-dose dual In addition to metabolism, which refers to chemical bio-
combination of d4T plus 3TC or individually transformation usually mediated by enzymes in the liver,
manufactured d4T plus 3TC during the elimination many drugs are subject to cellular influx or efflux mediated
phase of nevirapine. However, either approach by drug transport proteins [13, 14]. The best known of
may be unpopular locally as prescribing the these, P-glycoprotein (P-gp), is the product of the mdr1
individual component drugs or a PI increases the (multidrug resistance) gene first described as producing
drug acquisition costs and increases the complexity broad cross-resistance to certain kinds of cancer chemo-
of care in a public health setting where task shifting therapy. P-gp is expressed in epithelial cells lining the intes-
is increasing. This clinical issue is even further tinal mucosa, contributing to efflux of drugs back into the
complicated by the fact that certain ethnic groups, intestinal lumen. P-glycoprotein therefore contributes to
such as African-Americans, have an increased the low bioavailability of certain drugs, for example some
171
HIV PIs. P-gp is also present in cells making up the blood– inhibiting hepatic CYP 3A4 and thus decreasing systemic
brain barrier, and can limit central nervous system penetra- clearance [16].
tion of drugs via efflux back into the systemic circulation. Fortunately, ritonavir is much better tolerated at lower
Several HIV PIs are substrates for and inhibitors of P-gp. doses, which retain most of the CYP 3A4 inhibition of
higher-dose ritonavir. Today, ritonavir is used as a pharma-
cokinetic booster of other HIV PIs, and not for its own in-
Cytochrome P450 enzymes trinsic ARV properties. With the exception of NFV,
Cytochrome P-450 (CYP) enzymes are ubiquitous in combining a low dose of ritonavir with most available
higher vertebrates and are the major protective mechanism HIV PIs improves the concentrations of the active PI, and
for chemical detoxification of xenobiotics, and drugs. This may also allow a reduced dosing and dosing frequency of
system consists of more than 12 families of enzymes com- the co-administered drug. Aluvia/Kaletra is a fixed-dose
mon to all mammals [15]. In humans, the CYP1, CYP2, combination of the PI lopinavir with a low dose of ritonavir
and CYP3 families are primarily responsible for drug 400/100 mg twice daily, abbreviated LPV/r. (It is customary
metabolism, with the CYP3A subfamily accounting for me- to use a lower case “r” when abbreviating. The low doses of
tabolism of the largest number of drugs, including most ritonavir used as a PK enhancer, e.g. ritonavir-boosted SQV,
HIV PIs and NNRTIs. CYP450-mediated drug metabolism would be written SQV/r 1000/200 mg twice daily.) For dos-
largely takes place in the liver, although CYP enzymes are ing recommendations for ritonavir-boosted PI regimens,
also present in other sites, including the intestinal wall. please consult the websites recommended at the end of this
Intestinal drug metabolism contributes to the first-pass chapter.
metabolism of many orally administered drugs, including Cobicistat is a promising new pharmacoenhancer alter-
saquinavir (SQV). Drugs may interact with CYP450 en- native to ritonavir under development, although its toxicity
zymes in one of three ways: (1) as a substrate, (2) as an in- profile is still unclear [17].
ducer, and/or (3) as an inhibitor. Inhibitors of CYP3A4 can Patients who have failed multiple prior ARV regimens may
reduce drug metabolism in the intestinal tract and slow be treated with a combination of two different PIs plus ritona-
hepatic clearance, thus increasing systemic concentrations. vir in order to take advantage of the lack of cross-resistance
Inducers of CYP metabolism accelerate clearance and between certain PIs, and the chance to treat with two active
decrease absorption and/or systemic concentrations. agents instead of one. So-called double-boosted or dual-
boosted PI regimens utilize ritonavir to increase the concentra-
tions of two ARV drugs at the same time. The pharmacokinetics
Enzyme inhibition and boosted of such regimens may be complex and difficult to predict, since
there is the potential for both PIs to interact with ritonavir
protease inhibitor therapy and with each other and referral to drug interaction websites
Inhibitors of CYP-mediated biotransformation can be used is recommended (http://www.hiv-drug interactions.org and
to decrease the rate of hepatic clearance and increase con- http://www.hivpharmacology.com).
centrations of drugs subject to metabolism by the same
pathway. HIV PIs can be CYP inducers, inhibitors, and sub-
strates. As a consequence, these drugs can increase the con-
centrations of co-administered metabolized drugs, and are Enzyme inhibition and drug
subject to having their own concentrations increased by interactions
other CYP inhibitors. Most of the currently approved HIV
PIs are metabolized primarily by CYP3A4. The number Ritonavir not only boosts the concentrations of PIs but also
and magnitude of potential drug interactions associated the combination itself can inhibit the metabolism of other
with these agents varies widely as a function of the relative drugs metabolized by the CYP system. Therefore when ini-
potency of enzyme inhibition and induction. tiating a ritonavir-boosted PI regimen it is important to
Saquinavir was the first PI licensed for use in HIV- check all other concomitant medications to check for po-
infection in the USA. The original formulation of this drug, tential drug interactions. It is equally important to check
a hard gel capsule, had low oral bioavailability. Ritonavir, for potential drug interactions when withdrawing ritona-
the second HIV PI licensed for use in the USA, was poorly vir-boosted PI therapy as previously efficacious concomi-
tolerated at the initially recommended dose of 600 mg tant medications may be less effective in the absence of
twice daily, producing frequent nausea and vomiting. Rito- the inhibitory effect. Broadly speaking, guidance on drug
navir is a very potent inhibitor of CYP3A4, and as a result interactions resulting from inhibition of the CYP system
combined administration of SQV and ritonavir produced falls into three categories:
a mean 20-fold increase in steady-state SQV concentra- • Contraindicated—Lovastatin plus lopinavir/ritonavir
tions. Ritonavir affects SQV concentrations in two ways: as the inhibitory effects of the boosted protease
first, by improving oral bioavailability through inhibition inhibitor results in unacceptable rates of myopathy and
of intestinal CYP3A4 and possibly P-gp, and second, by rhabdomyolysis [18].
172
• Dose adjustment recommended—Amprenavir, NFV, Endemic diseases and drug

and indinavir are less potent inhibitors of CYP3A4 than interactions
ritonavir. All of these drugs increase the mean rifabutin
AUC approximately twofold, but can be co- While these principles of pharmacology apply to drug
administered if the rifabutin dose is decreased by 50%. interactions for any co-infection or co-morbidity, it is
• Careful co-prescribing and clinical monitoring—This is worth mentioning that at the time of writing there are
recommended when the magnitude of the interaction very limited data on drug interactions between ARVs
is small or when the co-prescribed drug has a wide and drugs used to treat co-endemic diseases such as
therapeutic index, e.g. co-administration of malaria. While there are limited data on co-treatment
fosamprenavir with diltiazem may increase the of HIV-TB-infected individuals there are few treatment
concentration of the calcium channel blocker and close options in resource-limited settings for patients on
clinical monitoring of the patient is recommended. second-line ARV therapy.
Enzyme induction and drug

Drug–food interactions
interactions
A number of environmental influences, besides concomi-
Enzyme induction refers to an increase in the rate of hepatic tant medications, can influence pharmacokinetics. An es-
metabolism, mediated by increased transcription of mRNA pecially important influence is food. Food can either
encoding the genes for drug-metabolizing enzymes. This increase or decrease the bioavailability of several drugs
leads to a decrease in the concentrations of drugs metabo- commonly used in HIV-infected patients. Furthermore,
lized by the same enzyme. Rifampicin is a potent inducer of drug–food interactions may require a modification of the
CYP3A4 and can result in clinically significant decreases in scheduling of administration of drugs during the day,
plasma concentrations of many concomitant medications and this can have a major effect on the quality of life of pa-
including PIs, non-nucleoside reverse transcriptase inhibi- tients. Didanosine enteric-coated capsules must also be
tors, integrase inhibitors, and entry inhibitors. It is impor- given on an empty stomach because administration with
tant to keep in mind that the doses of many concomitant food decreases bioavailability [20]. The neuropsychiatric
medications will need to be adjusted when starting or stop- effects of efavirenz are exacerbated by taking the drug with
ping enzyme inducers. Similar to the clinical recommenda- food; hence the recommendation to take following a meal.
tions for enzyme inhibitors, the dosing guidelines for Specific food restrictions of ARVs are summarized in
enzyme inducers fall into three broad categories: Table 13.2. This information must be incorporated into
• Contraindicated—e.g. rifampicin plus etravirine as
co-administration may cause significant decreases in Table 13.2 Recommendations for food for approved
etravirine concentrations and lack of clinical efficacy. antiretroviral drugs
• Dose adjustment recommended—e.g. Current
guidelines recommend increasing the dose of efavirenz TAKE TAKE ON TAKE FOLLOWING
from 600 to 800 mg daily when co-administered with WITH EMPTY A MEAL/AVOID HIGH
rifampicin to overcome the inducing effects of FOOD STOMACH FAT MEAL
rifampicin.
• Careful co-prescribing and clinical monitoring—Co- TDFa IDVb EFVa
administration of diltiazem (240 mg once daily) and
SQV ddI ETR
efavirenz (600 mg for 14 days) results in a two-way
drug interaction with decreases in diltiazem and RTV
increases in efavirenz levels, and current guidelines
recommend that diltiazem dose adjustments should be NFV
guided by clinical response but no dose adjustment of
LPV/r
efavirenz is necessary.
Many drugs exhibit complex effects on multiple CYP iso- ATV
forms and drug transporters. For example, in addition to
DRV
being inhibitors of CYP3A4, ritonavir and NFV are moder-
ate hepatic enzyme inducers. They can increase activity of FPV/r
so-called phase 2 enzymes such as hepatic glucuronosyl
transferase, as well as CYP. Both PIs decrease the AUC of TPV
the oral contraceptive ethinyl estradiol by about 40%. Pa- a
TDF and EFV can be taken with or without food.
tients taking ritonavir or NFV are advised to use alternative b
IDV can also be taken with a light, low-fat snack.
forms of birth control [19].
173
the counseling required for patients starting or modifying

many ARV regimens. This can be particularly difficult for SPECIAL POPULATIONS
patients in the resource-limited setting who may only have
one meal per day, or for patients who observe religious pe-
riods of fasting. It is important to consider these factors Renal and hepatic impairment
when prescribing ARVs. Since the majority of drugs are eliminated by renal or he-
patic clearance, diseases altering the function of these or-
gans can affect the concentrations of drugs. Table 13.3
Drug–traditional medicines lists ARVs for which the prescribing information recom-
interactions mends dose modification in the setting of renal or hepatic
impairment. It is important to continuously monitor pa-
Herbal remedies and nutritional supplements are widely tients and adjust the drug doses accordingly to any identi-
used in HIV-infected patients, although the potential fied changes in renal and hepatic function.
pharmacokinetic effects of these compounds are often In particular, patients with HIV-related renal dysfunction
ignored. Some herbal therapies contain ingredients capa- may have marked improvements in renal function once
ble of CYP inhibition or induction and have been impli- started on effective ARV therapy. For further guidelines
cated in drug interactions. For example, St John’s wort on dosing, please consult websites at the end of this
contains a potent inducer of CYP3A4, and decreases the chapter.
AUC of indinavir by over 50% [21]. There is also evidence
that St John’s wort decreases nevirapine concentrations by
a similar magnitude [22]. The mechanism of this interac- Low-weight individuals
tion appears to involve induction of both CYP3A4 and
P-gp [23]. Patients taking HIV PIs and non-nucleoside There are limited data on the optimal dosing of ARV drugs
reverse transcriptase inhibitors should be instructed to in low-weight adults. This is particularly important in mal-
avoid St John’s wort or any dietary supplement containing nourished patients with advanced HIV disease in Africa,
this herb. who may have a low body mass index, and also in many
Some nutritional supplements may also contain ingredi- Asian patients who naturally tend to have lower body
ents capable of affecting the concentrations of co- weights. It is currently recommended that the doses of
administered ARVs. Raw garlic inhibits the activity of d4T (Zerit) and ddI (Videx) be reduced in patients who
CYP3A4 in vitro and in animals [24]. One study conducted weigh <60 kg [20, 27]. It is unclear whether the dose
in healthy volunteers found that garlic capsules taken b.i.d. of ddI should be reduced to 200 mg/day in patients
for 3 weeks led to a mean decrease in the SQV AUC of ap-
proximately 50%, probably as a consequence of reduced
bioavailability [25]. Other herbs with reported in vitro ef- Table 13.3 Antiretroviral drugs whose clearance is altered
fects on CYP450-mediated metabolism include silymarin in patients with renal or hepatic insufficiency
(milk thistle), ginseng, and skullcap, although clinical
pharmacokinetic interaction data with these agents are RENAL INSUFFICIENCY HEPATIC INSUFFICIENCY
contradictory or lacking [26]. Traditional and herbal med-
icines could be added to the list of agents capable of causing ddi ABC
significant drug interactions. Clinicians could record infor-
3TC/FTC NVP
mation about use of these agents when taking medical his-
tories, and consider them when adverse events or treatment TDF ETR
failure appears with no other identifiable cause.
This is particularly important in resource-limited set- D4T SQV
tings, where the majority of patients consult traditional
NVP IDV
healers prior to or in addition to medical doctors. It is
important to include traditional healers in efforts to ex- ATV APV/FPV
pand access to ARV in resource-limited settings, as they
are key opinion leaders in the communities and have a MVC RTV
significant impact on the health belief model for pa-
TPV
tients. Furthermore, the metabolism of many compo-
nents of the traditional herbal medicines may be DRV
inhibited by drugs such as ritonavir. It is possible there-
fore, that Western medicines may be responsible for re- ATV
duced clearance and heretofore unseen side effects of RAL
traditional medicines.
174
of ddI should be reduced to 200 mg/day in patients weigh- age lower than those in the non-pregnant woman [28–31].
ing <60 kg who are also receiving tenofovir, and it may be The mechanism for the difference in pharmacokinetic pro-
prudent to avoid this combination in such patients. It is im- files during pregnancy is multifactorial. Possible contribu-
portant to continuously monitor weight, as patients who tors include induction of hepatic drug metabolizing
have been very ill may gain significant weight once they enzymes, changes in gastrointestinal transit times, in-
respond to ARV therapy. creases in body water and fat, and changes in expression
of drug transporters such as P-gp [32].
There is no evidence that pregnancy increases the risk of
Pediatrics nevirapine toxicity over that of non-pregnant women but it
Growth and development may result in rapid changes in is not recommended that nevirapine-based regimens be
the activity of some drug-metabolizing enzymes. In addi- initiated in pregnant women with CD4 counts of >250
tion, changes in body surface area and liver blood flow cells/mm3.
can alter the elimination of metabolized drugs. Other de-
velopmental changes that can effect drug concentrations
include changes in gastric function, intestinal motility, per- Ethnic variations in pharmacokinetics
centage body fat, concentrations of plasma proteins, and
The influence of genetic factors on drug metabolism and
renal function.
drug concentrations is an important area of clinical re-
Unlike the developed world, children represent a signif-
search, particularly as ARVs are being initiated in different
icant proportion of HIV-infected individuals in the devel-
geographic regions. The field of pharmacogenetics iden-
oping world. Frequently encountered problems include
tifies specific genetic polymorphisms that might explain
inaccurate dosing, unpalatable formulations, and formula-
inter-individual differences in drug concentrations. As dis-
tions that are cumbersome to administer. There are an in-
cussed above, emerging data suggest differences in drug
creasing number of pediatric formulations available for
concentrations of ARVs in certain ethnic groups.
HIV-infected children for facilitating ease of administration
for the caregivers.
CONCLUSION
Pregnancy
The current guidelines for the care of a HIV-infected Clinical pharmacology is an integral part of the manage-
woman during pregnancy and after delivery for both ment of patients with HIV infection. The increasing num-
mother and newborn child vary from country to country, ber of ARVs and the increasing availability of ARVs in
largely dictated by the local finances and healthcare resource-limited settings raises new logistical and prescrib-
delivery capacity. However, there are common basic phar- ing issues that need to be addressed in order to ensure
macological principles regardless of geography. Avoidance optimal outcomes for patients in diverse regions.
of teratogenic drugs like efavirenz during the first trimester
of pregnancy, in women who wish to become pregnant or
in women who do not use a reliable form of contraception
is recommended. In addition, the concentrations of some ACKNOWLEDGMENTS
medications may be altered during pregnancy. Available
data suggest that the concentrations of some ARVs mea- Thank you to David Burger for providing the HIV drug-
sured at various time points during pregnancy are on aver- interactions websites.
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Pharmacological Basis of Natural health product–antiretroviral
176
Chapter | 14 |
Complications resulting from antiretroviral
therapy for HIV infection
David Nolan, Simon Mallal, Peter Reiss
inhibitors (e.g. raltegravir) and CCR5 inhibitors (e.g. mara-

INTRODUCTION viroc), which thus far have proven to be safe and effective
additions to the already wide range of available treatment
The treatment of HIV infection has passed through a number options. Clinical experience with these newer agents is still
of distinct phases over the three decades of the HIV/AIDS pan- relatively limited, however, and vigilance will need to be main-
demic, accompanied by significant shifts in both patients’ tained to ensure that adverse events (for example, isolated
and clinicians’ perceptions of antiretroviral drug toxicity case reports of rhabdomyolysis [2] and CNS toxicity [3]
(Fig. 14.1). Prior to the introduction of ‘highly active antire- associated with raltegravir treatment) are reported and further
troviral therapy’ (HAART) regimens around 1996, any con- characterized where possible. It is also apparent that while the
cerns regarding long-term drug toxicities were dramatically incidence of adverse HIV drug reactions has decreased [4],
outweighed by the obvious short-term benefits and improved previous drug toxicities involving end-organ damage (for ex-
survival associated with these combination drug regimens. ample, neuropathy and lipoatrophy) can provide an ongoing
These benefits were soon realized, and the dramatic reduction burden of disease that may in turn contribute to an increased
in AIDS-related deaths following the introduction of HAART risk of diseases associated with aging. In this context, there is
regimens marks a turning point in the progression of the HIV an ongoing need not only to prevent these complications
pandemic. At the same time, however, the ‘early HAART era’ whenever possible but also to develop effective treatment
from 1996 to around 2002 was characterized by the emer- strategies for those affected by these complications of HIV
gence of antiretroviral therapy (ART)-associated adverse therapy.
events, which became an important source of morbidity Antiretroviral drug toxicities cover a broad spectrum, due
and even mortality, threatening to outweigh AIDS-related in part to the large number of drugs used for HIV treatment.
events in frequency and overall detrimental effects on quality These drug side effects will be considered in turn, with an
of life even in advanced HIV disease [1]. With evidence that emphasis on clinical management based on an under-
numerous ART regimens have comparable efficacy in the standing of individual drug toxicity profiles. The influence
treatment of HIV infection, the choice of therapy is now of host and disease-related factors in determining the risk
largely determined by the differential tolerability and risk of these adverse effects will also be considered.
of drug toxicity associated with individual HIV drugs.
We have now moved into a ‘late HAART era’, characterized
by the availability of newer-generation antiretroviral drugs ADVERSE EFFECTS OF
that combine durable potency with improved safety profiles
ANTIRETROVIRAL TREATMENT
(Fig. 14.2), in which the realistic prospect of survival with
HIV infection into old age has increasingly focused our at- IN THE EARLY PHASE OF THERAPY
tention on the prevention and management of prevalent
diseases among those who have survived with HIV infection Antiretroviral therapy complications that can occur in
for many years. This new era has also seen the introduction the early weeks of HIV treatment (i.e. within 12 weeks
of new classes of antiretroviral drugs, most notably integrase of treatment initiation) are of particular concern to
177
Pre-HAART era ‘Early’ HAART era ‘Late’ HAART era
HIV uncontrolled/poorly HIV well controlled, long- HIV well controlled, long-
controlled, poor long-term prognosis term prognosis improved term prognosis improved
High-dose mono/dual NRTI Multiple ART regimens: Multiple ART regimens:

therapy: limited treatment greater choice but uncertain greater choice of equally
options relative efficacy highly effective HAART
Issues of drug toxicity Drug toxicity assumes more Improved drug safety and
outweighed by need for importance, but efficacy tolerability, but ongoing burden
survival benefit paramount of chronic toxicity (e.g. lipoatrophy,
metabolic syndromes) leading to
prevention and treatment options
Advocacy focused on Advocacy focused on access Advocacy focused on drug

access to therapy and improved therapy tolerability, long-term outcomes
tolerability and long-term and specific management of
outcomes complications
1987 1995 2000–2002 onwards
Figure 14.1 Management priorities and perceptions through successive eras of HIV treatment.
Abacavir hypersensitivity reactions

patients and clinicians, as adverse events in the early phase
of treatment can affect patients’ perceptions of HIV Abacavir hypersensitivity reaction (HSR) was the most fre-
treatment and can result in non-adherence or treatment quent adverse event associated with use of this drug, con-
discontinuation. sistently reported in 8% of predominantly Caucasian
Mild cutaneous drug reactions can occur during the abacavir-exposed individuals in the pre-marketing phase
initial weeks of treatment, most notably associated with of development. Fortunately, more recent, widespread
non-nucleoside reverse transcriptase inhibitors (NNRTIs; genetic screening for HLA-B*5701, an allele strongly asso-
nevirapine, efavirenz, etravirine), protease inhibitors (PIs, ciated with abacavir hypersensitivity, has led to elimination
especially fosamprenavir and darunavir), and less com- of immunologically confirmed hypersensitivity. Abacavir
monly with nucleoside analog reverse transcriptase inhib- HSR is commonly characterized by constitutional and gas-
itors (NRTIs; tenofovir, or abacavir in the setting of the trointestinal symptoms (fever, malaise, lethargy, vomiting,
abacavir hypersensitivity reaction). These reactions are abdominal pain, diarrhea), with possible respiratory in-
usually maculopapular in appearance, are generally non- volvement and skin exanthema as a possible late manifes-
progressive, and may not require cessation of therapy. tation. Symptoms associated with abacavir HSR overlap
However, assessment for the presence of mucosal involve- with many other clinical syndromes associated with HIV
ment, fever, or signs of systemic involvement should be un- and ART, such as immune restoration inflammatory syn-
dertaken in order to exclude less common cases of more dromes (IRIS), opportunistic diseases, and other drug hy-
severe cutaneous drug reactions or systemic drug hypersen- persensitivity reactions (e.g. associated with NNRTIs or
sitivity reactions [5]. These more severe drug hypersensitiv- trimethoprim-sulfamethoxazole), which led to overdiag-
ity reactions occur most commonly with abacavir or nosis and false-positive clinical diagnosis of abacavir hy-
nevirapine therapy, although in both cases there have been persensitivity. Abacavir patch testing has been used as a
significant advances in understanding the pathogenesis of research tool in clinical studies to overcome this problem
these syndromes, which in turn have had a dramatic impact and by identifying true immunologically mediated abaca-
on clinical management. vir HSR (Fig. 14.3) [6].
178
Chapter | 14 | Complications resulting from antiretroviral therapy for HIV infection
Pre-HAART era ‘Early’ HAART era ‘Late’ HAART era

AZT (1987)
ddl (1991)
ddC (1992) ABC (1999)
d4T (1994) TDFTDF (2001)

(2001): Tenofovir
NRTIs 3TC (1995) FTC (2003)
SQV, RTV, IDV, NFV (1995–1997)

LPV/r, ATV, FPV
(2000–2003)
PIs TPV (2005), DRV (2006)
NVP (1996)
EFV (1998)
NNRTIs ETR (2007)
ENF (2004)
MVC (2007)
Other RAL (2009)
1987 1995 2000–2002 onwards
Figure 14.2 Timeline of antiretroviral treatment availability. Dates of FDA approval are indicated. Abbreviations: NRTIs, nucleoside
and nucleotide reverse transcriptase inhibitors; AZT, zidovudine; ddl, didanosine, ddC, Zalcitabine, ABC, abacavir; d4T, stavudine;
TDF, tenofovir; 3TC, lamivudine; FTC, emtricitabine; PIs, HIV protease inhibitors; SQV, saquinavir; RTV, ritonavir; IDV, indinavir: NFV,
nelfinavir; LPVr, lopinavir; ATV, atazanavir; FPV, fosamprenavir; TPV, tipranavir; DRV, darunavir; NVP, nevirapine; EFV, efavirenz;
NNRTIs, non-nucleoside reverse transcriptase inhibitors; ETR, etravirine; ENF, enfurvitide (fusion inhibitor); MVC, maraviroc (CCR5
antagonist); RAL, raltegravir (integrase inhibitor).
Figure 14.3 Abacavir hypersensitivity demonstrated by

erythematous and vesicular skin changes in response to a
range of abacavir concentrations (as shown) in a
petrolatum vehicle.
179
The large PREDICT-1 clinical trial, as well as numerous or in men with CD4 counts >400 cells/mm3 unless the
subsequent population-based studies, have demonstrated benefit outweighs the risk. Subsequent studies have shown
that HLA-B*5701 screening eliminates abacavir HSR con- that the risk of nevirapine HSR among treatment-
firmed by patch testing [7], in keeping with studies of the experienced patients with undetectable plasma HIV RNA
immunological basis of this reaction [8]. The SHAPE study levels (i.e. <400 copies/mL) prior to commencing nevira-
further demonstrated a 100% negative predictive value gen- pine treatment is comparable to that of “low risk” treat-
eralizes in both black and white patients [9]. Prospective ment-naı̈ve patients [11]. Conversely, studies in resource-
genetic testing for HLA-B*5701, therefore, effectively pre- limited settings where nevirapine is used as first-line therapy
vents at-risk individuals being exposed to abacavir. It is have not consistently confirmed an increased risk of adverse
an excellent example of cost-effective, personalized genetic drug reactions (rash or hepatic injury) associated with base-
medicine that has been incorporated into international line CD4 counts [13].
HIV guidelines and widely implemented in primary Nevirapine HSR appears to be relatively heterogeneous
practice [10]. in nature, with variable expression of the component fea-
tures of rash (Fig. 14.4), fever and constitutional illness, pe-
ripheral eosinophilia, and hepatotoxicity. It is particularly
noteworthy that severe hepatic injury can occur in the ab-
Nevirapine hypersensitivity reactions sence of other clinical features. With regard to genetic risk
factors, modest predictive values for nevirapine hypersensi-
Adverse drug reactions associated with nevirapine lead to tivity have been associated with HLA-DRB1*0101 (hepato-
discontinuation of this treatment in 6–7% of treated toxicity, fever, and/or rash in Caucasians with CD4 >25
individuals, and unfortunately, rare fatal cases associated percent) [14] and HLA-B*3505 (rash alone in Asian (Thai)
with fulminant liver injury and/or severe cutaneous erup- patients) [15].
tions such as toxic epidermal necrolysis continue to be
reported [11]. Nevirapine safety data compiled prior to
2003 demonstrated that severe (grade 3–4) hepatotoxicity
and rash occur during the early phase of treatment (within Other potential pharmacogenetic
12 weeks of treatment initiation) in 5% of nevirapine strategies for preventing early
recipients, and that low CD4 counts are relatively protec-
treatment discontinuation
tive against the development of these severe toxicity syn-
dromes [12]. These findings were subsequently reflected in Many antiretroviral medications can cause symptoms that
the Federal Drug Administration (FDA) and European Med- are prominent in the initial weeks of treatment and then
icines Agency (EMA) recommendations that nevirapine not generally abate with time (for example, vivid dreams, sleep
be initiated in women with CD4 counts >250 cells/mm3 disturbance, dizziness, and concentration difficulties with
A B
Figure 14.4 (A) Maculopapular rash in a patient with light skin receiving nevirapine. (B) Maculopapular rash in a patient with dark
skin receiving nevirapine.
180
efavirenz; diarrhea associated with lopinavir/ritonavir; my- vigilance when used in selected at-risk populations. In this
algias and nausea with zidovudine), and in these instances section they will be considered first because of their more
it is often useful to educate patients that these symptoms frequent use, rather than because of a greater propensity
can be expected but are unlikely to persist. Other symp- for complications.
toms, such as the benign unconjugated hyperbilirubinemia
associated with atazanavir, can become evident in the early
weeks of treatment, but do not require a change in therapy
unless associated with clinically apparent jaundice or Tenofovir renal safety
scleral icterus. The renal safety of tenofovir has been a topic of interest
Nevertheless, these side effects can persist in some since early reports (involving >30 cases) of significant renal
patients, and although these symptoms are not generally toxicity with renal tubular damage and/or acute renal fail-
severe, they are a relatively frequent cause for treatment ure, with evidence of distinct renal pathological changes
modification. This has in fact become a fruitful area of characterized by prominent proximal tubular injury [17].
pharmacogenetic investigation in recent times, with several In the large Gilead 903 study, in which participants had nor-
robust genetic associations suggesting that the tolerability mal renal function at baseline, no evidence of significant
of several HIV medications may have a strong genetic com- renal toxicity could be identified over a 3-year treatment
ponent [16]. For example, relatively frequent (>10%) period using serum creatinine measures [18]. However,
genetic variants associated with Gilbert syndrome (espe- subsequent studies analyzed in a recent meta-analysis
cially UDP-glucuronosyltransferase (UGT)1A1 polymor- have demonstrated reproducible but modest reductions in
phism) are associated with high rates of early atazanavir glomerular filtration rate (of approximately 4 mL/min),
discontinuation (62 versus 15%); while genetic variants with no discernible influence of tenofovir therapy on rates
that influence efavirenz metabolism are also associated of acute or chronic renal injury or chronic renal failure,
with early discontinuation (71 versus 20%) [16]. No ge- or of heavy proteinuria (>2 g/day), at the population
netic risk factors for tenofovir or lopinavir discontinuation level [19].
were identified in this study. The overall prevalence of renal impairment or significant
proteinuria in tenofovir-treated patients appears to have
remained low at approximately 3% in both HIV-infected
ADVERSE EFFECTS OF [20] and hepatitis B virus (HBV)-infected [21] populations,
and attempts to identify useful clinical risk factors have not
ANTIRETROVIRAL TREATMENT
proved conclusive. Pre-existing renal impairment is known
DURING LONG-TERM THERAPY to be associated with risk of acute renal injury associated
with tenofovir, and there is some evidence that alternative
Here we will consider complications of ART that generally or additional explanations for renal impairment are fre-
occur after the initial phase of treatment (i.e. beyond quent among tenofovir-treated patients with declining re-
3 months). Clinical syndromes that appear to have a clear nal function [22]. However, current or previous renal
association with antiretroviral medications will be consid- impairment does not necessarily preclude the use of
ered first, with an emphasis on those conditions that are tenofovir in patients with limited treatment options [23],
relatively rare in the general population (or confined to as long as renal function is appropriately monitored and
specific at-risk groups) but that are found more commonly proper dose adjustment is employed.
in treated HIV-infected patients. A subsequent section will In this regard, simple measurements of serum creatinine
explore the more complex relationships between prevalent levels have a limited capacity for capturing medication
diseases of aging (e.g. cardiovascular disease) and the effects on renal function, so that the use of calculated
impact of HIV infection and treatment. methods such as the Cockcroft–Gault or CKD-EPI equation
that adjust for body weight and gender are more useful for
monitoring purposes. Assessment and monitoring of uri-
Complications of nucleoside and nalysis for glycosuria and proteinuria, with quantification
nucleotide reverse transcriptase of urinary protein excretion (urinary protein/creatinine
and microalbumin/creatinine ratio) in those with evidence
inhibitor (NRTI) therapy
of proteinuria, is also recommended, in light of the predi-
The spectrum of NRTI treatment complications has shifted lection for tenofovir to affect proximal tubular function.
significantly since the decline in the use of the thymidine There have also been case reports of osteomalacia caused
analogue NRTIs, stavudine and zidovudine, as preferred by phosphate wasting due to tenofovir-induced proximal
NRTIs, in favor of the NRTI tenofovir and the non- renal tubular dysfunction. In addition to having protein-
thymidine NRTI abacavir (a guanosine analogue). These uria and/or glycosuria, patients with this problem may
newer drugs have demonstrated an improved safety profile have hypophosphatemia and/or an elevated fractional
compared with their predecessors, but continue to require excretion of phosphate.
181
managing this and other drug toxicity syndromes associ-

Lactic acidosis, hyperlactatemia, and acute
ated with these thymidine analogue NRTI drugs [26], will
hepatic steatosis soon change this situation.
Lactic acidosis is probably the most severe clinical manifes-
tation of mitochondrial dysfunction, in which loss of mito-
chondrial oxidative function leads to increased reliance on
Pancreatitis
“anaerobic” metabolism and the inevitable accumulation The differential diagnosis for pancreatitis occurring in an
of lactate. In the setting of NRTI therapy, there is now an HIV-infected individual includes direct didanosine and
appreciation of a spectrum of clinical disease associated stavudine toxicity, severe PI-induced hypertriglyceridemia,
with elevated systemic lactate levels [24]. At one end of and the effects of other drugs such as pentamidine. A diag-
this spectrum is a relatively common syndrome of mild, nosis of pancreatitis includes clinical symptoms of abdom-
asymptomatic, nonprogressive hyperlactatemia (generally inal pain combined with elevated serum amylase and/or
>2.5 mmol/L), which appears to represent a “compen- lipase levels, thus excluding cases of isolated hyperamylas-
sated” homeostatic system in which elevated lactate pro- emia that have been associated with moderate to severe im-
duction is balanced by effective mechanisms of lactate mune deficiency where the relationship between this
clearance. While the degree of hyperlactatemia appears to biochemical abnormality and pancreatitis is uncertain.
be greater in the presence of stavudine or didanosine ther- The most comprehensive data concerning risk factors for
apy than of zidovudine or abacavir, this syndrome appears NRTI-associated pancreatitis comes from the Johns Hop-
to be benign irrespective of the choice of NRTI therapy. kins AIDS Service cohort (n ¼ 2,613 cases) [27], with sup-
An “intermediate” syndrome has also been described, char- porting data from the ACTG 5025 study. In these analyses,
acterized by symptomatic hyperlactatemia or hepatic steato- didanosine and stavudine were associated with roughly
sis without systemic acidosis, which is almost uniformly equivalent risk of pancreatitis, with estimated incidence
associated with stavudine therapy (incidence 13/1,000 rates of 0.8 and 1.1 cases per 100 person-years, respectively.
person-years). In this setting, lactate levels and symptoms Combining these drugs increased the risk approximately
can be controlled following modification of NRTI therapy. twofold, while concurrent didanosine and hydroxyurea
The severe life-threatening hyperlactatemia syndromes, use increased the relative risk approximately eightfold, in-
with lactic acidosis and hepatic steatosis, are relatively un- cluding several fatal cases. More recently, cases of pancrea-
common (1–2/1,000 person-years). A critical aspect of lac- titis have been reported with concurrent use of didanosine
tic acidosis is its unpredictability, as it typically occurs in and tenofovir, including with reduced doses of didanosine
patients who have been on stable NRTI regimens for (250 mg/day), presumably due to the ability of tenofovir to
months or even years, and is not heralded by increased lac- “boost” didanosine effects in vivo [28].
tate levels before the development of the fulminant syn-
drome. Host risk factors for NRTI-associated lactic acidosis
include concurrent liver disease, female gender, and obesity,
Non-cirrhotic portal hypertension
and while the majority of reported cases in recent years have A relatively rare syndrome (estimated prevalence 8/
involved stavudine-based ART, cases involving zidovudine 10,000 patient-years) [29] of progressive portal hyperten-
therapy also occur. The cornerstone of management of this sion associated with the development of ascites and varices
condition is early recognition of the clinical manifestations: has been noted among antiretroviral-treated patients.
abdominal symptoms including nausea, vomiting, anorexia, This syndrome is characterized by exuberant nodular re-
abdominal pain and distention, fatigue, with biochemical generative hyperplasia and microvascular portal venopathy
evidence of hepatocellular liver damage and lactate level pathologically, and has been associated with didanosine
generally >5 mmol/L. These clinical and laboratory abnor- exposure (odds ratio 2), either alone or in combination
malities should lead to prompt cessation of NRTI therapy. with stavudine [29, 30], although cases have been de-
A more recently identified clinical syndrome accompanying scribed in the absence of exposure to these NRTIs [29].
lactic acidosis is progressive, severe neuromuscular weakness Given the prominent role of venous thrombosis in the
mimicking the Guillain–Barré syndrome. Overall, the mor- hepatic pathology, it is also proposed that additional fac-
tality associated with NRTI-associated lactic acidosis remains tors such as enhanced microbial translocation from the
high (approximately 50%). gut and prothrombotic conditions may contribute to
It is unfortunate to note that while this treatment compli- disease predisposition [31].
cation has become exceedingly rare in developed countries
with limited use of stavudine (or zidovudine), there are in-
creasing reports of severe and fatal hyperlactatemia syn-
Neuropathy
dromes from resource-limited settings where stavudine is The prevalence and long-term clinical impact of neuropa-
still frequently prescribed [25]. It is hoped that the imple- thy is likely to be underestimated, as the symptoms are
mentation of updated treatment guidelines, along with in- of gradual onset, and clinical signs of nerve damage are
creased recognition of the high costs associated with not always assessed in clinical practice. There is a definite
182
contribution of HIV disease per se to the pathogenesis of a (pathological loss of subcutaneous fat), as well as metabolic
form of distal sensory neuropathy that is clinically and elec- complications including dyslipidemia and insulin resistance
trophysiologically indistinguishable from so-called “toxic that may be accompanied by abdominal or localized fat ac-
neuropathy” from antiretroviral drugs [32]. It is therefore cumulation (Fig. 14.5). Examining the component features
difficult to determine the relative contributions of disease- of the syndrome separately appears to be the best approach
and drug-associated factors in the syndrome, as these to clinical management. This is most apparent in the case of
effects are likely to be synergistic. The clinical syndrome com- lipoatrophy, which is extremely uncommon in the general
mon to both HIV-associated and toxic sensory polyneuropa- community, and is therefore strongly and specifically linked
thy is dominated by peripheral pain and dysesthesia, with to ART [37]. Lipoatrophy is highly stigmatizing, as it has be-
rare motor involvement. come a visible marker of HIV infection, causing the appear-
In an international cohort study in which the overall ance of chronic illness and/or aging.
prevalence of symptomatic peripheral neuropathy was ap- Thymidine analogue NRTI therapy alone is sufficient to
proximately 50%, exposure to stavudine (odds ratio, OR cause lipoatrophy and is an independent risk factor for its
7.7) or didanosine (OR 3.2) were dominant risk factors, occurrence in ART-treated individuals, with a 40–50% risk
along with age >40 years (OR 2.9) [33]. of clinically apparent lipoatrophy among stavudine recipi-
Reversal of established neuropathy appears to be a slow ents over a period of 3 years, compared with 10–20% in
process that is dependent on cessation of the offending zidovudine-treated individuals [38]. Longitudinal studies
NRTI, and there is limited evidence for treatment strategies have also demonstrated that body fat tends to remain stable
other than topical capsaicin 8% [34], although several or even increase in the first 6–12 months of therapy, and
other agents such as gabapentin and tricyclic antidepres- then to decline over the subsequent 12–24 months among
sants have been used. As with any clinical neuropathy, patients receiving zidovudine- or stavudine-based treat-
a search for contributing factors such as diabetes, excessive ment. Some degree of fat loss is common in patients receiv-
alcohol consumption, and vitamin deficiencies (e.g. thia- ing these drugs, so that lipoatrophy can be viewed as a
mine, B12, and folate) should be undertaken in patients pathological process of variable severity rather than a phe-
who have neuropathy. nomenon that can be readily defined as “present” or “ab-
sent” [39]. In this context, the ability to recognize milder
forms of lipoatrophy and to assess the rate of fat loss in
Hematological complications of NRTI therapy the critical period from 6 to 24 months after initiating treat-
Zidovudine therapy has been associated with increased risk ment with stavudine or zidovudine may allow for thera-
of anemia in ART recipients compared with other NRTIs peutic intervention before fat loss becomes severe.
(relative risk 1.15), suggesting that this drug should be Substituting abacavir or tenofovir in patients with
used with caution when hemoglobin levels are low prior clinically apparent lipoatrophy has been associated with
to treatment. This may be particularly relevant when initi- statistically significant but modest improvements in fat wast-
ating ART in resource-poor countries where patients may be ing [40], although increases in limb fat are often not apparent
more prone to have reduced hemoglobin levels as a result to either clinicians or patients. Therefore, it would seem pru-
of concomitant parasitic infection (malaria, hookworm), dent to focus on prevention of lipoatrophy, as fat restoration
malnutrition, or genetically determined hemoglobinopa- appears to be a slow and possibly incomplete process. Over
thies. In this setting, monitoring for the presence of anemia 30 trials investigating HIV protease inhibitor discontinuation
appears to be a particularly cost-effective strategy when as a therapeutic strategy [40] have failed to demonstrate rever-
zidovudine therapy is being considered [35]. sal of lipoatrophy, although metabolic abnormalities such as
Recent studies have also suggested that combined full- dyslipidemia and insulin resistance and occasionally intra-
dose didanosine and tenofovir treatment may contribute abdominal visceral fat accumulation may improve.
to a targeted toxicity against lymphocytes, resulting in re- The choice of NRTI therapy is therefore the primary man-
duced CD4 counts, despite the presence of undetectable agement decision that affects the risk of lipoatrophy, irre-
viral loads [36], affecting approximately half of patients respective of which additional drugs are included in the
ceiving this drug combination in one clinical trial. Hence, regimen (e.g. NNRTIs or PIs). Host factors are also impor-
drug toxicity should be considered as a potential explanation tant in determining the severity of lipoatrophy among
when there is significant discordance between virological patients receiving stavudine or zidovudine, with increased
suppression and CD4 T cell responses in patients taking this risk of lipoatrophy among those aged >40 years and
non-recommended NRTI combination. among those with low pre-treatment CD4 count (<200
cells/mm3), irrespective of the virological or immunologi-
cal response to therapy. This argues against recommending
Lipoatrophy delayed introduction of HIV treatment due to concerns re-
The “lipodystrophy syndrome” represents a combination of garding drug toxicities.
complications first recognized among ART recipients in For those individuals affected by lipoatrophy, definitive
1998. The clinical syndrome incorporates lipoatrophy treatments beyond NRTI switching are limited at present,
183
A B
C D
Figure 14.5 (A) Abnormal fat distribution with joint peripheral lipoatrophy and abdominal fat accumulation. (B) Subcutaneous fat
atrophy of buttocks in the same patient. (C) Subcutaneous fat atrophy of the legs in the same patient. (D) Facial subcutaneous
fat atrophy in the same patient.
and while there is some optimism regarding the potential causative NRTI drug has been removed, as the end-organ
role of pioglitazone treatment [41], consideration will need damage to subcutaneous adipose tissue depots means that
to be given to long-term safety data before this treatment this fat tissue is unable to effectively take up dietary fat,
strategy can be widely recommended. In the case of facial thereby increasing the risk of unwanted side effects such
lipoatrophy, the dermal filler poly-L-lactic acid (“Newfill” as visceral/abdominal fat accumulation and hypertriglycer-
or “Sculptra”) has been approved by the US Food and Drug idemia. In this respect, the presence of lipoatrophic damage
Administration (FDA) for this indication, and has proved to adipose tissue does appear to increase the long-term risk
safe and effective over extended follow-up. The use of of “metabolic syndrome” complications, suggesting that
high-fat or high-energy diets to promote fat gain in patients vigilant monitoring for these complications needs to be
with lipoatrophy cannot be supported, even after the maintained in patients with a history of lipoatrophy [42].
184
Complications of HIV protease that metabolic effects of these drugs can no longer be con-
inhibitor therapy sidered “class effects.” For example, indinavir has been
shown to induce significant insulin resistance following
These adverse effects tend to be strongly associated with in- short-term drug exposure in healthy control subjects [45],
dividual drugs within the PI class, rather than representing while lopinavir/ritonavir therapy under similar conditions
drug “class effects.” is associated with elevated triglyceride levels but no sig-
nificant impact on insulin sensitivity [46]. The newer PIs
atazanavir [47] and darunavir [48] do not appear to have
Abnormal liver function/liver enzyme significant unfavorable effects on lipid or glucose
abnormalities metabolism, paving the way for intra-class PI switching
strategies in response to treatment-induced dyslipidemia.
Full-dose (but not low-dose) ritonavir has been associated
The effect of PI therapy on vascular disease risk is obvi-
with increased risk of hepatoxicity as defined by transami-
ously strongly related to this issue, and will be discussed
nase elevation (i.e. >five fold elevation of ALT and/or AST
further below.
levels), with a relative risk of approximately four compared
with other PI drugs. However, the presence of chronic viral
hepatitis (i.e. hepatitis B or C) and/or alcohol abuse remain
the most important risk factors for such hepatoxicity,
which may reflect altered hepatic drug metabolism as well TOXICITY PROFILES OF NNRTIs
as the restoration of pathogenic inflammatory responses to
hepatitis viruses following successful HIV therapy [43]. The NNRTIs efavirenz and nevirapine have proven to be
highly effective HIV drugs that carry minimal risk of meta-
bolic and gastrointestinal side effects, although differences
Gastrointestinal intolerance in toxicity profiles attributable to “class effects” of NNRTI
Persistent diarrhea is a relatively frequent complication of and PI drugs have become far less relevant with the devel-
nelfinavir therapy, affecting 20–50% of recipients. Of the opment of more tolerable second-generation HIV protease
other PI drugs, lopinavir and fosamprenavir have also been inhibitors.
associated with diarrhea, particularly in the early weeks of
treatment (incidence 10%). Diarrhea seems to be much
less common with the use of ritonavir-boosted atazanavir Efavirenz and central nervous
or darunavir.
system side effects
The efficacy of efavirenz-containing regimens and the
Nephrolithiasis and renal dysfunction much lower likelihood of severe hepatic and skin toxicities
associated with nevirapine treatment have led to the adop-
Indinavir is associated with risk of renal calculus forma-
tion of efavirenz as a recommended first-line agent in var-
tion, affecting 10% of recipients, and can also be associ-
ious treatment guidelines. As mentioned earlier, the most
ated with nephropathy in the absence of overt calculus
frequent adverse effects associated with this drug are cogni-
formation. Indinavir-induced renal calculi (which are
tive and neuropsychiatric, affecting approximately 15% of
radiolucent) generally respond to hydration, diuresis, and
efavirenz recipients to at least a moderate extent within
urinary acidification. Indinavir is also associated with “reti-
1 month of initiating treatment. While these side effects
noid” side effects, including dry lips and skin (30%), and
generally resolve in the first 2–4 weeks of treatment, cohort
hair and nail changes including paronychia (5%). There
studies have identified ongoing symptoms including dizzi-
have now been >30 reports of renal calculi in atazanavir
ness, sadness, irritability, nervousness and mood changes,
recipients, although clinical risk factors are not yet known.
impaired concentration, and abnormal dreams [49]. Sui-
Atazanavir and lopinavir/ritonavir may also be associated
cidal ideation has also been reported in a minority of
with increased risk of chronic kidney disease [44].
patients, indicating that neuropsychiatric manifestations
may be severe in some cases. While this list would appear
to constitute a significant burden of toxicity, it is interesting
Metabolic complications: dyslipidemia and
to note that patients on efavirenz or nevirapine regimens
insulin resistance consistently report equivalent improvements in quality of
There is now definitive evidence that treatment with se- life. In cases where CNS side effects of efavirenz warrant
lected PIs can rapidly induce significant metabolic abnor- treatment revision, substitution with an alternative medica-
malities, including but not limited to changes in plasma tion, including etravirine, is associated with significant
lipids and lipoproteins, in both HIV-infected and HIV- improvements in insomnia, abnormal dreams, and ner-
uninfected subjects, although it must also be acknowledged vousness within weeks [50].
185
Rash [52, 53], cerebral function [54], and atherosclerotic burden

[55] are 10–15 years more advanced than expected. It is not
All NNRTI can cause rash during the initial weeks of ther- known whether accelerated aging continues throughout
apy. Nevirapine is the most like to cause serious rash, which the course of HIV infection and treatment, but proposed as-
is discussed above under ‘Nevirapine hypersensitivity reac- sociations with persistent immune activation [56] appear
tions.’ Rash due to efavirenz is often self-limited without to have a sound basis in recent research [57], with parallel
the need for discontinuation. Etravirine may be associated examples in other branches of medicine [58]. One of the
with skin rash of varying severity, generally occurring most profound insights in this area has come from the
within the first 4–6 weeks of treatment. In phase 3 trials SMART study [57] and numerous substudies that have
approximately 2% of patients needed to discontinue arisen from it, which have demonstrated increased adverse
etravirine because of rash. events, including all-cause mortality, among patients with
untreated HIV infection. Importantly, CD4 counts and/or
plasma HIV RNA levels did not deteriorate substantially
in patients who interrupted treatment temporarily, and
IMPACT OF ANTIRETROVIRAL these standard markers of HIV disease progression did
THERAPY ON PREVALENT not predict the study’s adverse outcomes. On the other
hand, markers of immune activation and coagulation dis-
DISEASES ASSOCIATED WITH AGING turbance, which are generally not monitored in routine
clinical practice, were more strongly associated with both
The long-term success of ART has created new challenges infectious and non-infectious complications.
relating to the management of HIV infection in aging These findings place the effective treatment of HIV infec-
patients, and in particular the potential effects of HIV infection, with the maintenance of plasma aviremia, as the high-
tion and its treatment on the onset and severity of prevalent est priority for clinical management during aging, and have
age-associated diseases (Fig. 14.6). It will soon be the case also paved the way for consideration of earlier initiation of
that the majority of HIV-infected individuals in developed treatment in uncomplicated HIV infection [59]. While this
settings will be older than 50 years of age, and while this question will soon be addressed formally in clinical trials,
proportion is lower in resource-limited settings (approach- current treatment guidelines already recommend initiation
ing 15%), it has been pointed out recently that the absolute of ART in asymptomatic patients with normal CD4 counts
number of older Africans living with HIV infection is (>500 cells/mm3) when the risk of co-morbid illness is
already substantial at >3 million [51]. elevated, as well as in older age groups [60], while treatment
There is now some evidence of premature physiological is recommended for all asymptomatic patients with CD4
aging with HIV infection, so that markers of physical frailty counts below this threshold.
Figure 14.6 Multifactorial pathogenesis

of aging-associated co-morbidities in
the context of HIV infection.
HIV-associated
Modifiable Cell and tissue damage immune activation
lifestyle-related resulting in clinical co-morbidity and activation of
risk factors traditionally associated inflammatory and
with aging coagulation pathways
Antiretroviral toxicity Age, gender

genetic factors
186
The role of selected PIs has been discussed above. With

CARDIOVASCULAR RISK AND regard to NNRTI therapy, it is notable that treatment with
HIV INFECTION nevirapine, and to a lesser extent efavirenz, has specific and
potentially anti-atherogenic effects on HDL-cholesterol
levels. For example, in the large 2NN trial, nevirapine
There is an increasing appreciation of the association between therapy was associated with a 42.5% increase of HDL-
ART and metabolic complications such as dyslipidemia and cholesterol, while efavirenz had a more modest effect
insulin resistance, although considering specific “treatment on HDL-cholesterol (33.7%) [65]. These differences
phases” can help to clarify these issues. A central issue is that remained, or even increased, after adjusting for changes
many of the metabolic endpoints are common in the general in viral loads and CD4 counts indicating an independent
population and are therefore subject to many genetic (non- effect of the drugs on lipids that could not be explained
modifiable) and environmental (potentially modifiable) risk by suppression of HIV infection.
factors not specific to HIV infection nor its treatment. This is
not to downplay the important role that antiretroviral agents
have in the pathogenesis of metabolic complications, but to
place these effects in a broader clinically relevant context. Monitoring and managing
cardiovascular risk: incorporating
Metabolic profile in the
multiple risk factors
‘pre-treatment’ phase: background
risk and the influence of HIV infection Large-scale cohort studies have consistently shown that
ART is associated with an increased risk of cardiovascular
The “metabolic syndrome” incorporates lipid parameters disease endpoints [66, 67], although traditional cardiovas-
(high triglyceride and low HDL-cholesterol values), cular risk factors, particularly smoking [68], which is highly
abdominal obesity, and impaired glucose tolerance into prevalent among HIV-infected patients, remain important
a clinical entity that is present in more than 30% of adults independent predictors of cardiovascular events within
(both male and female) in population studies [61]. This HIV-infected patient populations [69]. It is therefore im-
phenotype has a striking resemblance to the metabolic portant to assess and manage global cardiovascular risk
complications that have been incorporated into the “lipo- in HIV-infected patients, with particular attention to base-
dystrophy syndrome,” in that both are characterized by the line (pre-treatment) values and metabolic responses to HIV
presence of high levels of triglyceride-enriched lipopro- treatment. Given that HDL-cholesterol levels as well as total
teins, which manifests as an atherogenic lipid profile and LDL-cholesterol levels are modulated by progressive
including high triglycerides, high apolipoprotein CIII, HIV infection, and the importance of the non-HDL-
B and E, and elevated non-HDL-cholesterol levels [62]. Im- cholesterol fraction in determining cardiovascular risk in
portantly, this syndrome is associated with a significantly the context of the metabolic syndrome, it may be useful
increased risk of cardiovascular disease, even after adjust- to monitor the non-HDL-cholesterol fraction (total choles-
ment for known cardiovascular risk factors, including terol minus HDL-cholesterol) in these individuals in order
LDL-cholesterol levels [61]. As may be expected, high satu- to capture the total burden of atherogenic triglyceride-rich
rated fat and calorie intake and low dietary fiber along with lipoproteins.
a sedentary lifestyle are significant risk factors. With regard to the effects of HIV medications on cardio-
Untreated HIV disease and immune deficiency are accom- vascular risk, data from the large international D:A:D
panied by changes in lipoprotein metabolism characterized cohort have implicated three medications as potential
by decreased levels of total, LDL-cholesterol, and HDL- risk factors [66, 67], and these effects have been incor-
cholesterol as well as decreased apolipoprotein B [63]. These porated into a cardiovascular risk calculator specific to
metabolic parameters fall in parallel with CD4 counts, while HIV-infected populations [70]. Cumulative exposure to
progression to AIDS is associated with elevated triglyceride indinavir and lopinavir-ritonavir was associated with an
levels and an increase in more atherogenic small dense increased risk of MI (relative rate per year, 1.1), with evi-
low-density lipoprotein particles [64]. dence that this effect was mediated at least in part by the
effects of these medications on lipid levels. Current expo-
Metabolic profile in the ‘treatment’ sure to abacavir has also emerged as a possible risk factor,
phase: metabolic complications of associated with a relative risk of 1.9 in the D:A:D study
[71], although this association has not been seen in clin-
specific antiretroviral drugs
ical trials or some other cohort studies [72]. When consid-
The use of any effective treatment regimen may counteract ering the need to avoid these medications, it is important
the lipid changes associated with HIV infection per se and to consider the underlying absolute risk of cardiovascular
to some extent restore plasma lipoprotein levels to those disease attributable to traditional risk factors (including
present prior to infection. non-modifiable risk factors such as age and gender), in
187
order to understand the benefit or harm that may result 50 years of age) for low bone density, as well as assessing
from this strategy. A useful approach to this issue has been serum vitamin D levels [78, 84]. These guidelines also es-
provided by the Copenhagen HIV Programme [70], which tablish criteria for treatment of established osteoporosis
has created a calculator that estimates the influence of ART based on overall fracture risk, calculated using the FRAX
based on the “number needed to harm.” With respect to tool [85], as well as the severity of bone loss and the
the true impact of abacavir treatment on cardiovascular presence of secondary factors.
risk, this remains an area of controversy [73, 74], and a
pathogenic mechanism linked to myocardial events has
been elusive thus far. Among those with existing cardio- CONCLUSION
vascular disease or increased cardiovascular risk (20%
10-year predicted risk), statins are recommended for their
prognostic and survival benefit, irrespective of the baseline • The toxicity profiles of antiretroviral drugs can to some
extent be grouped based on drug classes, but important
lipid values [75]. When choosing between particular statins,
distinctions have also emerged among drugs within
the potential for drug–drug interactions with particular anti-
each class. Hence, the notion of “class effects” is not
retrovirals needs to be taken into account. Excellent and
useful when considering the toxicity profiles of
comprehensive guidelines have been established for the as-
antiretroviral regimens.
sessment and treatment of non-infectious co-morbidities,
including cardiovascular risk and metabolic complications, • Antiretroviral medications that are now commonly
used in resource-rich settings are characterized by
in HIV-infected patients [76, 77], which recommend the
favorable safety profiles as well as high levels of efficacy,
use of standard treatment approaches based on global
so that severe treatment-associated toxicities have
cardiovascular risk assessment.
become an uncommon cause of morbidity and
mortality.
• Adverse effects that occur during the early phase of
BONE DENSITY AND HIV INFECTION treatment (i.e. <12 weeks) are now well characterized,
and risk of some of these events appears to have a
This topic has been the subject of a recent comprehensive significant genetic component. This is most notable in
review [78], which provides a practical approach for the case of abacavir hypersensitivity reactions, where
assessing and managing bone disease in the setting of genetic screening for HLA-B*5701 has dramatically
HIV infection. The overall prevalence of osteoporosis in increased medication safety.
HIV-infected subjects is approximately 15%, more than • There is a range of adverse effects associated with long-
three times greater than reported in HIV-uninfected con- term antiretroviral therapy, which are both medication-
trols, and there is strong evidence from the SMART study and organ-specific. Appropriate monitoring strategies
[79] and elsewhere that there is a decline in bone density are therefore determined by an understanding of the
during HIV treatment, particularly in the first year of toxicity profiles of individual antiretroviral
therapy, of approximately 2–5%. With regard to specific medications.
antiretroviral agents, several studies have indicated an ad- • Understanding the relationships between diseases
ditional but non-progressive effect of tenofovir therapy associated with aging and HIV infection is becoming
on bone loss [80, 81] and increased bone turnover increasingly important in contemporary clinical
[81], which may relate to the effects of tenofovir on renal practice, given that the majority of individuals living
proximal tubular function. The clinical significance of with HIV infection in the developed world will be >50
this effect is uncertain [82] and needs to be considered years of age within this decade.
in light of the overall risk factor profile for osteoporosis, • In this setting, establishing and sustaining effective
a list that includes highly prevalent factors among virological suppression remains a high priority in
HIV-infected patients, such as low body mass (especially HIV management, given evidence that viremic
lean body mass), smoking, drug and alcohol abuse, and infection and associated inflammation is associated
hypogonadism. with an increased risk of serious infectious and
There has also been considerable recent interest in the non-infectious complications. The continued
effects of vitamin D deficiency on bone health in HIV infec- risk associated with residual inflammation in those
tion, given that vitamin D deficiency has been observed in with aviremic infection is an area of active research.
the majority of HIV-infected individuals, that treatment • Guidelines for the assessment and management of
with efavirenz appears to be associated with greater risk metabolic and other non-infectious complications of
of this complication [83], and that of osteomalacia has HIV treatment are evolving, which emphasizes
been associated with tenofovir therapy. the value of a holistic approach to risk management in
Management guidelines have provided pathways for order to prevent end-organ diseases such as
screening HIV-infected patients (particularly those over cardiovascular events and bone fractures.
188
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191
Chapter | 15 |
Oral complications of HIV infection
John S. Greenspan, Deborah Greenspan
lesions are also common in HIV-infected women [9–13] and

INTRODUCTION children [14, 15]. While their overall frequency has fallen
with the introduction of antiretroviral therapy (ART), in
both resource-rich and resource-poor countries among those
Oral lesions have been recognized as prominent features of who are treated for HIV infection, changes in their nature
the acquired immunodeficiency syndrome (AIDS) and hu- and relative frequency have been seen, with major decreases
man immunodeficiency virus (HIV) infection since the in Kaposi’s sarcoma, lymphoma, oral candidiasis, and hairy
beginning of the epidemic, and continue to be important leukoplakia, no changes in aphthous ulcers, and often in-
[1, 2]. Some of these changes are reflections of reduced creases in oral papillomavirus warts [16–18]. Some of the
immune function manifested as oral opportunistic condi- post-ART increases may represent oral aspects of the im-
tions, which are often the earliest clinical features of HIV mune reconstitution inflammatory syndrome (IRIS) [19].
infection. Some, in the presence of known HIV infection, However, oral lesions are more common in people who
are highly predictive of the ultimate development of the full smoke cigarettes [20].
syndrome, whereas others represent the oral features of AIDS
itself. The particular susceptibility of the mouth to HIV dis-
ease is a reflection of a wider phenomenon. Oral opportu-
nistic infections occur in a variety of conditions in which
the teeming and varied micro-flora of the mouth take advan- CANDIDIASIS (ORAL CANDIDOSIS)
tage of local and systemic immunologic and metabolic
imbalances. They include oral infections in patients with pri- The pseudomembranous form of oral candidiasis/candido-
mary immunodeficiency, leukemia, and diabetes, and those sis (thrush) was described in the first group of AIDS pa-
resulting from radiation therapy, cancer chemotherapy, and tients and is a harbinger of the full-blown syndrome in
bone marrow suppression. Oral lesions seen in association HIV-infected individuals [21, 22]. We have shown that
with HIV infection are classified in Table 15.1, and our gen- both oral candidiasis and hairy leukoplakia predict the de-
eral approach to the diagnosis and management of oral HIV velopment of AIDS in HIV-infected patients independently
disease is summarized in Table 15.2. Standardized defini- of CD4 counts [23]. However, it is not well recognized that
tions and diagnostic criteria for these lesions have been oral candidiasis can take several forms, some of them with
established and recently revised [3, 4]. subtle clinical appearances [24]. The most common form,
In the prospective cohorts of HIV-infected homosexual pseudomembranous candidiasis, appears as removable
and bisexual men in San Francisco, hairy leukoplakia was white plaques on any oral mucosal surface (Fig. 15.1).
the most common oral lesion (20.4%), and pseudomem- These plaques may be as small as 1–2 mm or may be exten-
branous candidiasis the next most common (5.8%) [5]. sive and widespread. They can be wiped off, leaving an
The relationships between prevalence of oral lesions erythematous or even bleeding mucosal surface.
and CD4 count or HIV viral load shows fairly close corre- The erythematous form (Fig. 15.2) is seen as smooth red
lations [6–10]. These lesions occur at an early stage after patches on the hard or soft palate, buccal mucosa, or dorsal
seroconversion and are predictors of progression [11]. Oral surface of the tongue. These lesions may seem insignificant
195
Section | 3 | Diseases associated with HIV infection
Table 15.1 Oral lesions in HIV infection
FUNGAL BACTERIAL VIRAL NEOPLASTIC AUTOIMMUNE/

IDIOPATHIC
Candidiasis: Periodontal disease Herpes simplex Kaposi’s sarcoma Salivary gland disease
pseudomembranous Necrotizing Chickenpox Non-Hodgkin’s Aphthous ulcers
erythematous, stomatitis Herpes zoster lymphoma ITP
angular cheilitis Tuberculosis Cytomegalovirus Hodgkin’s lymphoma Other
Histoplasmosis MAC lesions Lip cancer
Cryptococcosis Bacillary Hairy leukoplakia
Penicillinosis angiomatosis HPV lesions
Other
Table 15.2 Diagnosis and management of oral HIV disease
CONDITION DIAGNOSIS MANAGEMENT
Fungal
Candidiasis Clinical appearance Antifungals
KOH preparation Treatment for 2 weeks with systemic or topical agents
Culture Topical creams for angular cheilitis
Histoplasmosis Biopsy Systemic therapy
Geotrichosis KOH preparation Polyene antifungals

Culture
Cryptococcosis Culture Systemic therapy

Biopsy
Aspergillosis Culture Systemic therapy

Biopsy
Bacterial
Linear gingival Clinical appearance Plaque removal, chlorhexidine
erythema
Necrotizing Clinical appearance Plaque removal, debridement, povidone-iodine,

ulcerative metronidazole, chlorhexidine
periodontitis
Necrotizing Clinical appearance Debridement, povidone-iodine, metronidazole,

stomatitis Culture and biopsy (to exclude chlorhexidine
other causes)
Mycobacterium Culture Systemic therapy

avium complex Biopsy
Klebsiella Culture Systemic therapy (based on antibiotic sensitivity testing)

stomatitis
Viral
Herpes simplex Clinical appearance Most cases are self-limiting
Immunofluorescence on smears Oral acyclovir or valacyclovir
Herpes zoster Clinical appearance Oral or intravenous acyclovir
196
Chapter | 15 | Oral complications of HIV infection
Table 15.2 Diagnosis and management of oral HIV disease—cont’d
CONDITION DIAGNOSIS MANAGEMENT
Viral—cont’d
Cytomegalovirus Biopsy, immunohistochemistry Ganciclovir
ulcers for CMV
Hairy leukoplakia Clinical appearance Not routinely treated

Biopsy; in situ hybridization Oral acyclovir or valacyclovir for severe cases
for Epstein–Barr virus
Warts Clinical appearance Excision

Biopsy
Neoplastic
Kaposi’s sarcoma Clinical appearance Palliative surgical or laser excision for some bulky or unsightly
lesions; intralesional chemotherapy or sclerosing agents;
radiation therapy; chemotherapy
Non-Hodgkin’s Biopsy Chemotherapy

lymphoma
Squamous cell Biopsy Excision or radiation therapy or both

carcinoma
Other
Recurrent History Topical steroids, such as fluocinonide mixed 50/50 with
aphthous ulcers Clinical appearance orabase, applied to lesions 4 times a day
Biopsy (to exclude other causes) Thalidomide for most severe cases
Immune Clinical appearance

thrombocytopenic Hematological work-up
purpura
Salivary gland History Salivary stimulants or change in systemic medication or both

disease Clinical appearance, Salivary flow Consider use of Salagen or Evoxac
measurements Topical fluorides, toothpastes and rinses
Biopsy (to exclude other causes);
needle or labial salivary gland
biopsy)
Figure 15.1 Pseudomembranous candidiasis. Figure 15.2 Erythematous candidiasis.
197
is usually not useful for diagnosis. It may be helpful in

cases of oral candidiasis unresponsive to antifungal therapy
to determine Candida spp. and/or possible azole-resistant
candidiasis.
Treatment
Oral candidiasis in patients with HIV infection can be
treated with oral or systemic therapy and sometimes a
combination of both [25]. Our approach is as follows.
Oral topical agents include troches, tablets, creams, and
suspensions. For an oral topical agent to be effective, ade-
quate contact time is crucial. Suspensions are therefore
probably not the best first choice. It is also important that
sucrose is not used as a flavoring agent for several reasons,
Figure 15.3 Angular cheilitis.
most particularly because of the risk of development of
caries and the possibility of increased dental plaque pro-
and may be missed unless a thorough oral mucosal exam- duction. For intraoral candidal lesions, effective agents in-
ination is performed in good light. clude topical and systemic antifungal agents. Topical agents
Angular cheilitis (Fig. 15.3), due to Candida infection, are effective if used consistently. They include nystatin vag-
presents as erythema, cracks, and fissures at the corner of inal tablets (Mycostatin), 100,000 units t.i.d., dissolved
the mouth. We have found that erythematous candidiasis slowly in the mouth; or clotrimazole oral tablets (Mycelex),
is as serious a prognostic indicator of the development of 10 mg, one tablet five times daily. Nystatin oral suspen-
AIDS as pseudomembranous candidiasis [24]. sion, used as a mouthrinse and expectorated, is generally
Denture stomatitis is frequently a form of erythematous a less effective topical agent because of short contact time.
candidiasis that occurs in association with the fitting sur- Miconazole has recently become available in the USA as a
face of dentures. Clinically it appears as a smooth red area, 50-mg buccal tablet, to be placed by the patient at the
often demarcating the outline of the denture on the palate. mucogingival junction and left in place, where it dissolves
Candida also colonizes/inhabits the fitting surface of a plas- slowly over several hours. The effectiveness of topical med-
tic denture, and if the fitting surface of the denture is ications depends on adherence to recommended dosing
pressed into a Candida culture plate, prolific growth of regimens. Topical tablets and troches need adequate saliva
colonies of the fungus will subsequently be seen. to be effective. For those people with dry mouth, sipping a
Diagnosis of oral candidiasis involves potassium hydrox- little water before use and occasionally during use of the
ide preparation of a smear from the lesion (Fig. 15.4). medication can be helpful. When topical medications con-
Culture provides information about the species involved. taining sucrose or dextrose that have the potential to cause
However, because a positive candidal culture can be caries are used, daily topical fluoride rinses should be used
obtained from over 50% of the normal population, culture by those taking these medications frequently.
For those individuals who find it difficult to use these
medications 4–5 times a day, systemic therapy can be con-
sidered. The azoles are frequently used for systemic therapy.
There are many drug interactions, so care must be taken
before these drugs are prescribed.
Fluconazole (Diflucan) is a systemic antifungal agent.
The recommended dose is a 100-mg tablet, once daily
for 14 days. Oral fluconazole is an effective antifungal
agent that does not depend on gastric pH for absorption.
Side effects include nausea and skin rash. Two 100-mg tab-
lets are used on the first day, followed by one 100-mg tablet
daily until the lesions disappear. Fluconazole is also avail-
able as an oral suspension, 10 mg/mL, and 10 mL used as
a swish and swallow once per day [26]. Itraconazole is a
systemic, triazole antifungal agent and is available as a cap-
sule and suspension. Itraconazole oral solution has been
Figure 15.4 Potassium hydroxide preparation. Fungal hyphae evaluated in clinical trials as being an effective agent
and blastospores. in the treatment of oral candidiasis, and salivary levels
198
of itraconazole persist up to 8 h after dosing. Itraconazole

capsules are now available as 100-mg caps, 2 to be taken
once or twice/day for 2 weeks. This may be useful in cases
that do not respond to fluconazole or clotrimazole. Anti-
fungal therapy should be maintained for 2 weeks, and
some patients may need maintenance therapy because of
frequent relapse.
In the years before ART was widely used, many cases of
oral candidiasis resistant to fluconazole were reported.
Such complications are now rarely seen in countries where
ART is widely available. Factors associated with the devel-
opment of resistance include CD4 count < 100 cells/mm3,
previous use of fluconazole, and the emergence of new re-
sistant strains of Candida albicans or the emergence of Figure 15.5 Necrotizing ulcerative periodontitis in HIV
strains such as Candida glabrata, Candida tropicalis, and Can- infection.
dida krusei, which are inherently less sensitive to flucona-
zole [27]. However, in most cases, fluconazole is an
extremely well-tolerated and effective antifungal agent. periodontitis (Fig. 15.5) and is frequently seen in African
For patients who develop oral candidiasis that appears AIDS patients. Thus, there may be halitosis and a his-
unresponsive to therapy, voriconazole, a newer antifungal tory of rapid onset. There is necrosis of the tips of
agent, may be useful, rather than as first-line therapy, as it is interdental papillae, with the formation of cratered ul-
associated with more side effects than fluconazole. cers. However, in contrast to patients with ANUG, these
Angular cheilitis usually responds to topical antifungal patients complain of spontaneous bleeding and severe,
creams, such as nystatin-triamcinolone (Mycolog), clotri- deep-seated pain that is not readily relieved by analge-
mazole (Mycelex), or ketoconazole (Nizoral). Patients with sics. There may be rapid progressive loss of gingival
both intraoral candidiasis and angular cheilitis benefit and periodontal soft tissues and extraordinarily rapid
from treatment with topical creams for the corners of the destruction of supporting bone. Teeth may, therefore,
mouth as well as treatment for their intraoral lesions. Pa- loosen and even exfoliate. The periodontal disease often
tients with denture stomatitis should be asked to remove demonstrates alarming severity and a rapid rate of pro-
their dentures before using intraoral topical medications gression not seen by the majority of practicing dentists
and the dentures should be left out at night and left in a and periodontists prior to the AIDS epidemic. Exposure
solution of three or four drops of bleach in a denture bowl. and even sequestration of bone may occur, producing
The dentures should be thoroughly rinsed and cleaned necrotizing stomatitis lesions [36] similar to the noma
before placing them in the mouth. seen in severely malnourished people in the Second
Occasionally, other and unusual oral fungal lesions have World War, and more recently in developing countries
been seen. They include histoplasmosis [28], geotrichosis in association with malnutrition and chronic infection,
[29], aspergillosis [30], Penicillium marneffei lesions, and such as malaria. The pathologic and microbiologic
cryptococcosis [31]. features of these remarkable periodontal lesions are well
documented [37]. Standard therapy for gingivitis and
periodontitis is ineffectual. Instead, the therapeutic
regimen that is effective [38] involves thorough debride-
GINGIVITIS AND PERIODONTITIS ment and curettage, followed by application of a combi-
nation of topical antiseptics, notably povidone-iodine
Unusual forms of gingivitis and periodontal disease [32] (Betadine) irrigation followed with chlorhexidine (Peri-
are seen in association with HIV infection, notably in dex or PerioGard) mouthwashes, sometimes supple-
groups where ART is not available such as in many geo- mented with a 4- to 5-day course of antibiotics, such
graphic areas with high HIV prevalences. The gingivae as metronidazole (Flagyl) 250 mg q.i.d., Augmentin
may show a fiery red marginal line, known as linear 250 mg (1 tab t.i.d.), or clindamycin 300 mg t.i.d. Treat-
gingival erythema, even in mouths showing absence of ment will fail if thorough local removal of bacteria and
significant accumulations of plaque [33]. In early reports diseased hard and soft tissue is not achieved during the
in the USA and Europe, the periodontal disease necrotiz- initial treatment phase and maintained long term. Our
ing ulcerative periodontitis occurred in approximately impression has been that the diagnosis and management
30–50% of AIDS clinic patients [34] but was rarely of the periodontal complications of HIV/AIDS are chal-
seen in asymptomatic HIV-infected individuals [35]. It lenging and are less likely to be successful unless carried
resembles, in some respects, acute necrotizing ulcerative out by, or under the supervision of, experienced dental
gingivitis (ANUG) superimposed on rapidly progressive health professionals.
199
Cytomegalovirus ulcers
OTHER BACTERIAL LESIONS
Oral ulcers caused by cytomegalovirus (CMV; see
Chapter 34) occasionally occur [44]. These ulcers can occur
Cases have been described of oral mucosal lesions of tuber- on any oral mucosal surface, and diagnosis is made by bi-
culosis and of lesions associated with unusual bacteria, in- opsy and immunohistochemistry. Oral ulcers due to CMV
cluding Klebsiella pneumoniae and Enterobacter cloacae [39]. are usually seen in the presence of disseminated disease,
These have been diagnosed using aerobic and anaerobic but cases have occurred in which the oral ulcer was the first
cultures and have responded to antibiotic therapy based presentation. Whether to treat with ganciclovir or foscarnet
on in vitro sensitivity assays. Oral ulcers caused by Mycobac- depends on the severity of the viral infection, and a full
terium avium have also been described [40], as have the work-up is indicated. Ulcers simultaneously infected by
lesions of bacillary angiomatosis [41]. both HSV and CMV also occur [44].
VIRAL LESIONS Hairy leukoplakia

First seen on the tongue in men who have sex with men
Herpes simplex [45, 46], hairy leukoplakia has since been described in sev-
Oral lesions due to herpes simplex virus (HSV; see Chapter eral oral mucosal locations, including the buccal mucosa,
34) were a common feature of HIV infection and are still soft palate, and floor of mouth, and in all risk groups for
occasionally seen. Diagnosis is usually made from the clin- AIDS. Hairy leukoplakia produces white thickening of
ical appearance. The condition usually occurs as recurrent the oral mucosa, often with vertical folds or corrugations
intraoral lesions with crops of small, painful vesicles that (Fig. 15.6). The lesions range in size from a few millimeters
ulcerate. These lesions commonly appear on the hard pal- to involvement of the entire dorsal surface of the tongue.
ate or gingiva. Intraoral recurrent herpes simplex rarely oc- The differential diagnosis includes pseudomembranous
curs on keratinized mucosa. Smears from the lesions may candidiasis, idiopathic leukoplakia, smoker’s leukoplakia,
reveal giant cells, and HSV can be identified using mono- epithelial dysplasia or oral cancer, white sponge nevus,
clonal antibodies and immunofluorescence. The lesions and the plaque form of lichen planus. Biopsy reveals
usually heal within 5–7 days, although they may recur in pa- epithelial hyperplasia with a thickened parakeratin layer,
tients with lesions that have been present for 1–2 days treat- showing surface irregularities, projections resembling
ment with acyclovir or valacyclovir. For those with frequent ‘hairs,’ vacuolated prickle cells, and very little inflamma-
recurrence, it may be considered appropriate to treat them tion [47]. Epstein–Barr virus (EBV) can be identified in vac-
with oral acyclovir as soon as symptoms are reported. Usu- uolated and other prickle cells and in the cells of the
ally, one 200-mg capsule of acyclovir taken five times a day is superficial layers of the epithelium using cytochemistry,
effective. Acyclovir 5% ointment may be useful for early la- electron microscopy, Southern blotting, and in situ hybrid-
bial HSV lesions. Acyclovir-resistant herpes of the lips and ization [47, 48]. For cases in which biopsy is not considered
perioral structures have been described [42]. For herpes appropriate (e.g. hemophiliacs, children, large-scale epide-
labialis, treatment with penciclovir topical cream applied miologic studies), we and others have used cytospin and
to the lesions every 2 h for 4 days or the OTC preparation filter in situ hybridization techniques [49]. Langerhans’
Abreva may be effective. For multiple lip lesions, systemic cells are sparse or absent from the lesion [50]. Hairy
therapy may result in quicker resolution of the lesions.
Herpes zoster
Both chickenpox and herpes zoster (shingles; see
Chapter 34) have occurred in association with HIV infec-
tion [43]. In orofacial zoster, the vesicles and ulcers follow
the distribution of one or more branches of the trigeminal
nerve on one side. Facial nerve involvement with facial
palsy (Ramsay Hunt syndrome) may also occur. Prodromal
symptoms may include pain referred to one or more teeth,
which often prove to be vital and non-carious. The ulcers
usually heal in 2–3 weeks, but pain may persist. Oral acy-
clovir in doses up to 4 g/day for 7–10 days or valacyclovir
1 g t.i.d. for 7 days may be used in severe cases, but
occasionally patients must be hospitalized to receive
intravenous acyclovir therapy. Figure 15.6 Hairy leukoplakia.
200
leukoplakia is not premalignant [51]. Indeed, the keratin Sexual transmission thus seems to be rarely involved in
profile of the lesion suggests reduced, rather than increased, these warts. Instead, they may be attributable to activation
cell turnover [52]. of latent HPV infection or perhaps autoinfection from
Almost all patients with hairy leukoplakia are HIV- skin and face lesions. Histologically, dysplastic warts
infected and in the absence of modern ART, many would due to novel HPV types have also been described [66]
subsequently develop AIDS (median time 24 months) and but are not associated with malignant transformation. In-
die (median time 44 months) [23, 53, 54]. Rare cases have formed histopathological diagnosis is important because
been described in HIV-uninfected individuals, usually in as- these benign lesions have sometimes been mistakenly diag-
sociation with immunosuppression associated with organ nosed as premalignant dysplasia or even well-differentiated
transplantation [55]. Hairy leukoplakia has not been seen carcinoma.
at sites other than the mucosal surfaces of the mouth [56]. If large, extensive, or otherwise troublesome, as is the
Hairy leukoplakia apparently is an EBV-induced benign case in significant numbers of patients who are on ART
epithelial thickening. High doses of oral acyclovir appear to and present to specialized clinics with oral warts, these le-
reduce the lesion clinically [57]; however, these effects are sions can be removed using surgical or laser excision. In
soon reversed after cessation of acyclovir therapy. Hairy many cases, we have seen recurrence after therapy and even
leukoplakia occasionally may regress spontaneously [58]. extensive spread throughout the mouth. Furthermore, our
It is not clear whether hairy leukoplakia is caused by di- impression is that not only the frequency and severity
rect infection or reinfection of maturing epithelial cells by but also the response to therapy of oral warts are worse
EBV from the saliva, by EBV-infected B cells or pre-Langer- in patients receiving ART. Topical agents such as podofilox
han’s cells infiltrating the epithelium, or by latent infection (Condylox) and imiquimod (Aldara) have been tried, but
of the basal cell layer [59]. EBV variants, unusual EBV types, there have been no published placebo-controlled studies
and even multiple strains of EBV have been found in the showing efficacy with oral warts.
lesion [60]. Hairy leukoplakia is a fertile model for studies
of EBV gene expression [61, 62].
NEOPLASTIC DISEASE
Warts
Oral lesions caused by human papillomavirus (HPV) [63] Kaposi’s sarcoma
can occur as single or multiple papilliferous warts with multi-
ple white and spike-like projections, as pink cauliflower-like Kaposi’s sarcoma (KS; see Chapter 35) in patients with
masses (Fig. 15.7), as single projections, or as flat lesions AIDS produces oral lesions in many cases [67, 68]. The le-
resembling focal epithelial hyperplasia. In patients with HIV sions occur as red or purple macules, papules, or nodules
infection, we have seen numerous examples of each type. (Fig. 15.8). Occasionally, the lesions are the same color
Southern blot hybridization has rarely revealed (as might be as the adjoining normal mucosa. Although frequently
expected) HPV types 6, 11, 16, and 18, which usually are as- they are asymptomatic, pain may occur because of trau-
sociated with anogenital warts, but sometimes shows HPV matic ulceration with inflammation and infection. Bulky
type 7, which is usually found in butcher’s warts of the skin, lesions may be visible or may interfere with speech and
or HPV types 13 and 32, previously associated with focal ep- mastication. Diagnosis involves biopsy.
ithelial hyperplasia [64]. Novel HPV types are also found [65].
Figure 15.7 Papillomavirus warts. Figure 15.8 Kaposi’s sarcoma.
201
Lesions at the gingival margin frequently become in-

flamed and painful because of plaque accumulation.
Excision, by surgical means or by laser, is readily performed
and can be repeated if the lesion again produces problems.
Local radiation therapy has been used to reduce the size of
such lesions. Oral lesions usually regress when patients
receive chemotherapy for aggressive KS, and individual
lesions may respond to local injection of vinblastine [69]
or sclerosing agents. Unusual presentations of rapidly
growing and sometimes solitary oral lesions of KS may fol-
low initiation of ART. These may not respond well to local
excision and may be an expression of the immune reconsti-
tution inflammatory syndrome (IRIS) [70].
Lymphoma
Although not seen as frequently as with oral KS, oral lesions
are a feature in patients with HIV-associated lymphoma,
notably plasmablastic lymphoma (see Chapter 35) [71]. Figure 15.9 Recurrent aphthous ulcer.
A biopsy may prove that poorly defined alveolar swellings,
discrete oral masses, or non-healing ulcers in individuals
who are HIV-infected are non-Hodgkin’s lymphoma. No
treatment is provided for the oral lesions separate from These lesions occur as recurrent crops of small (1–2 mm)
the systemic chemotherapy regimen that usually is used to large (1 cm) ulcers (Fig. 15.9) on the non-keratinized
in such cases. oral and oropharyngeal mucosa. They can interfere signif-
icantly with speech and swallowing and may present con-
siderable problems in diagnosis. Location of RAU on the
Carcinoma non-keratinized mucosa help in the differential diagnosis
between RAU and HSV, as HSV lesions usually occur on
On the issue of possible relationships between oral cancer keratinized mucosa. History may also be helpful, as typi-
and HIV infection, some studies indicate an increased risk cally those with RAU have experienced episodes of lesions
of lip cancer, while one suggests an increase in several ep- occurring on areas such as the buccal mucosa, lateral mar-
ithelial malignancies including tongue cancer. Frisch [72] gin of the tongue or floor of mouth, over many years, often
examined cancer registry data from 11 US areas and found starting in childhood. When they are large and persistent,
an association between HIV infection and lip cancer (rela- biopsy may be indicated to exclude lymphoma. The histo-
tive risk 3.1 (1.9–4.8). Grulich and co-workers [73] in pathologic features of RAU are those of non-specific
Australia found increases in lip cancer of 2.6 times the stan- inflammation. Treatment with topical steroids is often ef-
dard incidence rate. Demopoulos and co-workers [74] used fective in reducing pain and accelerating healing. Valuable
cancer registry files at Bellevue Hospital in New York City agents include fluocinonide (Lidex), 0.05% ointment,
and compared cancers in HIV-infected and HIV-uninfected mixed with equal parts of Orabase applied to the lesion
individuals. HIV-infected patients with cancer were on av- up to six times daily, or clobetasol (Temovate), 0.05%
erage over a decade younger than HIV-uninfected patients mixed with equal parts of Orabase applied three times
(47.6 versus 60.3 years; p ¼ 0.04). The cancers in HIV- daily. These are particularly effective treatments for early le-
infected people included lung, skin, penis, larynx, tongue, sions. Dexamethasone (Decadron) elixir, 0.5 mg/mL used
colon, and rectum. These findings indicate that we cannot as a rinse and expectorated, is also helpful, particularly
exclude the possibility that these epithelial malignancies when the location of the lesion makes it difficult for the pa-
may be seen as HIV-infected people survive much longer tient to apply fluocinonide. Thalidomide, in defined proto-
under the influence of current and emerging ART. cols, has been found to be useful in very severe cases of
steroid-resistant ulcers [76], but lower continuing doses
do not prevent recurrences [77].
OTHER LESIONS Immune thrombocytopenic purpura may produce oral
mucosal ecchymoses or small blood-filled lesions. Sponta-
Recurrent aphthous ulcers (RAU) are a common finding in neous gingival bleeding may occur. Diagnosis by hemato-
the normal population. There is an impression [75], not logical evaluation is usually straightforward, but, as with
substantiated by prospective studies of incidence, that any systemic condition presenting as oral lesions, full
RAU are more common among HIV-infected individuals. work-up is indicated.
202
latter condition may be seen in association with HIV infec-

tion in the absence of salivary gland enlargement. The pa-
tient may complain of oral dryness, and there may be signs
of xerostomia, such as lack of pooled saliva, failure to elicit
salivary expression from Stensen’s or Wharton’s ducts, and
obvious mucosal dryness. Tests of salivary function, nota-
bly stimulated parotid flow-rate determination, show re-
duced salivary flow. Some of these cases are attributable
to side effects of the many medications that reduce saliva-
tion. Stimulation of salivary flow by use of sugar-free candy
or sugar-free chewing gum or the use of Salagen or Evoxac
may alleviate some of the discomfort. Topical fluorides and
other preventive dentistry approaches are used to reduce
the frequency of caries.
Figure 15.10 Parotid enlargement as part of diffuse infiltrative
lymphocytosis syndrome (DILS).
Salivary gland enlargement, predominantly involving CONCLUSION

the parotids, is seen in pediatric AIDS patients [14] and
among adults (Fig. 15.10) who are HIV-infected. This is The oral manifestations of HIV infection occur as a variety
one feature of the diffuse infiltrative lymphocytosis syn- of opportunistic infections, neoplasms, and other lesions.
drome (DILS) [50, 78, 79]. HIV-infected children with Some of them are common, perhaps the most common,
parotid enlargement progress less rapidly than those features of HIV disease and are highly predictive of the de-
without that condition [80]. No specific cause for HIV- velopment of AIDS. Their pattern, nature, and relative fre-
associated salivary gland disease has been determined, quency appear to change in those on retroviral therapy.
although viral causes are suspected. The salivary gland en- Clinicians caring for HIV-infected persons should become
largement of DILS in adults may be accompanied by ele- familiar with the diagnosis and management of this group
vated CD8 counts and labial salivary gland biopsy of conditions.
shows a CD8 lymphocytic infiltrate, reminiscent of the The oral lesions of HIV infection present challenges of
focal lymphocytic sialadenitis of Sjögren’s syndrome, diagnosis and therapy. They also offer unrivaled opportunities
where, however, the infiltrate is predominantly of CD4 to investigate the epidemiology, cause, pathogenesis, and
cells. Diagnosis to exclude lymphoma, leukemia, and other treatment of mucosal diseases. As the epidemic progresses, it
causes of salivary gland enlargement may involve labial sal- can be expected that further lesions will be observed and that
ivary gland biopsy and major salivary gland needle biopsy. additional rational and effective therapeutic approaches
Some of these cases show xerostomia. Furthermore, the will be developed.
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Plasmablastic lymphoma of the oral investigation and pathogenesis. virus-1 infection has the phenotypic
cavity: a review. Oral Oncol Oral Dis 1997;3(Suppl):190–3. appearance of an antigenically
2010;46:146–53. [76] Jacobson JM, Greenspan JS, driven response. J Clin Invest
[72] Frisch M, Biggar RJ, Engels EA, et al. Spritzler J, et al. Thalidomide for the 1993;91:2216–25.
AIDS-Cancer Match Registry Study treatment of oral aphthous ulcers in [79] Itescu S, Brancato LJ, Winchester R.
Group. Association of cancer with patients with human A sicca syndrome in HIV infection:
AIDS-related immunosuppression immunodeficiency virus infection. association with HLA-DR5 and CD8
in adults. JAMA 2001;285:1736–45. National Institute of Allergy and lymphocytosis [Letter]. Lancet
[73] Grulich AE, Li Y, McDonald A, et al. Infectious Diseases AIDS Clinical 1989;2:466–8.
Rates of non-AIDS-defining cancers Trials Group. N Engl J Med [80] Leggott PJ. Oral manifestations of
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206
Chapter | 16 |
Ocular manifestations of AIDS
James P. Dunn
annual cost of treating patients with conditions such as

INTRODUCTION CMV retinitis or progressive multifocal leukoencephalopa-
thy (PML) can be significantly reduced.
Ocular complications include both infectious and non- It is important that persons with HIV/AIDS undergo reg-
infectious disorders, and can affect virtually any part of ular eye examinations. While there is no standard fre-
the eye. Not only is prompt diagnosis and treatment of quency recommended, it should be remembered that
the more serious of these disorders essential in order to pre- these individuals often have limited access to healthcare,
serve vision and to help maintain quality of life, but simply and may be at risk for many of the ocular complications
recognizing HIV/AIDS-related eye disease can in many of aging, including cataract, diabetic retinopathy, glau-
cases impact the systemic management of affected patients. coma, and refractive errors. Simply providing a proper pair
This chapter will focus on the ocular manifestations of HIV/ of glasses to correct presbyopia in a patient over the age of
AIDS and the enormous impact over the past 15 years of 40 can have a huge benefit on that person’s quality of life.
potent antiretroviral therapy (ART).
EPIDEMIOLOGY NON-INFECTIOUS RETINAL

VASCULOPATHY
Although several of these conditions constitute AIDS-
defining illnesses, most are not reportable diseases and The most common ocular manifestation of HIV infection is
the overall incidence of ocular complications is not pre- a non-infectious retinal microvasculopathy (Fig. 16.1) [2].
cisely known. In general, however, ocular involvement in The cause is unknown but is probably multifactorial; vascu-
a person with AIDS is much more common in advanced lar sludging likely plays an important role. Clinical features
disease—that is, patients with a CD4 count < 200 cells/ include cotton-wool spots and, less commonly, intraretinal
mm3. In the pre-ART era, up to 49.1 events of vision loss hemorrhages, Roth spots, and capillary non-perfusion.
to 20/200 or worse occurred per 100 eye-years, with the in- Vision is usually unaffected, and patients are otherwise
cidence of legal blindness as high as 14.8 per patient-year. asymptomatic. The cotton-wool spots are evanescent and
The cost of treatment for, and loss of economic productivity appear clinically and histologically similar to cotton-wool
from, ocular diseases is substantial [1]. spots found in other diseases such as diabetes. The signifi-
The benefits of ART are numerous as regards to ocular cance of the non-infectious retinopathy is the correlation
manifestations. Not only is the incidence of ocular opportu- with the degree of immunosuppression. In one study,
nistic infections such as cytomegalovirus (CMV) retinitis the retinopathy was found in 45% of patients with a
dramatically lower in the ART era but also many ophthalmic CD4 count < 50 cells/mm3 compared with only 16% of pa-
conditions may resolve with immune recovery alone, which tients with CD4 counts > 50 cells/mm3 [3]. Furthermore,
allows for discontinuation of expensive and potentially the finding of a cotton-wool spot in a patient on routine
toxic therapy for that specific condition. Consequently, the examination with no other evident explanation (diabetes,
207
patients [7], multiple or bilateral herpes simplex virus

lesions, and microsporidiosis. Jeng et al. have more
extensively discussed anterior segment complications of
AIDS [8].
Molluscum contagiosum virus (MCV) causes a severe,
typically unilateral follicular conjunctivitis in otherwise
healthy individuals. In contrast, MCV infection in patients
with HIV infection tends to produce much more numerous
and larger, often confluent lesions, but without itching or
conjunctivitis, even when lesions are found on the ocular
surface [9]. The lesions usually fade away with immune re-
covery, although patients with elevated CD4 counts can de-
velop immune recovery inflammatory syndrome [10].
The differential diagnosis of cutaneous MCV includes bacil-
lary angiomatosis and disseminated histoplasmosis or cryp-
tococcosis. Treatment for cosmetically bothersome lesions
includes surgical excision, chemocautery, or cryoablation.
Herpes simplex virus (HSV) can cause periocular, con-
junctival, or corneal lesions. The disease is usually unilateral.
Cutaneous vesicles can cross dermatomal distributions and
the corneal epithelial lesions often have prominent den-
Figure 16.1 Cotton-wool spots (non-infectious retinal drites, two features that help distinguish HSV from zoster
microvasculopathy). keratitis. One large retrospective study that compared the in-
cidence and clinical course of HSV keratitis in HIV-infected
hypertension, etc.) should prompt consideration for HIV and HIV-uninfected patients found no difference in the in-
testing. cidence or type (epithelial or stromal) of keratitis, peripheral
There appears to be a cumulative dysfunction of the inner versus central location, or time needed for treatment re-
retina in patients with HIV disease, even in those taking ART, sponse. However, recurrences were nearly 2.5 times more
who have not had ocular opportunistic infections [4]. It is frequent in the HIV-infected patients [11]. Therapy includes
not clear whether this phenomenon represents an AIDS- topical trifluridine or ganciclovir or systemic acyclovir or
associated primary neuropathy or secondary damage from similar drugs. Many ophthalmologists recommend second-
non-infectious microvasculopathy. The retinopathy may ary prophylaxis with oral antiviral therapy to reduce the
be an indicator of vascular disease elsewhere in the body, risk of recurrence.
in that the presence of non-infectious retinal microangiopa- Varicella zoster virus (VZV) can cause cutaneous, con-
thy has been significantly associated with mortality [5]. junctival, or corneal disease in addition to intraocular dis-
Retinal macrovasculopathy, including retinal artery and ease (discussed below). The V1 dermatome is affected in
vein occlusions, occurred in 1.3% of nearly 2,500 consec- herpes zoster ophthalmicus (HZO) and is the single most
utive HIV-infected patients [6]. There was a strong associa- commonly affected dermatome in patients with shingles,
tion between non-infectious retinal microvasculopathy but multidermatomal distribution is not uncommon.
and retinal vein occlusions (odds ratio 5.76). Complica- Keratitis, uveitis, and post-herpetic neuralgia are all more
tions, including severe vision loss, were common, with common in HZO in HIV-infected patients. These patients
vision of 20/200 or worse in 40% of eyes. Hypertension should be monitored closely after the development of
or thrombotic disease was common in affected patients. HZO because of an increased risk of developing acute ret-
inal necrosis [7]. Therapy includes intravenous acyclovir or
high-dose oral valacyclovir; topical antivirals are ineffective
DISEASES OF THE ANTERIOR for zoster keratitis, but topical corticosteroids may be
necessary to control uveitis or stromal keratitis.
SEGMENT Microsporidiosis due to Encephalitozoon species can cause
a chronic keratoconjunctivitis in HIV-infected patients with
While there are no AIDS-defining corneal infections, and low CD4 counts. Symptoms include tearing and foreign
with the exception of herpes zoster ophthalmicus their in- body sensation. Clinical features include a bilateral papil-
cidence does not appear to be significantly greater than lary conjunctivitis with prominent hyperemia and diffuse
in immunocompetent individuals, the presence of certain punctate corneal epithelial erosions with intraepithelial
conditions should prompt consideration of possible im- infiltrates. In contrast to HIV-uninfected patients with
munosuppression. These include multiple molluscum con- microsporidiosis, the corneal stroma is not affected. The
tagiosum lesions, herpes zoster ophthalmicus in young chronicity of the disease may be due to concurrent upper
208
Chapter | 16 | Ocular manifestations of AIDS
respiratory colonization. The diagnosis requires corneal pattern throughout the retina, causing full-thickness necro-
scraping for Gram stain or electron microscopy. Therapy in- sis and blindness. Lesions may be single or multiple and
cludes ART to improve host immunity, topical fumagillin, unilateral or bilateral, affecting any part of the retina.
and systemic itraconazole or albendazole to control naso- Symptoms include visual field loss, decreased visual acuity,
pharyngeal colonization [12]. floaters, and photopsias, but pain, redness, and photopho-
Numerous other bacterial and fungal pathogens may bia are not features, and it is not uncommon for patients
cause ocular surface disease. Use of appropriate cultures, to be completely asymptomatic. The presence of subjective
stains, fluorescent microscopy, electron microscopy, and/ scotomata varies with the location of the lesions. CMV retini-
or PCR to identify the causative organism and allow specific tis may appear as intraretinal yellow necrotic lesions with
therapy is essential. retinal hemorrhages (fulminant/edematous retinitis), as less
A variety of miscellaneous anterior segment disorders densely necrotic without hemorrhage (indolent/granular ret-
have been reported. Dry eye is more common in HIV- initis), or some combination of the two (Fig. 16.2). Both
infected patients, with nearly 18% of patients affected in types, however, are characterized by a dry-appearing, granu-
one study [13]. As dry eye of any cause can increase the risk lar border. There is often a mild vitritis and anterior chamber
of contact lens-related problems, HIV-infected patients inflammation. The disease is described according to the loca-
should be monitored closely for keratopathy and treated tion within the retina—zone 1 is within 3000 mm of the
with supplemental ocular lubricants as needed. Whether center of the fovea or 1500 mm of the optic nerve; zone 2 is
HIV-infected patients are at increased risk for complica- located from the periphery of zone 1 to the ampulla of the
tions of keratorefractive surgery, or if such surgery poses vortex veins; and zone 3 from the periphery of zone 2 to
a risk of HIV transmission due to viral particles released the ora serrata. Zone 1 lesions are generally considered imme-
in the laser plume, is unclear. diately sight-threatening and usually require more urgent
Use of both inhaled crack cocaine and methamphet- therapy than do more peripheral lesions. Causes of vision loss
amine has been associated with infectious and non- include central retinal necrosis, rhegmatogenous retinal de-
infectious corneal ulceration. Putative mechanisms include tachment, secondary optic nerve involvement, or exudative
direct toxic epitheliopathy, neurotrophic keratopathy, alka- swelling along an active border adjacent to the fovea.
line chemical keratopathy, and/or eye rubbing. Atypical CMV retinitis is usually diagnosed clinically. Serologic
pathogens are common [14], even though the conjunctival testing is usually not helpful, since most adults are seropos-
flora in patients with AIDS appears to be similar to that in itive for CMV. In indeterminate cases, polymerase chain re-
HIV-uninfected individuals. action (PCR) testing of aqueous or vitreous samples can
Atopic dermatitis and blepharitis may be more common help distinguish CMV retinitis from herpes simplex virus
or more severe in HIV-infected patients than in the general or varicella zoster retinitis. An elevated CMV viral load in
population, although definitive studies are lacking. Treat- blood samples may be the most predictive risk factor for
ment for these conditions is similar to that for patients
without HIV infection, although topical tacrolimus or other
T-cell inhibitors should be avoided if possible because of
the possible increased risk of Kaposis’ sarcomas [8].
Pathanapitoon et al. examined 40 HIV-infected patients
with uveitis and found 13/40 patients (32%) had detect-
able HIV-1 RNA [15]. The intraocular HIV load was greater
than that found in plasma in three patients undergoing in-
traocular surgery, all of whom had bilateral anterior uveitis
and/or vitritis without retinal lesions, with no identifiable
cause of the uveitis otherwise noted. The uveitis in all three
patients resolved after initiation of ART.
DISORDERS OF THE POSTERIOR

SEGMENT
Cytomegalovirus retinitis is the most common ocular op-

portunistic infection in patients with AIDS. In the pre-
ART era, more than 30% of patients with AIDS and ad-
vanced immunosuppression developed CMV retinitis,
and median survival after the diagnosis was on the order
of one year [2]. The infection spreads in a “brushfire” Figure 16.2 CMV retinitis. Note the granular border.
209
end-organ disease. In rare cases, endoretinal biopsy taken 3. Cessation of anti-CMV therapy is routinely possible in
at the junction of necrotic and actively infected tissue ART-treated patients who have maintained a CD4
may be necessary. count >100 cells/mm3 for at least 3 months [17].
There are five drugs currently FDA-approved for treating 4. The risk of retinal detachment in eyes with CMV
CMV retinitis: intravenous ganciclovir, an intravitreal gan- retinitis is decreased in patients taking ART [17].
ciclovir implant, oral valganciclovir, intravenous foscarnet, 5. Mortality is decreased in patients with CMV retinitis
and intravenous cidofovir. In addition, intravitreal injec- taking ART compared to those patients not on ART.
tions of ganciclovir and foscarnet are commonly used 6. ART-experienced patients who develop CMV retinitis
off-label to provide rapid intraocular drug levels in zone have more asymptomatic disease, better visual acuity in
1 lesions (i.e. most immediately vision-threatening). Most the better eye, more bilateral disease, and less zone 1
patients do not require intravitreous therapy, although it involvement compared to ART-naı̈ve patients [19].
may be necessary in patients unable to undergo implant ART is not a cure for CMV retinitis, and patients with
surgery and intolerant of the hematopoietic side effects CMV retinitis and immune recovery remain at increased
of systemic ganciclovir. The ganciclovir implant provides risk of mortality and for progression of retinitis, retinal de-
intraocular drug levels roughly fourfold higher than those tachment, and vision loss [20]. Nonetheless, the risk of
obtained with intravenous ganciclovir and controlled clin- each of these complications is greater for patients with
ical trials have demonstrated its superiority over systemic newly diagnosed retinitis than for patients with previously
therapy for control of retinitis. However, the implant does diagnosed, inactive retinitis and immune recovery.
not reduce the risk of retinitis in the fellow eye or of extra- The use of ART has resulted in the phenomenon known
ocular CMV disease. Controlled studies have shown that as immune recovery uveitis (IRU) [17], a term for a spec-
a combination of the implant plus systemic therapy is trum of inflammatory processes that include vitreous haze,
the most effective, as it effectively controls retinitis while optic disc edema, cystoid macular edema, epiretinal mem-
reducing the incidence of other end-organ CMV disease. brane formation, and vitreomacular traction (Fig. 16.3). In
Furthermore, presumably because of the reduction in the most, but not all, cases of IRU, the CMV retinitis is inactive;
cross-activation of CMV and HIV, systemic anti-CMV ther- IRU does not occur in eyes without CMV retinitis or in pa-
apy reduces mortality. Therefore, oral valganciclovir should tients without immune recovery. Affected patients usually
always be used in the absence of specific contraindications. complain of decreased vision and floaters but not of pain.
As with other HIV-related infections, however, the most Posterior synechiae are uncommon. IRU must be distin-
important treatment for CMV retinitis is immune recovery; guished from other causes of intraocular inflammation in
all patients with CMV retinitis should be treated with patients with CMV retinitis, including cidofovir-associated
ART unless there are medical contraindications or non- uveitis or ganciclovir implant-associated endophthalmitis,
adherence to therapy is anticipated. All currently available as well as non-CMV-associated uveitis, such as syphilis.
therapy is virostatic, not virocidal, so patients who remain Treatment for topical or periocular injections of corticoste-
immunosuppressed require lifelong suppressive therapy, roids is usually initiated, but the results are variable [21].
adding substantially to the cost and potential morbidity Vision loss is usually moderate but not severe [21] and
of treatment. Patients without immune recovery will on av- can be due to cataract, vitreous haze, cystoid macular
erage get progression or breakthrough of retinitis, manifest- edema, and epiretinal membrane formation. IRU is now
ing as new lesions or reactivation of a previously inactive a leading cause of visual loss in patients with CMV retinitis.
lesion, within 2–3 months, even while continuing therapy. Necrotizing herpetic retinopathy encompasses a spec-
Development of ganciclovir resistance through UL97 or trum of infectious retinitides caused by herpes simplex
UL54 mutations is common within 6 months of therapy, virus and varicella zoster virus. At one end of the spectrum
but limited intraocular penetration across the blood–retina is progressive outer retinal necrosis (PORN), which is al-
barrier with systemic therapy likely accounts for the initial most always caused by VZV and occurs in patients with pro-
episodes of recurrence. Antiviral resistance and break- found immunosuppression [22]. The retinitis can start in
through retinitis is much less common in ART-treated pa- the macula or in the periphery with patchy, multifocal
tients, but the increased mortality associated with the outer retinal lesions coalescing rapidly over several days
development of resistant CMV is of comparable magnitude throughout the retina in the absence of retinal vasculitis,
in patients in the pre- and post-ART eras [16]. vitreitis, or anterior uveitis. Retrolaminar optic nerve in-
The widespread use of ART has had an enormous impact volvement may precede the retinitis, causing significant
on the incidence, complications, and treatment of CMV pain and decreased vision with an otherwise unremarkable
retinitis, as summarized below, when compared to the examination, delaying the diagnosis for several days. Severe
pre-ART era: visual loss from the diffuse retinal necrosis, optic atrophy,
1. The incidence of CMV retinitis has fallen 80–90% [17]. and retinal detachment occur in the majority of patients.
2. Visual field loss is decreased six- to sevenfold in patients Treatment with intravenous acyclovir is usually ineffective
with immune recovery (CD4 count > 100 cells/mm3) [18]. [22]. Combination therapy with systemic foscarnet and
210
A
Figure 16.3 Immune recovery uveitis. (A) Keratic precipitates. (B) Optical coherence tomography showing macular edema.
211
intravitreal foscarnet or the ganciclovir implant may result in The presence of a placoid choroidopathy or retinal arterio-
better visual outcomes by halting progression of retinitis and litis with punctate inner retinitis may be pathognomonic.
reducing the risk of retinal detachment [23]. It is essential to Conventional staging of syphilis may be difficult to apply
start patients on ART as soon as possible, as immune recov- to ocular disease, and it is recommended that all patients
ery offers the best chance of long-term control of PORN. with ocular syphilis undergo neurosyphilis-type treatment
At the other end of the spectrum is acute retinal necrosis regimens with intravenous penicillin to avoid the risk of in-
(ARN), which is characterized by a fulminant panuveitis adequate therapy [25]. Rapid resolution of fundus abnor-
with well-demarcated confluent areas of full-thickness ret- malities with intravenous penicillin is characteristic. The
initis, choroiditis, and papillitis. Unlike in PORN, the CD4 diagnosis should be based on clinical features and both re-
count is usually >60 cells/mm3 in patients with ARN. Var- agin and specific (fluorescent treponemal antibody absorp-
icella zoster virus and herpes simplex virus have both been tion test [FT-ABS] or microhemagglutination assay for
associated with this disease. The retinitis is marked by deep Treponema pallidum [MHA-TP]) testing because of the risk
retinal whitening, limited hemorrhage, and a rapid proof false-negative reagin tests. Despite the common associa-
gression over days to weeks (that is, somewhat slower than tion of HIV and syphilis, however, one large study did
in PORN but more rapid than in CMV retinitis). Traction not find an increased incidence of ocular syphilis in
retinal detachments occur in up to 75% of patients and HIV-infected compared to HIV-uninfected patients [26].
blindness in 64% of patients within 2–3 months if treat- Tuberculosis (TB), like syphilis, is one of the “great
ment is not initiated. Late in the course of the disease, ret- mimickers” among ocular infections, and should always
inal breaks and detachments in the area of necrosis are be considered in the differential of panuveitis. The presence
common. Proliferative vitreoretinopathy often accom- of a choroidal nodule in patients at high risk of TB is highly
panies the retinal atrophy in the end stages of the suggestive of a tuberculoma. Findings that suggest a possi-
disease. The treatment for ARN in AIDS patients is similar ble tuberculous cause of uveitis include broad-based poste-
to that advocated in non-HIV patients. Therapy includes rior synechiae, retinal vasculitis, and a serpiginous-like
intravenous acyclovir or high-dose valacyclovir followed choroiditis. The diagnosis can be difficult to make because
by indefinite oral therapy with acyclovir, valacyclovir, or chest films are often normal in extrapulmonary TB, organ-
famciclovir. While those immunocompetent patients with isms may be sparse in histopathologic specimens, and
ARN are sometimes treated with oral corticosteroids to re- tuberculin skin tests have limited sensitivity [27]. Treat-
duce vitreous inflammation, this approach is controversial ment with a four-drug regimen and oral corticosteroids is
in HIV patients because of concerns about additional im- recommended for patients with tuberculous uveitis.
munosuppression; short-term prednisone therapy proba- Pneumocystis carinii choroidopathy (PCC), or choroidal
bly does not put the patient at significant risk. Laser pneumocystosis, is a rare disseminated form of P. carinii in-
demarcation along the posterior border of the retinitis is fection that occurs only in patients treated with aerosolized
indicated to reduce the risk of retinal detachment. Some pa- pentamidine for P. carinii pneumonia (PCP) prophylaxis.
tients have necrotizing retinitis with features of both ARN The aerosolized treatment is effective for prevention of pul-
and PORN; in such cases, it seems wise to err on the side of monary disease but does not achieve adequate serum levels
the more aggressive therapy used for the latter. to prevent extrapulmonary infection. Affected patients typ-
Ocular toxoplasmosis in HIV-infected patients is more ically show severe wasting but have normal chest X-rays.
likely to be bilateral and multifocal and to occur in the ab- Ocular findings include multiple cream- or orange-colored
sence of pre-existing retinal scars (suggesting a higher inci- choroidal infiltrates ranging from 300 to 3000 (two optic
dence of acquired disease) compared to infection in HIV- disc diameters) in size, which can become confluent.
uninfected patients [24]. A necrotizing retinopathy mimick- The overlying retinal vasculature is completely normal
ing CMV retinitis may occur, but the borders of the lesion in and there is no vitreitis. Vision is usually unaffected. Treat-
toxoplasmosis are usually smooth without granularity, reti- ment with intravenous pentamidine or trimethoprim-
nal hemorrhage is less common, and vitreous and anterior sulfamethoxasole (TMP-SMX) is effective. Widespread use
chamber inflammation is usually much greater in toxoplas- of prophylaxis against PCP with TMP-SMX or other
mosis. A wide variety of treatments are used, with some systemic agents has virtually eliminated PCC.
variation of sulfa drugs and pyrimethamine the most com-
monly used. Intravitreal clindamycin may be helpful in pa-
tients who cannot tolerate systemic therapy. Secondary
NEURO-OPHTHALMOLOGIC
prophylaxis to prevent recurrence of disease was necessary
in the pre-ART era. The incidence of both ocular toxoplas- DISORDERS
mosis and toxoplasmic encephalitis has decreased in the
era of ART, and discontinuation of secondary prophylaxis There are numerous causes of neuro-ophthalmic com-
is possible in patients with immune recovery [17]. plications of AIDS, including infections, neoplasms, and
Ocular syphilis in HIV-infected patients can cause optic degenerative disorders. Manifestations include optic neu-
neuritis, neuroretinitis, uveitis, and necrotizing retinitis. ropathy, cranial nerve palsies, loss of vision, diplopia,
212
papilledema, visual field deficits, and abnormal eye move-

ments. Cryptococcosis and toxoplasmosis are the most
common central nervous system (CNS) infections in pa-
tients with AIDS [28]. Diseases caused by these organisms
have become less frequent in the ART era but remain signif-
icant causes of morbidity and mortality, especially in pa-
tients with limited access to care [29]. The diagnosis is
usually based on clinical findings, serology, spinal fluid
analysis (including PCR), and imaging studies; brain bi-
opsy is occasionally necessary, particularly when distin-
guishing intracranial toxoplasmosis from CNS lymphoma.
In contrast to immunocompetent patients with ocular
toxoplasmosis, patients with AIDS are more likely to have
acquired disease (as opposed to reactivation of congenitally
acquired disease) and intracranial involvement. Jabs
reported a relative risk of 19.9% for the development of
CNS disease in patients with ocular toxoplasmosis, whereas
only 12% of patients with CNS involvement had ocular dis-
ease [2]. Ocular manifestations are usually due to the mass
effect of the infection within the brain, causing cranial nerve
palsies and visual field defects. The manifestations of retinal
involvement are discussed elsewhere in this chapter. Life- Figure 16.4 Cryptococcal choroiditis. The patient had
long maintenance therapy is indicated to prevent recurrence concurrent meningitis.
in patients who remain immunosuppressed, but most oph-
thalmologists discontinue therapy in ART-treated patients if Choroidal involvement is associated with systemic NHL,
the CD4 count increases above 200 cells/mm3 [30]. whereas retinal involvement is more commonly associated
Over 75% of those affected with cryptococcal disease have with CNS lymphoma and may mimic the necrotizing
a CD4 count of <50 cells/mm3. The most common presen- retinitis caused by CMV, toxoplasmosis, or syphilis.
tation is chronic meningitis, with headache, nausea, and pho- The effect of direct HIV infection in neuro-ophthalmic
tophobia. Mass lesions (cryptococcomas) can cause focal disease is less well established. Although primary HIV infec-
neurologic deficits. Cryptococcal meningitis is the most com- tion can cause neurologic disease, optic neuropathy directly
mon cause of papilledema in patients with AIDS, although it attributed to HIV is uncommon [36]. Patients with AIDS
is seen in less than 10% of affected patients [31]. Ocular man- show a decrease in optic nerve axons, even in the absence
ifestations include sixth nerve palsies, decreased peripheral of visual signs or symptoms. Reversal of optic neuropathy
vision, and loss of central vision. A small subset of patients has been successful in some patients after initiation of
can develop sudden, severe, bilateral vision loss, with or with- ART. Furthermore, 10–15% of patients with AIDS but with-
out papilledema, presumably due to perineuritic adhesive out ocular opportunistic infections will have a presumed
arachnoiditis [32]. Metastatic choroidal lesions, similar to neuroretinal disorder (HIV-NRD), manifested by reduced
those seen in TB, may be present (Fig. 16.4). contrast sensitivity and abnormal visual fields [37]. Pro-
Progressive multifocal leukoencephalopathy (PML) is a posed mechanisms include direct infection of neural tissue,
demyelinating disease caused by the polyoma JC virus indirect damage due to immune reaction against HIV infec-
and occurs in patients with profound immunosuppression tion, and HIV microangiopathy-related cumulative damage
from AIDS or iatrogenic immunosuppression [33]. In the to the optic nerve and retina.
pre-ART era, PML was a terminal diagnosis [34], but im- CNS disease may paradoxically worsen after initiation of
mune recovery from ART can result in substantial improve- ART due to the immune recovery inflammatory syndrome
ment. Ocular manifestations include retrochiasmal visual in virtually all of these conditions. The exact pathophysiology,
field defects, occipital blindness, and nuclear and supra- primary risk factors, and appropriate treatment remain uncer-
nuclear palsies. A high index of suspicion is necessary to tain, although systemic corticosteroids are often used [10].
make the diagnosis, as the remainder of the ocular exami-
nation may be unremarkable.
Other causes of neuro-ophthalmic disorders include tu-
berculous meningitis, AIDS-related dementia complex, in- NEOPLASTIC DISORDERS
tracranial zoster, and CNS lymphoma. The incidence is
greater in developing countries [35]. Ocular non-Hodg- Guech-Ongey et al. have identified three eye cancers
kins’s lymphoma (NHL) is much less common than CNS that are significantly more common in patients with
disease but can occur within the retina, choroid, or orbit. HIV/AIDS in the United States: conjunctival squamous cell
213
carcinoma (SCC), primary ocular lymphoma, and Kaposi’s mimicking HLA-B27-associated uveitis or endophthalmitis.
sarcoma [38]. While the overall incidence is low (73 eye Treatment is aggressive topical corticosteroid therapy and ces-
cancers among nearly half a million patients with HIV/AIDS sation of rifabutin therapy. Retinal vasculitis has also been
in the US Cancer Match Registry Study from 1980 to 2004), reported [44]. Less commonly, asymptomatic peripheral cor-
the standardized incidence ratios per 100,000 population neal endothelial deposits may occur, for which treatment is
for the three cancers were 12.2, 21.7, and 109, respectively. not necessary.
Kaposis sarcoma is the most common ocular neoplasm Cidofovir, now used most commonly to treat ganciclo-
in patients with HIV/AIDS; however, the incidence has de- vir- and foscarnet-resistant CMV retinitis, can cause acute
creased markedly in the era of ART [39]. The causative agent anterior uveitis, often with hypotony and extensive poste-
is human herpesvirus type 8, which is sensitive to ganciclo- rior synechiae formation [45]. Onset usually occurs after
vir [40]. Lesions are usually found in the inferior conjunc- the patient has received 3–5 doses of the medication. The
tival fornix, mimicking a subconjunctival hemorrhage, or risk is increased in patients taking other nephrotoxic med-
less often on the eyelid, where they appear as raised, purple ications and irreversible hypotony may develop if cidofovir
nodules. There is no intraocular spread and vision is not af- therapy is continued. Cessation of the drug and treatment
fected. As with many viral eye diseases, ART is the most ef- with topical corticosteroids is usually effective. Subsequent
fective definitive therapy. Lid lesions requiring more acute resumption of cidofovir should be undertaken with great
intervention because of entropion or trichiasis may re- caution and only if no other treatment options for CMV
spond to intralesional or systemic chemotherapy, cryother- retinitis are available.
apy, surgical debulking, or radiation, but this is not usually Ritonavir was recently linked with a developed retinal
necessary. pigment epitheliopathy, macular telangiectasis, and intra-
Traditional risk factors for conjunctival SCC include age retinal crystalline deposits [46]. The three patients reported
< 50 years, Hispanic race, and residence in regions with all had CD4 counts >100 cells/mm3.
high-solar ultraviolet radiation, but AIDS patients tend to Interferon-a can cause an ischemic retinopathy with cotton-
be younger and more commonly female [41]. There is a wool spots, retinal hemorrhages, arteriolar hemorrhages,
strong association of SCC with human papillomavirus, and capillary non-perfusion. Cystoid macular edema has also
but not all conjunctival tumors demonstrate presence of been reported. In one study, 35% of patients co-infected
HPV [42]. Clinical features include a gelatinous or scaly le- with HCV and HIV developed intraocular pathology [47].
sion overlapping the limbus with extension onto the cor-
nea of one eye only; leukoplakia is common. Treatment
involves wide excision with freeze–thaw cryotherapy to
the adjacent margins. The resulting epithelial defect may
be left to heal by secondary intention, or more commonly
FUTURE DIRECTIONS
is covered by an amniotic membrane graft or conjunctival
autograft. Topical antimetabolites such as mitomycin-C, Clearly, the most important intervention that can be under-
cidofovir, interferon-a, or 5-flurouracil are usually given taken both to prevent and to treat the ocular complications of
postoperatively, but the recurrence rate is high. The disease HIV/AIDS is the initiation and maintenance of ART. Immune
can be fatal if it metastasizes to regional or distant lymph recovery inflammatory syndrome (IRIS) is a broad term for
nodes or spreads intracranially. the paradoxical exacerbation of inflammation in immuno-
suppressed patients with a variety of pathogens and who
are treated with ART. The most well-known ocular manifesta-
tion is immune recovery uveitis in patients with CMV retinitis
DRUG-INDUCED OCULAR
[17]. Identification of patients at risk for IRU and im-
COMPLICATIONS provement in the treatment of this disorder remain a high pri-
ority for ophthalmologists managing patients with AIDS.
Several drugs used in the treatment of HIV-related eye dis- Nonetheless, the overwhelming benefits in terms of reduced
ease can cause ocular side effects. The most well known is incidence of disease, better outcomes in patients with ocular
ethambutol, which can cause a dose-related optic neurop- manifestations, enhanced quality of life, and reduced cost
athy with decreased color vision and central or centrocecal would appear to far outweigh the risks of IRU.
scotomata. Patients with renal failure or taking doses of Rapid diagnosis of intraocular infections is critical for
more than 15 mg/kg/day are at greatest risk. initiation of the most directed therapy. The utility of PCR
Rifabutin can cause acute anterior uveitis, particularly testing appears greatest for viral infections, but is less useful
when taken in high doses (600 mg per day) or concurrently for bacterial and protozoal infections, in which the more
with other drugs such as clarithromycin or ethambutol cumbersome intraocular antibody analysis may be more
that may affect metabolic clearance of rifabutin [43]. The sensitive [48]. Development of multiplex PCR testing for
pathophysiology remains unclear. Manifestations include all common ocular pathogens will enhance diagnostic
unilateral or bilateral acute uveitis with or without hypopyon, speed and accuracy.
214
Among the promising new areas of research is the field of

genomics. In recent years, host genetic factors have been iden- CONCLUSION
tified that indicate different haplotypes can either increase or
decrease the risk of CMV retinitis as a result of how they mod-
The incidence of ocular complications in patients with
ulate host immune reactions through an IL-10 receptor medi-
HIV/AIDS has declined significantly since the widespread
ated immune-suppression pathway [49]. Similarly, variants in
usage of ART. Non-infectious retinal microvasculopathy re-
the IL-10-related pathway and chemokine receptor ligand
mains the most common ocular manifestation and CMV
polymorphisms in RANTES may alter the risk of developing
retinitis the most common ocular opportunistic infection.
a neuroretinaldysfunction that results in reduced contrast sen-
Many virally mediated ocular diseases are responsive to
sitivity, abnormal visual fields, and impaired reading speed
ART alone. Although initial specific therapy (e.g. in CMV
[37]. Another study by Hendrickson et al. found that, among
retinitis) is still indicated because of enhanced ocular
HIV-infected patients of western European descent who car-
and systemic outcomes, ongoing immune recovery fre-
ried the mitochondrial haplogroup J, there was an 80% de-
quently allows discontinuation of these specific therapies,
crease in this neuroretinal disorder compared to matched
resulting in decreased morbidity and medical care costs.
patients without haplogroup J [50].
Identifying and treating patients who develop ocular com-
Finally, ongoing epidemiological studies such as the
plications as a result of intolerance, poor adherence, or lack
Longitudinal Studies of the Ocular Complications of AIDS
of access to ART remains a priority. For patients who expe-
(LSOCA) hope to determine whether disorders such as cat-
rience immune recovery, emphasis by ophthalmologists is
aracts are more common in patients with AIDS indepen-
gradually shifting toward surveillance of treated disorders
dent of CMV retinitis and whether careful evaluation of
and monitoring for other chronic eye diseases such as cat-
the retinal vasculature may help clinicians identify those
aracts and diabetic retinopathy.
patients at greatest risk for development of dyslipidemia
syndromes associated with ART.
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217
Chapter | 17 |
Global HIV and dermatology
Toby Maurer, Robert Michelleti
presenting with these symptoms [9]. Patients with primary

SKIN DISEASE IN HIV HIV infection may be highly infectious because of the pres-
ence of a high viral burden in blood and genital secretions
HIV-infected patients carry a heavy burden of cutaneous ill- [10]. Confirmation of ARS can be made by finding positive
ness. As many as 90% have at least one skin disease; most plasma HIV RNA and negative HIV antibody [11]. Treat-
have several [1, 2]. Mucocutaneous diseases in HIV patients ment with ART early in this phase may decrease the severity
are a significant source of morbidity. They can cause of the disease, alter the initial viral set point, and reduce the
chronic itching or pain, lead to secondary superinfection, rate of viral replication. However, therapy may cause drug
or reflect the presence of a life-threatening malignancy or toxicities and potential resistance if it fails [8]. Studies to
invasive infection. determine the optimal time to start therapy are ongoing.
Importantly, skin disease is also a clinical marker of im-
munosuppression. Many conditions are seen preferentially
in those with low CD4 counts, while a high number of PIGMENTATION
skin diseases correlate with low CD4 and worse prognosis
[3, 4]. Skin conditions in HIV-infected patients may occur HIV infection is associated with pigment disorders, both
as a manifestation of HIV itself, an opportunistic infection, hyperpigmentation and hypopigmentation. Hyperpigmen-
a neoplastic process, a primary dermatologic condition, a tation has been reported in HIV-infected persons with
drug reaction, or as part of the immune reconstitution background pigment. Advanced HIV infection and immu-
inflammatory syndrome. Appropriate recognition and nosuppression has also been associated with more diffuse
treatment of these conditions is vital to the care of patients hyperpigmentation. In a Chinese HIV-infected population
with HIV. in Malaysia, hyperpigmentation was the most common
skin disorder, representing 36% of the whole group stud-
ied, while 47% of an Indian population in a separate study
PRIMARY HIV were affected [4, 12]. Pigmentation is most commonly seen
in sun-exposed areas but becomes more diffuse over the
Acute retroviral syndrome (ARS) or primary HIV infection body. Photodistributed hyperpigmentation has been noted
may be the presenting sign in 40–90% of patients. It is of- with CD4 counts < 100 cells/mm3 and may be the present-
ten asymptomatic and non-specific. ARS consists of a ing sign of HIV infection [13]. Gray coloration of the nails
mononucleosis-like illness with fever, lymphadenopathy, and pigmented oral mucosa may be other markers of more
pharyngitis, and neurologic symptoms. The skin rash advanced stages of immunosuppression with CD4 counts
may be recognized in about half of symptomatic patients < 200 cells/mm3 [14, 15]. Cutaneous hyperpigmentation
and typically is a non-specific maculopapular exanthem has also been linked with eczematous features, in both
[5, 6]. Oral and genital ulcers may also occur, as may infil- the acute and chronic forms [16].
trated plaques on the chest and back [7, 8]. There should be Several reasons for hyperpigmentation have been postu-
a high index of suspicion for HIV infection in patients lated [17]. Medications used for the treatment and
219
prophylaxis of AIDS-related conditions can cause photo- and in fact is often the presenting sign [29, 30]. A marker
sensitivity [18]. These drugs include trimethoprim-sulfa- of more advanced immunosuppression, it may improve
methoxazole, azithromycin, dapsone, ketoconazole, and dramatically with effective ART [31]. Biopsy findings in-
anti-tuberculosis drugs. Antiretroviral medications like include a mild to moderate dermal perivascular and periad-
dinavir, saquinavir, and efavirenz have been associated nexal infiltrate. Early lesions biopsied in Uganda have
with photosensitivity [19]. Zidovudine (AZT) may result revealed histology consistent with arthropod bites [32]. It
in the hyperpigmentation of the nails, oral mucosa, and has been hypothesized that this condition represents an
skin and appears to be related to increased melanogenesis altered and hyperactive immune response to arthropod
and not to drug deposition or photosensitivity [20]. Con- bites [33, 34]. Cytokine profiles of individuals with PPE
comitant diseases in HIV-infected individuals, such as Por- show lower levels of interleukin-2 and g-interferon, arguing
phyria cutanea tarda, which causes photosensitivity, and for a dysregulated immune system [35]. In addition to
Mycobacteria avium intracellulare, which can affect the adre- immune reconstitution, potent topical steroids, antihis-
nal glands and cause adrenal suppression, can eventuate in tamines, and ultraviolet light may bring symptomatic
hyperpigmentation [21]. Sunscreen (SPF15 or higher) and relief [36–39]. Eosinophilic folliculitis (EF) has been
avoidance of sun exposure can improve symptoms. reported in Southeast Asia, Africa, India, Europe, and North
Pigmented oral lesions are not uncommon, particularly America [16, 22, 40, 41]. This disease presents with pruritic
in India and Africa [22]. Similar oral lesions are noted in urticarial papules and nodules on the scalp, neck, face, up-
Caucasians with HIV infection who have not been on per chest, and back and is therefore differentiated clinically
any medications. from PPE. It is usually associated with a nadir CD4 count
Hypopigmentation in HIV infection in the form of < 100 cells/mm3 and a current CD4 count < 200 cells/
vitiligo has been reported. Vitiligo has been considered mm3. This condition can also be seen in individuals starting
to be an autoimmune disorder like alopecia areata, possi- ART as part of an immune reconstitution syndrome [42].
bly reflecting concomitant B-cell dysfunction in HIV infec- Clinicians should be aware of this possibility and should
tion, though the mechanism is poorly understood. Both not confuse the eruption with a medication reaction or stop
the onset and resolution of vitiligo have been reported in therapy. The pathogenesis of EF remains elusive [43]; how-
persons with increasing CD4 cell counts on antiretroviral ever, it presumably involves an enhanced Th2 response
therapy (ART) [23, 24]. with elevated interleukin-4, interleukin-5, and chemokine
recruitment of eosinophils [44]. Histologically, there is a
predominant perifollicular infiltrate of eosinophils [38,
45]. Biopsy of lesions can differentiate this condition from
ITCHING other pruritic disorders. Treatment [46] options include
waiting out the immune reconstitution period (the first
Itching is a common complaint among HIV-infected pa- 12 weeks of ART), potent topical steroids and antihista-
tients. Pruritus without a rash is less common than origi- mines, itraconazole, UVB therapy, and isotretinoin [47].
nally thought and can be associated with concomitant Prurigo nodularis has been reported globally and is char-
systemic diseases like hepatitis C, chronic renal failure, acterized by pruritic dome-shaped nodules initially pre-
lymphomas, and methamphetamine use. When a pruritic senting on the photoexposed areas of the extremities and
dermatitis is noted, a careful history and physical examina- eventually involving the trunk [16]. These nodules are bi-
tion usually reveals a primary dermatologic condition for lateral and symmetric and appear in persons with back-
which standard treatment for the underlying condition ground pigment, usually with CD4 counts < 100 cells/
can proceed. Included in this heterogeneous group of dis- mm3. The incessant rubbing and scratching of these lesions
eases are xerosis, eczema, seborrheic dermatitis, psoriasis, can lead to lichenification of the skin as well as pigment
Staphylococcal aureus folliculitis, eosinophilic folliculitis, change, both hyper- and hypopigmentation. A search for
prurigo nodularis, pruritic papular eruption (PPE) of an underlying, treatable condition like scabies or eczema
HIV, arthropod assaults, scabies, and drug rashes. Biopsy is warranted [48, 49]. Immune reconstitution and reduc-
and cultures of lesions can be helpful in distinguishing tion of viremia with ART are helpful. Regimens that include
these conditions [16]. raltegravir may be particularly useful in refractory cases
As early as 1983, reports from sub-Saharan Africa, Haiti, [50]. Potent topical steroids and antihistamines are of ben-
Brazil, and Thailand described an eruption of intensely pru- efit. Ultraviolet light and thalidomide have been somewhat
ritic papules and nodules that begins on the extensor sur- helpful when other therapies have failed [51].
faces of the extremities and subsequently involves the Scabies is noted globally and usually presents with pru-
trunk and face [25–28]. Called the pruritic papular eruption ritic papules with accentuation in the intertriginous areas,
of HIV, these lesions have not been reported in Europe or genitalia, and fingerwebs [48, 49]. With advancing immu-
America but are exceedingly common in the tropics, affect- nosuppression, the infestation may become more wide-
ing 11–46% of HIV-infected patients in those regions. spread and refractory to treatment [52]. Crusted scabies
When present, PPE is highly predictive of HIV infection may also occur with advanced HIV and presents with thick
220
Chapter | 17 | Global HIV and dermatology
crusts that are non-pruritic and teeming with mites [53]. should guide empiric therapy. Increasing resistance to b-
Outbreaks of scabies in institutional settings like orphanages, lactam drugs and fluoroquinolones has been reported.
hospitals, and hospices are particularly challenging [54]. Erythromycin, clindamycin, sulfamethoxazole, gentami-
Topical treatment of scabies is with benzyl benzoate 10%, cin, and intravenous vancomycin are still used. Tetracycline
sulfiram 2% (in Europe), or permethrin 5% cream (available drugs are being used with more frequency [71]. Linezolid is
in the USA and UK). Gamma-benzene hexachloride (lin- an expensive alternative and should be reserved for cases
dane) is contraindicated in HIV, as it has been associated in which there is documented resistance to the above-
with the development of peripheral neuropathies. Oral iver- mentioned antibiotics [72]. Incision and drainage of ab-
mectin can also be used for treatment of scabies in an institu- scesses is critical. Hibiclens and Betadine washes may have
tion or for crusted scabies. Treatment of contacts and proper a role but can often dry out the skin, leading to eczematous
cleaning of garments and linens is essential in treatment eruptions prone to secondary bacterial infections. Mupiro-
and infection control, particularly in institutional settings cin ointment reduces carriage rates in HIV but does not de-
[55, 56]. The risk of secondary staphylococcal and streptococ- crease infection rates and there is concern for emerging
cal infection of scabietic lesions is high in tropical environ- mupirocin resistance [73, 74]. Rifampin can be used in com-
ments, so antibacterial therapy should also be used when bination with other antibiotics to reduce carriage rates of
necessary [57–59]. S. aureus. It acts synergistically with other antibiotics but can-
not be used with many of the antiretroviral medications,
particularly the protease inhibitors, because of drug–drug in-
STAPHYLOCOCCAL AUREUS teractions [75]. In Mali, an algorithm for treatment of skin
diseases was developed. Patients were first evaluated for
SKIN INFECTIONS signs of pyoderma by looking for presence of yellow crusts,
pus, sores, or blisters. Depending on the degree of pyo-
Staphylococcus aureus is the most common cutaneous bacte- derma, patients were treated with topical antiseptics or oral
rial infection in patients with HIV disease [60]. Commu- antibiotics and returned for a follow-up visit. Abscesses were
nity-acquired infections of subcutaneous and deep tissues incised and drained and not treated with antibiotics. The use
are common throughout the world [61]. In the Caribbean of this algorithm correctly identified pyodermas and second-
Islands and Africa, bacterial infection in HIV represent up arily infected eczemas 96–98% of the time and decreased the
to 40% of all skin diseases as either primary infection or use of steroids and antifungals [48].
secondary superinfection of eczema or scabies [62].
Rates of S. aureus carriage are high, and persistent colo-
nization among HIV-infected patients is common. These
factors increase the risk of soft tissue infections [63–65]. BACILLARY ANGIOMATOSIS
Staphylococcus aureus in the skin can manifest in many ways,
including bullous impetigo, ecthyma, folliculitis, abscesses, Bacillary angiomatosis (BA), a treatable opportunistic in-
and furuncles. Occasionally, infected follicles coalesce fection, can present with vascular, easily friable papules
to form violaceous plaques that may be studded with pus- or subcutaneous nodules in patients with advanced HIV
tules. Rarely, abscesses of the muscle (pyomyositis) as disease. The agents causing this infection have been classi-
well as deep tissue involvement in the form of necrotizing fied as Bartonella, and at least 15 species have been identi-
fasciitis may occur. fied worldwide in association with various vectors [22, 76].
Over the past decade, HIV-infected patients have shown Cutaneous manifestations of BA in the HIV-infected
a high and growing rate of soft tissue infection with meth- population are primarily caused by two species, Bartonella
icillin-resistant S. aureus (MRSA). In Cook County, Illinois, henselae and Bartonella quintana [77, 78]. Epidemiologi-
the incidence of MRSA infection among HIV-infected pa- cally, B. henselae has been associated with cat and flea expo-
tients was six times higher than among HIV-uninfected pa- sure. B. quintana has been associated with low income,
tients, while between 2000–2003 and 2004–2007, the homelessness, and exposure to lice [79]. BA has been
incidence of MRSA among HIV patients increased 3.6-fold reported in North and South America, Europe, India, and
[66]. Risk factors for the development of MRSA in HIV in- Africa [76, 80–84]. Studies from multiple regions have
clude low CD4 counts, recent hospitalization or antibiotic shown that the seroprevalence among HIV-infected pa-
exposure, high-risk sexual practices, intravenous drug use, tients is high [85–87]. In countries where Kaposi’s sarcoma
and environmental exposures [67, 68]. Some studies sug- (KS) is prevalent, BA may be under-recognized, as it can
gest the widespread use of trimethoprim-sulfamethoxazole mimic the vascular lesions typically associated with KS. Di-
prophylaxis may increase rates of S. aureus resistance to that agnostic accuracy is important because the response of BA
medication [69]; however, this does not always appear to to prompt antibiotic therapy can be excellent, whereas the
be the case [70]. prognosis of untreated, disseminated BA or KS is more
Knowing the organism and its sensitivities is imperative guarded. Lesions of BA may also be confused with pyogenic
where at all possible. Otherwise, local resistance patterns granuloma and lymphoma [88].
221
Bacillary angiomatosis initially was considered a disor- [111]. Lesions include chancres, sometimes with rapid evo-
der of the skin, but systemic involvement is common. lution to secondary stages, papulosquamous lesions on the
Visceral disease may present as osseous lesions, hepatic trunk and palmar/plantar regions, patchy alopecia, and
and splenic tumors, lymph node disease, pulmonary le- osteochondritis of the sternal region [112–114]. Uveitis
sions, brain lesions, bone marrow, and widespread fatal with or without rash is another common manifestation
systemic involvement. Bacillary angiomatosis can present [115]. Oral lesions are also common [22]. Tertiary cutane-
with unexplained fever, bacteremia, or endocarditis in ous lesions are characterized by verrucous or hyperkeratotic
HIV-infected patients [89]. Lesions should be biopsied nodules. Lues maligna has been reported in HIV infection
and examined with hematoxylin and eosin staining and [116]. Skin biopsies or dark field microscopy of cutaneous
Warthin–Starry silver staining, which reveals the organ- lesions demonstrates spirochetes and establishes the diag-
isms. Culture, indirect fluorescent antibody testing, and nosis [110]. Negative serologic tests may not be adequate
polymerase chain reaction can be performed on lesions for ruling out secondary syphilis, as HIV infection may
and serum. Immunohistochemical staining for anti-HHV8 delay development of serologic evidence of Treponema pal-
can be used to differentiate KS from BA [90]. lidum. However, for the majority of patients, serologic
Treatment with erythromycin or doxycycline for at least testing is adequate [117].
3 months is recommended even though cutaneous lesions Central nervous system (CNS) involvement may mani-
resolve in 3–4 weeks. Relapses can occur if treatment is not fest early in HIV, and relapse in the CNS may be more com-
continued appropriately. Severely ill patients should be mon even after standard treatment. Clinicians should
treated with i.v. doxycycline with either gentamicin or carefully follow HIV-infected patients who have been trea-
rifampin for at least 4 months. ted with standard therapies for early syphilis. If CNS signs
or symptoms develop, clinicians should perform appropri-
ate evaluation for early CNS relapse, including lumbar
CANCRUM ORIS puncture and VDRL of the cerebrospinal fluid [118]. Lum-
bar puncture of patients with CD4 < 350 cells/mm3 and/or
rapid plasma reagin (RPR) titer 1:32 without regard to
Noma, or cancrum oris, is an infectious disease that starts
stage may improve the ability to diagnosis neurosyphilis
as necrotizing ulcerative gingivitis, progresses with tume-
[119] in asymptomatic patients.
faction, and destroys adjacent structures around and deep
The CDC recommends treating primary and secondary
to the area [91]. It occurs in countries where there is
syphilis with 2.4 million units of benzathine penicillin
extreme poverty, malnutrition, and HIV, particularly in
given intramuscularly at a single session. Some specialists
sub-Saharan Africa [92]. It tends to occur in children and
recommend benzathine penicillin 2.4 million units intra-
young adults (2–16) [93]. Local debridement and antibi-
muscularly, once per week for 2 or 3 weeks. In late latent
otics are established treatments, but in the absence of
disease, three doses of benzathine penicillin are recom-
timely therapy, mortality is high [94].
mended 1 week apart. For penicillin-allergic patients, doxy-
cycline and tetracycline are recommended. Erythromycin is
not recommended because treatment failures have been
SYPHILIS noted with azithromycin [120]. Since the relapse rate of
neurosyphilis is approximately 17% in patients treated
Worldwide, there has been a dramatic increase in the re- with standard regimens, HIV-infected patients should be
ported number of cases of syphilis in recent years [95–99]. evaluated clinically and serologically for treatment failure
The majority of cases in large urban settings have been in at 3, 6, 9, 12, and 24 months after therapy. Although of
men, particularly men having sex with men [100, 101]. unproven benefit, some specialists recommend a CSF ex-
In Europe and the USA, the overall proportion of syphilis amination 6 months after therapy [117].
patients co-infected with HIV is 50% [102]. Over 70% Serologic clearance of syphilis appears largely unaffected
of these co-infected patients were already aware of their by HIV status in the “highly active” ART era (91.8% in
HIV infection at the time that they were diagnosed with HIV-infected versus 98.3% in HIV-uninfected, p ¼ 0.14)
syphilis [98, 103–106]. Methamphetamine use has been [121]. HIV-infected patients who meet the criteria for treat-
implicated in the rising incidence of syphilis in the USA ment failure should be managed in the same manner
and Europe, particularly with cases of re-infection of syph- as HIV-uninfected patients (i.e. a CSF examination and
ilis [107, 108]. Among women with syphilis and HIV, sex re-treatment). CSF examination and re-treatment also
work, limited or no use of condoms, and alcohol and drug should be strongly considered for patients whose non-
use were found to be risk factors [95, 98]. Screening of syph- treponemal test titers do not decrease fourfold within 6–12
ilis, even in asymptomatic HIV-infected patients, is recom- months of therapy. Most specialists would re-treat patients
mended [109, 110]. with benzathine penicillin G administered as three doses
Primary and secondary cutaneous presentations of syph- of 2.4 million units i.m. each at weekly intervals, if CSF
ilis are similar in HIV- and non-HIV-infected individuals examinations are normal [117].
222
Patients with neurosyphilis should be treated with crys- medications with varying success. While leprosy may
talline penicillin G, 2.4 million units i.v. every 4 hours for worsen during the first few weeks of ART when there is im-
at least 10 days [117]. mune reconstitution, lesions improve with appropriate mul-
tidrug therapy for leprosy [138].
CUTANEOUS TUBERCULOSIS
NOCARDIOSIS
Cutaneous and intraoral tuberculosis (TB), like pulmonary
TB, appear to be more common among HIV-infected pa- Nocardiosis is a localized infection or disseminated infection
tients [122] than in the general population. Lesions have caused by an aerobic actinomyces that is geographically dis-
been described most frequently in India, Brazil, Thailand, tributed worldwide. It has been reported in HIV-infected pa-
and Africa [22, 123–127]. Many such cases have been asso- tients in the USA, Africa, and Thailand [139, 140]. There are
ciated with pulmonary disease, but this need not be the fewer reports of Nocardia and HIV infection from Europe, al-
case [123]. In several instances, unsuspected pulmonary though there have been recent reports from Spain and
disease was discovered on chest X-ray and sputum samples France. Nocardia predominantly affects the pulmonary sys-
after the diagnosis of cutaneous disease was made. This is tem. Skin is the second most common site of infection
particularly true of TB in the oral cavity [124]. Lesions pre- and presents as cutaneous or subcutaneous abscesses
sent most often as scrofuloderma [125] or the infiltrated [141]. Intravenous drug use has been identified as a risk fac-
plaques of lupus vulgaris. Single or multiple lesions, nod- tor in HIV-infected patients. Most HIV-infected patients with
ules, or papillomas are also seen such that cutaneous TB Nocardia have CD4 cell counts <200 cells/mm3, with the
can mimic fungal or bacterial infections, KS, neoplastic majority having a known diagnosis of AIDS at the time of
processes, and herpetic infections and should be consid- infection [142]. Diagnosis can be made by using a modi-
ered in the differential diagnosis of those diseases [126]. fied acid fast stain on tissue or by culturing tissue, fluid, or
Disseminated military TB may also mimic the papular blood [142]. The treatment of choice is trimethoprim-
pruritic eruption of HIV and should be considered if sulfamethoxazole, though dual therapy is often used
the eruption fails to improve with antiretrovirals alone. Bi- [143]. Sensitivities to cultured material can be done. In a
opsy and tissue culture confirm the diagnosis [123, 127]. study from Thailand, patients who were resistant to trimeth-
An id reaction in the form of papulonecrotic id has also oprim-sulfamethoxazole succumbed to death [139]. Imipe-
been described in a patient with immune reconstitution nem, amikacin, minocycline, amoxicillin-clavulanic acid,
[128, 129]. and third-generation cephalosporins have been proposed
Mycobacterium avium-intracellulare (MAI) infrequently pre- with unclear outcomes. Where possible, debridement of skin
sents with skin manifestations, although it has been reported lesions is indicated as adjunctive therapy to antibiotics. Pre-
to form single or multiple nodules and cervical lymphadeni- vious studies have reported that most patients respond to
tis in persons whose CD4 counts are < 200 cells/mm3 [130]. therapy in an average of 4 months. Cessation of therapy
A search for systemic disease should be undertaken with can be followed by recurrence and progression of disease de-
blood cultures and bone marrow aspirates for culture spite reinitiation of therapy. Some authors have suggested
[131]. MAI is seen more frequently in the developed world that lifelong therapy should be instituted in the treatment
and has been infrequently reported in Trinidad, Kenya, and of nocardiosis in HIV co-infected patients, particularly those
other places [132]. who have evidence of advanced HIV disease. It is unclear
what role ART has in this group of patients.
LEPROSY
LEISHMANIA
Studies have indicated that HIV infection does not affect
the clinical presentation or incidence of leprosy [133]. Leishmania—cutaneous, mucocutaneous, and visceral—
However, immunosuppression due to HIV infection may has been reported in HIV co-infected persons [144, 145].
cause a relapse of leprosy in persons already treated This is a protozoan disease transmitted by the sandfly
[134]. Several reports document inflammatory and vas- and occurs in HIV-infected patients who live in or have
culo-ulcerative reactions of leprosy within 2–6 months af- traveled to endemic areas. In Spain and southwest Europe,
ter starting ART [135–137]. This is thought to be part of the there is a high prevalence of visceral leishmaniasis (kala-
immune reconstitution syndrome and has been documen- azar) among HIV-infected patients [146, 147]. The absence
ted particularly in patients whose CD4 counts were < 100 of an effective TH1 immune response, as seen in HIV infec-
cells/mm3 when initiating ART. Occasionally, anti- tion, increases the risk of progression from asymptomatic
inflammatory medications such as prednisone and thalid- disease to visceral leishmaniasis. It may also lead to poor
omide have been used in addition to leprosy and HIV treatment response and frequent relapses [148]. Conversely,
223
leishmania induces more robust HIV replication [149]. be used selectively for patients in whom potential benefits
Co-infected patients with cutaneous leishmaniasis can outweigh risks. Relapse rates for onychomycosis are high,
present with a few spontaneously healing lesions, diffuse while transaminitis and drug–drug interactions through
non-healing lesions, mucocutaneous lesions, or localized or the cytochrome P450 system can complicate treatment.
diffuse hyperpigmentation. Diagnosis is made by biopsy dem- Oral terbinafine can be taken daily for 3 months at a dose
onstrating amastigotes in the tissue [145]. Bone marrow of 250 mg. Itraconazole can be taken 7 days per month
can be biopsied in cases of suspected visceral involvement for 3 months at a dose of 400 mg. Griseofulvin requires
[144]. However, it should be noted that in persons with vis- a 12- to 18-month course; the success rate is lower, but it
ceral leishmaniasis, any skin lesion (not only those of is the least hepatotoxic. The efficacy and relapse rates
leishmania) can harbor amastigotes due to generalized in- of onychomycosis in the HIV-infected population bear
volvement of macrophages [150]. Culture of tissue is standard further study.
so that the species of leishmania can be identified and correct
therapy can proceed, particularly for Leishmania braziliensis
and L. panamensis, so that the risk of mucocutaneous disease DEEP (SYSTEMIC) FUNGAL
can be reduced [145]. Local therapy can be used for localized INFECTIONS
lesions and includes cryotherapy and paromycin ointment.
Proven therapies include antimonials, pentamidine, ampho-
Invasive or systemic fungal infections reported in HIV
tericin B, interferon with antimony, and miltefosine [151]. All
include cryptococcosis, histoplasmosis, sporotrichosis,
HIV-infected patients should be carefully monitored after
aspergillosis, coccidiomycosis, actinomycosis, phaeohy-
treatment to ensure that treatment was successful and that re-
phomycosis, and chromoblastomycosis.
lapses do not occur.
Cryptococcosis
SUPERFICIAL FUNGAL
Approximately 10–15% of patients with HIV disease and
(DERMATOPHYTE) INFECTIONS
cryptococcosis have skin lesions [158]. By definition, these
patients have disseminated disease, for which skin lesions
Superficial mycoses are particularly prevalent in developing may be the only clue. While the prognosis is poor, early dis-
countries and account for up to 50% of dermatologic disease recognition may be advantageous. Patients presenting
ease in HIV-infected patients [152]. It is not clear whether with cryptococcosis have CD4 counts under 200. Skin le-
the prevalence among HIV patients is increased compared sions can occur anywhere on the body and present as pearly
to the general population, but cutaneous involvement may 2- to 5-mm translucent papules that resemble molluscum.
be more widespread, severe, or atypical [153, 154]. However, unlike molluscum, they present over a short period
of time [159]. Large gelatinous plaques with umbilicated
areas may also occur. Diagnosis is established by skin biopsy
TINEA OF THE SKIN, HAIR, AND NAILS and culture. A systemic work-up should be performed with
particular attention to possible CNS disease. Treatment is
Clinically, tinea corporis is characterized by well-demar- with systemic antifungals that include amphotericin B, flucy-
cated, annular, erythematous, scaling plaques with central tosine, fluconazole, and itraconazole. Maintenance therapy
clearing. The hands, feet, lower trunk, groin, and buttocks should be continued for life. The role of successful ART
are commonly involved. Onychomycosis is characterized therapy is unknown with regard to maintenance therapy.
by opacification and thickening of the nails. It is quite
common among HIV-infected patients despite the use of
Histoplasmosis
ART [155]. Tinea can spread to hair-bearing areas, espe-
cially on the face and lower legs, presenting like plaques The incidence of disseminated histoplasmosis is between 5
of folliculitis known as Majocchi’s granuloma. Direct ex- and 20% in patients with AIDS living in endemic areas
amination of skin scrapings and culture for identification [160]. Histoplasma capsulatum is endemic to Texas and the
of species is helpful. The most common causal organism Ohio and Mississippi River Valleys in the USA, Mexico, Pan-
is Trichophyton rubrum [156]. ama, and South America [161–163]. Histoplasmosis has
Tinea of the palms, soles, and other localized areas of the also been described in Europe and is probably under-
body can be treated with topical imidazoles or terbinafine. diagnosed in Africa. Skin involvement occurs in 10–17%
If extensive areas are involved, oral antifungals may be a of patients with advanced HIV disease (CD4 < 100 cells/
more effective alternative that can be used for shorter pe- mm3). The cutaneous lesions are not specific and present as
riods of time [157]. For tinea involving hair follicles, oral erythematous macules, papules, pustules, acneiform lesions,
antifungals are required for approximately one month. ulcerations, and crusting plaques, mostly on the face and
For nail infections, oral antifungals are required but should chest [164]. The diagnosis should be suspected in persons
224
living in or coming from endemic areas who present with fe- [174], presenting symptoms include molluscum-like skin le-
ver, respiratory symptoms, weight loss, and diarrhea. Most sions, acneiform, and folliculocentric lesions with fever, ane-
patients have concomitant pulmonary disease [165]. Sepsis, mia, and weight loss. Diagnosis can be established by analysis
disseminated intravascular coagulopathy, and renal failure of blood and bone marrow aspirates with Wright stain. Touch
can be seen [166]. Histologic analysis of the skin may dem- smears of tissue as well as biopsies of lymph node and skin
onstrate granulomas. Organisms are seen with methamine can be used to establish a diagnosis. Tissue culture is definitive
silver stain. Bone marrow is positive in 75% of cases, and and reveals a dimorphic fungus. CD4 counts are usually well
blood culture is positive in 50–70% of cases. Treatment con- below 100 in patients presenting with this diagnosis. Mortal-
sists of amphotericin B and itraconazole. In those who sur- ity is very high for untreated patients. Treatment consists
vive, relapse is common, so lifelong maintenance treatment of amphotericin B or itraconazole [172]. An immune recon-
is required. Histoplasma duboisii has been identified on the stitution syndrome has been described in patients with
African continent, both West and Central African countries, penicilliosis initiation ART [175].
and presents most commonly with mucocutaneous lesions
in 38–82% of cases. Ulcerated and crusted papules are seen.
Cutaneous lesions tend to be papules with ulceration and
crusting.
HERPES SIMPLEX VIRUS (HSV) AND
VARICELLA-ZOSTER VIRUS (VZV)
Sporotrichosis Herpes simplex virus and varicella-zoster virus infection
Sporotrichosis has been reported worldwide and is seen with are commonly seen in HIV patients worldwide. The pre-
increased incidence among immunosuppressed patients sentation is generally typical, with multiple tiny vesicles,
[167]. Sporotrichosis in HIV can disseminate either from lo- punched-out erosions, or crusts. Atypical or extensive ulcer-
cal lesions or from asymptomatic pulmonary infections that ative, vegetative, or tumor-like lesions may also occur [176].
spread hematogenously to the skin and joints. It can present HSV infection leads to increased transmission of HIV, but
with widespread cutaneous ulcers and subcutaneous nod- randomized, controlled trials have failed to show lower
ules. Disseminated sporotrichosis occurs in patients with HIV transmission among those treated with daily suppres-
CD4 counts <200 cells/mm3 and in alcoholics. Skin biop- sive therapy for HSV [177]. VZV re-activation is 10 times
sies and cultures establish the diagnosis. Amphotericin B more common in HIV than the general population [178].
and itraconazole are used for treatment. Potassium iodide Complications such as blindness (when the V1 distribution
solution (SSKI) should not be used in patients with HIV is affected) and post-herpetic neuralgia can cause significant
and sporotrichosis because of a lack of efficacy. Lesions morbidity.
may initially worsen when starting ART because of immune
reconstitution [168]. Like the other systemic fungal diseases,
lifelong therapy is needed to prevent relapses [169]. HUMAN PAPILLOMAVIRUS (HPV)
Aspergillosis Cutaneous warts occur more frequently in HIV-infected

men and women. They are more extensive and more diffi-
Cutaneous aspergillosis can occur as a primary or second-
cult to treat than warts in immunocompetent patients.
ary infection. The latter is from hematogenous spread or ex-
Unusual wart types and an epidermodysplasia verrucifor-
tension from underlying structures. Primary cutaneous
mis-like syndrome called acquired epidermodysplasia
aspergillosis is associated with local skin injury (from tape
verruciformis have been reported in HIV-infected individ-
and intravenous catheter sites) and neutropenia [170]. Le- uals [179, 180]. The warts themselves rarely cause symp-
sions can appear as erythematous or violaceous indurated
toms unless they are on the soles of the feet and around
papules or plaques with overlying pustules, ulcers, or es- the fingernails, where they may cause excruciating pain.
char. Treatment includes local debridement and systemic
Due to the frequent presence of high-risk HPV types, there
antifungal therapy with amphotericin B, voriconazole, itra- is a risk of malignant transformation. Unfortunately, the
conazole, or caspofungin [171].
advent of ART has not reduced the number or severity of
warts, while the incidence of intraoral warts has actually
increased [181].
PENICILLIUM Treatment of warts in HIV patients is the same as for
those without HIV and has an approximately 50% success
Penicillium marneffei is a common fungal infection pre- rate. Relapse of warts is especially common. Destructive
senting in HIV co-infected persons in Southeast Asia, modes of therapy include liquid nitrogen every 3–6 weeks,
particularly Thailand and the Southern part of China. salicylic acid, laser, and excision. Immunomodulatory ther-
[12, 172, 173] Most common during the rainy season apy in the form of imiquimod has had less promising
225
results on cutaneous warts. Topical cidofovir has been used inverse (flexural), guttate, and erythrodermic forms are
but is very expensive to formulate [182]. seen most often.
Pruritus can be a frequent problem with psoriasis and
can lead to significant discomfort and secondary S. aureus
MALIGNANCIES OF THE SKIN infections. In KwaZulu-Natal, South Africa, psoriasis af-
fected young black patients and was the most frequent
The incidence of cutaneous malignancies, including basal reason for admission to dermatology wards [190].
cell carcinoma, squamous cell cancer, and melanoma, is in- Psoriasis may appear early in HIV infection and can be
creased in HIV-infected patients compared to the general exacerbated by declining CD4 count and increasing viral
population [60, 183–185]. Risk factors for development load. Thus, the severity of psoriasis can be a marker for
of these cancers include Caucasian/non-Hispanic race, in- worsening immunosuppression [191]. ART is considered a
creasing age, and longer duration of HIV infection, inde- first-line treatment for moderate-to-severe psoriasis in HIV
pendent of age and history of opportunistic infections. patients [192]. It has shown efficacy in case reports [193]
Tumors may develop throughout the range of CD4 counts. and in an open-label study of zidovudine [194]. Effective
This risk remains elevated and unchanged despite ART treatment of HIV decreases the inflammatory mediator
[186]. The diagnosis of cutaneous malignancies is the same TNF-a, which is elevated in HIV infection and plays a key role
in the HIV-infected patient as in the uninfected patient in the pathogenesis of psoriasis. Other first-line treatments of
[187, 188]. Basal cell and squamous cell cancers should mild-to-moderate psoriasis include topical medications,
be treated in the same manner as non-melanoma skin can- such as corticosteroids and vitamin D analogs (calcipo-
cers in the general population. Close follow-up for meta- triene). Ultraviolet light therapy has shown efficacy without
static squamous cell cancer is recommended because evidence of adverse immunologic effects. Oral retinoids can
tumor surveillance may be altered in the HIV-infected pa- be used as second-line agents [195]. Immunosuppressants
tient. Similarly, in HIV-infected patients with melanoma, such as cyclosporine, methotrexate, and TNF-a inhibitors
tumors may be more aggressive, independent of CD4 have been used to treat psoriasis in HIV patients. There are
count. ART may maintain the immune and tumor surveil- precautions that need to be taken in the HIV population when
lance systems, so ART is suggested for patients with HIV and considering TNF blockers like underlying TB, hepatitis B, and
malignancy, regardless of CD4 count. Close follow-up for propensity to leukoencephalitis [192, 196]. To date, there are
recurrent or metastatic tumors is recommended in persons few long-term data, so these agents should be used cautiously
with melanoma and HIV, as there is a higher incidence of and reserved for severe, refractory cases [197, 198].
metastasis and recurrence.
Kaposi’s sarcoma (KS) is frequently seen in patients with
AIDS, particularly in Africa. A low-grade vascular tumor as- SEBORRHEIC DERMATITIS
sociated with human herpesvirus 8, KS typically presents as
asymptomatic, flat, violaceous or reddish-brown patches, Seborrheic dermatitis is an inflammatory eruption usually
papules, or plaques favoring the head and neck, palate, up- affecting the scalp and central areas of the face, particularly
per chest, genitals, thighs, legs, and plantar surfaces. Skin bi- around the eyebrows and nasolabial folds. Early in the
opsy is necessary to differentiate KS from clinically similar AIDS epidemic, the prevalence of this disease ranged from
cutaneous conditions such as bacillary angiomatosis, lym- 40 to 80%, whereas in the general population, the preva-
phoma, pyogenic granuloma, lichen planus, warts, sarcoid, lence approximated 5% [16, 199]. More recent studies show
or even postinflammatory hyperpigmentation. Immune re- that the burden of disease in HIV-infected patients remains
constitution with ART is the treatment of choice in early dis- high [4, 200]. A larger percentage of patients with advanced
ease. Chemotherapeutic agents for advanced disease are less disease present with seborrheic dermatitis compared to
often available in the developing world. Thus, recognition those with early-stage disease. However, seborrheic dermati-
and confirmation of KS at its earliest stages when ART can tis can be seen throughout the disease spectrum. Seborrheic
be started may be the best hope of controlling disease. dermatitis has been noted worldwide [201–203]. One study
noted that persons on ART had less seborrheic dermatitis than
those who were not on ART. As CD4 counts increased on
PSORIASIS ART, seborrheic dermatitis was reduced by half compared with
those not treated with ART [204, 205]. With HIV infection,
Psoriasis in HIV has been reported since the early days occasionally seborrheic dermatitis will occur on the center
of the epidemic [16, 27]. It presents in HIV as in non- of the chest, axilla, and groin. The scale is usually fine, loose,
HIV-infected persons with large, marginated silvery-scaled or waxy on red or pink poorly defined patches. Pruritus is gen-
plaques. Often, there is nail pitting. Arthritis may be a erally mild. In individuals with background pigmentation,
component of psoriasis, particularly in HIV disease, pre- seborrheic dermatitis can appear as hypopigmented areas.
senting as a Reiter’s-like syndrome [189]. All clinical man- When seborrheic dermatitis presents in the groin or axilla,
ifestations of psoriasis occur in HIV patients, but the it can be intensely red and can present like inverse psoriasis.
226
This morphology has been termed sebopsoriasis. The etiology

of seborrheic dermatitis remains unclear, but it appears DRUG ERUPTIONS
that Malassezia species (Pityrosporum ovale) may play a
role [206].
Many drugs used in the treatment of HIV and AIDS-
Treatment consists of mild topical steroids (e.g. 1%
associated opportunistic infections can cause hypersensi-
hydrocortisone ointment) and topical imidazole creams
tivity reactions. Though the pathophysiology of these reac-
(clotrimazole or ketoconazole) applied together twice
tions is poorly understood, both immunologic and genetic
daily, which reduce both the inflammatory response and
factors (through the major histocompatibility complex)
the amount of P. ovale. For the scalp, tar, zinc, ketocona-
play a role [216]. Whatever the cause, drug eruptions are
zole, or selenium sulfide shampoos can be used. Because
many times more common among HIV patients than in
seborrheic dermatitis is a chronic condition, maintenance
the general population [217] and should be recognized
therapy is required, usually consisting of therapy with these
promptly to minimize morbidity and mortality [218]. Aba-
agents twice weekly [207].
cavir hypersensitivity, a serious drug reaction characterized
by at least two of the following symptoms—morbilliform
dermatitis, lymphadenopathy, fever, gastrointestinal symp-
XEROSIS AND ATOPIC DERMATITIS
toms, respiratory symptoms, myalgia, and malaise—occurs
in about 5% of patients within the first 8 weeks of therapy
Xerosis affects 20–30% of patients with HIV, while a sub- and can be fatal on rechallenge [219]. HLA-B*5701 positiv-
stantial subset are affected by atopic dermatitis or xerotic ity represents a strong genetic predisposition to abacavir
eczema [208, 209]. These conditions are more commonly hypersensitivity. It is much less common among those
seen in those with lower CD4 counts, reflecting a possible of African descent than among those of other ethnicities.
immunologic role. HIV infection, particularly advanced A history of allergy to nevirapine and naivety to ART also in-
disease, is characterized by a TH1/TH2 imbalance [210] crease the risk of developing abacavir hypersensitivity [219].
that likely exacerbates or predisposes to atopic dermatitis, Cutaneous side effects to protease inhibitors are few and
a Th2-mediated condition [211]. Epidermal barrier dysfunc- occur within the first 4 months of treatment, with the ma-
tion, a key pathogenetic feature of atopic dermatitis [212], jority of reactions occurring within the first 4 weeks [220].
has been demonstrated in HIV-infected patients, even those Hypersensitivity reactions have been reported frequently
without clinical xerosis or background atopy. Data suggest with the non-nucleoside reverse transcriptase inhibitors
Th2 cytokines provoke barrier dysfunction, thereby enabling (NNRTIs) nevirapine and efavirenz, usually presenting as
a cycle of antigen penetration and cutaneous inflammation a morbilliform rash, with or without fever, developing
in Th2-predominant HIV patients [213]. 1–3 weeks after initiation of the drug. Drug photosensitiv-
Clinically, atopic dermatitis is characterized by pruritic ity has been reported with efavirenz. Amprenavir has a
scaly plaques, particularly in flexural areas. The distribution cutaneous hypersensitivity profile similar to that of the
of atopic dermatitis may differ with ethnicity. In Black NNRTIs [221]. Nevirapine rash is seen in about 17% of pa-
Africans, atopic dermatitis involves the extensor surfaces, tients and may be related to HLA type and depletion of
affecting the elbow and wrist joints. The face is predomi- CD4 cells. Antihistamine or prednisone pretreatments do
nantly involved. Treatment for xerosis and atopic dermati- not appear to decrease the development of NNRTI drug
tis is the same as in the non-HIV-infected population. eruptions [222, 223]. Nevirapine has been associated with
Bathing should be minimized, and gentle soaps should serious reactions, including DRESS (drug rash with eosin-
be used. Frequent application of emollients is essential. ophilia and systemic symptoms), Stevens–Johnson syn-
Topical steroids and sedating antihistamines are useful drome, and toxic epidermal necrolysis. Thus, this drug
for flares. Initiation of ART leads to resolution of xerosis and others in its class should be discontinued at the first
and atopic dermatitis in some patients [214]. sign of rash [224].
Sulfonamide rashes and drug hypersensitivity are com-
mon among HIV-infected patients, presenting with a wide
RECURRENT APHTHOUS STOMATITIS variety of cutaneous reactions [225]. Clindamycin has also
been implicated as a common antibiotic cause of cutane-
Aphthoses in HIV-infected patients can be larger and more ous reactions [226]. The mechanism of hypersensitivity re-
difficult to treat. They can occur intraorally or in the anogen- actions to antibiotics in HIV has been explored and
ital region. They can be extremely painful, and the diagnosis includes the inability of HIV-infected cells to deal with re-
should be established by biopsy to rule out other infectious active metabolites of these drugs. Desensitization protocols
causes or neoplasms. The worst of these has been seen in pa- for sulfonamides may allow for continued use of the drug.
tients who present with profound neutropenia as well as HIV TB drugs can also play a role in drug eruptions. In
disease with CD4 counts < 200 cells/mm3. Local injection many countries, multiple TB medications are combined
with steroids, application of high-potency steroids, and tha- into one drug and it can be impossible to sort out the
lidomide can be useful in the treatment of these ulcers [215]. culprit [227].
227
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Drinkwater T. The prevalence of et al. Transient high levels of Pigmentation: a potential
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235
Chapter | 18 |
Gastrointestinal disorders in HIV
including diarrhea
Marie-Louise C. Vachon, Douglas T. Dieterich
CD4 T cell compartment and the GALT contains the largest

INTRODUCTION number of lymphocytes of any organ in the body, approxi-
mately 80% of the entire T cell population. The majority of
Gastrointestinal complaints are common among patients gut and peripheral CD4 T cells are lost during the acute
infected with human immunodeficiency virus (HIV). In the phase of HIV [1, 2]. This depletion of gut CD4 T cells and
early days of the HIV epidemic, gastrointestinal (GI) illnesses, the resulting altered mucosal immunity persist into the
mostly diarrhea caused by opportunistic pathogens, were a chronic phase and despite effective antiretroviral therapy
major cause of death. Often, odynophagia caused by Candida (ART) and peripheral CD4 T cell recovery [3–5]. This breach
esophagitis prevented patients from eating, and cryptosporid- in the integrity of the gut mucosa allows bacteria and bacterial
iosis and cytomegalovirus (CMV) infections prevented them products, such as the endotoxins lipopolysaccharides (LPS)
from absorbing nutrients. The treatment of opportunistic to cross over and reach the portal and systemic circulations.
pathogens has progressed only slightly in the almost 30-year This process, referred to as microbial translocation, may con-
history of HIV, but the successful treatment of HIV itself has tribute to the pro-inflammatory state characterizing chronic
caused mortality due to GI illnesses (excluding liver disease) HIV infection [6]. Microbial translocation also occurs in in-
to fade into the background. While many patients with HIV flammatory bowel disease (IBD) and is involved in its path-
continue to have GI issues, the major cause of death in most ogenesis [7]. In a study of 26 patients with AIDS with a CD4
cohorts is shifting from acquired immunodeficiency syn- count < 300 cells/mm3 and high plasma LPS levels, 65% of
drome (AIDS) to liver disease. Understanding the importance patients had at least one positive serological marker of IBD
of the gut-associated lymphoid tissue (GALT), commencing when tested for ASCA (anti-Saccharomyces cerevisiae anti-
with the acute HIV infection, has highlighted the role the GI body); pANCA (perinuclear anti-neutrophil antibody);
tract plays in the pathogenesis of HIV. Indeed the infection anti-OmpC (antibody against outer membrane porin C of E.
of the GALT by HIV may even contribute to liver disease. While coli); and anti-CBir1 (antibody against bacterial flagellin) [8].
the causes of GI illnesses have changed since the early days of Forty-six percent of patients had an IBD-like serological pat-
the epidemic, there are numerous disorders of the GI tract that tern; 75% of them had a Crohn’s disease-like pattern. This
have a large impact on morbidity and mortality of HIV suggests that IBD markers may be useful for monitoring
patients today: for example, drug-induced diarrhea and anor- HIV-related inflammatory gut disease and requires further
ectal cancer. study. Massive depletion of the gut T cells may also make the
gastrointestinal tract more susceptible to common pathogens.
GUT-ASSOCIATED LYMPHATIC
TISSUE (GALT) ESOPHAGEAL DISORDERS
Recent research has emphasized the importance of the The epidemiology of esophageal disorders has changed
GALT in the pathogenesis of HIV in the gut, in the liver, in parallel with ART-induced immune reconstitution
and in the body overall. The primary target of HIV is the and consequent aging of the HIV-infected population.
237
Opportunistic GI disease has decreased significantly with immunosuppression due to leukemia, lymphoma, trans-
combination ART (cART) [9]. In the developed world, plantation, or antineoplastic agents. Primary and secondary
HIV-infected patients presenting with esophageal symp- (except when recurrences are frequent or severe) prophylaxis
toms often receive diagnoses similar to that of an immuno- of mucosal candidiasis disease are not recommended because
competent host [10]. Dysphagia and odynophagia were of the low mortality of the disease, effectiveness of therapy in
common complaints of HIV-infected patients prior to the acute setting, and the risk for development of antifungal
cART [11]. Most of the time, the etiology was Candida resistance [14].
esophagitis and, not infrequently, esophageal ulcers caused When the CD4 count decreases <100 cells/mm3, other
by either CMV or herpes simplex virus (HSV), or were idio- pathogens are found alone or, most commonly, in
pathic. Today, most patients have good control of their association with candidiasis such as HSV and, as immuno-
HIV infection with suppressed HIV RNA and CD4 T cell suppression further increases, CMV, mycobacterial infec-
counts >200 cells/mm3. Reflux symptoms are a major tions, and other opportunistic pathogens, at a lesser
complaint and patients are found to have inflammatory frequency (Fig. 18.1A). Symptoms from HSV and CMV
gastropathy, gastroesophageal reflux disease (GERD), esophagitis are similar to candidiasis. Dysphagia, odyno-
Helicobacter pylori infections, Barrett’s esophagus, and gas- phagia, nausea, fever, and epigastric pain are the most
tric ulcers [11]. Since the HIV population is aging, these common presenting symptoms. The diagnosis of HSV
are all appropriate illnesses for these patient’s age groups. esophagitis is made at upper endoscopy. Classically, multi-
In a given patient, the differential diagnosis depends on ple small superficial ulcers with or without vesicles are seen
the degree of immunosuppression, reflected by the CD4 in the distal third of the esophagus (Fig. 18.1B) [17]. Recov-
count, but also on other specific risk factors associated with ery of the virus in culture is diagnostic, although typical
each condition. herpetic lesions can be seen on biopsy as well. Although
Although cART can help restore immunity and prevent HSV-1 is found in the majority of cases, HSV-2 has been
opportunistic infections, those not taking ART, not adher- reported [17]. Acyclovir, oral, or IV is the usual treatment.
ent to ART, failing ART, or not optimally responding to ART CMV esophagitis is also diagnosed at upper endoscopy.
may present with upper GI complaints and CD4 counts Unique or multiple large, shallow ulcers in the middle or
< 200 cells/mm3 [12]. Among these patients, upper endos- distal esophagus are seen (Fig. 18.1C) [18]. Culture is neither
copy is diagnostic in about 75% of cases [13]. Opportunis- sensitive nor specific. Definitive diagnosis is made by (1) his-
tic infections are likely involved and should be ruled out. topathology showing large intranuclear inclusions with an
Candida esophagitis caused by Candida albicans is the most owl-eye appearance (Fig. 18.1D) and (2) positive immuno-
common. (See Chapter 15 on oropharyngeal candidiasis.) histochemical or direct fluorescent staining techniques for
At endoscopy, the typical appearance of the esophagus CMV. Treatment is oral valganciclovir or IV ganciclovir.
is hyperemic with yellow-white mucosal plaques that, Kaposi’s sarcoma (KS), caused by human herpesvirus type
when removed, uncover a friable mucosa. For Candida 8 (HHV-8), is more common at CD4 counts < 200 cells/
esophagitis, upper endoscopy with biopsy and culture is mm3, but can occur at any CD4 count. Treatment of esoph-
the diagnostic method of choice, although when presenta- agitis in the HIV immunosuppressed patient should also
tion is highly suggestive of it, antifungal therapy can be include timely instituted cART. Guidelines for prevention
attempted first [14]. Oral fluconazole is the drug of choice and treatment of specific opportunistic infections in HIV-
[15], but intravenous (IV) fluconazole can be used as needed. infected patients are available [14]. Idiopathic (aphthous)
Other azoles (itraconazole, ketoconazole, posaconazole, ulcerations of the esophagus are found in approximately
voriconazole) and echinocandins (caspofungin, micafungin, 5% of patients with AIDS and esophagitis [19]. Thalidomide
anidulafungin) are also effective against Candida and can be and corticosteroids have been used to treat these [20]. HIV-
used in certain cases [14]. Advanced immunosuppression, es- infected patients without immunosuppression presenting
pecially with CD4 counts < 50 cells/mm3, increases the risk of with upper GI complaints can be evaluated the same way
developing refractory candidiasis that has a poor prognosis as immunocompetent hosts.
[16]. Refractory candidiasis is usually defined as mucosal
candidiasis that fails to resolve despite 7–14 days of daily flu-
conazole ( 200 mg daily). Long-term exposure to azole an-
tifungal agents also predisposes to selection of fluconazole- GASTRIC DISORDERS
resistant Candida strains, such as C. glabrata and C. krusei,
although most cases of refractory candidiasis are caused by The most common gastric disorders diagnosed in HIV pa-
C. albicans with high minimal inhibitory concentrations tients are similar to those seen in non-HIV-infected patients
(MIC) to fluconazole [16]. Esophageal candidiasis should although opportunistic infections must be considered, espe-
also be suspected when other risk factors are present whether cially in those with lower CD4 counts. Helicobacter pylori
the CD4 count is above or below 200 cells/mm3. These infections are often identified in HIV-infected patients and
risk factors include acute HIV infection, use of broad- can lead to gastritis and gastroduodenal ulcers in these pa-
spectrum antibiotics, corticosteroids, diabetes mellitus, and tients, similar to the general population. Helicobacter pylori
238
Chapter | 18 | Gastrointestinal disorders in HIV including diarrhea
A B
C D
Figure 18.1 Endoscopic and microscopic appearance of opportunistic infections of the lower GI tract. (A) Cytomegalovirus (CMV) in
association with candida esophagitis. (B) Herpes simplex virus (HSV) esophagitis with classic HSV vesicles. (C) CMV esophageal
ulcer. (D) CMV inclusion bodies or owl’s eye appearance of CMV ulcer biopsy demonstrated by arrows.
is a small, microaerophilic, curved rod that has the ability to detection, and culture. In a recent report of upper GI endo-
live and multiply in the acid gastric milieu, establishing col- scopic findings in the cART era, H. pylori infections were
onization or infection. Data on incidence of H. pylori infec- identified in 40% of endoscopic biopsies and were more
tions among HIV-infected patients compared to the general frequent than during the pre-ART era (11%) [11]. The
population are conflicting, but it seems that patients with two main indications for performing an endoscopy were ab-
AIDS have a lower incidence than HIV-infected patients dominal discomfort (31%), and reflux symptoms (16%).
without AIDS or HIV-uninfected patients [21]. The cause The clinical presentation and treatment options for H. pylori
for this is unknown. It may be explained by repetitive anti- infection do not differ from those for HIV-uninfected pa-
biotic treatments in AIDS patients and widespread use of tients [21]. However, careful attention must be paid when
antacids medications for upper GI symptoms [22]. Helico- choosing treatment regimens because of potential drug–
bacter pylori is usually diagnosed by serology, urea breath drug interactions (DDIs) between proton pump inhibitors
testing, stool antigen detection, or endoscopy with biopsy (PPIs) and certain antiretrovirals, mostly the protease inhib-
specimens that allows for microscopic examination, urease itor (PI) atazanavir (see Table 18.1).
239
Table 18.1 Preferred and alternative initial therapies of Helicobacter pylori infection,a treatment duration, eradication rate,
and potential for drug–drug interactions (DDIs) with ART
REGIMEN [23] DURATION ERADICATION POTENTIAL FOR DDIs [24]

RATE
Preferred initial therapyb

Not penicillin-allergic
(1) Proton pump inhibitor (PPI)c þ 7–14 days 70–85% Atazanavir (ATZ) has pH-dependent absorption
(2) Clarithromycin 500 mg twice and is both a substrate þ inhibitor of CYP3A.
daily þ Co-administration with a PPI may result in loss
(3) Amoxicillin 1 g twice daily of therapeutic effect of ATZ and emergence
of ATZ resistance.
Co-administration is not recommended
Penicillin-allergic
(1) PPIc þ 7–14 days 70–85% Clarithromycin can increase plasma levels
(2) Clarithromycin 500 mg twice of delavirdine
daily þ
(3) Metronidazole 500 mg twice daily
Alternative initial therapyd

(1) PPIc þ 10–14 days 75–90% Indinavir, saquinavir, and delavirdine have
(2) Bismuth sub-salicylate 525 mg acidic pH-dependent absorption and can raise
4 times daily þ gastric pH.
(3) Metronidazole 250 mg 4 times Spacing of PPIs with these medications and
daily þ ritonavir boosting are recommended to
(4) Tetracycline 500 mg 4 times daily overcome the potential interaction
OR
(1) PPIc þ 10–14 days 75–90%

(2) Bismuth sub-citrate 420 mg 4
times daily þ
(3) Metronidazole 375 mg 4 times
daily þ
(4) Tetracycline 375 mg 4 times daily
a
Recommendations for HIV-infected patients do not differ from HIV-uninfected patients [23].
b
For patients who have not recently or repeatedly received macrolide and/or metronidazole treatment.
c
Lanzoprazole 30 mg twice daily, omeprazole 20 mg twice daily, pantoprazole 40 mg twice daily, rabeprazole 20 mg twice daily, or esomeprazole
40 mg daily.
d
For patients from areas of high prevalence (> 20%) of resistance to clarithromycin or metronidazole, or with recent exposure to clarithromycin or
metronidazole.
Upper GI illnesses in patients with HIV-related immu- gastric infections that have been reported in HIV-infected
nodeficiency may be caused by opportunistic infections patients include cryptosporidiosis, histoplasmosis, cryp-
or neoplasms. CMV may cause erosive gastritis with or tococcosis, leishmaniasis, toxoplasmosis, syphilis, bacil-
without aphthous ulcerations, and solitary superficial lary angiomatosis, schistosomiasis, and strongyloidosis.
and deep ulcerations that may be associated with esopha- The incidence of KS and non-Hodgkin lymphoma
geal involvement [25]. Since CMV usually arises in deep- (NHL), two of the three AIDS-defining malignancies,
ly immunosuppressed patients (CD4 T cell count < 50 has declined significantly in the post-cART era [26]. KS,
cells/mm3), concomitant opportunistic pathogens such caused by HHV-8, may affect any part of the GI tract with
as Candida species and HSV may be present. Other rare or without concurrent mucocutaneous involvement.
240
Gastric KS is rarely symptomatic but can present with ab- (see below). Patients with CD4 T cell counts >200 cells/
dominal discomfort, nausea, vomiting, and dyspepsia. mm3 are likely to be diagnosed with diseases similar to
Rare severe complications such as bleeding and perfora- those of HIV-uninfected patients unless ART-induced diar-
tion can occur [27]. At endoscopy, KS typically appears as rhea is the likely diagnosis. PIs are the ART class most likely
red or purple, small submucosal vascular nodules with- to cause diarrhea. The inevitable use of ritonavir for PI
out ulceration. The mainstay of treatment in patients boosting contributes to this risk. The two preferred PIs as
with HIV is cART for restoring immunity. Additional initial HIV therapy in 2011 according to the DHHS guide-
treatment options include local treatment for bleeding lines [34], atazanavir/ritonavir and darunavir/ritonavir,
lesions and systemic chemotherapy. The stomach is the have been reported to cause diarrhea in 3 and 4%, respec-
more common site of gastrointestinal NHL. Diagnosis tively, compared to 10–11% for lopinavir/ritonavir and
and treatment are similar to those for HIV-uninfected 13% for fosamprenavir/ritonavir after 1 year of treatment
patients. in previously naı̈ve-to-ART patients [35–37]. Causes of di-
arrhea other than opportunistic infections should also be
considered in HIV-infected patients and diagnosed with
conventional tests. The most frequent pathogens causing
DIARRHEA non-opportunistic infectious diarrhea in HIV-infected pa-
tients are the bacteria Salmonella, Shigella, Campylobacter,
Since the beginning of the HIV epidemic, chronic diarrhea Yersinia, Vibrio, E. coli, C. difficile, and others; the viruses
has been one of the signature manifestations of advanced rotavirus, Norwalk, and adenovirus; and the parasites Giar-
HIV infection and AIDS. In developing countries, diarrhea dia, Entamoeba, and Blastocystis. Antibiograms of isolated
is often due to opportunistic infections in patients with bacteria are helpful since resistance to commonly used an-
decreased immunity and remains a major cause of malnu- tibiotics has been described [38]. Salmonellosis, although
trition, wasting syndrome, and mortality [28, 29]. In devel- not considered an opportunistic infection, is about 100
oped countries in which patients have wide access to cART times more frequent in HIV patients than in immunocom-
and therefore live longer, the incidence of opportunistic in- petent hosts [39]. Recurrent Salmonella bacteremia in an
fections is less, although the incidence of chronic diarrhea HIV patient establishes a diagnosis of AIDS. Celiac disease,
has remained stable, reflecting a change in underlying inflammatory bowel disease, diverticulitis, ischemic colitis,
causes [30]. In these patients with a partially reconstituted appendicitis, and others must also be considered, depend-
immune system due to cART, diarrhea is still a common ing on the clinical presentation.
complaint and can lead to significant discomfort. ART The degree of immunosuppression, represented by the
(mostly PI)-associated diarrhea, and causes of diarrhea CD4 T cell count, is one of—if not—the most useful
seen in HIV-uninfected patients, including Clostridium pieces of information when evaluating such patients. Those
difficile-associated diarrhea, are predominant in this patient with CD4 T cell counts < 200 cells/mm3, but mostly
population [31, 32]. those with CD4 T cell counts < 100 cells/mm3, are more
Diarrhea can be acute or chronic. Acute diarrhea is de- likely to be diagnosed with opportunistic infections and
fined as the occurrence of at least three loose or watery special diagnostic studies should be undertaken. See
stools daily for 3 days and up to 2 weeks. Chronic diarrhea Figure 18.2 for a suggested approach to the HIV-infected
is diagnosed when symptoms have been present for more patient with diarrhea. In patients with severe immunodefi-
than 4 weeks [33]. When evaluating a patient with acute ciency (CD4 T cell < 100 cells/mm3), opportunistic
or chronic diarrhea, a careful history is essential to help pri- pathogens, such as cryptosporidia (Cryptosporidium parvum,
oritize the differential diagnosis and decide on pertinent di- C. hominis, and others), microsporidia (Enterocytozoon
agnostic studies to request. Key elements of the history of bieneusi, Encephalitozoon intestinalis, and others), CMV,
diarrhea in HIV-infected patients include the most recent and mycobacteria (Mycobacterium avium complex [MAC]
CD4 T cell count, past history of opportunistic infections, and M. tuberculosis) are expected, alone or in combination,
past history of diarrheal illnesses, practice of unsafe sex, re- and should be ruled out carefully [40, 41]. Studies per-
cent and present antibiotic use, HIV regimen, and adher- formed in men who have sex with men (MSM) with AIDS
ence to treatment. All other pertinent elements of the and diarrhea before cART became available identified one
questionnaire of patients with diarrhea should also be or more enteric pathogens in 68–85% of patients [42, 43].
obtained. Characterization of the diarrhea (volume, dura- Cryptosporidiosis is diagnosed by microscopic examination
tion, frequency) and associated symptoms (nausea, ab- of stool samples. It should be specifically requested when
dominal cramps, bleeding, weight loss, fever, and others) stool samples are sent to the laboratory since they can easily
can be helpful for attempting to differentiate small- versus be missed during routine stool examinations. Acid-fast stain-
large-bowel disease, but symptoms can easily overlap. Up- ing methods (usually the modified Ziehl–Neelsen stain) can
per abdominal cramping and bloating suggest small-bowel be used. They allow differentiation of the small Cryptosporid-
involvement or enteritis; hematochezia, tenesmus, and ium oocysts (which stain pink or red) from yeasts and stool
lower abdominal cramping suggest colonic involvement debris (which stain green or blue). Immunofluorescent
241
History and physical examination

CD4 T-cell count CD4 ≥ 200 cells/mm3
1 Stool studies*
CD4 ≤ 200 cells/mm3
2 Blood cultures if febrile Diagnosis
3 Imaging studies if localized identified
abdominal pain
1 Same as for CD4 > 200 and
No diagnosis
2 Special stool studies** Diagnosis identified
3 Mycobacterial blood cultures identified
Diarrhea persists?
No diagnosis
identified Treat and follow-up
Yes
Continue evaluation as for non-HIV Treat and follow-up

Diarrhea persists?
1 IBD and celiac disease po

2 EGD with small-bowel biopsies
3 Colonoscopy with random
biopsies
* Stool studies include Bacterial culture and sensitivity, viral assays (in selected cases, such as stool antigen
detection and electron microscopy, when available), ova and parasites (3 different samples), and C. difficile
cytotoxin assay.
** Special stool studies include special stains (discussed in text) to communicate to lab for ova and parasite
detection with light microscopy examination for microsporidia and cryptosporidia, and immunofluorescent
assay/antigen detection for cryptosporidia.
IBD, inflammatory bowel disease; EGD, esophagogastroduodenoscopy.
Figure 18.2 Suggested approach to the HIV-infected patient with diarrhea. IBD, Inflammatory bowel disease; EGD,
Esophagogastroduodenoscopy; po, by mouth.
assays and antigen-detection assays are also available. Cryp- The yield of upper endoscopy in HIV patients with chronic
tosporidium can also be detected with hematoxylin and eo- diarrhea is between 11 and 36%, with cryptosporidia and
sin staining of small intestinal biopsies. Microsporidia can microsporidia being the most frequently identified patho-
be found in stool samples when special staining methods gens [44]. For colonoscopy, the yield is 27–42%, with CMV
such as modified trichrome stain (chromotrope 2R) and being the most common diagnosis [44]. MAC can infect the
calcofluor white are used. Small intestinal biopsies stained small bowel of severely immunosuppressed patients (usu-
with these two techniques, Giemsa, hematoxylin and eosin, ally with CD4 count <50 cells/mm3) and results in dissem-
and other methods can make the diagnosis. Electron mi- inated disease. Patients can present with malabsorptive
croscopy is used to identify microsporidia at the species diarrhea, abdominal pain, fever, night sweats, and weight
level. The two other protozoa, Isospora belli and Cyclospora loss. Mycobacterial blood cultures are helpful for diagnos-
cayetanensis, can be detected with the modified Ziehl– ing disseminated disease. Blood cultures are positive in ap-
Neelsen stain (which appears red) and both are autofluor- proximately 90% of patients with disseminated disease and
escent blue under ultraviolet fluorescence microscopy. were as high as 99% when two specimens were taken in one
When stool samples are repeatedly negative and diarrhea study [45]. Endoscopy with small-bowel biopsy and acid-
persists, upper endoscopy and colonoscopy with random fast staining can identify MAC, which can also grow in ap-
biopsies of small intestine and colon are recommended. propriate media.
242
Acute and chronic diarrhea can come from the small intes- was the most commonly recognized cause of bacterial di-
tine, large intestine, or both, respectively referred to as enter- arrhea in HIV patients, accounting for 4.1 cases per 1000
itis, colitis, and enterocolitis. The main symptoms of persons-years [31]. Diagnosis is typically made, similarly
enteritis are bloating, abdominal cramps, and profuse diar- to HIV-uninfected patients, by the detection of C. difficile
rhea (>2 L/day) associated with dehydration and malab- cytotoxins in stools or at colonoscopy by demonstration
sorption, leading to weight loss. Protozoa are the most of colitis with pseudomembranes (Fig. 18.3C). Treatment
common pathogens causing enteritis in these patients. Cryp- is similar to that of HIV-uninfected patients; however,
tosporidia (mostly C. parvum) and microsporidia (mostly the incidence of metronidazole-resistant C. difficile seems
Enterocytozoon bieneusi and Encephalitozoon intestinalis) are anecdotally to be increasing and, often, treatment will
most frequently isolated in immunosuppressed patients. require combination treatment with both metronidazole
Other common infectious pathogens of the small intestine and oral vancomycin. Non-infectious colon diseases
are the bacteria Shigella, Salmonella, Campylobacter, E. coli, such as diverticulitis, inflammatory bowel disease, and
Yersinia, and Vibrio; the parasites Giardia lamblia, Entamoeba cancer must also be part of the differential diagnosis, as
histolytica, Isospora belli, and Cyclospora cayetanensis; the myco- appropriate.
bacteria MAC and M. tuberculosis; and the viruses CMV, Treatment of diarrhea in HIV-infected patients depends
herpes simplex, and HHV-8 presenting as KS. Rare agents on the underlying cause. Adequate fluid and electrolyte
of enteritis include, but are not limited to, Pneumocystis support is given to dehydrated patients; nutritional sup-
jiroveci, Candida sp., Paracoccidiosides braziliense, Mucor sp., plements and symptomatic treatment of diarrhea with
Histoplasma capsulatum, Treponema pallidum, and Schistosoma antimotility agents are often needed. Restoration of the
sp. Noninfectious causes of enteritis, such as diverticulitis, is- immune system with effective cART is the mainstay of
chemic enteritis, appendicitis, sarcoidosis, lymphoma, and treatment in patients with diarrhea due to opportunistic
carcinoma, should be included in the differential diagnosis. infections, especially in patients with cryptosporidia
In addition, idiopathic AIDS enteropathy, profuse diarrhea and microsporidia for which truly effective targeted ther-
associated with malnutrition and wasting without an infec- apies are not available. For cryptosporidia, nitazoxanide
tious pathogen identified, has been recognized in HIV/AIDS in conjunction with cART has shown some benefit [52].
patients, and is a diagnosis of exclusion. Viral pathogens, No effective targeted therapy is available for E. bieneusi;
including HIV itself, and associated inflammatory and E. intestinalis may respond to albendazole [53, 54].
immunological responses, are potentially involved in the TMP-SMX is effective against Isospora belli and Cyclospora
pathogenesis [46]. cayetanensis. A lifelong suppressive therapy is usually
Symptoms suggestive of colitis are lower abdominal recommended in patients with AIDS due to the high re-
cramps, frequent small loose stools, rectal bleeding, and currence rates. Comprehensive reviews of treatment of
tenesmus. CMV colitis in patients with AIDS may lead opportunistic infections, including treatment of CMV
to profuse watery diarrhea, abdominal pain, fever, and and mycobacterial infections, have been published re-
bloody diarrhea. Before effective cART was available, cently [14, 46].
CMV colitis was a frequent cause of diarrhea. In immuno-
suppressed patients in whom a cause for diarrhea is iden-
tified on colonic biopsies, CMV is still one of the most
frequently encountered pathogens [47, 48]. The typical ANORECTAL DISORDERS
colonoscopic finding in patients with CMV colitis is dis-
tal patchy colitis with ulcerations (Figs 18.3A and 18.3B) Anorectal disorders are an important component of HIV GI
[49]. In a study of 56 HIV/AIDS patients with CMV coli- care, especially in HIV MSM. The incidence of anorectal pa-
tis, colonoscopy showed colitis associated with ulcers thologies has been affected by cART [55]. Anorectal pathol-
in 39% of patients, ulceration alone in 38%, and colitis ogies seen in HIV patients are diverse and include anal
alone in 21%. Subepithelial hemorrhage was frequent fissures, fistulae, perirectal abscesses, ulcerations, proctitis,
[49]. Ulcerations at colonoscopy combined with the and cancer. Human papillomavirus (HPV) infects anal ep-
typical CMV inclusion bodies or owl-eye appearance at ithelia in men and women similarly to cervical epithelia in
microscopic examination of colonic biopsies signal the women. Infections with oncogenic HPV genotypes (mostly
diagnosis of CMV colitis. CMV can also be cultured, HPV-16 and HPV-18) can lead to anal condyloma, anal
but a positive culture alone is not diagnostic. Treatment squamous intraepithelial lesions (SIL), and anal squamous
is usually with IV ganciclovir or IV foscarnet, although carcinoma [56]. Abnormal anal Papanicolaou smears are a
oral valganciclovir can be administered [14, 50, 51]. Clos- common finding in men with AIDS (39% in one study)
tridium difficile is associated with antibiotic use, although and are significantly associated with lower CD4 T cell
it can present in the absence of such history. The absence counts [57]. Indeed, the incidence of high-grade anal
of recent antibiotic use in the history of a patient with intraepithelial neoplasia (AIN), the likely anal cancer pre-
HIV and diarrhea should not be a reason for excluding cursor lesion, and the incidence of anal cancer are higher
C. difficile-associated diarrhea. In one study, C. difficile in patients with HIV/AIDS than in HIV-uninfected patients
243
A B
C D
Figure 18.3 Endoscopic appearance of opportunistic infections of the lower GI tract. (A) Cytomegalovirus (CMV) patchy colitis.
(B) CMV ulcers of colon mucosa. (C) Clostridium difficile colitis with pseudomembranes. (D) Raised red, confluent lesions of Kaposi’s
sarcoma (KS) of the rectum.
[58]. Although no recommendations exist for routine anal CMV infections, as described with esophagitis and colitis,
cytology screening of HIV-infected patients in 2011, some can cause perianal and rectal ulcerations, with associated
experts recommend routine anal cytology in HIV-infected pain, tenesmus, and bleeding. Endoscopy can also reveal
MSM [14]. The quadrivalent HPV vaccine Gardasil is KS that typically appears as red or purple submucosal vas-
now approved by the FDA for use in both women and cular nodules, similar to its appearance in the upper GI
men aged 9 to 26 years, but data on safety and efficacy in tract (Fig. 18.3D).
HIV-infected patients, especially HIV-infected MSM, are
not yet available. Proctitis is one of the possible clinical pre-
sentations of sexually transmitted infections, usually asso-
ciated with unprotected anal intercourse. Purulent anal CONCLUSION
discharge, tenesmus, and rectal pain are the classical symp-
toms. The pathogens usually involved are Neisseria gonor- The role of the GI tract in HIV has changed dramatically
rhoeae, Chlamydia trachomatis, herpes simplex, Treponema over the 30þ years of the HIV epidemic. In the early days
pallidum, and CMV. Chlamydia trachomatis serovars L1, it served as the portal of entry, and the major infected or-
L2, or L3, causing lymphogranuloma venereum (LGV), gan system. The huge advances in ART of the past three
can lead to severe proctitis [59]. Diagnosis and treatments decades have changed our perspective on the GI tract in
are similar to those for HIV-uninfected patients. The rectum HIV patients. In developed countries, we rarely see pa-
can also be the site of opportunistic infections. HSV and tients with low CD4 counts and opportunistic infections,
244
except in liver and kidney transplant recipients with HIV. antibiotic treatment, probably due to alterations in nor-
That prospect was totally inconceivable at the beginning mal colonic flora. As new research sheds light on the GALT
of the epidemic. We see the diseases of the aging GI tract and the importance of the gut immune system, the GI tract
in our aging HIV population, like Barrett’s esophagus is assuming a more important role in the pathogenesis of
and C. difficile infections, either with or without prior HIV again.
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Chapter | 19 |
Primary neurological manifestation of HIV/AIDS
David B. Clifford, Mengesha A. Teshome
providing factors that may well alter the natural history

INTRODUCTION of HIV neurological disease.
NeuroAIDS issues may be considered as primary com-
In the past 30 years we have learned much about the biol- plications, including conditions that are in some way the
ogy and treatment of human immunodeficiency virus direct consequence of the HIV infection, or secondary
(HIV). Emphasis on prevention and a laudable global ef- complications (Box 19.1). The primary complications in-
fort to increase access to treatment are encouraging devel- clude a spectrum of HIV-associated neurocognitive disorders
opments. In 2010, UNAIDS reported declining new HIV (HAND), HIV-associated myelopathy, and HIV-associated
infections in many countries most affected by the epidemic. peripheral neuropathy. Secondary complications result as a
Between 2001 and 2009, HIV incidence fell by more than consequence of the immunodeficient state of the host
25% in 33 countries, 22 of which were in sub-Saharan (Box 19.1). Neurological infections that fall into this cate-
Africa. Countries that were most affected in sub-Saharan gory include cryptococcal meningitis, toxoplasmic enceph-
Africa—Ethiopia, Nigeria, South Africa, Zambia, and alitis, cytomegalovirus encephalitis and radiculomyelitis,
Zimbabwe—have either stabilized or are showing signs progressive multifocal leukoencephalopathy, and varicella
of decline. Unfortunately, in 7 countries, 5 of them in zoster complications. This chapter will focus on the primary
Europe and Central Asia, HIV incidence increased by more neuroAIDS complications while many of the secondary
than 25%. However, realizing that 33.3 million people live complications are described elsewhere in the text.
with HIV, HIV remains a major health challenge, particu- The frequency of neurological complications has chan-
larly in sub-Saharan Africa where 22.5 million (68% of ged as the epidemic has evolved, being profoundly im-
the global total) live. pacted by therapeutic practices and perhaps by varying
Neurological complications of HIV infection continue to underlying risks in various affected populations. Both the
cause significant morbidity. Reports from a growing num- primary HIV-associated complications and the secondary
ber of countries confirm tragic persistence of cognitive and complications occur more frequently in advanced stages
neuropathic complications of HIV. Our descriptions in this of HIV, when the immune system is most impaired. HIV-
chapter are often based on more detailed observations associated dementia (HAD), HIV-associated myelopathy,
made in the Western world. However, reports from the de- and peripheral neuropathy all are seen most commonly
veloping world are increasingly replicating the experience after the CD4 count drops below 200 cells/mm3. Often pri-
from the West, suggesting that neurological conditions mary neurological manifestations are not noticed when
are important throughout the global epidemic. While no early development of opportunistic illnesses supervene,
firm evidence contradicts this expectation, the importance masking the anticipated course of disease progression. As
of viral and host genetics in determining disease manifesta- more subjects in developing countries are managed to pre-
tions is undeniable, as is knowledge that these factors are vent and treat secondary complications we anticipate a rapid
different in various parts of the world. It is also certain that emergence of clinical recognition of primary HIV-associated
co-infections influence the course of HIV disease, and these neurological complications. Furthermore, with more suc-
are well known to differ in the developing world, again cessful HIV therapy, most patients retain a higher level of
249
The risk of impairment was higher in those with co-

Box 19.1 HIV-associated neurological morbidities. The same study also found evidence of periph-
complications eral neuropathy in more than half of the subjects. Early
studies in Uganda support the prevalence of neurologic im-
Primary HIV-associated neurological pairment in less developed settings [3]. A recent report
complications: found HAND in 23.5% of HIV-infected patients seen at
• HIV-associated dementia (HAD) HIV care centers in South Africa [4].
• HIV-associated mild neurocognitive disorder (MND)
• Asymptomatic neurocognitive impairment (ANI)
• HIV-associated myelopathy PATHOPHYSIOLOGY, PATHOGENESIS,
• HIV-associated peripheral neuropathy
AND GENETICS
Notable secondary neurological
complications: Primary HIV-associated complications result from infection
• Cryptococcal meningitis in the nervous system, and respond to antiretroviral therapy.
• Toxoplasmic encephalitis The mechanism by which HIV infection leads to HAD is
• Cytomegalovirus encephalitis and radiculomyelitis likely multifactorial. HIV enters the brain and CSF almost
• Progressive multifocal leukoencephalopathy immediately after systemic infection, probably via HIV-
• Varicella zoster (shingles) infected monocytes, which then differentiate into macro-
• Neurosyphilis phages. The virus can be recovered from the nervous system
• M. tuberculosis meningitis
throughout the illness. However, productive infection is al-
most exclusively localized in monocytes and macrophages
and mainly occurs late in the disease. Neurons are rarely if
ever infected, and astroglial cells, while they may be infected,
immunity and live longer, resulting in an actual increase in do not seem to support replication. The consequences of
the prevalence of HAND in populations of long-term astroglial infection remain uncertain. However, recent re-
survivors. search supports an association of HAD with astrocyte infec-
Diagnostic rules in the setting of HIV deserve some spe- tion, suggesting that these cells controlling the environment
cial cautions. While in most fields of medicine, a single dis- in the brain could be critical and require further study [5].
ease should be sought to understand most patients’ It seems likely that much of the pathological consequence
complaints. In AIDS, neurological complications often of the HIV infection in the brain is driven by immune re-
are superimposed on an ongoing process with a different sponse to infection rather than directly correlated to the viral
etiology. Drug toxicity may add other facets to neurological load in the CNS. Cytokine production is more closely linked
conditions. Clinical features often reflect the sum of deficits with the degree of HAD than the viral load. However, repli-
from multiple pathophysiologic perturbations. In addi- cative HIV infection in the CNS, reflected by increasing HIV
tion, AIDS patients are susceptible to the same neurological RNA viral loads in the CSF, has been loosely associated with
diseases as patients who do not have HIV infection and primary HAD prior to the cART era [6]. Pathologic changes
thus the clinician must not always leap to unusual diagno- are found in the deep gray matter of the brain, in white mat-
ses in the setting of HIV disease, considering as well condi- ter, and eventually in the cortex, resulting in loss of neurons
tions common in the immunocompetent population. and simplified dendritic structures [7].
While most people are susceptible to HIV, infection re-
quires both CD4 receptors and chemokine receptors. Viral
isolates may evolve in a host from CCR5 receptor de-
EPIDEMIOLOGY pendent (R5) to viral tropism using the CXCR4 (X4) co-
receptors. Generally, primary brain isolates are of the R5
Neurological complications of HIV infection are common class consistent with the fact that CCR5 is the predominant
manifestations of the AIDS illness [1]. Pre-combination an- receptor on monocytes and macrophages, the primary cells
tiretroviral therapy (cART) era investigations documented with replicative infection in the brain. It is interesting that
that two-thirds of patients with AIDS developed HAD. Al- some people are protected from HIV infection by a genetic
though, after successful introduction of antiretroviral ther- mutation in the CCR5 chemokine receptor that prevents it
apy, the incidence of frank dementia declined significantly, from participating as a co-receptor for cellular infection. A
milder cognitive difficulties and HIV-associated peripheral leukemia patient who received a bone marrow transplant
neuropathies have persisted. The CNS HIV Antiretroviral from a donor with a non-binding CCR5 cell surface protein
Therapy Effects Research (CHARTER) study, a multicenter has been reported as showing evidence of a cure of HIV
NIH study, evaluated over 1,500 HIV-infected individuals infection 3 years after receiving the transplant, including
in the USA and found 53% had cognitive impairment [2]. no evidence of the virus on brain biopsy [8].
250
Chapter | 19 | Primary neurological manifestation of HIV/AIDS
Understanding factors predicting the subset of HIV-

infected persons who develop neurological disease is a fun- Box 19.2 Salient clinical features
damental problem of great significance. There are likely to of HIV-associated dementia
be both host and viral factors that predispose to develop-
ment of the primary HIV complications. Understanding Cognitive changes
these should provide greater understanding of the diseases • Reduced concentration, inability to focus thoughts
as well as opportunities to protect people from their or finish tasks
consequences. • Decreased reading, less interest in TV
• Decreased memory, making lists, needing reminders
• Speech changes, slowing, sometimes word-finding
difficulty
HIV-ASSOCIATED NEUROCOGNITIVE
DISORDERS (HAND) Motor changes
• Slow initiation of movement
• Imbalance, clumsiness
Clinical features • Weakness
HIV-associated neurocognitive disorders (HAND) include a • Sometime myoclonus
spectrum of cognitive impairments that range from asymp- • Changes in bladder function, urgency, incontinence
tomatic neurocognitive impairment (ANI) to a severe form,
HAD. Early on, it had been noted that HAND varied in se- Behavioral changes
verity and affected different domains of brain function, • Personality changes, flat affect
resulting in a variety of cognitive, motor, and behavioral • Depressed appearance
manifestations. A consensus nomenclature for study of • Sleep disturbance, generally hypersomnia
HAND was developed in 2007 by experts who presented a • Rarely psychotic thought
modified comprehensive classification of HAND [9]. In
this classification, three HAND conditions are characterized:
ANI, HIV-associated mild neurocognitive impairment
(MND), and HAD. The work group emphasized the possi- behavioral problems that develop in advancing HIV infec-
bility of bidirectional temporal changes in diagnosis. These tion (Box 19.2). Early signs and symptoms of HAND may
conditions should be classified using a variety of specific be subtle, but evolution to HAD occurs mainly in untreated
clinical and laboratory-based methods, depending upon HIV. Before cART, patients often presented with insidious
the resources available where the patients are being evalu- onset of reduced work productivity, poor concentration,
ated. Ideally, baseline neuropsychological (NP) assessment mental slowing, and forgetfulness. The cognitive decline
should be part of the clinical evaluation. Where NP testing was often characterized by slowed thought and speech,
is not available, presence of cognitive impairment involving which the patient as well as examiners may recognize.
two or more ability domains may be suggested by quantita- Habits of reading and recreation are impacted early, while
tive neuropsychological testing using demographically ap- productivity drops. Apathy and withdrawal from hobbies
propriate normative cutoffs. Tools of value for screening and social activities are common and must be differ-
include the HIV Dementia Scale, the International HIV De- entiated from depression. Motor slowing is also typical,
mentia Scale, Mattis Dementia Rating Scale, and the Mon- and has provided convenient means of documenting ad-
treal Cognitive Assessment (MoCA). Recent interest in use vancing neurological involvement. Imbalance, clumsiness,
of the MoCA includes availability in multiple languages, bal- and weakness are common motor complaints. Behavioral
anced simple assessment of several domains, and low cost changes are less common, but may be dramatic manifesta-
(free access at http://www.mocatest.org). tions of the neurological involvement. Flattened affect is
ANI and MND must both have documented neurocogni- typical, and develops even without overt affective disorder.
tive impairment, but only in the case of MND does this Other manifestations include sleep disturbance, psychosis,
impact on activities of daily living. The Frascati-proposed and seizures. Occasional frank psychotic episodes develop.
diagnostic criteria defines ANI and MND by performance As the disease advances, global dementia with memory
at least 1 standard deviation (SD) below the mean of loss and language impairment develops, culminating in a
demographically adjusted normative scores in at least virtual vegetative state. Neuropsychological evaluation re-
two cognitive areas (attention-information processing, lan- veals features suggestive of a subcortical dementia, such
guage, abstraction-executive, complex perceptual motor as is seen in Parkinson’s disease. Early in the course of
skills, memory, including learning and recall, simple motor CNS disease, patients develop psychomotor slowing, mem-
skills, or sensory perceptual abilities), with MND having ory loss, and word-finding difficulties. As the stage of
evidence of functional impairment in daily living. HAD the disease advances, severe psychomotor retardation and
has a more profound impact on motor, cognitive, and language impairment become obvious, leading to akinetic
251
mutism. Clinicians sometimes comment on parallels with

Parkinson’s disease, and indeed the earliest regions of the
brain affected in HIV include the basal ganglia. More recent
studies reveal that loss of dopamine transporters in basal gang-
lia correlate with progressive cognitive disability. The greater
dopamine transporter decrease in the putamen than in the
caudate parallels that observed in Parkinson’s disease [10].
While this description is important in untreated popula-
tions, it is almost never encountered in treated patients.
HAND is most commonly seen today as either ANI or
MND in early stages of the disease, or in treated patients,
function may reveal subtle changes best documented by
formalized neuropsychological testing. While progression
to HAD on treatment is exceedingly rare, a new uncommon
condition of an acute or subacute encephalitis occurring
while patients are on therapy, potentially consistent with Figure 19.1 MR scan of a patient with HIV-associated
HIV cerebral immune reconstitution inflammatory syn- dementia. Note the marked, widespread cortical atrophy,
drome (IRIS), has been described. This causes white matter ventricular enlargement and diffuse changes in the subcortical
changes in scans, and on brain biopsy is characterized by white matter (arrows).
intense CD8 lymphocyte infiltration. Corticosteroid ther-
apy as well as enhanced HIV therapy may be most effective
deteriorates, recruitment patterns change, engaging larger
in managing this serious encephalitic complication [11].
brain regions to perform tasks in affected individuals. Brain
perfusion measured with MR by arterial spin labeling stud-
ies has suggested that HIV infection results in decreased
Diagnosis perfusion to the brain which is only partially corrected
by ARV [12]. Positron emission tomography (PET) has
Diagnosis of HAND is achieved by excluding alternative
revealed abnormalities in subcortical metabolism early,
causes and recognizing patterns of illness associated with
with advancing hypometabolism globally in later stages;
primary disease. While challenging in advanced patients,
however, use of PET is limited due to costs and complexity.
these conditions are even harder to fulfill in milder condi-
CSF is rarely completely normal in HAND but the mild
tions, particularly when many co-morbid issues might also
lymphocytic cellular response and mild elevation of protein
contribute to the findings. These conditions are generally
most often encountered are not diagnostic. Elevated immu-
clearest when the HIV disease is advanced, as defined by
noglobulins, not rarely with oligoclonal banding, may be
low CD4 counts (most often < 250 cells/mm3). While
detected. Even after complete viral suppression with cART,
HAND is now often diagnosed in patients with a higher
there is the suggestion that there remains at least somewhat
CD4 count, it remains problematic to ascribe neurologic
elevated inflammatory response in the CSF [13]. Careful
problems to the viral disease in well-controlled patients
analysis of CSF helps to exclude other etiologic causes of al-
with an intact immune system. Nevertheless, most investi-
tered neurologic status. In untreated patients more elevated
gators believe evidence supports HAND even in the pres-
HIV viral loads in CSF are typical but not diagnostic of pri-
ence of virologically successful antiretrovirals (ARV) and
mary HIV neurological disease, but the association of cogni-
functional immune reconstitution.
tive impairment with viral load appears even less reliable in
Recommended investigations for HAND include asses-
the era of cART. CSF cytokine elevations have correlated
sing HIV control by current and nadir CD4 count and viral
with HAD, but the more common mild HAND manifesta-
load measurements, including CSF viral loads. Brain MR
tions do not have substantial elevations.
and CT imaging studies are most important for ruling
There is a critical need for better-validated, quantitative
out alternative diagnoses, but may support a diagnosis of
biomarkers of early neuroAIDS disease, particularly means
HAND when typical atrophy or white matter disease is
of determining which subjects may suffer progressive
demonstrated (Fig. 19.1). MR spectroscopy has been exten-
deterioration and thus be candidates for interventions
sively used in the research setting seeking non-invasive
and clinical trials.
means of monitoring CNS disease. Markers of gliosis or in-
flammation appear to occur early with late loss of neuronal
markers. Some reports correlate these measures with treat-
Treatment
ment as well as disease progression, but to date MR spec-
troscopy has been of little practical use in tracking the There is no specific therapy available for cognitive decline
CNS disease in the clinic. Functional MRI is not yet widely in AIDS. Optimal therapy of HIV is a uniform goal once the
applied, but early studies suggest that before performance diagnosis is established. Because lower nadir CD4 has been
252
suggested to increase the risk of HAND, neurological man- is suboptimal. CNS penetration of ARV may contribute
ifestations are a good rationale driving expert recommen- to efficacy, while active transport of other drugs out of
dations for earlier and more aggressive use of ARV in HIV the central compartment could drive outcomes [18]. De-
infection. The central importance of antiretroviral therapy spite these theoretical concerns, decline in the incidence
with relation to CNS manifestations is undeniable. Prior to of neurological complications has closely followed im-
introduction of ARV, the prevalence of HAD was typically provement in systemic HIV therapy, and concerns about
at least 60–70% in advanced disease. Introduction of zido- CPE of therapies remain to be validated. Thus, the clini-
vudine was associated with improvement in cognitive per- cian’s first task is to construct the most effective and
formance and in a small placebo-controlled trial of high best-tolerated HIV therapy overall. If HAND is present,
doses of zidovudine in subjects with active dementia it is reasonable to consider CPE in the choice of therapies,
[14]. In the early years of HIV therapy, incidence of HAD but this should not yet be considered an overriding con-
dropped to 7% per year, with roughly 20% prevalence sideration, pending more information about this ap-
in the population. HAD has become rare in patients proach to therapy. Based primarily on CSF penetration
responding well to ARV with controlled viral loads, with es- (which is not necessarily the same as brain penetration),
timated incidence now much less than 5%. Thus, amelio- optimal nucleoside reverse transcriptase inhibitors (NRTIs)
ration of marked cognitive impairment can be added to include zidovudine, stavudine, and abacavir. Nevirapine ap-
the other major benefits of cART. However, even the lower pears to cross the blood–brain barrier well and is theoreti-
incidence of dementia when coupled with much longer cally a favorable drug from the non-nucleoside reverse
survival has resulted in stable or even increasing numbers transcriptase inhibitors (NNRTIs) class, but there is also doc-
of cognitively impaired patients in some clinics [1]. umentation of therapeutic efficacy with efavirenz [19]. From
Antiretroviral drugs may vary in their effectiveness in the protease inhibitors (PIs) class of ARV, indinavir is the
the CNS compartment with several, particularly highly least protein bound and has best evidence of efficacy in
protein-bound protease inhibitors, probably having lim- the CNS, but is rarely prescribed due to side effects and fre-
ited access to the brain. Determining whether designing quent dosing. Relatively better PI drugs for CPE include rito-
therapy for CNS penetration could improve cognitive out- navir-boosted lopinavir or darunavir. The newer CCR5
comes is an active topic for investigation [15]. The CNS antagonist maraviroc and the integrase inhibitor raltegravir
penetration effectiveness (CPE) ranking of different ARV both seem to have moderately good CPE scores, making
agents derived from information about the properties of in- them reasonable additions to salvage regimens with drug-
dividual ARV is used to study this issue. At present observa- resistant virus.
tions are not conclusive regarding the value of CPE for Measuring the efficacy of primary neuroAIDS therapy re-
managing therapy. Some reports show correlation between mains more challenging than systemic therapy. In cases of
poor penetration score and higher CSF viral loads [16]. clear-cut neurological impairment, a rather dramatic clini-
However, other studies do not uniformly support the im- cal improvement may at times be noted, and the benefits
portance of CPE since mild HAND may be seen unrelated of therapy are easily appreciated. However, with more sub-
to CPE scores [17]. Neuroprotective strategies distinct from tle disabilities, it is much harder to document a response
ARV continue to be investigated but none have been dem- to therapy. For clinical trial development of treatment,
onstrated to be effective beyond HIV therapy. repeated well-validated neuropsychometric measures to
The latest expert recommendations for HIV therapy reflect the clinical response to therapy are generally
continue a trend toward earlier initiation of ARV at higher employed. Viral load in CNS, which generally is lower than
CD4 counts, often in patients < 500 cells/mm3 (http:// systemic values, has poor correlation with severity of neu-
aidsinfo.nih.gov). There is general support for aggressive rological disease and often provides little guidance for ther-
and consistent use of cART once symptomatic disease, in- apy. However, occasional cases of CSF viral replication
cluding neurological disease, is identified. Data analysis even when viremia is controlled are reported, and neuro-
from the CHARTER study showed an association of logical improvement may be directed by the characteristics
HAND with lower nadir CD4 rather than current CD4 sta- of the CSF virus [20].
tus. A challenge for therapeutic development resides in Driven by the concern that viral infection is not eli-
balancing the degree and durability of viral response with minated from the brain by antiviral therapy, considerable
the cost and complications of the therapy, including side effort has been placed in protective strategies to block
effects and secondary toxicities. With declining toxicity, presumed neurotoxic brain damage [21]. To date, small
earlier therapy has become more attractive and now dom- controlled studies have evaluated the toxicity, safety, and
inates treatment recommendations. Treatment of HIV tolerability of different presumed protective drugs and
within the CNS may be even more difficult than systemic failed to demonstrate neuroprotective properties. Recent
infection, since the virus is harbored in longer-lived cells trials of minocycline have also failed to reverse cognitive
and may be exposed to lower and less effective levels of deficits during controlled trials [22]. At present no adjuvant
ARV due to the blood–brain barrier. The quantity and therapy can be recommended outside of the clinical trial
quality of information on CNS efficacy of HIV therapy setting.
253
caused by dideoxynucleoside drugs used to treat HIV, in-

HIV NEUROPATHY cluding didanosine (DDI), stavudine (D4T), and in the
past by zalcitabine (DDC). While both DSN and ATN
can coexist in a single patient, temporal profile of symp-
Clinical features toms in relation to introduction and termination of neuro-
HIV-associated sensory neuropathy (HIV-SN) is a major toxic medications can help in distinguishing the active
source of morbidity among AIDS patients, affecting ap- pathophysiologic process. PIs have also been associated
proximately 30% of AIDS patients. Other potentially treat- with neuropathy, although this association has not been
able peripheral nerve diseases occur in HIV related to other consistent, or strong [26].
infectious agents and immune-mediated mechanisms. Predisposing conditions for neuropathy, including diabe-
However, the most common forms of distal sensory poly- tes, nutritional deficiency, alcohol abuse, or prior chemo-
neuropathy (DSN) are HIV-SN and antiretroviral toxic neu- therapy, may contribute to development of symptomatic
ropathy (ATN). These two forms are phenotypically neuropathy. Prior to cART, DSN was associated with ad-
identical. They present as a length-dependent neuropathy vanced HIV disease, with lower CD4 count and higher viral
with distal to proximal development of symptoms. A mix- load. Advancing age remains a consistent and significant
ture of negative symptoms including numbness and sen- risk factor of increasing importance with the aging of
sory loss along with positive dysesthetic and painful HIV patients [27]. In the developing world, ATN is still im-
aching or burning is typical. Symptoms are generally worse portant. Symptoms typically begin from a few weeks to 6
at night and can be aggravated by innocuous stimuli, such months after introduction of toxic medications. Symptoms
as bed sheets or wearing shoes. Abnormalities on neurolog- may worsen at least for a few weeks after discontinuation
ical examination are limited to sensory nerve function and of the offending agent, followed by at least partial improve-
include reduced or absent ankle reflexes and increased vi- ment in most, but not all, patients.
bratory and pin sensation thresholds. International studies The main pathologic features that characterize DSN and
in Southeast Asia have confirmed that taller patients are ATN include “dying back” axonal degeneration of long
more likely to suffer neurotoxic neuropathy, and thus an axons in distal regions, loss of unmyelinated fibers, and
algorithm making greater effort to avoid stavudine in tall variable degree of macrophage infiltration in peripheral
patients would make sense [23]. In the USA and Europe, nerve and dorsal root ganglia. Marked activation of macro-
the decline in use of stavudine and didanosine has been ac- phages as well as the effect of proinflammatory cytokines
companied by a reduction in toxic neuropathies, but the appears to be the main immunopathogenic factor in
overall burden of neuropathies remains high in most DSN [28]. Interference with DNA synthesis and mitochon-
HIV clinics, and is particularly troublesome in interna- drial abnormalities produced by nucleoside antiretroviral
tional sites where frequent use of stavudine continues. A drugs have been postulated as pathologic factors involved
study from South Africa revealed a 57% prevalence of in ATN.
symptomatic neuropathy among stavudine-exposed South
Africans [24].
Treatment
Treatment for HIV-SN includes optimizing the environ-
Diagnosis
ment for the nerves by assuring excellent nutritional status
Without a definitive test, diagnosis of HIV-associated neu- and minimal toxic insults. In case of ATN, the suspected
ropathy requires typical presentation and exclusion of al- agent should be discontinued or at least the dose should
ternative diagnoses. The typical pattern of symmetric be reduced. In the current era, it is rarely necessary to con-
distal sensory loss is characteristic. Asymmetric neuropa- tinue toxic nucleosides when there is access to the full selec-
thies, or those with substantial motor involvement, suggest tions of ARV. Symptomatic therapy is often needed for
an alternate diagnosis. Physiologic testing may be of lim- pain. Several drugs often used for neuropathic pain are ap-
ited value in HIV-SN. Affected patients can often test nor- parently less effective in HIV-SN. Currently, the only ther-
mally on routine nerve conduction study. This reflects apies shown to be effective against pain by randomized,
the prominent small-caliber sensory nerve involvement placebo-controlled clinical trials are smoked tetrahydro-
in HIV-SN while nerve conduction tests preferentially eval- cannabinol [29] and lamotrigine [30]. Gabapentin in doses
uate larger nerve fibers. Skin biopsy and visualization of of 1,800 to 3,600 mg/day has provided helpful ameliora-
epidermal nerve fibers is a useful diagnostic tool in research tion for chronic pain, but it is often necessary to employ
settings and theoretically could allow monitoring treat- long-acting narcotic drugs to provide reasonable quality
ment aimed at nerve regeneration [25]. Reduced fiber den- of life in the face of troubling pain. A randomized clinical
sity, increased frequency of fiber varicosities, and fiber trial testing pregabalin, a related anticonvulsant used for
fragmentation are prominent features of skin biopsy from neuropathic pain syndromes, failed to confirm activity in
patients with HIV-SN. A clinically similar syndrome is often the face of a very potent placebo response [31].
254
A sometime lethal neuromuscular syndrome seen after lac- Diagnosis

tic acidosis remains important in developing countries where
stavudine is used extensively [32]. It typically occurs several Laboratory studies focus on exclusion of treatable causes
weeks after lactic acidosis associated with d-drug toxicity like vitamin B12 deficiency and compressive myelopathy.
[33]. Patients develop severe weakness and subacute painful It is critical not to ascribe myelopathy to HIV without im-
neuropathic symptoms. Reflexes are depressed, and muscle aging the spinal cord for treatable compressive lesions. A
biopsies suggest mitochondrial myopathy as well as neuro- negative imaging study with MRI, normal level for vitamin
pathic changes. It occurs more commonly in women than B12, and negative HTLV-1 status are important exclusions
men. Eye movements may be restricted. Supportive therapy, before HIV-associated vacuolar myelopathy is accepted as
and avoidance of mitochondrial toxins allow recovery of a diagnosis.
many of these patients, but notable mortality has been
associated with this condition. Treatment
Treatment for myelopathy is best addressed by optimized
ARV. The high prevalence of this disorder in untreated
HIV disease is substantially different from the experience
HIV-1-ASSOCIATED VACUOLAR in the era of cART where myelopathy is very rarely encoun-
MYELOPATHY tered in treated subjects. When treatment is started in pa-
tients beginning to demonstrate signs of myelopathy, it is
arrested and partially reversed in many cases. In addition
Clinical features to ARV treatment, care in nutrition is likely to contribute
Vacuolar myelopathy is the most common chronic mye- to better outcomes.
lopathy associated with HIV infection. It occurs during
the late stage of HIV infection, when CD4 counts are very
low. It is often seen in conjunction with HAD, peripheral CONCLUSION
neuropathies, opportunistic CNS, and peripheral nervous
system infections. In the early years of HIV when therapy Primary neurological complications at every level of the
was quite limited, myelopathy was clinically noted in up nervous system have been a significant part of the impact
to 20% of adult HIV patients, while pathologic study of of HIV infection throughout the world. While these mani-
the spinal cord indicated involvement in over half of AIDS festations may be veiled by the acute illnesses complicating
autopsies. Pathophysiologic data are limited but it has been untreated disease, they are present in the much larger group
suggested that infiltration of the cord with HIV-infected of people suffering HIV in developing countries, and are
cells secreting neurotoxic factors, neurotoxic HIV proteins, likely to be noted more prominently as therapy is intro-
or underutilization of vitamin B12 could underlie this dev- duced. Because the actual manifestations of these diseases
astating disorder. The vacuolar degeneration of heavily my- are likely to be dependent on both viral and host genetics,
elinated tracts including the corticospinal tract results in each having significant differences in various parts of the
progressive spastic diplegia (paraplegia), often with urinary world, it will be critical to study the presentation and course
bladder involvement and sensory ataxia. Both dorsal col- of these complications in the different settings where HIV
umn and spinothalamic sensory deficits are often observed is prevalent, as unique features that could influence
in these patients. outcomes are likely to emerge.
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256
Chapter | 20 |
Psychiatric barriers and the international
AIDS epidemic
Chiadi U. Onyike, Andrew F. Angelino, Glenn J. Treisman
disorder is highly prevalent worldwide—the 12-month prev-

INTRODUCTION alence (interquartile range, IQR) is 18.1–36.1% for DSM-IV
disorders and 0.8–6.8% for Serious Mental Illness (i.e., a
The analysis of causation and intervention in the HIV/AIDS DSM-IV disorder, other than substance abuse, that causes se-
epidemic has relied on the classic epidemiologic triad of rious disability). Furthermore, neuropsychiatric disorders
host, agent, and environmental factors. Yet the HIV/AIDS are also major contributors to disability; Serious Mental Ill-
epidemic differs from earlier pandemics in the sense that ness results in 49–184 days/year out of role, Moderate Men-
behavior is the principal vector of its spread. HIV infection tal Illness in 21–109, and Mild Mental Illness in 12–67 [3].
is propagated by behaviors that involve intimate physical The WHO Mental Health Gap Action Programme [4] has
contact or exposure to blood or body secretions. In the reported that depression, with lifetime prevalence of major
early years of the epidemic the identified vulnerable host depression or dysthymia estimated at 12.1%, is the single
groups were homosexuals, heroin addicts, Haitians, and he- largest contributor to non-fatal burden of disease and is re-
mophiliacs (the 4-H group), which pointed to the specific sponsible for a high number of lost disability adjusted life
behaviors that served as vectors for the viral agent. It is now years (DALYs) worldwide. It is the fourth leading cause of
recognized, especially in high-income countries, that psy- disease burden (in terms of DALYs) globally and is projected
chiatric disability has facilitated the spread of this virus to increase to the second leading cause in 2030. Suicide, an
[1]. Nearly 30 years later health promotional efforts in important complication of depression, is the third leading
high-income countries has slowed the epidemic consider- cause of death worldwide in people aged between 15 and
ably, in terms of overall prevalence, but transmission has 34 years, and the thirteenth leading cause of death for all
continued apace among subgroups who are unable to ages combined. It also represents 1.4% of the global disease
modify their behavior without active assistance. It has be- burden (in DALYs). Alcohol use disorders, schizophrenia,
come clear that psychiatric disorders, besides their role in and dementia are also important contributors to disease bur-
the spread of the virus through the risk behaviors that they den. An estimated 24.3 million people have dementia
provoke or promote, also impact outcomes adversely by worldwide, a figure predicted to double every 20 years,
undermining help seeking and treatment adherence and 60% of those with dementia live in middle- or low-
(Fig. 20.1). HIV/AIDS is also associated with secondary psy- income countries.
chiatric states, such as depression, anxiety, mania, delirium, Global disparities in the global HIV/AIDS situation are
cognitive impairment, and dementia [2]. Therefore the in- also substantial, despite notable progress in the prevention
tersections of HIV/AIDS and psychiatric disorder require of new infections and expansion of treatment in the past
examination in any discussion of HIV/AIDS prevention, decade. According to the latest Global Summary of the
treatment, and prognosis. HIV and AIDS Epidemic published in 2010 [5], there has
It is well established that psychiatric disorders generally been a 19% decline in HIV-related deaths since 1999, a
have adverse impacts on health awareness, health-seeking 25% drop in the incidence of new infections in 33 countries
behavior, and treatment adherence. The World Health Orga- (22 of these in Africa), and a 26% reduction worldwide in
nization (WHO) estimates [3] show that neuropsychiatric the frequency of mother-to-child transmission. In 2009
257
Figure 20.1 Psychiatric disorders play an important

Depression role in both the spread of the virus through behavior and
Demoralization the impact on treatment response.
Substance abuse
Cognitive impairment
Risk for getting, spreading

Mental Illness
and developing AIDS
Paranoia
Depression
Impulsivity
Substance abuse
Cognitive impairment
Poor adherence to treatment
alone, 1.2 million patients received treatment for the first psychiatric hospital beds reaches as low as 0.33 per
time, representing an increase in the number of people re- 10,000 in Africa and Southeast Asia [8]. Ultimately the
ceiving treatment of 30% in a single year! Still there is much principal factor limiting psychiatric care in middle- and
work to be done. The majority of new infections (69%) still low-income countries is the scarcity of professionals.
occur in sub-Saharan Africa, and also seven middle- and Low-income countries have a median of 0.05
low-income countries in Eastern Europe and Central Asia ex- psychiatrists and 0.16 psychiatric nurses per 100,000 pop-
perienced a 25% increase in HIV incidence in the past de- ulation, whereas high-income countries have a 200-fold
cade. Today almost 50% of the 33.3 million adults and higher ratio of psychiatric mental health-workers to popu-
children living with HIV reside in middle- and low-income lation [8]. Treatment of psychiatric disorders is further
countries [5], and the reduction in mother-to-child trans- constrained by the unavailability of essential medicines
mission still translates to 370,000 new children with the in- in low-income countries; about a quarter of these countries
fection who mostly reside in low-income countries. Also do not provide any psychotropic medicines in primary-care
35% (5.3 million) of the 15 million in need living in these settings and in many others supplies are insufficient or ir-
countries are receiving anti-retroviral treatment. regular [8]. Therefore, patients and families are often forced
Economically disadvantaged people have limited access to pay for medicines. Since these costs are relatively high in
to psychiatric treatment and chronic psychiatric illness con- low-income countries, the result is that treatment, where it
tributes to this problem through the tendency to restrict exists, is unaffordable for many. It is also worth noting that
and deplete economic resources and cause economic over 85% of controlled trials for cost-effective treatments
“downward drift” into poverty. Generally, psychiatric care are conducted in high-income countries [9]. Another key
is least available to those who will need it the most (i.e., in- factor, and one that limits prospects for progress in the de-
dividuals suffering severe mental illness). This applies in velopment of psychiatric services, is the lack of prioritiza-
high- and low-income countries [6], but is probably more tion of mental health in national health policies and of
acute in low-income countries where public mental health advocacy for it at the community level [10]—a problem
services may be deficient or practically absent. Generally, exacerbated by misperceptions about the cost–benefits of
the countries most severely affected by HIV have the least providing these services.
developed resources for HIV treatment and for mental Cultural values and beliefs play a substantial role in
health. The 15 million living with HIV in low- and mid- mental health care in middle- and low-income countries
dle-income countries have very limited access to psychiatric [7, 11, 12]. Mental illness carries a high stigma and is often
services. The unmet need for mental disorders and serious attributed to religio-magical phenomena, in which the ill-
mental illness is high in these countries: a survey in Nigeria ness represents retribution meted out by ancestors or pos-
found that only 1.2% of individuals received any treatment session by evil spirits. In some countries, such as in
in the 12 months preceding the study [7]. This problem re- Uganda, those who are mentally ill are excluded from em-
flects a scarcity of treatment resources: 52% of low-income ployment or voting. In many others, they are excluded from
countries provide community-based care, compared with full social participation in a variety of ways that limit
97% of high-income countries. The median number of schooling, marriage opportunities, and forming of social
258
Chapter | 20 | Psychiatric barriers and the international AIDS epidemic
networks. On the other hand, there is reliance in some experience have a profound influence on their ability to ac-
areas on traditional healers who are frequently included cept treatment as well. For instance, those persons who
in policy initiatives and form a substantial component of have experienced misuse at the hands of trusted paternal
the community mental health resource. In East Africa, figures will manifest their distrust when accessing medical
70–100% of individuals consult a traditional healer as first care, as they do in other areas of their lives. Likewise, those
line of care [13–15]. However, utilization of traditional who experienced abnormal sexual experiences at vulnera-
methods for psychiatric care is low in many places. In Ni- ble developmental stages are at high risk for manifesting
geria, for example, less than 5% of individuals with a psy- promiscuity and prostitution. The treatment of these issues
chiatric illness consult a traditional healer and about the here is intended to deliver on breadth, rather than depth; a
same number seek formal psychiatric care. Cultural factors detailed review of these subjects is beyond the scope and
are also critical in the expression of psychological distress space of this chapter.
and psychiatric disorders and to their detection during
screening programs and clinical care—lack of sophistica-
tion regarding local expressions and/or reliance on stan-
CHRONIC MENTAL ILLNESS
dard screening instruments that have not been culturally
adapted may result in failure to detect cases. AND HIV INFECTION
As a consequence of the low coverage of both anti-
retroviral and psychiatric treatment in middle- and low- A subset of patients with chronic mental illnesses such as
income countries, many patients who have psychological recurrent severe major depression, schizophrenia, and bi-
distress and/or psychiatric disorders go without anti- polar affective disorder have been identified as constituting
retroviral treatment— from either not having sought it or a high-risk population that manifests HIV risk behaviors
not being able to maintain adherence. Generally, psycho- at higher-than-average rates, but these observations have
logical distress and social isolation are factors in seeking been made in high-income countries. The prevalence rate
antiretroviral treatment and yet often go unnoticed, espe- of HIV among the chronically mentally ill in the USA
cially when there is no overt symptomatology [16–18]. has been estimated to be between 4 and 20% [23–28].
Longitudinal studies also confirm what had already been Risk behaviors associated with HIV infection are also
demonstrated in high-income countries, that psychological frequently observed in this population; early studies of
distress and psychiatric disorders contribute to low initia- chronically hospitalized patients in New York [29] and
tion and non-adherence in young [16, 19] and older [20] patients attending community mental health clinics in
individuals suffering HIV and AIDS. A newly emerged issue Melbourne, Australia [30] showed that patients with men-
is the nature of relationships between aging, cognitive dys- tal illness were more likely to participate in unprotected
function (discussed below) and adherence to antiretroviral casual sex and injection drug use when compared with
therapy. Cognitive dysfunction and dementia have been as- the general population. This observation has been repli-
sociated with higher rates of non-adherence [20, 21], and cated in other studies [31–34], cementing the observation
reciprocity in the adverse relationship between cognition that individuals who suffer chronic mental illness manifest
and adherence has also been demonstrated [22]. higher rates of behaviors that put them at risk for HIV
Thus far we have covered two aspects to the relationship infection.
between psychiatric disorders and the HIV epidemic. One Besides increasing their exposure to the virus, patients
aspect involves the effects of psychiatric disorders on self- with mental illnesses are impaired in their ability to adhere
management of exposure risk, and the other had to do with to the complicated medication regimens necessary to sup-
effects on access and utilization of treatment services. There press viral replication and HIV disease (discussed earlier,
is yet another dimension to the psychiatric aspects of the see also Campos et al. [35] and Venkatesh et al. [36]). Suc-
HIV/AIDS infection, having to do with secondary psychiat- cessful treatment requires consistently taking at least 90%
ric disorders developing as a consequence of the infection. of prescribed antiretroviral medications, with faithfulness
We now address this issue. to the dosage and to the schedule. Unfortunately, adher-
Psychiatric disorders differ in their etiology, causal path- ence rates vary widely in individuals with chronic mental
ways, and correlates, and also in their treatments. While in illness, ranging from 32 to over 80%, depending on the
the USA there has been a great focus on “disease” psychiatry group and the duration over which adherence is being
and the use of disease-based criteria for conditions (such as monitored. For example, an analysis of data from a sample
those used in the DSM-IV), many psychiatric conditions are of 115 patients attending a Los Angeles HIV clinic found
not diseases and do not fit well into this model but still three-day, one-week, and one-month adherence success
have a huge impact on HIV infection. We will discuss psy- rates (taking 95% of doses) of 58.3, 34.8, and 26.1%, re-
chiatric diseases, which are (or are presumed to involve) spectively. Three-day adherence was strongly associated
brain lesions first, and then discuss problems of addictions with mental health status, social support, patient–physician
and problems of temperament and endowment. We also relationship, and experience of adverse effects [37]. Another
acknowledge that problems originating in a person’s study estimated sustained viral suppression in only 25–40%
259
of patients [38]. In both studies, mental illness was a factor

in non-adherence to treatment. Psychosocial interventions Box 20.1 ‘I WATCH DEATH’ mnemonic
geared toward improving autonomy, self-efficacy, and com- for delirium
munity support can improve adherence and may, therefore, Infectious: sepsis, encephalitis, meningitis, syphilis,
be useful adjuncts to psychiatric regimens in optimizing ad- urinary tract infection, pneumonia
herence. For example, a study evaluated predictors of high Withdrawal: alcohol, barbiturates, sedatives-hypnotics
ART adherence (90%), measured by electronic drug mon- Acute metabolic: acidosis, electrolyte disturbance,
itors, after enrollment in a randomized controlled trial test- hepatic or renal failure
ing behavioral interventions to improve ART adherence Trauma: head trauma, burns
[39]. High motivation, positive coping styles, and high levels CNS disease: hemorrhage, CVA, vasculitis, seizures,
of interpersonal support were positively associated with ad- tumor
herence, whereas passive belief in divine intervention was Hypoxia: acute hypoxia, chronic lung disease,
negatively associated with adherence. hypotension
Deficiencies: cobalamin (B12), hypovitaminosis, niacin,
thiamin
Environmental: hypothermia, hyperthermia,
MOOD DISORDERS IN HIV/AIDS endocrinopathies
Acute vascular: hypertensive emergency, subarachnoid
Affective disorders (mood disorders), particularly major hemorrhage, sagittal vein thrombosis
depression, are the most common co-morbid psychiatric Toxins/drugs: medications, street drugs, alcohol,
pesticides, industrial poisons
conditions in patients suffering from HIV disease. The prev-
Heavy metals: lead, mercury
alence of major depression in those with HIV in the USA
has been estimated at 15–40%. The prevalence exceeds With permission from Cohen BJ. Theory and Practice of Psychiatry.
Oxford: Oxford University Press; 2003:110.
50% in persons with HIV seeking psychiatric treatment
[40]. Nevertheless, any evaluation for depression must also
consider other states such as demoralization, dementia,
and delirium, all of which are common in those with understanding of mental illness in African, South Ameri-
HIV and AIDS. While checklists can be useful for screening, can, or Central Asian contexts. An excellent example derives
a detailed history that explores the patient’s mood, self- from a study conducted in Uganda that examined local per-
attitude, vital sense, hedonic capacity, and neurovegetative ceptions of the impact HIV had on mental health. Inter-
symptoms (i.e., appetite and sleep) will help in establishing viewees described two local syndromes, Yo’kwekyawa
the diagnosis. The importance of identifying and treating (translated as “hating oneself”) and Okwekubaziga (trans-
depression rests on the opportunity to improve quality of lated as “pitying oneself”), as resulting from HIV infection
life, reduce high-risk behaviors, and improve treatment [44]. Both terms encompass many aspects of what we un-
adherence. derstand as major depression and give strength to the no-
While some cases appear to have developed as adverse tion that those affected with HIV anywhere in the world
reactions to anti-retroviral agents, it is also well established are likely to have similar mental health manifestations (like
that advanced HIV can trigger a secondary mania. An early depression), though they may not describe it in a manner
study in a large clinical cohort showed 8% of the patients familiar to the Western world.
with AIDS had mania, a tenfold higher 6-month prevalence
than in the general population [41], also characterizing the
phenotype of the mania showing its association with the
late stage of HIV infection with an appearance similar to HIV-ASSOCIATED NEUROCOGNITIVE
a delirium. Secondary mania has also been documented
in Africa, with high prevalence and a phenotype showing DISORDERS
marked euphoria, irritability, aggression, and combina-
tions of auditory and visual hallucination [42, 43]. The pre- HIV-associated neurocognitive disorder (HAND), dis-
dominant mood appears to be irritability and an involved cussed more fully in Chapter 19, remains common in the
work-up for delirium (Box 20.1) needs to be completed era of antiretroviral therapy (ART) [45, 46]. HIV infection
prior to making this diagnosis. of the CNS occurs early in the illness. Studies show that
Diagnosis of mood disorders is complicated in the global ART treatment ameliorates HAND, but it appears that res-
community by different standards and beliefs regarding olution is usually incomplete [47]. Thus, HAND prevalence
mental illness, and variation in the manner of presentation. rates still range from 30 to 50%. While the profile of cog-
As we noted earlier, depression inventories familiar to prac- nitive impairment has changed little in the ART era, nosol-
titioners and researchers in high-income Anglophone ogy has changed in tandem with new discoveries. The latest
countries can show low utility in the diagnosis or nosology defines three states according to formal criteria
260
[48], representing a continuum of HIV-associated cognitive psychological, genetic, and psychiatric factors. In the Western
disorder: hemisphere addictions have been for sometime conceptual-
(1) HIV-associated asymptomatic neurocognitive impairment ized as diseases, a useful approach for de-stigmatizing pa-
(ANI, a subclinical state demonstrated by testing in tients who suffer these chronic problems and for
two or more cognitive domains); mobilizing family and community support for their care.
(2) HIV-associated mild neurocognitive disorder (MND, While some data show that brain pathology can foster or per-
manifesting cognitive impairment with mild petuate certain substance use disorders, descriptions of these
functional disability); and behaviors in terms that emphasize or illustrate how they be-
(3) HIV-associated dementia (HAD, characterized by come self-perpetuating as a result of recruitment of the brain’s
marked cognitive impairment and marked functional normal reward systems (the reader is referred to McHugh and
disability). Slavney [51] for more discussion) has proved to be a profit-
able approach to their analysis and treatment.
Impairments of attention, abstraction, memory and learning,
To understand how this works, it is necessary to examine
speech, and language, and abnormal psychomotor and fine
what behavior is and how it is perpetuated. In simple terms,
motor functions are the most common features of the
behavior can be defined as self-directed actions; thus, some-
dementia. AIDS dementia also manifests apathy, irritability,
thing one does. In general, behaviors are elicited by stimuli
hyperactivity, agitation, insomnia, euphoria, and psychosis.
(typically environmental but sometimes endogenous). The
Given its features, HAD may mimic (or be mimicked by
behavior reshapes, extinguishes, or modifies stimuli such
HIV-associated delirium, depression, or mania). AIDS delir-
as to elicit CNS-mediated reward responses such as pleasure
ium presents with fluctuating levels of alertness, attention,
or satiation. It is conditioning by this reward that “drives”
and arousal, along with lapses in memory and perceptual ab-
behaviors such as the insertion of a needle into your arm,
normalities, and may co-occur with dementia in advanced
“chasing the dragon,” visiting a brothel, or having high-risk
cases of AIDS. Thus it may present a diagnostically frustrating
sex. In other words a positive response elicited within the
picture that relies on interviews of close relatives and friends,
brain not only increases the likelihood the behavior will
careful observation, and diagnostic testing for clarity. Delir-
be repeated in the future but also that it will be the preferred
ium in AIDS can reflect metabolic disturbances, electrolyte
behavioral response.
imbalance, encephalitis, sepsis, or the adverse effects of med-
Behaviors stimulate the brain’s internal reward circuitry.
ications. Opportunistic CNS infections such as progressive
Neurotransmitters mediating the reward response are re-
multifocal leukoencephalopathy (PML), cytomegalovirus
leased, leading to a sense of pleasure. With the waning of
encephalitis, cryptococcal meningitis, toxoplasmosis, and
the pleasure comes an urge, or craving, to accomplish the be-
varicella-zoster virus encephalitis may cause or contribute
havior that originated in the good feelings. Such a positive
to delirium. Delirium in AIDS has an unfavorable prognosis
feedback loop can be very helpful when increasing the fre-
[49], particularly when untreated. Therefore, aggressive eval-
quency of behaviors needed for survival such as sleeping, eat-
uation and management is always warranted.
ing, and sex. However, such a loop, if not tightly regulated,
can lead to an excessive focus on a particular behavior. If
you eat enough or sleep enough, you lose interest in that ac-
HIV AND SUBSTANCE ABUSE tivity temporarily. The loop is “off.” Drugs and alcohol can
activate this loop and drive it out of control. Genetics, envi-
Intravenous drug use holds a prime place in the discussion of ronment, and circumstances all play a role in both the predis-
substance abuse, as it is a direct route of infection and spread position to drug use and the intensity of reward their use
of HIV. It is a major player in the ongoing AIDS epidemic in elicits. Psychiatric illnesses also play a role in determining
Asia, Eastern Europe, Latin America, and developed coun- the disposition to using drugs and the vulnerability of the re-
tries. From India to China, HIV prevalence in communities inforcement loop. Understanding and appreciation of the
of injection drug users (IDUs) has increased from 0 to 50% stimulus–behavior–reward cycle provides opportunity for in-
within 6 months; and the map of HIV spread throughout tervention by removing the stimulus, proscribing (and stig-
Southeast Asia by virus strain follows, not coincidently, her- matizing) the behavior, or blunting the reward experience
oin trafficking patterns in the region [50]. Other substance (see Treisman and Angelino [52] for further discussion).
use disorders play an important role in the transmission of
HIV through the promotion of high-risk behaviors. Since be-
havior is the principal vector of HIV transmission everywhere, PERSONALITY, TEMPERAMENT,
it is the main factor driving the epidemic.
Substance abuse, whether of alcohol, narcotics, stimu- AND HIV
lants, or other substances, is a problem of worldwide scope.
The global burden of disease ranks substance use disorders Since ancient times, healers have recognized personality
among the top 10 causes of morbidity globally. The suscep- types and pointed to behaviors associated with those types.
tibility to addiction is complex, involving cultural, social, Today the four humors of Greek medicine—melancholic,
261
choleric, sanguine, and phlegmatic—still carry heuristic value with others who might provide guidance and restraint. Peo-
as personality descriptors. Today there are a great many apple who are risk-taking or those that are highly anxious are
proaches to characterizing personality, from Freudian and also more likely to overuse alcohol, or other substances,
other psychodynamic theories proposing failure to complete and thus are vulnerable to these complications, each of
stages of formative experience (e.g., oral, anal types), to others which compound the risk for acquiring HIV and related
that describe personality in terms of their impact on others conditions, such as hepatitis C, gonorrhea and other STDs,
(antisocial, avoidant), and yet others that describe in terms and a host of other behaviorally transmitted infections.
of behavioral characteristics (risk-taking, pleasure-seeking).
Regardless which set of descriptors, one can see that careful,
anxious, and risk-avoidant people are at lower risk for HIV, PSYCHOPHARMACOLOGY
while those who are risk-taking, emotion-driven, and rela-
tively unconcerned with their future well-being are at higher IN HIV-INFECTED INDIVIDUALS
risk for acquiring the infection. Likewise those who tend to be
unconcerned about their responsibilities to others might The core requirement of treatment is accurate diagnosis.
knowingly continue to spread HIV, showing little regard For the last half of the 20th century, the international ef-
for the impact they have on others. A small amount of re- forts in psychiatry focused on whether the same conditions
search has examined the roles personality type plays in HIV exist across cultures and if they have similar courses and re-
infection and outcomes, mostly in Western and high-income sponses to treatment. With the exception of some culture-
cultures, and this issue continues to be of crucial importance specific conditions, the common psychiatric disorders have
to halting the HIV epidemic. People with certain personality similar prevalence around the world and appear to respond
types are “vulnerable” to situations that might expose them to similarly to treatment. While there are differences in the ap-
HIV, and need adequate coaching in advance to help them proved drugs from one country to another, the majority of
avoid the trap their vulnerabilities might set for them. the pharmacological classes are available, although there
Lastly, psychiatric disorders often compound each other are distinct cultural beliefs about the use of medications
in co-morbid situations. Major depression increases the to treat psychiatric disorders.
likelihood of alcohol abuse, and alcohol abuse worsens Psychopharmacologic agents can be divided up into the
major depression, clouds judgment and erodes self- classes in Table 20.1. We have given generic names for sev-
discipline and self-attitude, and undermines relationships eral of the common drugs in each class, but the list is not
Table 20.1 Commonly used psychotropic medications in HIV-infected patients
CLASS OF GENERIC NAMES ADVANTAGES DISADVANTAGES

AGENT
Antidepressant
SSRI Citalopram, Dapoxetine, Easy to use, well tolerated, now Serotonin syndrome, decreased
Fluoxetine, Paroxetine, Sertraline, mostly off patent and inexpensive, sexual drive and anorgasmia,
Vilazodone (others) relatively few drug interactions GI activation
SNRI Duloxetine, Milnacipran, Easy to use, well tolerated, helpful Serotonin syndrome, decreased
Venlafaxine (others) for chronic pain, relatively few sexual drive and anorgasmia,
drug interactions GI activation
Tricyclic Desipramine, Doxepin, Hypnotic (for sleep), increased Need monitoring for narrow
antidepressant Nortriptyline (others) appetite, useful for chronic pain, margin of safety, anticholinergic
meaningful therapeutic blood and alpha-blocking, cardiotoxic
levels and can be fatal in overdose,
lowers seizure threshold
Aminoketone Bupropion (originally called No sexual side effects, activating, Jittery feelings, lowers seizure
Amfebutamone) no weight gain threshold
Tetracyclic Mianserin, Mirtazepine Appetite stimulating, safer in Weight gain, sedation

overdose than tricyclic
antidepressants, useful in pain,
promotes sleep
262
Table 20.1 Commonly used psychotropic medications in HIV-infected patients—cont’d
CLASS OF GENERIC NAMES ADVANTAGES DISADVANTAGES

AGENT
Antipsychotic
Typical (or first Chlorpromazine, Haloperidol Inexpensive, sedating and Dystonia, bradykinesia, tardive
generation) (many others) tranquilizing dyskinesia, anticholinergic,
alpha-blocking, neuroleptic
malignant syndrome
Atypical (or Amisulpride, Aripiprazole, Much less dystonia, bradykinesia, Many still on patent, weight
second Asenapine, Blonanserin, tardive dyskinesia, anticholinergic, gain, metabolic syndrome, QT
generation) Clotiapine, Clozapine, alpha-blocking, possibly less prolongation (agrualocytosis
Iloperidone, Lurasidone, neuroleptic malignant syndrome with clozapine)
Mosapramine, Olanzapine,
Paliperidone, Perospirone,
Quetiapine, Remoxipride,
Risperidone, Sertindole, Sulpiride,
Ziprasidone, Zotepine
Sedative-hypnotic (anxiolytic)
Benzodiazepine Alprazolam, Bromazepam, Pleasant sedation, effective Numerous drug interactions with
Chlordiazepoxide, Cinolazepam, anxiolytic, good panic attack HIV medications, addictive,
Clobazam, Clonazepam, abortive agents, most widely used cognitive impairment, physical
Cloxazolam, Clorazepate, psychopharmacologic agents dependence with potentially
Diazepam, Estazolam, life-threatening withdrawal,
Flunitrazem, Flurazepam, respiratory suppression
Halazepam, Ketazolam,
Loprazolam, Lorazepam,
Lormetazepam, Medazepam,
Midazolam, Nitrazepam,
Nordazepam, Oxazepam,
Phenazepam, Pinazepam,
Prazepam, Quazepam,
Temazepam, Tetrazepam,
Triazolam
Non- Eszopiclone, Zaleplon, Zolpidem, Possibly less addictive, less physical Rapid sleep habituation with
benzodiazepine Zopiclone dependence, less respiratory subsequent dependence for
suppression sleep in many patients, cognitive
impairment
exhaustive. Studies in a variety of settings have shown that • Care should be taken in using psychotropic
these agents are similarly effective in HIV-infected patients medications in debilitated patients—they should be
when compared with those at risk or in control groups. We started at low doses and titrated up slowly to effective
have put in only the most major advantages and disadvan- doses (Start Low-Go Slow).
tages by class, but there are numerous subtle issues within • In general, in contrast to sedative-hypnotic agents,
each class. The long lists of antipsychotics and benzodiaz- antidepressant and antipsychotic medications have few
epines demonstrate the heterogeneity of the availability of clinically significant drug–drug interactions with
the drugs in different countries. antiretrovirals, but each individual patient should be
Generally, as compared with non-HIV-infected patients, monitored for onset of side effects and reduced efficacy
the following guidelines are useful in HIV settings: to avoid poor outcomes.
• Psychotropic medications for every psychiatric • Benzodiazepines should be used with great caution, as
condition have been shown to work as well in HIV- some interact with certain antiretrovirals and can lead
infected individuals as in non-infected individuals. to serious adverse outcomes.
263
• Psychotherapy and education are essential to successful in the sense of the challenges posed for designing and
treatment. Patient adherence is driven mostly by implementing public health interventions. Fortunately
patient attitudes toward taking psychotropic there is international consensus and action for HIV/AIDS
medication—if the patient does not take the treatment and prevention worldwide, and indications of
medication it cannot work. On the positive side, progress. What is needed next is the scaling up of mental
adherence to psychiatric medications predicts health services in middle- and low-income countries, to
adherence to ART. eliminate the mismatch between need and services. Scal-
• There are clinically significant drug–drug interactions ing up of services will involve community education activ-
between methadone and efavirenz and ritonavir for ities, consensus building, engagement of community
which dose adjustments of methadone are required. resources, establishment of secure funding, training of
Buprenorphine (a partial agonist for the opioid psychiatrist and other psychiatric health workers, infra-
receptor) may require less adjustment. Many patients structure development, and monitoring and evaluation
on opiates will experience changes with the initiation activities [10, 53]. There is also evidence that simple phar-
of ART, and will require careful monitoring with macologic regimens and community-based rehabilitation
treatment initiation and regimen changes. models can be implemented in low-income countries [9].
By addressing the psychiatric morbidity surrounding HIV,
we can reduce the global burden of disease and reduce fur-
CONCLUSION ther spread of AIDS. Separately, programs might be imple-
mented to increase the rates of ART compliance through
Recognition and treatment of mental illness in the global programs that promote knowledge and self-efficacy, espe-
fight against HIV/AIDS is paramount: mental and behav- cially in those who suffer psychiatric disorders. While the
ioral disorders are not only more likely to develop in the HIV/AIDS situation in low-income countries remains ur-
infected patient, but also they are important risk factors gent, the latest global reports show that we are making
for HIV acquisition and transmission of the infection. Fur- progress in the fight against this epidemic. WHO initia-
thermore, these disorders deplete their victims economi- tives aimed at addressing mental health gaps in middle-
cally and socially and undermine the potential for and low-income countries promise additional means for
treatment success by impairing adherence. The complex increasing and extending successes against the HIV/AIDS
interplay of HIV/AIDS and mental illness can be daunting, epidemic.
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266
Chapter | 21 |
Cardiovascular complications of HIV infection
Rakesh K. Mishra
INTRODUCTION CORONARY ARTERY DISEASE
The landscape of cardiovascular disease in HIV-infected pa- With the advent of ART and improved survival with HIV
tients has changed significantly since the introduction of infection, there is now increasing epidemiological overlap
potent antiretroviral therapy (ART). In the early years of between patients with HIV infection and those at risk for
the epidemic, the principal cardiovascular manifestations coronary artery disease (CAD). In addition to traditional
of HIV were dilated cardiomyopathy, pericardial disease, risk factors for CAD, HIV infection itself and certain antire-
pulmonary hypertension, and neoplastic involvement of troviral combinations may also contribute to the increased
the heart. ART has been revolutionary in the care of HIV, risk of CAD. Many large cohort studies have found a higher
significantly reducing the incidence of opportunistic infec- prevalence of traditional CAD risk factors among HIV-
tions and, thereby, prolonging life [1]. However, ART, espe- infected patients, including higher rates of smoking, lower
cially one of its components, the protease inhibitors, can be high-density lipoprotein cholesterol (HDL-C), and higher
associated with significant metabolic abnormalities includ- triglyceride levels [3, 4]. However, the increased risk of
ing insulin resistance, lipid abnormalities such as decreased CAD events persists despite adjustment for these traditional
high-density lipoproteins (HDL) and increased triglycer- risk factors [5]. This suggests a role for both the HIV infec-
ides, and fat redistribution with loss of peripheral fat and tion itself and, perhaps, certain components of ART in car-
intra-abdominal fat accumulation [2]. Therefore, it is not diovascular risk. HIV accelerates atherosclerosis through
surprising that, as the incidence of dilated cardiomyopathy, direct effects on cholesterol processing and transport, at-
pericardial disease, and neoplastic involvement of the heart traction of monocytes to the intimal wall, and activation
has decreased, the incidence of cardiovascular disease has of monocytes to induce an inflammatory response and en-
increased since the introduction of ART. The prolongation dothelial proliferation [6]. In a large study of patients en-
of life with ART and the consequently longer exposure to rolled in the Kaiser Permanente database, the overall
this therapy and HIV itself may all be factors in the increas- CAD event rate among HIV-infected patients was signifi-
ing incidence and prevalence of cardiovascular disease in cantly greater than that of HIV-uninfected controls [7].
HIV-infected patients. Interestingly, the age-adjusted CAD and myocardial infarc-
This review will discuss the most common cardiovascu- tion (MI) hospitalization rates were not significantly differ-
lar complications of HIV diseases (Box 21.1), including ent before and after the introduction of protease inhibitors
coronary artery disease, cardiomyopathy and congestive (PI) or before and after the initiation of other antiretroviral
heart failure, pericardial disease, pulmonary hypertension, agents. Carotid intimal medial thickness (IMT), a marker of
endocarditis, and neoplastic involvement of the heart. subclinical CAD, is increased in HIV-infected patients com-
For each of these conditions, there will be a focus on trends pared with those without HIV [8]. The fat redistribution
in the incidence, prevalence, and disease course from the and metabolic change in HIV infection (FRAM) investiga-
pre-ART to the current era. tors found that the statistically significant increase in
267
and increasing levels of triglycerides and VLDL-C; decreas-

Box 21.1 Common cardiovascular complications ing CD4 counts are associated with lower levels of HDL-C
observed in patients with HIV infection [20]. After the initiation of ART, lipid levels return to
• Coronary artery disease
either baseline levels or higher levels, except HDL-C,
which remains low [18]. These changes may represent
• Cardiomyopathy and congestive heart failure
a general restoration to health or may be the result of
• Pericardial disease
direct medication effects. Most PIs raise lipid levels [6].
• Pulmonary hypertension Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Endocarditis are also associated with lipid abnormalities but to a
• Neoplasms lesser extent than PIs. However, the effects on lipids vary
with each specific drug within a class. For example,
within the class of PIs, lopinavir/ritonavir and tip-
ranavir/ritonavir are associated with more significant in-
carotid IMT in HIV-infected patients persisted after adjust- creases in lipid levels, particularly triglycerides, while
ment for both demographics and traditional CAD risk fac- atazanavir/ritonavir and darunavir/ritonavir cause more
tors [9]. In this study, the effect of HIV on carotid IMT was modest lipid changes [6]. Several mechanisms by which
similar to the effects of male sex, current smoking, and di- ART could lead to dyslipidemia have been proposed
abetes. In a recent study of non-smoking HIV-infected male (Box 21.2) [21].
patients, duration of HIV infection, not ART use, was asso- The Infectious Disease Society of America (IDSA) and
ciated with increased carotid IMT [10]. Moreover, the rate the Adult AIDS Clinical Trials Group (ACTG) have pro-
of MI in HIV-infected patients, though still higher than in vided guidelines for the evaluation and management of
controls, has declined in recent years [11]. This reduction in dyslipidemia in HIV-infected adults receiving ART.
risk is likely associated with increasing use of lipid-lowering These guidelines draw heavily upon the National Cho-
therapy in these patients, along with the use of newer ART lesterol Education Program Adult Treatment Panel III
agents. guidelines. A subsequent implications paper should be
In addition to HIV itself, ART has been implicated in considered in conjunction with these guidelines [22].
increasing the risk of CAD. The HIV Outpatient Study These topics have been reviewed extensively elsewhere
(HOPS), a large prospective observational study, found [23] and a summary of these guidelines is provided in
an increase in the incidence of MI after the introduction Figure 21.1.
of PIs in 1996 [12]. The Data Collection on Adverse
Events of Anti-HIV Drugs (D:A:D) Study Group, another
large prospective observational study, found an increas-
ing incidence of MI with increasing exposure to com-
bination ART [13]. In a follow-up study from the same Box 21.2 Possible mechanisms for protease
group, there was an increased risk of MI per year of ex- inhibitor-associated dyslipidemia [21]
posure to PIs [14]. Adjustment for serum lipids attenu-
ated, but did not obliterate, this effect. And, finally, Impaired lipoprotein clearance
there have been conflicting findings on the association • Inhibition of LDL receptor-related protein with down-
between abacavir use and an increased risk of MI regulation of the LDL receptor
[15, 16]. A recent meta-analysis by the US Food and • Abnormal regulation of apo C-IIIa
Drug Administration of 26 randomized control trials – Inhibition of lipoprotein lipase
showed no increase in the risk of MI with abacavir use – Impaired lipoprotein–cell surface interactions
[17], whereas a large observational study has suggested – Impaired cellular retinoic acid binding protein-1
a possible link [15]. The expert opinions in the field
have concluded that the overall increase in risk of Increased hepatic cholesterol
CVD events associated with ART is modest, is out- and triglyceride synthesis
weighed by their effectiveness in controlling HIV disease, • Increased hepatocyte accumulation of sterol regulatory
and should be combated with modulation of traditional element binding protein-1
cardiovascular risk factors. – Decreased proteasome activity
Both HIV and ART are associated with dyslipidemia. – Improved nutritional status
After seroconversion, there is a decrease in total choles- – Impaired cellular retinoic acid binding protein-1
terol, low-density lipoprotein cholesterol (LDL-C), and • Increased hepatic substrate deliverya
HDL-C [18]. This is followed by increases in levels of tri-
glycerides and very low-density lipoprotein cholesterol LDL, low-density lipoprotein.
a
(VLDL-C) [19]. In fact, increasing plasma HIV RNA levels May be exacerbated by insulin resistance.
are associated with decreasing levels of HDL-C and LDL-C
268
Chapter | 21 | Cardiovascular complications of HIV infection
Figure 21.1 General approach to lipid disorders

and cardiovascular risk in HIV-infected patients Obtain fasting liquid profile, prior to starting
receiving ART per the guidelines of the Infectious antiretrovirals and within 3–6 months of
Disease Society of America and the Adult AIDS starting new regimen
Clinical Trials Group. CHD, coronary heart disease;
HDL, high-density lipoprotein; LDL, low-density
lipoprotein. Count number of CHD risk factors and
Adapted from Dubé MP, Stein JH, Aberg JA, et al. Guidelines determine level of risk. If ≥ 2 risk factors.
for the evaluation and management of dyslipidemia in perform a 10-year risk calculation
human immunodeficiency virus (HIV)-infected adults receiv-
ing antiretroviral therapy: recommendations of the HIV
Medical Association of the Infectious Disease Society of
America and the Adult AIDS Clinical Trials Group. Clin Infect Intervene for modifiable non-lipid risk factors,
Dis 2003; 37:613–27. including diet and smoking
If above the lipid threshold based on risk group

despite vigorous lifestyle interventions,
consider altering antiretroviral therapy or
lipid-lowering drugs
If lipid-lowering drugs are necessary
Serum LDL cholesterol above the threshold,

or triglycerides 200–500 mg/dL with OR Serum triglycerides > 500 mg/dL:
elevated non-HDL cholesterol: STATIN FIBRATE
retrospective study comparing the prevalence of cardiovas-

CARDIOMYOPATHY AND cular complications of HIV disease before and after ART,
the prevalence of DCM decreased from 8.1 to 1.8% [29].
CONGESTIVE HEART FAILURE A more recent report from the Study to Understand the Nat-
ural History of HIV/AIDS in the Era of Effective Therapy
Heart muscle disease is one of the most important cardio- (SUN Study) showed a persistently high prevalence of sub-
vascular manifestations of HIV infection. This may present clinical cardiac structural and functional abnormalities in
as dilated cardiomyopathy (DCM), myocarditis, or isolated outpatients with HIV on ART [30]. While nearly two-thirds
left or right ventricular dysfunction [24]. In the pre-ART era, of the patients had LV systolic or diastolic dysfunction, left
clinical and pathological studies showed a nearly 30% ventricular hypertrophy, left atrial enlargement, or pulmo-
prevalence of cardiomyopathy in patients with HIV, with nary hypertension, less that 2% had moderate or severe LV
an annual incidence of 15.9/1000 cases [25, 26]. DCM systolic dysfunction and 11% had moderate or severe dia-
carries a poor prognosis in patients with HIV. In a 4-year stolic dysfunction. However, DCM continues to be a signif-
prospective echocardiographic study survey of 296 patients icant cardiovascular complication of HIV where access to
with HIV infection, DCM was associated with a CD4 ART is limited. In a recent study of 416 HIV-infected pa-
count of < 100 cells/mm3 and significantly reduced sur- tients in Rwanda, DCM was documented by echocardiog-
vival time [27]. DCM tends to occur late in the course of raphy in 71 (17.7%) of them [31]. By both univariate
HIV infection. The exact prevalence of myocarditis in pa- and multivariate analysis, low socioeconomic status, esti-
tients with HIV infection has been difficult to establish, mated duration of HIV-1 infection, CD4 count, HIV-1 viral
with estimates ranging from 6 to 52% [26, 28]. It is likely load, CDC stage B and C of HIV disease, and low plasma
that myocarditis and DCM represent a continuum of dis- level of selenium were factors significantly associated with
ease progression. the development of cardiomyopathy.
Since the introduction of ART, there has been a decline in The pathogenesis of DCM continues to be an area of in-
the incidence and prevalence of DCM. In a single-center tense study (Box 21.3). HIV may damage cardiac myocytes
269
particularly the HIV heart muscle disease group (21%), than

Box 21.3 Common causes of HIV-associated in HIV-uninfected controls (3.5%) [38]. In addition, abnor-
dilated cardiomyopathy [24] mal anti-a myosin autoantibody concentrations were found
• Myocarditis: HIV, Coxsackie virus group B, Epstein–Barr
more often in HIV patients with heart muscle disease (43%)
virus, cytomegalovirus, echovirus, Toxoplasma gondii than in HIV-infected patients with normal hearts (19%) or
in HIV-uninfected controls (3%).
• Autoimmunity
Nutritional abnormalities also may play a role in some pa-
• Metabolic: selenium, vitamin B12, carnitine deficiency
tients, especially late in HIV infection and particularly in the
• Endocrine: thyroid hormone, growth hormone,
resource-poor setting. Deficiencies of selenium, vitamin B12,
adrenal insufficiency, hyperinsulinemia
and carnitine have been reported and associated with left
ventricular dysfunction [31, 39]. Other metabolic and endo-
crine abnormalities that have been associated with cardiac
dysfunction include hypothyroidism, growth hormone
by a direct cytolytic effect or through an “innocent bystander” deficiency, hypoadrenalism, and hyperinsulinism [34, 36].
reaction [25, 28]. Infection of myocardial cells by HIV-1 The role of certain drugs used to treat HIV in the develop-
has been demonstrated in a patchy distribution [28]. The ment of cardiomyopathy remains controversial. The nucleo-
mechanism by which HIV infection enters cardiac myocytes, side reverse transcriptase inhibitor (NRTI) zidovudine has
which do not possess CD4 receptors, is not clear. It has been been associated with diffuse destruction of ultra-structures
hypothesized that other cells in the myocardium—such as and inhibition of mitochondrial DNA replication, resulting
dendritic cells—play a role not only as a reservoir but also in lactic acidosis that contributes to myocardial dysfunction
as antigen-presenting cells in the context of the major histo- [40, 41]. However, zidovudine neither improved nor wors-
compatibility complex and as activators of cytokines that con- ened the cardiac abnormalities in a prospective study of 24
tribute to tissue damage [32]. In a more recent study children [42], and in adults, it does not seem to be associated
comparing histopathological sections from HIV-infected pa- with myocardial dysfunction [43].
tients with and without cardiomyopathy, the expression Drugs used to treat complications of HIV infection
of HIV envelope protein glycoprotein 120 (gp120) and also have been associated with dilated cardiomyopathy.
HIV replication were noted to be more prominent in T-cells Amphotericin B, used to treat disseminated fungal infec-
and macrophages, which also produce higher levels of pro- tions, is associated with a reversible dilated cardiomyopathy
inflammatory cytokines, than in cardiac myocytes, in which and may cause hypertension and bradycardia [44]. Doxoru-
HIV does not replicate [33]. Although HIV has been detected bicin, which is used to treat Kaposi’s sarcoma, is associated
in cardiac tissue, these findings suggest that an indirect with cardiomyopathy in a dose-related manner [45]. Foscar-
mechanism initiated by inflammatory cells and cytokines net treatment of cytomegalovirus infection may cause
or perhaps even a secondary viral infection such as cytomeg- cardiomyopathy as well [46]. Interferon-a, an immunomod-
alovirus, group B Coxsackie virus, Epstein–Barr virus, or ad- ulator that is used as an antineoplastic and antiviral for
enovirus mediates the high incidence of myocarditis with concomitant hepatitic C infection, can also cause cardiomy-
potential progression to DCM among HIV-infected patients opathy, although arrhythmia and myocardial ischemia are
rather than an HIV-specific infection of cardiomyocytes [34]. more common [47]. Finally, as survival with HIV infection
There is a growing body of evidence that suggests that au- increases and risk factors for atherosclerosis develop due to
toimmune mechanisms may also play an important role in aging and the use of ART, CAD and MI are increasingly com-
the development of cardiomyopathy in HIV-infected pa- mon phenomena that may contribute to left ventricular
tients [32, 35]. Uncontrolled hypergammaglobulinemia systolic dysfunction, as discussed above.
from T-helper cell dysfunction and increased concentra-
tions of circulating immune complex have been associated
with cardiac inflammation [36]. HIV protein transcription
also may alter the surface of cardiac myocytes with induc- PERICARDIAL DISEASE
tion of cell-surface immunogenic proteins leading to pro-
duction of cardiac autoantibodies that, in turn, could In the pre-ART era, pericardial effusion was one of the
trigger cardiomyocyte destruction. In patients with LV dys- most common clinically relevant cardiac complications in
function and evidence of myocarditis, immunohistologic patients with HIV infection, with an annual incidence of
findings have revealed induced expression of major histo- 11% [48]. Pericardial effusion can have a wide range of
compatibility class I antigen on myocytes and increased manifestations including the asymptomatic effusion inci-
numbers of infiltrating CD8þ T lymphocytes [37]. In a dentally detected by echocardiography or routine chest im-
study of 74 HIV-infected patients including 28 with echo- aging, cardiac tamponade, acute or chronic pericarditis, and,
cardiographic evidence of heart muscle disease, cardiac au- uncommonly, constrictive pericardial disease. A review of 15
toantibodies detected by indirect immunofluorescence autopsy and echocardiographic studies that included 1139
were more common in the HIV-infected patients (15%), HIV-infected patients revealed that approximately 21%
270
had a pericardial effusion, most of which were without an prevalence of PAH in HIV-infected individuals (0.5%) is
identifiable cause and were asymptomatic [49]. A male pre- higher than in the general population and has not changed
dominance in the development of pericardial effusions has significantly since the introduction of ART [54–56]. How-
been reported [50]. Dyspnea and edema were common pre- ever, the annual incidence of PAH has declined from 0.21%
senting symptoms, whereas chest pain was uncommon [50]. in the pre-ART era to 0.03% recently and this may be due to
Most of the effusions were small, with a lower prevalence of higher CD4 counts with a decrease in overall immune ac-
moderate to large pericardial effusions [48, 50, 51]. Vari- tivation [54]. Though overall survival has improved in
ables associated with moderate to large pericardial effusions the ART era, patients with HIV-associated PAH continue
were congestive heart failure, Kaposi’s sarcoma, tuberculosis, to have a worse prognosis, with reduced median survival,
and pulmonary infections of all etiologies [51]. Tamponade than HIV-infected patients without PAH [54, 57]. About
requiring emergent pericardiocentesis was rare, as was acute two-thirds of deaths in HIV-infected patients with PAH
pericarditis [48, 51]. In the pre-ART era, the development of are due to the direct sequelae of PAH, such as right ventric-
a pericardial effusion was a poor prognostic marker in pa- ular failure, cardiogenic shock, and sudden cardiac death
tients with HIV [48]. HIV-infected patients with pericardial [58, 59]. The histopathological findings in HIV-infected pa-
effusion had shorter survival (36% at 6 months) than indi- tients with PAH are similar to those seen in idiopathic PAH:
viduals without effusions (93% at 6 months, relative risk the majority have pulmonary arteriopathy with medial hy-
2.2, 95% CI, 1.2–4, p < 0.01). Pericardiocentesis is currently pertrophy, intimal thickening and/or plexiform lesions
recommended only in large, symptomatic effusions, for di- (89%), with veno-occlusive disease in 7% and thrombotic
agnostic evaluation of systemic illness, or for the manage- pulmonary arteriopathy in 4% [58]. Though HIV infection
ment of acute cardiac tamponade [39]. The prevalence of is regarded as a risk factor for the development of PAH, it is
pericardial effusions has declined dramatically since the in- unlikely that direct infection of the pulmonary vascular en-
troduction of ART [29, 52]. However, in sub-Saharan Africa, dothelium is the mechanism. Even with the use of highly
pericardial disease continues to be a frequent initial manifes- sensitive techniques such as polymerase chain reaction
tation of HIV-related cardiac disease [53]. (PCR) and in situ hybridization, the virus has not been
In the developed world, most pericardial effusions in identified in the pulmonary endothelium of HIV-infected
patients with HIV infection are idiopathic. However, in patients with PAH [60]. It is thus likely that HIV plays
sub-Saharan Africa, Mycobacterium tuberculosis was the un- an indirect role in the pathogenesis of PAH, through medi-
derlying cause in up to 70% of cases of pericardial effusion ators such as growth factors and cytokines. The HIV
[53]. Culture of pericardial fluid usually is unrevealing envelope glycoprotein (gp120) stimulates macrophage se-
(although pericardial biopsy has a higher yield), but other cretion of endothelin-1, a potent vasoconstrictor that is im-
uncommon opportunistic infections and neoplasms can be plicated in other forms of PAH [61]. Pro-inflammatory
diagnosed (Box 21.4). cytokines such as interleukin-1b, interleukin-6, and tumor
necrosis factor-a are elevated in HIV-infected patients
and are also implicated in the development of PAH [62].
Interleukin-1b is also linked to the production of plate-
PULMONARY HYPERTENSION let-derived growth factor, a growth factor implicated in vas-
cular remodeling in PAH [63]. In addition to primary
Pulmonary arterial hypertension (PAH) is a rare but serious pulmonary hypertension, secondary causes due to talc ex-
cardiovascular complication of HIV infection. The most posure in injection drug users, chronic liver disease, inter-
common presenting symptom is dyspnea (83%), followed stitial lung disease, and coagulopathies also contribute to
by peripheral edema, syncope, and chest pain [54]. The HIV-associated pulmonary hypertension.
Box 21.4 Common causes of HIV-associated

pericardial effusion ENDOCARDITIS
• Idiopathic: capillary leak
Before the introduction of ART, non-bacterial thrombotic
• Malignant: Kaposi’s sarcoma, lymphoma endocarditis (“marantic” endocarditis) was relatively com-
• Infectious: bacterial—Staphylococcus, Streptococcus, mon, with a prevalence of 3 to 5% in AIDS patients, partic-
Proteus, Nocardia, Pseudomonas, Klebsiella, ularly in those with HIV-wasting syndrome [25]. Marantic
Enterococcus, Listeria, Mycobacteria endocarditis is characterized by the presence of fibrin-rich
• Viral: HIV, herpes simplex virus, cytomegalovirus collections of platelets and erythrocytes that adhere to
• Fungal/protozoan: Cryptococcus, Histoplasma, valves, forming a fibrin mesh with relatively little inflam-
Toxoplasma matory reaction. Systemic embolism is common, but most
• Hypothyroidism episodes are clinically silent. The diagnosis of non-bacterial
thrombotic endocarditis is usually made post mortem.
271
Infective endocarditis (IE) occurs at a similar rate among advanced immune suppression. The prognosis of patients
patients with HIV infection, as in other groups of individuals with HIV-associated cardiac non-Hodgkin’s lymphoma is
at increased risk such as intravenous drug users [39]. Re- poor, although remission has been observed in patients trea-
cently the incidence of IE in HIV-infected patients who ted with combination chemotherapy.
use intravenous drugs has decreased from 20.5 per 1,000 Autopsy studies have demonstrated that cardiac involve-
person-years in the pre-ART era to 6.6 per 1,000 person-years ment with Kaposi’s sarcoma was usually due to disseminated
[64]. Those with advanced immunosuppression are more disease with metastases involving the pericardium [70].
likely to develop IE. Intravenous drug users frequently have Metastases to subepicardial adipose tissue adjacent to major
right-sided valvular infections due to Staphylococcus aureus, coronary arteries have also been described [70]. Though car-
Streptococcus pneumonia and Streptococcus virideans [39, 65]. diac involvement with Kaposi’s sarcomas has usually been
Although presentations of IE usually are similar among discovered at autopsy, bloody pericardial effusions may be
HIV-infected and non-infected patients, survival with endo- discovered by imaging or pericardiocentesis in patients with
carditis is worse in individuals with HIV infection, particu- advanced disease.
larly in those with more advanced HIV disease [64, 65].
NEOPLASMS CONCLUSION
The most common cardiac neoplasms in HIV-infected pa- HIV infection and AIDS have reached global epidemic pro-
tients are Kaposi’s sarcoma and non-Hodgkin’s lymphoma. portions. Although ART is very effective at improving sur-
A recent autopsy study demonstrated a marked decline in vival with HIV infection, it is not widely available in
the prevalence of Kaposi’s sarcoma from 17 to 3% since regions of the world that are most affected. In patients
the introduction of ART [66]. Although malignant lympho- who are not on ART, end-stage complications of AIDS that
mas of the heart are rare, lymphomas were identified in 5 to affect the heart, including dilated cardiomyopathy, myo-
10% of patients with HIV infection in the pre-ART era, carditis, pericardial effusion, pulmonary hypertension, en-
which is a 60–100 times higher prevalence than expected docarditis, and involvement of the heart with neoplasms,
in the general population [36, 67]. A statistically significant are not uncommon. In parts of the world where ART is used
reduction in the incidence of non-Hodgkin’s lymphoma frequently, complications related to aging, HIV replication
has been demonstrated since the widespread introduction itself with consequent immune activation, the use of ART
of ART, although this reduction has not been as dramatic as and the high prevalence of risk factors such as diabetes mel-
that for Kaposi’s sarcoma [68]. litus, smoking, hyperlipidemia, and obesity all contribute
HIV-associated lymphomas are typically derived from to the overlapping epidemiology and disease manifesta-
B-lymphocytes and are high grade. Metastatic lymphomas tions of CAD in patients with HIV infection.
of the heart are more common than primary cardiac lympho-
mas, which tend to be rare. Most patients have disseminated
disease at the time of their initial presentation, although some
patients may have primary lymphomas involving only the ACKNOWLEDGMENT
pericardium [69]. In general, AIDS-associated lymphomas
are found in patients with low CD4 counts; however, non- I acknowledge the use of content written by J. H. Stein, au-
Hodgkin’s lymphoma may occur in patients with less thor of this chapter in the previous edition.
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274
Chapter | 22 |
Endocrine complications of HIV infection
Steven A. Taylor, Carl Grunfeld, Morris Schambelan
of specimens [1]. Pathogens infecting the thyroid included

INTRODUCTION Pneumocystis jiroveci, cytomegalovirus (CMV), Cryptococcus
neoformans, Aspergillus fumigatus, Rhodococcus equi, Haemo-
A wide spectrum of endocrine complications is associated philus influenzae, Microsporidia, Histoplasma capsulatum,
with HIV infection and AIDS. Although these disorders Paracoccidioides brasiliensis, Mycobacterium avium intracellu-
may reflect changes induced by HIV itself, more often they lare, and Mycobacterium tuberculosis. Pneumocystis jiroveci
are a consequence of systemic illness, opportunistic infec- was the most common OI of the thyroid, occurring primar-
tions (OIs), neoplasm, body composition changes, HIV- ily among patients receiving aerosolized pentamidine [2].
related therapies, and/or restoration of health. The use of Clinical manifestations of thyroiditis are variable and
highly active antiretroviral therapy (HAART) clearly altered may include signs and symptoms of either hyper- or hypo-
the endocrinologic manifestations of HIV. As the incidence thyroidism. Palpation of the thyroid gland may reveal
of glandular infiltration by OIs and neoplasm has declined, localized tenderness and/or fluctuance; systemic signs of
attention has focused on the metabolic complications of infection may be present. Functional testing may reveal
therapy. Studies performed in the pre-HAART era remain transient hyperthyroidism (that may not require treat-
relevant, however, to the management of patients where ment), euthyroidism, or hypothyroidism. HIV has also
there is limited access to HIV care and to those who become been isolated from thyroid tissue of infected patients with
resistant to antiretroviral therapy (ART). Understanding Graves’ disease (GD), though it is unclear whether HIV is
these disorders is crucial to the ongoing care of HIV- involved in the pathogenesis of this autoimmune thyroid
infected patients. This chapter describes the endocrine disorder [3].
complications of HIV disease and provides a general ap- Neoplastic infiltration of the thyroid is uncommon in
proach to management, primarily referencing high-quality patients with AIDS. Only two cases of thyroid lymphoma,
review articles, rather than the primary references, due to one case of thyroid carcinoma, and one case of acute mye-
space limitations. logenous leukemia presenting as a thyroid mass [4] have
been reported. There have been a few cases of Kaposi’s sar-
coma (KS) involving the thyroid gland in patients with
pre-existing cutaneous lesions. Other frequent pathologic
THE THYROID changes of the thyroid include non-specific focal chronic
inflammation, colloid goiter, and lipomatosis [1].
Thyroid pathology
Clinically significant OIs of the thyroid occur very rarely
Alterations in thyroid function
in patients with AIDS, and the advent of ART has further
reduced the frequency. In an autopsy study, two-thirds of Although asymptomatic HIV-infected patients with stable
thyroids examined demonstrated pathologic changes, body weight are usually clinically euthyroid, abnormal thy-
though no patients had pre-mortem clinical thyroid dis- roid homeostasis is often present in patients with AIDS. In
ease. Indeed, more than one OI was found in the majority non-thyroidal illness (NTI), inhibition of peripheral T4 to
275
T3 conversion and reduced reverse T3 (rT3) clearance re- to document resolution of abnormalities. Use of exoge-
sults in low T3 and elevated rT3, usually accompanied by nous thyroid hormone is not indicated in the setting
normal thyroid-stimulating hormone (TSH) levels. The of NTI.
characteristic changes of NTI differ from those observed
in AIDS patients, who often have higher T3 levels and lower
rT3 levels than would generally be expected. The increased Effects of antiretroviral
thyroid hormone-binding globulin (TBG) levels associated and other therapies
with HIV infection do not explain these findings [5]. The
abnormalities of thyroid testing in HIV-infected individ- Rifampin, ketoconazole, and ritonavir may alter thyroid
uals compared with seronegative patients with NTI are pre- function by accelerating the metabolic clearance of thyroid
sented in Table 22.1. The maintenance of normal T3 levels hormone and can precipitate hypothyroidism in patients
among AIDS patients has led to concern that the protective with marginal thyroid reserve; thus, higher doses of thyrox-
effects that reduction of T3 provides in NTI, such as lower- ine may be necessary in patients receiving concomitant
ing metabolic rate, ameliorating weight loss, and decreas- replacement therapy [2].
ing protein catabolism, may be compromised. Lower T3 Treatment of hepatitis C infection with interferon-a
levels are observed, however, during secondary infection (INF-a) has been associated with the development of auto-
and anorexia. Patients with asymptomatic HIV infection immune thyroid diseases (AITD) such as GD, Hashimoto’s
have been reported to demonstrate characteristics of com- thyroiditis, and subacute or destructive thyroiditis. Since
pensated hypothyroidism including high-normal range individuals with pre-existing or recently detected thyroid
24-h TSH profiles, lower free T4 levels, and a greater TSH autoantibodies (i.e. thyroid peroxidase [TPOAb] and thyro-
response to TRH infusion [6]. These alterations in thyroid globulin [TgAb] antibodies) are at higher risk for INF-a-
hormone physiology may be adaptive to chronic illness, induced AITD, practitioners should test TSH, free T4, and
decreased energy intake, or the increased metabolic de- thyroid antibodies before initiation of INF-a treatment,
mands of HIV infection. Still, there is little evidence to sug- followed by measurement of TSH every 8–12 weeks during
gest those with asymptomatic HIV infection be routinely treatment [8]. IFN-a treatment should be delayed until
screened for thyroid dysfunction [7]. If hyper- or hypothy- correction of pre-existing thyroid dysfunction. If thyroid
roidism are clinically suspected, a physical examination dysfunction develops during treatment, IFN-a need not
that includes an assessment of the thyroid gland should be discontinued unless destructive thyroiditis with severe
be performed followed by measurement of TSH level. symptoms refractory to b-blockers or GD requiring high
HIV-infected patients with an acute illness, such as local doses of anti-thyroidal medications develops. Although
or systemic infection, may have thyroid function test most patients who develop thyroid dysfunction during
(TFT) results consistent with NTI. In this instance, TFTs treatment with INF-a normalize after it is discontinued, a
should be repeated a few weeks after recovery from illness minority continue to require treatment [8].
Since the introduction of HAART, AITD has been
reported as a late complication of immune reconstitution,
typically presenting as GD 1–2 years after initiation of ther-
Table 22.1 Alterations in thyroid function in HIV infection apy [9]. The onset of AITD is temporally consistent with
thymic production of naı̈ve CD4 T cells (the “late” phase
of T cell repopulation), and immune dysregulation in those
SERONEGATIVE HIV- HIV-
with genetic predisposition may result in thyroid-specific
NTI INFECTED, INFECTED,
STABLE SICK autoimmunity.
T3 ## Normal #
Treatment considerations
rT3 " # # or Normal
Subtle alterations in thyroid function in HIV-infected in-
TBG " " "" dividuals must be interpreted in their clinical context.
In patients with clinically significant and biochemically
T4 Normal or # Normal Normal
confirmed hypothyroidism, low doses of replacement ther-
TSH Normal, may be " Normal Normal apy (levothyroxine 25–50 mg daily) should be prescribed
during recovery initially, with gradual titration and monitoring of TSH
levels. Clinical management for patients with hyperthy-
NTI, non-thyroidal illness. roidism and coexisting HIV infection is similar to that for
From Sellmeyer DE, Grunfeld C. Endocrine and metabolic immunocompetent individuals, except that a tender or
disturbances in human immunodeficiency virus infection and the
nodular thyroid gland in a patient with advanced HIV
acquired immune deficiency syndrome. Endocr Rev 1996;
17:518–532. disease should prompt further investigation for an OI or
malignancy of the thyroid. Diagnostic evaluation includes
276
Chapter | 22 | Endocrine complications of HIV infection
fine needle aspiration (FNA) biopsy of the affected gland. DHEA showed improved quality of life in patients with
Pneumocystis jiroveci organisms can be demonstrated with AIDS without change in CD4 T cell count [12]. However,
Gomori’s methenamine silver stain. FNA should also be con- a recent 6-month randomized, double-blind, placebo-
sidered in patients with disseminated KS who present with a controlled study of 40 HIV-infected subjects with sup-
thyroid nodule to identify the rare case of KS of the thyroid. pressed viral loads showed no changes in immune param-
eters, lean muscle mass, or bone density following
treatment with oral DHEA [13]. DHEA cannot be recom-
THE ADRENAL mended in the routine treatment of HIV-infected patients
until its efficacy has been proven in larger, randomized
clinical trials evaluating multiple outcomes.
Adrenal pathology
Although pathologic involvement of the adrenal gland was
frequently noted during autopsy in the pre-HAART era, Effects of antiretroviral
clinical adrenal insufficiency (AI) was relatively rare. This and other therapies
is likely explained by the fact that greater than 90%
Although the dorsocervical fat pad enlargement and vis-
of the adrenal cortices must be destroyed for AI to ensue.
ceral adiposity seen in some HIV-infected patients appears
Cytomegalovirus adrenalitis was the most common
phenotypically similar to Cushing’s syndrome, overt hyper-
finding. Mycobacterium tuberculosis, M. avium intracellulare,
cortisolism has not been found in affected patients [14].
C. neoformans, and Toxoplasma gondii also infect the adrenal
The demonstration of both normal diurnal cortisol excre-
gland. Infiltration with KS or lymphoma, hemorrhage, fibro-
tion and normal response to exogenous CRH administra-
sis, infarction, and focal necrosis were also reported [2].
tion provides additional evidence that the development
of central lipohypertrophy cannot be attributed to abnor-
mal cortisol metabolism, though some have hypothesized
Alterations in adrenal function
that it may be related to the increased cortisol/DHEA ratio
HIV-infected individuals may demonstrate changes in ste- observed in these patients. Iatrogenic Cushing’s syndrome,
roid metabolism, including an elevation in basal cortisol however, can occur in patients treated concomitantly with
levels that may be accompanied by decreased responsive- ritonavir and nasal or inhaled fluticasone (for allergic rhi-
ness to ACTH stimulation. Lower levels of ACTH and the nitis or asthma). Ritonavir prolongs the half-life of flutica-
weak adrenal androgen dehydroepiandrosterone (DHEA) sone via effects on CYP3A4, leading to much higher plasma
are often observed, along with impaired adrenal reserve levels of fluticasone than pharmacologically intended and
of the 17-deoxysteroids (corticosterone, deoxycorticoster- classic physical manifestations of glucocorticoid excess.
one, and 18-OH-deoxycorticosterone) [10]. Factors such When given in conjunction with ritonavir, intra-articular
as cytokines, acting independently of the pituitary gland, triamcinolone used in the treatment of osteoarthritis may
may directly enhance cortisol biosynthesis in the absence also be associated with signs and symptoms of glucocorti-
of an increase in ACTH. In some HIV-infected patients, coid excess, though the mechanism for this is unclear.
however, the combination of increased cortisol and Upon steroid withdrawal, secondary adrenal suppression
ACTH levels suggests hypothalamic activation, although may ensue. Associated conditions such as osteoporosis or
those with late-stage HIV disease often have an attenuated diabetes may be induced or exacerbated. Practitioners
pituitary–adrenal response to corticotropin-releasing hor- should be aware of these potential interactions in order
mone (CRH). Compensatory rises in ACTH levels may also to avoid delays in diagnosis among patients who have
develop in those with subclinical AI due to physiologic hor- pre-existing central lipohypertrophy that might mask the
monal feedback mechanisms. In AIDS patients who preclinical features of Cushing’s syndrome. These patients
sent with elevated levels of both cortisol and ACTH but should be examined for cardinal signs of Cushing’s syn-
manifest paradoxical Addisonian features, peripheral glu- drome, including violaceous striae, bruising, and proximal
cocorticoid resistance may be present [11]. Levels of DHEA muscle weakness.
decline with advancing age and chronic illness, in contrast Multiple medications used to treat complications of HIV
to levels of cortisol, which remain relatively stable. Interest may affect adrenocortical function. AI may be induced
in DHEA therapy among the HIV community was moti- in patients with impaired adrenal reserve by conazoles
vated by studies showing that DHEA inhibits HIV-1 repli- (keto-, flu- and itraconazole) through inhibition of cortisol
cation and activation in vitro. Cross-sectional studies have biosynthesis. Rifampin may also induce AI by increasing the
associated low DHEA levels and elevated cortisol/DHEA ra- metabolic clearance of cortisol. A syndrome of mineralocor-
tios with advanced HIV infection, and low serum concen- ticoid excess has been reported in patients on high-dose itra-
trations of DHEA have been significantly correlated with conazole [15]. Megestrol acetate, a progestational agent used
CD4 T cell count, weight loss, and progression to AIDS. as an appetite stimulant in the treatment of AIDS-wasting,
Small placebo-controlled trials of oral administration of can suppress both the hypothalamic–pituitary–adrenal
277
(HPA) axis and the hypothalamic–pituitary–gonadal exposure. Administration of short-term, supplementary

(HPG) axis due to its intrinsic glucocorticoid-like activity. glucocorticoids to symptomatic patients who demonstrate
Some patients receiving long-term therapy may develop a subnormal rise in cortisol levels during periods of stress is
iatrogenic Cushing’s syndrome and/or diabetes mellitus, reasonable.
as well as adrenal failure when treatment is suddenly dis-
continued. Opiate use, often seen coexisting with HIV
infection, can blunt cortisol secretion in response to ACTH THE PANCREAS
stimulation [16].
Pancreatic pathology
Treatment considerations Morphologic abnormalities of the pancreas are common at
autopsy in AIDS patients (up to 90%); however, most le-
The alterations in steroid metabolism observed in patients sions are asymptomatic [17]. Pancreatic OIs such as myco-
with HIV infection may be adaptive to chronic illness and bacteria, toxoplasmosis, CMV, and P. jiroveci have been
may not require treatment. Estimates of the prevalence of documented, with presentation similar to that of pancreati-
AI vary considerably, depending on the population stud- tis due to other causes [18]. The most common pancreatic
ied, whether patients manifest clinical signs and symptoms, OI is tuberculosis, presenting with diverse manifestations,
and the method of diagnostic testing used. AI is clearly such as masses mimicking carcinoma, obstructive jaundice,
more common in HIV-infected patients than in the general pancreatitis, gastrointestinal bleeding, and generalized
population. The diagnosis should be considered in patients lymphadenopathy. It may be diagnosed by abdominal com-
who present with malaise, orthostatic hypotension, nau- puted tomography followed by FNA biopsy. HIV-associated
sea, abdominal pain, weight loss, hyponatremia, and hypo- neoplasms rarely affect the pancreas, although primary pan-
glycemia. The appropriate method of adrenal function creatic lymphoma [19] and KS have been reported, the latter
testing, however, is controversial. Although the ACTH stim- successfully treated with intensive ART and paclitaxel [20].
ulation test (administration of 250 mg cosyntropin) is the
most widely used, it may not identify all patients with im-
paired pituitary reserve. In several reported cases, insulin- Alterations in glucose homeostasis
induced hypoglycemia or the metyrapone test was used
and effects of antiretroviral therapy
to diagnose AI in HIV-infected patients. Further, the sensi-
tivity of the ACTH stimulation test falls with acute or Prior to the advent of HAART, symptomatic HIV-infected
chronic illness, which is associated with impaired cortisol men were found to have increased insulin sensitivity of
protein binding and reduced cortisol binding protein peripheral tissues compared with non-infected controls.
levels. Total cortisol levels may be low due to these factors, Recent studies found conflicting evidence as to whether in-
though biologically active free cortisol levels may be normal sulin sensitivity is altered among asymptomatic HIV-
or high. Several factors limit the reliability of free cortisol infected individuals who are ARV-naı̈ve. Following the
assays in the clinical assessment for AI. If AI is suspected introduction of HAART with protease inhibitors (PIs), ab-
in the setting of intercurrent illness, an assessment for typical normalities of glucose metabolism including insulin resis-
risk factors—especially recent use or discontinuation of tance, impaired insulin secretion, hyperglycemia, and frank
glucocorticoids—should ensue. If suspicion persists based diabetes were reported. However, it was unclear whether
on results of dynamic laboratory testing, treatment should restoration of health, immune reconstitution, body com-
be instituted. position changes, or other antiretrovirals contributed to
Patients with documented AI should be treated with glu- these disturbances. Subsequent studies of individual PIs
cocorticoid replacement therapy and require increased among healthy, HIV-seronegative volunteers minimized
doses during periods of stress. If primary adrenal failure confounding by HIV-related factors and demonstrated
is present with evidence of concomitant mineralocorticoid a spectrum of effects of PIs on glucose metabolism
deficiency (hyperkalemia and metabolic acidosis), the ad- [21–28]. For instance, although a single dose of indinavir
dition of fludrocortisone should be considered. Contro- and ritonavir-boosted lopinavir were found to acutely
versy exists regarding whether patients with elevated induce insulin resistance, amprenavir and boosting-dose
basal cortisol levels, but a blunted response to standard ritonavir did not. After 4 weeks of treatment, insulin resis-
single-dose ACTH stimulation, should be treated with glu- tance and increased fasting glucose occurred with indinavir
cocorticoid therapy. Some of these patients probably do but not with ritonavir-boosted lopinavir. Endogenous glu-
not require chronic glucocorticoid replacement, as they cose production (EGP) was increased following adminis-
show adequate cortisol response after receiving supraphys- tration of indinavir compared to placebo. This finding,
iologic ACTH stimulation for 3 consecutive days [10]. indicating an indinavir-induced reduction in the ability
These challenging cases must be evaluated individually, of insulin to blunt EGP that may lead to hyperglycemia
with the goal of minimizing unnecessary glucocorticoid and a predisposition to diabetes, was not shown with
278
amprenavir. More recently, though it was initially reported patients with pre-existing glucose intolerance or those with
that PIs as a class impair pancreatic b-cell insulin secretion first-degree relatives with diabetes.
in HIV-infected patients, there was no effect on insulin se- Treatment of diabetes in HIV-infected patients should em-
cretion after healthy HIV-seronegative volunteers were phasize healthy diet, regular exercise, and maintenance of
given ritonavir-boosted lopinavir for 4 weeks. Thus, PIs normal body weight. Among the accepted first-line oral
do not have a singular class effect on glucose metabolic medications for diabetes, preference may be given to metfor-
pathways, and the distinct effects of individual PIs on glu- min. Metformin should be avoided in those with a history of
cose metabolism must be taken into account when tailor- renal disease or lactic acidemia, a recognized adverse effect of
ing antiretroviral regimens. NRTIs. Agents from other oral hypoglycemic classes may be
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) used in the management of HIV-infected type 2 diabetics,
have not been associated with derangements in glucose me- but results will likely not differ from the general population.
tabolism. Impaired glucose homeostasis occurs in PI-naı̈ve The thiazolidinedione (TZD) pioglitazone may be used, but
patients treated with nucleoside reverse transcriptase inhib- TZDs reduce bone mineral density (BMD) and increase frac-
itors (NRTIs). The effects of NRTIs on glucose metabolism tures; pioglitazone should be used with care in a population
should, therefore, also be systematically studied. already at risk of low BMD and fracture. If adequate glycemic
control is not achieved with oral agents, an insulin-based
regimen should be started. Metformin and pioglitazone
Effects of other therapies do not necessarily need to be discontinued in this instance.
In addition, clinicians should be aware of potential
Pentamidine, used in the prevention and treatment of P. jir-
interactions between PIs and hypoglycemic agents. Ritona-
oveci, may cause pancreatic b-cell toxicity when adminis-
vir and nelfinavir induce CYP2C9, which may reduce
tered either intravenously or aerosolized. Acute insulin
concentrations of selected sulfonylureas and TZDs [29].
secretion and resultant hypoglycemia may be followed
by b-cell destruction and diabetes mellitus [2]. Acute
pancreatitis rarely occurs with pentamidine, trimethoprim-
sulfamethoxazole, the NRTIs ddI and ddC, ritonavir-induced ABNORMALITIES OF LIPID
hypertriglyceridemia and antifungal treatment with liposo-
METABOLISM
mal amphotericin B, micafungin, griseofulvin, fluconazole,
itraconazole, and voriconazole [15].
The intrinsic glucocorticoid-like activity of megestrol ac- High-density lipoprotein (HDL) levels decrease early in
etate may exacerbate or cause hyperglycemia, although the untreated HIV infection, often by as much as 50%, fol-
incidence of this complication is low. Growth hormone lowed by smaller decreases in low-density lipoprotein
(GH) can induce insulin resistance and predispose to hy- (LDL) and then by increases in triglycerides. The circulating
perglycemia and diabetes. A small increase in hemoglobin level of HIV RNA accounts for some of the change. Lower
A1c accompanies tesamorelin treatment to reduce visceral CD4 T cell counts are associated with lower HDL levels.
adipose tissue. Ketoconazole, fluconazole, and voricona-
zole have been associated with hypoglycemia, though the
underlying mechanisms are unknown [15]. Additionally, Effects of antiretroviral drugs and
co-administration of fluconazole with the oral hypoglyce- other therapies
mic medications tolbutamide, glimepiride, and nateglinide
In early studies of AZT therapy, triglycerides were reduced.
increase their peak plasma concentrations, increasing risk
Triglycerides increase with specific antiretroviral drugs,
of hypoglycemia.
including efavirenz and ritonavir. The latter increases
triglycerides in a dose-dependent manner in both HIV-
infected patients and healthy volunteers.
LDL levels increase with most ART regimens, but not to
Recommendations for managing the metabolic complica- high levels, which may reflect restoration to health. LDL
tions of HIV infection, including abnormalities in glucose levels are not increased by PIs in healthy volunteers.
homeostasis, have been published [29]. If ART includes a PI NNRTIs raise HDL levels, though usually not back to nor-
associated with changes in glucose homeostasis, fasting mal. Nevirapine can induce a 50% increase in HDL, while
glucose should be monitored before initiation, at the time efavirenz induces smaller increases. Nevirapine increases
of a change in therapy, 3 to 6 months after starting or HDL in non-infected infants treated to prevent vertical trans-
switching therapy, and at least annually during therapy. mission. Small changes in HDL may occur with other anti-
For patients with risk factors for type 2 diabetes and those retroviral drugs, but results have varied. Tenofovir may
with lipoatrophy or lipohypertrophy, an oral glucose improve the atherogenic lipid profile.
tolerance test may be considered. If possible, PIs most Anabolic steroids, especially oral preparations, increase
associated with insulin resistance should be avoided for LDL and decrease HDL levels. The combination of HIV
279
and oxandrolone can induce extremely low HDL levels. Ke- 4.4% of 339 asymptomatic HIV-infected patients in a
toconazole causes a dose-dependent reduction in LDL and cross-sectional study compared to none of the seronegative
total cholesterol and an increase in triglycerides without controls [32]. The shoulder may also be affected. Osteone-
affecting VLDL or HDL levels [15]. Case reports describe crosis may be associated with prior glucocorticoid use. Un-
hypercholesterolemia and hypertriglyceridemia with itra- fortunately, surgical intervention remains the only available
conazole and voriconazole, though the mechanism is treatment for symptomatic osteonecrosis.
unclear.
Alterations in bone and

Treatment considerations mineral metabolism
PIs, which inhibit CYP3A4, may cause up to a 32-fold in- Reduced bone mineral density (BMD) is more common in
crease in simvastatin and lovastatin levels; these statins HIV-infected individuals, though the reasons for this re-
should be avoided when PIs are used. Atorvastatin activity main unclear. Histomorphometric analyses found altered
increases twofold with PIs, and high doses of atorvastatin bone remodeling prior to the introduction of HAART [33].
should not be used. Conversely, pravastatin levels decrease Multiple studies have shown increased prevalence of
with PI co-administration. Lopinavir/ritonavir and ataza- osteopenia and osteoporosis in treated HIV-infected patients.
navir/ritonavir increase rosuvastatin levels by an unknown Reduced BMD in HIV infection is likely multifactorial, with
pathway. Statins reduce cholesterol levels in HIV-infected possible contributions from weight loss, malnutrition, malab-
subjects similar to those in the general population. Due sorption (leading to vitamin D deficiency), hypogonadism,
to the many contributors to hypertriglyceridemia, triglycer- antiretrovirals, and traditional risk factors for osteoporosis
ide levels are less likely to reach goals in HIV-infected (gender, low BMI, age, menopause, smoking, and injection
patients. drug use). Increased fracture rates have been reported.
Calcium and phosphate homeostasis, critical in bone
remodeling, may be altered in HIV infection and have un-
BONE toward skeletal consequences. Some patients with HIV dis-
ease and low BMD may have vitamin D insufficiency with
secondary hyperparathyroidism. Vitamin D insufficiency
Bone pathology may result in hypocalcemia, which may also be related to
inadequate parathyroid hormone responses, compromised
Osteomyelitis is associated with mortality rates in excess
nutritional state, or medications used to treat opportunistic
of 20% in HIV-infected patients, underscoring the need to
infections. Primary hypoparathyroidism resulting in hypo-
quickly recognize and treat this entity [30]. As in immuno-
calcemia and hyperphosphatemia may rarely occur due to
competent individuals, Staphylococcus aureus is the pathogen
direct glandular infiltration by malignancy or infection, in-
most commonly implicated in osteomyelitis in HIV-infected
cluding P. jiroveci. Alternatively, hypercalcemia may occur
individuals. Osteomyelitis in HIV-infected patients has also
from increased production of 1,25-dihydroxyvitamin D
been reported to be caused by Salmonella spp., Nocardia
by NHL or granulomas from infectious pathogens, includ-
asteroides, Streptococcus pneumoniae, Neisseria gonorrhoeae,
ing M. tuberculosis, M. avium intracellulare, P. jiroveci, and C.
CMV, Aspergillus spp., T. gondii, Torulopsis glabrata, C. neofor-
neoformans. Treatment of C. immitis has been associated
mans, Mycobacteria and Coccidioides immitis [30]. Bartonella
with hypercalcemia of unclear etiology. Immune reconsti-
infection particularly occurs with CD4 counts <100 cells/
tution has been associated with hypercalcemia in the
mm3. Systemic signs of infection and complaints of local
setting of CMV infection.
bone pain should raise suspicion for osteomyelitis. Radio-
logic evaluation assists in the diagnosis, and bone biopsy
isolates causative organisms to direct therapy. Effects of antiretroviral
Systemic non-Hodgkin’s lymphoma (NHL) and KS may
and other therapies
invade bone, typically with CD4 counts < 200 cells/mm3.
Twenty to thirty percent of patients with systemic NHL Following the introduction of PI-based ART, decreased
have bone involvement [31]. In contrast, widespread KS BMD was reported among treated HIV-infected individ-
rarely involves the skeleton, but may result from direct in- uals. Most cross-sectional studies have since demonstrated
vasion from a nearby soft tissue lesion. Bone biopsy is nec- that HIV-infected men and women treated with any ART
essary to diagnose NHL and KS; both portend a poor regimen have lower BMD. Several studies have shown re-
response to treatment. duction of BMD after initiation of ART, with the greatest
Osteonecrosis, death of bone resulting from circulatory reductions seen in regimens using tenofovir. Medications
insufficiency, is another complication of HIV infection that used in the treatment of complications that may contribute
may present as either unilateral or bilateral bone or joint to development of osteoporosis include corticosteroids, pent-
pain. Osteonecrosis of the hip was detected by MRI in amidine, megestrol acetate, and ketoconazole. Heroin users
280
have 11% lower lumbar BMD than controls. This effect may be with decreased testosterone and bioavailable testosterone,
partially attributed to opiate-associated hypogonadism. Renal as well as increased serum gonadotropin levels [34]. Not sur-
electrolyte wasting leading to hypocalcemia and hypophos- prisingly, testicular atrophy is more likely to be found in
phatemia can occur with cidofovir for CMV treatment or with AIDS patients with lower BMI and may be caused by HIV in-
ART with tenofovir or adefovir. Amphotericin B and nystatin fection itself, medication-related toxicity, or OIs including
have been associated with renal magnesium wasting, leading CMV, T. gondii, and M. avium intracellulare. AIDS patients
to hypomagnesemia, resultant hypoparathyroidism, and are also at greater risk for the development of testicular ma-
hypocalcemia [15]. Foscarnet, used in the treatment of CMV lignancies, including KS, lymphoma, and germ cell tumors.
retinitis, may cause hypocalcemia or hypomagnesemia. It
binds circulating calcium and magnesium and can result in
reductions in the ionized forms of both. Foscarnet-complexed
Alterations in sex hormones
calcium can precipitate in tissues, including the kidney. This
may contribute to renal magnesium wasting, which also Early in the course of HIV infection, hyperresponsiveness
occurs with foscarnet administration. Pentamidine can also of luteinizing hormone (LH) to infusion of gonadotropin-
cause hypocalcemia and hypomagnesemia, while trimetho- releasing hormone (GnRH) may explain the normal or,
prim-sulfamethoxazole, ketoconazole, and aminoglycosides in some cases, elevated, total and free testosterone
are associated with hypocalcemia. Hypercalcemia has been levels [35]. As HIV disease progresses to AIDS, testosterone
reported with caspofungin, though the mechanism by levels usually decrease. With the advent of HAART, the inci-
which it occurs is unclear [15]. Ketoconazole, rifampin, and dence of hypogonadism in HIV-infected men has declined
rifabutin alter vitamin D metabolism but rarely change from 40 to 20%. Hypogonadism may be accompanied by
ionized calcium levels. decreased muscle mass and strength, generalized fatigue,
reduced libido and mood, gynecomastia, normocytic
anemia, and reduced bone mineral density.
Treatment considerations In the post-HAART era, direct testicular and pituitary pa-
thology causing hypogonadism have become far less com-
Screening for osteoporosis with bone densitometry among
mon. Hypogonadotropic hypogonadism is now more
HIV-infected individuals remains controversial. However, if
likely to be multifactorial in nature and may be due to
osteoporosis is present or a fragility fracture occurs in the set-
chronic illness, altered cytokine profiles, OIs, medications,
ting of osteopenia, work-up for secondary causes of osteopo-
weight loss, or cachexia and associated malnutrition. The
rosis, including vitamin D insufficiency and hypogonadism,
loss of lean body mass (LBM) and muscle strength in
should be initiated. If present, these disorders should be treat-
patients with the AIDS-wasting syndrome may be partially
ed. Patients should be encouraged to address modifiable risk
attributable to coexisting hypogonadism. In contrast to
factors (e.g. smoking), engage in weight-bearing exercise, and
the decreased levels of testosterone, serum and urinary
increase intake of calcium and vitamin D. Studies investigat-
levels of estrogens may be elevated in HIV-infected
ing the effects of switching antiretroviral regimen on BMD
men [36].
have been small and of short duration; therefore no clear
Increased sex hormone-binding globulin (SHBG) levels
recommendations can be made in this regard.
have been observed in this population. Increased SHBG
Once reversible causes of bone loss are addressed, the use
can increase total testosterone levels; therefore, assessment
of bisphosphonates should be considered in the treatment
of free or bioavailable testosterone in a special endocrine
of HIV-related osteoporosis. Both alendronate and zole-
referral lab may be required to diagnose male hypogonad-
dronic acid, administered with or without supplementa-
ism in some cases. Primary hypogonadism is marked by el-
tion with calcium and vitamin D, improve BMD at the
evated LH and follicle-stimulating hormone (FSH) levels,
lumbar spine and hip in HIV-infected individuals. Cur-
while LH and FSH levels are either low or inappropriately
rently, data on other agents that increase BMD in the setting
normal in secondary hypogonadism.
of HIV-associated bone loss are inadequate.
Sexual dysfunction is a common complaint among
men with advanced HIV disease, with an estimated preva-
lence of nearly 60%. Although erectile and ejaculatory
dysfunction, as well as loss of libido, are often attributed
REPRODUCTIVE HEALTH IN MEN to low testosterone levels, other factors may also be con-
tributory, including neurologic disease, systemic illness,
drug effects, weakness, low energy, and psychosexual
Testicular pathology
issues [35].
Histopathologic changes in the testes were commonly Gynecomastia in HIV-infected men may be due to hypoan-
found in autopsy studies among men with AIDS and in- drogenism and/or elevated estrogen levels, liver disease, or
cluded hypospermatogenesis, interstitial inflammation, the use of commonly implicated medications. Gynecomastia
and atrophy. Pathologic damage to the testes is associated is also common among healthy men as they age.
281
Effects of antiretroviral and other sildenafil, tadalafil, and vardenafil. To reduce the risk of
therapies PDE5-I-associated toxicities, low doses of PDE5-Is should
be used cautiously in PI-treated patients.
A number of medications used in the treatment of HIV and its
related disorders affect the reproductive health of men. Sys-
temic glucocorticoid therapy, megestrol acetate, and opiates Fertility and reproduction
can cause hypogonadotropic hypogonadism. Ketoconazole,
particularly at higher doses, and chronic use of alcohol and Analysis of semen among men with early HIV disease is
marijuana impair testosterone production [16]. These drugs, usually normal and compatible with fertility. In contrast,
as well as ART, may lead to gynecomastia in HIV-infected men with advanced stages of HIV often have oligospermia
men. Though gynecomastia was initially attributed to and morphologically abnormal sperm [35]. ART with zido-
PIs, other antiretroviral medications, such as the NNRTI vudine does not adversely affect sperm production or qual-
efavirenz, have been associated with its development. ity. Treatment with testosterone or anabolic steroids is
Sexual dysfunction has been associated with PI therapy associated with azoospermia.
in reports of affected men without any other apparent eti- Sperm washing has been described as a safe and effective
ology. In some of these patients and in those with low method of achieving pregnancy among HIV-discordant
libido, raised serum estradiol levels were found. couples, though concern about the risk of infection trans-
mission to seronegative women is not completely eradi-
cated by this process [39].
After both confirming hypogonadism with repeated morn- REPRODUCTIVE HEALTH IN WOMEN
ing measurements of testosterone utilizing a reliable labora-
tory assay and excluding reversible etiologies, symptomatic
patients with primary or secondary hypogonadism should
Ovarian pathology
be offered therapy with replacement doses of testosterone. In contrast to those describing testicular pathology, there
Testosterone is usually administered by intramuscular have been no autopsy series examining the ovaries in the
injection every 2–3 weeks using testosterone esters (e.g. setting of AIDS. Case reports of CMV oophoritis and ovar-
enanthate and cypionate) or by transdermal delivery via ian non-Hodgkin’s lymphomas suggest the ovaries are sus-
patch or gel. Although the testosterone patch and gel avoid ceptible to OIs and HIV-associated neoplasms. HIV can
the large fluctuations in circulating testosterone levels seen directly infect cells and tissues from both the upper and
with injections, transdermal therapy does not always pro- lower female reproductive tract, including the vaginal
duce therapeutic testosterone levels at recommended doses. mucosa, fallopian tubes, uterus, and cervix [40].
Clinical assessment of the response and subsequent labora-
tory monitoring of testosterone concentration should be
performed, along with periodic measurements of HDL cho- Ovarian function and alterations
lesterol, hematocrit, and prostate-specific antigen. Hypogo-
in sex hormones
nadal men with HIV-associated weight loss treated with
physiologic testosterone therapy with or without concurrent The menstrual cycle may have an effect on viremia, as HIV-
resistance training show improvement in LBM, muscle 1 RNA levels decline from the early follicular phase to the
strength, bone mineral density, and quality of life [37]. Ane- luteal phase. Conversely, several studies suggest that HIV
mia associated with hypogonadism is ameliorated by testos- infection has little effect on the menstrual cycle. Narcotics,
terone. Caution should be used when treating sedentary marijuana, and chronic alcohol consumption are known to
obese men with hypogonadism, as testosterone increases affect menstrual function and ovulation and should be
cardiac events in this population. Given the potential risks, addressed in HIV-infected women with menstrual irregu-
use of supraphysiologic testosterone therapy in eugonadal larities. As expected with any chronic illness, amenorrhea
HIV-infected men with weight loss is not recommended. is more common in women with AIDS wasting. Meno-
Treatment options for reversing HIV-associated gyneco- pause does not appear to alter the progression of HIV or re-
mastia have not been systematically evaluated. Cosmetic sponse to therapy. It is uncertain whether HIV has an effect
surgery to debulk mammary tissue may be considered. A on the onset of menopause and the severity of related
case report describes successful treatment of an HIV- symptoms. Similar to findings in men, women with AIDS
infected man with the selective estrogen receptor modula- wasting demonstrate reduced androgen levels. This
tor tamoxifen [38]. hypoandrogenism appears to be a result of shunting of ad-
In managing erectile dysfunction in HIV-infected men renal steroid metabolism away from androgenic pathways
on ART, clinicians should be aware that PIs increase levels toward cortisol production and is not due to decreased
of phosphodiesterase type 5 inhibitors (PDE5-Is) including ovarian androgen production [41]. Hypoandrogenism in
282
women may be associated with decreases in energy, libido, Pregnancy does not appear to have an effect on the pro-
mood, strength, and BMD. gression of HIV, though it may increase HIV-1 expression in
Although a small initial study linking hyperandrogen- the genital tract, thus increasing the risk of vertical disease
emia and hyperinsulinemia in HIV-infected women with transmission. ART in the perinatal period reduces this risk.
HIV-associated lipodystrophy suggested these patients HIV-1 RNA levels may increase in early postpartum, though
may have features of polycystic ovary syndrome, later re- the significance of this is unclear.
ports from the same group found reduced free testosterone
levels and LH-to-FSH ratios, normal menstrual function,
and normal ovarian morphology by ultrasound [42]. Se- THE PITUITARY
rum testosterone in the range of an androgen-secreting tu-
mor was reported in one HIV-infected woman with
peripheral lipoatrophy and central lipohypertrophy [43]. Pituitary pathology
Systematic postmortem examination of pituitary glands in
patients with AIDS, performed before the introduction of
Effects of antiretroviral
HAART, found direct infectious involvement in 12% of ad-
and other therapies enohypophyses by either CMV or P. jiroveci, rarely involving
Several PIs and some NNRTIs alter the metabolism of the the neurohypophyses [45]. Since pituitary involvement was
estrogen component of hormonal contraceptives. Nevira- always accompanied by generalized and/or cerebral infec-
pine and ritonavir accelerate ethinyl estradiol metabolism, tion, these results may not apply to patients who do not
reducing contraceptive efficacy. Rifabutin, rifampicin, and yet have significant immunosuppression or who are effec-
itraconazole—when used in the treatment of HIV-related tively treated with ART. Additional patients have presented
infections—may do the same. Fluconazole and voricona- with panhypopituitarism resulting from cerebral toxoplas-
zole may inhibit exogenous estrogen metabolism, resulting mosis, and central diabetes insipidus has been reported
in a hyperestrogenic state. Although ketoconazole has little in an AIDS patient with herpetic meningoencephalitis.
effect on estrogen, it may interfere with early pregnancy by Neoplastic infiltration of the pituitary gland is very rare,
decreasing the production of progesterone and reducing although one case of pituitary lymphoma in a patient with
early uterine implantation and the subsequent decidual re- AIDS has been reported [46]. Hypopituitarism, independent
sponse [15]. of cause, is treated with physiologic hormone replacement.
Treatment considerations Alterations in pituitary function

Contraception for HIV-infected women should include a Studies employing GnRH or thyrotropin-releasing hormone
combination of barrier method and another form of ac- (TRH) have consistently found the functional reserve of the
ceptable contraception. Treatment with oral contraceptives anterior pituitary is normal. Prolactin levels, in the absence
may increase cervical and vaginal shedding of HIV [35]. of medication effect, are usually normal and respond to TRH
Though many women with AIDS-wasting syndrome stimulation appropriately [46]. Posterior pituitary function,
may have symptoms and signs of hypoandrogenism, labo- however, may be abnormal, as hyponatremia and the syn-
ratory diagnosis of androgen deficiency is difficult in drome of inappropriate antidiuretic hormone (SIADH)
women. Further, the lack of long-term studies of the effi- secretion was reported in hospitalized AIDS patients. A pri-
cacy and side effects of testosterone treatment in women mary pituitary disorder cannot be concluded from this
with AIDS-wasting limits the ability to advocate its use at study, however, because there were other factors influencing
present. the development of hyponatremia, including pulmonary in-
fection (most notably, P. jiroveci pneumonia) and treatment
with medications (e.g. trimethoprim) [47].
Fertility and reproduction
Studies of HIV-infected women who did not receive prenatal
Somatotropic axis
ART showed a threefold higher risk of fetal loss as a result of
HIV transmission and fetal thymic dysfunction [44]. Lower HIV infection per se does not appear to affect the somato-
pregnancy and birth rates in HIV-infected women may be tropic axis, based on frequent sampling studies among men
partially due to knowledge of HIV seropositivity, as rates with asymptomatic HIV infection, clinically stable AIDS,
of therapeutic abortion are also higher. Even though effec- and healthy controls [48]. GH and insulin-like growth
tive ART is available during pregnancy and at delivery for factor-1 (IGF-1) secretion and action, however, are influ-
prevention of mother-to-child transmission, there are com- enced by nutritional status and body composition;
plex ethical and social issues regarding conception in therefore, distinct abnormalities have been observed in
women with HIV infection. patients with AIDS wasting or central lipohypertrophy.
283
AIDS wasting may resemble an acquired GH-resistant state, wasting syndrome, as it is present in up to 50% of men
explaining the decreased levels of IGF-1 and IGF-1 binding and women with wasting and has been directly
protein-3 that have been found in the setting of increased correlated with decreases in both LBM and fat.
GH. In contrast, patients with HIV-associated central lipo-
hypertrophy demonstrate an inverse correlation between
GH levels and visceral obesity, consistent with the reduced
GH levels found in generalized obesity [49]. In light of the poor prognosis associated with wasting,
clinicians should emphasize the prevention of weight loss
by addressing weight and nutritional status as a routine
Effects of antiretroviral and other part of HIV care. Patients should be weighed at each visit
therapies and encouraged to maintain a nutritional diet with ade-
quate caloric intake while engaging in moderate exercise.
Effects of specific antiretroviral drugs on the somatotropic
Those with active weight loss require comprehensive as-
axis have not been investigated. Galactorrhea and marked
sessment of the potential co-morbidities described above,
hyperprolactinemia were reported in four patients follow-
including ruling out secondary infection and optimizing
ing initiation of PIs for ART or post-HIV exposure prophy-
ART. Nutritional counseling should consider psychosocial
laxis [50]. Although three of these patients had received
factors, as access to food, depression, and socioeconomic
medications that may increase serum prolactin levels
standing can affect both the quantity and quality of food
(metoclopramide or fluoxetine), symptoms resolved only
intake.
after the PIs were discontinued. Amphotericin B is associ-
Randomized, placebo-controlled trials have investigated
ated with a reduction in renal tubular sensitivity to anti-
approaches to the treatment of AIDS-associated weight loss
diuretic hormone and may result in reversible nephrogenic
such as progressive resistance training, nutritional supple-
diabetes insipidus (DI). Nephrogenic DI occurs, though far
mentation, cytokine suppression, and the administration
less commonly, with use of liposomal formulations of
of appetite stimulants, androgenic steroids, and GH [51].
amphotericin B.
Dronabinol improves subjective appetite but results in
little or no weight gain. Megestrol acetate effectively stimu-
lates appetite and achieves weight gain but predominantly
WASTING SYNDROME increases fat tissue rather than LBM. When given in con-
junction with testosterone, changes in body composition
Although the incidence of AIDS wasting has declined are no different [52]. Among men with AIDS wasting
since the introduction of ART, weight loss and muscle and hypogonadism, physiologic testosterone replacement,
wasting remain significant problems for individuals with which induces gain of LBM, may be instituted. However,
HIV infection, particularly patients without access to ART. treatment with supraphysiologic doses of testosterone is
Increased mortality, accelerated disease progression, loss controversial due to concerns about its effects on lipid pro-
of muscle protein mass, and impairment of strength and file and cardiovascular risk. Treatment with anabolic ste-
functional status occur with wasting [51]. Weight loss that roids, including nandrolone decanoate and oxandrolone,
does not meet the CDC case definition of AIDS wasting also increases LBM but is frequently complicated by the de-
(> 10% of baseline body weight with clinical symptoms) velopment of abnormal liver enzymes and dyslipidemia.
still predicts increased morbidity and mortality in this These changes occur particularly with oral preparations.
setting. Wasting is multifactorial and may represent the In randomized, placebo-controlled trials, 3 months of
common endpoint of several pathophysiologic processes recombinant GH treatment at high doses (0.1 mg/kg/day)
related to the progression of HIV infection, including re- induced significant increases in LBM with reductions in
duced caloric intake due to anorexia or malabsorption fat [53]. In other studies, treatment of similar duration with
and cachexia, a state marked by disproportionate loss of lower doses of GH showed little to no change in body com-
muscle. Increased resting energy expenditure (REE) in position. Side effects of GH include arthralgias, myalgias,
HIV-infected individuals indicates the presence of a edema, diarrhea, carpal tunnel compression, and perhaps
hypermetabolic state. AIDS wasting appears to be an epi- most importantly, glucose intolerance. Though GH is the
sodic process, exacerbated by acute secondary infections only treatment specifically FDA-approved for AIDS-wasting
or gastrointestinal disease that may result in anorexia syndrome that increases LBM, it remains an expensive ther-
and diminished caloric intake. Failure of the normal ho- apy for which long-term side effects are unclear. Its use
meostatic response to decrease REE with reduced food may be considered for rapid weight loss associated with
intake synergistically contributes to loss of LBM. Hypogo- acute infection or for persistent wasting refractory to other
nadism may also be involved in the pathogenesis of therapies [51].
284
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286
Chapter | 23 |
Renal complications of HIV infection
Jula K. Inrig, Lynda A. Szczech, Trevor E. Gerntholtz, Paul E. Klotman
INTRODUCTION OVERVIEW OF GLOBAL

HEALTHCARE/DELIVERY
In the early 1980s, a unique form of kidney disease was de-
scribed among HIV-infected patients [1, 2]. Patients usually
presented with significant proteinuria and rapid progres- Healthcare and its delivery vary drastically around the
sion to end-stage renal disease (ESRD) [2]. When initially world. In the USA and Europe, healthcare is available to
described, this renal failure was attributed to heroin ne- a greater proportion of the population than in many other
phropathy, as it clinically appeared similar. As clinicians parts of the world. In Africa, unfortunately, the availability
continued to see renal disease associated with HIV infection, of health services is considerably more limited. Despite the
the existence of a distinct disease called HIV-associated ne- growing AIDS epidemic, limited resources are available for
phropathy (HIVAN) was debated. As more patients with the majority of patients needing therapy. Due to limited
HIV infection without a history of heroin use were noted preventive services in Africa, screening for renal disease is
to have renal disease, HIVAN was established as a unique en- essentially non-existent and because of more pressing
tity [2]. From a once rare complication of HIV infection, and immediate health concerns, screening assumes a lower
HIVAN has emerged as the most common cause of ESRD priority. As a result, patients are often diagnosed late in the
in HIV-infected patients [3]. In addition, as patients with course of their disease after presenting to a hospital with
HIV/AIDS are surviving longer, the prevalence of HIV- another illness or overt nephrotic syndrome. Thus, treat-
infected patients with chronic kidney disease continues to ment is limited by late diagnosis, co-morbid conditions,
rise [4]. With up to 33 million people infected with HIV/ and shortage of resources. In contrast, patients in the
AIDS worldwide and a prevalence of renal disease in HIV- USA and Europe with known HIV may undergo screening
infected black patients of 3.5–12%, up to 4 million people for renal involvement and thus may be offered therapy
worldwide may be affected by HIV-related kidney disease earlier in the course of their disease.
[2, 5]. This chapter will review the epidemiology and clinical
course of HIV-related renal disease using US, European, and
African studies to compare results based on regions of the EPIDEMIOLOGY
world. Such a comparison requires initial insight into
methods and infrastructure for delivery of healthcare within One of the first clinical reports of HIVAN occurred in 1984
regions to provide a framework for the understanding of in the USA [1]. Not surprisingly, the initial description en-
study comparisons. gendered a debate that was focused mainly on whether this
287
was a different entity from heroin nephropathy. As children was described. A study from Zaire in 1993 reported the
and patients without a history of heroin use were identified pathologic findings of 92 patients with documented ne-
with renal disease and the disease became better defined phrotic syndrome systematically biopsied between 1986
histologically, the term HIVAN emerged to describe the and 1989. A total of 41% of these patients were found to
combination of clinical and histological findings. In the have focal and segmental glomerulosclerosis (FSGS), a sev-
early era of HIV, patients with HIVAN were diagnosed late enfold increase from previous prevalence rates of only 6%.
in the course of HIV infection, usually after they had been The investigators were uncertain as to the cause of the in-
diagnosed with AIDS. Predictably, renal survival for those crease in FSGS but proposed that AIDS might be responsi-
diagnosed with HIVAN was 1–4 months without therapy ble [16]. This study cannot assess the predisposition of
[1, 2, 6, 7]. With the advent of potent antiretroviral therapy blacks to HIVAN but does suggest that HIVAN has become
(ART) and the decline in mortality from AIDS, kidney dis- an increasing health problem in this population. Early in
eases have become major contributors to HIV morbidity the HIV epidemic, epidemiologic data from the USA and
and mortality [8]. Europe found that HIVAN was diagnosed primarily in areas
While no data on global prevalence exist, HIVAN is with large populations of HIV-infected black patients [14].
likely to have the highest prevalence in Africa. According Two series from France and London have reported that 97/
to the 2009 report on the global AIDS epidemic, almost 33 102 and 17/17 of patients diagnosed with HIVAN were
million people are living with AIDS in the world [5]. black, respectively [17, 18].
Within sub-Saharan Africa alone, nearly 22.5 million peo- In contrast to the high rate of HIVAN in predominantly
ple are currently infected. In the USA, the prevalence of re- black-populated regions, Caucasians are noted to have a
nal disease has been noted to be between 3.5 and 12% in much lower prevalence of classic HIVAN. A postmortem
HIV-infected African Americans [2, 9]. If one assumes a analysis of 239 consecutive Swiss patients who died from
similar prevalence among persons of African descent, then AIDS between 1981 and 1989 demonstrated pathologic re-
up to 2.7 million patients may have renal disease in sub- nal findings in 43% of patients, with HIVAN in only 1.7%
Saharan Africa alone. Any estimate of prevalence, how- (4/239) of the patients [13]. Given that 95% of the patients
ever, needs to account for the different mortality rates were Caucasians, this study emphasizes the low prevalence
among HIV-infected patients and its variation by country. of classic HIVAN in Caucasians.
Without having an exact estimate, the prevalence of renal Another study reviewed the pathologic features of 120 con-
disease could be hypothesized to be quite high. One re- secutively autopsied HIV-infected Caucasian patients in Italy.
port in 2003 in the Nigerian Journal of Medicine assessing Of these patients, 68% had pathologic renal changes, and
the prevalence of renal disease in consecutive patients none of the renal specimens had classic HIVAN. The most
with AIDS seen in the infection unit suggested that these common pathologic abnormality was immune-mediated glo-
estimates are conservative. Of 79 patients with AIDS, renal merular diseases (25 patients) and tubulointerstitial lesions
disease was present in 51.8% (41 patients) as compared (19 patients) [15]. A similar study of 26 Caucasian patients
with 12.2% (7 patients) of non-HIV-infected controls. in northern Italy with HIV who underwent renal biopsy failed
Of these 79 patients, 19% (n ¼ 15) had azotemia, 25% to reveal any lesions of HIVAN. The majority of diagnoses
had proteinuria alone, and 7.6% had both proteinuria were immune complex-mediated glomerulonephritis [11].
and azotemia [10]. While patients of African descent are at the highest risk for
The current leading cause of death from AIDS worldwide HIVAN, other ethnic groups have renal disease related to other
is infection; but as ART becomes more available and sur- pathologic entities.
vival is prolonged, renal disease is likely to become a major
secondary cause of mortality and morbidity as it has in the
Patterns of renal disease in Africa
USA. As the mortality rate from AIDS declined in the early
1990s, the number of black patients living with HIV in- There is a large variation in the patterns of renal diseases
creased significantly. As a result, this at-risk group lived lon- reported in different geographic regions of Africa. Unfortu-
ger, and HIVAN became one of the most rapidly growing nately, accurate and comprehensive statistics are not available
causes of end-stage renal disease in the USA [3]. [19]. For example, a single available study of 368 patients
with chronic kidney disease (CKD) in Nigeria demonstrated
that 62% had an undetermined etiology of renal failure [20].
The prevalence of CKD in sub-Saharan Africa is not known.
Racial distribution of HIVAN
Data from the South African Dialysis and Transplant registry
As demonstrated by US and European epidemiologic and regarding etiologies of ESRD reflect only patients selected
pathologic data, HIVAN has an overwhelmingly higher for dialysis. As only patients eligible for transplantation are
prevalence in HIV-infected patients of African descent than offered dialysis, and few patients with diabetic ESRD are of-
in Caucasians [9, 11–15]. With the emergence of HIV fered dialysis or transplantation due to co-morbid condi-
throughout the world in the 1980s, a change in the patho- tions, the available data are unlikely to reflect the spectrum
logic findings in African patients with nephrotic syndrome of renal diseases in the population as a whole.
288
Chapter | 23 | Renal complications of HIV infection
In North Africa, the incidence of renal disease appears to glomerular epithelial cells are infected by HIV in patients with
be much higher than in the USA, but the prevalence is HIVAN [28]. Furthermore, Marras and co-workers demon-
lower due to higher mortality and fewer available treatment strated that the renal tubular epithelial cells support viral rep-
options [21]. The reported annual incidence of ESRD lication and subsequent divergence, and act as a separate
ranges between 34 and 200 patients per million population compartment from blood [29]. According to a study by Win-
(pmp), and the respective prevalence ranges from 30 to 430 ston and co-workers, renal parenchymal cells can serve as a
patients pmp. Despite the high mortality from ESRD, the reservoir for HIV, and the presence of the virus can persist
prevalence of CKD appears to be increasing. The principal in glomerular and tubular epithelial cells despite ART [30].
causes of CKD are interstitial nephritis (14–32%), glomer- The mechanisms by which HIV gains entry into epithelial
ulonephritis (11–24%), diabetes (5–20%), and nephro- cells remain unclear. The major co-receptors for HIV-1 have
sclerosis (5–31%). Trends in Egypt suggest an increasing not been detected using immunocytochemistry, but more sen-
prevalence of interstitial nephropathies and diabetes [14]. sitive methods including PCR suggest that CD4 and CXCR4
FSGS is reported in 23–34% of the glomerulonephritides can be detected in cultured renal epithelial cells [31]. The
(GN) and is mostly clustered in black patients [21]. data are less clear for the other co-receptors. Whether the recep-
Overall, glomerular disease appears to be more prevalent tors are in sufficiently high density or functional enough to
and more severe in Africa than in Western countries. It has mediate entry into the cell also remains unknown [31].
been estimated that between 0.2 and 2.4% of medical admis- The observation that HIV DNA has been found in
sions in tropical countries are due to renal disease (0.5% Zim- glomeruli of HIV-infected patients without HIVAN suggests
babwe; 0.2% Kwa Zulu Natal, South Africa; 2.0% in Uganda; that some additional factor (such as a genetic predisposi-
and 2.4% Nigeria) [22]. It has been observed that the majority tion) may be required [32]. The pathologic findings of
of these admissions are related to glomerulonephritis, which collapsing focal glomerulosclerosis combined with tubular
responds poorly to treatment and progresses to ESRD. In microcystic disease have been thought to be specific to
addition, glomerulonephritis in South Africa is more fre- HIVAN. However, a recent report of collapsing GN in seven
quent in blacks and less frequent in Indians and Caucasians. HIV-uninfected Caucasian patients who were treated with
This is a similar pattern to the distribution of HIVAN. Given high-dose pamidronate suggests that other environmental
the high prevalence of HIV/AIDS in South Africa, it can be agents can also induce collapse [33]. Thus, Caucasian pa-
postulated that some of these renal disorders may be caused tients can develop a collapsing phenotype, but the mecha-
by HIVAN or other HIV-related renal diseases. nism appears to be different from those observed in
response to HIV infection in blacks.
The racial predilection for HIVAN in blacks strongly
NATURAL HISTORY suggests that genetic factors play an important role in the
pathogenesis of HIVAN. In support of this, Gharavi and
co-workers assessed the influence of genetic background
Among patients with HIVAN, severe proteinuria (often in
on the development or progression of HIVAN by crossing
the nephrotic range >3 g/day) with progression to ESRD
the HIVAN transgenic mouse with mice of different genetic
within 1–4 months of diagnosis was initially described
backgrounds [34]. These investigators found that the HIVAN
[1, 2, 6, 7, 23]. Subsequent data in the setting of monother-
phenotype varied from severe renal disease to no renal dis-
apy with zidovudine and ART suggest a much slower pro-
ease based on the background strain of the mice. In addition,
gression [23–25]. While early reports suggested that HIVAN
genome-wide analysis of linkage in 185 heterozygous trans-
was a late manifestation of AIDS, occurring when CD4
genic backcross mice identified a locus on chromosome
counts were well below 200 copies/mL, subsequent data
3A1-3, HIVAN1, which showed highly significant linkage
suggest that a lower CD4 count may be associated with a
to renal disease. This locus, HIVAN1, is syntenic to human
faster progression and greater likelihood of biopsy [17,
chromosome 3q25-27, which is an interval showing sugges-
24]. A case report of HIVAN demonstrates its presence as
tive evidence of linkage to various nephropathies [34]. More
early as the time of acute HIV seroconversion [26].
recent investigations have identified 2 genomic loci that
regulate podocyte gene expression and which confer an
increased susceptibility in mice to HIVAN [35].
PATHOGENESIS
Early in the description of HIVAN, it was uncertain whether

HIV caused injury through a direct effect on renal cells or PATHOLOGY
an indirect effect from immune dysregulation. Studies by
Bruggeman and co-workers using a murine model of HIVAN HIV-associated nephropathy has pathologic findings similar
demonstrated that HIV-1 expression in renal epithelial cells is to idiopathic and heroin-related FSGS; however, there are
necessary for the development of the HIVAN phenotype [27]. several unique findings suggestive of HIV infection [12].
They went on to demonstrate that both tubular and First, in HIVAN there is a tendency for the entire glomerular
289
A B
Figure 23.1 Kidney biopsy specimens. (A) Low-power view of a biopsy specimen from a patient with HIVAN in the USA. There are
5 glomeruli with collapsing sclerosis and podocyte hyperplasia. The tubules are separated by edema, mild fibrosis, and patchy
interstitial inflammatory infiltrates. Some tubules show degenerative changes with focal tubular microcysts containing large casts.
(B) High-power view of a biopsy specimen from a patient with HIVAN in Brazil. Note the collapsing sclerotic glomerulus, tubular
atrophy, and interstitial inflammation.
(Courtesy of CE Poli de Figueiredo, MD, DPhil, Medical School PUCRS, Porto Alegre, Brazil.)
tuft to sclerose and collapse rather than finding only a seg-

mental glomerular lesion (Fig. 23.1). In the tubules, there Box 23.1 Diagnosis in HIV-infected patients
is often severe injury with proliferative microcyst formation with proteinuria
and tubular degeneration. The tubular disease is character-
• HIV-associated nephropathya
ized by the development of tubular dilation accompanied
• Membranoproliferative GN (often with HCV)a
by flattening and atrophy of the tubular epithelial cells. Elec-
• Mesangioproliferative GN
tron microscopy can reveal the presence of numerous tubu-
loreticular structures in the glomerular endothelial cells. The • Immune complex GN
tubuloreticular inclusions are composed of ribonucleopro- • Membranous nephropathy
tein and membrane structures; their synthesis is stimulated • IgA nephropathy
by a-interferon. The only other disorder in which these struc- • Post-infectious GN
tures are prominently seen is lupus nephritis, which is also • Minimal change disease
associated with chronically high levels of circulating a-inter- • Diabetic nephropathy
feron. The finding of tubuloreticular inclusion had been • Tubulointerstitial nephritis
noted to be a common pathologic abnormality in the pre- • Thrombotic microangiopathy
ART era; however, this pathologic abnormality is now found • Amyloidosis
less frequently. This is potentially related to the advent of ef-
fective ART, resulting in reduced levels of plasma interferon a
Most common pathologic findings.
[12, 36]. In HIV-infected patients with kidney disease, sev-
eral different glomerular syndromes have been described
(Box 23.1). The most common pathologic finding is HIVAN. nephropathy, and 6% mesangioproliferative GN, and 9%
In the USA, the second most common pathologic findings other nonspecified GN; 3% had tubulointerstitial nephritis;
are membranoproliferative GN (often with HCV coinfection) 3% had acute tubular necrosis; and 4% had other [38]. How-
or mesangioproliferative GN, followed by immune complex ever, among hospitalized HIV-infected patients with acute re-
GN, membranous, and IgA nephropathy [12, 24]. Less com- nal failure, the most common diagnosis is acute tubular
monly, HIV-infected patients have been found to have necrosis.
thrombotic microangiopathy, minimal change disease, and
amyloidosis [24, 37]. This is in comparison to patients seen CLINICAL FEATURES
in Baragwanath, South Africa. Among 99 HIV-infected pa-
tients, 27% had classic HIVAN; 21% had immune complex HIVAN typically presents in the setting of poorly controlled
rich “lupus-like” disease; 41% had other GN including HIV infection with high viral loads. Rarely, HIVAN can pre-
13% membranous, 8% post-infectious GN, 5% IgA sent as part of the acute retroviral syndrome (primary HIV
290
infection) or within the first few months of infection. cohort of 19 patients with a clinical diagnosis of HIVAN,
HIVAN typically presents with a rapid decline in renal func- protease inhibitor (PI) treatment was associated with a
tion with significant proteinuria. Typically the proteinuria slower decline in creatinine clearance (0.08 mL/min per
is in the nephrotic range with >3 g protein per 24 hours or month versus 4.30 mL/min per month for those not
a spot protein/creatinine ratio of >3 mg/g. Most patients treated with a PI) [25]. In another analysis, among patients
with HIVAN do not have significant peripheral edema, with HIVAN, the use of ART was associated with a slower
and despite the high prevalence of hypertension in blacks, progression to end-stage renal disease (HR 0.24, p ¼ 0.03)
patients with HIVAN are not usually hypertensive. Labora- [24]. In a cohort of 36 patients with biopsy-confirmed
tory data are non-specific. Serologic studies for glomerular HIVAN, patients receiving ART had a significantly lower
diseases (i.e. ANA, dsDNA, complements, antistreptolysin odds of developing end-stage renal disease (odds ratio
O antibodies, ANCA, anti-GBM, hepatitis B surface antigen, 0.30, p < 0.05) [41]. In this cohort, those with complete vi-
hepatitis C AB, cryoglobulins) are usually negative except in rologic response to ART also had better renal survival. In a
patients with hepatitis C co-infection. Urinalysis is typically study of 3,313 patients enrolled in a randomized antiretro-
bland without hematuria but with varying numbers of hy- viral trial in Uganda and Zimbabwe, there was stabilization
aline casts and renal tubular epithelial cells. Ultrasonogra- or slight improvement in glomerular filtration rate (GFR)
phy typically reveals bilaterally echogenic and enlarged following initiation of ART, and very few patients (1.6%) de-
kidneys, in contrast to other conditions, in which the kid- veloped severe reductions in GFR during 96 weeks of follow-
neys shrink in size as function deteriorates. Diagnosis of up [42]. Recent evidence also suggests that classic HIVAN is
specific histology requires a renal biopsy; it is difficult to unlikely among patients with viral loads <400 copies/mm3
distinguish HIVAN from other pathologic lesions on clin- [39]. Despite a variety of study designs, it would appear that
ical grounds alone. There are no valid non-invasive surro- these reports are generally consistent in that either suppres-
gate markers for HIVAN. For example, nephrotic range sion of viral replication or ART significantly slowed the
proteinuria even in the presence of a low CD4 count does progression of renal disease among patients with HIVAN.
not reliably predict HIVAN. Detectable viremia is a typical Among HIV-infected patients with renal disease other
feature of HIVAN, and the diagnosis is unlikely if the HIV than HIVAN, a single study suggests that ART may not be as-
viral load is <400 copies/mm3 [39]. Therefore, if there sociated with a similar benefit [24]. Additional studies to
are no contraindications to a renal biopsy, it should be confirm this are required.
performed for histologic diagnosis.
Patient evaluation, diagnosis, Angiotensin-converting

and differential diagnosis enzyme inhibitors
Angiotensin-converting enzyme inhibitors (ACE-I) have
Figure 23.2 proposes a screening algorithm for kidney
been shown to be efficacious in a variety of renal disorders
disease in HIV-infected patients.
associated with proteinuria, such as diabetes mellitus. In
patients with HIVAN, retrospective analyses suggest that
the use of ACE-I is associated with improved renal survival.
TREATMENT
Kimmel and co-workers reported delayed progression of re-
nal failure in a retrospective cohort of nine patients with
Despite the high prevalence of kidney disease in HIV- HIVAN compared with a group of controls [7]. Burns
infected patients, no prospective randomized controlled and co-workers prospectively evaluated 20 patients with
trials have been performed to assess the effect of various “early” HIVAN (baseline creatinine <2.0 mg/dL, 177
treatments on outcome. However, a number of retrospec- micromol/L), all of whom were offered fosinopril [6]. In
tive analyses for assessing the association effects of ART, the 12 patients who were adherent with treatment, renal
angiotensin-converting enzyme inhibitors, and steroids function remained stable at 12 and 24 weeks of follow-
on outcomes have been performed (Box 23.2). up. In the eight untreated patients, serum creatinine in-
creased from 88.4 to 433.2 micromol/L. Long-term effects
have also been reported with ACE inhibitors. In a single-
Antiretroviral therapy
center prospective study, 44 patients with biopsy-proven
Initial reports of the efficacy of monotherapy with zidovu- HIVAN and early renal disease (mean serum creatinine
dine on HIVAN were conflicting. FSGS was noted to develop <2.0 mg/dL, <177 micromol/L, <50% with proteinuria
in many patients despite treatment with zidovudine and >3 g/day) were all offered treatment with fosinopril [43].
thus was suggested to be of little benefit [40]. Other studies In the 28 patients who consented to fosinopril, serum cre-
suggested that zidovudine might delay the progression of atinine remained stable after a median of 479.5 days of
HIV nephropathy if begun when patients had mild protein- follow-up in all but one patient, who progressed to ESRD.
uria and near-normal renal function [23]. In a retrospective All of the 16 patients who refused treatment progressed to
291
Figure 23.2 Screening algorithm for kidney

HIV diagnosis disease in HIV-infected patients.
(Adapted from Gupta SK, Eustace JA, Winston JA, et al.
Guidelines for the management of chronic kidney disease
in HIV-infected patients: recommendations of the HIV
• Urinalysis for protein Medicine Association of the Infectious Diseases Society of
• Serum creatinine (for estimating renal function) # America. Clin Infect Dis 2005;40:1559–1585.)
• +Proteinuria • No proteinuria (<1+ on dipstick)

(≥1+ on dipstick) • Normal renal function
or
• Abnormal renal function
(CrCl or GFR <60 mL/min
per 1.73m2) Low risk High risk (black race,
CD4 < 200 cells/mm3,
viral load > 4000
copies/mL, diabetes
• Quantify proteinuria with Reassess if
mellitus, hypertension,
spot protein/creatinine clinically
hepatitis C)
ratio indicated
• Renal ultrasound
• Nephrology referral for
further studies and Screen annually or
possible biopsy every 3–6 months
when CD4 counts
or viral loads are
assessed
# Cockcroft–Gault: [140–age (years)] × weight (kg) [× 0.085 if female]

=
CrCl (mL/min) 72 × serum creatinine (mg/dL)
# Simplified MDRD: 186 × [serum creatinine (mg/dL)]–1.154 ×[age (years)]–0.203 ×
=
GFR (mL/min/1.73 m2) [0.742 if female] × [1.212 if black]
ESRD after a median period of 146 days. Initial serum cre-

Box 23.2 Management of kidney disease atinine and proteinuria were similar in both groups but ex-
in HIV-infected patientsa posure to ART prior to the study appeared different (57% in
the ACE-I group versus 31%, p ¼ 0.12) as was CD4 count
• Control blood pressure to < 130/80, initial agents should (172 versus 120 cells/mm3, p ¼ 0.06).
be ACE inhibitors for patients with proteinuria The potential benefit of ACE-I on HIVAN was also dem-
• Prepare for dialysis by placing dialysis access onstrated by Gerntholtz among 99 HIV-infected patients
• Discuss renal transplantation who underwent renal biopsy in South Africa [38]. In 27 pa-
• If proven HIVAN, treat with ART tients with HIVAN, use of an ACE-I was associated with
• If patient with HIVAN fails to respond to ART, consider improved renal survival (personal communication). All
adding ACE inhibitor (if not already initiated) and/or patients progressed to ESRD by 15 weeks of follow-up in
prednisone the absence of ACE-I compared with 30% with ESRD at
160 weeks of follow-up in the ACE-I-treated group. As pa-
a
Adapted from Gupta SK, Eustace JA, Winston JA, et al. Guidelines tients were not randomized to treatment groups, baseline
for the management of chronic kidney disease in HIV-infected
patients: recommendations of the HIV Medicine Association of the characteristics were different and included a lower creati-
Infectious Diseases Society of America. Clin Infect Dis 2005; nine (448 micromol/L versus 1082 micromol/L), higher al-
40:1559–1585. bumin, and higher cholesterol level in the ACE-I group.
ACE-I therapy appeared to have no effect on proteinuria.
292
As only 8 patients in this cohort were taking antiretrovirals, urban regions in Africa and are thus inaccessible to patients
further research is required to define the benefit of ACE-I living in poorer, rural areas [19].
among patients using ART. In South Africa, there is strict rationing of dialysis due to
the lack of resources and funding. The National Health De-
partment has formalized a protocol for the management of
Steroids ESRD: state facilities will only offer long-term dialysis if pa-
tients are eligible for a kidney transplant. Currently, HIV-
Initial observations in children with HIVAN suggested that
infected patients with acute renal failure may be supported
corticosteroids were ineffective. However, later research has
by dialysis on a short-term basis, but HIV-infected patients
found that some patients may respond to steroid therapy
are not candidates for renal transplantation and thus are
[44, 45]. In a retrospective cohort, 13 of 21 patients with
not offered long-term dialysis [19].
biopsy-proven HIVAN received corticosteroids for one
Dialysis and transplant programs in the rest of Africa
month followed by a taper over several months. Seven pa-
are dependent on the availability of funding and donors. Ni-
tients treated with corticosteroids remained off dialysis at 6
geria, Tanzania, Ethiopia, Cote d’Ivoire, and Cameroon offer
months of follow-up compared with only one of the non-
limited dialysis to a small number of patients for short time
corticosteroid group (p ¼ 0.06) [44]. A second group
periods. Peritoneal dialysis is limited due to the high cost of
reported a series of 20 patients (17 with biopsy-proven
peritoneal fluids and the high rate of peritonitis [21].
HIVAN) who were treated with prednisone 60 mg/day
In the USA and Europe, renal transplantation has in-
for 2–11 weeks followed by a slow taper. After a mean fol-
creasingly become an option for HIV-infected patients with
low-up of 44 weeks, 8 patients required maintenance
ESRD. A recent comprehensive review that included 12 case
dialysis, 11 died from AIDS-related complications, and 7
series of renal transplants among 254 HIV-infected patients
were alive and free from dialysis [45]. Unfortunately, in
demonstrated 1-year patient survival at 93% [47]. While
both groups, infection-related complications were high.
1-year renal allograft was slightly lower at 87% (compared
Gerntholtz retrospectively analyzed HIV-infected patients
to national averages of 91%), these data suggest that among
in South Africa with kidney disease and found that predni-
stable HIV-infected individuals on ART, renal transplanta-
sone had no effect on outcome [38]. Szczech and co-
tion is a viable option [47].
workers retrospectively studied 19 patients with suspected
HIVAN or other HIV-related kidney disease. The 5 patients
who received prednisone experienced an increase in creat-
inine clearance of 5.57 mL/min per month, whereas the 14 COURSE AND OUTCOME
patients who did not receive prednisone experienced a de-
cline in creatinine clearance of 3.32 mL/min per month
In the absence of treatment with ART, reports from the
(p ¼ 0.003) [25]. Given the small number of observational
early 1990s suggested that patients progress to ESRD
studies, the short follow-up, and the likelihood of relapse
within 1–4 months of diagnosis [6, 7, 23]. Subsequent
and adverse events, definitive conclusions cannot be made
data in the setting of zidovudine monotherapy and later
regarding the efficacy or safety of steroids for the treatment
with ART suggest a much slower progression [23–25].
of HIVAN.
Clinical variables associated with increased risk of pro-
gressive renal failure include decreased CD4 count [17,
24], elevated serum creatinine [24], increased proteinuria
Renal replacement therapy
[17], higher viral load [17, 24], and the presence of
With the rapid progression of renal failure in patients with hepatitis C co-infection [24].
HIVAN, renal replacement therapy (RRT) becomes the ma- Patients with a pathologic diagnosis of HIVAN had worse
jor therapeutic option. Unfortunately, the availability of renal survival than patients with lesions other than HIVAN.
RRT to patients with ESRD is not uniform globally. In In a cohort of 89 HIV-infected patients with renal disease
the USA, the survival of HIV-infected ESRD patients is sim- biopsied between 1995 and 2000, 17 of 47 patients with
ilar to that of HIV-uninfected patients with ESRD, and in- lesions other than HIVAN required the institution of RRT
creasing numbers of transplant centers are performing at an average time of 731 days (642 days) from renal bi-
kidney transplantation in stable HIV-infected patients. opsy as compared to 25/42 patients with HIVAN who re-
However, the availability of dialysis and transplantation quired initiation of RRT at an average time of 254 days
are particularly variable in Africa. According to the Dialysis (31 days) from renal biopsy (p ¼ 0.0003 comparing time
Registry, only 30 patients were on renal replacement therapy with initiation of RRT) [24]. The prolonged renal survival
in Rwanda, 290 in Kenya, and >3,000 in South Africa [46]. of patients with HIVAN as compared to earlier reports is
Treatment rates in Africa are 99 pmp and of 30–186.5 pmp arguably related to a number of factors, including the use
in North Africa [19, 22]. This is in contrast to treatment rates of ART.
of 1,090 and 800 pmp in the USA and Germany, respectively In a retrospective review of 99 HIV-infected patients in
[46]. Dialysis services are predominantly available only in Baragwanath, South Africa, who underwent renal biopsy,
293
the investigators could not distinguish a difference in renal or sence of other life-threatening illnesses, life expectancy
overall survival between patients with HIVAN and those with can be dramatically shortened.
other pathologic findings. In the 27 South African patients
with biopsy-proven HIVAN at 17 weeks of follow-up, 13/27
(48%) died, 9/27 (33%) were lost to follow-up, and the CONCLUSION
remaining 5/27 (19%) were free of dialysis. In 72 HIV-infected
patients with other pathologic diagnosis at an average of 14– Kidney disease in HIV-infected patients is common, and
28 weeks of follow-up, 31/72 (43%) died, 14/72 (19%) were HIVAN is the leading cause of CKD, particularly in patients
lost to follow-up, and the remaining 27/72 (38%) were free of of African descent. Patients with HIVAN are often diag-
dialysis [38]. However, very few of the patients were treated nosed late in the course of their HIV illness and present
with ART. Further research on international differences is re- with proteinuria and renal insufficiency. Without treat-
quired to reconcile these conflicting results. ment, renal survival is only a few months. However, small
In the USA, ESRD patients with HIVAN have decreased clinical trials and epidemiologic data strongly suggest
overall survival compared with other patients with ESRD. a benefit of ART therapy in the treatment of HIVAN
In an analysis of 3,374 patients with incident ESRD in [23–25]. In addition, similar studies have noted that
1996, those with a diagnosis of HIVAN (n ¼36) had a ACE-I therapy is associated with improved renal survival
4.74-fold increased risk of mortality after adjusting for clin- [6, 7, 38, 43]. Based on the best available data, if ACE-I
ical variables other than HIV. The 1-year survival in this co- and ART are available, they should be utilized to try to pro-
hort of patients with HIVAN was 53%. However, more long renal survival. As ART becomes more widely available
recent data from 1999–2000 report a 1-year survival of in resource-limited settings, patients can be expected to live
up to 74% in dialysis patients with HIVAN, which presum- longer, and an increasing number of HIV-infected patients
ably reflects the benefit of ART in this patient population will have advanced kidney failure. Decisions regarding
[48]. Unfortunately, dialysis is not always available for RRT, including transplantation, will become significant
HIV-infected patients with renal failure; thus, in the ab- issues, especially in resource-limited settings.
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295
Chapter | 24 |
Pneumocystis pneumonia
Robert J. Blount, J. Lucian Davis, Laurence Huang
with HIV/AIDS reside and where access to combination an-

INTRODUCTION tiretroviral therapy and even PCP prophylaxis with trime
thoprim-sulfamethoxazole (TMP/SMX) is more limited
Prior to the HIV/AIDS epidemic, Pneumocystis pneumonia (Table 24.1). At present, most of the data on PCP in these
(PCP) was an unusual cause of pneumonia, occurring al- regions is limited to single institution studies [3]. These
most exclusively in immunocompromised persons. The studies include different study designs, study populations,
causative organism, previously known as Pneumocystis car- diagnostic procedures, and specific criteria for defining
inii, was long thought to be a protist on the presumption PCP (clinical versus microscopic confirmation) that limit
that cystic and trophic forms represented distinctive phases firm conclusions. Nevertheless, PCP appears to be a signif-
of a protozoan life cycle. However, mounting evidence, in- icant opportunistic infection in HIV-infected people
cluding the identification of genetic sequence homologies throughout the world. Importantly, a substantial propor-
with fungi, led to the recategorization of this pathogen as a tion of these HIV-infected patients with PCP have been
fungus, and its renaming as Pneumocystis jiroveci. In 1981, found to have concurrent tuberculosis, a finding that com-
the description of PCP in previously healthy men who ei- plicates the diagnosis and treatment [4]. As the HIV/AIDS
ther had sex with men (MSM) and/or who were injection epidemic progresses in these regions, it is increasingly im-
drug users (IDUs) heralded the onset of the HIV/AIDS ep- portant to develop diagnostic and treatment algorithms
idemic that currently affects greater than 33 million people that can be used in settings where resources, diagnostic
worldwide. Since these initial reports, tremendous ad- tests, and medications are limited.
vances have occurred in our understanding of HIV infec-
tion and PCP. This chapter focuses on the clinical aspects
of PCP, our current understanding, and emerging concepts RISK FACTORS FOR PNEUMOCYSTIS
of clinical importance to the global community. PNEUMONIA
A CD4 count < 200 cells/mm3, a history of oropharyngeal

EPIDEMIOLOGY candidiasis, and prior PCP are all well-established risk fac-
tors for PCP [5]. PCP was the first disease to illustrate the
Although its incidence has declined dramatically, PCP role of the CD4-lymphocyte count as a tool for assessing
remains a leading AIDS-defining opportunistic infection the risk for the development of an HIV-associated opportu-
in the USA and in the countries that comprise the World nistic infection [6]. Several studies demonstrate that the
Health Organization (WHO) Western European Region risk of PCP is increased in persons with a CD4 count
[1]. PCP is also a frequent opportunistic infection in < 200 cells/mm3 and that the majority of PCP cases occur
HIV-infected patient cohorts, and it is an important cause in patients whose CD4 count is < 200 cells/mm3 [6, 7].
of HIV-associated mortality [2]. Of concern, PCP is de- Thus, a CD4 count that is significantly > 200 cells/mm3
scribed in Africa, Asia, and Latin America, regions of the argues against the presence of PCP. Unfortunately,
world where >90% of the estimated people living CD4-lymphocyte determination is unavailable in some
297
Section | 3 |
298
Table 24.1 Clinical and autopsy studies of undifferentiated pneumonia in HIV-infected individuals in Africa, Asia, and Latin America
REFERENCE SUBJECTS SPECIMEN(S) STAIN FREQUENCY FREQUENCY

OF PCP OF OTHER
LUNG DISEASES
Autopsy studies of pneumonia in HIV-infected children in Africa

Ansari NA et al., Pediatr Cross-sectional autopsy study of 35 children who died in Lung MS 31% CMV 23%
Diseases associated with HIV infection

Infect Dis J 2003 hospital in Francistown, Botswana, 1997–1998 TB 11%
RSV 11%
Rennert WP et al., Clin Cross-sectional study of 93 children (CDC AIDS category Core Bx MS 11% CMV 32%
Infect Dis 2002 B & C) dying of lung disease in Soweto, South Africa, IF Ab BPNA 14%
1998–1999 TB 4.3%
Chintu C et al., Cross-sectional autopsy study of 180 children dying Lung MS 29% BPNA 41%
Lancet 2002 in hospital in Lusaka, Zambia, 1997–2000 CMV 22%
TB 18%
Nathoo KJ et al., Trans R Cross-sectional autopsy study of 24 children dying FNA Giemsa 67% BPNA 33%
Soc Trop Med Hyg 2001 of pneumonia in Harare, Zimbabwe, 1995 Core Bx MS CMV 10%
PCR
Ikeogu MO et al., Arch Cross-sectional autopsy study of 122 children dying Lung MS 16% BPNA 86%
Dis Child 1997 on arrival to hospital in Bulawayo, Zimbabwe, 1992–1993 TB 4%
Lucas SB et al., Cross-sectional autopsy study of 78 children dying in Lung N/A 14% BPNA 42%
BMJ 1996 hospital in Abdijan, Ivory Coast, 1991–1992 CMV 31%
TB 1.3%
Jeena PM et al., Ann Prospective case-control autopsy study of 31 infants dying in ETA MS 52% CMV 29%
Trop Paediatr 1996 intensive care units in Durban, South Africa, 1993–1994 Core Bx IF Ab BPNA 26%
PCR TB 3.2%
Clinical studies of pneumonia in HIV-infected children in Africa

Ferrand RA et al., Prospective study of 139 adolescents admitted to a IS MS 0.7% TB 8.6%
PLoS Med 2010 hospital in Harare, Zimbabwe, 2007–2008 BPNA 17%
Morrow BM et al., Prospective study of 124 children with pneumonia admitted to a IS IF Ab 27% CMV 36%
Pediatr Infect Dis J 2010 children’s hospital in Cape Town, South Africa, 2006–2008 BAL MS RSV 8.1%
Lung TB 3%
Rabie H et al., J Trop Retrospective chart review of 47 consecutive children NPA IF Ab 33% CMV 8.5%
Pediatr 2007 admitted to an intensive care unit in Cape Town, South Africa, 2003 ETA TB 2.1%
Bii CC et al., Int J Tuberc Cross-sectional study of 30 infants and toddlers with IS IF Ab 17% N/A
Lung Dis 2006 severe pneumonia in Nairobi, Kenya, 2002–2003
Chapter | 24 |
Kouakoussui A et al., Prospective study of 98 ART-naı̈ve children in a clinic in N/A N/A 0.36 per 100 LRTI 6.07,
Paed Resp Rev 2004 Abdijan, Ivory Coast, 2000–2003 child-months TB 0.71 per 100
Ruffini DD et al., Prospective study of 105 hospitalized infants with severe pneumonia, IS MS 49% CMV 44%
AIDS 2002 18 undergoing autopsy in Soweto, South Africa, 1999 NPA IF Ab Viral 8.3%
Core Bx TB 2.9%
Madhi SA et al., Cross-sectional study of 231 episodes of pneumonia IS IF Ab 44% of all Viral 12%
Clin Infect Dis 2002 in 185 children in hospital in Soweto, South Africa, 2000–2001 NPA episodes BPNA 8.1%
Zar HJ et al., Acta Cross-sectional study of 151 children admitted to an intensive NPA MS 9.9% BPNA 47%
Paediatr 2001 care unit with pneumonia in Soweto, South Africa, 1998 IS IF Ab CMV 14%
Lavage TB 7.3%
Madhi SA et al., Cross-sectional study of 548 infants in hospital with severe Clinical N/A 15% BPNA 15%
Clin Infect Dis 2000 LRTI in Soweto, South Africa, 1997–1998
Graham SM et al., Cross-sectional study of 93 children in hospital with severe pneumonia NPA IF Ab 17% BPNA 13%
Lancet 1999 by WHO criteria in Blantyre, Malawi, 1996
Kamiya Y et al., Cross-sectional study of 19 infants with clinical AIDS and NPA IF Ab 16% N/A
Arch Dis Child 1997 acute LRTI in Lilongwe, Malawi, 1995
Autopsy studies of pneumonia in HIV-infected adults in Africa

Garcia-Jardon et al., Retrospective (2000–2005) and prospective (2006–2008) Lung Giemsa 8.9% TB 13%
Trop Doct 2010 autopsy study of 86 patients dying at a tertiary care hospital in rural BPNA 22%
South Africa KS 1.3%
Murray et al., Retrospective autopsy study including 89 HIV-infected gold miners Lung MS 13% TB 35%
AIDS 2007 in South Africa, 1990–2002 BPNA 8%
KS 2%
Martinson NA et al., Prospective autopsy study of 47 adults with a premortem diagnosis of Lung MS 11% TB 79%
AIDS 2007 tuberculosis in Soweto, South Africa, 2003–2005 BPNA 26%
CMV 66%
Ansari NA et al., Cross-sectional autopsy study of 104 adults dying Lung MS 11% TB 40%
Int J Tuberc Lung Dis in hospital in Francistown, Botswana, 1997–1998 BPNA 23%
2002 KS 11%
Lucas SB et al., Cross-sectional autopsy study of 247 adults dying in Lung MS 2.8% TB 38%
AIDS 1993 hospital in Abdijan, Ivory Coast, 1991–1992 Nocardia 4%
Abouya YL et al., Am Rev Cross-sectional autopsy study of 53 adults dying on Lung MS 9.4% TB 40%
299
Respir Dis 1992 a pulmonary ward in Abdijan, Ivory Coast, 1989 KS 5.7%
Continued
Section | 3 |
300
Table 24.1 Clinical and autopsy studies of undifferentiated pneumonia in HIV-infected individuals in Africa, Asia, and Latin America—cont’d

OF PCP OF OTHER
LUNG DISEASES
Clinical studies of pneumonia in HIV-infected adults in Africa

Kyeyune R et al., Prospective cohort study of 353 adults with cough > 2 weeks BAL Giemsa 3% TB 56%

J Acquir Immun Defic admitted to a referral hospital in Kampala, Uganda, 2007–2008 Crypto 1%
Syndr 2010 KS 4%
Aderaye G et al., Scand J Prospective cohort study of 131 AFB smear-negative adults presenting BAL IF Ab 30% TB 24%
Infect Dis 2007 with respiratory symptoms to a referral hospital in Addis Ababa, BPNA 34%
Ethiopia, 2004–2005 KS 3.1%
Zouiten F et al., Cross-sectional study of 92 women seen in a specialty clinic N/A N/A 12% BPNA 25%
AIDS 2002 in Tunis, Tunisia, 1986–2001 TB 6.5%
Corbett EL et al., Clin Prospective study of 1792 adult men in Welkom, South Africa, N/A MS 1.3% TB 21%
Infect Dis 2002 599 in hospital, 1998–1999 BPNA 17%
Karstaedt AS et al., Retrospective case series of 120 adults with AIDS in hospital IS 54% IF Ab N/A TB 19%
Trans R Soc Trop Med with PCP in Soweto, South Africa, 1996–1998 ES 42% BPNA 12%
Hyg 2001 BAL 4%
Daley CL et al., Am J Cross-sectional study of 127 adults in hospital with respiratory BAL 25% N/A 0.8% TB 75%
Respir Crit Care Med symptoms in Dar es Salaam, Tanzania, 1991–1993 BPNA 14%
1996
Sow PS et al., AIDS 1993 Cross-sectional study of 27 adults in hospital in Dakar, IS Tol Blue 22% N/A
Senegal, 1992
Cheval P et al., Med Trop Cross-sectional study of 307 patients in hospital in N/A N/A 4.9% N/A
(Mars) 1993 Pointe-Noire, Republic of Congo, 1989–1991
Atzori C et al., Trans R Cross-sectional study of 83 adults in hospital for respiratory symptoms IS Tol Blue 6% TB 39%
Soc Trop Med Hyg 1993 in Malenga Makali, Tanzania, 1991 MS
Karstaedt AS, S Afr Cross-sectional study of 181 adults in Soweto, N/A N/A 0.5% TB 15%
Med J 1992 South Africa, 1987–1990 BPNA 12%
Serwadda D et al., Cross-sectional study of 40 patients with fever, BAL Giemsa 0% TB 15%
AIDS 1989 pulmonary infiltrates in Kampala, Uganda, 1987–1988 MS
Chapter | 24 |
Clinical studies of pulmonary disease of undetermined etiology in HIV-infected adults in Africa
Worodria W et al., Int J Cross-sectional study of 83 adults with 3-week history of undiagnosed BAL IF Ab 39% TB 24%
Tuberc Lung Dis 2003 lung disease in hospital in Kampala, Uganda, 1999–2000 BPNA 19%
Aderaye G et al., Cross-sectional study of 199 adults in hospital for ES IF Ab 30% N/A
AIDS 2003 undiagnosed lung disease, in Addis Ababa, Ethiopia, 1996 PCR
Lockman S et al., Int J Cross-sectional study of 121 adults, most in hospital, with IS Tol Blue 3.3% TB 50%
Tuberc Lung Dis 2003 undiagnosed lung disease in Gaborone and Francistown, MS BPNA 25%
Botswana, 1997 PCR
Chakaya JM et al., East Cross-sectional study of 51 adults in hospital with BAL Tol Blue 37% BPNA 37%
Afr Med J 2003 undiagnosed lung disease in Nairobi, Kenya, 1999–2000 IF Ab
Hargreaves NJ et al., Cross-sectional study of 164 adults with undiagnosed BAL IF Ab 9.1% TB 39%
Trans R Soc Trop Med lung disease in Lilongwe, Malawi, 1997–1999 PCR
Hyg 2001
Mahomed AG et al., Cross-sectional study of 67 adults with undiagnosed lung disease, IS BAL Tol Blue 43% TB 13%
East Afr Med J 1999 negative for PCP, in Johannesburg, South Africa, 1985–1992 TBBx MS
Dieng Y et al., Cross-sectional study of 29 adults in hospital for BAL Tol Blue 6.9% N/A
Dakar Med 1999 undiagnosed lung disease in Dakar, Senegal, 1996–1997 Giemsa
Malin AS et al., Am J Cross-sectional study of 64 adults (median CD4 183) in hospital with BAL Tol Blue 33% TB 39%
Respir Crit Care Med undiagnosed lung disease in Harare, Zimbabwe, 1992–1993 Giemsa KS 9.3%
1994 MS, PCR CMV 1.6%
Batungwanayo J et al., Prospective cohort study of 111 adults (42% with AIDS by WHO BAL Giemsa 5% TB 23%
Am J Respir Crit Care criteria) with undiagnosed lung disease in Kigali, Rwanda, 1990 TBBx MS Crypto 11%
Med 1994 KS 8.1%
Autopsy studies of pneumonia in HIV-infected adults and children in Asia

Bychkov AV et al., Int J Cross-sectional autopsy study of 32 adults who died in Smolensk, Lung MS 13% TB 72%
Collab Res Int Med Pub Russia, 2003–2008 BPNA 24%
Health 2009 CMV 6%
Asp 3%
Hsiao CH et al., J Cross-sectional autopsy study of 16 adults who died in Lung N/A 50% CMV 88%
Microbiol Immunol hospital in Taipei, Taiwan, 1986–1996 TB 44%
Infect 1997
Continued
301
Section | 3 |
302

OF PCP OF OTHER
LUNG DISEASES
Bhoopat L et al., Asia Pac Cross-sectional autopsy study of 29 children who died Lung N/A 66% CMV 48%
J Aller Imm 1994 with AIDS in Chiang Mai, Thailand, up to 1994 TB 3.4%

Clinical studies of pneumonia in HIV-infected adults and children in Asia
Gautam H et al., J Int Cross-sectional study of 46 ART-naı̈ve adults with CD4 IS IF Ab 45% TB 42%
Assoc Physicians AIDS < 200 presenting for the first time to a tertiary care center in BPNA 13%
Care (Chic) 2009 New Delhi, India, 2006
Mishra M et al., Indian J Cross-sectional study of 1101 hospitalized adults in IS Giemsa 25% N/A
Med Microbiol 2006 Nagpur, India, 1999–2005 Tol Blue
MS
Knauer A et al., Wien Cross-sectional study of 59 adolescents and adults in hospital with Clinical N/A 25% TB 44%
Klin Wochenschr 2005 interstitial lung disease in Nonthaburi, Thailand, 2002–2003 BP NA 20%
Crypto 8.5%
Udwadia ZF et al., Cross-sectional study of 119 adults in hospital with lung N/A N/A 32% N/A
J Assoc Physicians India disease in Mumbai, India, 2000–2003 BAL
2005
Sharma SK et al., BMC Cross-sectional study of 135 adults in hospital for Clinical N/A 7.4% TB 71%
Infect Dis 2004 opportunistic disease in New Delhi, India, 2000–2003 IS (All sites)
Kay Thwe H et al., SE Cross-sectional study of 60 adults (mean CD4 132, not on IS Giemsa 30% TB 17%
Asian J Trop Med Pub PCP prophylaxis) with >2 weeks of dry cough in Waibargi, Myanmar, MS
Health 2003 2000–2001
Usha MM et al., Indian J Cross-sectional study of 32 adults with AIDS and a IS Tol Blue 28% TB 47%
Pathol Microbiol 2000 respiratory complaint in Chennai, India, up to 1997 Giemsa
IF Ab
Mathews MS et al., Cross-sectional study of 15 adults with AIDS in ETA Tol Blue 33% N/A
Indian J Chest Dis Allied Vellore, India, 1992–1997 IS Giemsa
Sci 2000 IF Ab
Lumbiganon P et al., J Prospective cohort study of 90 children with AIDS (WHO N/A N/A 36 cases TB 8 cases
Med Assoc Thai 2000 criteria) in Khon Kaen, Thailand, 1989–1998
Chapter | 24 |
Tansuphasawadikul S Cross-sectional study of 2261 hospitalized adults in Nonthaburi, Clinical N/A 4.8% TB 37%
et al., AIDS 1999 Thailand, 1993–1996 Pen 3.2%
Autopsy studies of pneumonia in HIV-infected adults and children in Latin America

Soeiro AM et al., Clinics Retrospective autopsy study of 250 children and adults Lung MS 27% TB 14%
(São Paulo) 2008 who died at a tertiary care center in São Paulo Brazil, 1990–2000 BPNA 36%
KS 4.4%
Histo 1.3%
CMV 13%
Eza D et al., Pathol Res Retrospective autopsy study of 16 adults who died at a Lung MS 13% TB 13%
Pract 2006 public hospital in Lima, Peru, 1999–2004 Histo 19%
Crypto 6%
KS 6%
Asp 6%
Cury PM et al., Pathol Cross-sectional autopsy study of 92 adults who died with Lung MS 17% TB 27%
Res Pract 2003 AIDS in São Paulo, Brazil, 1993–2000 Histo 5.4%
Crypto 4.3%
Drut R et al., Pediatr Retrospective autopsy case series of 74 children registered Lung N/A 20% BPNA 15%
Pathol Lab Med 1997 in a database after dying of AIDS throughout Latin America, CMV 5.4%
1992–1994 Histo 2.7%
Mohar A et al., AIDS Cross-sectional autopsy study of 177 adults who died Lung MS 24% TB 25% (all sites)
1992 with AIDS in Mexico City, Mexico, 1984–1989
Michalany J et al., Ann Cross-sectional autopsy study of 15 adults who died with Lung Giemsa 13% CMV 47%
Pathol 1987 AIDS in São Paulo, Brazil, 1981–1985 MS TB 20%
Clinical studies of pneumonia in HIV-infected adults in Latin America

Chernilo S et al., Rev Cross-sectional study of 236 cases of lung disease in 171 hospitalized BAL PCR 38% BPNA 24%
Med Chile 2005 adults in Santiago, Chile, 1999–2003. Two or more conditions were TB 12%
present in 14% of subjects KS 3.3%
Villasis-Keever A et al., Cross-sectional study of 909 adults in an outpatient clinic N/A N/A 18% TB 18%
Arch Med Res 2001 in Mexico City, Mexico, 1984–1995 Histo 1.4% (all
sites)
Lambertucci JR et al., Rev Cross-sectional study of 55 hospitalized adults with AIDS with fever of Clinical N/A 15% TB 33% (all sites)
Inst Med Trop São Paulo undetermined etiology in Minas Gerais, Brazil Histo 3.6% (all
1999 1989–1997 sites)
Fonseca L et al., Int J Prospective study of 145 asymptomatic adults in São Paulo, N/A N/A 17% TB 19%
303
Epidemiol 1999 Brazil, followed for 4 years between 1985 and 1997
Continued
Section | 3 |
304

OF PCP OF OTHER
LUNG DISEASES
Clinical studies of pneumonia in HIV-infected adults in Latin America—cont’d

Santoro-Lopes G et al., J Cross-sectional study of 124 hospitalized adults with newly developed N/A N/A 14% N/A

AIDS Hum Retrovirol AIDS in Rio de Janeiro, Brazil, 1991–1995
1998
Rodriguez French A Cross-sectional study of 55 hospitalized adults with AIDS in Panama ES or IS Giemsa 45% N/A
et al., Rev Med Panama City, Panama, 1995 TTA MS
1996 BAL
Santos B et al., Int J STD Cross-sectional study of 224 adults with AIDS in a referral N/A N/A 17% TB 19% (all sites)
AIDS 1994 center in Porto Alegre, Brazil, 1986–1991
Weinberg A et al., Rev Cross-sectional study of 35 adults with respiratory complaints ES Tol Blue 55% TB 41%
Inst Med Trop São Paulo in São Paulo, Brazil, 1988–1989 BAL MS CMV 7.4%
1993 TBBx
Moreira ED Jr et al., Am J Cross-sectional study of 111 adults with AIDS in an outpatient Clinical MS 22% TB 24%
Trop Med Hyg 1993 clinic in Salvador, Brazil, 1989–1991 TBBx BPNA 22%
Specimen(s): BAL, bronchoalveolar lavage; BW, bronchial wash; Core Bx, core biopsy; ES, expectorated sputum; ETA, endotracheal aspirate; IS, induced sputum; Lavage, blind BW; Lung, fixed lung
tissue; NPA, nasopharyngeal aspirate; TBBx, transbronchial biopsy; TTA, transtracheal aspirate.
Stains: MS, methenamine silver; Tol Blue, toluidine blue O; IF Ab, immunofluorescence antibody; PCR, polymerase chain reaction.
Other lung diseases: BPNA, bacterial pneumonia; CMV, cytomegalovirus; Crypto, cryptococcosis; Histo, histoplasmosis; KP, Kaposi’s sarcoma; LRTI, lower respiratory tract infection; PCP,
Pneumocystis jiroveci pneumonia; Pen, penicilliosis; RSV, respiratory syncytial virus; TB, tuberculosis; Viral, other viral infection; Asp, bronchopulmonary aspergillosis.
All categories: AFB, acid-fast bacilli; ART, antiretroviral therapy; N/A, not available.
Chapter | 24 | Pneumocystis pneumonia
parts of the world, and clinicians are left to infer the degree to admit a patient to the hospital to receive supplemental
of immunocompromise from indirect measures such as the oxygen, whether to administer adjunctive corticoster-
absolute lymphocyte count. oids (PaO2 < 70 mmHg or an alveolar-arterial oxygen
gradient > 35 mmHg), and to assess response to PCP
therapy.
CLINICAL FEATURES
The clinical presentation of PCP in HIV-infected persons

CHEST RADIOGRAPH
differs from the presentation in other immunocompro-
mised persons. In general, HIV-infected patients present
with a subacute onset and longer symptom duration than The chest radiograph is the cornerstone of the diagnostic
other immunocompromised patients [8]. Compared with evaluation of patients with suspected PCP. Classically, pa-
HIV-negative patients, HIV-infected patients with PCP pre- tients with PCP present with bilateral, diffuse, symmetric
sent with a higher arterial oxygen tension and a lower reticular (interstitial) or granular opacities on their chest ra-
alveolar-arterial oxygen gradient. In addition, bronchoscopy diograph (Fig. 24.1) [12]. PCP often begins with central or
with bronchoalveolar lavage (BAL) examination reveals sig- perihilar opacities and a middle-lower lung zone predom-
nificantly greater numbers of Pneumocystis organisms and inance. As with the classic radiographic presentation, these
fewer neutrophils in HIV-infected patients [9]. opacities are bilateral and symmetric and can progress to
diffuse involvement if the disease is left undiagnosed and
untreated. However, patients with PCP can occasionally
SYMPTOMS AND SIGNS present with unilateral, focal, or asymmetric opacities on
their chest radiograph, and the specific pattern seen is often
more important than the exact distribution. Thus, PCP
Classically, patients with PCP present with fever, cough,
must be considered in any HIV-infected patient who is at
and dyspnea of 2–4 weeks, duration [10]. The cough is usu-
risk for PCP, has a compatible clinical presentation, and
ally dry and non-productive unless a concurrent bacterial
presents with reticular or granular opacities on chest radio-
infection is present. Fatigue is a frequent complaint,
graph, regardless of whether the findings are unilateral or
whereas chest pain (unless due to an associated pneumo-
bilateral, focal or diffuse, asymmetric or symmetric. Clearly
thorax), chills, and night sweats are less common. Symp-
though, the presence of bilateral, diffuse, and symmetric re-
toms are often subtle at the onset but are gradually
ticular (interstitial) or granular opacities increases the prob-
progressive and may be present for weeks and occasionally
ability of PCP significantly. In one study, patients who had
months before diagnosis.
Physical examination is non-specific. Vital signs often re-
veal an oral temperature >38.5oC, tachypnea, and a de-
creased oxygen saturation. Typically, the pulmonary
examination is unremarkable, even in the presence of sig-
nificant disease and hypoxemia. One maneuver that has
been reported to be sensitive for PCP is the elicitation of
a cough after deep inspiration. Bilateral fine inspiratory
crackles are the most frequent abnormal finding on lung
auscultation, although the chest exam is often normal.
LABORATORY TESTS
No current laboratory test is specific for PCP. The serum

lactate dehydrogenase (LDH) is usually elevated in patients
with PCP [11]. Published studies report the sensitivity of an
elevated serum LDH for PCP to range from 82 to 100%.
Unfortunately, the serum LDH is a non-specific test, and ele-
vations are seen in many pulmonary and non-pulmonary
conditions. The arterial blood gas (ABG) is an essential lab- Figure 24.1 Chest radiograph of an HIV-infected person, CD4
oratory test in patients with PCP. A patient with PCP will count <200 cells/mm3 demonstrating the characteristic
usually have a decreased arterial oxygen tension, an in- bilateral, diffuse, symmetric reticular-granular opacities of PCP.
creased alveolar-arterial oxygen gradient, and a respiratory Bronchoscopy with bronchoalveolar lavage (BAL) fluid
alkalosis. The ABG should be used to decide whether examination revealed Pneumocystis organisms.
305
interstitial infiltrates noted on their radiograph had a 4.4

greater odds of having PCP than those without this pattern,
and patients who had interstitial infiltrates that involved
five or six of the six defined lung zones (upper, middle,
and lower lung zones on the right and left lungs) had a
5.3 greater odds of having PCP [13].
Thin-walled cysts or pneumatoceles were reported in 7%
of PCP cases in one large radiology series [12]. Pneumato-
celes may be present at the time of diagnosis, may develop
while on therapy, and may persist despite successful ther-
apy. The pneumatoceles may be single or multiple in num-
ber and small or large in size. Usually, pneumatoceles are
multiple in number and located in the upper lobes. Impor-
tantly, the presence of pneumatoceles predisposes patients
to the development of pneumothorax, a difficult man-
agement problem for clinicians caring for PCP patients. Figure 24.2 Chest high-resolution computed tomographic
However, pneumothoraces may also occur in the absence (HRCT) scan of an HIV-infected person, CD4 count <200 cells/
mm3, whose chest radiograph was normal. Because of a clinical
of radiographically demonstrable pneumatoceles.
suspicion for PCP, the patient underwent HRCT, which
Less commonly, patients with PCP may present with a demonstrated the characteristic patchy ground-glass opacities
lobar or segmental consolidation, and with cavitary and of PCP. Induced sputum examination revealed Pneumocystis
non-cavitary nodules of varying size. Apical or upper lung organisms.
zone disease that resembles tuberculosis has been associ-
ated with aerosolized pentamidine prophylaxis, although
this presentation can also occur in patients receiving other
forms of PCP prophylaxis or no preventive therapy. While decreased diffusing capacity for carbon monoxide (DLCO),
reported, intrathoracic adenopathy and pleural effusions and gallium scanning showing increased pulmonary uptake
are rarely due to PCP. The presence of these radiographic can all be used in the diagnostic evaluation of patients with
findings should prompt a search for an alternate or coexist- suspected PCP [11]. Typically, these studies are performed
ing process such as bacterial pneumonia, tuberculosis, in patients whose clinical presentation is strongly suggestive
fungal pneumonia, or pulmonary Kaposi’s sarcoma. of PCP but whose chest radiograph is normal or minimally ab-
Patients with PCP may present with a normal chest ra- normal. However, these tests are relatively expensive and typ-
diograph, which has been reported in 0–39% of cases in ically unavailable in many parts of the world. One simple test
published studies. While patients with PCP and a normal for PCP is non-invasive exercise oximetry, since patients with
chest radiograph have a better prognosis than patients with PCP will often have a decline in their oxygen saturation with
bilateral diffuse opacities, they often represent a diagnostic exertion.
challenge and require a timely evaluation before their dis-
ease progresses.
There are a few studies on the course of respiratory symp- DIAGNOSIS
toms and chest radiographic abnormalities in patients suc-
cessfully treated for PCP [12, 14]. Patients with PCP often There is no universally agreed upon approach to the diag-
experience a transient clinical and radiographic worsening nostic evaluation of suspected PCP. Some institutions treat
in the first 3–5 days of PCP therapy. In one study of 104 patients with suspected PCP empirically, while others pur-
patients with PCP, 46% experienced a deterioration in ra- sue a definitive microscopic diagnosis (Fig. 24.3) [15]. In
diographic findings at 1 week [12]. In this same study, ap- patients with suspected PCP, it is generally advantageous
proximately one-third of the patients showed no change in to make a definitive diagnosis. A false presumptive diagno-
their radiograph over the first 3 weeks. A general rule is that sis of PCP may lead to failure or delay in making the correct
the more severe the PCP, the more prolonged the time to diagnosis. Additionally, the drugs used to treat PCP have
clinical and chest radiographic resolution. significant side effects, incurring unnecessary risk in the
PCP-negative patient (see Treatment below). As Pneumocys-
tis cannot be routinely cultured, the diagnosis of PCP
traditionally relies on microscopic visualization of the
OTHER TESTS characteristic cysts and/or trophic forms on stained respira-
tory specimens. Typically, these respiratory specimens are
Tests including high-resolution computed tomography obtained from sputum induction or bronchoscopy. How-
(HRCT) of the chest, typically demonstrating ground-glass ever, institutions report different degrees of success with
opacities (Fig. 24.2), pulmonary function tests demonstrating sputum induction and bronchoscopy with BAL with and
306
Figure 24.3 Diagnostic algorithm for the

evaluation of HIV-infected persons with suspected Diagnostic and management algorithm for PCP –
PCP in high-resource settings. CDC, Centers for high-resource settings
Disease Control; COPD, chronic obstructive • HIV+ and CDC AIDS-defining illness or CD4 ≤200 cells/mm3
pulmonary disease; DLCO, single-breath diffusing • Exertional dyspnea, non-productive cough, fever
capacity for carbon monoxide; HRCT, high-
• >2 weeks of symptoms
resolution computed tomography; GGO, ground-
glass opacities; BAL, bronchoalveolar lavage; MTB,
Mycobacterium tuberculosis; OI, opportunistic
infection. Chest radiograph
Reticular or granular Normal

opacities
Sputum induction DLCO or chest HRCT
PCP positive PCP negative DLCO≤75%, or DLCO>75%, or

HRCT w/ GGO HRCT w/o GGO
BAL
Consider
bronchitis,
asthma,
Treat PCP PCP positive Negative COPD, or
non-
respiratory
Positive for MTB, illness
fungi or other OI
without transbronchial biopsiy (TBBx). Advances in poly- as a potential biomarker for PCP. SAM is an important bio-
merase chain reaction (PCR) technology have enabled chemical intermediate involved in methylation reactions
the use of rapid, non-invasive procedures such as oropha- and also polyamine synthesis [17, 18]. Pneumocystis was
ryngeal washing as a method for specimen acquisition. In thought to lack a SAM synthetase to synthesize its own
one study, a non-invasive, 60-s gargle (oropharyngeal SAM; therefore, it needed to scavenge this intermediate
wash) specimen paired with a PCR-based quantitative as- from its host (a subsequent study has demonstrated that
say had a sensitivity of 88% and specificity of 85% [16]. Pneumocystis has a functional SAM synthetase) [19]. Thus,
However, in the absence of prospective studies comparing patients with PCP might be expected to have low SAM
various management and diagnostic strategies, the specific levels. A series of studies from New York found that plasma
approach to a patient with suspected PCP is often based on AdoMet levels could be used to distinguish between HIV-
the prevalence of PCP, clinician and institutional prefer- infected patients with PCP and those with non-PCP pneu-
ences and experiences, and availability of diagnostic proce- monia and healthy controls [17, 18]. Patients with PCP had
dures and microbiologic techniques and assays. In areas of significantly lower plasma AdoMet levels compared to pa-
the world where tuberculosis is prevalent and where re- tients with non-PCP pneumonia and there was no overlap
sources are limited, the examination of sputum for acid-fast in AdoMet levels between these two groups of patients in
bacilli may be a prudent diagnostic and public health prac- one study [18]. A subsequent study that measured serum
tice (Fig. 24.4). Studies designed to examine practical, cost- SAM found overlapping levels between HIV-infected pa-
effective diagnostic approaches to the patient with sus- tients with PCP and those with non-PCP pneumonia
pected PCP in a resource-limited setting are needed. [20]. Whether the differing results from these studies
Blood-based plasma and serum assays have also been relates to differences between plasma and serum SAM
studied for the diagnosis of PCP and may be a more levels, as has been hypothesized, or to other factors is
practical option in resource-limited settings. Plasma unclear, and further studies are needed. Serum (1-3)-
S-adenosylmethionine (SAM or AdoMet) has been studied beta-D-glucan, a cell wall component of all fungi including
307
Figure 24.4 Algorithm for evaluation of HIV-

Diagnostic and management algorithm for PCP – infected persons with suspected PCP in resource-
low-resource settings limited settings. AFB, acid-fast bacilli; COPD, chronic
obstructive pulmonary disease; SI, sputum induction;
• HIV+ and WHO clinical stage 3–4 or CD4 ≤200 cells/mm3
BAL, bronchoalveolar lavage; TB, tuberculosis;
• Exertional dyspnea, non-productive cough, fever NAAT, nucleic acid amplification test; WHO, World
• >2 weeks of symptoms Health Organization. *For patients with severe
• Not severely ill* illness (temperature >39 C, HR>120, RR>30,
inability to walk) consider empiric TB treatment. **If
patient has negative workup but symptoms persist,
Chest radiograph consider repeating algorithm.
Reticular or granular Normal

opacities
Sputum AFB Ambulatory pulse oximetry
Positive Negative Desaturation Normal
Treat TB SI or BAL to Consider

confirm PCP bronchitis,
or asthma,
If no Treat PCP COPD, or
improvement empirically non-
in 2 weeks, respiratory
consider illness**
Pneumocystis, has also been investigated as a potential bio- Trimethoprim and sulfamethoxazole each inhibit an impor-
marker for PCP, as patients with PCP might be expected to tant enzyme in folate metabolism; trimethoprim inhibits
have high levels [21, 22]. Patients with PCP with and with- dihydrofolate reductase, while sulfamethoxazole inhibits
out underlying HIV infection had significantly higher dihydropteroate synthase. Since many microorganisms
serum (1-3)-beta-D-glucan levels compared to patients cannot transport folate into cells as mammalian cells can,
without PCP in one early study [21]. Using a 100 pg/mL most prokaryotes and lower eukaryotes must synthesize
cutoff, another study reported a diagnostic sensitivity folates de novo. Thus, the fixed-dose combination of trimeth-
of 100% and a specificity of 96.4% [22]. Of note, (1-3)- oprim-sulfamethoxazole offers excellent activity against
beta-D-glucan is elevated in a number of fungal pneu- Pneumocystis and many other important HIV-associated bac-
monias, and this test cannot distinguish among fungal terial and protozoan pathogens. The availability of tri-
etiologies (e.g., PCP and Aspergillus species). Thus, methoprim-sulfamethoxazole in both intravenous and oral
although results from these non-invasive diagnostic or bio- formulations, its favorable toxicity profile (compared to
marker tests are promising, additional validation is needed, intravenous pentamidine), and its low cost are all
and bronchoscopy with BAL remains the gold standard additional advantages. However, the use of trimethoprim-
diagnostic test for PCP at the present time. sulfamethoxazole for PCP prophylaxis has led to concerns
about the possible development of drug-resistant Pneumocys-
tis as mutations in the dihydropteroate synthase gene are
reported in association with prophylaxis use and, in some
TREATMENT studies, are associated with increased mortality and increased
PCP treatment failure using trimethoprim-sulfamethoxazole
The standard treatment duration for HIV-infected patients [23–26]. Since trimethoprim-sulfamethoxazole is often the
with PCP is 21 days [5]. Trimethoprim-sulfamethoxazole is only PCP treatment available in many regions of the world,
recommended as first-line treatment for PCP (Table 24.2). the development of high-level drug resistance may have
308
Table 24.2 Treatment options for Pneumocystis pneumoniaa,b
TREATMENT DOSE(S), ROUTE, FREQUENCY SIDE EFFECTS

REGIMEN
Trimethoprim 15–20 mg/kg/day TMP and 75–100 mg/kg/day SMX, Nausea, vomiting, rash, fever, cytopenia, elevated
(TMP)- IV divided every 6–8 h or 2 DS tabs PO thrice daily liver transaminases, hyperkalemia
sulfamethoxazole for adults and adolescents with mild to moderate
(SMX)c disease
Pentamidine 3–4 mg/kg IV daily (infused slowly Nephrotoxicity, electrolyte disturbances,

over >60 min) pancreatitis, hypo- and hyperglycemia, cardiac
arrhythmias
Clindamycin plus clindamycin 600–900 mg IV every 6–8 h or 300–450 Nausea, vomiting, diarrhea, rash, hemolytic
primaquine mg PO every 6–8 h plus primaquine 15–30 mg base anemia (screen for G6PD deficiency prior to
PO once daily primaquine use), methemoglobinemia
Trimethoprim plus trimethoprim 5 mg/kg PO every 8 h plus Nausea, vomiting, rash, hemolytic anemia (when
dapsone dapsone 100 mg PO daily possible, screen for G6PD deficiency prior to
dapsone use in African and Mediterranean
populations), methemoglobinemia
Atovaquone 750 mg PO twice daily (suspension, Nausea, vomiting, diarrhea, rash

take with food)
DS, double-strength (160 mg TMP/800 mg SMX); IV, intravenous; PO, oral; G6PD, glucose-6-phosphate dehydrogenase.
a
Standard treatment duration is 21 days for all regimens.
b
Patients with moderate to severe PCP (oxygen saturation <93%, PaO2 <70 mmHg OR an alveolar-arterial oxygen gradient >35 mmHg) should
receive adjunctive corticosteroids—either prednisone 40 mg po twice daily 5 days, then 40 mg PO once daily 5 days, then 20 mg PO once daily
11 days or methylprednisolone equivalent—as soon as possible and within 72 h of treatment onset.
c
TMP-SMX is recommended first-line treatment for PCP.
severe consequences for patients with PCP residing in these mortality rates in patients randomized to corticosteroids
resource-limited areas [27–29]. [30]. Thus, the potential survival benefits associated with cor-
There are several treatment alternatives in patients ticosteroid therapy outweigh the risks of this additional im-
who are allergic to, intolerant of, or failing trimethoprim- munosuppressive therapy potentially unmasking an occult
sulfamethoxazole [5]. Intravenous pentamidine isethionate opportunistic infection such as tuberculosis.
and clindamycin plus primaquine are the main alternatives The ideal time to start antiretroviral therapy (ART) in pa-
in patients with moderate to severe PCP. Compared with tients with PCP who are not yet taking ART is not clear, but
trimethoprim-sulfamethoxazole, pentamidine has compara- growing evidence supports starting ART early rather than
ble efficacy but is associated with more frequent and severe waiting until after completion of PCP treatment. A ran-
toxicities that relegate it to second-line status. Clindamycin domized controlled trial compared early ART versus
plus primaquine is reported to be an excellent salvage therapy delayed ART in 282 HIV-infected patients diagnosed with
option for PCP. In patients with mild to moderate PCP, opportunistic infections (63% had PCP) [31]. Early ART
widely used alternatives to trimethoprim-sulfamethoxazole was associated with a significant decrease in AIDS progres-
include trimethoprim plus dapsone, atovaquone, or clinda- sion and death, with no increase in immune reconstitution
mycin plus primaquine. syndrome.
Finally, patients with moderate to severe PCP, demon-
strated by an oxygen saturation 93%, a PaO2 < 70 mmHg
or an alveolar-arterial oxygen gradient > 35 mmHg, should
receive corticosteroid therapy in addition to specific PCP PROPHYLAXIS
treatment [30]. Adjunctive corticosteroids, either oral predni-
sone or intravenous methylprednisolone, should be started Perhaps the single most effective PCP prevention strategy is
at the same time that specific PCP treatment is begun. Several the use of combination ART to increase the CD4 count to
studies document a reduction in respiratory failure and above the threshold associated with an increased risk of
309
PCP (i.e., 200 cells/mm3). Multiple studies conclusively subsequent prophylaxis is based on age-specific CD4
demonstrate that the risk of PCP is low in patients whose count thresholds: for children 1–5 years of age, CD4
CD4 count has risen from below to above 200 cells/mm3 count < 500 cells/mm3 or CD4 percentage <15%; chil-
as a result of ART [5]. In these persons, both primary and dren 6 years of age, CD4 count <200 cells/mm3 (as
secondary PCP prophylaxis can be safely discontinued for adults and adolescents) or CD4 percentage < 15%
once the CD4 count has remained > 200 cells/mm3 for at [34]. Once started, persons should remain on prophylaxis
least 3 months [32, 33]. One exception is that those with for life, unless their CD4 counts increase from below
a history of PCP that occurred at a CD4 count > 200 cells/ to above 200 cells/mm3 for at least 3 months as a
mm3 should remain on PCP prophylaxis for life, regardless result of ART. As with PCP treatment, trimethoprim-
of the degree of antiretroviral-associated rise in CD4 sulfamethoxazole is recommended as first-line prophy-
count [5]. laxis against PCP (Table 24.3). Dapsone, atovaquone,
In regions where ART is unavailable or in persons who and aerosolized pentamidine are alternatives in patients
are unable or unwilling to use combination ART or who who are allergic to or intolerant of trimethoprim-
are unresponsive to these therapies, PCP prophylaxis is sulfamethoxazole.
effective at decreasing rates of PCP. Current guidelines One final aspect of PCP prevention that warrants addi-
recommend that HIV-infected adults and adolescents tional study is the prevention of exposure to the source
who have a CD4 count <200 cells/mm3 or a history of of human Pneumocystis. Serologic studies suggest that expo-
oropharyngeal candidiasis receive primary PCP prophy- sure to Pneumocystis occurs early in life [35–37]. Unfortu-
laxis and that those with a history of PCP receive second- nately, the natural reservoir for human Pneumocystis
ary prophylaxis [5]. Adults and adolescents who do not remains unknown, although emerging studies in humans
meet these criteria but who have a CD4-lymphocyte per- indicate that humans are one reservoir [38]. In well-
centage of <14% or a prior AIDS-defining illness should controlled laboratory experiments, animal-to-animal
be considered for PCP prophylaxis. These recommenda- transmission of Pneumocystis via aerosol has been conclu-
tions also apply to HIV-infected women who are preg- sively demonstrated to occur under a variety of different
nant. Infants born to HIV-infected mothers should conditions [39–41]. Furthermore, immunocompromised
receive prophylaxis starting at 4–6 weeks of age, until laboratory animals may develop PCP after a brief exposure
the infant’s HIV serostatus can be conclusively deter- to a same-species animal with PCP. Thus, recommenda-
mined. Those infants who are subsequently determined tions for immunocompromised persons to avoid contact
to be uninfected with HIV can discontinue prophylaxis. with patients with PCP may be reasonable. However, stud-
HIV-infected infants and any infant whose HIV serostatus ies in humans also suggest that immunocompetent as well
remains unknown should continue to receive prophylaxis as immunocompromised persons without clinical PCP
for the first year of life. After the first year, the need for may be colonized with human Pneumocystis and may
Table 24.3 Prophylaxis options for Pneumocystis pneumonia
PROPHYLAXIS REGIMEN DOSE(S), ROUTE, COMMENT

FREQUENCY
Trimethoprim Preferred: 1 SS or DS tablet Recommended first-line prophylaxis against PCP

(TMP)-sulfamethoxazole PO daily
(SMX) Other options: 1 DS tablet
PO thrice weekly
Dapsone 100 mg PO daily or 50 mg —May also be combined with pyrimethamine and leucovorin
PO twice daily for dual protection against toxoplasmosis
—When possible, screen for G6PD deficiency prior to use
in African and Mediterranean populations
Atovaquone 1500 mg PO daily
Aerosolized pentamidine 300 mg aerosolized Via Respirgard II nebulizer

monthly
DS, double-strength (160 mg TMP/800 mg SMX); SS, single-strength (80 mg TMP/400 mg SMX); PO, oral; G6PD, glucose-6-phosphate
dehydrogenase.
310
serve as an additional source of infection to unsuspecting

immunocompromised persons [42–46]. Thus, even if an CONCLUSION
immunocompromised person avoids contact with a pa-
tient with PCP, the person may still be exposed to Pneumo-
The HIV/AIDS epidemic brought prominence and clinical
cystis through someone who is colonized or subclinically
importance to PCP, a previously uncommon pneumonia.
infected with the organism. Studies for defining the epi-
In the past 30 years, tremendous advances have occurred
demiology and transmission of human Pneumocystis are
in our understanding of HIV infection and PCP. However,
needed to identify the potential methods of disease
gaps in our knowledge remain and continued study of this
prevention.
important disease is still needed.
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312
Chapter | 25 |
Other HIV-related pneumonias
John G. Bartlett
bacterial causes, the most frequent were Streptococcus pneu-

INTRODUCTION moniae, Haemophilus influenzae, Pseudomonas aeruginosa,
and Staphylococcus aureus. Atypical agents (Legionella, Myco-
The lower respiratory tract has been and continues to be a plasma pneumoniae, and Chlamydophila pneumoniae) were
major site of opportunistic infections in patients with HIV rarely encountered [3].
infection. The infections that are encountered are quite dif-
ferent in the developed world and in the developing world,
based on availability of antiretroviral therapy (ART), diag- BACTERIAL PNEUMONIA
nostic testing, and the epidemiology of tuberculosis. There
is a substantial spectrum of pathogens that are involved in There are four bacterial agents that have been associated with
pulmonary infections, although the great majority of cases HIV infection and immunodeficiency: S. pneumoniae, H.
are presumably bacterial or viral but are never definitively influenzae, P. aeruginosa, and Nocardia. This listing does not
diagnosed. The purpose of this chapter is to review pneu- include mycobacteria, which are discussed elsewhere. Of
monia, with emphasis on appropriate diagnostic studies these, pneumococcal pneumonia is clearly the most frequent
and treatment. Emphasis will also be placed on the experi- and most important cause of pulmonary consolidation.
ences in distinct geographic areas. Pneumocystis jiroveci and
mycobacteria are discussed elsewhere. The focus of atten-
tion here will be on bacterial pathogens and fungi other Pneumococcal pneumonia
than P. jiroveci and Mycobacterium tuberculosis. The frequency of pneumococcal bacteremia is estimated to
be 150–300 times higher in HIV-infected individuals than
in those seronegative for HIV. The increased rate appears to
FREQUENCY apply to all CD4 cell strata, but is most common in those
with low CD4 counts [3, 5]. This frequency has changed
Bacterial pneumonia was a common cause of HIV-related substantially in developed countries due to the notable im-
complications in the era before the availability of highly ac- pact of HAART, the induction of herd immunity due to the
tive ART (HAART) and has continued to be a major prob- use of the Prevnar 7 vaccine in children, and the demon-
lem in the developing world. A prospective study of 1,100 strated impact of PCP prophylaxis in reducing bacterial in-
HIV-infected patients from 1988 through 1994 in the USA fections [4, 7].
found an incidence of approximately 100 cases per 1,000 The clinical presentation of pneumococcal pneumonia is
person-years (PY), approximately eight times higher than similar for patients with or without HIV infection, except
for an age-matched control population [1, 2]. The major for the high rates of bacteremia in HIV-infected patients.
pathogens encountered in this study of 521 cases of pneu- Extrapulmonary involvement (meningitis, septic arthritis,
monia (in which the likely pathogen was identified) were and endocarditis) are infrequent. The classic presentation
bacterial infection, 44%; P. jiroveci, 42%; tuberculosis, is the acute onset of chills and fever, usually accompanied
5%; and other opportunistic infections, 8%. Of the by cough, dyspnea, and pleurisy. These symptoms clearly
313
Table 25.1 Correlation of chest X-ray changes and causes
CHANGE COMMON UNCOMMON
Consolidation Pyogenic bacteria, Kaposi’s sarcoma, cryptococcosis Nocardia, M. tuberculosis, M. kansasii, Legionella,
Bordetella bronchiseptica
Reticulonodular Pneumocystis jiroveci, M. tuberculosis, Kaposi’s sarcoma, toxoplasmosis, CMV,

infiltrates histoplasmosis, coccidioidomycosis leishmaniasis, lymphoid interstitial pneumonitis
Nodule M. tuberculosis, cryptococcosis Kaposi’s sarcoma, Nocardia
Cavity M. tuberculosis, S. aureus (IDU), Nocardia, M. kansasii, MAC, Legionella, Pneumocystis

P. aeruginosa, cryptococcosis, coccidioidomycosis, jiroveci, lymphoma, Klebsiella, Rhodococcus equi
histoplasmosis, aspergillosis, anaerobes
Hilar nodes M. tuberculosis, histoplasmosis, coccidioidomycosis, M. kansasii, MAC

lymphoma, Kaposi’s sarcoma
Pleural effusion Pyogenic bacteria, Kaposi’s sarcoma, M. tuberculosis Cryptococcosis, MAC, histoplasmosis,
(congestive heart failure, hypoalbuminemia) coccidioidomycosis, aspergillosis, anaerobes,
Nocardia, lymphoma, toxoplasmosis, primary
effusion lymphoma
distinguish this pulmonary infection from Pneumocystis demonstrating clinical benefit are sparse. In other popula-
pneumonia (PCP) and tuberculosis (TB). The chest radio- tions, the only benefit convincingly shown was a 50% re-
graph demonstrates the usual focal infiltrate (Table 25.2). duction in the frequency of pneumococcal bacteremia,
Cavity formation, atypical infiltrates, and hilar adenopathy suggesting that patients with AIDS may continue to be a
are rare and suggest an alternative diagnosis. Most patients high priority for vaccination, especially when the CD4
produce sputum, which becomes a diagnostic resource count is high enough to allow for an immunologic re-
using Gram stain, Quellung tests, and culture [9]. As noted, sponse [14]. More recent data suggest that the new Prevnar
blood cultures are often positive. The urinary antigen assay 13 vaccine may be useful in adults at high risk for pneumo-
has a sensitivity of approximately 80% and a specificity of coccal bacteremia [15].
95% in adults with pneumococcal bacteremia [10]. The
treatment of pneumococcal pneumonia is the same for
Haemophilus influenzae
persons with HIV infection as for others.
The preferred drugs are summarized in Table 25.2. In This organism is second to the pneumococcus as a cause of
Africa, most strains of S. pneumoniae appear to respond bacterial pneumonia in patients with HIV infection [16, 17].
to beta-lactams, which are the preferred drugs. In the The frequency of H. influenzae bacteremia is 10- to 100-fold
USA ceftriaxone or cefotaxime are active against about higher in HIV-infected patients. Most cases involve non-
94% of strains; if there is a reason to suspect resistance or typeable strains [17]. This infection is similar to that of pneu-
if the patient is critically ill, most experts recommend a flu- mococcal pneumonia, with an acute onset of fever, cough,
oroquinolone, either alone or in combination with one of sputum production, and dyspnea. Chest X-rays usually show
the preferred beta-lactams. One curious observation is that a bronchopneumonia. The diagnosis is best established by
patients who are critically ill with bacteremic pneumococ- Gram stain and culture of sputum and culture of blood.
cal pneumonia involving penicillin-sensitive strains appear Approximately 40% of these strains produce beta-lactamase,
to do better with a beta-lactam combined with a macrolide so amoxicillin is often ineffective. The preferred drugs are
than with a beta-lactam alone [11]. The reason is unclear, a third-generation cephalosporin, a beta-lactam/beta-
but some suspect a role of the anti-inflammatory activity of lactamase inhibitor, fluoroquinolone, azithromycin, or sul-
the macrolide. The duration of therapy is arbitrary; the famethoxazole-trimethoprim [18]. The response is generally
usual recommended duration is 5–7 days after the patient good, and treatment is continued for 5–7 days after the
becomes afebrile. The rate of recurrent pneumococcal bac- patient becomes afebrile. Trimethoprim-sulfamethoxazole
teremia is high: 8–25% within 6 months. These are gener- prophylaxis should prevent this infection, but other forms
ally infections involving new strains rather than relapses, so of PCP prophylaxis will not. Haemophilus influenzae vaccine
longer treatment does not appear to be beneficial [12, 13]. is not indicated in adults because the rates of this infection
Administration of the 23-valent pneumococcal vaccine is are relatively low and the majority involve non-typeable
recommended in HIV-infected patients, although data strains not included in the vaccine.
314
Chapter | 25 |
Table 25.2 Bacterial infections
AGENT COURSE FREQUENCY, SETTING TYPICAL FINDINGS DIAGNOSIS TREATMENT
Gram-negative Acute, Uncommon, except with Lobar or Sputum Gram Stain (GS) and Need in vitro susceptibility
bacilli purulent nosocomial infection or bronchopneumonia culture (sensitivity is >80%, but tests.
sputum neutropenia. Pseudomonas specificity is poor) Long-term ciprofloxacin usually
aeruginosa is relatively common in results in relapse and resistance
late-stage disease, cavitary disease, to P. aeruginosa.

or chronic antibiotic exposure
(median CD4 count 50 cells/mm3)
Haemophilus Acute, Incidence is 100-fold higher than in Bronchopneumonia Sputum GS and culture Oral: amoxicillin/clavulanate,
influenzae purulent healthy controls; most infections are (sensitivity of culture is 50%; azithromycin, TMP-SMX,
sputum caused by unencapsulated strains prior antibiotics usually preclude fluoroquinolone,
growth) cephalosporin.
Intravenous: cefotaxime,
ceftriaxone
Legionella Acute Uncommon, HIV-associated risk is Bronchopneumonia; Sputum culture; urinary antigen Fluoroquinolone, macrolide,
mucopurulent debated sometimes multiple (Legionella pneumophila doxycycline
sputum infiltrates in serogroup 1)
non-contiguous
segments
Nocardia Chronic or Uncommon; frequency higher with Nodule or cavity Sputum or fiberoptic Sulfonamide or TMP-SMX
asymptomatic; chronic corticosteroid use (median bronchoscopy (FOB); GS,
sputum CD4 count 50 cells/mm3) modified acid-fast bacillus (AFB)
production stain and culture; should alert
lab if suspected
Staphylococcus Acute, Uncommon, except with injection Bronchopneumonia, Blood sputum GS and culture MSSA: nafcillin or oxacillin,
aureus subacute, or drug use and tricuspid valve cavitary disease, (sputum culture is sensitive, but cefuroxime, TMP-SMX,
chronic, endocarditis with septic emboli septic emboli with specificity is poor). clindamycin
purulent cavities effusion Blood cultures are nearly always MRSA: TMP-SMX or
sputum positive with endocarditis clindamycin if sensitive;
vancomycin
Streptococcus Acute, Common, all stages HIV infection; Lobar or Blood cultures often positive, Oral: amoxicillin, macrolide,
pneumoniae purulent incidence is 100-fold higher than in bronchopneumonia sputum GS Quellung, culture cefdinir, cefprozil,
sputum healthy controls; recurrence rate at pleural effusion (sensitivity of culture is 50%; cefpodoxime, fluoroquinolone.
pleurisy 6 months is 6–24%; higher with low prior antibiotics usually preclude Intravenous: cefotaxime,
CD4 counts and with smoking growth) ceftriaxone, fluoroquinolone
315
Staphylococcus aureus standard microimmunofluorescence (MIF) serology; never-

theless, C. pneumoniae accounted for only 13 of 319 (2.5%)
Patients with HIV infection have not been clearly defined as of pneumonias in patients with HIV infection [25].
being at higher risk for infections involving S. aureus. Those Chlamydophila pneumoniae and M. pneumoniae have not been
infected with HIV as a result of injection drug use have in- generally associated with infections in compromised hosts,
creased rates of infections involving S. aureus that appear to which presumably accounts for the paucity of cases. By con-
be independent of HIV. Most of these infections are soft tis- trast, Legionella has a clear association with compromised
sue infections at injection sites or pyomyositis [18, 19]. cell-mediated immunity, so one would expect more cases
There is a relatively new form of staphylococcal pneumonia with HIV infection [26–29]. One early report indicated a
that is at present quite rare, but might become more prev- 50-fold increase in the frequency of Legionnaires’ disease
alent and is important to recognize. This is the strain that with HIV infection, but this has remained an isolated report
has the Panton-Valentine leukocidin (PVL) recognized in not substantiated by others. Blatt and co-workers [26]
the late 1990s that is often resistant to all beta-lactams, reviewed eight cases of Legionnaires’ disease encountered
but sensitive to most other drugs active against S. aureus, in the HIV Natural History Study of the US Air Force; the me-
including trimethoprim-sulfamethoxazole, clindamycin, dian CD4 count was 83 cells/mm3; five cases were noso-
and doxycycline. It is most frequently associated with se- comial; six had coexisting pulmonary pathogens; none
vere soft tissue infections, including necrotizing fasciitis acquired this infection while receiving prophylaxis with tri-
and furunculosis. HIV-infected patients infected through methoprim-sulfamethoxazole; and all responded well to
homosexual sex or injection drug use are at higher risk standard therapy with a macrolide. The conclusion is that
for these soft tissue infections. This organism may also atypical agents play a minimal role in the etiology of bacte-
cause pneumonia characterized by a fulminant course, rial pneumonia in patients with HIV infection or AIDS.
with shock, necrosis of the lung, and empyema. As noted,
the unique strain of S. aureus involved in these cases in the
USA is usually referred to USA300, although similar strains
with similar properties are found in other parts of the Miscellaneous pathogens
world. The pathogenic mechanism is not clear, but a char- Rhodococcus equi is a relatively rare cause of pneumonia in
acteristic feature of these strains is that they possess the HIV-infected patients with late-stage disease (CD4 count
genes for the PVL as well as the mecIV mechanism of meth- usually <50 cells/mm3). Cavitation is common, and bac-
icillin resistance [20, 21]. Optimal treatment of pneumonia teremia is found in 50–80% of cases with an established di-
is not clear, but many authorities recommend the use of agnosis. Standard treatment is vancomycin or imipenem;
vancomycin or linezolid, often in combination with other one of these is usually combined with rifampin, a fluoro-
drugs such as rifampin or clindamycin [21]. quinolone, or erythromycin.
Mycobacteria other than tuberculosis (MOTT) are occa-
Pseudomonas aeruginosa sional pulmonary pathogens in this population. Mycobacte-
rium avium complex (MAC) is an important cause of
Pneumonia with this organism is infrequent, but it is a se- pneumonia in selected patients without HIV infection,
rious complication of late-stage disease indicating pro- but seems to cause disseminated disease involving nearly
found immunosuppression [22–24]. Most patients have all organs other than the lungs in patients with late-stage
a CD4 count <50 cells/mm3, and some have additional HIV. The major MOTT pathogen in patients with HIV is
risk factors such as neutropenia or corticosteroid therapy. Mycobacterium kansasii, which can present like M. tuberculo-
Many have bacteremia, and the mortality rate is relatively sis with pulmonary infiltrates, a chronic course, and posi-
high. The organism is usually easy to recover from sputum tive AFB smears. As with tuberculosis, it can occur in
and refractory to eradication despite aggressive antimicrobial patients with relatively high CD4 counts. An important
therapy. The usual treatment is a combination of antipseudo- clue to early diagnosis is a negative rapid molecular diag-
monal beta-lactams combined with tobramycin. Treatment nostic test in a patient with a positive AFB smear or culture.
with an oral fluoroquinolone such as levofloxacin or cipro- The usual treatment is isoniazid plus ethambutol plus ei-
floxacin often results in relapse with a fluoroquinolone- ther rifampin or rifabutin. Immune reconstitution inflam-
resistant strain. matory syndrome (IRIS) has been reported.
Norcardia is an important pathogen in patients with defec-
tive defenses, especially defective cell-mediated immunity.
Atypical agents
However, Nocardia is a relatively rare pathogen in HIV-
Chlamydophila (formerly Chlamydia) pneumoniae and Myco- infected patients for unclear reasons. The organism is weakly
plasma pneumoniae appear to be relatively uncommon in acid fast, looks like Actinomycetes on Gram stain, and causes
patients with HIV infection [1–3, 16]. A major problem an indolent pneumonia, consolidation, abscess formation,
is the limited accuracy of the diagnostic test for these two or fibronodular infiltrates. Trimethoprim-sulfamethoxazole
atypical agents [9]. One study reported results with the (10 mg/kg/day TMP) is the preferred treatment.
316
Chapter | 25 | Other HIV-related pneumonias
Diagnostic approach [26]. Treatment should be initiated rapidly, preferably

within 6 hours of registration. Pathogen-directed treat-
Key clues to the probability of a bacterial pneumonia in a ment is always preferred but often unrealistic due to time
patient with HIV infection are the features that characterize delays in establishing the etiologic agent. Recommenda-
bacterial pneumonia in other populations: the acute onset tions based on the pathogen are provided in Table 25.3.
and rapid progression, the usual clinical features of cough, Note that HIV infection with a CD4 count <200/mm3
sputum, and dyspnea, and the radiographic findings, must raise concerns for an opportunistic infection, as dis-
which almost invariably include a pulmonary infiltrate. cussed below.
Key factors in the assessment are the CD4 count (to evalu- In HIV-infected patients the diagnosis of community-
ate susceptibility to opportunistic pathogens), measures of acquired pneumonia should be established radiogra-
oxygenation and vital signs (to assess severity of illness), phically and empiric therapy should be started with a
and the characteristic features of the infiltrate [23]. Radio- macrolide or doxycycline. In the UK the recommended
graphic features that suggest specific etiologic causes are treatment is amoxicillin, which should be equally effective.
summarized in Table 25.1. In many cases, this will be The assumption is that most of these cases are caused
the initial presentation, and the CD4 count may be pend- by S. pneumoniae, other streptococci, or H. influenzae. In
ing when diagnostic and therapeutic decisions need to be HIV-infected patients, the concern is for other conditions
made. The absolute lymphocyte count (ALC) may be help- that may present in a slowly progressive form such as PCP
ful: an ALC of <1200 cells/mm3 correlates roughly with or tuberculosis, but these can usually be distinguished based
a CD4 count of <200 cells/mm3. Patients with advanced on radiographic finings, time course, symptoms, and CD4
HIV infection may also demonstrate evidence of chronic count. For hospitalized patients with community-acquired
disease with anemia, hypoalbuminemia, weight loss, etc. pneumonia, the standard treatment in most of the world
If HIV infection is suspected but has not been diagnosed, is with a penicillin. In the USA the standard is to cover
a rapid serologic test can be helpful. This test and the S. pneumoniae, H. influenza, and atypical pathogens.
CBC are generally available in virtually all parts of the
world.
To establish an etiologic diagnosis, standard tests for pa-
tients sufficiently sick to require hospitalization are blood FUNGAL PNEUMONIA
cultures and, in many centers, Gram stain and culture of ex-
pectorated sputum [9]. Although emphasis has been placed
on the probability of bacterial pneumonia in patients with Aspergillosis
acute onset of symptoms and other characteristic features, Aspergillosis previously accounted for 1–4% of pneumo-
there must be a continued concern for the possibility of nias in patients with AIDS [30–34]. This was a relatively late
PCP in any patient who has a low CD4 count, substantial complication, usually in patients with a CD4 count <50
reduction in oxygenation, lack of PCP prophylaxis, and/or cells/mm3 who often had additional risk factors, such as
characteristic features on chest radiograph. In these cases, it neutropenia or use of chronic corticosteroid therapy. There
is important that the diagnostic evaluation include bron- are two distinct clinical forms of pulmonary infection
choscopy or induced sputum examination, or, if the prob- (Table 25.4). The first is invasive parenchymal aspergillosis,
ability is sufficiently great, empiric treatment that may or in which the chest radiograph shows either a diffuse inter-
may not include agents active against common bacterial stitial pneumonitis or the more characteristic pleural-based
pathogens. The same vigilance applies to TB, particularly wedge-shaped infiltrate. These patients present with fever,
in countries where this is highly endemic. The expectorated cough, dyspnea, pleurisy, hypoxemia, hemoptysis, and
sputum needs to be evaluated by stain and culture for the radiographic features noted [30, 31]. The second form
AFB. Since AFB smears have a sensitivity of only about of pulmonary aspergillosis is tracheobronchial disease with
50% in HIV-infected patients, it may be important to con- ulcers or pseudomembranes, often with obstruction from
sider empiric treatment here as well. This problem will di- mucus plugs [30, 31]. The diagnosis of aspergillosis is
minish with availability of polymerase chain reaction established by the presence of typical clinical features com-
(PCR) assays to rapidly detect M. tuberculosis and multi- bined with demonstration of the organism by histopathol-
drug resistant tuberculosis (MDR-TB) [25]. ogy; a presumptive diagnosis can be made by positive
cultures for Aspergillus from respiratory secretions or a
positive galactomanin assay when accompanied by the
Treatment
characteristic clinical features [32, 33]. The standard treat-
The standard practice in the USA for treatment of hospi- ment is voriconazole or amphotericin B (Table 25.5),
talized patients with bacterial pneumonia is treatment usually at high dose, preferably using a lipid formulation
with a fluoroquinolone or a cephalosporin (ceftriaxone of amphotericin. Itraconazole may also be used. In more
or cefotaxime), combined with a macrolide (azithromy- recent years, voriconazole has become the preferred agent
cin or clarithromycin or erythromycin) (Table 25.3) [16, 34, 35]. It has not been studied in clinical trials in
317
Table 25.3 Treatment of bacterial pneumonia (based on guidelines of IDSA)
Outpatient
Empiric
No antibiotics 3 months: doxycycline or macrolidea
Antibiotics within 3 months: fluoroquinolone,b telithromycin, or beta-lactam þ macrolide
Hospitalized patient
Non-ICU: fluoroquinoloneb or beta-lactamc þ macrolidea
ICU beta-lactam þ macrolide or beta-lactam þ fluoroquinoloneb
Aspiration
Beta-lactam/beta-lactamase inhibitor or clindamycin
Alternative: carbapenemd
Influenza þ superinfection
Beta-lactamc antiviral agent
Healthcare-associated
Ceftriaxone, fluoroquinolone,b ampicillin-sulbactam or ertapenem
Pathogen-specific
S. pneumoniae
Penicillin MIC <2 mg/mL: penicillin or amoxicillin; alternatives—macrolide,a telithromycin, cephalosporin-cefpodoxime, cefprozil,
cefuroxime, cefdinir, cefditoren, ceftriaxone or cefotaxime, doxycycline, clindamycin, fluoroquinoloneb
Penicillin MIC 2 mg/mL: cefotaxime, ceftriaxone, fluoroquinolone,b telithromycin
Alternatives: linezolid, amoxicillin (3 g/day—if MIC 4 mg/mL)
H. influenzae
Non-beta-lactamase- producing: amoxicillin
Beta-lactamase-producing: cephalosporin, amoxicillin-clavulanate
Alternatives: fluoroquinolones,b doxycycline, azithromycin, clarithromycin
Mycoplasma pneumoniae
Macrolidea or tetracycline
Alternative: fluoroquinoloneb
Chlamydophila pneumoniae
Macrolidea or tetracycline
Alternative: fluoroquinoloneb
Legionella
Fluoroquinolone,b azithromycin, clarithromycin
Alternative: doxycycline
S. aureus
MSSA: nafcillin, oxacillin. Alternative: clindamycin, cefazolin, trimethoprim-sulfamethoxazole
MRSA: vancomycin or linezolid
P. aeruginosa
Anti-pseudomonal beta-lactam (ticarcillin, piperacillin, ceftazidime, cefepime, aztreonam, imipenem, meropenem) þ
(ciprofloxacin or levofloxacin) or aminoglycoside
Alternative: aminoglycoside plus ciprofloxacin or levofloxacin
a
Macrolide: azithromycin or clarithromycin.
b
Fluoroquinolone: levofloxacin (750 mg/day), moxifloxacin, gemifloxacin.
c
Beta-lactam: ceftriaxone, cefotaxime.
d
Carbapenem: imipenem, meropenem, ertapenem.
Chapter | 25 |
Table 25.4 Fungal infections
AGENT COURSE FREQUENCY, SETTING TYPICAL FINDINGS DIAGNOSIS TREATMENT
Aspergillus Acute or Up to 4% of AIDS patients; usually with Focal infiltrate; cavity-often Sputum stain and culture; false-positive Amphotericin B
subacute advanced HIV infection (med. CD4 count pleural-based diffuse and false-negative cultures common. or itraconazole
30 cells/mm3); 60% have severe infiltrates or Best tests: tissue pathology or sputum or caspofungin
neutropenia (ANC <500 cells/mm3) reticulonodular infiltrates smear and typical CT and clinical features
chronic steroids; disseminated disease

uncommon
Candida Chronic or Common isolate, rare cause of Bronchitis; rare cause of Recovery in sputum or FOB specimen is Fluconazole or
subacute pulmonary disease (med. CD4 count 50 pneumonia (some say it meaningless (up to 30% of all amphotericin B
cells/mm3) does not exist) expectorated sputum and FOB cultures in
unselected patients yield Candida sp.);
must have histologic evidence of invasion
on biopsy
Coccidioides Chronic or Up to 10% of AIDS patients in endemic Diffuse nodular infiltrates, Sputum, induced sputum, or FOB stain Fluconazole,
immitis subacute area; usually advanced HIV infection focal infiltrate, cavity; hilar and culture; KOH of expectorated itraconazole, or
(med. CD4 count 50 cells/mm3); adenopathy [26] sputum is rarely positive; PAP stain or amphotericin B
disseminated disease in 20–40% silver stain of BAL positive in 40%; culture
of BAL usually positive; serology (CF)
positive in 70%; skin test positive in
<10%; blood cultures positive in 10%
Cryptococcus Chronic, Up to 8–10% in AIDS patients; late-stage Nodule, cavity, diffuse or Sputum, induced sputum, or FOB stain Fluconazole
subacute, or HIV infection (med. CD4 count 50 cells/ nodular infiltrates and culture; serum cryptococcal antigen without CNS
symptomatic mm3); 80% have cryptococcal meningitis usually positive; CSF analysis indicated if involvement;
antigen or organism found at any site amphotericin B
Histoplasma Chronic or Up to 15% of AIDS patients in endemic Diffuse nodular infiltrates, Best test for diagnosis and follow-up of Itraconazole or
capsulatum subacute area; usually advanced HIV infection with nodule, focal infiltrate, treatment is serum and urine amphotericin B
disseminated histoplasmosis (med. CD4 cavity, hilar adenopathy polysaccharide antigen assay, with yield
count 50 cells/mm3). Common features: [27, 28] of 85% (blood) and 97% (urine).
fever, weight loss, hepatosplenomegaly, Available only through J. White
lymphadenopathy (Indianapolis, IN) 800-HISTO-DG for US
$70/assay; serology positive in 50–70%;
yield with culture of sputum, 80%;
marrow, 80%; blood cultures positive in
60–85%
319
Table 25.5 Treatment of fungal infection of the lung
Aspergillosis
Preferred Voriconazole 400 mg IV or PO q12h 2 days, then 200 mg q12h
Duration Based on clinical response
Alternative Amphotericin B 1 mg/kg IV or lipid formulations of amphotericin B 5 mg/kg per day
Cryptococcosis: disseminated disease

Preferred Acute Amphotericin B 0.7 mg/kg IV flucytosine 25 mg PO 4 times daily 14 days, or liposomal
amphotericin 14 days
Consolidation Fluconazole 400 mg/day PO 8 weeks.
Maintenance Fluconazole 200 mg/day PO until CD4 count >100–200/mm3 þ asymptomatic 6 months
Alternatives Acute Fluconazole 400–800 mg/day IV or PO flucytosine 25 mg PO 4 times daily 14 days
Consolidation Itraconazole 200 mg/day PO 8 weeks
Maintenance Itraconazole 400 mg PO or IV once daily
Cryptococcosis: pulmonary without disseminated disease

Preferred Fluconazole 200–400 mg/day PO or itraconazole 200–400 mg/day or amphotericin B 0.5–1.0 mg/kg per day IV
(serious disease)
Duration Until asymptomatic þ CD4 count >100–200 cells/mm3 6 months
Histoplasmosis: severe disseminated

Preferred Acute Amphotericin B 0.7 mg/kg per day IV or liposomal amphotericin B 4 mg/kg per day 3–10 days
Continuation Itraconazole 200 mg caps PO twice daily
Alternative Acute Itraconazole 400 mg/day IV
Continuation Itraconazole oral solution 200 mg PO twice daily or fluconazole 800 mg/day PO
Histoplasmosis: mild disseminated disease

Preferred Itraconazole 200 mg cap PO 3 times daily 3 day, then 200 mg PO twice daily 12 weeks, then 200 mg/day PO
Alternative Fluconazole 800 mg/day PO
Cryptococcosis
HIV-infected patients, but it appears to be superior to Cryptococcosis is a relatively common complication of
amphotericin B in other populations. Particularly impor- late-stage HIV infection. This was previously a common
tant in the management is to reverse the predisposing fac- AIDS-defining diagnosis in the developed world and is well
tors as much as possible, including increasing CD4 count recognized as a major cause of severe disease in resource-
with ART, reversing of neutropenia, and discontinuing or limited countries. This is best known as a cause of menin-
reducing the dose of corticosteroids. The prognosis has gitis, but the lung is the portal of entry, and many patients
been poor, with a mortality rate exceeding 90% in the have pulmonary involvement concurrently or in the ab-
pre-HAART era [28]. The prognosis is presumably substan- sence of meningitis. Prior to HAART there were reports
tially better with ART-mediated immune reconstitution. that approximately 5–8% of all persons with late-stage
320
HIV infection acquired disseminated cryptococcosis [36– H. capsulatum microconidia. Infection generally remains lo-
40]. Typical pulmonary symptoms are fever, cough, and calized in the lung in patients with CD4 counts >300 cells/
dyspnea that evolve over a period of weeks [35–37]. The mm3, but disseminated disease is common when the CD4
chest radiograph usually shows interstitial infiltrates that count is <150 cells/mm3. Common clinical features of pul-
may suggest PCP [36–38]; other radiographic findings in- monary disease include cough, fever, and dyspnea that are
clude focal infiltrates, cavities that may be clinically silent, usually indolent in onset. With disseminated disease, there
hilar adenopathy, pleural effusions, and/or reticulonodu- are often typical lesions of the skin and mucosal surfaces,
lar infiltrates. The disease in the central nervous system weight loss with wasting, bone marrow suppression with
may be clinically silent, so the diagnosis of cryptococcal pancytopenia, hepatosplenomegaly with abnormal liver
pulmonary infection should always prompt a lumbar function tests in a cholangitic pattern, lymphadenopathy,
puncture to detect cryptococcal meningitis, the most com- and/or diarrhea [37]. The chest radiograph usually shows
mon recognized clinical form of the disease. Most patients a diffused interstitial infiltrate or a reticulonodular infil-
with cryptococcosis have a positive serum antigen assay for trate; other less common findings are focal infiltrates, hilar
C. neoformans [38]. The organism can also often be found in adenopathy, and pleural effusions [27, 43, 44]. A septic
respiratory secretions, including sputum or bronchoscopic shock-like syndrome occurs in <10% of patients. Detection
aspirates [40]. of the Histoplasma antigen in blood or urine is useful for the
The standard treatment for cryptococcal meningitis is diagnosis of disseminated disease, but these tests are rela-
amphotericin B, often combined with 5-flucytosine for 2 tively insensitive when the infection is restricted to the lung
weeks followed by the consolidation phase of fluconazole [34, 44]. The fungus can often be isolated from blood cul-
at 400 mg/day for 8 weeks and then fluconazole at 200 mg/ tures, bone marrow, or respiratory secretions, but recovery
day, until there is immune reconstitution [41, 42]. For pa- requires 2–4 weeks [45].
tients with pulmonary cryptococcosis, the recommenda- Patients with severe disseminated disease should be treat-
tion for mild disease restricted to the lung is fluconazole ed with liposomal amphotericin B, which has proven supe-
400 mg/day 6 months [42]. Itraconazole (400 mg/day) rior to deoxycholate amphotericin B with respect to
is the alternative. More serious pulmonary disease should therapeutic response and toxicity [42, 43]. Amphotericin
be managed like cryptococcal meningitis [42]. is usually given for 7–14 days, and treatment is then chan-
ged to itraconazole 200 mg twice daily for at least 12 weeks
and until there is immune reconstitution. Chronic pulmo-
Histoplasmosis nary histoplasmosis is treated with itraconazole (200 mg
Histoplasma capsulatum is endemic in the Mississippi, Ohio, twice daily) for 12–24 months until the CD4 count is
and St Lawrence River valleys. Histoplasmosis was previ- >100 cells/mm3 [34, 44]. Patients with acute pulmonary
ously diagnosed in over 5% of persons living in these en- histoplasmosis and a CD4 count >500 cells/mm3 may
demic areas [42–45]. The frequency has declined during not require therapy and can be managed in a fashion
the HAART era. The disease is acquired by inhalation of similar to patients without HIV infection.
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[19] Francis J, Doherty M, Lopatin U, Study Group. Am J Respir Crit Care Cryptococcal infections in patients
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Chapter | 26 |
HIV-associated tuberculosis
Leyla Azis, Edward C. Jones-López, Jerrold J. Ellner
INTRODUCTION EPIDEMIOLOGY
Over the last three decades, tuberculosis (TB) and HIV TB is a major global health problem, ranking as the lead-
epidemics have become inextricably connected in a bidirec- ing cause of death from an infectious agent and the sev-
tional interaction, often seen as a deadly association or “the enth cause of death in the world [3]. The combined
cursed duet” [1]. TB remains a major cause of morbidity burden of disease caused by HIV and TB is daunting. More
and mortality in HIV-infected individuals, especially in than 33 million people were living with HIV at the end
countries with a high burden of both infections. The HIV of 2009, and the death toll from HIV/AIDS in the same
pandemic has changed TB epidemiology, natural history, year was 1.8 million. It is estimated that one-third of the
and pathogenesis, affecting its clinical and radiographic HIV-infected population is co-infected with Mycobacterium
presentation, diagnosis, treatment, and prognosis. tuberculosis, the majority harboring latent TB infection.
In general, people living with HIV are 20 to 37 times In 2009, there were 9.4 million incident cases of TB
more likely to develop TB disease during their lifetimes globally, equivalent to 137 cases per 100,000 population.
than HIV-uninfected individuals [2]. Patients with ad- TB prevalence was estimated at 14 million cases, equiva-
vanced HIV disease who develop TB are more likely to lent to 200/100,000 [2]. Most of the estimated number
manifest atypical radiographic findings and develop extra- of cases in 2009 occurred in Asia (55%) and Africa
pulmonary and disseminated disease. The diagnosis of TB (30%), and smaller proportions of cases occurred in the
in HIV-infected patients is more difficult, and the treatment Eastern Mediterranean region (7%), the European region
is often complicated by drug interactions, cumulative tox- (4%), and the Americas (3%). Approximately 80% of all
icities and decreased efficacy. Furthermore, mortality rates estimated cases worldwide were concentrated in 22
are remarkably higher. Among individuals treated for TB, high–burden countries (HBCs), among which India alone
HIV-infected individuals have higher rates of recurrent TB accounts for an estimated one-fifth (21%), and China
than those who are HIV-uninfected. Conversely, active and India combined account for 35% of all TB cases
TB is associated with increased viral replication in HIV- worldwide (Fig. 26.1A).
infected patients, contributing to HIV progression and Of the 9.4 million incident cases in 2009, an estimated
shortening survival in dually-infected patients. 1.1 million (12%) were HIV-infected, with approximately
The goal of this chapter is to provide a general review of 80% of the TB-HIV cases occurring in Africa. In some south-
TB, focusing on the unique features of HIV-associated TB ern and eastern African countries, more than 50% of TB pa-
and addressing specific issues of co-infection management tients are co-infected with HIV (Fig. 26.1B). Approximately
and control strategies. 1.7 million people died of TB in 2009, including an
325
Estimated new TB
cases (all forms) per
100,000 population
0–24
25–49
50–99
100–299
300
No estimate
A
HIV prevalence in new

TB cases, all ages (%)
0–4
5–19
20–49
50
No estimate
Figure 26.1 (A) Estimated TB incidence rates by country in 2009. (B) Estimated HIV prevalence in new TB cases in 2009.
Reproduced from World Health Organization. Global Tuberculosis Control. [online]. 2010. Available from: http://whqlibdoc.who.int/publications/
2010/9789241564069_eng.pdf
326
Chapter | 26 | HIV-associated tuberculosis
estimated 0.4 million people with HIV, amounting to

about one in four of the deaths occurring among HIV- PATHOGENESIS AND NATURAL
infected individuals. HISTORY
TB drug resistance, including multi-drug resistant TB
(MDR-TB) and extensively-drug resistant TB (XDR-TB) is
an increasing global problem. MDR-TB is defined as resis- TB is caused by one of the pathogenic mycobacteria belong-
tance to at least isoniazid and rifampicin, and XDR-TB is ing to Mycobacterium tuberculosis complex, most commonly
defined as an MDR isolate that is also resistant to any flu- Mycobacterium tuberculosis and rarely M. bovis or M. africanum.
oroquinolone and at least one of the injectable second-line HIV infection is the most significant risk factor for TB
drugs (capreomycin, amikacin and kanamycin). There progression, accelerating the development of TB at all
were an estimated 440,000 cases of MDR-TB in 2008, of stages that follow the deposition of M. tuberculosis in the
which 85% occurred in 27 high MDR-TB burden countries; pulmonary alveoli.
150,000 deaths from MDR-TB occurred in 2008. The global TB stages are conventionally viewed as “primary TB,”
epidemiology of drug-resistant TB in HIV-infected persons “progressive primary TB,” “latent TB,” and “secondary or
is not known. A systematic review that included 32 studies post-primary TB”. There is, however, evidence supporting
from 17 countries failed to demonstrate an overall associ- the paradigm that the interaction between M. tuberculosis
ation between MDR-TB and HIV infection [4]. However, and the human host represents a continuum of immune re-
HIV is a potent risk factor for institutional outbreaks of sponses, pathologic manifestations, mycobacterial meta-
MDR-TB. In outbreak settings the case mortality rate has bolic activity and clinical disease [5]. Nonetheless, this
been extremely high. chapter will utilize the classical presentation for simplicity.
Since HIV was first recognized 3 decades ago, TB inci-
dence and notification rates have remained tightly associ-
ated with HIV prevalence rates. The global incidence of
Transmission of M. tuberculosis
TB per capita appears to have peaked in 2004 and is The chain of host–pathogen interactions begins with the
now in decline, following a similar pattern to the trend inhalation into the pulmonary alveoli of droplet aerosols
in HIV prevalence in the general population, but with a containing M. tuberculosis. When a patient with active pul-
6-year delay. monary or laryngeal tuberculosis coughs, speaks, sings or
Globally, the absolute number of cases is increasing sneezes, he or she generates respiratory droplets that trans-
slowly, reflecting population growth, although the number form into small droplet nuclei through water evaporation.
of cases per capita (expressed as the number of cases per The infected aerosols can remain dispersed in the air for
100,000 population) is falling by around 1% per year. prolonged periods of time. Particles smaller than 5 mm
In 2009, the per capita TB incidence rate was stable or reach the pulmonary alveoli, a process that is necessary
falling in five of the six World Health Organization for M. tuberculosis transmission.
(WHO) regions, with the exception of the South-East Asia Environmental characteristics such as ventilation, hu-
region, where the incidence rate is stable, largely explained midity or presence of UV light influence the likelihood
by apparent stability in the TB incidence rate in India. The of transmission. The likelihood of TB transmission also de-
most recent assessment for the 22 HBCs suggests that inci- pends on the infectiousness of the source case as measured
dence rates are falling or stable in all countries except South by the cough strength [6] and the grade of acid-fast bacilli
Africa. Mortality rates (excluding TB deaths among HIV- (AFB) sputum smear results. Patients with cavitary lesions
infected people) are falling in all six WHO regions. Among and intensely positive sputum smears have a higher risk of
the 22 HBCs, mortality rates appear to be falling, with the TB transmission. Bacterial factors such as virulence and vi-
possible exception of Afghanistan and Uganda. ability also influence M. tuberculosis transmission, as evi-
Since monitoring of the scale-up of integrated TB/HIV denced by the Beijing strain family of M. tuberculosis that
activities began in 2003, considerable progress has been has been associated with increased transmission, dissemi-
made. By 2009, 1.6 million TB patients knew their nation and outbreaks. Transmission of MDR-TB is compa-
HIV status, equivalent to 22% of notified cases, up rable to that of drug-susceptible M. tuberculosis.
from 4% in 2003. In 2009, there were 55 countries in In general, TB transmission occurs as a consequence of
which >75% of TB patients knew their HIV status, includ- household exposure, the prolonged and frequent contact
ing 16 African countries. Of the HIV-infected TB patients, with an active TB patient being much more likely to transmit
75% were receiving co-trimoxazole preventive therapy M. tuberculosis than a brief contact. This pattern is observed
(CPT), and 37% were enrolled on antiretroviral therapy in both low- and high-prevalence countries, irrespective of
(ART) in 2009. Despite the progress achieved over the HIV status and can be demonstrated by traditional epidemi-
past several years, the epidemic of HIV-associated-TB con- ological studies and confirmed by molecular approaches
tinues to rage in many parts of the world and greatly in- [7, 8]. Occasionally, M. tuberculosis transmission has been
creased collaboration between programs and services is reported after casual contact with an infectious case. Trans-
needed. mission after brief exposure has been linked more often to
327
outbreaks in shelters, nursing homes, hospitals, prisons or Adaptive immunity and delayed-type hypersensitivity
air travel. In such cases, transmission may be related to in- (DTH) develop after 3–8 weeks. Adaptive immunity is
creased virulence of the involved strain, environmental fac- characterized by decreased bacillary multiplication, macro-
tors or patient characteristics. There is, in fact, evidence that phage apoptosis, and granuloma formation at the site of
some patients with pulmonary TB are “super-transmitters.” the primary focus and disseminated areas. The immune
Remarkably, only about one-half of the household con- response usually controls the infection. Most often, the le-
tacts of active TB patients become infected [9], suggesting sions of primary TB undergo fibrosis and calcification and
that in addition to the type of exposure, host-related factors may be observed radiographically as calcified peripheral
may influence susceptibility to M. tuberculosis. The existence lung nodules (Ghon lesion), calcified adenopathy, or both
of innate immunity to TB is a certainty, although the immu- (Ranke complex), hallmarks of primary TB infection. Case-
nologic mechanisms that render some populations suscepti- ous necrosis at the center of the lesion, tissue destruction,
ble and other resistant to TB remain largely uncharacterized. and cavity formation are the result of DTH.
Several studies have demonstrated the association of various Primary TB in HIV-infected individuals may occasion-
human leukocyte antigens (HLA) with disease susceptibility ally progress directly to disease without an intervening pe-
in different ethnic populations [10, 11]. Genetic susceptibil- riod of clinical latency. This is termed progressive primary
ity to TB has also been associated with polymorphisms in the tuberculosis, a condition characterized by exudative, case-
human SLC11A1 (formerly NRAMP1) gene, some toll-like ous and ulcerative pulmonary lesions as a result of pneu-
receptor (TLR) genes, the genes for the vitamin D receptor monic progression of the primary focus. The host
and components of the interferon (IFN) gamma-signaling adaptive T cell-mediated response, mainly mediated by
pathways. interleukin (IL)-12 and interferon (IFN)-g production
The interplay between these multiple factors and possi- by Th1 cells and the local expression of tumor necrosis
bly others, still unknown, will determine the likelihood factor (TNF)-a, is important in the control of M. tubercu-
that the inhaled mycobacteria reach the alveoli and initiate losis infection, granuloma formation and prevention of
a host–bacterial interaction that culminates in M. tubercu- mycobacterial dissemination. HIV infection causes CD4
losis infection. T cell depletion and impairment of cytokine expression,
The effect of HIV on M. tuberculosis transmission has been which accounts for poor granuloma formation and TB
studied extensively with contradictory results. A meta- dissemination (extrapulmonary/miliary forms) in co-
analysis concluded that HIV infection does not significantly infected patients.
increase the risk of M. tuberculosis transmission, as patients
with HIV-1 infection and TB are no more infectious
than HIV–uninfected patients with TB [12].
TB disease
The reactivation of pulmonary TB in the host with pre-
existing immunity leads to a vigorous inflammatory
M. tuberculosis infection
response with the development of caseating granulomas
In most cases, the first lesion that develops as a result of and ultimately cavitary lesions. Pathologically, the lungs
M. tuberculosis infection (primary focus) is located in the of HIV-infected patients dying with TB are frequently char-
lung, whereas the initial inoculation of M. tuberculosis at acterized by caseous lesions containing tubercle bacilli;
extra-pulmonary sites is uncommon. however, the type of lesion is correlated with the degree
Transmitted M. tuberculosis bacilli are usually deposited of immunosuppression. In patients with high CD4 counts,
in the mid-lung, subpleural alveoli and are first ingested typical caseating granulomas can be seen, while in patients
by resident alveolar macrophages, dendritic cells and with low CD4 counts, the lesions tend to be diffuse, with
recruited monocytes. Within the alveolar macrophages, more extensive caseous necrosis, poor granuloma forma-
M. tuberculosis bacilli multiply, destroy the macrophages tion, reduced fibrosis and less frequent cavity formation,
(and are taken up by monocytes recruited to the inflamma- reflecting the impaired immune activation.
tory focus), giving rise to an initial exudative primary pul- In HIV-infected individuals, post-primary TB most com-
monary focus. The infected macrophages are transported to monly develops through the endogenous reactivation of
the regional hilar and mediastinal lymph nodes, where ba- the small foci of hematogenous dissemination occurring
cilli continue to multiply, events that define the primary TB in the course of primary infection, as in HIV-uninfected
infection. A discrete lympho-hematogenous dissemination populations. In both HIV-infected and uninfected individ-
may occur before the development of acquired immunity, uals, the most common site of TB reactivation is the lung.
giving rise to small, micronodular pulmonary foci (apical Extrapulmonary TB, which may occur in any organ, is
Simon foci) or extra-pulmonary foci that can harbor viable more common in HIV-infected patients. In contrast to
bacilli for prolonged periods of time. These are considered HIV-uninfected individuals, active TB occurring as a result
to be the origin of the future secondary pulmonary or extra- of TB re-infection, proved through restriction fragment
pulmonary TB (endogenous reactivation). length polymorphism (RFLP) analysis of strains, has been
328
observed frequently in HIV-infected patients, especially in bronchoalveolar lavage of untreated TB patients. These
countries where the prevalence of TB is high [13, 14]. studies imply that an imbalance in effector cell populations
In HIV-uninfected individuals, the lifetime risk of de- and modulation by regulatory T cells may determine
veloping TB disease by reactivating latent TB infection is progression from latent infection to disease.
approximately 5–10%. In HIV-infected individuals, this Although the precise immune mechanisms engendering
risk increases to 5–15% annually, rising as immune defi- protection in the acute or latent phase of TB remain incom-
ciency worsens. The increased risk is manifest even in pletely defined, current evidence supports the notion that
the absence of immunodeficiency. In South African gold effective acquired cellular immunity to M. tuberculosis is
miners, the risk of active TB was increased two- to three- critically dependent on the activation of the Th1 subset
fold within the first 2 years of HIV infection despite of CD4 T cells.
the absence of significant CD4 cell depletion [15]. In gen-
eral, the risk of TB progression correlates with the CD4
count. In an African cohort, the TB incidence rate was Impact of TB infection on HIV
17.5 cases/100 person-years in HIV-infected patients
Several studies indicate that active TB accelerates HIV pro-
with CD4 counts <200/mm3 versus 3.6 cases/100 per-
gression, shortening survival, although the underlying
son-years for CD4 counts >350/mm3 [16].
mechanisms are not completely understood.
Immunologic activation induced by M. tuberculosis is as-
Immunologic aspects sociated with an overproduction of cytokines, such as TNF
that increases HIV replication in latently-infected cells. One
Multiple distinct receptors, such as complement receptors
study demonstrated a 5- to 160-fold increase in viral repli-
CR1, CR3, CR4, the mannose receptor, CD14, surfactant
cation during the acute phase of untreated TB [18]. It is also
protein A (Sp-A) receptors and scavenger receptors, have
observed that active TB sometimes induces a transient CD4
the potential to recognize and bind M. tuberculosis in vitro.
T cell depletion, which may contribute to HIV progression.
M. tuberculosis can activate the alternative pathway of com-
plement and become opsonized by complement products
that facilitate uptake by complement receptors. M. tubercu-
losis also expresses surface polysaccharides that can directly CLINICAL MANIFESTATIONS
interact with complement receptors.
Besides expressing traditional phagocytic receptors for
antibody and complement, macrophages and dendritic TB is a complex, dynamic and multifaceted disease, with
cells also express Toll-like receptors (TLRs) that recognize protean manifestations in both HIV-uninfected and HIV-
conserved antigens expressed on pathogens. Binding of infected individuals. Depending of the involved organ
TLRs to these pathogen-specific ligands initiates a signal and the underlying immunological state (reflected by the
transduction pathway in the host cell that culminates in CD4 count), TB may present as a myriad of clinical syn-
the activation of NFkB and the induction of cytokines dromes ranging from asymptomatic disease to fever of un-
and chemokines that are crucial to eliciting the adaptive known origin to a fulminant presentation mimicking septic
immune response against M. tuberculosis. The sequence of shock. In general, HIV-infected patients with high CD4
the initial immune events following interaction of M. tu- counts tend to present with clinical and radiographic man-
berculosis with TLRs and other receptors is not completely ifestations of secondary TB disease similar to those seen in
understood. Nevertheless, it is clear that in the vast HIV-uninfected individuals, whereas HIV-infected patients
majority of individuals, the interaction culminates in with advanced degrees of immunosuppression are more
the development of a protective Th1 dominant immune likely to present with findings consistent with progressive
response [17]. Th1 lymphocytes are characterized by primary TB. Patients with low CD4 counts often present
expression of IL-2 and IFN-g. with atypical radiographic findings or extrapulmonary and
Several mechanisms, including induction of Th2 and disseminated TB, reflecting the inability of their immune
T-regulatory cells, contribute to host susceptibility to TB. system to contain the infection.
Th2 cells are characterized by secretion of IL-4 and IL-10.
T-regulatory cells are a distinct subset of T cells that sup-
press Th1 responses and are characterized by the cell Primary tuberculosis
surface expression of CD25, cytoplasmic expression of
FOXP3, and secretion of IL-10 and transforming growth
Occult primary tuberculosis
factor-b. TB disease and particularly disease with a poor In general, primary TB is asymptomatic in adults, and the
prognosis have been associated with increased production radiographic findings are entirely normal, primary TB be-
of IL-4 and IL-10. IL-10-secreting CD8 T cells have also ing diagnosed through the detection of tuberculin skin test
been described in anergic TB patients, and increased levels (TST) conversion. In contrast to normal hosts, HIV-infected
of CD4 CD25 regulatory T cells have been reported in patients with advanced immunosuppression are less likely
329
to have occult primary TB and are more likely to present nodes may perforate into the adjacent bronchus, causing a fis-
with symptoms that will allow clinical recognition. tula, through which the infectious caseous material can be ex-
pectorated. Clinical symptoms include low-grade fever,
productive cough with muco-purulent sputum and rarely he-
Uncomplicated primary tuberculosis moptysis. Radiologic examination is not revealing. Fistulas
Occasionally, the radiologic examination can identify ele- may be diagnosed through bronchoscopic examination,
ments of the primary complex. The primary focus (Ghon and AFB smear may be positive, allowing bacteriologic
lesion) appears as a millimetric opacity located peripher- confirmation.
ally, especially subpleural, often in the mid-lower pulmo- The spectrum of progressive primary TB includes exten-
nary fields, with a reported predilection for right lung sive lobar consolidation or bronchopneumonia, miliary
involvement. It is difficult to observe on conventional chest TB and TB meningitis, and is a syndrome clinically indistin-
X-ray and thus rarely identified. The predominant radio- guishable from secondary (active) TB. It represents a severe
graphic finding of primary tuberculosis is hilar and/or complication of primary TB, more likely to manifest in pa-
mediastinal (paratracheal) lymphadenopathy, usually uni- tients with advanced immunosuppression. The extensive
lateral (with right predilection), sometimes bilateral. On parenchymal involvement may lead to tissue destruction
contrast-enhanced CT scan, tuberculous lymph nodes, of- with cavity formation, fibrosis, and bronchiectasis, similar
ten measuring more than 2 cm, show a characteristic, but to secondary TB. Caseous bronchopneumonia evolves rap-
not pathognomonic “rim sign” consisting of a low-density idly with altered general status, fever, weight loss, produc-
center surrounded by a peripheral enhancing rim. HIV- tive cough, often with hemoptysis, and the physical exam
infected patients may have more prominent lymphadeno- may reveal findings of consolidation or show other HIV
pathy associated with primary TB. stigmata such as oral thrush or wasting. Sputum may be
The clinical manifestations associated with these radio- positive for AFB. Radiographically, there are extensive bilat-
graphic findings are subtle or absent in a host with normal eral dense, bronchopneumonic infiltrates. Miliary TB and
immunity. HIV-infected patients are more likely to have TB meningitis are discussed below.
prolonged fever and constitutional symptoms of fatigue,
anorexia, weight loss, and respiratory symptoms such as
persistent non-productive cough. The physical examina- Secondary tuberculosis
tion may reveal no abnormalities.
Pulmonary tuberculosis
Classically, the onset of post-primary pulmonary TB is in-
Primary tuberculosis with complications sidious, with non-specific constitutional symptoms such as
The primary TB complex may be associated with relatively fever, malaise, anorexia, weight loss, and nocturnal sweats
benign local complications, such as sero-fibrinous pleural that are often the earliest indicator of disease. Respiratory
effusion, epituberculosis, bronchial compression or bron- symptoms such as cough, dyspnea, or pleuritic chest pain
chial perforation by lymph nodes, complications that develop subsequently. A pattern of onset with flu-like
may regress spontaneously in the absence of advanced symptoms with fever, and upper respiratory tract conges-
immunosuppression. tion, may be more common in HIV-infected patients. An
A transient small sero-fibrinous pleural effusion associ- acute onset with hemoptysis or pleuritic chest pain is some-
ated with DTH may complicate primary TB, resolving with- times seen.
out specific treatment in patients able to develop an Cough, fever, fatigue, weight loss, and night sweats are
adaptive immune response. Patients may experience pleu- the most frequent symptoms of pulmonary TB used in clin-
ritic chest pain, and a pleural rub may be noted on the ical algorithms for TB screening in both HIV-infected and
physical exam. HIV-uninfected individuals. Several studies were con-
Epituberculosis is characterized radiographically by an ducted to determine the performance of these symptoms
extensive pneumonic opacity, related to the inflammatory in predicting the diagnosis of TB in HIV-infected patients.
changes associated with DTH and/or compression atelecta- Screening algorithms that combine multiple symptoms
sis from enlarged lymphadenopathy and with additional have demonstrated higher sensitivity, but lower specificity.
components related to bronchogenic spread. In contrast A Southeast Asian study of HIV-infected individuals has
to the extensive radiologic changes, the clinical symptoms shown that the presence of cough, fatigue, fever or weight
may be mild and include fever, cough, and dyspnea. The loss in the previous 4 weeks had a sensitivity greater than
physical findings may reveal signs consistent with lung 70% for each of the individual symptoms, with relatively
consolidation. lower specificities. However, the performance of clinical in-
Upper or middle lobe collapse due to bronchial compres- dicators was greatly increased if a combination of these
sion by enlarged lymph nodes may also be seen. Bronchial symptoms was used for TB screening [19]. Although the
stenosis may be manifested clinically by non-productive presence of cough for 2–3 weeks has traditionally served
cough, dyspnea, and localized wheezing. The enlarged lymph as a criterion for identifying the TB suspects, this duration
330
was found to have a relatively low (22–33%) sensitivity in may be best seen on apical lordotic chest radiographs or
this study, whereas a cough of any duration in the previous CT scan. HRCT scan may reveal early bronchogenic spread
4 weeks had a sensitivity greater than 70%. The combina- as 2- to 4-mm centrilobular nodules and linear branching
tion of cough of any duration, fever of any duration and opacities that represent caseous necrosis containing bacilli
night sweats lasting 3 or more weeks in the preceding 4 around terminal and respiratory bronchioles (“tree-in-
weeks was 93% sensitive for TB and had a negative predic- bud”). This pattern is not specific to mycobacterial infec-
tive value of 97%. A subsequent WHO meta-analysis of tion and may be seen in other infectious or inflammatory
12 studies that included more than 8,000 HIV-infected conditions. As the disease progresses, additional opacities
patients concluded that the absence of current cough, develop that may coalesce and include small areas of in-
fever, night sweats, and weight loss (all inclusive) had a creased lucency. These areas may establish communication
negative predictive value of 98% in a setting with TB with the tracheobronchial tree to form cavities. Aspergil-
prevalence >5% [20]. loma may form within old cavities. Coughing may result
If present, cough is usually characterized by mucopuru- in bronchogenic spread in the ipsi- or contralateral lower
lent sputum production, reflecting the expectoration of ca- lung zones (apico-caudal dissemination). There may be
seous material. If present, hemoptysis is usually mild, an associated pleural effusion or pyopneumothorax if the
manifested as bloody-streaked sputum. Moderate or severe cavities rupture into the pleural space. A marked fibrotic re-
hemoptysis may occur secondary to arterial rupture in the sponse may be associated with atelectasis of the upper lobe,
wall of a cavity (Rasmussen’s aneurysm) or in the setting of retraction of the hilum toward the apex, compensatory
bronchiectasis associated with fibrotic changes, as well as lower lobe hyperinflation, and mediastinal shift towards
secondary to the development of a mycetoma or fungus the fibrotic lung. Complete destruction of a whole lung
ball within an old cavity (aspergilloma). Occasionally, pa- can be seen in advanced cases.
tients may have dysphonia, suggesting laryngeal involve- In TB associated with HIV infection, radiographic mani-
ment, often associated with active pulmonary TB, as a festations correlate with the level of immunosuppression.
result of laryngeal contamination with highly contagious In patients with CD4 counts >350 cells/mm3, TB presents
caseous sputum. Pulmonary TB may often remain asymp- with classical radiographic findings of reactivation disease.
tomatic, particularly in the setting of HIV co-infection. In patients with fewer CD4 cells, the likelihood of atypical
The contribution of physical examination to the dia- radiographic findings increases, and up to 20% of patients
gnosis of TB is inferior to the radiologic examination. Fever, may have a normal or near-normal chest radiograph. In a
tachypnea, tachycardia, clubbing, or cyanosis may be seen. study of radiographic patterns of TB in HIV-infected pa-
The chest examination may be normal or reveal rhonchi, tients, diffused or localized infiltration were more frequent,
rales, wheezing, or altered breath sounds. Occasionally, as well as hilar or mediastinal lymphadenopathy. Pleural
amphoric (hollow, resonant) breath sounds may be heard disease, cavitation, and normal radiography were the least
in large cavitary disease. Dullness to percussion or decreased common findings [21]. However, studies conducted in
breath sounds may be present over pleural effusions. The Africa demonstrated a greater frequency of cavitation in
chest examination is often completely normal, contrasting HIV-infected patients with TB, possibly related to the high
with the advanced anatomic and radiographic abnormalities. incidence of TB in this region. Several radiographical forms
Laboratory evaluation may reveal mild leukocytosis of pulmonary TB are illustrated in Fig. 26.2.
with monocytosis. HIV-infected patients may show lym-
phopenia. Normochromic, normocytic anemia is often
associated with TB. Elevation of ESR and CRP is non- Extrapulmonary tuberculosis
specific. Hyponatremia secondary to SIADH is associated HIV infection is associated with a higher frequency of extra-
with extensive lung involvement. ABG usually shows nor- pulmonary disease, including the more serious forms, dis-
mal PaO2, except for extensive parenchymal disease or seminated (miliary) TB and TB meningitis.
miliary TB, which can be associated with hypoxia. Find-
ings of hypercapnia and respiratory acidosis can be en-
countered in the post-tuberculous syndrome or chronic Miliary TB
pulmonary TB, in relation to chronic structural lung dis- Miliary TB usually presents with fever, weight loss, night
ease. Pulmonary function testing is non-specific in active sweats, and minimal or absent localizing symptoms or signs.
TB, although a restrictive pattern with decreased DLCO Physical examination may show pathognomonic choroidal
may be seen in patients with chronic disease. tubercles in 15% of cases (bilateral, raised white-yellow pla-
Radiographically, the typical lesions are located in the ques on funduscopic examination), lymphadenopathy, and
apico-posterior lung segments or in the apical segments hepatomegaly. Chest radiograph may show multiple bilat-
of the lower lobes, most commonly manifesting as hetero- eral small opacities resembling millet seeds (miliary infil-
geneous opacities. Early stages are usually characterized by trates). The yield of sputum AFB microscopy and culture is
ill-defined areas of increased opacity often associated with low, averaging 30% and 50%, respectively, with variations
nodular and linear opacities. If the disease is minimal it across the reported series. The diagnosis can be improved
331
A B
C D
Figure 26.2 Representative chest radiographs from Ugandan HIV patients with culture-confirmed TB: (A) Left pleural effusion;
(B) right cavitary disease; (C) right lower lobe infiltrate; (D) miliary infiltrate; (E) right upper lobe infiltrate.
332
by using a combination of smear and culture from sputum, between 12% and 70%. In patients co-infected with HIV,
bronchoalveolar lavage, CSF, bone marrow, gastric aspirate the yield of pleural fluid and pleural biopsy culture may
and biopsies from multiple sites: transbronchial, pleural, be higher than in HIV-uninfected individuals with TB pleu-
bone marrow, liver or lymph nodes. In the HIV-infected risy [22]. Pleural biopsy may show granulomas in approx-
patients with advanced immunodeficiency, blood cultures imately half of the cases, and the yield is higher on pleural
are positive for M. tuberculosis in 20–40% of patients. biopsy culture. An elevated concentration (>70 U/L) of
pleural fluid adenosine deaminase (ADA) may suggest
TB meningitis the diagnosis of TB.
TB meningitis usually presents with fever, headache, and
meningismus and occasionally depressed levels of con- TB peritonitis
sciousness, diplopia or hemiparesis. Physical examination TB peritonitis may present with abdominal pain, fever,
shows stiff neck and occasionally cranial neuropathy night sweats, and weight loss. The physical examination
(nerves VI, III, IV, VII) and long tract signs. Chest radio- shows ascites, and abdominal tenderness may be present.
graph may be consistent with primary or miliary TB. Brain The classic sign is a “doughy abdomen,” because matted
imaging may show contrast enhancement over the basilar loops of bowel may be palpable. The peritoneal fluid anal-
meninges, hypodense areas consistent with infarcts, hydro- ysis reveals an exudative fluid with elevated cell count, typ-
cephalus and occasionally focal inflammatory lesions ically with lymphocytic predominance. The AFB smear is
(tuberculomas). CSF shows elevated protein level, low glu- rarely positive, and culture yield is generally low, averaging
cose concentration, and pleocytosis with lymphocytosis. 25–30%. The best method for diagnosis is a laparoscopic-
The AFB smear and culture are rarely positive, with less guided peritoneal biopsy, which has a diagnostic yield
than one-third of patients having a positive CSF smear or of 65–68% with culture and a histopathologic yield of
culture. Nucleic acid amplification tests (PCR) can be 85–97%. In areas endemic for TB and HIV, the finding of
used if available, although the use of this technology for intra-abdominal lymphadenopathy on abdominal ultra-
non-respiratory specimens has not been validated. sound or CT scan is often used to support the diagnosis
of abdominal TB.
TB lymphadenitis
The supraclavicular and posterior cervical lymph nodes are Gastrointestinal TB
most frequently involved, in contrast to scrofula due to
atypical mycobacteria or M. bovis, which usually involves The ileo-cecal area is the site most typically involved in gas-
the submandibular and high anterior cervical lymph trointestinal TB, although any other part of the gastrointes-
nodes. The lymphadenitis is not painful, and aspiration tinal tract may be affected. The patient usually presents with
of the lymph node with the finding of AFB or biopsy fever, abdominal pain, diarrhea, gastrointestinal bleeding
with findings of caseating granulomas can establish the or obstruction. Radiologic examination of the small bowel
diagnosis in 25–50% of the patients. and abdominal CT scan show involvement of the terminal
ileum resembling Crohn’s disease. The diagnosis is made
Pleural TB on clinical suspicion in areas endemic for TB and HIV or
by the finding of TB elsewhere. Occasionally intra-luminal
Pleural TB occurs by direct extension from an adjacent sub- biopsy of the terminal ileum or other involved sites is used
pleural pulmonary focus or through hematogenous seed- to establish the diagnosis.
ing. Typical presentation is the abrupt onset of fever, pleu-
ritic chest pain, and cough. Occasionally there is an
insidious presentation with fever, weight loss, and malaise. TB pericarditis
If the pleural effusion is large enough, there may be short- The usual presentation is chronic but may occasionally be
ness of breath. Physical examination shows dullness to per- subacute, with fever, night sweats, chest pain, shortness of
cussion and decreased breath sounds. Egophony is a breath, pedal edema, and other signs of right heart failure
helpful sign if present. Chest radiograph typically shows reflecting pericardial restriction. Physical examination
unilateral pleural effusion more frequently in the right shows signs of pericardial disease, right-sided heart failure
hemithorax. Bilateral disease is seen in 10% of cases. Pleu- or tamponade. Pulsus paradoxus, defined as an exaggera-
ral fluid analysis demonstrates high protein concentration, tion of the normal inspiratory fall of systolic blood
low glucose concentration, and lymphocytosis. The pres- pressure, may be an extremely helpful sign. Pericardial as-
ence of >5% mesothelial cells in the pleural fluid usually piration and biopsy are the diagnostic procedures of
argues against a diagnosis of TB pleural effusion, as the choice. Pericardial fluid is characterized by low bacterial
chronic pleural inflammation is thought to prevent the ex- burden, with frequent negative smear microscopy (yield
foliation of mesothelial cells in the pleural cavity. The AFB of 0–40% in different series) and culture (yield averaging
smear is positive in less than 10% of cases, and the yield of 50% with Lowenstein–Jensen media, higher with liquid
culture has been less than 30% in most series, with a range media or BACTEC). Histopathologic examination of
333
pericardial tissue may show caseating granulomas and/or infection with M. tuberculosis, using tuberculin skin tests
AFB, with a widely variable diagnostic yield (10–60%). (TSTs) or interferon-gamma releasing assays (IGRAs),
and the exclusion of active TB.
Renal TB
The patient may be asymptomatic or manifest dysuria, he- Tuberculin skin test
maturia, and flank pain. The diagnosis often is suggested by
the finding of sterile pyuria or hematuria as presenting ab- TST positivity is a marker of DTH directed towards antigens
normalities that trigger evaluation. Physical examination is of M. tuberculosis and other mycobacteria.
usually unremarkable. Intravenous pyelography or CT scan Until recently, the only available tool to diagnose M. tu-
shows cortical scarring, occasionally with mass or cavitary berculosis infection was TST, a well-validated, but 100-year-
lesions, papillary necrosis with caliceal and ureteral dila- old test with multiple limitations, including instability over
tion, and “beading” of the ureter due to ureteral strictures. time, poor specificity due to cross-reactivity with antigens
present in environmental mycobacteria and bacille Calm-
ette-Guérin (BCG) vaccine strains, as well as decreased sen-
Vertebral osteomyelitis
sitivity in certain clinical conditions such as advanced
The lower thoracic and lumbar vertebrae are involved most stages of HIV infection. In addition, the TST does not dis-
commonly. The disk space is initially spared, but involved tinguish TB disease from LTBI, and a single determination
later in the course of disease, with spread to adjacent verte- of TST does not indicate the time M. tuberculosis infection
brae. Paravertebral “cold abscesses” may dissect through occurred, which is important, as recent TST converters are
tissue planes. Patients present with back and sometimes at higher risk of disease progression.
radicular pain. Physical examination may show a gibbus TST is performed using the Mantoux technique, consist-
deformity due to anterior compression fractures and para- ing of the intradermal injection of purified protein deriva-
paresis may be present occasionally. Radiographic evalua- tive (PPD) or RT-23 on the inner surface of the forearm
tion of the spine including CT scan and MRI may show and measuring the induration (not erythema) 48 to 72
abnormalities in adjacent vertebrae with anterior compres- hours later.
sion or paravertebral inflammatory collections/abscesses. Interpretation of the tuberculin test depends on the
Vertebral biopsy for microbiological and histopathological epidemiological context, age, co-morbidities, and general
examination assists in the diagnosis. health of the skin-tested individuals, which could affect T
cell-mediated immunity. The tuberculin reaction can be
boosted by repeated tuberculin tests, BCG vaccination or
DIAGNOSIS infection with environmental mycobacteria. In defining a
positive TST in HIV-infected individuals, guidelines gener-
ally recommend the use of a lower cutoff, such as the pres-
The worldwide distribution of M. tuberculosis and its poten- ence of an induration 5 mm in diameter at 48 hours [25].
tial to involve most body organs should remind clinicians TST, when feasible, remains a useful tool to detect M. tu-
to keep TB in the differential diagnosis for a long list of berculosis infection. In resource-constrained settings, TST
acute, subacute, and chronic clinical syndromes. In the set- should not be a requirement for initiating IPT for people
ting of HIV the risk of TB is higher and diagnosis potentially living with HIV; however, TST-positive patients benefit
more difficult. more from IPT than those who are TST negative [24].
Diagnosis of latent TB infection (LTBI) Interferon-gamma releasing assays (IGRAs)

By definition, LTBI refers to asymptomatic M. tuberculosis IGRAs, QuantiFERON-TB Gold, QuantiFERON-TB Gold
infection with no evidence of active disease; however, the In-Tube (both from Cellestis, Victoria, Australia), and
distinction between LTBI and early TB disease may be dif- T-SPOT.TB (Oxford Immunotec, Oxford, United King-
ficult in clinical practice. The rates of subclinical TB are dom) measure the amount of IFN-g released from sensi-
higher in HIV-infected individuals [23]. Therefore, the tized human T cells after exposure to M. tuberculosis. The
WHO recommends that adults and adolescents living with development of IGRAs significantly improved the specific-
HIV should be screened for TB at every medical visit to fa- ity of the diagnosis of M. tuberculosis infection because the
cilitate either isoniazid preventive therapy (IPT) in people assay is based on early secretory antigenic target-6 (ESAT-6)
unlikely to have active TB or additional diagnostic evalua- and culture filtrate protein 10 (CFP-10) antigens which are
tion for TB in symptomatic people [24]. specific to M. tuberculosis and not present in most environ-
No direct methods for the identification of patients who mental mycobacteria or BCG strains.
are latently infected with M. tuberculosis are currently avail- A recent systematic review and meta-analysis that
able. Consequently, the diagnosis of LTBI relies on the included over 5700 HIV-infected individuals reported
quantification of immune responses induced by the that pooled sensitivity was higher for T-SPOT than for
334
QuantifERON-Gold (72 vs 61%, respectively); however, TB may also present with respiratory symptoms and a nor-
neither IGRA was more sensitive than TST [26]. The perfor- mal chest radiograph. Similarly, active pulmonary TB cannot
mance of IGRAs is decreased in HIV-infected individuals, be distinguished from inactive disease on the basis of radi-
especially if the CD4 counts are low. Other limitations in- ography alone, and readings of “fibrosis” or “scarring” do
clude the limited experience with IGRA use and the uncer- not exclude active disease.
tainty in result interpretation, especially when there is
discordance between IGRA and TST, and discordance be-
tween different IGRA types or serial IGRA results (rever- Sputum microscopy
sion/conversion). The WHO does not recommend IGRA The microscopic examination of stained sputum is the most
to screen for eligibility to receive IPT for HIV-infected pa- frequently relied upon diagnostic test, as it is feasible in
tients living in resource-constrained settings. nearly all settings, and the diagnosis of TB can be strongly
The Centers for Disease Control and Prevention (CDC) inferred by finding AFB by microscopic examination. In high
states that IGRAs can be used interchangeably with TST in prevalence areas, finding AFB in stained sputum is highly
all circumstances in which TST is indicated, including con- specific for TB and, thus is the equivalent of a confirmed di-
tact investigation, evaluation of recent immigrants who agnosis. Identification of AFB by microscopic examination
have had BCG vaccination, and TB screening of healthcare has multiple advantages: it is the most rapid method for de-
workers and others undergoing serial evaluation. The CDC termining if a person has TB, identifies persons who are
suggests that an IGRA might be preferred for testing persons at greatest risk of dying from the disease (although the
who will be unlikely to return for TST reading or those who case-fatality rate is high in smear-negative HIV-infected TB
have received BCG vaccine [27]. patients), and identifies the most likely transmitters of infec-
Although routine testing with both TST and an IGRA is tion. The main limitations of smear microscopy include its
not generally recommended, performance of both tests low sensitivity (50–60% in most studies), inability to allow
may be considered when the initial test (TST or IGRA) species identification and drug susceptibility testing, and in-
is negative in several situations associated with an increased ability to distinguish viable from dead bacteria while mon-
risk for infection, progression or poor outcome, such as itoring the response to treatment. Moreover, the prevalence
HIV infection. of smear-negative TB may vary between 30% and 50% and
increases in HIV co-infection proportional to the magnitude
of immunodeficiency [29].
Diagnosis of active pulmonary Smear-negative pulmonary TB constitutes a significant
tuberculosis public health problem leading to delays in diagnosis, over-
or under-treatment and increased M. tuberculosis transmis-
Clinical symptoms sion. A diagnosis of smear-negative pulmonary TB can be
Several studies evaluated the performance of different clin- made if two sputum specimens are smear-negative but
ical predictors of TB and proposed symptom-based algo- chest radiography findings suggest TB and the clinician de-
rithms for TB screening in people living with HIV, as cides to treat with a full course of TB therapy. Response to
discussed above. TB screening is potentially relevant to therapy may provide confirmatory evidence. In addition, a
the diagnosis of active TB, but also to exclude TB in candi- diagnosis of smear-negative TB can be established if a pa-
dates for preventive therapy. tient with AFB smear-negative sputum has a culture positive
At extremely high TB prevalence rates, symptomatic for M. tuberculosis.
screening is inadequate and ideally should be supplemen- The probability of finding AFB in sputum smears by mi-
ted with sputum culture. In this setting, consideration croscopy is directly proportional to the density of bacilli in
should be given to empirical TB treatment, particularly if the sputum. Sputum microscopy is likely to be positive
ART is to be initiated, given the inherent risk of “unmasking when there are at least 5000–10,000 organisms/mL of spu-
TB,” as discussed below. tum. At densities below 1000 organisms/mL of sputum, the
chance of observing AFB in a smear is less than 10%. In
contrast, properly performed culture can detect far lower
Chest radiography numbers AFB (detection limit is 100 organisms/mL).
Chest radiography is a sensitive but non-specific test to de- Several studies have examined the optimum number of
tect pulmonary TB. Radiographic examination of the thorax sputum specimens to establish a diagnosis of pulmonary
may be useful to identify persons for further evaluation, but TB. It has been conclusively shown that microscopy of
a diagnosis of TB should never be established by radiogra- two consecutive sputum specimens identifies the vast ma-
phy alone. Reliance on the chest radiograph as the only di- jority (95–98%) of smear-positive TB patients, whereas a
agnostic test for TB will result in both over-diagnosis and third sputum specimen adds minimally to the diagnosis.
missed diagnosis of TB. HIV-infected patients who present Therefore, in 2007 the WHO recommended reduction in
with an abnormal chest radiograph but no respiratory symp- the number of specimens examined from three to two, in
toms may still have significant pulmonary disease [28]. settings of good quality of microscopy.
335
Fluorescence microscopy, in which auramine-based has been confirmed, additional first- and second-line drug
staining causes the AFB to fluoresce against a dark back- susceptibility results should be obtained. The WHO recom-
ground, may be 10% more sensitive than conventional mends several non-commercial culture and DST methods
Ziehl–Neelsen (ZN) staining with light microscopy and such as microscopically observed drug susceptibility
have equivalent specificity. These characteristics make fluo- (MODS), nitrate reductase assay (NRA), and colorimetric
rescence microscopy a more accurate test, although the in- redox indicator (CRI) methods to be used in resource-
creased cost and complexity make it less applicable in many constrained settings in patients suspected of having
settings. MDR-TB. In general, these methods are not subjected to op-
Light-emitting diode (LED) microscopy is a novel diag- timal levels of standardization and quality control.
nostic tool that has demonstrated accuracy equivalent to
international reference standards, increase in sensitivity
6% over conventional ZN microscopy, and qualitative, op-
erational and cost advantages relative to both conventional Nucleic acid amplification tests (NAATs)
fluorescent and ZN microscopy. Multiple NAATs have been developed to detect mycobacte-
rial nucleic acid using polymerase chain reaction (PCR)
amplification, molecular beacons, transcription-mediated
Mycobacterial culture amplification (TMA), strand displacement amplification
Mycobacterial culture also improves TB detection, increas- (SDA), ligase chain reaction (LCR) amplification, and
ing the number of diagnosed cases by 30–50%. Conven- loop-mediated isothermal amplification (LAMP).
tional drug susceptibility testing (DST), in turn, allows a Conventional NAATs have been used for several years,
definitive diagnosis of drug-resistant TB. and they have high specificity, but limited sensitivity, espe-
Traditional solid culture media (Lowenstein–Jensen or cially for smear-negative pulmonary TB and for non-
Ogawa) are more sensitive than AFB microscopy, but re- respiratory specimens. The accuracy of both commercial
quire from 2–3 weeks to several months to yield colonies and non-commercial (in house- or “home brew”) assays
of M. tuberculosis and may have a high rate of contamina- was found to be highly variable in meta-analyses.
tion. Other solid media techniques (7 H9, 7 H10, and CDC recommends that NAAT be performed on at least
7 H11) have lower contaminations rates but are, in general, one respiratory specimen from each patient with suspected
too onerous for low-income laboratory settings. Newer liq- TB to aid in the initial diagnosis, and in persons for whom
uid culture automated systems for mycobacteria detection the test result would alter case management or TB control
and susceptibility testing can provide faster culture results activities [30].
(7–21 days) and are currently considered the gold-standard The newly approved Xpert MTB/RIF assay (Cepheid,
approach for isolating mycobacteria. The most commonly Sunnyvale, CA, USA) is a fully automated NAAT platform
used automated liquid culture systems are BACTEC 460 TB that can simultaneously detect TB and rifampicin resis-
which detects radiolabeled CO2 from replicating mycobac- tance. A validation study involving over 1,700 individuals
teria and the BACTEC MGIT 960 system which relies on a with suspected TB showed a sensitivity of 98.2% for smear-
fluorescent, non-radiometric method (both from Becton positive, culture-confirmed cases with a single test and
Dickinson, Franklin Lakes, NJ, USA). Other non-radiometric 90.2% for smear-negative cases with 3 tests, with a specific-
automated liquid culture systems include the BacT/ALERT ity of 99.2%. The test correctly identified 97.6% of rifampi-
MB system (bioMerieux Inc., Durham, NC, USA) and the cin-resistant bacteria [31]. The assay allows identification
VersaTREK system (Trek Diagnostic Systems, West Lake, of M. tuberculosis and detects resistance to rifampicin within
OH, USA). Studies have shown that liquid systems 90 minutes, is not prone to cross-contamination, requires
increase the yield by 10% compared with solid media minimal biosafety, and offers multiple advantages over
and significantly reduce time to results. For DST, the delay conventional NAATs. In 2010, the WHO endorsed this test,
may be reduced to 10 days, compared to 28–42 days strongly recommending its use as the initial diagnostic test
with conventional solid media. The WHO endorses the in individuals suspected of MDR-TB or HIV-TB. The limita-
use of liquid TB culture and drug susceptibility testing in tion is cost of the equipment and the sputum cartridges.
low-resource settings.
DST techniques include phenotypic methods on solid
and liquid media (culturing M. tuberculosis in the presence
of anti-TB drugs to detect growth which indicates drug Line probe assays (LPAs)
resistance) and genotypic methods that identify specific LPAs are used for molecular detection of drug resistance
molecular mutations associated with resistance against in- from smear-positive specimens or cultures, allowing the de-
dividual drugs. DST is most accurate for rifampicin and iso- tection of resistance to rifampicin, isoniazid, fluoroquino-
niazid and less reliable and reproducible for streptomycin, lones, aminoglycosides or ethambutol. In 2008, WHO
ethambutol and pyrazinamide. Rifampicin resistance is endorsed the use of LPAs for rapid detection of MDR-TB
a valid and reliable indicator of MDR-TB. Once MDR-TB at the country level.
336
Phage-based assays All recommendations comprise two phases. WHO-recom-

mended treatment regimens are summarized in Table 26.1.
Phage-amplification assays have high specificity, but lower
For smear-positive pulmonary TB patients treated with
sensitivity for the diagnosis of active pulmonary TB and can
first-line drugs, sputum smear microscopy may be per-
be used for the detection of rifampicin resistance on culture
formed at completion of the intensive phase of treatment:
isolates. However, studies evaluating this technology have
the end of the second month for the 6-month regimen or
shown inconsistent results.
the end of the third month for the 8-month retreatment
regimen (conditional/high and moderate grade of evi-
dence). If the specimen obtained at the end of the second
Serologic, antibody detection tests
month is smear-positive, sputum smear microscopy should
Available serologic tests have shown inconsistent results be obtained at the end of the third month (strong/high
and thus are of low clinical value. Marketing and use of grade of evidence) and, if positive, sputum culture and
sub-standard serodiagnostics in some resource-limited DST should be performed (strong/high grade of evidence).
environments is problematic. The available evidence shows that sputum positivity at the
end of the intensive phase is a poor predictor of relapse and
failure in individual patients. Therefore, the WHO is no
Antigen detection tests longer recommending the extension of the intensive phase
Studies evaluating the detection of urinary lipoarabino- if a positive sputum smear is found at completion of the in-
mannan (LAM), a lipoglycan in the mycobacterial cell wall, tensive phase in patients treated with a regimen containing
found variable test performance. However, recent data sug- rifampicin throughout treatment (strong/high grade of ev-
gest that LAM performance may be better in HIV-infected idence). However, the WHO continues to recommend per-
individuals. It may have a place in the diagnosis of TB in forming smear microscopy at this stage because a positive
the setting of advanced immunodeficiency. smear should trigger an assessment of the patient, as well as
additional sputum monitoring.
The WHO recommends obtaining sputum specimens
Serum biomarkers for smear microscopy at the end of months 5 and 6 for
all new pulmonary TB patients who were smear-positive
There is an enormous need for biomarkers for TB, such as at the start of treatment. Patients whose sputum smears
biomarkers that predict protection induced by vaccination, are positive at month 5 or 6 are considered to have failed
distinguish between latent or active disease or predict retreatment.
lapse or durable cure. Unfortunately, clinically relevant Previously treated TB is a strong risk factor for resistance,
biomarkers are not currently available. A recent study 15% of previously treated TB patients having MDR-TB at a
reported the identification of a gene expression signature global level. For previously treated patients, the WHO rec-
dominated by a neutrophil-driven IFN-inducible gene pro- ommends performing culture and DST for at least isoniazid
file that differentiates between latent and active TB [32]. Re- and rifampicin before the start of treatment. In settings
search on biomarkers needs additional evaluation and where rapid molecular-based DST is available, the results
validation, especially in people living with HIV. should guide the choice of regimen, whereas in settings
where testing is not routinely available, empirical treatment
should be started. TB patients whose treatment has failed or
other patient groups with high likelihood of MDR-TB
TREATMENT should be started on an empirical MDR regimen, in accor-
dance with country-specific resistance data. Empirical regi-
The treatment of TB focuses on both the patient and the mens for MDR-TB are often inadequate, contributing to
community and should be designed to cure the patient with- disease progression and propagation of drug-resistant dis-
out relapse, prevent transmission to others, and prevent the ease. TB patients returning after defaulting or relapsing from
development of resistant organisms. The decision to initiate their first treatment course may receive the retreatment reg-
anti-tuberculous therapy should be based on clinical and ra- imen containing first-line drugs 2HRZES/1HRZE/5HRE
diographic findings and epidemiological data. It is some- (H ¼ isoniazid, R ¼ rifampicin, Z ¼ pyrazinamide, E ¼ eth-
times necessary to initiate treatment before the results of ambutol, S ¼ streptomycin) if country-specific data show
smear and culture are known, particularly in high HIV prev- low or medium levels of MDR in these patients.
alence settings, where the prevalence of smear-negative TB is Patients with extrapulmonary TB should be treated with
increased. The threshold for initiation of empirical therapy the same regimen as patients with pulmonary TB. Some ex-
must be low in patients with potentially life-threatening in- perts recommend 9–12 months of treatment for TB menin-
fections such as meningitis, pericarditis, and miliary disease. gitis given the serious risk of disability and mortality, and 9
Several national and international organizations have months of treatment for TB of bones or joints because of
recommended treatment regimens for TB [33, 34]. the difficulties of assessing treatment response. Unless drug
337
Table 26.1 WHO-recommended treatment regimens
TREATMENT CATEGORY TREATMENT COMMENTS (GRADE OF EVIDENCE)
Intensive Continuation
phase phase
New TB (presumed, or known, to 2 months of 4 months of Optimal (strong/high grade of evidence)

have drug-susceptible TB) HRZEa daily HRb daily
2 months of 4 months of Acceptable alternative provided that the patient

HRZEa daily HRb three times is receiving directly observed therapy
per week (conditional/high or moderate grade of evidence)
2 months of 4 months of Acceptable alternative provided that the patient

HRZEa three HRb three times is receiving directly observed therapy and is not
times per week per week living with HIV or living in an HIV-prevalent
setting (conditional/high or moderate grade of
evidence)
Retreatment regimen with first-line 2 months of 5 months of Regimen should be modified once DST results are
drugs (relapse or default/low or HRZES and 1 HRE available
medium likelihood of MDR) month HRZE
MDR regimen (failure/high Empirical MDR regimen (country Regimen should be modified once DST results are
likelihood of MDR) specific) available
H ¼ isoniazid, R ¼ rifampicin, Z ¼ pyrazinamide, E ¼ ethambutol, S ¼ streptomycin.

a
In tuberculous meningitis, ethambutol should be replaced by streptomycin (2 months of HRZS in the intensive phase)
b
In populations with known or suspected high levels of isoniazid resistance, new TB patients may receive HRE as therapy in the continuation phase
as an acceptable alternative to HR (Weak/Insufficient evidence, expert opinion).
Based on World Health Organization. Treatment of tuberculosis guidelines-Fourth edition [online]. 2010. Available from— http://whqlibdoc.who.
int/publications/2010/9789241547833_eng.pdf
resistance is suspected, adjuvant corticosteroid treatment is woman who has TB should receive a full course of TB treat-
recommended for TB meningitis and pericarditis. ment and she can continue to breastfeed. After active TB is
The first-line drugs should be employed preferentially; excluded, the baby should receive 6 months of IPT, fol-
the use of second-line therapies should be restricted to pa- lowed by BCG vaccination. Most anti-TB drugs are safe
tients with documented resistance or patients with limiting for breastfeeding and are not significantly concentrated
conditions. The recommended dosing for the first- and sec- in breast milk.
ond-line drugs is presented in Table 26.2 and Table 26.3,
respectively. Discussion of the treatment of MDR-TB is
Liver disease
complex and beyond the scope of this chapter. It should
be restricted to referral treatment centers. The presence of concomitant liver disease has to be eval-
uated before TB treatment is initiated. Whereas hepatotox-
icity due to isoniazid is more likely as age increases, this
should not preclude treatment of TB. Any signs of liver
Treatment of TB in special toxicity should be investigated promptly. WHO re-
populations commends reducing the number of hepatotoxic drugs in
patients with advanced or unstable liver disease. Guide-
Pregnancy or breastfeeding lines recommend monitoring of liver enzymes in all
The WHO recommends the treatment of TB in pregnant patients with pre-existing liver disease (viral hepatitis, alco-
women using isoniazid, rifampicin, pyrazinamide, and holism, etc.). If a patient with liver failure requires treatment
ethambutol, whereas US guidelines do not recommend for TB, ethambutol, streptomycin, and a fluoroquinolone
pyrazinamide unless there is no alternative. Streptomycin may be used. The most important risk factor for isoniazid-
is ototoxic to the fetus and should not be used during preg- induced hepatotoxicity is alcohol consumption. Patients
nancy. The risks of untreated TB in a pregnant woman far receiving isoniazid should be counseled to abstain from
outweigh the risks of the medications. A breastfeeding alcohol use.
338
Table 26.2 Routes of administration, normal and adjusted doses for first-line TB drugs in adults and children
DRUG ROUTE NORMAL DOSES ADJUSTED DOSES
Daily dose (range) Three times per week
Children Adults Max Children Adults Max Renal Hepatic

mg/kg mg/kg mg mg/kg mg/kg mg impairment impairment
(range) (range) (range) (range)
Isoniazid p.o, i.m, 10 5 300 10 10 900 No change No change

i.v. (10–15) (4–6) (8–12)
Rifampicin p.o, i.v. 15 10 600 10 10 600 No change No change,

(10–20) (8–12) (8–12) frequent
monitoring
Rifabutin p.o — 5 300 — 5 300 No change No change,

frequent
monitoring
Pyrazinamide p.o. 35 25 — 35 35 — 25–35 mg/ No change,

(30–40) (20–30) (30–40) kg 3/week, frequent
not daily if monitoring
creatinine
clearance
<30 mL/min
Ethambutol p.o. 20 15 — 30 30 — 15–25 mg/ No change

(15–25) (15–20) (25–35) kg 3/week,
not daily if
creatinine
clearance
<70 mL/min
Streptomycin i.m, i.v. NR 15 NR 15 1000 15 mg/kg No change

(12–18) (12–18) 3/week,
not daily
Based on American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of Tuberculosis [online]. 2007. Available from:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm#tab15 and World Health Organization. Treatment of tuberculosis guidelines, 4th
edn [online]. 2010. Available from: http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf
Renal disease established neuropathy, higher doses of pyridoxine should

be used for neuropathy treatment (75–100 mg/day).
Isoniazid, rifampicin, and pyrazinamide are metabolized by
the liver and thus safe to use in patients with renal disease.
Ethambutol is excreted through urine and consideration New drugs
should be given to replacing it with a second-line drug.
Streptomycin should be avoided in patients with renal fail- Fluoroquinolones
ure because of nephrotoxicity. Patients should receive their Several fluoroquinolones, such as ciprofloxacin, levofloxa-
medications after hemodialysis. Patients with renal disease cin; and ofloxacin, have been used as second-line drugs for
are at risk for neuropathy and should receive pyridoxine. the treatment of MDR-TB. Gatifloxacin and moxifloxacin,
the most recently developed fluoroquinolones showed bet-
ter in vitro activity against M. tuberculosis than the older
Pyridoxine
compounds and better rates of sputum conversion at 2
All patients with HIV infection, diabetes, renal failure, malnu- months when substituted for ethambutol or isoniazid in
trition, pregnant and breastfeeding women, and persons with phase 2 trials; they are being evaluated in phase 3 trials
seizures should receive pyridoxine 25 mg/day for prevention for possible use in treatment of drug-susceptible TB to
of neuropathy while receiving isoniazid. In patients with shorten duration of therapy to 4 months.
339
Table 26.3 Routes of administration, normal and adjusted doses for the second-line TB drugs in adults and children
DRUG ROUTE NORMAL DOSES ADJUSTED DOSES
Daily dose (range)
Children Adults (usual Max Renal Hepatic

dose) impairment impairment
Cycloserine p.o. 10–15 mg/ 10–15 mg/kg/day 1000 mg Contraindicated No change

kg/day (500 mg twice if creatinine clearance
daily) <50 mL/min unless on
hemodialysis
500 mg/dose, 3/week
if on hemodialysis
Ethionamide, p.o. 15–20 mg/ 15–20 mg/kg/day 1000 mg 250–500 mg daily if No change,
prothionamide kg/day (500–750 mg daily creatinine clearance but use with
or 2 divided doses) <30 mL/min or on caution
hemodialysis
Amikacin, i.m, i.v. 15–30 mg/ 15 mg/kg/day 1000 mg 12–15 mg/kg/dose, No change
kanamycin kg/day 3/week, not daily
Capreomycin i.m, i.v. 15–30 mg/ 15 mg/kg/day 1000 mg 12–15 mg/kg/dose, No change
kg/day 3/week, not daily
P-aminosalicylic p.o. 200–300 mg/ 8–12 g/day (4 g Contraindicated in severe No change

acid kg/day in 2–4 thrice daily) renal impairment unless
divided doses on hemodialysis
4 g twice daily after
hemodialysis
Levofloxacin p.o, i.v. NR 500–1000 mg/day 750–1000 mg/dose, No change

3/week, not daily
Moxifloxacin p.o. NR 400 mg/day Decrease dose/increase No change

interval
Gatifloxacin p.o. NR 400 mg/day Decrease dose/increase No change

interval
Based on American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of Tuberculosis [online]. 2007. Available from:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm#tab15
Diarylquinolines resistant strains of M. tuberculosis. In addition, nitroimida-

zoles are active against replicating and non-replicating bac-
TMC 207 is a new ATP-synthase inhibitor that was shown
teria, suggesting their potential to shorten the duration of
to be highly potent against both drug-susceptible and drug-
treatment for active disease and a possible role in the man-
resistant strains of M. tuberculosis. The agent showed favor-
agement of latent infection. Two nitroimidazoles are in
able 2-month culture conversion rates for MDR-TB therapy
phase 2 clinical development: OPC-67683 and PA-824.
in a phase 2 trial. The second stage of the study is in pro-
gress to evaluate the microbiological outcomes at 6 months
with the addition of TMC 207 to the individualized treat-
ment for MDR-TB. Ethylenediamines
SQ-109 is a derivative of ethambutol that inhibits myco-
bacterial cell wall synthesis and acts synergistically with iso-
Nitroimidazoles niazid and rifampicin, suggesting its potential to shorten
Nitroimidazoles are agents that exert their antimycobacter- the duration of TB treatment. The compound has demon-
ial activity through a novel mechanism of bioreduction, strated excellent in vitro activity against drug-susceptible
shown to be active against drug-susceptible and drug- and drug-resistant bacteria, including XDR-TB, as well as
340
potent in vivo activity against pulmonary TB. A phase 2 trial A study of 91 patients in Botswana (68% HIV-infected)
for treatment of drug-susceptible pulmonary TB is currently found low serum drug concentrations in a significant pro-
recruiting subjects. portion of patients undergoing TB treatment: rifampicin
(78%), isoniazid (30%), and ethambutol (41%). Only
1% of patients had low levels of pyrazinamide. Impor-
Oxazolidinones tantly, 26% had low plasma levels of both rifampicin
Linezolid has modest in vitro activity against M. tuberculosis, and isoniazid, a factor that may contribute to poor out-
exerting its effect through the inhibition of ribosome syn- comes and the emergence of resistance in a clinical set-
thesis. It has been used off-label in combination regimens ting [36]. Clinical studies of high-dose rifampicin are
for the treatment of MDR-TB, but its effectiveness remains planned.
uncertain. It is presently evaluated in two distinct phase 2
trials for treatment of XDR-TB and MDR-TB. A close ana-
logue of linezolid, PNU-100480, demonstrated slightly Co-administration of TB and
better activity in vitro and significantly improved bacteri- HIV treatment
cidal activity in vivo when added to first-line TB drugs or
used in combination with moxifloxacin and pyrazinamide The rifamycins are a key component of TB regimen, but
and a phase 2 trial for treatment of drug-susceptible TB is their use in patients with HIV co-infection is complicated
under way. by drug interactions with ART. Rifampicin, a potent stimu-
lator of the cytochrome P450 CYP3A4 system is prone to
drug–drug interactions with several antiretroviral drugs in-
Rifamycins cluding non-nucleoside reverse transcriptase inhibitors
Rifamycins are potent inhibitors of bacterial RNA polymer- (NNRTIs) and protease inhibitors (PIs). Nucleoside reverse
ase. Rifapentine is a more potent analogue of rifampicin transcriptase inhibitors (NRTIs) are not metabolized by the
and has a longer half-life, characteristics that make it an at- cytochrome P450 system and thus are not susceptible to
tractive candidate for shortening the duration of treatment drug interactions with the rifamycins. Rifampicin is also
and for intermittent treatment. In a trial of once-weekly a potent inducer of UGT1A1 involved in the metabolism
rifapentine and isoniazid in the continuation phase of of raltegravir, an HIV-integrase inhibitor, and therefore
treatment, efficacy was suboptimal, especially in HIV- has the potential to reduce raltegravir concentrations.
infected patients who were at increased risk of relapse sec- The preferred first-line ART in treatment-naive adults
ondary to acquired rifamycin resistance. Several phase 2 with HIV-TB co-infection is zidovudine/lamivudine/efavir-
trials are in progress to assess the effects of daily rifapentine enz or tenofovir/emtricitabine/efavirenz. In patients start-
in the intensive phase of treatment from the perspective of ing ART while on TB treatment, the preferred NNRTI is
shortening treatment of drug-susceptible TB. efavirenz because of less drug interaction with rifampicin
A number of other novel TB drugs are in preclinical compared with nevirapine. For co-infected individuals
development. who are unable to tolerate efavirenz, a nevirapine-based
regimen is an alternative. Similarly, a triple NRTI regimen,
either zidovudine/lamivudine/abacavir, or zidovudine/
Special issues of treatment lamivudine/tenofovir, can be administered safely with stan-
dard TB therapy as an acceptable alternative when efavirenz
in HIV-infected individuals
cannot be used. However, this strategy should be weighed
Rifamycins are a key component of anti-tuberculous treat- against the risk of HIV drug resistance to NRTIs resulting
ment in HIV-infected patients. A systematic review of treat- from suboptimal virologic suppression, as triple NRTI reg-
ment of TB in the setting of HIV co-infection found lower imens have been shown to be inferior to NNRTI or PI-based
relapse rates in people living with HIV treated with 8 or regimens. Other triple NRTI regimens (abacavir/lamivudine/
more months of rifampicin-containing regimens compared tenofovir or tenofovir/didanosine/lamivudine) have demon-
with using 2 months of rifamycin [35]. The review showed strated unacceptably high rates of virologic failure and should
that, compared with daily therapy in the initial phase, not be used.
thrice-weekly therapy was associated with higher rates of If rifabutin is available, the second-line ART regimens for
failure and relapse. co-infected patients include the same agents used in adults
Rifapentine, a long-acting rifamycin, is not recom- without TB, such as an NRTI backbone tenofovir/emtricita-
mended in HIV-infected patients due to increased risks of bine or zidovudine/lamivudine and a ritonavir-boosted PI
development of drug resistance. such as atazanavir/ritonavir or lopinavir/ritonavir. With PI
Thiacetazone should never be given to HIV-infected use, the dose of rifabutin should be adjusted as recom-
patients because of its diminished efficacy and association mended below. If rifabutin is not available, second-line
with severe skin reactions. ART will include same NRTI backbones recommended
Low serum concentrations of antimycobacterial drugs in for adults plus lopinavir/ritonavir or saquinavir/ritonavir
HIV-infected patients may contribute to treatment failures. with adjusted doses of ritonavir.
341
Drug–drug interactions Rifabutin and ART

Rifampicin and efavirenz Rifabutin has similar in vitro antituberculous activity to ri-
fampicin, with less potential for drug–drug interactions,
Rifampicin causes an approximately 20% decrease in efa- and is currently recommended for the treatment of TB in
virenz concentration, which led some authorities to recom- HIV when available. The PIs, particularly if boosted with ri-
mend increasing the dose of efavirenz from 600 to 800 mg tonavir, increase serum concentrations of rifabutin; there-
daily in patients concomitantly treated with rifampicin. fore, the dose of rifabutin should be decreased from
The optimal dose of efavirenz in the presence of rifampi- 300 mg daily to 150 mg three times per week when used
cin-containing therapy remains controversial; however, with PIs. There is some concern for development of resis-
there is insufficient evidence to support increasing efavir- tance to rifabutin when the rifamycin is being administered
enz dose in this setting and CDC recommends the use of at the reduced dose of 150 mg three times a week, and some
standard dose of efavirenz in patients with HIV-related clinicians prefer to administer rifabutin at a dose of 150 mg
tuberculosis [37]. daily. Some experts recommend monitoring rifabutin se-
rum concentrations in patients taking PIs [38]. If rifabutin
is administered with efavirenz, the rifabutin dose is in-
Rifampicin and nevirapine creased to 450–600 mg daily. The pharmacokinetics of
the nevirapine/rifabutin interaction are favorable, and this
Rifampicin decreases serum concentrations of nevirapine would be a preferred combination. There are no data on
by 20–55%, and some investigators have suggested using combined use of rifabutin and either maraviroc, raltegravir
an increased dose of nevirapine in patients on rifampicin; or etravirine.
however, an increased risk of nevirapine hypersensitivity
was observed in patients receiving higher doses of nevira-
pine. Therefore, the CDC recommends the use of the stan-
dard dose of nevirapine in patients on rifampicin, starting Immune reconstitution inflammatory
with 200 mg daily for 2 weeks (lead-in dosing), followed syndrome (IRIS)
by 200 mg twice daily [37]. Although it has been suggested
that efavirenz should be preferred over nevirapine for eligi- IRIS comprises two distinct syndromes: paradoxical IRIS
ble patients if both NNRTIs are available, nevirapine-based and unmasking IRIS. Paradoxical IRIS refers to worsening
ART remains a reasonably effective option if efavirenz TB in patients started on ART (TB diagnosed prior to start-
administration is contraindicated. ing ART). Unmasking IRIS refers to a new presentation of
TB within 3 months after ART initiation, with heightened
intensity of clinical manifestations and excessive inflam-
matory response.
Rifampicin and protease inhibitors Major and minor criteria common to both syndromes
Rifampicin decreases serum concentrations of indinavir, have been defined; the diagnosis of IRIS requires one major
lopinavir, atazanavir boosted with standard dose of ritonavir and two minor criteria. Major criteria refer to new or wors-
(100 mg) by >90%, rendering them ineffective. Therefore, ening lymphadenopathy, new or worsening radiologic fea-
administration of standard doses of PIs with rifampicin is tures of TB, CNS TB or serositis (pleural effusion, ascites, or
contraindicated. The effects of rifampicin on serum concen- pericardial effusion). Minor criteria include new or worsen-
trations of PIs can be overcome with high doses of ritonavir ing constitutional symptoms including fever, respiratory
(400 mg twice-daily, “super-boosted” lopinavir or saquina- symptoms or abdominal pain associated with peritonitis,
vir) or by doubling the dose of co-formulated protease in- hepatomegaly, splenomegaly, or abdominal lymphade-
hibitors such as lopinavir/ritonavir (800/200 mg ritonavir nopathy. Although not part of the consensus diagnosis
twice daily). However, this approach is associated with high criteria, a rapid decline in HIV RNA and an increase in
rates of hepatotoxicity and gastrointestinal intolerance the CD4 count in response to ART are two factors clearly
and should only be used with close clinical and laboratory associated with IRIS. Patients typically develop TB-IRIS
monitoring [37]. symptoms 2–4 weeks after starting ART. IRIS can manifest
with different levels of severity. The duration of IRIS symp-
toms is typically 2–3 months, although there were reports
of IRIS symptoms lasting more than 1 year. IRIS remains a
Rifampicin and other antiretroviral agents diagnosis of exclusion, as similar symptoms may reflect
Rifampicin decreases the trough concentrations of etravir- progression of TB disease or treatment failure as a result
ine, raltegravir, and maraviroc, and caution is advised when of TB drug resistance or poor adherence, drug toxicity or
rifampicin is co-administered with these antiretroviral the development of a new opportunistic infection or malig-
agents given the limited clinical experience. nancy. Clinicians should screen for TB prior to ART
342
initiation, because patients with severe immunosuppres- reduced by 56% when ART was initiated before completion
sion may have subclinical, unrecognized active TB and de- of TB therapy (integrated versus sequential therapy). The
velop unmasking IRIS during early ART. mortality benefit was observed in both patients with
Although the immunopathogenesis of IRIS remains in- CD4 count <200/mm3 and CD4 count >200/mm3, suggest-
sufficiently characterized, it is generally thought that both ing that ART should not be deferred until TB treatment is com-
forms of TB-IRIS result from increased recognition of my- pleted; however, integrated therapy was associated with
cobacterial antigens by a recovering immune system. IRIS higher risk of IRIS [42]. Additional results from the SAPiT
appears to be a predominantly CD4-mediated phenome- study comparing the early ART (within 4 weeks of starting
non, with reconstituting T cells showing evidence of TB therapy) versus late ART (within 4 weeks of completing
increased activation from antigenic exposure. the intensive phase of TB treatment) showed a 68% reduction
The risk of both forms of IRIS is higher with lower CD4 in AIDS-defining illness and death rate with early integrated
counts, shorter interval between the initiation of TB ther- therapy in patients with CD4 counts < 50 cells/mm3 [43].
apy and the initiation of ART and extrapulmonary and dis- The analysis showed no significant differences in these out-
seminated TB [39]. The incidence of TB-IRIS was 15.7%, comes between the two arms for patients with CD4 counts
and mortality of IRIS-associated TB was 3.2% in a recent >50 cells/mm3.
systematic review [40]. The CAMELIA study (Cambodian Early Versus Late In-
In general, IRIS can be managed with NSAIDs or cortico- troduction of Antiretrovirals) found a mortality benefit in
steroids, and interruption of ART is not recommended, but starting ART 2 weeks after TB treatment initiation versus
may be considered with life-threatening TB-IRIS, such as in 8 weeks later in AFB smear-positive, HIV-infected patients
cases of severe neurological involvement. A randomized with CD4 counts less than 200 cells/mm3. Late ART in-
controlled clinical trial of prednisone (1.5 mg/kg/day for creased mortality by 52% in a multivariate analysis. The
2 weeks then 0.75 mg/kg/day for 2 weeks) in patients with majority of subjects in the CAMELIA trial had an average
paradoxical TB-IRIS in South Africa showed a reduced du- CD4 count of 25 cells/mm3. Earlier initiation of ART was
ration of hospitalization and a more rapid clinical and ra- associated with an increased rate of IRIS; however, early ini-
diographic improvement in the steroid-treated group [41]. tiation of ART appeared to decrease mortality in patients
The role of corticosteroids in unmasking TB has not been with advanced HIV disease [44].
defined. An international randomized clinical trial (A5221
A recent randomized controlled trial reported a greater STRIDE study) compared the strategy of immediate (within
than threefold risk of IRIS when ART was initiated during 2 weeks) versus early (8–12 weeks) initiation of ART in
TB therapy versus sequential treatment for TB and HIV HIV-infected patients with TB and CD4 counts <250
(12.4 vs 3.8%, respectively) [42]. Despite increased inci- cells/mm3 and found a significant reduction in AIDS-
dence of IRIS in patients receiving concurrent TB and related death with immediate ART (15.5 vs 26.6%) at 48
HIV treatment, the risk of death was significantly lower with weeks in the group of HIV-infected patients with CD4
integrated versus sequential therapy, and new evidence counts <50 cells/mm3 [45]. The study showed no signifi-
supports early initiation of ART. cant difference in AIDS-defining illness and death with im-
mediate versus early ART for patients with higher CD4
counts. These findings, together with the recent data from
the SAPiT trial, support the initiation of ART immediately
Timing of ART initiation
after starting TB therapy in patients with CD4 counts
The decision regarding the optimal time to start ART during < 50 cells/mm3. However, the same studies suggest that ini-
TB treatment must balance the risks of overlapping toxic- tiation of ART could be deferred to the start of the contin-
ities, drug interactions, and development of IRIS with early uation phase of TB treatment (8–12 weeks) in patients with
initiation of ART against the risks of increased mortality CD4 counts >50 cells/mm3. Pending the official recom-
and development of other opportunistic infections with mendations, the determination of the optimal timing for
delayed ART. The current WHO guidelines recommend ART initiation should rely on the current evidence and clin-
starting TB treatment first, followed by ART as early as ical judgment, balancing the risks of AIDS progression/
possible after starting TB treatment. death against risks of IRIS and cumulative drug toxicities.
Findings of recent randomized controlled studies sup-
port early initiation of ART in patients with TB. The South
African SAPiT trial (Starting Antiretroviral Therapy at Three Mortality in HIV-associated
Points in Tuberculosis Therapy) compared three different
tuberculosis
strategies of starting ART in smear-positive TB patients with
CD4 counts between 0 and 500 cells/mm3: during the in- HIV-infected individuals who develop TB are at higher risk
tensive phase of TB treatment, after the intensive phase, and of dying during treatment for TB than patients with TB
after completing TB treatment. Mortality was significantly without HIV infection, the death usually being secondary
343
to complications of HIV infection rather than to TB itself. Therefore, the WHO recommends INH as the drug of
The mortality is higher in the group of HIV-infected pa- choice for chemotherapy to prevent TB in adults living
tients with smear-negative pulmonary and extrapulmonary with HIV, administered at a dose of 300 mg/day in adults
TB, reflecting their more advanced degree of immunosup- and 10 mg/kg/day in children more than 12 months of
pression. The impact TB has on the mortality of HIV-infected age [24].
individuals is higher at lower CD4 counts. Moreover, people The WHO strongly recommends a minimum of 6
living with HIV who develop TB have an approximately months of IPT, regardless of the degree of immunosuppres-
twofold greater risk of death from all causes compared with sion. Recognizing the potential benefit of extended IPT,
HIV-infected patients without TB [46]. and preliminary data from the CDC-Botswana trial, the
ART reduces the mortality risk of HIV-infected patients with WHO conditionally recommends 36 months of IPT for
TB by 64–95%, substantially improving the prognosis [47]. people living with HIV in settings with high TB prevalence
Therefore, the WHO recommends ART for all HIV-infected pa- and transmission. The CDC recommends a 9-month
tients who develop TB, irrespective of the CD4 count and ART course of INH as the preferred regimen and a second-line
be initiated as soon as possible after the start of TB treatment. regimen of 4 months of rifampicin in patients intolerant
As detailed above, recent studies support this recommenda- of INH. However, this regimen is not as widely studied
tion for patients with CD4 counts <50 cells/mm3. and may be associated with an increased risk of relapse.
In addition to the mortality benefit, ART has a positive The risk of TB recurrence after completion of treatment is
impact on other TB outcomes, reducing the smear and cul- high in HIV-infected patients, and secondary prevention
ture conversion time [48] and decreasing the rates of TB with INH may be an effective strategy to prevent TB recur-
recurrence by 50% [49]. Moreover, ART initiated in HIV- rence in high-transmission areas. The WHO strongly rec-
infected individuals prior to TB development can reduce ommends that HIV-infected adults and adolescents who
the risk of TB by up to 90% at the individual level and successfully complete TB treatment should continue to re-
by approximately 60% at the population level. ceive INH for another six months, with the possibility of
The outcomes of HIV-infected patients with TB can be continuing INH for up to 36 months. However, this strat-
additionally improved with the use of CPT, a strategy egy should be carefully evaluated.
shown to be effective in decreasing the mortality rates by
45–50%, with the greatest impact seen in the first 12 weeks
and sustained at 72 weeks, with possible waning of the ef-
BCG vaccination
fect subsequently [50, 51]. CPT also improves the quality of
life across a broad range of levels of immunodeficiency. The Bacille Calmette-Guérin vaccine (BCG), the only currently
exact mechanism that makes co-trimoxazole beneficial in available TB vaccine, provides protection against life-
this setting is not well characterized, but it may be related threatening TB, such as TB meningitis and disseminated
to prevention of Pneumocystis jiroveci infection, malaria or (miliary) TB in children, but it does not prevent TB transmis-
other bacterial infections in HIV-infected patients. The sion, infection or reactivation of latent TB.
WHO recommends that all HIV-infected patients with TB The efficacy of BCG vaccination has been variable by age
should be initiated on CPT as soon as possible, and this and geographic location, possibly influenced by exposure
therapy should be given throughout TB treatment. to environmental mycobacteria or helminthic infections.
The deleterious effect TB has on HIV mortality suggests A meta-analysis found an overall efficacy of 50%, with ap-
that a substantial benefit could be derived from TB preven- proximately 80% efficacy in preventing the severe forms of
tion strategies. TB in childhood [53].
Despite BCG vaccine limitations, the WHO continues to
recommend that a single dose of BCG should be given to
neonates or as soon as possible after birth in countries with
TB PREVENTION a high prevalence of TB for protection against TB meningitis
and miliary TB [54]. Most high-burden countries use BCG
Treatment of latent tuberculosis vaccination as part of the national childhood immunization
programs, whereas in low-prevalence countries, vaccination
and secondary prevention
is limited to defined high-risk groups. BCG vaccination is
A recent meta-analysis of efficacy of treatment of LTBI in contraindicated in HIV-infected children with symptomatic
HIV-infected persons showed that preventive therapy re- disease; however, the WHO continues to recommend BCG
duced the risk of active TB by 32% compared to placebo vaccination in asymptomatic HIV-infected infants living in
[52]. Efficacy was similar for all regimens, regardless of highly endemic TB areas. Children infected with HIV are
the drug type, frequency, or duration of treatment; how- at higher risk of developing disseminated BCG disease.
ever, compared to isoniazid (INH) monotherapy, short- The development of efficient, safe, and affordable vac-
course multi-drug regimens were much more likely to cines against TB is seen as a global research priority, and
require discontinuation of treatment due to adverse effects. 12 vaccine candidates were in different phases of clinical
344
trials in 2009 [55]. The strategies to improve TB vaccination for laboratory strengthening as a major component, in-
include substituting primary immunization with recombi- cludes goals and targets for research and sets strategic
nant BCG strains (rBCG) that improve antigen presenta- frameworks for each major component in the plan [55].
tion and/or over-express immunodominant antigens or TB/HIV collaborative activities have been incorporated
an attenuated strain of M. tuberculosis. There is interest as well as major components of the Stop TB Strategy and the
in boosting BCG with an attenuated vaccinia or adenovirus Global Plan to Stop TB to reduce the burden of TB and
vector over-expressing immunogenic antigens or a subunit HIV in populations affected by both diseases [57]. The
vaccine composed of highly immunogenic proteins in adju- “3Is” (intensified case finding, INH prophylaxis, and im-
vant. A heat-inactivated M. vaccae (environmental saprophyte proved infection control) strategy has been proposed to
mycobacteria) vaccine administered to HIV-infected Tanzanian HIV control programs to reduce the burden of TB in people
adults (previously immunized with BCG) with CD4 counts living with HIV. Just as HIV programs should implement
>200 cells/mm3 reduced TB by 39% [56]. This can be con- TB prevention and control interventions, TB programs
sidered a useful proof-of-concept with respect to both the should also implement HIV testing and prevention
prime-boost strategy and the potential for safely immuniz- methods, ART and CPT as standard of care for patients af-
ing individuals even with advanced HIV disease. fected by both diseases.
Integration of TB and HIV responses is viewed as a key
strategy to control the dual epidemic. However, despite
CONTROL STRATEGIES clear guidelines, interventions known to be effective have
not been implemented. By 2008, only 4% of HIV-infected
Over the past years, the international community has de- individuals were actively screened for TB and only 48,000
veloped comprehensive strategies to fight the HIV and TB individuals (less than 0.2% of the eligible HIV-infected
pandemics. Building on previously implemented DOTS population) were offered IPT, data that reflect a minimal
strategy, the WHO launched a new six-point Stop TB Strat- level of implementation of TB prevention activities. Simi-
egy in 2006, aiming to ensure universal access to high- larly, the HIV care provided by TB programs is far from
quality diagnosis and treatment for all TB patients, includ- reaching the proposed targets. Almost 80% of patients
ing those co-infected with HIV, and supporting the devel- who develop TB are not tested for HIV, and a large propor-
opment of effective tools to prevent, detect, and treat TB. tion of HIV-infected individuals do not have access to CPT
In the same year, with its Global Plan to Stop TB 2006– and ART. By 2008, approximately 30% of HIV-infected TB
2015, the Stop TB Partnership published a comprehensive patients were not receiving CPT, and only 32% of the HIV-
assessment of the action and resources needed to imple- infected patients who developed TB started ART. These data
ment the Stop TB Strategy, with the UN Millennium Devel- highlight the need for a more aggressive approach to imple-
opment Goal of halting and beginning to reverse the menting integrated HIV and TB activities.
epidemic by 2015 and halving TB prevalence and death Globally, TB/HIV control efforts are hampered by multi-
rates by 2015, compared with 1990 levels. In 2010, taking ple challenges at different levels: scientific, political, eco-
into account the progress made since 2006, the Stop TB nomic, and cultural. Their implications should be taken
partnership has updated the plan, focusing on the 2015 tar- into account by the international community to find effec-
gets and adding the commitment to eliminate TB as a pub- tive solutions for a successful response to HIV/TB co-
lic health problem by 2050. The plan emphasizes the need infection in the new millennium.
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347
Chapter | 27 |
Disseminated Mycobacterium avium complex and
other atypical mycobacterial infections
Mark A. Jacobson
patients, whereas those in southwestern Europe had one-

EPIDEMIOLOGY sixth that risk [6]. After HAART became available, the inci-
dence of disseminated MAC dramatically decreased and
Prior to the AIDS epidemic, disseminated Mycobacterium has subsequently stabilized at a much lower level.
avium complex (MAC) infection had been reported only
rarely, yet after 1981 this infection became one of the most
important opportunistic infections associated with the Disseminated MAC in resource-poor
AIDS in many parts of the world. Disseminated MAC oc- countries
curs almost exclusively in AIDS patients with an absolute
Disseminated MAC has been less common in parts of the
CD4 count <50 cells/mm3 [1]. Localized MAC infection
world where tuberculosis is more prevalent, perhaps be-
can occur at higher CD4 counts, especially among patients
cause of cross-reactive immunity or perhaps because end-
with advanced AIDS who have experienced immune recon-
organ disease caused by tuberculosis tends to occur earlier
stitution on highly active antiretroviral therapy (HAART, or
in the course of HIV than disease caused by MAC. In
ART) [2].
the pre-HAART era, MAC was isolated from the blood of
18% of febrile AIDS patients in a study conducted in Brazil
[7]. The point prevalence of disseminated MAC in hospital-
Disseminated MAC in industrialized ized AIDS patients in South Africa has been reported to be
countries only 10% [8], and in Thailand, only 1% [9].
In the era prior to the widespread availability of HAART in

North America, Western Europe and Australia, one-third to Effect of MAC prophylaxis and ART
one-half of AIDS patients in these regions developed dis-
on incidence
seminated MAC infection. In the USA, a study reported
in 1986 that 53% of 79 autopsies of AIDS patients showed With the advent of MAC prophylaxis in the early 1990s,
evidence of disseminated MAC [3]. In another study from the incidence of the infection began to decline in Western
the late 1980s, conducted in patients with advanced HIV industrialized countries. Between 1993 and 1994, a 40%
disease who had serial blood specimens cultured for myco- decrease in the incidence of adult AIDS-defining disse-
bacteria over a median 1-year period, the 2-year actuarial minated MAC was noted by the US Centers for Disease
incidence of MAC bacteremia was 40% [1]. In Australia Control (CDC) that almost certainly resulted from the wide-
during this same time period, 50% of AIDS patients devel- spread introduction of rifabutin and macrolide MAC prophy-
oped disseminated MAC [4]. Similarly, an autopsy study laxis into clinical practice during this time period. After early
conducted in Japan in the pre-HAART era reported evi- 1996, when HAART became widely available in North Amer-
dence of disseminated MAC in 40% of 43 autopsies [5]. ica and Western Europe, the incidence decreased by more
The risk among European patients was more variable, with than 80% compared with the period before 1994. More
patients in northern Europe having a similar risk to US recently, a similar decrease in MAC bacteremia has been
349
reported in Brazil after the widespread introduction of patients who have experienced immune reconstitution on
HAART in that country [10]. In a recently published prospec- ART, there have been reports of localized, non-disseminated,
tive cohort study of 8,070 HIV-infected patients from the USA MAC infection associated with granuloma formation, tissue
with a median CD4 count of 298 cells/mm3, the incidence of destruction, and abscess formation in lymph nodes or skin.
disseminated MAC was only 2.5 new cases per 1,000 patient- These cases of MAC immune reconstitution inflammatory
years between 2003 and 2007 [11]. syndrome (IRIS) have usually occurred soon after antiretro-
viral therapy was initiated, suggesting that reconstitution
of either MAC-specific T-cell responses or of some innate,
Acquisition of MAC infection cytokine-related functions may have occurred.
MAC is a ubiquitous soil and water saprophyte, and epide-
miologic data suggest that disseminated MAC infection re-
sults from new environmental acquisition of the organism CLINICAL MANIFESTATIONS
(rather than reactivation of quiescent, endogenous infec-
tion). As an example, a common water source nosocomial Effect of disseminated MAC infection
outbreak of MAC disease was reported in an AIDS ward
on survival in AIDS
[12]. The route of MAC infection in AIDS patients may
be through the gastrointestinal or respiratory tract. The Because most AIDS patients with disseminated MAC infec-
presence of large clusters of mycobacteria within macro- tion have other concomitant infections or neoplasms, and
phages of the small bowel lamina propria suggests that because systemic MAC infection appears to cause little in-
the bowel might be the portal of entry. However, respira- flammatory response or tissue destruction in patients with
tory isolation of MAC frequently precedes disseminated in- advanced AIDS, the relationship between constitutional
fection, suggesting that MAC infection may begin in the symptoms, organ dysfunction, and MAC infection was ini-
lungs as well [13]. tially uncertain. Nevertheless, several large retrospective
studies from the pre-HAART era strongly suggested that dis-
seminated MAC increased mortality and morbidity in AIDS
PATHOGENESIS patients. Horsburgh and co-workers noted a median 4-
month survival among 39 patients with untreated dissem-
inated MAC infection compared with 11 months among 39
In AIDS, the key host defect allowing dissemination of
controls matched for CD4 lymphocyte count, prior AIDS
MAC is macrophage dysfunction, specifically the failure
status, history of antiretroviral therapy, history of Pneumo-
of macrophages to kill phagocytized MAC. The organism
cystis pneumonia (PCP) prophylaxis, and year of diagnosis
is able to survive within macrophages unless intracellular
(p<0.0001) [14]. At San Francisco General Hospital,
killing mechanisms, which become defective with ad-
among 137 consecutive patients who had a sterile body
vanced HIV infection, are activated. Defects in the activity
site cultured for mycobacteria within 3 months of their first
of cytokines that are essential for intracellular killing of
AIDS-defining episode of PCP, median survival was signif-
pathogens, such as interferon-gamma, tumor necrosis fac-
icantly shorter in those with disseminated MAC infection
tor, interleukin-12 and interleukin-2, have all been impli-
than in those who had negative cultures (107 vs 275 days;
cated in the pathogenesis of disseminated MAC infection
p < 0.01), even after controlling for age, absolute lympho-
among patients with rare heritable immune deficiencies
cyte count, and hemoglobin concentration [13].
and probably have a role in the pathogenesis of this oppor-
tunistic infection in AIDS patients. However, cytokine ther-
apy has shown benefit in AIDS patients with disseminated Clinical presentation of disseminated
MAC to date.
MAC
In AIDS, MAC causes high-grade, widely disseminated
infection. Nearly all AIDS patients with invasive MAC infec- The clinical presentation of disseminated MAC infection al-
tion (as opposed to stool, urine, or respiratory coloniza- most always includes fever and malaise. Weight loss is com-
tion) have positive mycobacterial blood cultures. In the mon, and anemia and/or neutropenia are often present.
majority of cases autopsied, MAC has been isolated from Diarrhea and malabsorption may occur as a result of
the spleen, lymph nodes, liver, lung, adrenals, colon, kid- MAC invasion of the gut wall. Abdominal pain may be pre-
ney, and bone marrow. The magnitude of mycobacteremia sent and can be severe as a result of bulky retroperitoneal
can range from 1 to 10,000 colony-forming units per mL of adenopathy. Rarely, extrabiliary obstructive jaundice caused
blood. Tissue specimens from bone marrow, spleen, lymph by periportal lymphadenopathy occurs. In a prospective nat-
nodes, and liver have yielded even higher amounts of the ural history study of MAC bacteremia conducted at San
microbe. Histopathologic studies of involved organs typi- Francisco General Hospital in the pre-HAART era, we ob-
cally have shown absent or poorly formed granulomas served, among patients with CD4 count <50 cells/mm3, that
and acid-fast bacteria within macrophages. In AIDS a history of fever for >30 days, a hematocrit <30%, or a
350
Chapter | 27 | Disseminated Mycobacterium avium complex and other atypical mycobacterial infections
serum albumin level <3.0 g/dL were all sensitive predictors be increased to 95% by obtaining a second blood culture
of MAC bacteremia [15]. However, neither severe fatigue, on a separate day.
diarrhea, weight loss, nor neutropenia discriminated be- The clinical significance of MAC isolated from sputum or
tween those who were subsequently found to be blood stool remains controversial. In our prospective natural his-
culture positive or negative for MAC. tory study, we found that only two-thirds of patients with
negative blood cultures but positive stool or sputum cul-
tures for MAC subsequently developed disseminated
MAC immune reconstitution MAC infection [18]. Hence, neither stool nor sputum cul-
inflammatory syndrome ture can be recommended as a screening test to identify
patients likely to develop MAC bacteremia.
As noted above, localized, non-disseminated MAC infec-
tion associated with granuloma formation, tissue destruc-
tion, and abscess formation in lymph nodes or skin can
occur in AIDS patients who have recently initiated antire- THERAPY
troviral therapy [2]. The clinical course is sometimes
explosive, with large abscess formations and high fever. In
MAC is not killed by standard antituberculous drugs at con-
general, these MAC IRIS cases have occurred in patients
centrations achievable in plasma. However, at least half of
who had an absolute CD4 count <50 cells/mm3 before ini-
MAC strains can be inhibited by achievable plasma concen-
tiating ART and have presented soon after the absolute CD4
trations of rifabutin, rifampin, clofazimine, cycloserine,
count rises to >100 cells/mm3. MAC IRIS sometimes in-
amikacin, ethionamide, ethambutol, azithromycin, clari-
volves the bone or lungs, with infiltrates apparent on chest
thromycin, ciprofloxacin, or sparfloxacin. Unfortunately,
X-ray. Mycobacterial blood cultures are usually negative at
drug levels necessary to kill MAC in vitro (minimum bacte-
the time of presentation. MAC IRIS can present either as a
ricidal concentration) have been 8 to >32 times that of in-
recrudescence of a clinically resolved infection (paradoxical
hibitory levels. While combinations of antimycobacterial
IRIS) or as the new clinical appearance of MAC infection
agents have shown in vitro inhibitory synergism, bacteri-
that was previously subclinical (unmasking IRIS). In some
cidal synergism has been more difficult to demonstrate.
observational studies, IRIS has occurred in up to one-third
In addition, for in vivo killing, drugs must penetrate macro-
of patients who had a diagnosis of disseminated MAC prior
phages as well as the MAC cell wall. Nevertheless, in animal
to initiating ART and in up to 4% of all patients who initiate
models of disseminated MAC infection, both single and
ART with a pre-treatment absolute CD4 count <100 cells/
combination antimycobacterial regimens have reduced
mm3. Unlike disseminated infection, these lesions have
mycobacterial colony counts by several logs and improved
responded remarkably well to drainage and antimycobac-
survival.
terial therapy, although a short course of prednisone is
Results of several sequential trials reported by the Cali-
sometimes needed before fever resolves. There is no need
fornia Collaborative Treatment Group (CCTG) highlight
to discontinue ART in such patients.
the caution needed when interpreting results of treatment
trials that have no control arm. In 1990, this group reported
striking microbiologic and clinical effects in previously
DIAGNOSIS untreated patients with disseminated MAC who were given
a combination regimen that included intravenous amika-
Special blood culture techniques for isolating mycobac- cin and oral rifampin, ethambutol, and ciprofloxacin
teria, such as the broth-based BACTEC system or agar-based [19]. Given the modest results that had previously been
Dupont Isolator system, are sensitive methods for diagnos- reported with oral antimycobacterial agents, many drew
ing disseminated MAC infection [16]. Specific DNA probes the conclusion from this uncontrolled trial that the amikacin
for MAC are also available and make it possible to differen- was primarily responsible for the efficacy of this regimen.
tiate MAC from other mycobacteria within hours when Subsequently, the CCTG reported similar microbiologic
there is sufficient mycobacterial growth in broth or agar and clinical results in another similarly designed uncon-
[17]. Time to culture positivity ranges from 5 to 51 days. trolled trial in which intravenous amikacin was replaced
It is uncommon for blood cultures to be negative when by oral clofazimine [20]. To address the question of amika-
there is a positive histologic diagnosis from lymph node, cin’s clinical utility, a randomized controlled trial was then
liver, or bone marrow biopsies. However, one advantage conducted by the AIDS Clinical Trials Group (ACTG) in
of obtaining biopsied specimens is that stains may demon- which 72 patients with previously untreated disseminated
strate acid-fast bacteria (AFB) or granuloma immediately, MAC were all given a combination oral regimen of rifampin,
thus confirming a clinical suspicion of the diagnosis weeks ethambutol, ciprofloxacin, and clofazimine and were also
before the blood culture turn positive. A single blood cul- randomly assigned to receive or not receive intravenous ami-
ture for mycobacteria is approximately 90% sensitive in di- kacin. In this controlled trial, there were no significant differ-
agnosing disseminated MAC infection; this sensitivity can ences in microbiologic or clinical outcomes, demonstrating
351
that the cost, inconvenience, and risk of toxicity of regimen combined with either azithromycin 250 mg daily,
intravenous amikacin were not balanced by increased clini- azithromycin 600 mg daily, or clarithromycin 500 mg
cal benefit [21]. After the uncontrolled CCTG study of twice daily [23]. The low-dose azithromycin arm was termi-
a clofazimine-containing regimen, data from a subsequent nated early in the trial due to poor microbiologic efficacy.
study found that this drug added no clinical benefit and There was no significant difference in either microbiologic
may actually be harmful when used in macrolide-based or survival outcomes between the high-dose azithromycin
combination regimens. A trial assigned 106 patients with and the clarithromycin arms; however, there were non-
MAC bacteremia to receive clarithromycin and ethambutol significant trends toward better survival, greater clearance
with or without clofazimine. Clofazimine was not associated of bacteremia, and lower relapse rates with clarithromycin
with any benefit in microbiologic response, and the patients in this trial. In another trial, 59 patients with disseminated
assigned to the clofazimine arm had significantly higher MAC were randomized to receive an ethambutol-based reg-
mortality. Clearly, neither clofazimine nor amikacin should imen with either clarithromycin 500 mg twice daily or azi-
be used in the initial treatment of disseminated MAC. thromycin 600 mg once daily. Clearance of bacteremia
occurred in 86% of subjects assigned to clarithromycin ver-
sus only 38% assigned to azithromycin (p < 0.007) [24].
Macrolides: clarithromycin and However, only 37 of the 59 patients were evaluable micro-
biologically, and only two deaths occurred during the short
azithromycin follow-up period, making it difficult to generalize the re-
In vivo data on microbiologic efficacy against MAC have sults of this trial.
been most impressive with two macrolides, clarithromycin
and azithromycin. A multicenter, randomized, placebo-
controlled, dose-ranging trial of clarithromycin monother-
Ethambutol
apy in patients with previously untreated disseminated
MAC reported a median decrease of >2 log in blood In order to determine which of the orally bioavailable non-
colony-forming units—a more potent microbiologic effect macrolide antimycobacterial agents was the most potent in
than reported in any earlier treatment trials [22]. This mi- vivo, a randomized, controlled trial was conducted in which
crobiologic effect was accompanied by significant clinical patients with previously untreated disseminated MAC were
improvement in symptoms and quality of life. However, assigned to receive a 4-week regimen of rifampin, ethambu-
unacceptably high gastrointestinal toxicity occurred at a tol, or clofazimine monotherapy [25]. In this trial, only
dose of 2,000 mg twice daily. Although a 1,000 mg twice- ethambutol resulted in a statistically significant reduction
daily dose had greater microbiologic efficacy than 500 mg in blood MAC colony-forming units. A subsequent trial
twice daily, there was actually a trend toward increased mor- confirmed the clinical benefit of ethambutol when com-
tality with the higher dose. This paradoxical dose–response bined with clarithromycin [26]. A total of 80 patients with
relationship was subsequently confirmed in another newly diagnosed disseminated MAC infection received
study, indicating that the optimal dose for this drug is clarithromycin and clofazimine and were randomized to
500 mg twice daily. Not surprisingly, drug resistance receive or not receive ethambutol 800 mg daily. Although
emerged after 2 months of monotherapy in this trial, affect- 69% of patients in both groups initially cleared their bac-
ing approximately half of patients in all dosing arms. Hence, teremia, the subsequent microbiological relapse rate at
one or more other antimycobacterial agents must be co- 36 weeks was 50% with ethambutol versus 91% without
administered with the macrolide in an attempt to prevent ethambutol (p ¼ 0.014).
or at least delay emergence of resistance, which is likely to
result in relapse and clinical deterioration. On the other
hand, these data should reassure clinicians that inadver-
Rifabutin
tently initiating MAC prophylaxis with clarithromycin in pa-
tients who already have subclinical MAC infection is When rifabutin was initially evaluated in the 1980s as
unlikely to lead to drug resistance as long as blood cultures a treatment for MAC at doses of 100–300 mg/day, it was
are obtained at the time that clarithromycin is started (i.e. found to be ineffective. However, a subsequent random-
blood cultures will be positive and additional medication ized, placebo-controlled trial demonstrated clinical bene-
can be added before the development of macrolide fit. Among patients with newly diagnosed disseminated
resistance). MAC randomized to receive either clofazimine/ethambu-
Azithromycin is another effective macrolide for the treat- tol or clofazimine/ethambutol/rifabutin (600 mg/day),
ment of MAC. The antimycobacterial efficacy of azithromy- half of the patients receiving the rifabutin-containing regi-
cin or clarithromycin, when combined with other agents, men had a >2-log decrease in blood MAC colony-forming
has been compared in two randomized trials. In one study, units or sterilization of the blood compared with none of
246 patients were randomized to an ethambutol-based those receiving only clofazimine/ethambutol [27].
352
Optimal combination treatment Table 27.2 Treatment regimen for disseminated M. avium
regimens complex infection
The long-term clinical benefit of combination regimens
that include both macrolide and non-macrolide agents FOR PATIENTS LIKELY TO FOR PATIENTS UNLIKELY
INITIATE ART SOON TO RECEIVE ART WITHIN
for treatment of disseminated MAC were confirmed in a
THE NEXT FEW MONTHS
randomized multicenter trial conducted by the Canadian
MAC Study Group in which 187 evaluable patients with Clarithromycin 500 mg Clarithromycin 500 mg
disseminated MAC were randomized to receive a regimen twice daily (or twice daily (or
of clarithromycin 1,000 mg twice daily, rifabutin 600 mg clarithromycin extended clarithromycin extended
once daily, and ethambutol 15 mg/kg/day versus ciproflox- release formulation release formulation
acin 750 mg twice daily, rifampin 600 mg once daily, clo- 1000 mg once daily)a 1000 mg once daily)a
fazimine 100 mg once daily, and ethambutol 15 mg/kg/
day. The in vivo quantitative antimycobacterial effect was plus plus
significantly better with the macrolide-containing regimen, Ethambutol 15 mg/kg once Ethambutol 15 mg/kg once
as was median survival (8.6 vs 5.2 months; p < 0.001) [28]. dailyb daily and rifabutin 300 mg
Currently, the best option for the treatment of dissemi- once dailyc
nated MAC is to combine one of the macrolides (clarithro-
a
mycin 500 mg twice daily or azithromycin 500–600 mg For patients intolerant of clarithromycin, azithromycin 500 or
once daily) with either ethambutol 15 mg/kg once-daily or 600 mg once daily can be substituted.
b
rifabutin 150–450 mg once daily (dose dependent on con- For patients intolerant of ethambutol, rifabutin 300 mg once daily
can be substituted (450–600 mg daily if co-administered with
current medications, Table 27.1), or both (Table 27.2). To azithromycin rather than clarithromycin; 450 mg daily if co-
address the issue of whether it is more effective to use one administered with efavirenz; 150 mg daily if co-administered with a
or both of these two drugs, in combination with a macrolide, ritonavir-boosted protease inhibitor).
c
Rifabutin dose should be dosed at 450–600 mg daily if
co-administered with azithromycin rather than clarithromycin,
Table 27.1 Recommended dosing adjustments when 450 mg daily if co-administered with efavirenz, 150 mg daily if
co-administered with indinavir or nelfinavir or a ritonavir-boosted
rifabutin is combined with antiretroviral drug
protease inhibitor.
ANTIRETROVIRAL ANTIRETROVIRAL RIFABUTIN

DRUG DOSE DOSE
Benson and co-workers randomized patients with dissemi-
Protease inhibitors nated MAC to receive clarithromycin and ethambutol, clari-
Fosamprenavir No change 150 mg daily thromycin and rifabutin, or clarithromycin plus ethambutol
and rifabutin [29]. A similar microbiologic response, defined
Nelfinavir No change 150 mg daily as a sterile blood culture at 12 weeks, occurred in all three
arms: 40, 42, and 51%, respectively (p ¼ 0.45). However,
Indinavir 1000 mg t.i.d. 150 mg daily higher survival was observed in the three-drug arm (hazard
Atazanavir No change 150 mg daily ratio of death approximately halved). There was no signifi-
cant difference in dose-limiting toxicity between the three
Any ritonavir- No change 150 mg daily arms. This difference in survival may not be generalizable
boosted protease to patients who initiate ART soon after diagnosis of MAC,
inhibitor and who are likely to experience immune reconstitution
and thus have a far lower risk of mortality than during the
Saquinavir Contraindicated Contraindicated
pre-HAART era when this trial was conducted.
Non-nucleoside reverse transcriptase inhibitors
Efavirenz No change 450 mg daily
MANAGEMENT OF TREATMENT
Nevirapine No change No change
FAILURE
Etravirine Contraindicated No change
with darunavir/ unless given
Since disseminated MAC infection has become a curable
ritonavir and with a ritonavir-
disease for AIDS patients who experience immune reconstitu-
etravirine boosted
tion on ART, treatment failure is now a rare event. However, in
combination protease
inihibitor patients who remain immunosuppressed, progressive resis-
tance to first-line drugs can eventually occur. Other than
353
testing for macrolide resistance, resistance testing of blood such patients who have completed at least one year of
culture isolates has not been correlated with clinical outcome an appropriate MAC regimen to discontinue chronic
and thus cannot be reliably used to guide treatment in pa- suppressive therapy.
tients. Since few drugs have demonstrated clinical efficacy These observations underscore the importance of initiat-
in randomized treatment trials (i.e. the macrolides, ethambu- ing effective ART and suppressing HIV replication as soon
tol, and rifabutin) and some drugs with in vitro activity against as possible after diagnosing disseminated MAC. While
MAC have been of no benefit (e.g. amikacin) or harmful (e.g. some observational studies have shown that a shorter time
clofazimine), there are limited salvage options for patients interval between initiatiation of MAC therapy and ART was
who are clinically failing treatment. It is not known whether associated with an increased risk of MAC IRIS [30], this is
continuing macrolide treatment is beneficial for such failing outweighed by the results of a randomized controlled trial
patients, but there is evidence that increasing the clarithromy- that demonstrated that in AIDS patients with newly diag-
cin dose above 500 mg twice daily is harmful. The only evi- nosed opportunistic infections, early initiation of ART
dence-based options for salvage therapy are to increase (i.e. within two weeks versus at least four weeks) reduces
doses of drugs with established clinical efficacy: for example, the risk of AIDS progression and death [31].
(1) increasing the ethambutol dose to 25 mg/kg/day while
monitoring the patient for signs of retrobulbar neuritis,
and/or (2) increasing the rifabutin dose until clinical toxicity Empiric treatment for disseminated
occurs (most commonly manifested as painful anterior uve- MAC and tuberculosis
itis, which typically resolves with rifabutin dose reduction).
Distinguishing tuberculosis from MAC disease in patients
Fluoroquinolones such as ciprofloxcin and moxifloxacin
with advanced HIV disease can be difficult. Therefore, em-
have demonstrated in vitro activity and have not been shown
piric antituberculous therapy should be considered when
to harm patients with disseminated MAC, so one might
acid-fast bacteria are demonstrated in a specimen from
consider adding such a drug.
an HIV-infected patient with clinical evidence of mycobac-
terial disease while awaiting speciation of the organism.
Drug interactions with antiretroviral MAC and tuberculosis can both be empirically treated by
adding clarithromycin to standard tuberculosis treatment
medications
regimens.
Azithromycin and ethambutol do not have clinically im-
portant drug interactions with antiretroviral medications.
Ritonavir can increase clarithromycin plasma levels PROPHYLAXIS
enough that clarithromycin dosing should be reduced
to 500 mg/day in patients on ritonavir-boosted protease
In countries where the incidence of AIDS-related dissemi-
inhibitor regimens who also have moderate renal insuffi-
nated MAC is high (e.g. Europe and the United States), pro-
ciency (estimated creatinine clearance <60 mL/min). Efa-
phylaxis should be given to at-risk AIDS patients (i.e. those
virenz accelerates clarithromycin metabolism and lowers
with CD4 counts <50 cells/mm3).
drug levels; combining this drug with clarithromycin is
contraindicated. Rifabutin has clinically significant drug in-
teractions with some antiretroviral protease inhibitors and Clarithromycin
non-nucleoside reverse transcriptase inhibitors that require
dosage adjustment (Table 27.1). The most convincing data regarding the efficacy of MAC
prophylaxis have been obtained with clarithromycin in a
placebo-controlled study in which 667 patients with
Initiating antiretroviral therapy and advanced HIV disease were randomized to receive either
stopping MAC treatment after clarithromycin 500 mg twice daily or placebo. During a
median 10-month follow-up, only 6% of clarithromycin-
immune restoration
assigned patients versus 16% of placebo-assigned patients
During the pre-HAART era, relapse of disseminated MAC developed mycobacteremia (p<0.001) [32]. More impor-
typically occurred rapidly when chronic suppressive ther- tantly, median survival was significantly longer in clari-
apy was discontinued. However, since the widespread thromycin- than placebo-assigned patients (32 vs 41%
availability of ART, there have been several reports describ- mortality, p ¼ 0.026). However, among the clarithromycin-
ing a series of patients who had taken prolonged therapy assigned patients who did develop disseminated MAC infec-
for disseminated MAC infection, then experienced immune tion, 58% had mycobacteremia with MAC isolates that were
reconstitution on ART with a rise in CD4 count to >100 highly resistant to clarithromycin (minimum inhibitory con-
cells/mm3, with resolution of all MAC-related symptoms. centration [MIC] 512 mg/mL). Clarithromycin at this same
After blood culture negativity was documented, these indi- dose has also been compared with rifabutin and to the
viduals discontinued MAC therapy and had no relapse combination of clarithromycin and rifabutin in a large ran-
during long-term follow-up. It now appears to be safe for domized trial involving 1,216 patients with absolute CD4
354
counts <100 cells/mm3. In this trial, clarithromycin was

significantly more effective than rifabutin in preventing OTHER ATYPICAL MYCOBACTERIAL
MAC (9 vs 15% of patients, p ¼ 0.01), but the addition of INFECTIONS IN HIV-INFECTED
rifabutin to clarithromycin provided no significant increase
in efficacy compared with clarithromycin alone [33].
PATIENTS
Disseminated and localized infections caused by M. kansa-

Azithromycin sii, M. celatum, M. xenopi, M. simiae, M. haemophilum, M.
A regimen of weekly azithromycin prophylaxis was evalu- marinum, M. scrofulaceum, M. gordonae, M. genavense, M. for-
ated in a placebo-controlled, double-blind trial in which tuitum, M. chelonae, M. malmoense, M. abscessus, M. triplex,
10.6% of 85 azithromycin recipients and 24.7% of 89 pla- and M. terrae also have been reported in patients with
cebo recipients developed MAC infection (hazard ratio, AIDS. Those with disseminated disease generally have
0.34; p ¼ 0.004) [34]. There was no difference between had clinical presentations similar to that of disseminated
the groups in survival or in the macrolide susceptibility MAC infection, although pulmonary involvement is more
of breakthrough MAC isolates. In another trial, 693 pa- common with M. kansasii infection. The in vitro sensitivity of
tients with CD4 count <100 cells/mm3 were randomized isolates to standard antituberculous drugs has been variable.
to azithromycin 1,200 mg once weekly, daily rifabutin or Of note, cases of disseminated M. simiae-avium infection
both. Azithromycin was more effective than rifabutin in have been reported in Thailand and Malawi.
preventing MAC (7.6 vs 15.3%, p ¼ 0.008), and
the combination of both agents was more effective than M. kansasii
either one alone (2.8%, p ¼ 0.03) [35]. Among the patients
in whom azithromycin prophylaxis was not successful, M. kansasii has been the most frequently reported of the other
only 11% of MAC isolates were resistant to azithromycin. atypical mycobacteria. A trend toward increased incidence of
Both clarithromycin and azithromycin prophylaxis are HIV-related M. kansasii was noted in Northern California in
well-tolerated. The main adverse effects of clarithromycin the mid-1990s. M. kansasii lung infection is also an emerging
are nausea and altered taste and the main effect of azithro- problem among HIV-infected people in South Africa, espe-
mycin is diarrhea. cially miners, and has been reported to occur at high CD4
counts [38]. This organism, like MAC, is acquired from the
environment, and no cases of human-to–human transmis-
Rifabutin sion have been documented. In three published series from
New Orleans, Kansas City, and Miami, the clinical features
Rifabutin alone at a dose of 300 mg once daily also has
of 119 cases of AIDS-related M. kansasii infection have been
been compared with placebo for MAC prophylaxis in
reported [39–41]. A total of 91% of these cases involved pul-
two randomized trials conducted in over 1,000 patients
monary disease; 32% had disseminated disease. The median
with advanced HIV disease. Rifabutin demonstrated effi-
CD4 count at diagnosis was <50 cells/mm3 in all three series.
cacy by reducing the incidence of MAC by half. Patients
Fever, cough and weight loss were common. Radiographic
who received rifabutin and subsequently developed MAC
manifestations of M. kansasii infection can include cavita-
had blood isolates that retained susceptibility to rifabutin.
tion, consolidation or nodular densities. Patients with
However, neither trial alone, nor the combined analysis,
AIDS-related M. kansasii infection have been reported to re-
demonstrated that rifabutin significantly reduced mortal-
spond to therapy with combinations of agents, including
ity. In addition, rifabutin requires dose adjustment when
isoniazid, rifampin, ethambutol, clarithromycin and cip-
used in combination with some antiretroviral agents
rofloxacin. Although the American Thoracic Society rec-
(Table 27.1).
ommends a combination of isoniazid, rifampin, and
ethambutol as therapy for this disease, clinicians must sub-
Discontinuation of primary stitute clarithromycin and/or rifabutin for rifampin in pa-
tients receiving protease inhibitors. The recommended
prophylaxis
duration of therapy is a minimum of 18 months. The in vitro,
Two randomized, placebo-controlled trials have addressed isoniazid resistance and clarithromycin sensitivity is com-
the question of whether chronic prophylaxis is needed for monly observed. Rifampin resistance is also an emerging
patients who at one time had a CD4 count <50 cells/mm3 problem. Thus, multi-drug therapy should be tailored to
but now have absolute CD4 counts above 100 cells/mm3 the results of in vitro sensitivities of a culture isolate.
on ART [36, 37]. Among the 583 patients who were
assigned to receive placebo in these combined trials, there
M. genavense
were only two cases of MAC infection, both localized to
the vertebral spine. Thus, MAC prophylaxis should be dis- M. genavense can cause disseminated infection that is clin-
continued in patients on ART who maintain CD4 counts ically similar to disseminated MAC in patients with CD4
>100 cells/mm3. counts <50 cells/mm3 [42]. This fastidious organism is
355
difficult to detect and does not grow on conventional solid M. haemophilum

media. Small colonies can be detected in specially supple-
mented Middlebrook media, and low growth index can M. haemophilum is an atypical mycobacterium with a pro-
be observed in BACTEC broth. Since susceptibilities to pensity to cause joint, bone, and ulcerative skin lesions
drugs cannot be reliably determined, an empiric treatment (perhaps related to the lower temperature it requires for op-
choice must be made. Clinical reports indicate that clari- timal growth). In addition, disseminated infection can oc-
thromycin-containing combination regimens may be cur in patients with advanced AIDS. A cluster of cases was
effective therapy. reported in the New York City area. Clarithromycin and
rifabutin appear to be the most active therapeutic agents.
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357
Chapter | 28 |
Candida in HIV infection
William G. Powderly
candidiasis. Recurrent episodes are frequent with progres-

EPIDEMIOLOGY sive immune deficiency. The incidence has declined since
the introduction of ART in the late 1990s. Higher HIV viral
Candidiasis is caused by fungi of the Candida species, load is significantly associated with increased oral or vagi-
which are yeasts that are ubiquitous in the environment. nal colonization and candidiasis, an association that has
Candida species are common human commensal organ- been reduced by ART [6]. However, in parts of the world
isms on skin and mucous membranes; between 30% and where ART is not widely available, mucosal candidiasis
80% of adults and children are colonized with Candida spe- continues to represent a significant cause of morbidity.
cies [1, 2]. The point prevalence of carriage is higher in Esophageal candidiasis affects between 10% and 20% of
at-risk groups, such as cancer patients and HIV-infected patients with AIDS. Candida infection is the most common
persons [3–5]. In general, such colonization with Candida cause of esophageal disease in persons with HIV infection.
does not cause infection. The primary defense mechanisms The epidemiology of mucocutaneous candidiasis has
involved in protection against local infection with Candida changed in the last 10 years primarily because of two factors.
involve the cell-mediated immune system. Progressive loss The first is the widespread use of antifungal agents, particu-
of T-cell function associated with HIV disease leads to an larly the azoles. Continuous use of azoles has led to a decline
increased risk of direct local invasion of Candida and local- in the prevalence of mucosal candidiasis but also led to the
ized infection. Other host factors important in the defense emergence of refractory infections caused by azole-resistant
against Candida infections include blood group secretor Candida. The second factor influencing Candida epidemiol-
status, salivary flow rates, epithelial barrier, antimicrobial ogy in AIDS has been the introduction of potent ART, which
constituents of saliva, and the presence of normal bacterial has resulted in a significant decline in the incidence of all op-
flora. Several studies suggest that HIV infection is associ- portunistic illnesses, including mucosal candidiasis. It is rea-
ated with impairment in a number of these local mucosal sonable to expect that the incidence of mucocutaneous
defense mechanisms. candidiasis in HIV-infected patients will continue to decline
Mucosal candidiasis is a common opportunistic infec- as more patients receive effective ART.
tion in HIV-infected individuals. Oropharyngeal candidia- The majority of cases of candidiasis in the setting of HIV
sis (OPC) usually occurs with low CD4 counts, but tends infection are confined to mucosal surfaces i.e. oropharyn-
to be one of the earliest opportunistic infections and geal, esophageal, and vulvovaginal; systemic candidiasis is
may be seen in patients with CD4 counts <200/mm3. rare and usually occurs in patients with advanced HIV/AIDS
The finding of oropharyngeal candidiasis should never (often in the setting of neutropenia) or occurs as a result of
be dismissed in an HIV-infected patient; it indicates pro- nosocomial acquisition. While oropharyngeal and esopha-
gressive immune deficiency and should prompt the geal candidiasis are clearly HIV-associated illnesses, it is
institution of effective antiretroviral therapy. likely that vulvovaginal candidiasis (VVC) is not. HIV-
Prior to the era of highly active antiretroviral therapy seropositive women have a higher prevalence of vaginal
(HAART, or ART), between 50 and 75% of HIV-infected colonization with Candida compared with seronegative
individuals developed at least one episode of mucosal women. However, the incidence of vulvovaginal candidiasis
359
is unrelated to HIV serostatus and tends to reflect other risk can be used for treatment, although specific antiviral
factors for vulvovaginal Candida infection such as sexual ac- treatment is not usually required as the condition is
tivity and socioeconomic status. The prevalence of vulvova- typically asymptomatic. OHL is an indication for ART.
ginal disease is also independent of CD4 count and does not 2. Oral ulcers. Extensive oral ulceration can be seen in the
increase with advancing immunodeficiency. However, the setting of HIV infection. It has many causes, including
severity and frequency of recurrence of vulvovaginal candi- herpes simplex virus (HSV) type I and II,
diasis may be linked to progressive HIV infection, and, as cytomegalovirus (CMV), drug toxicities (e.g. Stevens–
a consequence, this remains an important source of morbid- Johnson syndrome due to co-trimoxazole or
ity in infected women. This may indicate a difference in antiretrovirals). However, the most common cause is
pathogenesis of Candidal infection at the two sites, orophar- idiopathic aphthous ulceration. Patients typically have
ynx and vagina [7]. single or multiple discrete ulcers that are usually
The most common causative organism is Candida albicans painful and may coalesce or become secondarily
[8], found in over 90% of isolates from patients with their infected. Treatment involves identifying the cause and
first episode of oropharyngeal candidiasis. In patients with discontinuing the causative agent if relevant. In the case
recurrent disease, the same strain causes the relapse in ap- of viral ulceration, systemic antivirals such as acyclovir
proximately half of cases, but other strains or species may may be useful. With aphthous ulceration, topical
also be implicated. The majority of disease is caused by or- steroids or analgesic mouthwashes are helpful, and oral
ganisms that are part of the normal flora of an individual, thalidomide therapy has been shown to be effective in
although rare cases of person-to-person transmission have severe cases [12].
been documented. In patients with prolonged or recurrent 3. Gingivitis and periodontitis. Severe oral cavity disease has
antifungal use, non-albicans species with different antimicro- been seen in HIV infection. It usually presents with
bial susceptibilities become more commonly isolated. These painful bleeding gums, halitosis, and dental loosening.
include C. glabrata, C. tropicalis, C. krusei, and C. dubliniensis There may be ulceration of gums. It is caused by mixed
[9, 10]. Some of these species are more likely to be associated aerobic and anaerobic infection and responds to
with decreased susceptibility to azole antifungals [11]. topical agents; systemic therapy with metronidazole
may be required.
4. Kaposi’s sarcoma. When present in the oral cavity, the
CLINICAL MANIFESTATIONS typical purple lesions of KS are usually seen on the
palate. If large, the lesions may ulcerate due to local
trauma. Biopsy establishes the diagnosis.
Oropharyngeal candidiasis 5. Non-Hodgkin’s lymphoma can cause oral cavity disease
Almost all patients with OPC are symptomatic, complain- in HIV patients. It may present as a mass lesion,
ing of a sore mouth or oropharyngeal pain with swallow- tonsillar in origin, or as ulceration of the mucosa.
ing. On inspection, OPC is usually associated with visible Biopsy establishes the diagnosis.
creamy white plaques on the tongue, hard or soft palate.
If scraped, these plaques have an erythematous base (this
is the pseudomembranous form of OPC, often referred Esophageal candidiasis
to as thrush). Other clinical manifestations include angular Patients are usually symptomatic with dysphagia and/or
cheilitis, which is a non-specific inflammation of the angles odynophagia. Retrosternal pain or discomfort may be pre-
of the mouth, and acute or chronic atrophic candidiasis, sent. There may or may not be concurrent oropharyngeal
which can present as erythematous tongue and/or thinning involvement. Severe symptoms can lead to considerable
of the mucous membranes. Although usually associated difficulty in eating or swallowing liquids, which can inter-
with mild morbidity, OPC can be clinically significant. fere with nutrition or hydration. In a patient with OPC,
Severe OPC can interfere with the administration of med- complaints of swallowing difficulty or retrosternal symp-
ications and adequate nutritional intake, and may spread toms, should prompt a high clinical suspicion of esopha-
to the esophagus. geal candidiasis, and empiric antifungal therapy should
The differential diagnosis of oropharyngeal candidiasis be initiated. In atypical cases or those refractory to empiric
includes: antifungal therapy, direct visualization of the esophagus by
1. Oral hairy leukoplakia (OHL). OHL is characterized by endoscopy is the best way to make the diagnosis. The epithe-
raised white lesions in the oral mucosa, usually found lial lining of the esophagus is coated in a pseudomembrane
on the sides of the tongue. It is associated with herpes consisting of yeasts, epithelial cells, leukocytes, and necrotic
viruses in the epithelial cells, particularly Epstein–Barr debris. Erosions or ulcers may be seen. An experienced
virus (EBV). It can be differentiated from candidiasis by endoscopist will often make the diagnosis on macroscopic
inability to scrape off the plaque or by lack of response appearance. Definitive diagnosis is made by brushings or bi-
to antifungal therapy. Antiviral therapy with acyclovir opsy of the mucosa. The differential diagnosis includes viral
360
Chapter | 28 | Candida in HIV infection
esophagitis caused by CMV or HSV types I and II and severe

aphthous ulceration. A helpful clinical clue in differentiating DIAGNOSIS
the different infectious causes of esophagitis in HIV-infected
patients is that esophagitis due to C. albicans often results in
The diagnosis of mucosal candidiasis is usually a clinical
complaints of food ‘sticking in the throat,’ whereas esopha-
one. The presence of characteristic symptoms with or with-
gitis due to HSV or CMV more often produces complaints of
out clinical findings in an HIV-infected patient is often
actual pain with swallowing.
enough to warrant treatment. In many ways, this consti-
tutes a therapeutic trial, with lack of response to empiric
antifungal therapy prompting further diagnostic testing.
Vulvovaginal candidiasis Oropharyngeal cultures often demonstrate Candida species
As noted previously, this is a common clinical syndrome in but are not diagnostic because colonization is common.
women irrespective of HIV status or immune function. The diagnosis of OPC can be confirmed by examining a
There are many additional predisposing factors to the de- 10% potassium hydroxide (KOH) slide preparation of a
velopment of genital Candida infection, including diabetes, scraping of an active lesion. Pseudohyphae and budding
oral contraceptive use, pregnancy, and systemic antibiotic yeast are characteristic findings. Culture is usually not nec-
therapy. essary with initial episodes of OPC unless the lesions fail to
VVC generally presents with itching, a vaginal discharge clear with appropriate antifungal therapy. In patients with
(which may be watery or thick), vaginal erythema with ad- poorly responsive OPC, a culture should be obtained to
herent white discharge, dyspareunia, dysuria, and erythema look for drug-resistant yeast or those that respond poorly
and swelling of the labia and vulva. The cervix usually ap- to certain azoles (e.g. C. krusei or C. glabrata).
pears normal. Initial episodes tend to be uncomplicated, The diagnosis of Candida vaginitis is made by the pres-
mild to moderate in severity, and sporadic, usually caused ence of a characteristic clinical appearance and observation
by C. albicans. More complicated VVC tends to occur in more of yeast forms on microscopic examination. A KOH prep-
immunocompromised hosts, is often recurrent, and is more aration from vaginal lesions can confirm the diagnosis of
likely to be caused by non-albicans species. candidiasis and differentiate it from other conditions that
Unprotected intercourse with a partner with VVC may can be similar in appearance (e.g. trichomoniasis). Routine
lead to Candida balanitis in the male partner, manifested fungal cultures are rarely helpful in the absence of KOH-
by pruritic, erythematous patches on the glans penis. positive lesions because yeasts are normal inhabitants of
the vaginal mucosa. A fungal culture should be obtained
if a patient fails to respond to standard antifungal therapy
Disseminated candidiasis and to determine whether azole resistance is contributing to the
therapeutic failure.
candidemia
In the microbiology laboratory Candida spp. are rela-
In HIV-infected individuals, this is a rare and usually late tively easy to culture. They grow rapidly on simple media
event, typically occurring in patients with advanced immu- at 25–37 C. Candida colonies are smooth and creamy
nosuppression. It is most often a hospital-acquired infec- white in color on agar plates. Specialized media can differ-
tion, with non-albicans Candida playing a significant role entiate between species by colony color (CHROMagar Can-
in pathogenesis. There has been a significant reduction in dida) and are very useful. Germ tube testing is a relatively
the incidence of nosocomial candidemia in HIV-infected pa- quick method of determining whether the organism is Can-
tients in the post-HAART era [13]. Risk factors are those of dida albicans or a non-albicans species. Many microbiology
nosocomial acquisition, including presence of a central ve- laboratories report yeast cultures as either C. albicans or
nous catheter, use of gastric acid suppressants, nasogastric non-albicans species based upon the germ tube test; if spe-
tubes, antibiotics, ICU admission [14], severe esophageal cific identification is required, further discussion with the
mucosal disease, advanced AIDS, concomitant opportunistic microbiologist is often necessary.
infections, non-albicans species, and neutropenia. Virtually ev- Efforts to develop a standardized reproducible and clin-
ery body organ can be affected by Candida infection. Involve- ically relevant method of susceptibility testing for yeasts
ment of the eyes (endophthalmitis), central nervous system have resulted in development of the NCCLS M27-A2 meth-
(meningitis [15], encephalitis), and heart (endocarditis) odology [19], which has data-driven interpretive break-
are described but rare in the setting of HIV infection. points for susceptibility of Candida spp. to antifungal
Community-acquired candidemia and disseminated agents (Table 28.1). Data relating to fluconazole and itra-
candidiasis in HIV is sometimes seen in countries where conazole are more readily available than for other antifun-
injection drug users make up a significant proportion of gals. Susceptibility testing of Candida spp. is not routinely
the HIV-infected population. This can present as end-organ used in most laboratories. The identification of the species
disease such as endocarditis, endophthalmitis or skin is often enough to predict likely antifungal susceptibility,
lesions [16–18]. and further testing is not required. However, in the setting
361
Table 28.1 Definition of in vitro resistance for Candida species. Range of MICs (mg/mL)
ANTIFUNGAL AGENT SUSCEPTIBLE SUSCEPTIBLE—DOSE DEPENDENT RESISTANT
Itraconazole 0.125 0.25–0.5 1.0
Fluconazole 8.0 16–32 >64
Amphotericin B 1.0 – 2.0
Adapted from NCCLS standard definitions for antifungal susceptibilities using microbroth or macrotube dilution methodology.
of recurrent infection, failure to respond to initial therapy or Fluconazole

systemic infection with non-albicans species, susceptibility
Fluconazole is a triazole antifungal and is the most widely
testing may contribute to clinical decision making and can
available and commonly used agent to treat Candida infec-
also be used to support a decision to switch from a paren-
tion. It is available in oral and intravenous forms. It has
teral to oral agent. The dose and delivery of the antifungal
good bioavailability, with the same doses being adminis-
agent are important in interpreting the data, and host factors
tered both orally and intravenously (100–800 mg/day).
play a significant role in the clinical response to a particular
It is generally well tolerated but may cause headache (up
agent irrespective of laboratory susceptibility data [20].
to 13%), GI upset (<10%) or liver enzyme abnormalities,
especially at higher doses. It requires dose adjustment in se-
vere renal impairment. It is a CYP450 inhibitor and can in-
teract with other drugs metabolized by these enzymes, but
TREATMENT there are few important interactions described for the drugs
commonly used in HIV infection. Rifampin can decrease
Many antifungal agents with activity against Candida spp. are the concentrations of fluconazole and may lead to treat-
now available. In general, therapy for mucosal candidiasis ment failure. Nevirapine can also reduce fluconazole levels,
can be given as local preparations (usually as mouthwashes, but the clinical significance is unknown. Fluconazole is
troches, or suspensions for oropharyngeal disease or as FDA category C for use in pregnancy and should be used
creams or suppositories for vaginal disease), or as systemic with caution. It can be used for treatment of mucosal
preparations for more severe infections (Table 28.2). Treat- and disseminated candidiasis and for prophylaxis. Resis-
ment of OPC is usually straightforward. In trials, response tance to fluconazole has been seen in patients who receive
rates vary from 34 to 95%. However, most studies of antifun- continuous or intermittent fluconazole [21]. It is active
gal treatment for mucocutaneous candidiasis suffer from one against most C. albicans strains; primary resistance is rare
or more weaknesses, such as small numbers of patients, het- but strains with decreased susceptibility emerge over time
erogeneous populations, short follow-up, and non-blinded at rates varying between 5 and 30% in patients with pro-
designs. In the case of HIV-associated Candida infection, stud- longed exposure to fluconazole [22]. C. glabrata and C. kru-
ies have not stratified patients by CD4 counts. This is impor- sei often have decreased susceptibility to fluconazole [23].
tant because persons with low CD4 counts respond more
slowly to treatment, have lower rates of fungal eradication,
and higher relapse rates than persons with less advanced
disease. Itraconazole
Itraconazole is another triazole agent. It is available in oral
capsules, pastilles, suspension, and intravenous infusion
(100–200 mg/day). Oral bioavailability is not as good as
Azoles
that of fluconazole, and it requires gastric acidity for ab-
The azoles are the most commonly used drugs and are sorption. It has a similar side-effect profile to fluconazole,
available as local (topical) and systemic products. They but drug interactions are more frequent. It is also category C
act as inhibitors of the demethylase enzyme involved in er- for use in pregnancy. It is active against mucosal candidia-
gosterol synthesis, ergosterol being the essential sterol on sis. There is cross-resistance with fluconazole, particularly
the fungal cell membrane. Drugs in this class include clo- in non-albicans species [24–26], but there are strains of
trimazole, ketoconazole, itraconazole, voriconazole, and C. albicans with reduced susceptibility to fluconazole that
posoconazole. may respond to itraconazole.
362
Table 28.2 Treatment guide
CLINICAL DRUGS MODE OF PREPARATION DOSE DURATION

SYNDROME DELIVERY
Vulvovaginal Clotrimazole; Topical Cream, pessary 3–5 days

candidiasis Miconazole;
Butoconazole;
Tioconazole
Boric acid PV Gelatin capsules 600 mg once daily 14 days
Fluconazole PO Capsule 150 mg Single dose
Oropharyngeal Clotrimazole Topical Troche 10 mg 5/day 7–14 days

candidiasis Nystatin Topical Suspension or 4–6 mL q.i.d 1–2 pastilles 7–14 days
pastilles 4–5 times/day
Amphotericin B Topical Suspension 1 mL ¼ 100 mg q.i.d. 7–14 days
Fluconazole PO Capsule 100–400 mg once daily 7–14 days
Itraconazole PO Capsule or solution 200 mg once daily 7–14 days
Esophageal Fluconazole PO/IV Capsule or infusion 200 mg once daily 14–21 days
candidiasis Itraconazole PO Solution 200 mg once daily 14–21 days
Caspofungin IV Infusion 70 mg loading then 14–21 days
50 mg/day
Micafungin IV Infusion 150 mg/day 14–21 days
Anidulafungin IV Infusion 100 mg load then 14–21 days
50 mg/day
Amphotericin B IV Infusion 0.6–1 mg/kg per day; 14–21 days
deoxycholate; lipid- 3–5 mg/kg per day
associated AmB
Voriconazole PO/IV Tablet or infusion 100–200 mg twice daily 14–21 days
Posaconazole PO Solution 400 mg once daily 14–21 days
Candidemia Fluconazolea IV Infusion 400–800 mg once daily 14–21 days; # from

negative cultures
Amphotericin B IV Infusion 0.5–0.6 mg/kg per day
deoxycholate
Lipid-associated AmB IV Infusion 3–5 mg/kg per day
Caspofungin IV Infusion 70 mg loading then
50 mg/day
Anidulafungin IV Infusion 100 mg load then
50 mg/day
Micafungin IV Infusion 150 mg/day
a
Consider switch to oral dosing towards end of treatment.
Voriconazole and posoconazole Cell wall synthesis inhibitors

Voriconazole and posoconazole are newer azole agents (caspofungin, anidulafungin,
available in oral and parenteral forms Although they are
and micafungin)
effective for the treatment of oral and esophageal candidia-
sis, they are significantly more costly. Voriconazole is asso- These are a new class of antifungal agents, of which caspo-
ciated with reversible visual disturbances (23%) [27]. Both fungin was the first to become readily available. They are
drugs have significant interactions with efavirenz, ritonavir, only available in intravenous formulation. The dose of cas-
and rifampin; concurrent use is not recommended. These pofungin is 70 mg as a loading dose, followed by 50 mg/
agents are rarely indicated as initial therapy but may be day, anidulafungin is given as a 100 mg load followed by
effective in patients with fluconazole-resistant disease, 50 mg/day, and the micafungin dose is 150 mg/day. A dos-
including infection caused by C. krusei [28]. age increase of caspofungin to 70 mg/day is required with
363
concomitant use of enzyme inducers such as rifampin, resolve within 2–3 days of starting fluconazole. Recurrent
NNRTIs, phenytoin, etc. These agents have been shown episodes often require higher doses and a more prolonged
to be effective and well tolerated in the treatment of esoph- therapy.
ageal candidiasis [29–31], including fluconazole-resistant The best way to prevent further episodes of candidiasis is
infection. with ART. However, recurrent symptomatic episodes may
prompt the need for suppressive therapy in selected pa-
tients. Prophylactic therapy for patients with frequent
Polyenes symptomatic recurrences limited to the oral mucosa should
Previously the mainstay of antifungal therapy, the polyenes be tailored to suit the clinical situation, and either intermit-
are increasingly regarded as second-line therapies because tent or continuous therapy can be considered. Oral flucon-
of issues of toxicity and bioavailability. Polyenes are azole 100-400 mg daily is usually the treatment of choice.
not well-absorbed after oral administration. This character- The risk of developing azole-resistant disease appears to be
istic makes them potentially useful as topical therapy in the same with either continuous or intermittent therapy
the management of mucosal disease, and oral suspensions [32]. If resistance develops, doses of up to 800 mg/day
of nystatin and amphotericin B are available. However, may be effective in some cases. Fluconazole resistance is of-
they must be administered frequently (4–5 times daily) ten (but not always) associated with cross-resistance to the
and in relatively large volumes to be most effective, and other azole antifungal agents. About half of patients with
these characteristics, in addition to their bitter taste, has fluconazole-unresponsive esophageal candidiasis respond
made them less popular than the azoles for local therapy. to itraconazole cyclodextrin solution at 100 mg twice daily.
Several formulations of amphotericin B are available for If antifungal resistance seems likely, a variety of alterna-
systemic use, including amphotericin B deoxycholate (dose tive strategies can be employed. First, as noted, azole cross-
0.6–1 mg/kg per day), amphotericin B lipid complex resistance is not universal, and a trial of itraconazole at
(ABLC) (5 mg/kg per day), amphotericin B colloidal dis- 200 mg twice daily is warranted. Use of itraconazole solu-
persion (3–6 mg/kg per day), and liposomal amphotericin tion is preferred, due both to its local effects and its better
B (3–5 mg/kg per day). Most experience in the treatment of absorption. Second, individuals with refractory esophageal
systemic candidiasis is with the traditional form of ampho- candidiasis have had response rates of approximately 50%
tericin B. The three newer lipid-associated formulations with voriconazole at its standard dosage of 200 mg twice
have not been shown to be superior to traditional ampho- daily. Third, topical solutions of polyenes may be used.
tericin but have less nephrotoxicity and are better tolerated. Fourth, the echinocandins have had response rates of
With the advent of better tolerated agents such as flucona- 70–80% for esophageal candidiasis, including fluconazole-
zole and caspofungin, amphotericin B is now regarded as resistant cases.
second-line therapy in proven candidiasis; the lipid formu-
lations are preferred in patients felt to be at high risk of
toxicities (renal, infusion reactions) from the traditional Esophageal candidiasis
formulation. Esophageal candidiasis requires systemic treatment. Oral
fluconazole at 200 mg/day for 14–21 days will resolve
symptoms in over 80% of patients within a week. Initial
Treatment of oropharyngeal and
therapy with intravenous preparations may be needed in
esophageal candidiasis patients who have severe odynophagia or dysphagia.
Oropharyngeal candidiasis Azoles, echinocandins, and amphotericin B are the agents
of choice in descending order. Itraconazole solution and
Initial episodes of oropharyngeal candidiasis usually re- voriconazole are as effective as fluconazole but are gener-
spond well to any antifungal agent: topical azoles (clotri- ally reserved for refractory cases. Patients with advanced
mazole one 10 mg troche 5 times/day); oral azoles AIDS patients who are not taking ART are likely to suffer
(fluconazole 100 mg/day for 7–14 days; itraconazole solu- from recurrent infections, and long-term suppressive therapy
tion 100 mg/day 7–14 days or ketoconazole) or oral poly- with fluconazole 200 mg daily may be required.
enes (nystatin suspension/pastilles or oral amphotericin
B). Patients with mild OPC, especially those with less ad-
vanced immunosuppression can be treated with topical Treatment of vulvovaginal
agents, as these are less likely to have systemic side effects.
candidiasis
Of the systemic agents, fluconazole has been well studied
and is as effective or superior to topical therapy. Doses Symptomatic relief is the aim of treatment. Topical agents
can range from 50 to 200 mg daily for uncomplicated are often most effective, with systemic therapy needed for
OPC, but higher doses should be used if there is a suspicion severe or recurrent cases. Uncomplicated VVC usually
of esophageal involvement or if the patient has more ad- responds well to topical agents such as clotrimazole, mi-
vanced HIV disease. In general, the first episode of OPC will conazole, butoconazole, tioconazole creams, and pessaries
364
or boric acid 600 mg gelatin capsules administered intra- attributed to the restoration of cell-mediated immunity,
vaginally daily for 2 weeks. Oral fluconazole 150 mg as a sin- as reflected in the rise in CD4 count, there have been some
gle dose orally is very effective. Alternatively, itraconazole interesting data suggesting a direct anti-candidal effect
(200 mg twice daily for 1 day or 200 mg/day for 3 days) exhibited by HIV protease inhibitors both in vitro [34,
or ketoconazole (400 mg twice daily for 5 days) can be used. 35] and in vivo [36]. This has been attributed to inhibition
More complicated vaginitis requires longer duration of of secreted aspartic proteinases (Saps) by HIV protease in-
therapy, either topical treatment for 7 days or oral therapy with hibitors [37]. Saps are key virulence factors of C. albicans.
two doses of fluconazole 150 mg 72 h apart. Non-albicans Inhibition of Sap expression is not seen with other antire-
Candida infection may not respond as well to azole therapy troviral classes [38, 39]; however, there are little data to sug-
but is an infrequent cause of vulvovaginal candidiasis. gest that PIs are associated with better control of mucosal
Recurrent disease is usually due to azole-susceptible candidiasis than other antiretrovirals.
C. albicans and may require prolonged therapy or even One manifestation of the successful treatment of HIV-
long-term prophylaxis with weekly fluconazole. This may infected persons with effective ART is a risk of developing
select for non-albicans strains, but the significance of this immune reconstitution inflammatory syndrome (IRIS).
is not certain [33]. This manifests as the development of an acute inflammatory
reaction to opportunistic pathogens as the immune system
recovers. This is most commonly seen with mycobacterial
Treatment of candidemia disease; however, cases describing IRIS with candidiasis
This is a serious infection with a significant mortality and pro- (OPC) [40, 41] have been reported.
pensity to disseminate and cause end-organ disease. Along Candidiasis is a sign of the failure of the immune system,
with definitive antifungal therapy, removal of an infected in- which is usually well controlled with effective ART. The de-
travascular catheter and evaluation for metastatic disease (i.e. velopment of candidiasis should therefore be taken as an in-
ophthalmologic evaluation, echocardiography) are advised. dication to initiate ART or to look for evidence of virologic
Parenteral therapy is usually indicated initially with intrave- failure. The development of candidiasis in a patient already
nous fluconazole, caspofungin or amphotericin B. The choice taking ART suggests treatment failure due either to non-
of agent should be based on the individual patient’s status, adherence, the development of resistant HIV, or both.
prior antifungal exposure, likely causative organism or defin-
itive microbiological data. Most patients can be switched to
high-dose oral fluconazole (800 mg/day) when clinically sta-
ble. Therapy for candidemia should be given for at least 14
PREVENTION OF CANDIDA
days after sterilization of the blood cultures. INFECTIONS
As previously noted, several studies have shown that flu-

Candida and ART
conazole, given daily or even weekly, could significantly re-
Since the introduction of HAART in the late 1990s, the inci- duce the incidence of mucosal candidiasis in patients with
dence and prevalence of opportunistic infections (OIs) in advanced HIV disease. Fluconazole has also been shown to
HIV-infected individuals on therapy has declined. This is be effective in reducing the prevalence of other invasive
true not only for initial episodes of mucosal or esophageal fungal infections. However, in the developed world, rou-
candidiasis but also for more advanced disease. For example, tine prophylaxis for candidiasis has not been routinely
fluconazole-resistant candidiasis, which once had a preva- recommended, largely because of cost and fears of resis-
lence of over 20% in cohort studies, is now extremely un- tance. Prophylaxis can be used in certain recurrent cases
common. However, in the resource-limited setting where [42], especially with esophageal disease. However, the
ART is not widely available, candidiasis is still prevalent. availability of potent antiretroviral therapy has eliminated
A large number of studies published after the availability the need for specific antimicrobial prophylaxis, an observa-
of ART showed a decline in the incidence and prevalence tion that is as true for Candida infection as it is for other
of mucosal candidiasis. Although this can largely be opportunistic diseases.
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367
Chapter | 29 |
Cryptococcosis and other fungal infections
(histoplasmosis and coccidioidomycosis)
in HIV-infected patients
Kathleen R. Page, Richard E. Chaisson, Merle Sande
On the basis of antigenic differences in the capsule,

INTRODUCTION biochemical use of nutrients, and distinct DNA base se-
quences, four serotypes (A, B, C, and D) of Cryptococcus
Systemic fungal infections are generally late manifestations have been delineated. Serotypes A and D are classified as
of HIV disease. Overall, cryptococcal infection is the most C. neoformans var. neoformans, and serotypes B and C are
common systemic fungal infection in HIV-infected patients. classified as C. neoformans var. gatii [2]. Cryptococcus neofor-
However, in certain endemic regions, histoplasmosis or coc- mans var. neoformans is the major cause of cryptococcal dis-
cidioidomycosis are more prevalent. These diseases can affect ease worldwide. Serotype A is the most common serotype
patients without HIV, but among HIV-infected patients, they infecting AIDS patients [3, 4].
tend to occur when the CD4 count is < 200 cells/mm3. Im-
mune reconstitution with antiretroviral therapy (ART) has
led to significant declines in the incidence of fungal disease Epidemiology
among HIV-infected individuals. However, among patients Before the onset of the AIDS epidemic, cryptococcal infec-
with limited access to ART, opportunistic infections with tion occurred in a small number of immunocompetent in-
fungal pathogens remain a major cause of death. This chap- dividuals, but most often in patients with a compromised
ter reviews the approach to diagnosis and management of immune system, such as diabetics, transplant recipients,
the most commonly occurring systemic mycosis in HIV- patients with lymphoma, or patients requiring chronic ste-
infected patients: cryptococcosis, histoplasmosis, and roid therapy [5]. In the AIDS era, cryptococcal disease be-
coccidioidomycosis. came a leading opportunistic infection, affecting 6–10%
of HIV-infected patients [6–10]. It is the third most com-
mon central nervous system (CNS) disorder in AIDS pa-
tients after toxoplasmosis and HIV dementia [11].
CRYPTOCOCCUS In the past decade the incidence of disease caused by
C. neoformans in developed countries has decreased dra-
matically, in part due to more widespread use of azole ther-
Microbiology
apy [12], but primarily resulting from the introduction of
Cryptococcus neoformans is a round or oval yeast (4–6 mm in highly active antiretroviral therapy (HAART). Surveillance
diameter), surrounded by a capsule that can be up to 30 mm and clinical studies in the USA and Europe have shown a
thick. The organism grows readily on fungal or bacterial 2- to 10-fold decrease in the incidence of cryptococcosis
culture media and is usually detectable within 1 week after since the introduction of HAART [9, 11, 13, 14]. Demo-
inoculation, although in some circumstances up to 4 weeks graphic characteristics of patients with cryptococcosis show
are required for growth. It grows well at 37 C, does not that poor access to medical care is a major risk factor for
form pseudomycelin on cornmeal or rice-Tween agar, developing cryptococcal disease in the HAART era [14-17].
and hydrolyzes urea, a property that allows rapid presump- However, in areas of the world with limited access to
tive identification [1]. ART, cryptococcosis remains a major cause of morbidity
369
and mortality. It is estimated that there are approximately 1 but occasionally can present with focal neurologic signs as-
million cases of HIV-associated cryptococcosis annually, sociated with mass lesions (cryptococcomas). In a prospec-
the majority occurring in resource-limited settings [18]. tive study conducted in Uganda, 20% of HIV-infected
Studies from sub-Saharan Africa and Southeast Asia show patients presenting with headaches were diagnosed with
that up to one-third of patients infected with HIV develop cryptococcal meningoencephalitis [29]. Classic signs of
cryptococcal disease [19-21], which is a major cause of meningeal irritation are uncommon. HIV-infected patients
death among HIV-infected patients [22]. Despite antifun- presenting with seizures, altered mental status, psychosis,
gal therapy, mortality from cryptococcal disease in these and dementia should be evaluated for cryptococcal menin-
settings is exceedingly high [18, 22, 23], with an average goencephalitis. Pulmonary or disseminated disease may
survival of < 6 months after diagnosis [24, 25]. In sub- be associated, but usually CNS disease presents in isolation.
Saharan Africa, the estimated mortality attributed to cryp- The physical examination in patients with cryptococcal
tococcal meningoencephalitis ( 500,000 deaths per year) disease is non-specific, with fevers in approximately half
is higher that the mortality attributed to tuberculosis the cases, but less than one-third with nuchal rigidity or
(350,000 deaths/year) [18]. Poor outcomes may be related other neurologic deficits [7]. Altered mental status, which
to the late presentation of disease and suboptimal manage- is the most important predictor of poor outcome, is present
ment of raised intracranial pressure. in 20–30% of patients with cryptococcal disease. Papilledema
is seen in < 10% of patients. Raised, sometimes umbilicated,
typical skin lesions that resemble those caused by molluscum
Natural history, pathogenesis, contagiosum or Penicillium marneffei are reported in 3–10%
and pathology of patients with cryptococcal meningoencephalitis.
Cryptococcus neoformans infection is acquired from the envi- Immune reconstitution syndrome (IRIS) occurs in 8-49%
ronment. Because it is ubiquitous in soil and dust, exposure of patients with cryptococcosis treated with ART [30]. The
to the organisms is practically unavoidable. The organism, syndrome is characterized by a paradoxical clinical deterio-
most likely in an encapsulated form, is inhaled into the ration resulting from an exuberant inflammatory response
lungs and deposited in the small airways. Once there, yeast that may manifest itself as worsening or new lymphadenop-
multiply and compress the surrounding tissue but cause lit- athy, mediastinitis, pneumonitis, new headache and stiff
tle damage, and pulmonary infection is often asymptom- neck, CNS lesions, increased intracranial pressure, or subcu-
atic. Indeed, in 85–95% of patients with cryptococcal taneous abscesses [30–35]. The onset of IRIS usually occurs
meningoencephalitis, no evidence of pneumonitis is pre- between the first and tenth month of ART initiation [30].
sent [7, 26]. The organism has a strong propensity for dis- Several factors have been associated with the risk of IRIS, in-
semination to the CNS but also may infect skin, bone, and cluding high baseline viral load, initiation of ART during in-
the genitourinary tract. duction therapy, rapid rise in CD4 count, high cryptococcal
titers, and lack of CSF inflammation at baseline [30, 36–38].
Usually C. neoformans cultures are negative.
Clinical features
The onset of cryptococcal disease usually is insidious. The
most common symptoms are headache, malaise, and a pro- Patient evaluation, diagnosis,
longed febrile prodrome that may be indistinguishable and differential diagnosis
from symptoms caused by other opportunistic infections
Cryptococcal meningoencephalitis is by far the most com-
[7, 26–28]. The median time between the onset of symp-
mon manifestation of cryptococcosis in HIV-infected pa-
toms and the diagnosis of cryptococcal disease is 30 days
tients. The most common symptoms are fever, malaise,
[7, 26, 27]. Diagnosis is often delayed by the waxing and
and worsening headaches over the course of a few weeks,
waning course of the disease and the absence of specific
but the indolent and non-specific presentation requires a
symptoms.
high index of suspicion to diagnose the disease in a timely
manner. Although the presentation is subacute, and not
CRYPTOCOCCAL usually suggestive of bacterial meningoencephalitis, in a
study from Malawi, 10% of suspected bacterial meningoen-
MENINGOENCEPHALITIS cephalitis cases turned out to be cryptococcal meningoen-
cephalitis [39]. The CD4 count can help guide the work-up
CNS involvement is the most serious and common mani- and differential diagnosis. While cryptococcal meningoen-
festation of cryptococcal disease in HIV-infected patients. cephalitis is rare in patients with a CD4 count > 100 cells/
Over 75% of HIV-associated cryptococcal meningoenceph- mm3, it is the leading diagnosis for HIV-infected patients
alitis occurs in patients with CD4 counts < 50 cells/mm3. with low CD4 counts presenting with fever and headache.
In general, CNS disease presents as a chronic meningoen- The differential diagnosis depends to some extent on local
cephalitis, with headaches, nausea, and photophobia, epidemiology. Central nervous system (CNS) tuberculosis
370
Chapter | 29 | Cryptococcosis and other fungal infections (histoplasmosis and coccidioidomycosis)
Table 29.1 Differential diagnosis of HIV-associated fungal infections
CRYPTOCOCCAL SPECIFIC FEATURES DISSEMINATED SPECIFIC COCCIDIOIDOMYCOSIS

MENINGO- HISTOPLASMOSIS FEATURES
ENCEPHALITIS
Non-focal examination: Tuberculosis Tuberculosis
CNS tuberculosis Basilar involvement Pneumocystis Pneumocystis pneumonia

pneumonia
Coccidioidomycosis SW USA, Central and Coccidioidomycosis SW USA, Central Community-acquired

South America and South America pneumonia
Histoplasmosis Ohio/Mississippi river Paracoccidioidomycosis Central and South Histoplasmosis

valleys, Central America
America
Penicilliosis Southeast Asia Blastomycosis Ohio/Mississipi river Paracoccidioidomycosis

valleys, Central
America
Focal examination, also includes: Penicilliosis Southeast Asia Blastomycosis
Toxoplasmosis Usually no headache Melioidosis Southeast Asia, Penicilliosis

(Burkholderia Australia
pseudomallei)
CNS lymphoma Rhodococcus equi Rural exposure Melioidosis
(B. pseudomallei)
Cysticercosis Rhodococcus equi
(non-USA)
(TB) is a major concern in patients from TB-endemic areas. patients with advanced disease. In such scenarios, it is ap-
Other considerations include chronic fungal infections propriate to screen ambulatory HIV-infected patients pre-
such as penicillosis in patients from Southeast Asia and his- senting with headaches with a serum CRAG and a chest
toplasmosis or coccidioidomycosis in patients from Latin radiograph to rule out tuberculosis. Patients with a posi-
America. In patients who present with focal neurologic def- tive CRAG, negative chest radiograph, and no focal neuro-
icits or seizures, the differential diagnosis can also include logic signs, headache, or altered consciousness can be
toxoplasmosis, CNS lymphoma, and other non-HIV re- successfully treated with oral fluconazole. In Uganda,
lated conditions, such as cysticercosis or CNS malignancy. screening with serum CRAG detected cryptococcal infec-
Despite an extensive differential diagnosis, the diagnosis of tion 20 days before the onset of frank meningoencephali-
cryptococcal meningoencephalitis is generally straightfor- tis, and early therapy with fluconazole reduced mortality
ward due to the characteristic elevation in intracranial pres- rates and was cost-effective [29, 42]. However, patients
sure and the high sensitivity and specificity of cryptococcal with altered mental status or focal neurologic signs must
antigen tests (Table 29.1). have a lumbar puncture performed to confirm the diagno-
If available, the serum cryptococal antigen (CRAG) test sis and to appropriately manage elevated intracranial
is an excellent starting point for the evaluation of crypto- pressure [41]. The CSF CRAG has high sensitivity
coccal meningoencephalitis. Serum CRAG tests are posi- (93–99%) and specificity (93–98%) [7, 26, 43] and can
tive in over 99% of patients with cryptococcosis and can expedite or exclude the diagnosis of cryptococcal menin-
be used to rule out cryptococcal meningoencephalitis in goencephalitis (Table 29.2).
HIV-infected patients with a fever and a headache The CSF profile of HIV-infected patients with cryptococ-
(Fig. 29.1) [40]. In the USA, a lumbar puncture is recom- cal meningoencephalitis is normal in 25–50% of patients
mended if the serum CRAG is positive to evaluate for the [7, 26, 44–46]. Over 50% of patients have a low CSF white
presence of CNS involvement and to measure intracranial blood count (<20/mm3), and the India ink preparation is
pressure [41]. However, in resource-limited settings lum- positive in 74–88% of cases [7, 26, 45–47]. Interpretation
bar punctures may only be practically available for of the India ink stain should be performed by an
371
Figure 29.1 Algorithm for the work-up of

cryptococcal meningoencephalitis.
HIV-infected
Subacute headache
Fever
CD4 count < 100 CD4 count >100

cells/mm3 cells/mm3
Cryptococcal Cryptococcal
serum antigen serum antigen Cryptococcus
negative positive unlikely
Evaluate other Lumbar puncture

etiologies with opening pressure
(prior brain imaging
if feasible or
focal exam)
CSF cryptococcal CSF cryptococcal

antigen positive antigen negative
Treat for Treat for

cryptococcal non-CNS
meningo- cryptococcosis
encephalitis with
antifungals and
intracranial
pressure
management
experienced technician since false-positive tests have been improved with better therapeutic management and
reported. After staining, C. neoformans is visible as round ART, 10–20% of patients die or fail therapy despite access
cells 4–6 mm in diameter surrounded by a characteristic to tertiary care [28, 47]. In areas with limited medical re-
thick polysaccharide capsule (Fig. 29.2). Budding forms sources, mortality rates are even higher [22, 25, 33, 48]. In
can usually be detected with viable C. neoformans. the post-HAART era in Uganda, 20% of hospitalized pa-
The gold standard diagnostic test for cryptococcal menin- tients with CSF-confirmed cryptococcal meningoenceph-
goencephalitis is a positive CSF culture for C. neoformans. alitis died within the first two weeks of therapy and only
CSF fungal cultures require a minimum of 2 mL to obtain 41% survive 6 months [25]. The most important baseline
maximum sensitivity. By definition, 100% of cases of cryp- prognostic factor is mental status at the time of presenta-
tococcal meningoencephalitis have positive CSF fungal tion. Individuals with altered sensorium have a much
cultures. Approximately 50–80% of HIV-infected patients worse prognosis than those who are awake and alert
with cryptococcal meningoencephalitis have positive blood [27, 47, 49]. High fungal burden, a positive India ink test,
cultures for C. neoformans [27, 47, 48]. elevated intracranial pressure, and lack of inflammatory
cells in the CSF are also associated with poor outcomes
[25, 27, 28, 47, 49, 50]. Early detection of cryptococcal
Prognosis
infection with serum CRAG testing and treatment with
Left untreated, cryptococcal meningoencephalitis is uni- fluconazole can decrease the rate of progression and mor-
formly fatal [29]. Although survival in HIV-infected tality from cryptococcal disease in resource-limited set-
patients with cryptococcal meningoencephalitis has tings [42].
372
Table 29.2 Sensitivity of commercially available non-culture-based diagnostic methods
DISEASE SEROLOGY ANTIGEN DETECTION
Cryptococcosis
Disseminated N/A Serum: 99% [49]
Pulmonary N/A Serum: 96% [59]
Meningeal N/A Serum: 99%,a [54]

CSF: 93–100% [49]
Histoplasmosis
Disseminated Serum: 67–70%,b [108] Serum: 80% Urine: 90% [108, 112]
Pulmonary Serum: 90–100% [108] Urine: 15% [108]
Meningeal CSF: 70–88% [98, 107–109] CSF: 40–70% [108, 109]
Coccidioidomycosis
Disseminated Serum: 75–94% [133, 135, 145, 149] N/A
Pulmonary Serum: <10% [133] N/A
Meningeal CSF: 50% [147] N/A

a
Not specific for meningoencephalitis; must evaluate CSF.
b
Does not distinguish active disease from prior infection.
A B
Figure 29.2 (A) Mature Cryptococcus neoformans colony. (B) Microscopic appearance of C. neoformans.
Photographs courtesy of Dr William Merz, Department of Pathology, Johns Hopkins University School of Medicine.
Treatment
intracranial pressure and IRIS, and the use of lipid formula-
Early diagnosis is crucial to improving treatment outcomes tions of amphotericin B in patients with renal impairment
for HIV-infected patients with cryptococcosis. Other key [41]. However, in many settings, management options
factors for providing optimal care include early induction may be limited by the medical resources available. In all
therapy for meningoencephalitis followed by suppressive cases, treatment of the underlying immunosuppression
regimens, early recognition and management of elevated from HIV infection is critical to managing cryptococcosis
373
The treatment of cryptococcal meningoencephalitis mycologic clearance at 2 weeks of therapy [48]. Therefore,
in AIDS patients requires initial induction therapy with a amphotericin and flucytosine combination therapy is
fungicidal regimen, preferably amphotericin B and flucyto- recommended in the USA. Of note, flucytosine causes signif-
sine, followed by suppressive therapy with fluconazole icant hematologic toxicity, and levels and hematologic para-
(Table 29.3). Amphotericin B is more effective than azole menters should be monitored closely. Patients who develop
therapy during the initial phase of treatment, leading to fas- amphotericin-related nephrotoxicity or infusion reactions
ter sterilization of the CSF and fewer relapses [47, 51, 52]. can be treated with lipid formulations of amphotericin,
The addition of flucytosine increases the efficacy of ampho- which are associated with less toxicity and similar efficacy,
tericin [28, 41, 52]. A randomized study from Thailand but are more costly [54–56].
showed that the combination of amphotericin B and flucy- In resource-limited settings, optimal induction therapy
tosine cleared Cryptococcus from the CSF faster than ampho- with amphotericin B and flucytosine may not be feasible
tericin B alone, amphotericin B and fluconazole, or triple due to lack of medications or inability to monitor toxicity,
therapy with amphotericin B, flucytosine, and flucona- and oral fluconazole is an alternative for the treatment
zole [53]. The prospective multicenter study CryptoA/D of cryptococcal meningoencephalitis in patients with
also showed that flucytosine therapy was associated with mild symptoms and normal sensorium. Results from
Table 29.3 Therapy of HIV-associated cryptococcal meningoencephalitis
REGIMEN DURATION EVIDENCEa
Induction therapyb
Preferred
Amphotericin B (0.7–1.0 mg/kg/day)c þ flucytosine 2 weeks 1
(100 mg/day)d
If flucytosine intolerant:
Amphotericin B (0.7–1.0 mg/kg/day) or liposomal 4–6 weeks 2
amphotericin B (3–4 mg/kg/day or amphotericin
B lipid complex (5 mg/kg/day)
Alternatives for resource-limited settings

Amphotericin B (0.7-1.0 mg/kg/day) þ fluconazole 2 weeks 1
(800 mg/day)
Fluconazole (>800 mg/day) þ flucytosine 6 weeks 2
Fluconazole (>1200 mg/day) 10–12 weeks 2
Consolidation therapy
Fluconazole (400–800 mg/day)e 8 weeks 1
Maintenance therapy
Fluconazole (200 mg/day) Until CD4 count > 100 cells/mm3 and/or 1
viral load undetectable for > 3 months with
at least 1 year of total therapy
Primary prophylaxis Not recommendedf

a
Evidence 1 ¼ randomized clinical study, 2 ¼ clinical trial > 20 patients
b
Manage elevated intracranial pressure with serial lumbar puncture if necessary.
c
Alternative: liposomal amphotericin B (3–4 mg/kg/day) for patients with renal dysfunction.
d
Monitor renal function on amphotericin, and flucytosine blood levels and/or hematologic parameters.
e
Use higher-dose fluconazole (800 mg/day) during consolidation if using alternative induction regimen.
f
Consider checking serum cryptococcal antigen in areas with high incidence of cryptococcemia prior to ART initiation.
374
several studies evaluating the efficacy of fluconazole Management of elevated intracranial

monotherapy for cryptococcal meningoencephalitis have pressure
been mixed [57, 58], but a recent study found treatment
success rates over 60% using higher doses of fluconazole Elevated intracranial pressure is a common and potentially life-
(1,600–2,000 mg daily) [59]. Nausea and vomiting are threatening complication of cryptococcal meningoencephali-
common, but may be alleviated by administering 3 to 4 di- tis [7, 63]. Early recognition and treatment of increased
vided doses daily. Therefore, patients with cryptococcal me- intracranial pressure is a key principle for optimal manage-
ningoencephalitis without neurologic complications may ment [41]. In contrast to the usual pathophysiology of chronic
be appropriately treated with 10 weeks of oral high-dose meningoencephalitis, in which pro-inflammatory responses
(> 800 mg daily, 1,200 mg/day preferred) fluconazole fol- play an important role, cryptococcal meningoencephalitis
lowed by lower-dose maintenance therapy (200–400 mg in HIV-infected patients is notable for a lack of inflammatory
daily) [41]. Primary and secondary fluconazole resistance cells and seems to be directly related to high fungal titers
may be an issue in patients treated with fluconazole alone, which cause an outflow obstruction. However, immune recon-
and MIC testing may be indicated in some cases. In a small stitution in patients receiving ART may lead to an inflamma-
retrospective study of HIV-infected African patients with tory response that increases intracranial pressure.
cryptococcal meningoencephalitis treated with fluconazole In a retrospective study of 211 HIV-infected patients with
monotherapy, 76% of the isolates recovered during treat- cryptococcal meningoencephalitis, 60% were found to have
ment failure had reduced susceptibility to fluconazole initial opening pressures of 250 mmH2O, and 30% had a
[60]. If flucytosine is not available, fluconazole (800 mg/ pressure 350 mmH2O [49]. Those with opening pressures
day) can be used as a substitute in combination with 350 mmH2O had a significantly higher fungal burden and
amphotericin B during the first two weeks of induction were more likely to have papilledema, hearing loss, and
therapy [41]. meningismus [49]. Interestingly, this group was less likely
Following the 2-week induction phase with parenteral to have fever and night sweats, perhaps reflecting an impaired
therapy, patients can be switched to oral fluconazole ability to mount an inflammatory response. However, clini-
(400 mg/day) for 8 weeks (consolidation therapy). It is cal findings were not sensitive or specific predictors of intra-
commonly recommended that CSF be evaluated for steril- cranial pressure elevation, and opening pressures should be
ity after this period. The cryptococcal CSF antigen may re- measured in all patients with cryptococcal meningoenceph-
main positive for up to 1 year after successful therapy, so alitis without contraindication to a lumbar puncture. If avail-
fungal cultures of the CSF should be performed. Prolonga- able, radiologic imaging of the brain is recommended prior to
tion of induction therapy is appropriate in patients who re- lumbar puncture in patients with focal neurologic signs or
main comatose, have persistently elevated intracranial impaired mentation [63]. In resource-limited settings where
pressures, or are clinically deteriorating [41]. imaging is not available, no adverse outcomes have occurred
Persistent infection is generally defined as persistently in patients without focal neurologic deficits undergoing
positive CSF cultures after 4 weeks of adequately dosed lumbar puncture with adequate monitoring of opening
therapy [41]. Due to a paucity of relevant trials, recommen- and closing pressures [64].
dations for “salvage therapy” are predominantly based on The best intervention for elevated intracranial pressure as-
expert opinion. Patients with persistently positive cultures sociated with cryptococcal meningoencephalitis is drainage
should have their immune status optimized with ART and of the CSF. This can usually be accomplished by large-volume
induction therapy should be reinitiated, usually with lumbar punctures removing up to 30 mL of CSF at one time,
higher doses of amphotericin. If possible, drug resistance which should be repeated daily until the intracranial pressure
should be evaluated in persistent isolates. Small open-label normalizes and symptoms have been stabilized for at least 2
salvage trials have reported treatment success with vorico- days [41]. Patients who require frequent lumbar punctures or
nazole or posiconazole as salvage therapy in 40–50% of whose opening pressure is > 400 mm H2O may benefit from
patients with persistent cryptococcosis [41, 61, 62]. a lumbar drain. Ventriculoperitoneal shunting may be indi-
cated for persistently elevated pressures or progressive neuro-
logic deficits [41, 65–68]. Patients with rising intracranial
Cerebral cryptococcomas pressure while on treatment are at high risk of adverse out-
Cerebral cryptococcomas are rare but require prolonged comes and death [49].
courses of induction and maintenance therapy. Induction Perhaps due to the sparse cellular infiltrate and limited
therapy with amphotericin B and flucytosine is recom- host response, corticosteroids do not improve clinical out-
mended for at least 6 weeks, followed by consolidation comes in HIV-associated cryptococcal meningoencephalitis
therapy with fluconazole (400–800 mg daily) for 6 to 18 [49]. However, patients experiencing major complications
months, depending on clinical response. Corticosteroid from ART-associated IRIS may benefit from corticosteroids.
therapy may be necessary in cases of mass effect surround- A 2- to 4-week course of steroids is reasonable, but may be
ing the lesions, and surgery may be appropriate for large extended depending on the clinical scenario and patient
accessible lesions associated with mass effect [41]. response. There is not enough experience to recommend
375
non-steroidal anti-inflammatory agents or thalidomide for cryptococcal meningoencephalitis [41]. Prolonged delays
the treatment of IRIS. in ART initiation should be avoided to prevent other com-
plications and mortality from untreated HIV infection.
Screening for asymptomatic antigenemia should be consid-
Relapses ered in patients with CD4 counts < 100 cells/mm3 living in
Over one-third of patients successfully treated for cryptococ- high incidence areas, such as sub-Saharan Africa or South-
cal meningoencephalitis will relapse without maintenance east Asia. Subclinical antigenemia can successfully be trea-
therapy [69]. Relapse rates are even higher in patients treated ted with fluconazole, but without therapy is a major risk
only with fluconazole during induction therapy [60]. There- factor for IRIS [42, 78–80].
fore, following the 8 weeks of 400 mg/day fluconazole, pa-
tients must be placed on suppressive antifungal therapy [69].
Lower-dose fluconazole (200 mg/day) is the preferred main- EXTRANEURAL CRYPTOCOCCOSIS
tenance regimen. Fluconazole maintenance therapy is supe-
rior to amphotericin or itraconazole for preventing relapses The incidence of extraneural cryptococcal disease in AIDS pa-
[70]. Another major strategy to prevent relapses is the initi- tients ranges between 20 and 60% [7, 26, 81, 82]. Despite en-
ation of ART. Several studies in patients with a history of try through the lung, evidence of pulmonary symptoms
cryptococcal meningoencephalitis have shown that mainte- is present in only 20–30% of cases. Other sites of extraneural
nance therapy can be safely discontinued in patients on ART involvement include the joints, oral cavity, pericardium,
with sustained immunologic and virologic responses (CD4 myocardium, skin, mediastinum, and genitourinary tract.
counts > 100 cells/mm3 or undetectable viral load for more
than 3 months) [71–75]. In a retrospective multicenter study
of 100 patients with a history of cryptococcal meningoen- Diagnosis
cephalitis, the incidence of relapse after discontinuation of The serum CRAG test has excellent sensitivity and specific-
fluconazole was only 1.5/100 person-years among patients ity for the diagnosis of disseminated cryptococcosis with-
on ART with a CD4 counts > 100 cells/mm3 [73]. In a small out CNS involvement. Serum CRAF 1:8 should always
trial of 42 patients with cryptococcal meningoencephalitis be treated regardless of symptoms. Fungal blood cultures
randomized to continue or discontinue fluconazole mainte- are often positive and bone marrow examination does
nance therapy when the CD4 count increased to greater than not increase the diagnostic yield [83]. In contrast to immu-
100 cells/mm3 and the viral load was undetectable, there nocompetent patients with cryptococcal pneumonia, in
were no relapses in the discontinuation arm after 48 weeks whom the serum CRAG is often negative, HIV-infected pa-
of follow-up [75]. tients with pulmonary cryptococcosis usually have a posi-
tive test [84]. HIV-infected patients with pneumonia and
a CD4 count 100 cells/mm3 should also have fungal cul-
Timing of ART and IRIS
tures of sputum performed. C. neoformans can be readily
There are no large studies that definitively establish the best identified using methenamine silver, mucicarmine, and pe-
timing for ART initiation in patients with cryptococcal me- riodic acid-Schiff stains, but cannot be detected with regu-
ningoencephalitis. In a retrospective study from France, 10 lar Gram’s stain of tissue.
out of 120 patients with cryptococcal meningoencephalitis
who initiated ART developed IRIS, and 3 of the 10 died. De-
Treatment
velopment of IRIS was associated with initiating ART
within 2 months of the diagnosis of cryptococcosis [37]. In immunocompetent patients, asymptomatic pulmonary
In contrast, a recent prospective cohort study of 101 AIDS cryptococcosis often resolves spontaneously and does not
patients with cryptococcal meningoencephalitis found an require antifungal therapy. In HIV-infected patients, how-
association between high cryptococcal antigen titers and ever, pulmonary cryptococcosis should always be treated
the risk of IRIS, but not with the timing of ART [38]. In a to prevent disseminated disease [41]. Isolated cryptococc-
study of 282 AIDS patients with opportunistic infections, emia indicates deep tissue invasion and should also be trea-
early ART (within 14 days of starting opportunistic ted. In any presentation of extraneural disease, a lumbar
infections treatment) improved survival/AIDS progression puncture should be performed to rule out CNS involvement.
compared to delayed ART (after completion of acute op- The treatment of extraneural cryptococcosis does not
portunistic infections therapy), and there was no associa- usually require parenteral therapy except in cases of severe
tion between timing of ART and IRIS [76, 77]. Although pneumonia (acute respiratory distress syndrome) which
only 35 patients in this trial had cryptococcal meningoen- should be treated like CNS disease. Most cases of mild to
cephalitis, there was a trend towards improved survival in moderate disease are treated with daily oral fluconazole
patients receiving early ART [77]. The most recent guide- (400 mg/day) [57]. The length of therapy has not been well
lines from the Infectious Disease Society of America recom- established in clinical trials, though most experts advocate
mend initiating ART within 2 to 10 weeks of diagnosis of continuing lifelong therapy. In patients on ART, therapy
376
may be discontinued after 1 year of treatment if the CD4 humans: H. capsulatum var. capsulatum and H. capsulatum
count rises over 100 cells/mm3 and the cryptococcal var. duboisii. The former is smaller (1–4 mm) and is found
antigen titer is < 1:512 [41, 85]. in the Americas, parts of Africa, Asia, and Australia. The lat-
ter measures 10–12 mm, is found only in Africa, and is the
cause of African histoplasmosis [90].
Primary fungal prophylaxis
Three studies have evaluated the role of primary prophylac-
tic antifungal therapy for HIV-infected patients with low Epidemiology
CD4 counts [86–88]. Two studies conducted in the USA Histoplasmosis is endemic in the central and south regions
showed that fluconazole prophylaxis decreased the inci- of the USA [90]. The endemic area extends along the Ohio
dence of cryptococcosis, and itraconazole prophylaxis and Mississippi river valleys north into the Canadian prov-
decreased the incidence of both cryptococcosis and histo- inces of Quebec and Ontario and south into Mexico,
plasmosis, especially in patients with CD4 counts <50 Central and South America.
cells/mm3, but there was no survival benefit [87, 88]. Given HIV-infected patients often serve as sentinel markers
the relatively low prevalence of systemic fungal infections for histoplasmosis outbreaks [91]. During an outbreak
in the USA, the widespread use of ART, and the risk of pro- in Indianapolis before the HAART era, the incidence
moting drug resistance, routine antifungal primary prophy- of histoplasmosis in HIV-infected individuals was 27%,
laxis is not routinely advocated. However, it may be and among those afflicted, histoplasmosis was the initial
considered in HIV-infected patients with CD4 counts AIDS-defining illness in 50% [92]. The incidence of dissem-
< 100 cells/mm3 in areas where there is limited availability inated histoplasmosis has declined with the introduction of
of ART and the incidence of cryptococcosis or other fungal HAART [93].
infections, such as histoplasmosis or coccidioidomycosis, H. capsulatum prefers moderate, humid climates and is
is high. Asymptomatic cryptococcal antigenemia has been found in soil and droppings from birds and bats [94].
associated with increased mortality in patients initiating The organism has never been cultured from birds, but
ART. Screening patients with CD4 counts< 100 cells/mm3 it can infect bats, and rarely dogs, cats, horses, swine,
with CRAG testing and offering preemptive therapy for and a variety of rodents [90]. Certain areas, such as caves,
patients with a positive result is cost-effective in settings with chicken coops, bird roosts, and old buildings, are noto-
high incidence of cryptococcosis [42, 89]. rious for having high burdens of H. capsulatum, and
histoplasmosis can be an occupational hazard [90, 94].
HISTOPLASMOSIS
Natural history, pathogenesis,
Microbiology and pathology
Histoplasma capsulatum (Fig. 29.3) is a dimorphic fungus As with other systemic fungal infections, initial primary
that exists as a mold in soil and as a yeast in humans. There infection occurs in the lung after inhalation of arthroconi-
are two varieties of Histoplasma which cause disease in dia (spores), which are rapidly converted into yeast at
A B
Figure 29.3 (A) Histoplasma capsulatum colonies on Saboraud’s dextrose agar. (B) Microscopic appearance of H. capsulatum
showing tuberculate chlamydospores.
Photographs courtesy of Dr William Merz, Deparment of Pathology, Johns Hopkins University School of Medicine.
377
body temperature. The yeasts are phagocytosed by the re- Patient evaluation, diagnosis,
ticuloendothelial cells in the lung. Dissemination proba- and differential diagnosis
bly occurs within the first 2 weeks of infection, prior to the
onset of adaptive cell-mediated immunity. In immuno- Owing to the non-specific symptoms of disseminated histo-
competent individuals, the infection is often controlled plasmosis, the disease may be difficult to diagnose. This is es-
by the host response, and the patient may be minimally pecially true in non-endemic areas, where clinicians may not
symptomatic. Reactivation disease is a common form of consider the diagnosis, or pathologists may be unaccustomed
disseminated histoplasmosis, especially in patients with to identifying H. capsulatum in tissue specimens. Clinicians
defective T-cell immunity. In HIV-infected patients, histo- should remember that very transient exposures in an endemic
plasmosis usually occurs when the CD4 count is < 100 area can lead to infection, so that a history of previous resi-
cells/mm3 [95, 96]. dence is not particularly useful in excluding histoplasmosis.
The gold standard is a positive culture of the organism
from peripheral blood or tissue specimens. Blood cultures
are positive in 50–70% of cases of disseminated histoplas-
Clinical features mosis [91, 106, 109]. Lysis-centrifugation systems and
In immunocompetent individuals, infection with H. cap- BACTEC cultures have similar sensitivity, but the latter
sulatum is usually self-limited, while HIV-infected patients may take longer to become positive [109]. Culture of
usually develop disseminated disease [91]. The median lymph nodes, liver, skin, and bronchoalveolar lavage is less
CD4 count at the time of diagnosis is 50 cells/mm3 sensitive, but may be useful in establishing the diagnosis.
[91]. Fever, weight loss, and other constitutional symp- CSF cultures are positive in 65% of patients with Histo-
toms are present in over 95% of patients with dissemi- plasma meningoencephalitis [92, 110].
nated disease [91, 95, 97]. Pulmonary symptoms are Histopathologic examination of tissues is more rapid than
present in 50–60% of cases. On physical examination, ap- culture and establishes the diagnosis in 50% of patients. The
proximately 30% have hepatosplenomegaly, 20% have most accessible site to biopsy is the bone marrow and skin in
lymphadenopathy, and 5–15% develop a rash [91, 95, patients with dermatologic manifestations. The organism can
97]. Neurologic manifestations are reported in 10% of dis- be identified within macrophages with methenamine silver
seminated histoplasmosis cases [92, 98]. Most patients de- stains or periodic acid–Schiff stains. An experienced pathol-
velop a subacute meningoencephalitis, which may be ogist should review the samples since the organism may
basilar, one-third present with focal brain lesions [92, be confused with Cryptococcus, Blastomyces, Penicillium, Toxo-
98]. Up to 18% of HIV-infected patients with dissemi- plasma, Leishmania, or Pneumocystis jiroveci [94].
nated histoplasmosis present with septic shock and acute Serodiagnostic studies are positive in over 80% of all pa-
respiratory distress syndrome (ARDS) [91, 99]. Renal in- tients with disseminated disease and 90% of those with
sufficiency and low albumin at presentation are associated pulmonary disease, but the sensitivity may decrease with
with a worse prognosis, and the mortality for patients with profound immunosuppression and the presence of anti-
severe symptoms is 70% [99]. On rare occasions, histo- body does not differentiate active from past infection
plasmosis may present as retinitis, pericarditis, endocardi- (Table 29.2) [106, 111, 112]. Furthermore, the antibody
tis, prostatitis, pancreatitis, adrenal insufficiency, or may cross-react with Blastomyces, Coccidioides, or Paracocci-
nephritis [91, 95, 100, 101]. There are few reports of im- dioides antigens [111, 113]. Nonetheless, a negative anti-
mune reconstitution syndrome associated with histoplasmo- body test in a patient with histoplasmosis is rare and
sis in patients initiating ART, with various manifestations should prompt further diagnostic work-up.
such as splenic and liver abscesses, pulmonary nodules, A rapid and sensitive test for histoplasmosis is antigen
lymphadenitis, uveitis, and skin lesions [102–104]. In en- detection [114]. The urine antigen test is more sensitive
demic areas, initiation of ART may unmask previously than the serum antigen test for disseminated histoplasmo-
undiagnosed histoplasmosis [105]. sis (80 vs 90%, respectively) (Table 29.2) [107]. The overall
Routine laboratory test results are generally non-specific. specificity of the test is good, but the antigen test may cross-
Approximately one-third of patients present with leukope- react with Penicillium, Paracoccidioides, and Blastomyces
nia and anemia [106]. Occasionally the organism can be antigens [111]. Importantly, the test is useful in following
seen on peripheral blood mononuclear cells. Liver function the response to therapy [91, 115–117]. Persistent antige-
test abnormalities are common in HIV-infected patients, nuria implies ongoing infection and increased titers
but lactate dehydrogenase (LDH) levels > 600 mm3 may ( 2-fold) suggest relapse and should be treated [117].
suggest histoplasmosis in patients presenting with fevers
[107]. Chest radiographs are abnormal in approximately
Treatment
50% of patients [91, 107, 108]. The most common abnor-
malities include diffuse interstitial or reticulonodular infil- Untreated progressive disseminated histoplasmosis has a
trates. Mediastinal lymphadenopathy is evident in 20% of mortality of 80%. Amphotericin B is the drug of choice
cases, and cavitation is rare. for HIV-infected patients with moderate to severe disease,
378
but treatment failure occurs in approximately 20–35% also effective against severe disease and is commonly used
of patients [91, 118]. In a randomized study of 81 HIV- in patients who cannot tolerate amphotericin B. Itraconazole
infected patients with disseminated histoplasmosis, treat- absorption is highly variable and blood levels need to be
ment with liposomal amphotericin resulted in higher monitored. Itraconazole capsules should be taken with food
success rates (88%) compared with regular amphotericin or cola to increase gastric acidity and absorption, or liquid
B (64%) and was associated with less toxicity [118]. formulations can be used. Itraconazole is a potent inhibitor
Amphotericin lipid complex is a cheaper and adequate al- and substrate of CYP3A4, and drug interactions are common
ternative, and non-lipid formulations of amphotericin B [129–131]. In selecting an ART regimen, non-nucleoside
can be used in patients at low risk for nephrotoxicity reverse transcriptase inhibitors (NNRTI’s) should be used
[119]. For mild disease, itraconazole therapy is successful with caution since they can significantly decrease itracona-
in 85% of cases [120, 121]. Fluconazole is less effective zole levels. Ritonavir-boosted protease inhibitors increase
than itraconazole, with 74% response rate at a dose of itraconazole levels [132].
800 mg per day, but relapses occur frequently and are asso- Fluconazole (800 mg daily for 12 weeks, followed by
ciated with fluconazole resistance [121–123]. In experimen- 400 mg daily) can be used cautiously in patients who can-
tal models, the newer triazoles posaconazole, ravuconazole, not tolerate itraconazole, but clinical response should be
and voriconazole have good activity against H. capsulatum closely monitored since it is less effective than itraconazole
[124, 125]. Voriconazole may be less effective against iso- and resistance can develop [122, 123]. Ketoconazole is
lates resistant to fluconazole and should be used with cau- more affordable than itraconazole but has a worse toxicity
tion in patients with prior fluconazole exposure [125]. profile and should only be used for mild cases [128]. Pa-
Posaconazole and voriconazole have been used effectively tients with CNS involvement should be treated with 4–6
in a few patients with histoplasmosis [126, 127]. The role weeks of liposomal amphotericin B (5 mg/kg/day; total
of the echinocandins in the treatment of histoplasmosis 175 mg/kg), followed by itraconazole (200 mg two to three
has not been established. times daily) for at least one year with resolution of CSF
Current practice guidelines for HIV-infected patients with abnormalities.
histoplasmosis recommend an initial 12-week intensive As with other systemic mycoses, the relapse rate in
phase of therapy to induce remission, followed by chronic HIV-infected patients treated for histoplasmosis is high. There-
maintenance therapy to prevent relapse (Table 29.4) [128]. fore, itraconazole maintenance therapy should be prescribed
Liposomal amphotericin B (3 mg/kg/day) or amphotericin following induction therapy [133]. Maintenance therapy can
B lipid complex (0.7–1 mg/kg/day) should be used for in- be discontinued in patients with a CD4 count> 150 cells/
duction in hospitalized patients, and itraconazole (200 mg mm3 who have received > 12 months of antifungal therapy,
three times a day for 3 days, then twice a day) can be used have been on ART for more than 6 months, and have a
upon discharge or in ambulatory patients. Itraconazole is Histoplasma urinary antigen level <2 ng/ml (if available)
Table 29.4 Therapy for HIV-associated progressive disseminated histoplasmosis
PHASE OF SEVERITY OF PREFERRED DRUG DURATION OF EVIDENCEa

THERAPY DISEASE THERAPY
Induction Mild Itraconazoleb (200 mg twice daily) 12 weeks 2
Moderate to severe Liposomal amphotericin Bc 1–2 weeks 1

(3.0 mg/kg/day)
Meningoencephalitis Liposomal amphotericin B (5.0 mg/kg; 10–12 weeks 5
day; total 175 mg/kg)
Maintenance Itraconazole (200 mg twice daily) At least 12 monthsd 1
Primary Itraconazole (200 mg once daily) Consider in endemic 1

prophylaxis area if CD4 < 100
a
Evidence 1 ¼ randomized clinical study, 2 ¼ clinical trial > 20 patients, 3 ¼ clinical trial < 20 patients, 4 ¼ case series, 5 ¼ expert opinion, expert
committees.
b
Monitor itraconazole blood levels. If possible, avoid concomitant use with efavirenz.
c
Amphotericin B lipid complex (5.0 mg/kg per day) may be a cheaper alternative. Deoxycholate formulations of amphotericin B
(0.7–1.0 mg/kg daily) are an alternative for patients at low risk of nephrotoxicity.
d
Can discontinue after 12 months of therapy if CD4 > 200 cells/mm3 for > 6 months.
379
[128, 134]. The timing of ART in patients with histoplasmosis organism can occur in people with impaired cellular
has not been extensively studied, but IRIS related to histoplas- immune responses. The major risk factor for developing
mosis is generally mild. Concern over unmasking or worsen- HIV-associated coccidioidomycosis is a CD4 count < 250
ing histoplasmosis should not delay initiation of ART [34, 77, cells/mm3 [139, 144–146].
103, 105, 135]. Primary prophylaxis with itraconazole
for patients with low CD4 counts is not routinely
recommended, but should be considered in endemic Clinical features
areas where the risk of histoplasmosis is > 10/100 patient
years [87, 128]. Coccidioidal infection may occur in a wide variety of forms,
ranging from positive serologic tests to life-threatening
pneumonitis and meningoencephalitis [144, 145]. Patients
COCCIDIOIDOMYCOSIS usually present with fevers, chills, and night sweats [145].
Pulmonary involvement occurs in 66–80% of all HIV-
associated cases [144, 145]. The most common radiologic
Epidemiology finding is a dramatic, diffuse reticulonodular infiltrate
which may mimic Pneumocystis pneumonia and sometimes
Coccidioides immitis is endemic in the southwestern USA,
tuberculosis. Co-infection with coccidioidomycosis and tu-
northern Mexico, and portions of Central and South
berculosis has been reported in Hispanic patients living in
America. HIV-associated coccidioidal disease can occur in
Texas [146]. The mortality associated with bilateral pulmo-
non-endemic regions due to reactivation disease [136,
nary disease from coccidioidomycosis is exceeding high,
137]. Before the era of HAART, coccidioidomycosis was
ranging from 40 to 85% [144, 145, 147, 148].
an important opportunistic infection, accounting for
In HIV-infected patients with high CD4 counts or pa-
10% of hospitalizations among HIV-infected patients in
tients on ART, pulmonary coccidioidomycosis is less
Arizona between 1990 and 1995 [138]. In the post-HAART
severe, presenting with fever, cough, and focal infiltrates
era, the incidence and severity of coccidioidal disease
[141]. Mediastinal lymphadenopathy, peripheral eosino-
in HIV-infected patients has decreased dramatically
philia, and lack of response to antibiotics can help distin-
[140–142].
guish it from community-acquired pneumonia [149]. In
patients on ART and with suppressed viral load, mild cases
Natural history, pathogenesis, of coccidioidomycosis may resolve without antifungal
therapy or with shortened courses of therapy [141].
and pathology
Following pulmonary infection, C. immitis can dissemi-
C. immitis is a soil-dwelling dimorphic fungi that is inhaled nate to skin, bone, and CNS. Unique manifestations in
in the form of arthroconidia (spores). The organism lives in HIV-infected patients include liver, intestinal, genitouri-
the soil in the mycelial phase, and, when inhaled, aerosol- nary, and extrathoracic lymph node involvement [144].
ized infectious particles are inhaled into the lungs of For unclear reasons, skeletal coccidioidomycosis is dis-
potential hosts. Once in the alveolar space, the organism tinctly unusual in HIV-infected individuals.
multiplies, resulting in a giant spherule (Fig. 29.4). Histo- A subacute meningoencephalitis occurs in approxi-
pathologically, HIV-associated pulmonary coccidioidomy- mately 15% of HIV-infected patients with coccidioidomy-
cosis is characterized by poor granuloma formation cosis, and is associated with high morbidity and mortality
and high organism burden [142]. Dissemination of the (40%) [145, 150]. Headache is the most common
A B
Figure 29.4 (A) Coccidioides immitus colony. (B) Arthrospores in colonies from a patient with C. immitus infection.
380
presenting symptom, followed by symptoms of increased increase the sensitivity of serologic tests in HIV-infected pa-
intracranial pressure, such as nausea and vomiting. CSF tients with disseminated coccidioidomycosis to >90%
findings include hypoglycorrhachia, high protein, and a (Pappagianis, personal communication) [160]. The major-
moderate leukocytosis, which may have a polymorphonu- ity of patients with CNS coccidioidomycosis have positive
clear predominance, or less commonly, can be eosinophilic serologies, usually with a titer greater than 1:16 [150].
[151, 152]. Imaging studies may reveal hydrocephalus, bas-
ilar enhancement, or cerebral infarction [153]. Hydroceph-
alus associated with arachnoid fibrosis and meningeal
Treatment
inflammation is a serious complication that can develop
rapidly and should be considered in patients with worsen- In immunocompetent individuals, infection with C. immitis
ing symptoms, even if they are receiving appropriate often resolves spontaneously and does not require therapy.
antifungal therapy [150]. HIV-infected patients, however, have a high risk of dissem-
ination and should always be treated if infected with
C. immitis [158, 161]. Even with therapy (Table 29.5),
Patient evaluation, diagnosis, and coccidioidomycosis has a poor prognosis in HIV-infected
patients who are not receiving ART [137, 144, 145]. Out-
differential diagnosis
comes are much better in patients receiving ART, and no
Definitive evidence of C. immitis infection is obtained cases of IRIS associated with coccidioidomycosis have been
through direct visualization or culture of the organism reported [141]. Therefore, antifungal therapy should be
from respiratory or other tissues using standard histochem- complemented with control of HIV infection with ART.
ical staining techniques, such as the hematoxylin-eosin There has only been one controlled trial of antifungal ther-
stain. The organism grows easily and relatively rapidly apy for coccidioidomycosis, which found no significant dif-
(< 5 days) on nearly any laboratory media, and a nucleic ference in efficacy between fluconazole and itraconazole
acid probe is available to rapidly identify C. immitis once in primarily HIV-uninfected individuals with non-meningeal
isolated in culture [154]. The sensitivity of culture is high coccidioidomycosis [162]. Given the sparcity of data, treat-
for pulmonary disease but low for extrapulmonary disease, ment recommendations are primarily based on expert opin-
with <30% of blood culture positivity for disseminated ion [148, 149]. For diffuse pulmonary disease, which can
disease, and <15% recovery from the CSF in cases of me- be particularly severe, a combination of amphotericin B
ningoencephalitis. In tissue, Coccidioides can be easily iden- (0.7 mg/kg/day) and a triazole (itraconazole or fluconazole)
tified by its characteristic large (20–70 mm) spherules antifungal is recommended. After a total dose of 500–
which can be seen at 100–400 magnification with meth- 1,000 mg of amphotericin B is administered, the triazole
enamine silver or Papanicolaou stain [148]. However, can be continued alone indefinitely [148, 149]. Fluconazole
cytological staining has low sensitivity for the diagnosis is usually preferred over itraconazole because of fewer
of pulmonary disease. C. immitis can be an occupational drug–drug interactions with ART [162].
hazard and is listed by the Centers for Disease Control Other manifestations of coccidioidomycosis, including
and Prevention (CDC) as a potential agent of bioterrorism. focal pneumonia, disseminated disease, and meningoen-
Therefore, the laboratory should be notified if coccidioido- cephalitis, can be treated with triazole antifungal mono-
mycosis is suspected so that appropriate biohazard precau- therapy (usually fluconazole 400–800 mg/day) [163].
tions are taken. Several clinical trials have evaluated the efficacy of various
Serologic tests are commonly used to diagnose coccidioi- azoles, but none have specifically addressed outcomes
domycosis [155]. Anti-coccidioidal antibodies are quite in HIV-infected patients. In HIV-negative individuals, the
specific and tend to reflect active disease [156]. IgM anti- efficacy of fluconazole ranges from 55% in patients with
bodies are detectable 1 or 2 weeks after infection and persist chronic pulmonary disease to 86% in those with skeletal
up to 6 months. IgG antibodies appear later and persist un- involvement [164]. The overall efficacy of itraconazole
til the infection is resolved. Quantitation of coccidioidal (200 mg twice daily) and ketoconazole (400 mg once
IgG titers is useful to assess prognosis and response to ther- daily) is approximately 50% [162, 165, 166]. In a ran-
apy [155]. Complement fixation serologic tests can be per- domized study comparing fluconazole with itraconazole
formed on CSF samples, with high specificity and moderate for progressive, non-meningeal coccidioidomycosis,
sensitivity [157]. Asymptomatic HIV-infected patients with there was not a statistically significant difference between
positive serologies have a high risk ( 40%) of developing the two regimens, except for slightly improved outcomes
coccidioidomycosis within 2 years [158]. However, serol- in patients receiving itraconazole for bone disease [162].
ogy can be negative in 20–40% of HIV-infected patients CNS coccidioidomycosis does not respond to amphotericin
with coccidioidomycosis, especially in those with diffuse B and is generally treated with fluconazole [148, 149]. In a
pulmonary disease (Table 29.2) [144, 145, 159]. Therefore, study of 49 patients (9/49 HIV infected) with coccidioidal me-
a positive test can be diagnostic, but a negative test does not ningoencephalitis, 79% responded to fluconazole (400 mg/
exclude coccidioidal disease. Concentration of serum can day) [157]. Therapy was continued for 37 months (mean)
381
Table 29.5 Therapy for HIV-associated coccidioidomycosis
TYPE OF DISEASE PREFERRED DRUG DURATION OF THERAPY EVIDENCEa
Diffuse pneumonia Amphotericin Bb (0.7 mg/ Until clinical improvement, followed 5

kg/day) by azole
Fluconazolec (40 mg/day) Lifelong 5
Meningoencephalitis Fluconazole (400– Lifelong 2

800 mg/day)
Other (focal pulmonary, skin, Fluconazolec (400 mg/day) Lifelong 2

disseminated)
Note: Maintenance therapy should be continued even in patients with CD4 counts < 200 cells/mm3. Primary prophylaxis is controversial; consider in
endemic area with CD4 count < 100 cells/mm3.
a
Evidence 1 ¼ randomized clinical study, 2 ¼ clinical trial > 20 patients, 3 ¼ clinical trial < 20 patients, 4 ¼ case series, 5 ¼ expert opinion, expert
committees.
b
Alternative: liposomal amphotericin B (4 mg/kg/day).
c
Alternative: itraconazole (400–600 mg/day).
and clinical response was apparent after 4–8 months of ther- patients, ranging from 20 to 39% [162, 164]. Lifelong
apy. In a small study (n ¼10), itraconazole was reported to therapy is generally recommended for all patients with pro-
have comparable efficacy [167]. For refractory cases, some gressive pulmonary, disseminated, or meningeal disease
authorities recommend intrathecal amphotericin B [148, [161, 171]. HIV-infected patients on ART can relapse de-
150, 168]. Hydrocephalus usually requires ventricular shunt spite immune reconstitution; therefore, discontinuation
placement. Voriconazole and posaconazole are active against of secondary prophylaxis is not recommended even in pa-
C. immitis in vitro and have been successfully used in a few tients with a CD4 count >250 cells/mm3, except for
cases of coccidioidal meningoencephalitis [150, 169, 170]. patients with focal pulmonary disease [148, 172]. There
Response to therapy should be monitored by serial coc- are no data to support primary prophylaxis for the preven-
cidioidal IgG titers. The risk of relapse after therapy for tion of coccidioidomycosis, but ART may be the best
coccidioidomycosis is high even in immunocompetent preventive measure against severe disease [141].
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388
Chapter | 30 |
Infection due to Penicillium marneffei
Thira Sirisanthana, Khuanchai Supparatpinyo
At 37 C on artificial medium or in human tissue, the fun-

INTRODUCTION gus grows in a yeast-like form with the formation of fission
arthroconidium cells. The fission yeast cells represent
Penicillium marneffei infection is one of the most common the parasitic form of P. marneffei. This form is seen in the
opportunistic infections in persons with advanced human intracellular infection of the macrophages as well as
immunodeficiency virus (HIV) infection in Southeast Asia, extracellularly.
northeastern India, southern China, Hong Kong, and Tai- The first naturally infected case was reported in 1973 in an
wan. In northern Thailand. It is one of the four most American missionary with Hodgkin’s disease who had been
common opportunistic infections, which include tubercu- living in Southeast Asia. Between 1973 and 1988 less than
losis, cryptococcal infection, and Pneumocystis jiroveci pneu- 40 cases of P. marneffei infection had been reported in the
monia [1]. Cases have also been reported in HIV-infected literature [3]. The rarity of P. marneffei infection changed
patients from the USA, Europe, Japan, and Australia follow- when the global HIV/AIDS epidemic arrived in Southeast
ing visits to the endemic area [2]. Diagnosis depends on fa- Asia. The first case of P. marneffei infection in an HIV-
miliarity with the clinical syndrome and a high index of infected native of Southeast Asia was reported in 1989 from
suspicion. This can be problematic when the patient pre- Bangkok. The number of cases has markedly increased since
sents for medical care outside the endemic area. As in other then. At one tertiary hospital in Chiang Mai, northern Thai-
systemic fungal infections, confirmation of the diagnosis land, a total of 1,592 patients with P. marneffei infection were
requires demonstration of the fungus in the infected organ seen between January 1991 and December 2000; almost all
and culturing the organism from clinical specimens. The re- of these patients were also infected with HIV. Patients
sponse to antifungal treatment is good if the treatment is would typically be in the late stage of HIV disease with
started early. After the initial treatment, the patients need CD4 count <100 cells/mm3. Common manifestations
prolonged suppressive therapy to prevent relapse at least were fever, anemia, weight loss, lymphadenopathy, hepa-
until their immune system is sufficiently restored by antire- tosplenomegaly, and skin lesions. Cases had been reported
troviral therapy. in 21 children with perinatally acquired HIV infection from
the same hospital. The clinical manifestations in these chil-
dren were similar to those in adults [4]. There is extensive
seasonal variation in the incidence of P. marneffei infection,
EPIDEMIOLOGY with increased number of cases in the rainy season [5]. Be-
tween 1991 and 2003, more than 6,000 cases of P. marneffei
Penicillium marneffei was first isolated from a bamboo rat in infection in HIV-infected patients were reported to the Thai
Vietnam in 1956 [2]. It is the only known Penicillium spe- Ministry of Public Health (MOPH). However, between
cies that exhibits temperature-dependent dimorphic 2006 and 2010, when the Thai MOPH free access to anti-
growth. At temperatures below 37 C, the fungus grows as retroviral program was fully implemented, the average num-
mycelia with the formation of septate hyphae, bearing ber of cases reported to the MOPH fell to 148 cases per year.
conidiophores and conidia typical of the genus Penicillium. As the HIV/AIDS epidemic spread in the region, the
389
Figure 30.1 Geographic regions of Penicillium

marneffei infection. The endemic area of
P. marneffei infection includes Southeast Asia,
northeastern India, the Guangxi and Guangdong
provinces of China, Taiwan, and Hong Kong.
With kind permission from Springer Science þ Business
Guangdong
Media. From Supparatpinyo K, Sirisanthana T. Penicillium
Guangxi marneffei infections. In: Kauffman CA, ed. Atlas of Fungal
Infections, 2nd edn. Philadelphia; Springer,
2006:191–201.
Taiwan
Manipur Hong Kong

Myanmar Laos
Thailand
Cambodia Vietnam
Malaysia
P. marneffei infection has also increased in other countries, familiar with and had seen bamboo rats; 31.3% of cases
including Vietnam [6], India [7, 8], China [9, 10], Hong and 28.1% of controls had eaten bamboo rats but this dif-
Kong [11], and Taiwan [12]. Figure 30.1 shows the ference was not statistically significant. Reported cases of
endemic area of this fungal pathogen. P. marneffei in HIV-infected infants also suggest that human
and bamboo rat infection are not connected [4]. Bamboo
rats live in the wild and have limited or no contact with
NATURAL HISTORY AND these infants. In another study from Chiang Mai, it was
found that disseminated P. marneffei infections have been
PATHOGENESIS markedly seasonal, with a doubling of cases during the
rainy season [5]. This suggested that there might be an
Many important features of the natural history and patho- expansion of the environmental reservoir with favorable
genesis of P. marneffei infection remain unknown. Human conditions for growth during these rainy seasons and that
and bamboo rats are the only known animal hosts. The both humans and bamboo rats are infected with P. mar-
fungus can infect four species of bamboo rats: namely, neffei from this common reservoir. A recent genotypic
Rhyzomys sinensis, R. pruinosus, R. sumatraensis, and the study of P. marneffei isolated from humans and bamboo
reddish-brown subspecies of Cannomys badius [13]. These rats in China also supports the existence of a common
infected animals showed no signs of illness. The geographic reservoir [16]. However, attempts in culturing the fungus
ranges of these bamboo rats (Cannomys spp. and Rhizomys from environmental sources, for example, soil samples,
spp.) broadly follow the distribution of human cases of air samples (using high-volume air samplers), domestic
P. marneffei infection: namely, Southeast Asia, northeastern animals, and vegetation including bamboo, have been
India, and southern China [14]. This suggests that bamboo unsuccessful [17, 18].
rats may be an obligate stage in the life cycle of the fungus. The mode of transmission of P. marneffei to humans is
However, an attempt to epidemiologically link bamboo not known. Analogous to other endemic fungal pathogens,
rats and human infection was not successful. Chariyalert- such as Coccidioides immitis and Histoplasma capsulatum, it
sak and colleagues compared 80 patients with AIDS who is likely that P. marneffei conidia are inhaled from an envi-
had P. marneffei infection with 160 AIDS patients who ronmental reservoir. Also by analogy to histoplasmosis, it is
did not have P. marneffei infection, in a case–control study likely that subclinical infections with P. marneffei may oc-
[15]. The main risk factor found was a recent history of cur commonly in persons living in endemic areas who
occupational or other exposures to soil, especially during are exposed to the fungus in nature. The existence of sub-
the rainy season. Both cases and controls were often clinical infection in humans is supported by a case report
390
Chapter | 30 | Infection due to Penicillium marneffei
from Australia of an HIV-infected patient who had a latent infection of the reticuloendothelial system. These include fe-
period of more than a decade between exposure in an en- ver, generalized lymphadenopathy, hepatomegaly, and
demic area and the subsequent onset of clinical infection in splenomegaly. Clinical manifestations associated with late
Australia [19]. However, in many other instances, the clin- HIV infection such as anorexia, asthenia, anemia, diarrhea,
ical appearance of disseminated infection occurred within a weight loss, and cachexia are also seen in the majority of the
few weeks of exposure to the organism. The seasonal vari- patients. Other presentations, such as skin lesions, mucosal
ation of cases with disseminated P. marneffei infection, as lesions, and bone and joint infection [22], are secondary to
well as cases of P. marneffei in HIV-infected infants reported dissemination of the fungus via the bloodstream. Skin le-
from northern Thailand [4], also suggest that progress from sions are seen in more than 70% of the patients in most case
infection to clinical dissemination is usually brisk. There is series and, when present, are the best clues to the diagnosis
no evidence of person-to-person spread. (see Fig. 30.2). They are usually found as papules on the face,
chest, and extremities. The center of the papule subsequently
becomes necrotic, giving the appearance of an umbilicated
papule (also called papulonecrotic skin lesion or mollus-
CLINICAL FEATURES cum-contagiosum-like skin lesion). Biochemical and hema-
tologic laboratory values are non-specific and may include
Penicillium marneffei infection occurs late in the course of elevation of liver enzymes and bilirubin, anemia, and leuko-
HIV infection. The Thai MOPH as well as the health author- cytosis or leukopenia. In patients with symptoms and signs
ity of Hong Kong have included P. marneffei infection as one of the respiratory system, the chest radiograph may show dif-
of the AIDS-defining illnesses in those countries [11, 20]. fuse reticular infiltration, diffuse or localized alveolar infil-
The CD4 count at the time of the diagnosis of P. marneffei trates, or pleural effusion [23].
infection is usually <100 cells/mm3. Cases were reported As the HIV epidemic spread and more patients were seen,
in which P. marneffei infection occurred with other late other less common clinical presentations of P. marneffei in-
HIV-related infections, such as cryptococcal meningitis, fection in HIV-infected patients were encountered. Cases
Pneumocystic jiroveci pneumonia, cerebral toxoplasmosis, with chest radiographs showing lung mass or single or mul-
tuberculosis or Salmonella bacteremia. Table 30.1 shows tiple cavitary lesions have been reported [24, 25]. Bone
the more common clinical presentations of HIV-infected pa- infections have been reported in the ribs, long bones, flat
tients with P. marneffei infection from case series from Thai- bone of the skull, mandible, lumbar vertebrae, scapula,
land [20, 21], India [7], Hong Kong [11], and Vietnam [6]. and small bones of the fingers. Arthritis involving both
Patients commonly present with symptoms and signs of large peripheral joints and small joints of the fingers has
Table 30.1 Clinical features of HIV-infected patients with Penicillium marneffei infection from 5 case series
THAILAND [20] THAILAND [21] INDIA [7] HONG KONG [11] VIETNAM [6]
AUG 87–JUN 92 JUN 90–AUG 97 APR 98–OCT 99 JAN 94–FEB 04 JUL 05–JUN 08
(n ¼ 80) (n ¼ 74) (n ¼ 36) (n ¼ 47)a (n ¼ 94)
Clinical features
Fever 93% 96% 97% 96% 99%
Skin lesion 71% 85% 81% 28% 86%
Anemia 78% 76% 86% 79% 77%
Hepatomegaly 51% 65% 39%b 28% 69%c
Splenomegaly 16% 23% — 15% —
Lymphadenopathy 58% 84% 33% 62% 68%
CD4 count NA Mean: 63.8 NA Median: 20 Mean: 29

(cells/mm3) SD: 47 IQR: 8.0–43.5 Range: 2-196
NA, not available; SD, standard deviation; IQR, interquartile range.

a
44 of the 47 subjects are confirmed HIV-infected.
b
Hepatosplenomegaly.
c
Hepatomegaly and/or splenomegaly.
391
diagnosed to have HIV infection at the time of diagnosis

of P. marneffei infection [11, 20]. Taking time to explain
and answer the patient’s questions about HIV infection,
the course of the disease, and what it means to them is im-
portant to ensure the patient’s trust and cooperation in
the process of establishing the diagnosis and management.
Also, because the disease is usually seen in the advanced
stage of HIV infection, the majority may have other
concurrent opportunistic infections such as cryptococcal
meningitis, Pneumocystic jiroveci pneumonia, cerebral toxo-
plasmosis, tuberculosis, or Salmonella bacteremia. These
should be watched out for. For physicians who are not in
the endemic area, a high degree of suspicion and a careful
travel history are essential. Antinori et al. have reviewed
the literature and found reports of 36 HIV-infected patients
whose diagnosis of P. marneffei infection were made in Eu-
ropean countries, the USA, the UK, Japan, and Australia.
Figure 30.2 Skin lesions of HIV-positive patient with Practically all patients had a clear history of exposure in
P. marneffei infection. Some of the papules had central the endemic area before their subsequent diagnosis [33].
umbilication resembling lesions of molluscum contagiosum.
The diagnosis of P. marneffei infection rests on the micro-
Reprinted from the Lancet. From Supparatpinyo K, Khamwan C,
scopic demonstration of the fungus in the tissues and/or
Baosoung V, et al. Disseminated Penicillium marneffei infection in
isolation of the fungus from clinical specimens. Penicillium
southeast Asia. Lancet 1994; 344:110–113. Copyright Elsevier 1994.
marneffei can be seen in histopathological sections stained
with Grocott methenamine silver or periodic–acid Schiff.
been seen [22]. Ukarapol and colleagues reported three
The organisms appear as unicellular round to oval cells that
children who presented with fever, mesenteric lymphade-
divide by cross-wall formation in macrophages or histio-
nitis, and abdominal pain. Two of the patients had had
cytes. Extracellular elongated or sausage-shaped cells with
unnecessary abdominal operations for the diagnosis of
one of two septa may also be seen. Neither the cell wall
peritonitis and acute appendicitis, respectively. All three
nor the cytoplasm of P. marneffei cells takes up the hema-
cases had positive blood and bone marrow cultures for
toxylin-eosin stain well (see Fig. 30.3).
P. marneffei [26]. Kantipong and colleagues reported six pa-
Penicillium marneffei can be readily cultured from various
tients who presented with fever, hepatomegaly, and mark-
clinical specimens. Both automated blood culture system and
edly elevated serum alkaline phosphatase levels. Penicillium
blood culture medium for mycobacteria (for example, BD
marneffei was demonstrated in the liver and cultured from
the blood [27]. Mucosal lesions in the oral cavity, orophar-
ynx, hypopharynx, stomach, colon, and genitalia have
been reported [20, 28–30]. Penicillium marneffei could be
demonstrated in or cultured from these lesions. Twenty-
one patients from Vietnam whose cerebrospinal fluid
(CSF) culture grew P. marneffei have been reported. They
presented with fever and symptoms of altered mentation
including confusion, agitation, or drowsiness. Symptoms
of increased intracranial pressure and signs of meningeal
inflammation were uncommon. CSF pleocytosis was seen
in only one-third of the cases. A total of 71% of the cases
had elevated CSF protein and 24% had a CSF glucose/se-
rum glucose ratio <0.5. The disease course was rapidly
progressive with a high mortality rate [31].
PATIENT EVALUATION, DIAGNOSIS,

AND DIFFERENTIAL DIAGNOSIS [32] Figure 30.3 Photomicrograph of a tissue section stained with
Gomori methenamine silver, showing the black fungal elements
in subcutaneous tissue underneath the skin lesion. Note the
In evaluating an HIV-infected patient with the possible typical yeast-like organism with central septation. (1000)
diagnosis of P. marneffei infection, it is important to keep From Hay RJ. Fungal infections. Clin Dermatol 2006; 24:201–212.
in mind that the majority of the patients were first Copyright Elsevier 2006.
392
Table 30.2 Sources of isolation in 80 HIV-infected patients

with disseminated Penicillium marneffei infection in
northern Thailand [20]
SPECIMEN TYPE NUMBER OF SPECIMENS
Total Positive (%)
Blood 78 59 (76)
Skin biopsy 52 47 (90)
Bone marrow 26 26 (100)
Sputum 41 14 (34)
Figure 30.4 Photomicrograph of Wright’s-stained touch smear
Lymph node biopsy 9 9 (100) of skin-biopsy specimen from patient infected with HIV and
P. marneffei. Note spherical, oval, and elliptical yeast-like
organisms with central septation in a macrophage. (1000)
Reprinted from the Lancet. From Supparatpinyo K, Khamwan C,
Baosoung V, et al. Disseminated Penicillium marneffei infection in
BACTEC Myco/F Lytic Medium) support the growth of P. southeast Asia. Lancet 1994; 344:110–113. Copyright Elsevier 1994.
marneffei. Bone marrow culture is the most sensitive, fol-
lowed by culture of a specimen obtained from skin biopsy,
and blood culture (Table 30.2). At 25–30 C on Sabouraud pre-emptive treatment with an antifungal agent similar
dextrose agar, the colonies of P. marneffei are granular with to isoniazid treatment in asymptomatic persons with a
shade of greenish-yellow color and a characteristic red positive tuberculin skin test.
diffusible pigment. The fungus grows as mycelia with the In the endemic area when a patient in late-stage HIV infec-
formation of septate hyphae, bearing conidiophores and tion presents with fever, generalized lymphadenopathy,
conidia typical of the genus Penicillium. Mold-to-yeast hepatosplenomegaly, and papular lesions of the skin, the dif-
conversion is achieved by subculturing the fungus on ferential diagnoses include P. marneffei infection, cryptococ-
to brain–heart-infusion agar and incubating at 35–37 C. cosis, and histoplasmosis. If the patient does not have skin
Demonstration of this conversion is required before con- lesions, additional differential diagnoses should include tu-
cluding that the isolate is P. marneffei. berculosis, Salmonella bacteremia, and lymphoma. Evalua-
Several methods of obtaining cytology specimens such as tion should include blood culture, skin and/or lymph node
fine-needle aspiration of lymph nodes, bone-marrow aspi- biopsy for histopathology, fungal culture, and cytology.
ration, touch-smears of skin, or lymph-node biopsy speci-
mens allow rapid presumptive diagnosis of P. marneffei
infection. In one such method, a knick of the skin lesion TREATMENT
is made with a surgical blade or the tip of a hypodermic
needle, and a small amount of tissue is scraped from under The mortality rate of patients with disseminated P. marnef-
the skin and smeared on a glass slide. The slide is stained fei infection has been high, mostly because of a lack of
with Wright’s stain. Examination under the microscope timely diagnosis [20]. The outcome has been much better
shows intracellular and extracellular basophilic, spherical, in the hospital where physicians have been aware of the
oval, and elliptical yeast cells. Some of these cells have clear clinical features of the infection and the diagnosis has been
central septation, which is a characteristic feature of P. mar- made early. Although there is no standardized technique
neffei (see Fig. 30.4) [20]. In addition, in patients with ful- for susceptibility testing for dimorphic fungus, a study of
minant infection, P. marneffei can be seen in the peripheral 30 clinical isolates from northern Thailand revealed that
blood smear [34]. all were susceptible to amphotericin B, itraconazole, keto-
Several tests that detect antigen or antibody specific to P. conazole, and miconazole [35]. Sirisanthana and col-
marneffei, as well as molecular tests such as PCR, have been leagues conducted an open-label non-comparative study
described [2]. However, these tests are not widely used be- to evaluate the combination of 0.6 mg/kg/day of ampho-
cause commercial reagents are not available. Also, large tericin B given intravenously for 2 weeks followed by 400
clinical trials are needed to show the usefulness of these mg/day of itraconazole taken orally for 10 weeks [36]. Of
tests in the diagnosis of active P. marneffei infection or to the 74 patients treated, 72 (97.3%) responded. No serious
predict relapses, as well as to identify individuals who are adverse drug effects were observed. This regimen is recom-
infected with P. marneffei but who are still asymptomatic. mended as the treatment of choice in HIV-infected patients
This latter group of individuals may then benefit from with disseminated P. marneffei infection [37]. However, in
393
a report of 46 patients from northeastern India treatment infection. However, in an open-label historical-controlled
with oral itraconazole alone was effective in all but one pa- study, no relapse of P. marneffei infection occurred after
tient [7]. Thus, oral treatment with 400 mg/day of itracona- discontinuation of itraconazole in patients receiving com-
zole for 8 weeks is an alternative recommendation in bination antiretroviral treatment and a CD4 count >100/
patients with less severe disease [37]. A new antifungal mm3 [41]. Thus, discontinuation of secondary prophylaxis
drug, voriconazole, has been evaluated, but further study is recommended for patients who receive combination an-
involving more patients is needed [38]. tiretroviral treatment and have a CD4 count >100/mm3
Relapses of P. marneffei infection are common. In one for 6 months [37].
study, 12 out of 40 patients who responded to initial treat- Primary prophylaxis with an antifungal agent should be
ment relapsed within 6 months [35]. Secondary prophylaxis considered in areas where fungal infections are common
is required for as long as a significant immunocompromised AIDS-associated opportunistic infections. In northern
status persists. Supparatpinyo and colleagues conducted a Thailand, disseminated fungal infections due to P. marnef-
controlled trial of 71 patients in northern Thailand [39]. A fei, Cryptococcus neoformans, and Histoplasma capsulatum
total of 20 of the 35 patients (57%) assigned to the placebo as well as other fungal infections, such as candidiasis,
group relapsed, whereas none of the 36 patients given itra- are common, accounting for over one-third of the
conazole 200 mg orally once daily relapsed. The drug was reported AIDS-defining illnesses [1]. Chariyalertsak and
well tolerated. colleagues evaluated the efficacy of primary prophylaxis
With the increased access to combination antiretroviral with 200 mg/day of itraconazole given orally in a con-
treatment for patients in the endemic area, the immune res- trolled study [42]. The trial was conducted in 129 HIV-
toration inflammatory syndrome (IRIS) has increasingly infected patients who had CD4 counts <200/mm3 and
been reported in patients with P. marneffei infection [40]. had not experienced a systemic fungal infection. In the
It usually occurs within a few weeks or months after starting intention-to-treat analysis, disseminated P. marneffei in-
combination antiretroviral treatment. Antifungal therapy fection developed in 1 of 63 patients (1.6%) assigned to
should be started or continued (if the patient is already tak- receive itraconazole and a systemic fungal infection
ing it). Antiretroviral therapy should not be stopped. Short- developed in 11 of 66 patients (16.7%) given placebo
course glucocorticosteroids may be given in patients with (7 patients had cryptococcal meningitis, and 4 patients
severely symptomatic IRIS [37]. had disseminated P. marneffei infection). However, there
No controlled study exists that demonstrates the safety of was no survival advantage of being on itraconazole when
discontinuation of secondary prophylaxis for P. marneffei compared to placebo.
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eight cases and review of the Sirisanthana T, et al. A controlled
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395
Chapter | 31 |
AIDS-associated toxoplasmosis
Pablo A. Moncada, Jose G. Montoya
decline <50 cells/mm3 and who are not taking anti-

INTRODUCTION AND EPIDEMIOLOGY Toxoplasma prophylaxis. TE can be the presenting illness
in patients with AIDS [7]. In two European studies TE still
Toxoplasma gondii is among the most prevalent causes of la- was the most prevalent central nervous system infection in
tent infection of the central nervous system (CNS) through- HIV-infected patients during the past decade [8, 9].
out the world. After an acute infection, cysts of T. gondii Primary infection is rarely symptomatic in HIV-infected
persist in the CNS and in multiple extraneural tissues. patients or in those with AIDS. However, Toxoplasma-
Although normal human hosts maintain infection in a qui- seronegative individuals infected with HIV should be coun-
escent state, immunocompromised individuals may be at seled about how to avoid exposure to the parasite. Inges-
risk for reactivation and dissemination of chronic (latent) tion of undercooked or raw meat containing tissue cysts
infection. Defective T cell-mediated immunity in HIV- and of vegetables or other food products contaminated
infected patients results in loss of the primary arm of host with oocysts is a major means of transmission of the para-
defense against this parasite. Reactivation of latent infec- site, as is direct contact with contaminated cat feces. Al-
tion in patients with AIDS may lead to clinically apparent though cats are the definitive host for T. gondii, antibody
disease (toxoplasmosis), which most frequently manifests seroconversion in adult HIV-infected individuals appears
as life-threatening toxoplasmic encephalitis (TE) [1]. unrelated to cat ownership or exposure [10]. Recently,
Seroprevalence varies among geographic locales and drinking of unfiltered drinking water and ingestion of
even within subpopulations of the same locale [2, 3]. raw mussels, oysters, and clams have also been implicated
The seroprevalence of the infection with the parasite in as a source of acute T. gondii infection [11].
HIV-infected individuals usually reflects the seroprevalence
of the population they come from. Studies performed
in the United States reveal an age-adjusted seroprevalence CLINICAL PRESENTATION
of approximately 10% [4], with a higher prevalence
(>25%) among certain ethnic groups. Early studies indi- AIDS patients who develop TE can do so after the diagnosis
cated that 20–47% of T. gondii-seropositive patients with of AIDS has been made [12, 13]. Because multifocal involve-
AIDS ultimately developed TE [5]. The risk of toxoplasmo- ment of the CNS frequently occurs in TE in AIDS patients,
sis has significantly decreased since the introduction of there may be a wide spectrum of clinical findings, including
primary prophylaxis against T. gondii and antiretroviral alteration of mental status, seizures, motor weakness, sensory
therapy (ART). The incidence in the USA among patients abnormalities, cerebellar dysfunction, meningismus, move-
who had developed AIDS declined from 2.1/100 person- ment disorders, and neuropsychiatric manifestations [14].
years (PY) in 1992 to 0.7/100 PY in 1997 [6]. However, The characteristic presentation is usually one of subacute
TE remains a prevalent opportunistic infection in patients onset, with focal neurologic abnormalities in 58–89% of pa-
with signs and symptoms of central nervous system in- tients. Altered mental status, manifested by confusion, leth-
volvement even in the late ART era, particularly among argy, delusional behavior, frank psychosis, global cognitive
severely immunosuppressed patients whose CD4 counts impairment, anomia, or coma, may be present initially in
397
as many as 60% of patients. Seizures are the reason for loss of visual acuity are typical complaints, and fundu-
seeking medical attention in approximately one-third of scopic examination typically reveals findings consistent
AIDS patients with TE. Focal neurologic deficits are evident with necrotizing retinochoroiditis. The lesions are yellow-
on neurologic examination in approximately 60% of pa- white areas of retinitis with fluffy borders. In reported series,
tients. Although hemiparesis is the most common focal neu- the lesions were multifocal in 17–50%, bilateral in 18–40%,
rologic finding, patients may have evidence of aphasia, ataxia, and accompanied by optic neuritis in approximately 10% of
visual field loss, cranial nerve palsies dysmetria, hemichorea- the cases. Scant retinal inflammation is frequently observed
hemiballismus, tremor, parkinsonism, akathisia, or focal in AIDS-associated toxoplasmic retinochoroiditis [26]. Thus
dystonia [10]. In addition, infection of the spinal cord with the features of toxoplasmic retinochoroiditis commonly ob-
T. gondii has been described in cases of transverse myelitis, served in the immunocompetent host may be absent in pa-
conus medullaris syndrome [15], and of ventriculitis accom- tients with AIDS. Vitreal inflammation may vary from mild
panied by hydrocephalus [16]. localized vitreal haze to extensive vitreous inflammation.
A rapidly fatal panencephalitis form of diffuse cerebral Vasculitis and hemorrhage are uncommon. In most patients
toxoplasmosis has also been described [17]. Unfortunately, the ocular lesions are located away from areas of pre-existing
computed tomography (CT) of the head was unrevealing scars. This suggests that the pathogenesis of these lesions
in these cases [17, 18]. In case reports involving HIV- may be secondary to hematogenous seeding rather than lo-
uninfected, severely immunocompromised patients with cal reactivation of infection. The presence of concurrent TE
biopsy-proven diffuse TE, no changes were reported on in AIDS patients with ocular toxoplasmosis has varied from
magnetic resonance imaging (MRI) with gadolinium in 29 to 63% [27, 28].
the majority of patients, and only minimal changes were Most AIDS patients with TE (80–95%) have CD4 counts
detected in one patient (e.g. minimal enhancement of of <100 cells/mm3. Cerebrospinal fluid (CSF) may be
the cortex and subcortical white matter) [19, 20]. Hence, normal or reveal mild pleocytosis (predominantly lympho-
although rare, diffuse TE should be suspected as a possible cytes and monocytes) and an elevated protein level, whereas
cause of severe encephalitis in patients with advanced im- the glucose content usually is normal [13].
munosuppression (e.g. those with CD4 count below 50
cells/mm3) in whom other causes have been ruled out
and the suspicion for TE is high despite the lack of brain- Congenital toxoplasmosis and the
occupying lesions in MRI. Extracerebral sites with or with-
HIV-infected woman
out concomitant TE may be involved in HIV-infected
individuals. As is true for TE, extracerebral toxoplasmosis As with HIV-uninfected women, women infected with HIV
usually occurs in patients with CD4 counts of <100 are at risk for transmission of T. gondii infection to their fe-
cells/mm3 [21–23]. In patients with extracerebral toxoplas- tus if they are seronegative for Toxoplasma and acquire infec-
mosis, ocular and pulmonary sites are most commonly tion during pregnancy [29]. In addition, maternal–fetal
involved (50 and 26% of patients, respectively) [10]. transmission can occur in HIV-infected pregnant women
Significant pulmonary disease, including acute respira- who are chronically infected with T. gondii; however, the
tory distress syndrome caused by toxoplasmosis, has been risk of transmission is low (less than 4%) [30, 31]. Studies
reported. Mortality, even in the presence of treatment for that addressed this problem were conducted in cohorts of
toxoplasmosis, is high in these patients [24]. The most primarily asymptomatic women, most of whom had a CD4
common clinical syndrome is a prolonged febrile illness count >200 cells/mm3 [32, 33]. The risk of transmission may
with cough, hypoxemia, and dyspnea that is clinically in- be higher in severely immunocompromised HIV-infected
distinguishable from Pneumocystis pneumonia. This pre- women, particularly in those in whom clinical reactivation
sentation has also been reported as a manifestation of an occurs (e.g. TE) [34]. However, there are insufficient data to
undiagnosed HIV infection [25]. Associated extrapulmonary accurately estimate this risk. In one study, one of the three du-
disease caused by T. gondii has been reported in approxi- ally infected mothers with CD4 counts <100 cells/mm3
mately 50% of the patients at the time of clinical presenta- transmitted T. gondii infection to her baby [32]. When dually
tion. TE may precede or follow pulmonary toxoplasmosis infected women developed toxoplasmosis during preg-
if maintenance therapy is not instituted. A highly lethal syn- nancy, 75% of their infants were born with congenital toxo-
drome of disseminated toxoplasmosis has been described in plasmosis and HIV infection [3]. All infants with congenital
AIDS patients that present with fever and a sepsis-like syn- toxoplasmosis born to mothers who were HIV-infected were
drome with hypotension, disseminated intravascular coagu- also infected with HIV. The initial clinical presentation of
lation, elevated lactate dehydrogenase, and pulmonary congenital toxoplasmosis in the HIV-infected infant is similar
infiltrates [23]. This syndrome is usually not associated with to that in HIV-uninfected infants but appears to run a more
clinical or radiologic evidence of TE [21]. rapid and progressive course. The infants often appear nor-
Ocular disease caused by toxoplasmosis occurs relatively mal at birth. In the ensuing months, they fail to gain weight
infrequently in AIDS patients (compared with the inci- or develop appropriately. The majority develop multisystem
dence of cytomegalovirus retinitis) [26]. Ocular pain and organ involvement, including the CNS, heart, and lungs [30].
398
Chapter | 31 | AIDS-associated toxoplasmosis
Thus, a brain biopsy should be strongly considered in cases

DIAGNOSIS where the likelihood of TE is low if lumbar puncture is not
possible or if PCR testing is non-diagnostic. In addition to
TE, examination of the CSF by PCR can also be diagnostic
At present, the definitive diagnosis of toxoplasmosis in
for JCV-associated progressive multifocal leukoencephalo-
AIDS patients can only be made by demonstration of the
pathy (PML), EBV-associated central nervous system lym-
organism in tissues or amplification of T. gondii DNA from
phoma, and CMV ventriculitis. The likelihood of TE is
body fluids (i.e. CSF, BAL, vitreous fluid, peripheral blood,
low in Toxoplasma-seronegative patients, those with CD4
urine) (Box 31.1). In cases where TE is highly likely (see
counts >200 cells/mm3, those with single space-occupying
Management), brain biopsy can be deferred while awaiting
lesions on brain MRI, and those who have been compliant
results of empiric anti-T. gondii therapy. The likelihood
with anti-Toxoplasma prophylaxis [10].
of TE is high in AIDS patients who are seropositive for
T. gondii, whose CD4 count is <200 cells/mm3 (risk is
greater when it is <100 cell/mm3 [35]), have multiple Serology
ring-enhancing lesions on MRI of the brain, and who are
Because TE in patients with AIDS almost always represents
not taking anti-Toxoplasma prophylaxis. In this clinical sce-
reactivation of chronic (latent) infection, the presence of
nario, an optimal response to anti-Toxoplasma therapy fur-
T. gondii-specific IgG antibodies in an HIV-infected patient
ther supports the diagnosis of TE. In these patients an
must be regarded as a marker for the potential development
inadequate clinical response to treatment (e.g. lack of
of toxoplasmosis. If the serologic status of an HIV-infected
50% improvement in the patient’s neurological exam by
patient with suspected TE is unknown, the IgG and IgM
day 7) makes the diagnosis less likely and should prompt
antibody status should be determined.
a lumbar puncture, if safe and feasible, for examination
Although almost all AIDS patients with TE have detect-
of the CSF by polymerase chain reaction (PCR), and/or a
able IgG T. gondii in their serum, published series have
brain biopsy. The morbidity associated with brain biopsy
reported a 0–3% seronegativity rate [14].
for the evaluation of focal brain lesions in HIV-infected pa-
Toxoplasma gondii IgM antibodies, routinely measured in
tients is less than that from an erroneous diagnosis [36].
an attempt to diagnose acute toxoplasmosis in non-AIDS
patients, are rarely demonstrable in AIDS patients with
TE. In HIV-infected patients whose Toxoplasma serology re-
sults are unknown, both IgG and IgM should be measured
Box 31.1 Methods for the diagnosis of T. gondii initially. Positive results on both tests should suggest re-
infection and toxoplasmosis in patients with cently acquired infection, though this is not diagnostic of
HIV infection or AIDS toxoplasmosis [3]. Positive or equivocal IgM results are
• Serology (including titer in differential agglutination
not necessarily diagnostic of an acute infection; in fact they
assay, IgG, IgMa) may be false positive or observed in chronically infected in-
dividuals. Thus, HIV-infected patients with equivocal or
• Visual demonstration of T. gondii in body fluids (CSF,
BAL) by microscopic examination (i.e. using Wright-
positive Toxoplasma IgM results should undergo confirma-
Giemsa stain) tory testing at a reference laboratory when feasible (e.g. in
the USA, at the Palo Alto Medical Foundation Toxoplasma
• Amplification of T. gondii DNA by PCR examination of
body fluids (i.e. CSF, peripheral blood, BAL, vitreous
Serology Laboratory [PAMF-TSL]).
fluid) or tissue biopsies
• Histologic evaluation, including immunoperoxidase Isolation studies
staining of tissue biopsies
Isolation of T. gondii from body fluids or from tissue in the
• Isolation of T. gondii from tissue biopsies or body fluids
appropriate clinical setting, obtained from a patient with
(i.e. CSF, blood, BAL)
AIDS, should be considered diagnostic of active infection.
• CT scans and/or MR images of the brain in an attempt to
Because isolation of the organism may not be evident for 6
demonstrate the presence of multiple ring-enhancing
days to 6 weeks after mice or tissue cultures are inoculated,
lesions
the results are rarely helpful in initial management of the pa-
BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; CT, tient. Nevertheless, isolation of the organism may obviate
computed tomography; Ig, immunoglobulin; MR, magnetic the future need for brain biopsy.
resonance; PCR, polymerase chain reaction. Toxoplasma gondii readily forms plaques in tissue cultures
a
Useful, mainly in areas of high seroprevalence, IgM positive results
should undergo confirmatory testing at a reference laboratory (e.g. of human foreskin fibroblasts and most other cultured cells
in the USA, at the Palo Alto Medical Foundation Toxoplasma [37, 38]. It has been isolated from the blood in 14–38% of
Serology Laboratory [PAMF-TSL]; Palo Alto, CA; http://www.pamf. AIDS patients with toxoplasmosis [39, 40]. Toxoplasma gon-
org/serology/; telephone number (650) 853-4828; e-mail
[email protected]).
dii may also be isolated from bronchoalveolar lavage (BAL)
fluid in patients with toxoplasmic pneumonitis [41].
399
DNA detection (PCR) CT scans, subependymal location, and crossing of the cor-
pus callosum suggest the possibility of lymphoma [59].
The high specificity of PCR testing for T. gondii DNA makes Other imaging techniques appear to be useful for distinc-
this method of diagnosis useful when positive. The use of tion between CNS lymphoma and infectious processes in
the PCR has enabled detection of T. gondii DNA in brain HIV-infected patients with focal brain lesions. Magnetic
tissue [42, 43], CSF [44, 45], BAL fluid [46, 47], peripheral resonance techniques, positron emission tomography scan-
blood [44, 48, 49], aqueous humor [42, 46], and vitreous ning and radionuclide scanning have been used to evaluate
fluid [50] of AIDS patients with toxoplasmosis. Because AIDS patients with focal CNS lesions, specifically to
T. gondii cysts persist in certain organs (i.e. brain, skeletal differentiate between toxoplasmosis and primary CNS lym-
and heart muscle, and eyes) for years after infection, a pos- phoma. Magnetic resonance spectroscopy (MRS), although
itive PCR in these tissues does not necessarily reflect active widely available, is not usually performed; differences be-
infection. tween CNS lymphoma and TE in levels of lipids and lactate
Of note, attempts to use PCR from amniotic fluid to have been reported. However, the improper choice of voxel
make a prenatal diagnosis of congenital infection have positions in clinical practice may have contributed to the
been hampered by concerns about potential of transmis- failure to accurately distinguish differences between the
sion of HIV to the fetus during amniocentesis [51]. How- spectra of lymphoma and toxoplasmosis [60–62]. Fluoro-
ever, in a recent study by Mandelbrot and colleagues, the deoxyglucose [18F]-positron emission tomography (FDG-
risk of mother-to-child transmission was negligible in PET) is used for the diagnosis of tumors in the CNS; uptake
mothers taking ART. Thus, in HIV-infected women who ac- of [18F] is significantly higher in patients with CNS lym-
quired primary T. gondii infection during gestation or in phoma compared to patients with TE [63–66]. Although
women with AIDS who develop toxoplasmosis, amniocen- the studies reported high sensitivity and specificity for the
tesis can be performed, if they are taking effective ART [52]. diagnosis of CNS lymphoma, the number of patients was
small, patients were receiving empirical treatment for TE,
and the procedures were performed several days after treat-
Neuroimaging studies
ment was initiated, which can decrease the uptake of the le-
Imaging studies of the brain are essential for diagnosis and sions. Similarly, several studies demonstrated increased
management of patients with TE [53]. Typically, multiple, uptake by thallium-201 single-photon emission computer
bilateral, hypodense, enhancing mass lesions are found on tomography (201Tl SPECT) as highly sensitive and specific
CT scan. Lesions have a predilection for, but are not limited for the diagnosis of CNS lymphoma in HIV-infected patients
to, the basal ganglia and hemispheric corticomedullary [67–69]. It has also been used as a complementary imaging
junction. Significant enhancement of intracerebral lesions procedure for MRI with improved diagnostic accuracy [70].
201
is usually seen on CT scan. However, Toxoplasma abscesses Tl SPECT may have decreased diagnostic utility in
may fail to enhance or may be solitary and located any- HIV-infected patients receiving ART [71].
where in the brain. MRI is more sensitive than CT scan Although MRS, FDG-PET, and 201Tl SPECT, have demon-
for detection of brain lesions in patients with TE. Masses strated usefulness in the diagnosis of brain lesions in HIV-
demonstrated by MRI may be absent on CT scan [54], infected patients, they are infrequently utilized in clinical
whereas the converse is not true. Abnormal contrast- practice due to variability in uptake, high cost, and low
medium enhancement, both on CT and MRI, appears to availability.
correlate with the CD4 count: pathological uptake may
be absent or mild with CD4 count <50 cells/mm3 and in-
creases accordingly with increasing CD4 count [55, 56].
The neuroradiologic response of TE to specific treatment HISTOPATHOLOGY
is seen on CT as a reduction in mass effect, number and ex-
tent of lesions, and enhancement. Although the time to res- Definitive diagnosis of TE often requires demonstration of
olution of lesions may vary from 20 days to 6 months, the organism on histopathologic section of brain tissue
the vast majority of patients who respond clinically will obtained at biopsy. Some evidence suggests the superiority
also show radiographic improvement [57, 58]. The MRI re- of open excisional biopsy compared to needle biopsy in mak-
sponse to therapy also varies with the location and coming the histopathologic diagnosis of TE. The response of the
plexity of the mass lesion. Persistent enhancement on CT brain to T. gondii infection can vary from a granulomatous re-
scans or MRI after treatment for TE has been associated with action with gliosis and microglial nodule formation to a se-
a higher incidence of subsequent relapse. Findings on MRI vere focal or generalized necrotizing encephalitis [72].
and CT scans are not pathognomonic for TE. Primary CNS Perivascular and intimal inflammatory cell infiltrates can lead
lymphoma cannot be distinguished from toxoplasmosis to fibrosis necrosis, which can result in hemorrhage or throm-
solely on the basis of neuroradiologic criteria, as both pre- bosis, accounting for neurologic signs and symptoms.
sent as contrast-enhancing lesions with mass effect. How- The presence of numerous T. gondii tachyzoites or cysts
ever, the presence of hyperattenuation on non-enhanced surrounded by an inflammatory reaction is diagnostic.
400
Cysts or free organisms (tachyzoites) not demonstrable on neurologic impairment 40% [78, 79]. Therefore, preven-
routine histopathologic examination can be identified tion of the disease is critical.
using the peroxidase-antiperoxidase method [73]. Thus, Primary prophylaxis is recommended for those who are
when routine histopathologic studies fail to provide a de- seropositive with CD4 counts of <200 cells/mm3 [35, 80,
finitive diagnosis, appropriately fixed brain tissue should 81]. It is important to emphasize that the threshold sug-
be stained by the immunoperoxidase technique in an gested in this chapter is different than the threshold of
attempt to identify T. gondii antigens or organisms. <100 cells/mm3 suggested by Guidelines for Prevention
Wright–Giemsa-stained smears or touch preparations and Treatment of Opportunistic Infections in HIV-infected
should be made as soon as is feasible from tissue obtained Adults and Adolescents [35]. We suggest using a threshold
at surgery. Similarly, Wright–Giemsa stain of a cytocentri- of 200 cells/mm3 because all of the North American studies
fuge preparation of CSF or BAL may reveal the presence demonstrating the efficacy of primary prophylaxis were
of tachyzoites. evaluating the efficacy of PCP prophylaxis, in which the
threshold for intervention was CD4 counts <200 cells/
mm3. Using different CD4 thresholds for the primary pro-
DIFFERENTIAL DIAGNOSIS phylaxis of PCP and TE may also be confusing for non-
expert physicians, and might make it more difficult for phy-
sicians in resource-limited settings, where frequent CD4
The main differential diagnosis of HIV-infected patients testing is unavailable. Several authors have reported that
with focal brain lesions is between CNS lymphoma and in South America [82, 83] and in some areas of the United
TE. In Toxoplasma-seropositive, HIV-infected patients with States, more aggressive strains of T. gondii circulate that may
a CD4 count of <200 cells/mm3 who are not receiving reactivate at higher CD4 count thresholds.
anti-T. gondii prophylaxis, the presence of multiple enhanc- MRI is more sensitive than a CT scan and thus is the pre-
ing lesions is strongly suggestive of TE. In patients with a ferred imaging technique, especially in patients without fo-
low probability of having TE, the initial differential diagno- cal neurologic abnormalities. Patients with a solitary lesion
sis should also include PML, fungal abscess (e.g. cryptococ- or no lesions on CT scan should undergo MRI to determine
coma), tuberculosis, pyogenic brain abscess, syphilitic whether more than one lesion is present. Because a single
lesions (gummas) [74] or cytomegalovirus disease, and lesion on MRI is uncharacteristic of TE, CNS lymphoma
Kaposi’s sarcoma in addition to TE. Because therapy is and other causes of focal brain lesions should be suspected.
available for most of these disorders, brain biopsy for his- Early brain biopsy should be considered in this situation.
topathologic diagnosis in patients with low likelihood of CSF examination by PCR for T. gondii, EBV, JC, and CMV
having TE (e.g. single lesion by MRI, negative anti- viruses should also be considered if lumbar puncture is
Toxoplasma IgG, CD4 count >200 cells/mm3, use of anti- deemed safe.
Toxoplasma prophylaxis, lack of response to therapy) may TE used to be the most common cause of focal brain
be necessary for successful management of the patient. lesions in AIDS patients. Therefore, empiric therapy was
The characteristic appearance of PML on neuroimaging stud- considered appropriate for all Toxoplasma-seropositive
ies often facilitates differentiation of this disorder from other HIV-infected patients with multiple focal brain lesions,
causes of intracerebral mass lesions. Generally, lesions are Toxoplasma IgG antibodies, and CD4 counts <200 cells/
multifocal and asymmetric at presentation, predominantly mm3. Brain biopsy was recommended in those who did
involve white matter, and progress in size and number. Ring not improve clinically within 7–10 days of initiation of spe-
enhancement, edema and mass effect are rare [74–76] and cific therapy. However, the incidence of TE in AIDS patients
more often seen with immune reconstitution inflammatory has decreased in recent years due to the use of primary pro-
syndrome (IRIS) [77]. However, brain biopsy remains the phylaxis and ART. In contrast, the primary CNS lymphoma
gold standard for definitive diagnosis. is now a more common cause of focal brain lesions [84].
Thus, empiric therapy for all patients with focal brain le-
sions without an aggressive diagnostic work-up may delay
MANAGEMENT initiation of appropriate therapy and expose patients to
potentially unnecessary and toxic regimens.
CSF for PCR should be obtained in patients with a low
General principles
likelihood of TE, provided that these tests are available
Because TE generally reflects reactivation of a latent infec- and it is safe to perform a lumbar puncture. Patients who
tion, all HIV-infected individuals should be tested for may benefit from these studies include those with negative
anti-Toxoplasma IgG antibody. For those who are seronega- T. gondii IgG antibodies, CD4 counts of >200 cells/mm3,
tive, we recommend periodic repeat testing. Those who are single lesions on MRI, or multiple lesions on MRI/CT scan
seropositive are at risk for development of TE (Fig. 31.1). while receiving primary T. gondii prophylaxis. If these tests
Studies have associated TE with a more rapid progression are not available, early brain biopsy without awaiting
of HIV, high TE mortality 16–40%, and persistent response to therapy should be considered. The presence
401
Approach to the HIV-positive patient with CNS signs/symptomsa
Single lesion Brain MRIb No lesions TE unlikelyf
Toxoplasma serology Multiple lesions Toxoplasma serology
Positive Negative Positive Negative
Institute Tx for TE If Recommend Taking Consider brain

no clinical response brain biopsyc prophylaxis biopsyc or CSFd
by day seven, Consider CSFd for TEg? for PCRe
consider biopsyc or for PCRe
CSFd for PCRe
Yes No
Treat empirically for TE

Consider brain biopsyc or CSFd for PCRe if
inadequateh to Tx
Figure 31.1 Guidelines for the evaluation and management of patients with suspected toxoplasmic encephalitis (TE). (a) Patients
with TE may present with a non-focal neurological examination. (b) MRI is superior to CT scan. (c) T. gondii-specific
immunoperoxidase stain is both highly sensitive and specific for the diagnosis of TE. (d) CSF should be obtained only if safe to perform
a lumbar puncture. (e) In addition to PCR for T. gondii, consider PCR for EBV (PCNSL), JCV (PML), and CMV. (f) If CD4 T count <50
cells/mm3, Toxoplasma IgG is positive, and no other cause of encephalitis has been identified, suspect diffuse TE. (g) For regimens
considered to be effective for TE prophylaxis see Table 31.2. (h) Inadequate response to therapy is defined as deterioration of the
neurological findings within 3 to 5 days of institution of an appropriate anti-Toxoplasma regimen or no significant clinical response
(less than 50% improvement in neurological examination) within 7 to 10 days. CMV, cytomegalovirus; CSF, cerebrospinal fluid; CT,
computed tomography; EBV, Epstein–Barr virus; JC virus; MRI, magnetic resonance imaging; PCNSL, primary central nervous system
lymphoma; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy; Tx, treatment.
of multiple brain lesions in a Toxoplasma-seropositive, HIV- should be considered in patients whose condition worsens
infected patient with a CD4 count <200 cells/mm3 who is early in the course of therapy or in patients who do not
not receiving prophylaxis is still considered highly predic- show clinical improvement by 10–14 days [57]. Repeat
tive of TE. Thus, awaiting clinical response to empiric anti- neuroradiologic study by the same modality as originally
Toxoplasma therapy still appears to be an appropriate selected should be performed 2–4 weeks after initiation
approach in this setting. of therapy in patients who demonstrate a satisfactory clin-
Diffuse TE is rare but it frequently goes under-diagnosed ical response (or earlier if response is poor). Lesions should
and should be suspected when a patient with severe CD4 have diminished in size and possibly in number. Patients
cell depletion and a positive T. gondii serology experiences with extraneurologic toxoplasmosis should be evaluated
unexplained fever and neurologic disease. When diagnostic for CNS disease, because a significant number of them will
investigations fail to disclose a specific cause in these cases, also have intracerebral involvement.
a trial of empiric therapy should be urgently considered. Corticosteroids should be considered in patients with
A prospective study demonstrated that 71% of patients intracranial hypertension caused by the mass effect from
with TE had a complete or partial response [57]. The neu- T. gondii abscesses. A study reported that there was no dif-
rologic response was rapid, with 51% of patients showing ference in the response rate and the time to response in pa-
signs of improvement by day 3 and 91% by day 14 [57]. tients who received corticosteroids when compared with
Thus, brain biopsy with or without change of therapy those who did not [57]. At present, AIDS patients with
402
TE should receive corticosteroids only when necessary,

Table 31.1 Guidelines for acute or primary treatment of
preferably for no more than 2 weeks. Anticonvulsant agents
AIDS patients with TE
should be administered to those patients with TE and sei-
zures during initial therapy but are not recommended for
DRUGS DOSAGE
routine prophylaxis [35].
It is important to distinguish between two forms of ther- Recommended regimens
apy for TE in patients with AIDS: primary therapy and
maintenance therapy. Primary therapy is administered dur- Pyrimethamine PO: 200 mg loading followed by
ing the acute disease. Maintenance therapy is administered 50 (<60 kg) to 75 (>60 kg) mg
after an adequate clinical and neuroradiologic response has once daily
been observed. Unless ART-induced immune reconstitu- Folinic acid PO, IV, or IM: 10–20 mg once daily
tion takes place, maintenance therapy should be continued (max. 50 mg)
for life, because the rate of relapse is prohibitively high
when treatment is discontinued. plus sulfadiazine PO: 1000 (<60 kg) to 1500 (>60 kg)
Once the CD4 T count has increased to >200 cells/mm3 (preferred) mg q6h
and the HIV viral load has been non-detectable for 3
or clindamycin PO or IV: 600 mg q6h (up to
months or longer, maintenance therapy can be safely
1200 mg IV q6h recommended in
discontinued in clinically stable patients. severe cases with altered mental
status as an IV medication)
Alternative regimens
Primary (induction) therapy
TMP-SMX PO or IV: 10 mg/kg/day (TMP
Pyrimethamine, a potent dihydrofolate reductase inhibi- component) divided in two doses
tor, is the cornerstone of current treatment of AIDS- (15–20 mg/kg per day has been used).
associated TE. It is standard practice to administer the com-
bination of pyrimethamine plus sulfadiazine or pyrimeth- Pyrimethamine plus As in recommended regimen
amine plus clindamycin (Table 31.1). folinic acid
Prospective, randomized studies of treatment of TE
plus one of the following:
showed that pyrimethamine plus clindamycin and pyri-
methamine plus sulfadiazine were equally efficacious dur- • Atovaquone PO: 1500 mg twice daily
ing the acute phase of therapy. Several studies have found • Clarithromycin PO: 500 mg twice daily
that trimethoprim-sulfamethoxazole (TMP-SMX) may also • Azithromycin PO: 900–1200 mg once daily
be effective for acute therapy of TE [85–87]. A randomized, • Dapsone PO: 100 mg once daily
prospective study revealed that the clinical response rate to
TMP-SMX (10 mg/kg per day of the trimethoprim compo- Atovaquone PO: 1500 mg twice daily
nent) was similar to that of pyrimethamine (50 mg/day) sulfadiazine
plus sulfadiazine (60 mg/kg per day) [86]. In a recent ob- PO: 1000 (<60 kg) to 1500 (>60 kg)
servational retrospective cohort study, improvement was mg q6h
observed in 71 patients (85.5%) [88].
A study of the combination of atovaquone (administered
orally as a suspension) plus either pyrimethamine or sulfa-
diazine as treatment for acute disease reported 6-week In view of the dramatic immune reconstitution observed
response rates of 75 and 82%, respectively [89]. Thus, as a result of ART, it is critical that HIV be treated to add
atovaquone/pyrimethamine can be used as an alternative antiretroviral drug regimens as soon as possible after the
treatment for patients intolerant of sulfonamides, and diagnosis of toxoplasmosis. Although Toxoplasma IRIS has
atovaquone/sulfadiazine for patients who are intolerant been reported, including IRIS-mediated TE [91–93] and
of pyrimethamine. However, large variation among indi- IRIS-mediated placental toxoplasmosis with fetal loss [34],
viduals in the absorption of atovaquone has been reported. prompt institution of ART is warranted in the setting of acute
Levels above 18.5 mg/mL are ideal, although measurements TE [94].
are not usually available in general practice [90]. Primary or Almost all the studies on the use of antimicrobial agents
induction therapy is recommended for at least 6 weeks as- for the treatment of toxoplasmosis have focused on patients
suming the patient experiences clinical and radiological with TE. Limited data suggest that patients with extracerebral
improvement. Longer treatment duration should be con- toxoplasmosis also respond to therapy with pyrimethamine-
sidered in patients with an incomplete clinical or radiolog- sulfadiazine or pyrimethamine-clindamycin, but the mortal-
ical response. Changes in anti-Toxoplasma IgG titers are not ity rate in patients with pulmonary or disseminated toxo-
useful for monitoring response to treatment. plasmosis may be higher than in patients with TE alone.
403
Maintenance treatment (secondary acceptable safety profile. Although TE can recur during
prophylaxis) maintenance therapy, it is important to be aware that some
of these failures are due to non-adherence.
While the combination of pyrimethamine plus sulfadia- The regimen of pyrimethamine plus sulfadiazine appears
zine is highly active against the proliferative form of T. gon- to have a lower rate of relapse than other regimens and
dii, neither it, nor any of the other currently used drugs is is recommended. Patients on maintenance therapy with
effective in eradicating the cyst form of T. gondii. It is be- pyrimethamine-sulfadiazine do not require additional Pne-
lieved that persistence of the cyst form accounts for relapse umocystis prophylaxis. Although most investigators favor
of TE after therapy is discontinued. The relapse rate of TE in the daily use of pyrimethamine-sulfadiazine, many pa-
patients who are not receiving ART and maintenance ther- tients requiring alternative regimens continue this regimen
apy for toxoplasmosis is 50–80% at 12 months [95]. The because of drug toxicity (Table 31.2).
CT scans or MRI images in patients who relapse often dem- Relapse rates with pyrimethamine plus clindamycin have
onstrate mass lesions in the same location as at initial pre- been reported to be relatively high (e.g. 22%) [97]. Whether
sentation. Thus it is essential that patients who complete a the high relapse rate was due to the low dose of clindamycin
course of primary therapy and who have had a favorable (1.2 g/day) used remains to be determined. In addition, it
clinical and radiologic response to therapy for TE receive is important to be aware that pyrimethamine-clindamycin
lifelong anti-Toxoplasma therapy unless they experience does not prevent Pneumocystis pneumonia. Pyrimeth-
ART-induced immune reconstitution (e.g. CD4 count amine-sulfadoxine (Fansidar), administered as a single
>200 cells/mm3 and undetectable HIV viral load for at tablet twice weekly, has been reported to be effective as
least 3 months) [96]. maintenance therapy. Side effects were relatively common
After successful primary therapy, drug dosages are gener- (40%), with 7% of patients discontinuing therapy because
ally decreased for maintenance therapy (Table 31.2). There of adverse effects [98]. Atovaquone may be an alternative
is no single regimen that is both effective and has an for secondary prophylaxis in patients with intolerance to
standard therapy or for whom such therapy failed.
Table 31.2 Guidelines for maintenance treatment of AIDS

patients with TE (secondary prophylaxis)
Considerations during pregnancy
ORAL DOSE FREQUENCY Women who are co-infected with HIV and T. gondii and who
have developed AIDS are at risk of reactivating their T. gondii
Recommended regimens
infection, developing severe toxoplasmosis (i.e. toxoplas-
Pyrimethaminea 25–50 mg PO once daily mic encephalitis, pneumonia, etc.), and/or transmitting
the parasite to the fetus [51].
plus 2000–4000 2-4 divided doses daily Pregnant HIV-infected women should receive the same
sulfadiazine mg PO treatment for TE as non-pregnant adults [35]. Although py-
Pyrimethaminea 25–50 mg PO once daily rimethamine has been associated with birth defects in an-
imals, limited human data have not suggested an increased
plus 600 mg PO 3 times daily risk of birth defects. However, the use of pyrimethamine
clindamycin should be limited to the second and third trimesters [3, 51].
Acute maternal Toxoplasma infection in HIV-infected
Alternative regimens
women can result in the transplacental transmission of
Pyrimethaminea 25–50 mg PO once daily Toxoplasma. There have been case reports of congenital
transmission of the parasite in HIV-infected women with
plus one of the following: significant immunosuppression who develop symptoms
Dapsone 50 mg PO once daily due to toxoplasmosis. At present, data are insufficient to deter-
mine the effectiveness of treatment intended to prevent verti-
Atovaquone 1500 mg PO once daily cal transmission of T. gondii in an HIV-infected woman. We
suggest that asymptomatic Toxoplasma-seropositive pregnant
Clarithromycin 500 mg PO once daily
women whose CD4 count is below 200 cells/mm3 receive
Azithromycin 600 mg PO once daily trimethoprim-sulfamethoxazole (160 mg trimethoprim and
800 mg sulfamethoxazole in a double-strength tablet, 1 tablet
a
Folinic acid (leucovorin calcium) 10–25 mg once daily (can increase per day), which is also used to prevent Pneumocystis pneumo-
up to 50 mg) is recommended for all patients receiving nia. The goal is to prevent both reactivation of latent Toxo-
pyrimethamine to help ameliorate the hematologic side effects
plasma infection and transmission of the parasite to their
associated with pyrimethamine. The dose of folinic acid is titrated
against the patient’s hematologic indices.
offspring. Trimethoprim can increase the risk of kernicterus
and should be avoided in the first trimester, because it is a
404
folic acid antagonist. In asymptomatic women with evi- HIV-infected individuals has been reported to occur in
dence of acute toxoplasmosis infection during pregnancy 2% after a mean follow-up of 2 years.
whose CD4 count is above 200 cells/mm3, spiramycin, a Despite the availability of effective antimicrobial regi-
macrolide reported to decrease the frequency of vertical trans- mens, toxoplasmosis in AIDS patients is associated with a
mission treatment, is suggested for the duration of the preg- mortality rate of 70% by 12 months after the diagnosis of
nancy [35, 51]. TE if ART is not instituted [99]. Among AIDS patients the
The fetus should be examined monthly by ultrasound to 1-year probability of HIV disease progression or death after
detect evidence of congenital infection (hydrocephalus) [51]. a diagnosis of TE has been reported to be 40 and 23%, re-
spectively [79]. Numerous studies have reported the efficacy
of TMP-SMX, pyrimethamine-dapsone or pyrimethamine-
sulfadoxine, in the prevention of TE in HIV-infected patients
Prevention (primary prophylaxis) (Table 31.3). It must be emphasized that among patients
Serologic testing for T. gondii antibodies will distinguish receiving primary prophylaxis with TMP-SMX [100], pyri-
those HIV-infected individuals who are at risk for reactiva- methamine-dapsone [101], or pyrimethamine-sulfadoxine,
tion of infection from those at risk for acquisition of infec- 40–60% will have untoward side effects, and 2–12% of the
tion. All patients who are seronegative for T. gondii total number of patients will require discontinuation of
antibodies, and especially patients with deficient cellular therapy.
immunity, should be educated about appropriate precau- Pyrimethamine alone is not recommended as primary
tions to take to prevent acquisition of T. gondii infection prophylaxis against TE in patients who cannot tolerate
(Box 31.2). Seroconversion to T. gondii positivity in TMP-SMX [102].
Although there are no data available on the use of pro-
phylaxis against congenital toxoplasmosis in HIV-infected
women who are seropositive for T. gondii antibodies and
Box 31.2 Methods for preventing toxoplasmosis
whose T. gondii infection was acquired prior to pregnancy
in patients with HIV infection*
and in the distant past, administration of TMP/SMX 1
Individuals should take the following precautions: double-strength tablet daily throughout pregnancy for
• Cook meat to “well done” or thoroughly to 67 C women with CD4 count <200 cells/mm3 has been
(153 F).
• Meat should not be “pink” in the center.
• Freeze meat to 20 C (4 F) for at least 24 hours.
• Note that meat that is smoked, cured in brine or dried Table 31.3 Regimens used for primary prophylaxis
may still be infectious. against toxoplasmosis
• Avoid touching mucous membranes of mouth and eyes
while handling raw meat. DRUG DOSAGE SCHEDULE
• Wash hands thoroughly after handling raw meat.
TMP-SMX 1 DS tab PO once daily
• Wash kitchen surfaces that come into contact with raw
1 SS tab PO once daily
meat, wearing gloves.
• Wash fruits and vegetables before consumption. Pyrimethaminea þ Pyrimethamine 50 mg PO once
• Avoid drinking unpasteurized goat’s milk. dapsone weekly þ dapsone 50 mg PO
• Avoid eating raw oysters, clams, or mussels. once daily
Pyrimethamine 75 mg once
• Prevent access of flies, cockroaches, and the like to fruits
weekly þ dapsone 200 mg once
and vegetables.
weekly
• Avoid contact with materials that are potentially
contaminated with cat feces (e.g. cat litter boxes) or Pyrimethamine- 3 tabs PO every 2 weeks
wear gloves when handling such materials or when sulfadoxine 1 tab PO twice weekly
gardening. (Fansidar)a,b
• Wearing gloves is recommended when these activities
cannot be avoided. Atovaquone Atovaquone1500 mg once daily
• Avoid drinking untreated water, including that from pyrimethamine 25 mg plus folinic
wells or reservoirs that have not been secured from acid 10 mg PO once daily
potential contamination by feces from wild or domestic DS, double strength; SS, single strength.
cats. a
Folinic acid (leucovorin) 25 mg weekly is recommended for all
*
patients receiving pyrimethamine to help ameliorate the
Note that up to 50% of individuals can get infected with T. gondii hematologic side effects associated with pyrimethamine. The dose
even if they do not occur in behaviors associated with the acute
of folinic acid is titrated against the patient’s hematologic indices.
infection [108]. b
Each tablet contains pyrimethamine 25 mg, sulfadoxine 500 mg.
405
recommended. Pyrimethamine-sulfadiazine after the sev- <200 cells/mm3 had significantly lower lymphocyte prolif-
enteenth week of pregnancy should be considered for those erative and functional responses. These data are consistent
who are more severely immunosuppressed and in whom with previous studies indicating that TE secondary prophy-
fetal infection is highly suspected or documented. laxis can be safely withdrawn after ART-mediated recovery
of the CD4 count to >200 cells/mm3 [96, 104].
Discontinuation of primary and Observational and randomized studies indicate that it is
safe to discontinue primary prophylaxis against T. gondii in
secondary prophylaxis
adults and adolescents whose CD4 counts increase to >200
Although in vitro studies indicate that ART does not fully cells/mm3 for at least 3 months in response to ART. It is im-
restore cell-mediated immunity against T. gondii in all portant to note that the majority of these patients were on
HIV-infected patients, the use of ART has been associated protease inhibitor-containing regimens, had a CD4 count
with a decline in mortality and incidence of opportunistic >200 cells/mm3 for an average of 8 months, had a median
infections, including TE, in HIV-infected patients [9, 103]. CD4 count at study entry of more than 300 cells/mm3, and
These findings prompted studies that explored the safety of had undetectable plasma viral load [105].
discontinuing prophylaxis against opportunistic pathogens It appears reasonable to consider stopping maintenance
in patients receiving ART. According to a recent study on therapy in patients who have completed acute-phase treat-
the restoration of T cell responses to T. gondii antigens in ment for TE, are free of signs and symptoms attributable to this
patients with AIDS and T. gondii infection, similar lympho- disease, and have experienced sustained (>3 month) increase
cyte proliferative response against T. gondii antigens and in- in CD4 count to >200 cells/mm3 [35, 80, 96, 106, 107].
terferon gamma production were observed among HIV- Although no studies have directly addressed criteria for
infected patients on ART whose CD4 count is >200 cells/ restarting prophylaxis, it would be prudent to reinitiate pri-
mm3, and those who were HIV-uninfected. However, mary and secondary prophylaxis in patients whose CD4
HIV-infected patients on ART whose CD4 counts were count decreases to <200 cells/mm3.
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410
Chapter | 32 |
Hepatitis virus infections
Marion G. Peters, Monika Sarkar
INTRODUCTION Hepatitis B is a partially double-stranded DNA virus and

a member of the Hepadnaviridae family. Worldwide, over
400 million individuals are infected with HBV, approxi-
Viral hepatitis has become one of the major causes of mor- mately two-thirds of cases in Asia and 25% in Africa [6].
bidity and mortality in HIV-infected individuals worldwide The majority of individuals in these areas acquire HBV in-
[1]. For those on antiretroviral therapy (ART), co-infection fection vertically at birth or in infancy, but infections can
with either hepatitis B (HBV) or hepatitis C (HCV) leads to also be acquired by parenteral or sexual routes in adults. Af-
accelerated progression to chronic hepatitis, cirrhosis, and ter exposure, the risk of development of chronic disease
hepatocellular carcinoma [2]. For those initiating ART, co- varies with age and immune status. While over 95% of neo-
infection is associated with higher rates of hepatotoxicity nates, compared to 5% of adults exposed to HBV, develop
and immune recovery may be associated with reactivation chronic hepatitis, approximately 20% of HIV-infected indi-
of viral hepatitis, especially with HBV [3]. For these reasons, viduals who are exposed as adults develop chronic HBV [7].
understanding the basic epidemiology, natural history, and The eight known genotypes vary in distribution geograph-
therapy of viral hepatitis is essential in HIV-infected indi- ically: predominantly genotypes B and C in Asia; genotype
viduals. Since the introduction of ART, immune restoration A in Northern Europe; genotype D in the Mediterranean
has prolonged the lives of HIV-infected patients. As a result, and Middle East; genotype F in South America; and geno-
morbidity and mortality associated with chronic liver dis- types A and E in Africa [6]. Because of the diversity of the
ease have emerged as a significant problem facing HIV population in the United States, genotypes A through D
and viral hepatitis co-infected patients and their caregivers. are commonly found. Co-infection with HBV in seen in
Hepatotoxicity associated with ART complicates the treat- two distinct settings: in regions of high endemicity (Asia
ment of HBV/HCV-HIV-co-infected patients, and anti- and Africa), HIV may affect populations with a high back-
HCV treatment is complicated by lower response rates ground incidence of HBV; or both HIV and HBV infection
and toxic drug interactions. may be acquired in adulthood through similar modes of
transmission (USA, Europe). Thus, co-infection with HBV
and HIV varies geographically, with high rates in sub-
EPIDEMIOLOGY Saharan Africa (up to 25.9% of HIV positive Nigerians in
Nigeria are HBsAg positive) compared to 6–10% of HIV
Hepatitis A virus (HAV) is an RNA virus that occurs world- positive individuals in the United States [8].
wide in sporadic or epidemic forms. It is transmitted almost Hepatitis C virus is an RNA flavivirus that infects ap-
exclusively by the fecal–oral route, but can also be transmit- proximately 4.1 million persons in the United States and
ted from person to person as a sexually transmitted disease, an estimated 170 million persons worldwide. HCV is
described primarily among homosexual men [4]. Risk mainly transmitted parenterally, with the highest preva-
factors for HAV infection in homosexual men include high lence of HCV infection found among injection drug users,
numbers of sexual partners and sexual practices that hemophiliacs who received pooled clotting factor concen-
involve oro–anal contact [5]. trates, and recipients of multiple blood transfusions prior
411
to testing. The recent epidemic of acute HCV in men who involve oro-anal contact [5]. A case-control study MSM
have sex with men (MSM) is associated with traumatic found that during a prolonged outbreak of acute HAV,
sex and sexually transmitted diseases and likely predomi- the HAV viral load was higher and the duration of viremia
nantly transmitted via blood contact [9]. Due to the shared was longer in HIV-infected patients as compared to those
modes of transmission, co-infection with HCV and HIV is without HIV during a single, prolonged outbreak of acute
common; there are an estimated 150,000 to 300,000 HIV– HAV. It also found that, at the onset of symptoms, HAV viral
HCV co-infected individuals in the United States. Twenty- load was higher and the duration of HAV viremia was longer
five to 30% of HIV-infected persons in the United States in HIV-infected subjects compared to HIV-uninfected
and Europe are infected with HCV, while 5 to 10% subjects [4]. In this study, the alanine transaminose (ALT)
of HCV-infected persons are also infected with HIV [10]. level in the HIV-infected subjects was also lower than in
The prevalence of HCV-HIV-co-infection differs by the pop- HIV-uninfected subjects, corresponding to a less severe
ulation studied. Approximately 50–90% of HIV-infected illness in HIV-infected individuals. Since hepatic injury in
injection drug users, the majority of HIV-infected hemophil- HAV is the result of host immune response, immunosup-
iacs, but only 4–8% of HIV-infected homosexual men are pression in HIV may result in a less severe and more
infected with HCV, which is similar to the prevalence found prolonged HAV infection. Though this study was conducted
in HIV-uninfected homosexuals [11]. Sexual and vertical after the introduction of ART, no information on ART use
transmission of HCV is, at best, inefficient (see earlier com- was provided and no correlation between duration or
ment about MSM epidemic) but co-infection with HIV and severity of HAV infection and CD4 counts were noted.
HCV increases the risk of perinatal transmission of either vi-
rus. Percutaneous exposure to infected blood carries a 30%
risk of HBV transmission and a 3% risk of HCV transmis- Hepatitis B
sion, compared to <0.3% risk of HIV transmission. HCV
Co-infection with hepatitis B and HIV leads to increased chro-
HIV-co-infection is associated with higher HCV RNA levels
nicity [14], accelerated progression of liver disease to end-
and an accelerated rate of progression to cirrhosis [10]. In
stage liver disease, and higher mortality [15]. In addition,
the United States, HIV individuals are usually infected with
HIV infection can lead to reactivation of HBV and higher
genotype 1, but in Europe, genotypes 2 and 3 are also found
HBV DNA levels, likely due to immunosuppression as is seen
in HIV co-infection, and genotype 4 is frequent in some
after organ transplantation and chemotherapy. Serum ami-
injection drug user populations [10].
notranferases are usually lower in HIV co-infected individuals
Hepatitis D (HDV) infection occurs in the setting of
and are less useful in determining the need for therapy. The
HBV. HDV is a defective RNA virus that requires HBV for
majority of patients with HBV worldwide have immune-
replication and utilizes the hepatitis B surface antigen
controlled and inactive disease with HBsAg positivity but
(HBsAg) as its envelope protein. It occurs most commonly
normal liver enzymes and low HBV DNA titers. Reactivation
in HIV-infected drug users [12].
of HBV can occur at any time and is manifest by the presence
Hepatitis E (HEV) is a zoonotic, single-stranded RNA vi-
of HBeAg, elevated serum aminotransferases and elevated se-
rus with an incidence of approximately 7/100,000 in the
rum HBV DNA (2,000 IU/mL). Mutations in the core gene
US [13]. HEV is most commonly transmitted through
may lead to inability to produce HBeAg in the presence of ac-
fecally contaminated water and consumption of under-
tive viral replication (elevated HBV DNA and serum amino-
cooked or raw meats, and is less readily transmitted be-
transferases with no HBeAg in serum), so-called “precore
tween humans. The most common animals reservoirs of
mutant” HBV infection. This type of infection is increasing
HEV include fish, swine, deer, chicken, wild rats, and shell-
worldwide, particularly in those infected since birth with ge-
fish. There are four HEV genotypes: genotypes 1 and 2 in-
notypes B and C (Asia) and D (Mediterranean). In immune
fect humans almost exclusively while genotypes 3 and 4
suppressed patients, serum HBV DNA is higher and reactiva-
infect animals and humans. The incubation period ranges
tion of HBV (with flares in serum aminotransferases) may oc-
from 15 to 60 days and the clinical presentation ranges
cur with recovery of immune control, usually 8–12 weeks
from asymptomatic disease to subacute and acute liver fail-
after starting ART therapy. In addition, seroconversion to
ure. Chronic HEV has been reported in HIV-infected pa-
anti-HBe and anti-HBs are less commonly achieved with
tients and after organ transplantation.
HIV co-infection, therefore long-term therapy is the rule.
NATURAL HISTORY
Hepatitis C
Co-infection with HIV is associated with increased levels
Hepatitis A
of HCV RNA and accelerated progression of HCV-related
Hepatitis A virus is an RNA virus that occurs worldwide in liver disease [16]. HIV seropositivity, alcohol consumption,
sporadic or epidemic forms and does not cause chronic dis- older age at the time of HCV infection, and CD4 count
ease. Risk factors for HAV infection in MSM include high < 200 cells/mm3 are associated with a higher rate of
numbers of sexual partners and sexual practices that fibrosis progression [17]. Prior to the widespread use of
412
Chapter | 32 | Hepatitis virus infections
ART, HIV-HCV co-infection was associated with more rapid particularly those in the third trimester. Severe presenta-
progression to cirrhosis by 1–2 decades [17, 18]. Overall tions are also more common in individuals with underly-
progression to cirrhosis is three-fold higher in HIV-infected ing liver disease. Although chronic HEV is less common
patients, and more than a third progress to cirrhosis in less than an acute self-limited hepatitis, this chronic carrier
than 20 years [19]. ART has improved liver-related out- state does afflict immunocompromised patients. HEV sero-
comes in patients with HIV and HCV but they are still in- prevalence is actually higher among HIV-infected than HIV
creased over those with HCV alone [19, 20]. The risk of negative patients, and chronic HEV has been reported in
hepatocellular carcinoma is also increased in patients with HIV-infected individuals [27].
HIV–HCV co-infection and occurs at a younger age [21].
Liver-related deaths are now the most common cause
of non-AIDS-related mortality among HIV-infected pa- PATIENT EVALUATION
tients, an observation that is mainly due to concurrent
HCV infection [1].
The effect of HCV infection on the natural history of HIV Patients with viral hepatitis and HIV co-infection should
is controversial. The Swiss HIV Cohort Study [22], a probe evaluated for the presence of chronic liver disease
spective cohort study of 3,111 HIV-infected subjects receiv- (Table 32.1). This includes history and physical examination
ing ART, demonstrated an increased risk of progression to for signs of chronic liver disease, as well as measurement of
AIDS and death, as well as decreased CD4 cell recovery, in serum albumin, aminotransferases (AST and ALT), bilirubin,
co-infected individuals compared with HCV-uninfected prothrombin time, and platelet count. Histologic evaluation
individuals. Even among those with well-controlled HIV– by liver biopsy is at present the most reliable method to deter-
HCV-infected people had over three times the risk of devel- mine disease activity and fibrosis stage. However, discor-
oping AIDS-defining opportunistic illnesses and death dance of at least one stage of fibrosis has been noted in up
compared with those without HCV infection. Though the to 30% of paired liver biopsies [28]. Sampling error, hetero-
study initially reported delayed CD4 cell recovery one year geneity of liver fibrosis and associated procedural risks have
after the start of ART among HCV-infected compared with encouraged investigation of non-invasive measures of fibro-
HCV-uninfected people, further data showed no difference sis. These measures include ultrasound-based images such a
in recovery of CD4 cells after four years of follow-up [23]. transient elastometry (FibroScan) [29] and serological mea-
A prospective cohort study of 1,955 patients in an urban sures of fibrosis markers. FibroScan is not currently available
HIV clinic in Baltimore, Maryland, found no difference in the USA. Serum markers of fibrosis that are available in-
in progression to AIDS, death, or decline in CD4 count be- clude APRI [30], FIB-4 [31], and fibrotest [32]. These tools
low 200 cells/mm3 when comparing HCV-infected with are generally accurate in identifying patients with no fibrosis
HCV-uninfected patients, even after controlling for ART or existing advanced fibrosis/cirrhosis but do not distinguish
use and well-controlled HIV replication [24]. A 20-year between moderate stages of fibrosis. Screening for hepatocel-
prospective study of IV drug using HIV-infected and HIV- lular carcinoma with abdominal imaging, with or without
uninfected individuals also found that despite ART, liver- alpha feta protein, is recommended for all cirrhotic patients.
related deaths were significantly higher among these In addition, for those with HBV, HCC screening should start
HIV-infected individuals [25]. These and other data suggest in Asian males at age 40 years, asian females at age 50 years,
that HCV may affect the natural history of HIV disease
and supports early introduction of HCV therapy in
Table 32.1 Monitoring clinical status of patients with liver
HIV-infected patients.
disease
Hepatitis D SYNTHETIC FUNCTION PROTHROMBIN TIME,

SERUM ALBUMIN
HDV is the most aggressive viral hepatitis. Its poor progno-
sis is accentuated in HIV patients [26]. The prevalence of Inflammation AST, ALT, liver biopsy
HDV antibodies in HIV and HBV patients ranges from 15
to 50%, depending on geographical region and risk group Fibrosis Liver biopsy, serum
category. In Western countries, HDV is more frequent in in- markers, transient
travenous drug users than persons sexually infected with elastography
HIV. HDV viremia is common in HIV positive patients with Hepatocellular carcinoma Alpha-fetoprotein,
detectable antibodies to HDV. imaging studies
Check HAV (HAV IgG) and Vaccinate to HAV and

Hepatitis E HBV status (HBsAg, anti-HBc, HBV if not immune
HEV is most commonly manifest as an acute, self-limited anti-HBs)
icteric hepatitis, though fulminant hepatic failure occurs Check HCV Ab
at disproportionally high rates among pregnant women,
413
sub-Saharan African males over age 20 years, and those with a should undergo HCV RNA testing if there is unexplained
family history of HCC [33]. It is not clear how frequently to liver disease, such as elevated liver enzymes.
image HIV/HCV or HIV/HBV patients who acquire infection Acute hepatitis A is diagnosed with IgM antibody to hep-
as adults and do not have cirrhosis. atitis A (HAV IgM). HAV IgG is evidence of immunity.
Patients should also be vaccinated against hepatitis A Acute hepatitis E infection is diagnosed with IgM antibody
and hepatitis B if they are susceptible [34]. Vaccination to hepatitis E (HEV IgM).
against HAV is safe and well-tolerated and confers protec-
tive immunity in virtually all healthy recipients. However,
lower responses are noted in older subjects, patients with TREATMENT
liver disease, and immune suppressed individuals [34].
Prior to the introduction of ART, vaccination with two
The goal of treatment of viral hepatitis is to decrease viral
double doses of HAV vaccine, given either 1 or 6 months
replication, to lessen symptoms, to improve histology with
apart, resulted in a protective serologic response in 88%
decrease in inflammation and fibrosis, and thus to decrease
of HIV-infected MSM compared with 100% response in
progression to cirrhosis and hepatocellular carcinoma and
HIV-uninfected MSM [5]. A CD4 count > 200 cells/mm3
ultimately to improve long-term survival.
correlated with an increased chance of seroconversion
and a higher titer of anti-HAV antibody, but those initiating
ART after a nadir CD4 count of > 50 cells/mm3 demon-
HBV therapy
strated even lower response rates to HAV vaccination, with
only 46% seroconverting after two vaccinations. For HBV Current recommendations are to start ART regardless of HBV
vaccination, the responses are low (47%): even using double DNA level in co-infected individuals who have HBV [41].
dose (40 mg), in those with CD4 counts 350 cells/mm3, Two anti-HBV drugs must be included as part of the ART
only 64% of individuals responded [35]. This suggests that, regimen. Currently licensed therapies for the treatment of
even with ART-induced restoration of immune function, HBV infection are interferon-alpha (IFN-a) an immunomod-
HIV-infected patients may have an inadequate response to ulatory agent, and nucleos(t)ide analogs lamivudine (3TC),
HAV and HBV vaccinations. Two large randomized clinical adefovir dipivoxil, entecavir, and tenofovir. In addition,
trials of HEV vaccines are promising, with efficacy rates emtricitabine (FTC) is licensed for HIV but has activity against
of 95–100% [36, 37]. These vaccines have not been studied HBV. Tenofovir, entecavir, lamivudine, emtricitabine, and
in HIV-infected individuals and are not commercially telbivudine should not be used in HIV-infected patients in
available. the absence of ART because of the development of resistance
to HIV [3, 42].
Recombinant IFN-a’s were the first drugs approved for the
treatment of hepatitis B infection. However, their use in HIV
DIAGNOSIS co-infection is limited, as response rates have generally been
poor. Studies of newer pegylated interferons in HBV are lim-
Given the high prevalence of co-infection in certain popu- ited to those without HIV infection and show benefit of pegy-
lations, all HIV-infected persons should be screened for lated forms over standard conventional IFN in both HBV
HCV and HBV infection. For diagnosis of acute HBV infec- HBeAg positive and negative disease, with control of HBV
tion, hepatitis B surface antigen (HBsAg) and IgM antibody DNA in 41–73% of cases [43]. Predictors of response are fe-
to hepatitis B core antigen (anti-HBc) are used. For chronic male gender, low serum HBV DNA levels, and high serum
HBV infection, both HBsAg and total anti-HBc should be ALT. The latter two are uncommonly found in HBV-HIV
tested. If either is positive, then serum HBV DNA should co-infection, limiting its use. In addition to the goals of ther-
be tested as atypical serologies occur with HBV and HIV apy noted above, goals specific for the management of HBV
co-infection. Some studies have shown HBV viremia in infection are seroconversion from HBeAg to anti-HBe and ul-
subjects whose only marker for HBV in the serum was total timately loss of HBsAg with seroconversion to anti-HBs [6].
anti-HBc for over 2 years [38]. The prevalence of serum Nucleos(t)ides are competitive inhibitors of HBV DNA
HBV DNA in HIV individuals whose sole marker for HBV polymerase (reverse transcriptase), causing premature ter-
is total anti-HBc varies from 2 to 45% depending on the mination of DNA chain elongation, resulting in inhibition
study, but viremia is rare in HBV mono-infected individ- of viral replication. However, the inhibition of polymerases
uals [39, 40]. is not entirely specific, and can also bind to human DNA
For chronic HCV infection, serum HCV antibody should polymerase. Thus, there is a potential to induce mitochon-
be tested using an enzyme immunoassay (EIA). Positive EIA drial toxicity and multi-organ failure, and mitochondrial
results should be confirmed by quantitative testing for HCV toxicity has been implicated in the etiology of some of the
RNA. There is a 4 to 6% false-negative rate with EIA in HIV dose-limiting adverse effects such as peripheral neuropathy,
infection, especially in those with low CD4 counts [10]. lactic acidosis, and steatosis associated with nucleoside ana-
HIV-infected patients with undetectable HCV antibody logs. Entecavir and tenofovir are potent antivirals with a
414
high barrier of resistance. Tenofovir is active against both load, HCV genotype 2/3 compared to genotype 1/4, and
wild-type HBV and HBV with lamivudine (3TC)/emtricita- higher CD4 count [41]. Ideally, CD4 counts over 350
bine resistance mutations (YMDD and other compensatory cells/mm3 should be achieved to optimize response to in-
mutations). Resistance to lamivudine increases with time terferon/ribavirin. A recently discovered single nucleotide
on therapy and is more rapid in patients co-infected with polymorphism (SNP) near the IL28B gene on chromosome
HIV, with 90% of subjects who have HIV and HBV devel- 13 also correlates highly with spontaneous HCV clearance
oping HBV resistance to lamivudine by 4 years [44]. Adefo- and is one of the strongest predictors of treatment response
vir has been used successfully in co-infected individuals for in HIV-uninfected patients, particularly with HCV geno-
up to 4 years with no reports as yet of resistance [44]. How- type 1 [48]. This susceptibility allele is more common in
ever, resistance up to 18% after 4 years has been reported in Caucasians and Asians compared to African Americans
mono-infected HBV individuals who have HBeAg-negative and may explain much of the racial/ethnic discrepancies
disease [3]. in response to HCV therapy. IL28B studies in HIV/HCV
co-infected patients also suggest a prognostic utility of IL-
28B in predicting interferon-based response to HCV
Acute HCV
treatment.
Indications for treatment of acute HCV in HIV infection are Treatment of chronic HCV in HIV-infected patients has
the same as those in HIV-uninfected individuals. Treatment traditionally included pegylated interferon and ribavirin
is generally not initiated until 12 weeks after initial HCV for 48 weeks, regardless of HCV genotype. Pegylated inter-
infection to allow for possible spontaneous clearance, feron (PEG/R) has documented superiority over standard
which occurs in 30–50% of mono-infected patients, and interferon [3]. Guidelines recommend 48 weeks of treat-
in 15–20% of HIV-infected individuals. Sustained virologic ment in HIV treatment experienced HCV patients, regard-
response (SVR: absence of detectable HCV RNA 6 months less of genotype. However, in those who achieve a
after cessation of therapy) occurs in 60–80% of subjects negative HCV RNA at week 4 of therapy, treatment may
with acute HCV [45, 46]. Delaying treatment after this time be shortened to 24 weeks [49]. In patients who fail to
is associated with progressively reduced rates of SVR. Ro- achieve an early virologic response (EVR), defined by < 2
bust studies of pegylated interferon without ribavirin have log drop in HCV viral load by week 12 of treatment, or
not been conducted in HIV-infected patients with acute who have detectable HCV RNA at week 24, HCV treatment
HCV. Many experts use combination pegylated interferon should be discontinued. Patients with evidence of decom-
and weight-based ribavirin for 48 weeks. In contrast, riba- pensated liver disease, including ascites, hepatic encepha-
virin is not used with acute HCV in HIV-uninfected patients lopathy, and liver-related gastrointestinal bleeding,
and only 24 weeks of pegylated interferon is recommended. should generally not initiate HCV therapy due to the risk
Recent studies have suggested that in patients who achieve a of further liver decompensation related to interferon ther-
rapid virologic response, defined by undetectable HCV viral apy. Select patients that are concurrently listed for liver
load by week 4 of treatment, a shortened 24-week course transplantation may be treated with caution.
of treatment may be appropriate [45]. The introduction of direct-acting antivirals (DAAs) has
opened a new era of therapy in HCV, including studies
of HCV protease inhibitors and polymerase inhibitors in
Chronic HCV patients with HCV genotype 1. PEG/R remains the standard
Treatment of chronic HCV in HIV-infected patients is more of care for non-genotype 1 HCV patients. Studies in HCV
complex and less algorithmic than treatment of acute HCV. genotype 1 HCV mono-infection show that combination
The general approach involves weighing the morbidity as- DAA and PEG/R have yielded higher SVR rates than
sociated with pegylated interferon and ribavirin (PEG/R) PEG/R alone, in both treatment-naı̈ve and treatment-
with the benefits of therapy, while considering the likeli- experienced patients [50]. Two HCV NS3 protease inhibi-
hood that an individual patient may actually respond to tors, telaprevir and boceprevir, were FDA approved in
treatment. Given improved response to HCV therapy in 2011 for use in combination with PEG/R in genotype 1
those with well-controlled HIV, treatment of HIV is gener- HCV mono-infected patients [51, 52]. These drugs cannot
ally initiated prior to treatment of HCV. However, in cases be used as monotherapy to the rapid emergence of drug re-
where ART-related toxicity precludes continuation of ART, sistance. These drugs are currently approved for genotype 1,
HCV may need to be treated first, allowing for improved although studies including genotypes 2/3 are underway.
tolerability of ART. The benefits of HCV treatment in HIV Ribavirin remains essential to prevent relapse. Both pro-
infection include decreased ART-associated hepatotoxicity, tease inhibitors markedly improve the response rates in
regression of liver fibrosis, decreased risk of decompen- both naı̈ve and treatment-experienced patients with
sated liver disease, decreased liver-related death, and as chronic HCV.
decreased all-cause mortality [47]. Boceprevir (Merck, PA, USA) 800 mg must be adminis-
Predictors of response to HCV therapy in HIV-infected tered every 8 hours with food in combination with PEG/R.
patients include younger age, lower baseline HCV viral For HCV mono-infected patients, response-guided therapy
415
is recommended: IFN/R is given for a 4-week lead-in, fol- for each drug). Telaprevir is a substrate of and inhibitor
lowed by IFN/R and boceprevir. If HCV RNA is undetect- of CYP3A and P-glycoprotein. Contraindicated drugs
able at weeks 8 and 24, therapy is stopped at week 28 include rifampin, lovastatin, simvastatin, atorvastatin, tria-
in treatment-naı̈ve patients and week 36 in treatment- zolam, and St John’s wort [55]. Limited data were pre-
experienced patients [53]. If HCV RNA is not undetectable sented in abstract form of in vitro studies between
until week 24, then triple therapy is continued for 36 weeks telaprevir and ART. Telaprevir is not recommended for
followed by 12 additional weeks of PEG/R [51]. Treatment use with fosamprenavir, darunavir, and lopinavir. Use with
should be stopped for futility if HCV RNA is 100 IU/mL atazanavir, efavirenz, and tenofovir lead to changes in both
at week 12 or confirmed detectable at week 24. SVR rates telaprevir and ART levels (Van Heeswijk R et al. Abstract
were increased from 38% (PEG/R) to 63–66% (triple ther- 119 CROI 2011).
apy) in treatment-naı̈ve HCV genotype 1 patients and from Boceprevir is a strong inhibitor of CYP3A4/5 and is par-
20% (PEG/R) to 59–66% (triple therapy) in treatment- tially metabolized by CYP3A4/5. Multiple drugs require
experienced patients [51, 52]. Among patients with an unde- dose adjustment because of drug–drug interactions and
tectable HCV RNA level at week 8, the SVR rate was 88%. are listed in the package insert [53]. Other drugs and herbs
Limited data show that triple therapy increases response utilized in HIV patients are contraindicated with bocepre-
rates most in those with unfavorable IL28B genotypes (CT vir, including rifampin, phenytoin, carbamazepine, lova-
or TT) although CC patients have the overall highest statin, simvastatin, and St John’s wort [53]. Studies of
response. However, SVR rates still increased from 28 to interactions of boceprevir and ART [56] are limited. Efavir-
65–71% in patients with CT and to 55–59% in patients with enz appears to decrease boceprevir levels and boceprevir in-
TT genotype [53]. Anemia is significantly more common creases efavirenz levels. Interactions with many HIV
and erythropoietin must be administered more frequently protease inhibitors are not yet available.
in those receiving PEG/R and boceprevir than in those on Despite promising results of DAAs in HIV-uninfected in-
PEG/R alone [51, 52]. dividuals, several issues unique to HIV-infected patients
The second protease inhibitor, telaprevir, (Vertex, MA, must be considered. HIV patients have higher baseline
USA) is a 750 mg dose administered every 8 hours with food HCV viral loads than HIV-uninfected patients, contributing
in combination with PEG/R for 12 weeks followed by PEG/ to their overall lower response rates. Drug interactions may
R alone for 24–48 weeks. If HCV RNA is undetectable at adversely affect ART and DAA serum levels as well as many
weeks 4 and 12, the total duration of PEG/R therapy is other medications in HIV patients and further studies are
24 weeks. If HCV RNA is detectable but 1,000 IU/mL at needed to investigate these interactions. Limited available
weeks 4 and 12, the total duration of PEG/R therapy is data on DAA effects on ART show that interactions are
48 weeks (12 weeks of triple therapy and 48 weeks of not entirely predictable (see PI interactions above) such
PEG/R). Reported SVR rates with triple therapy are 79%, that each drug may need careful study with individual
compared to 46% in patients receiving PEG/R in treat- DAAs to elucidate interactions. In addition more HIV-
ment-naı̈ve HCV genotype 1 patients; 86% in prior re- infected genotype 1 patients are infected with genotypes
lapsers; 59% in prior partial responders; and 32% in prior 1a than 1b, and genotype 1a is associated with higher resis-
null responders [54, 55]. The most common side effects tance rates to current HCV protease inhibitors [57]. This is
are rash, pruritus, and anemia. because only one nucleoside substitution is required for
Studies in HIV/HCV-infected subjects with genotype 1 HCV resistance to HCV genotype 1a, compared to two sub-
HCV have not been completed as yet. An interim analysis stitutions required for HCV resistance to genotype 1b. Tox-
of telaprevir in combination with PEG/R was presented icities of PEG/R are significant in HIV/HCV co-infected
in abstract form at CROI 2011 (Sulkowski et al., CROI patients such that all oral DAA regimens are eagerly awaited
2011). Sixty patients received 12 weeks of triple therapy in the next few years.
(telaprevir and PEG/R), followed by 36 weeks of PEG/R. HCV therapy should be monitored closely for side effects
Undetectable HCV RNA was noted at weeks 4 and 12 in of interferon and ribavirin therapy (Table 32.2). Side effects
70 and 68% of those receiving triple therapy, compared include flu-like symptoms; interferon-associated thyroid
to 5 and 14%, respectively, of those who received PEG/R dysfunction; neuropsychiatric disorders such as depres-
alone. Similar results were noted in those not on ART as sion, irritability, and insomnia; and cytopenias, such as
in those receiving efavirenz/tenofovir/emtricitabine but a neutropenia, lymphopenia, anemia, and thrombocytope-
lower response was noted in those receiving atazanavir/ nia. The frequency of IFN- and RBV-related side effects in
tenofovir/emtricitabine. the treatment of HCV-HIV-co-infected patients does not
These protease inhibitors have not been approved for use differ significantly from that observed in the treatment of
in HIV/HCV co-infected patients. Caution is required as HCV-monoinfected subjects [3]. As seen in the major pegy-
drug–drug interactions are predicted between ART and lated interferon treatment trials, lymphopenia may be asso-
HCV protease inhibitors but few drug–drug interactions ciated with a decrease in absolute CD4 count; however,
have been performed (updated information is available CD4 cell percentage is typically unchanged or increased, with
at www.hep-druginteractions.org and package inserts no observed additional risk for infection [58]. In addition
416
Table 32.2 Monitor therapy in HIV patients co-infected

with HCV or HBV
ANTIRETROVIRAL-ASSOCIATED
HEPATOTOXICITY
THERAPY MONITOR
All classes of antiretroviral drugs have been associated with
HBV • Nucleos(t)ide • AST, ALT for the development of hepatotoxicity, defined by significant
analogs inflammation
elevations in liver enzymes [63, 64]. Hepatotoxicity may
• Long-term therapy • HBV DNA 3–4
be dose-dependent or idiosyncratic (unpredictable due to
the rule monthly
hypersensitivity or a metabolic abnormality). In studies
• Always use with
ART
of hepatotoxicity associated with ART, the risk of hepato-
• Need 2 anti-HBV toxicity has been consistently associated with elevated base-
drugs with ART line transaminases and the presence of HBV or HCV
• Monitor for co-infection. Proposed mechanisms of hepatotoxicity in-
resistance clude decreased drug metabolism, immune restoration,
and mitochondrial dysfunction. Despite the increased risk
HCV • Pegylated IFN and • CBC closely for of hepatotoxicity in the setting of HCV or HBV co-infection,
ribavirin pancytopenia most (80–90%) co-infected patients do not develop hepa-
• 48 weeks for all • AST, ALT monthly totoxicity [63, 65]. Studies that have followed subjects after
genotypes • ANA, TSH the onset of biochemical hepatotoxicity have demonstrated
• Stopping rule: HCV 3-monthly that significant clinical hepatotoxicity is rare, and transam-
RNA decrease is < 2 • If 2 log drop in
inases return to baseline in the majority of cases even if the
log at 12 weeks or HCV RNA from
offending medication is continued (adaptation) [66, 67].
HCV RNA detected baseline, continue
Therefore, it is probably not necessary to discontinue ART
at 24 weeks for 48 weeks
if hepatotoxicity develops, unless the patient is symptom-
• Cytokine support
for cytopenias atic, has associated hypersensitivy (fever, lymphadenopathy,
rash), is jaundiced or there are significant elevations in the
aminotransferases.
Although the incidence of antiretroviral-associated
hepatotoxicity increased with the introduction of HIV
potential drug–drug interactions between ribavirin and nu-
protease inhibitors (PIs), establishing a direct link be-
cleoside reverse transcriptase inhibitors may be an issue in
tween PIs and liver impairment has been difficult.
HIV/HCV co-infection. Ribavirin, a guanosine nucleoside an-
High-dose ritonavir is associated with increased hepato-
alogue, interferes with the intracellular phosphorylation of
toxicity compared to boosted ritonavir [63]. While there
pyrimidine 2’, 3’-dideoxynucleosides, including zidovudine,
are reported associations between indinavir use and liver
zalcitibine, and stavudine. Ribavirin also increases the phos-
toxicity, the risk of developing severe liver impairment
phorylation of didanosine and may lead to increased toxicity,
with saquinavir, nelfinavir, lopinavir, and amprenavir
including pancreatitis and mitochondrial dysfunction [59,
is low [63].
60]. The combination of didanosine and ribavirin should
Of the non-nucleoside reverse transcriptase inhibitors
be avoided, and the combination of zidovudine or stavudine
(NNRTIs), nevirapine (NVP) is consistently associated with
with ribavirin should be used with caution.
an increased risk of hepatotoxicity [63]. Cases of severe
liver toxicity, some fatal, are associated with NVP use for
post-exposure prophylaxis [68]. Risk factors proposed for
HDV NVP-induced hepatotoxicity are conflicting but have in-
cluded higher baseline CD4 count, female sex, HBV or
Treatment of chronic HDV in HIV patients with interferon HCV co-infection, alcohol consumption, wasting, con-
is rarely effective [61]. Whether long-term PEG/R is safe and comitant use of stavudine, and abnormal baseline liver
efficacious in HIV-uninfected persons is unknown. function abnormalities. Nevirapine hepatotoxicity com-
monly occurs early in treatment, suggesting an idiosyn-
cratic mechanism. However, later-onset hepatotoxicity of
NVP-containing regimens occurs > 120 days, with the risk
HEV increasing with an increasing duration of treatment and in
Due to its typically self-limited course, few studies have cirrhotic patients. Some studies have shown a direct corre-
investigated HEV treatment. However, case reports have lation between plasma NVP concentrations and hepatotox-
documented successful treatment of chronic HEV using icity independent of the presence of HCV co-infection,
pegylated interferon and ribavirin [62]. while others have shown higher NVP levels in subjects with
417
higher transaminase levels and in HBV- or HCV-co-infected patients after liver transplantation [72]. However, data fo-
subjects [63]. cusing on liver transplant in HIV/HCV co-infected patients
Efavirenz (EFV) is generally considered to have a lower are less encouraging, with higher rates of graft failure due to
risk of hepatotoxicity compared with NVP [63]. There is HCV re-infection and greater mortality among co-infected
clearly an increased risk of hepatotoxicity with the use of as compared to mono-infected patients [71, 73]. Given the
both NVP and EFV compared with the use of either drug additional complexity of liver transplant in HIV-infected
alone. The NNRTIs are substrates for cytochrome P450 met- patients, careful selection of transplant candidates is
abolic pathways, so variability in drug metabolism between critical, and multidisciplinary care, including pharmacolo-
individuals may explain hepatotoxicity. It remains unclear gists, infectious disease specialists, hepatologists, and trans-
whether NNRTI-associated hepatotoxicity is dose-dependent plant surgeons, is crucial.
or idiosyncratic.
The majority of nucleoside reverse transcriptase inhibitors
(NRTIs) can cause mitochondrial toxicity and have the poten- SUMMARY
tial to cause liver injury [63]. NRTIs inhibit g-DNA poly-
merase, the enzyme responsible for mitochondrial DNA Viral hepatitis is increasingly being recognized in HIV-
replication. Cases of lactic acidosis and steatosis are more fre- infected individuals and has become one of the major
quently reported with didanosine, stavudine, or zidovudine. causes of morbidity and mortality. Co-infection with either
It is believed that cumulative exposure to NRTI is a factor in HBV or HCV leads to accelerated progression to chronic
the development of lactic acidosis. hepatitis, cirrhosis, and hepatocellular carcinoma. In addi-
tion, co-infection with either HBV or HCV is associated
with higher rates of hepatotoxicity. Immune recovery
LIVER TRANSPLANTATION may be associated with reactivation of viral hepatitis, espe-
cially with HBV. Selection of therapy for HIV mandates un-
Liver transplantation is now considered a therapeutic derstanding the HBV and HCV status of the individual. All
option for HIV-infected patients. In the post-HAART era, individuals should be evaluated for co-infections and vac-
initial studies of liver transplant in HIV-infected patients cinations for HAV and HBV performed if needed. Our un-
reported no significant differences in patient or graft sur- derstanding of the natural history of viral hepatitis and HIV
vival when compared to HIV-uninfected patients [69– in the current ART era and the response to anti-HCV and
71]. HIV/HBV patients do as well as HBV mono-infected HIV treatment has improved significantly over recent years.
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Chapter | 33 |
Bartonella infections in HIV-infected individuals
Jane E. Koehler
[11]. B. henselae also is associated with lymphadenopathy,

HISTORICAL PERSPECTIVE and B. quintana with subcutaneous nodules in late-stage
HIV infection [11].
Bacillary angiomatosis (BA), a unique vascular proliferative le-
sion, was first described by Stoler and colleagues in 1983 [1] CLINICAL PRESENTATION
in an HIV-infected patient with multiple subcutaneous nod-
ules. Numerous bacilli were observed by Warthin–Starry stain- OF BARTONELLA INFECTIONS
ing of the biopsied nodules, and the subcutaneous masses
resolved during erythromycin therapy. Subsequently, the BA In patients with severe immunosuppression due to HIV in-
bacilli visualized using the Warthin–Starry silver stain were fection, organ transplantation or chemotherapy, infection
noted to have an appearance similar to that of the cat-scratch with B. henselae or B. quintana can produce focal BA lesions
disease (CSD) bacillus [2, 3]. The BA bacillus remained refrac- composed of proliferating endothelial cells [12, 13]. BA oc-
tory to isolation attempts for many years, impeding identifica- curs as a late manifestation of HIV infection; in a study of
tion efforts. Studies of bacterial DNA extracted from BA lesions 42 patients with BA, the median CD4 count was 21 cells/
subsequently identified the bacillus as closely related to Barto- mm3 [14]. These vascular proliferative lesions can form
nella (Rochalimaea) quintana [4], and after isolation of the ba- in many different organs, including skin, bone, brain
cillus from the blood of two HIV-infected patients without parenchyma, lymph nodes, bone marrow, and the gastro-
BA [5], the organism was further characterized and named intestinal and respiratory tract. A histopathologically differ-
B. henselae in 1992 [6, 7]. The BA bacillus was directly culti- ent vascular proliferative response to Bartonella infection,
vated from cutaneous BA lesions for the first time in 1992, known as bacillary peliosis hepatis (BP), is seen in the liver
which led to the identification of two species of the genus Bar- and spleen [15]. One notable aspect of focal Bartonella in-
tonella as causative agents of BA: B. henselae and B. quintana [8]. fection, especially cutaneous BA, is the chronic, indolent
The Bartonella genus has expanded from a single species nature of the disease: lesions can be present for as long
in 1993 to 29 officially recognized species (http://www. as one year before a diagnosis is made [14, 16].
bacterio.cict.fr/b/bartonella.html) [9, 10], and at least six HIV-infected individuals also can develop manifestations
unofficial Bartonella species. Of these, eight Bartonella species of Bartonella infection other than vascular proliferation. Bac-
have been isolated from humans: B. henselae, B. quintana, teremia with [17] or without [5, 18] endocarditis has been
B. elizabethae, B. bacilliformis, B. rochalimae, B. washoensis, reported in HIV-infected individuals, in the absence of focal
B. tamiae, and B. vinsonii subsp. arupensis. Although the Bar- BA or BP involvement. Patients with higher CD4 counts can
tonella species causing BA has been identified in more than develop focal necrotizing infections due to B. henselae in
60 AIDS patients, only two species have been found to cause lymph nodes, liver or spleen that have an appearance similar
BA or bacillary peliosis hepatis [8, 11]. Interestingly, the two to that of CSD in immunocompetent individuals. Rarely,
different species differ in their predilection to form a specific HIV-infected individuals with CD4 counts < 50 cells/
type of lesion. B. henselae, but never B. quintana, has been mm3 can develop this necrotizing lymphadenitis without
associated with peliosis of the liver or spleen, or both vascular proliferation [19].
421
A case-control study comparing clinical findings of 42

patients with BA and/or BP compared with 84 control pa-
tients found that cases were significantly more likely than
controls to have fever, abdominal pain, lymphadenopathy,
hepatomegaly, splenomegaly, a low CD4 count, anemia
and/or an elevated serum alkaline phosphatase [14]. With
the exception of cutaneous lesions, many of the clinical
findings are not specific, and the major obstacle to diagno-
sis of Bartonella infection in the presence of concomitant
HIV infection is recognition of the disease by the physician.
BP and BA can be indistinguishable from a number of other
infectious or malignant conditions, and the diagnosis can
usually be made only after biopsy and careful histopatho-
logical evaluation of tissue, or by direct culture of Bartonella A
species from blood or the affected organ [20].
Cutaneous bacillary angiomatosis

The most frequently diagnosed BA lesions are those affect-
ing the skin [20]. Cutaneous BA lesions can have myriad
presentations, including vascular proliferative lesions with
a smooth red or eroded surface (Fig. 33.1, groin BA lesion)
or papules that enlarge to form friable, exophytic lesions
(Fig. 33.1, finger BA lesion). These vascular lesions of cuta-
neous BA are particularly difficult to distinguish clinically
from Kaposi’s sarcoma (KS), and thus histopathological ex-
amination of biopsied tissue is essential. BA may appear as
a cellulitic plaque, usually overlying an osteolytic lesion B
(Fig. 33.2). Less vascular-appearing lesions can be dry
and scaly (Fig. 33.3) and some lesions are subcutaneous, Figure 33.2 (A) A tense, firm, erythematous wrist mass due to
with or without overlying erythema (Fig. 33.4). BA lesions BA. (B) A radiograph of the wrist of the same patient,
demonstrating cortical bone erosion of the radius, with active
periostitis, adjacent to the vascular soft-tissue mass.
(Reproduced with permission from Koehler JE, LeBoit PE, Egbert BM,
Berger TG. Cutaneous vascular lesions and disseminated cat-scratch
disease in patients with the acquired immunodeficiency syndrome
(AIDS) and AIDS-related complex. Ann Intern Med 1988; 109:449–455.)
also can develop as very deep, highly vascular soft-tissue

masses (Fig. 33.5) [16].
Osseous bacillary angiomatosis

Bartonella infection of the bone causes osteolytic lesions
that are extremely painful. The long bones, including tibia,
fibula, and radius, are most commonly involved [20, 21],
although osseous BA has occurred in a rib [21] and verte-
bra [22, 23]. A radiograph usually demonstrates well-
Figure 33.1 A friable, exophytic angiomatous BA nodule of the circumscribed osteolysis and deep soft-tissue swelling
finger and an evolving dome-shaped vascular papule in the same (Fig. 33.2B). The BA lytic lesions can be detected by techne-
patient. tium-99m methylene diphosphonate bone scans, and
(Reproduced with permission from Koehler JE, LeBoit PE, Egbert BM, bone scintigraphy allows screening of the entire skeleton
Berger TG. Cutaneous vascular lesions and disseminated cat-scratch disease for multifocal osteomyelitis [24]. Osseous BA should be
in patients with the acquired immunodeficiency syndrome (AIDS) and a primary consideration in the differential diagnosis of a
AIDS-related complex. Ann Intern Med 1988; 109:449–455.) lytic bone lesion in HIV-infected patients.
422
Chapter | 33 | Bartonella infections in HIV-infected individuals
Figure 33.3 Unusual appearing erythematous, dry, scaling

plaque of cutaneous BA mimicking staphylococcal pyoderma. Figure 33.5 Magnetic resonance imaging showing a deep,
Bartonella quintana was cultured from this lesion. highly vascular subcutaneous soft-tissue mass of BA in the
(Reproduced with permission from Koehler JE, Tappero JW. Bacillary anterior right thigh.
angiomatosis and bacillary peliosis in patients infected with human (Reproduced with permission from Koehler JE, Tappero JW. Bacillary
immunodeficiency virus. Clin Infect Dis 1993; 17:612–624.) angiomatosis and bacillary peliosis in patients infected with human
immunodeficiency virus. Clin Infect Dis 1993; 17:612–624.)
massive hemoperitoneum and hypotension, and bleeding

from the liver was the only source of hemorrhage that could
be identified during laparotomy [25]. Abdominal CT of the
peliotic liver usually reveals numerous hypodense lesions
[20, 26] as shown in Figure 33.6, but this appearance is
not specific for BP; thus the diagnosis of Bartonella infection
must be confirmed by histopathological evaluation. Addi-
tionally, some HIV-infected patients with hepatic Bartonella
infection develop inflammatory nodules in the liver with-
out the vascular proliferative characteristics of peliosis
hepatis [27]. Patients with splenic BP can have thrombocy-
topenia or pancytopenia and abdominal ascites [28, 29].
Figure 33.4 Multiple subcutaneous BA nodules in a patient

with concomitant KS of the medial left eye canthus.
(Reproduced with permission from Koehler JE, Tappero JW. Bacillary
angiomatosis and bacillary peliosis in patients infected with human
immunodeficiency virus. Clin Infect Dis 1993; 17:612–624.)
Splenic and hepatic bacillary peliosis

Bacillary peliosis hepatis, a vascular lesion of the liver asso-
ciated with infiltration of Bartonella bacilli, was first de-
scribed in eight HIV-infected individuals by Perkocha
and co-workers [15]. The symptoms of patients with BP
hepatis usually include abdominal pain and fever. All eight
Figure 33.6 Computed tomography of the abdomen, showing
patients had hepatomegaly, and six also had splenomegaly
hepatosplenomegaly with numerous low-density hepatic
[15]. Two of the patients underwent splenectomy, and his- parenchymal lesions, in addition to pelvic ascites and pulmonary
topathological examination revealed BP of the spleen. One- effusions. Percutaneous biopsy of the liver demonstrated peliosis
quarter of the patients also had cutaneous BA lesions. The hepatis by histopathology.
serum alkaline phosphatase was more prominently ele- (Reproduced with permission from Koehler JE, Tappero JW. Bacillary
vated than the hepatic transaminases in these patients with angiomatosis and bacillary peliosis in patients infected with human
BP hepatis. In one HIV-infected patient, BP presented as immunodeficiency virus. Clin Infect Dis 1993; 17:612–624.)
423
Gastrointestinal and respiratory tract a single suprasellar lesion [38]. Examination of biopsied
bacillary angiomatosis brain tissue revealed an inflammatory infiltrate primarily
involving the leptomeninges, and clumps of bacillary organ-
Histopathologically proven BA of the gastrointestinal tract isms by Warthin–Starry staining. B. henselae DNA was ampli-
has been described by several groups [30–32]. The lesions fied from the biopsy material. The lesions and symptoms
can involve oral, anal, peritoneal, and gastrointestinal tissue resolved after treatment with doxycycline and rifampin.
appearing as raised, nodular, ulcerated intraluminal mucosal Retinal disease can occur in patients with AIDS and infec-
abnormalities of the stomach and large and small intestine tion with B. henselae. The manifestations are often more
during endoscopy [31]. Extraluminal, intra-abdominal BA severe than those seen in immunocompetent patients
presenting with massive upper gastrointestinal hemorrhage and can include neuroretinitis and retinochoroiditis [39].
has also been described [32]. Hemorrhage in this patient oc- Warren and co-workers [40] described an HIV-infected pa-
curred when the highly vascular mass eroded through the tient who developed severe and progressive retinal disease
small intestine; B. quintana was cultured from tissue obtained that did not respond to treatment for Toxoplasma or CMV.
by transabdominal needle biopsy of the mass. Retinal biopsy revealed vascular proliferation consistent
Bacillary angiomatosis lesions of the respiratory tract with BA. Sequencing of amplified DNA extracted from the
have been observed in the larynx [30, 33]; in one of these biopsy specimen identified B. henselae DNA. The patient
patients, the BA lesions enlarged to cause an asphyxiative was treated with minocycline or doxycycline, with resolu-
death [30]. Endobronchial BA lesions have been visualized tion of the retinitis and improvement in his visual acuity.
during bronchoscopy, and described as polypoid lesions
located in the segmental bronchi and the trachea [34, 35].
Several of these patients also had cutaneous BA. Bartonella Unusual bacillary angiomatosis
infection can also cause pulmonary nodules in the immuno- presentations
compromised patient: a renal transplant patient with che-
Several cases of BA involving the bone marrow have been
motherapy-induced immunocompromise developed high
reported [4, 28, 41]. Hepatosplenomegaly and thrombocyto-
fever (41 C) and bilateral pulmonary nodules [36]. Barto-
penia were noted in both of these patients, and both resolved
nella henselae DNA was demonstrated in parenchymal lung
with antibiotic treatment. Venous thrombosis of the left up-
nodule biopsy specimens.
per extremity occurred in an AIDS patient with B. quintana
bacteremia during relapse [16]. This was characterized by
Lymph node bacillary angiomatosis multiple non-contiguous, erythematous, tender superficial
thromboses in the absence of trauma or intravenous drug
Lymph node involvement has been described frequently in use. All rapidly resolved after institution of antibiotic therapy.
association with cutaneous lesions or peliosis of the liver or Cutaneous BA complicating pregnancy in an HIV-infected
spleen [20]. In these cases, the lymph nodes most commonly woman was reported by Riley and co-workers [42]. Cutane-
affected are those draining the BA lesion, and histopatholog- ous lesions resolved after antibiotic treatment, and the subse-
ical examination may reveal angiomatous changes within quent pregnancy and delivery were uneventful. BA lesions
the lymph node. In other cases, however, BA involves only have been described in several pediatric patients: one patient
a single or several lymph nodes, in the absence of cutaneous was immunocompromised due to chemotherapy [43]; the
or other organ involvement. other was 3.5 years old and had been infected with HIV
perinatally [44].
Central nervous system
manifestations of Bartonella Bacteremia with Bartonella species
infection and fever of unknown origin
Bartonella infection has been associated with aseptic men- Many patients with BA and BP also have Bartonella bacter-
ingitis [19] or parenchymal brain masses [37] in HIV- emia. One-half of our patients with culture-positive focal
infected individuals. A left temporal lobe mass due to BA BA or BP also had the corresponding Bartonella species si-
developed in an HIV-infected patient with new onset of sei- multaneously isolated from the blood [11]. Bartonella bac-
zures and facial nerve deficit [37]. The etiology of the mass teremia in the absence of focal BA disease has been reported
remained undetermined for 8 months until the patient de- by a number of groups [5, 6, 45], and may be more com-
veloped a cutaneous BA lesion. Treatment with erythromy- mon than focal Bartonella disease. In a study of 382 patients
cin led to resolution of the cutaneous lesion and neurologic with fever of undetermined etiology, 68 patients (18%)
deficit; the parenchymal mass decreased in size during an- had evidence of Bartonella infection by serology and/or cul-
tibiotic treatment. Another patient developed fever, head- ture. A total of 12 patients had bacteremia with B. henselae
ache, diabetes insipidus, and altered mental status with or B. quintana (six each) [45]. When examined carefully by
multiple, small contrast-enhancing brain lesions, including a healthcare provider experienced in the recognition of BA,
424
six of the 12 bacteremic patients were found to have lesions yield appears to be excisional wedge biopsy of the liver or
suspicious for BA, and the other six had isolated bacteremia splenectomy; however, peliosis hepatis has been diagnosed
without focal Bartonella disease. The median CD4 count by either transvenous liver biopsy [47] or percutaneous
was 33 cells/mm3 for the case patients in this study, indicat- liver biopsy [29]. As with cutaneous lesions, several oppor-
ing that both BA and Bartonella-related fever with bacter- tunistic infections and malignancies can have a similar ap-
emia are usually identified in late-stage HIV infection. pearance on computed tomography of the abdomen; thus,
Also of note, endocarditis was described in one patient with biopsy is extremely important to direct specific treatment.
HIV infection and culture-proven B. quintana [17]. No case of hemorrhage following percutaneous biopsy of
a peliotic liver has been reported, although this remains
a theoretical concern.
DIAGNOSIS OF BARTONELLA
INFECTIONS Histopathological characteristics
A characteristic vascular proliferation is seen on routine hema-
Histopathological diagnosis toxylin and eosin staining of BA or BP tissue (Fig. 33.7A).
Numerous bacilli also can be demonstrated in these lesions
Obtaining tissue for diagnosis by modified silver staining (e.g. Warthin–Starry, Steiner,
Biopsy is the principal procedure available for the diagnosis Dieterle) or electron microscopy (Fig. 33.7B) [13, 15]. Other
of cutaneous BA. Because KS lesions can be clinically indis- stains, such as those for tissue Gram-staining, fungi or acid-fast
tinguishable from those of BA, any new vascular lesion mycobacteria do not stain Bartonella bacilli.
should be biopsied. In patients with previously diagnosed Cutaneous BA lesions can be misdiagnosed histopatho-
KS, any vascular lesion that has a different appearance or logically, most often as KS [2, 3, 34, 48], angiosarcoma
rate of growth should also be biopsied, because KS and cu- [22, 23, 30, 48], and pyogenic granuloma [33, 49]. The his-
taneous BA can occur simultaneously in the same patient topathological appearance of cutaneous BA lesions can be
[46]. Pedunculated lesions can be biopsied by shave exci- indistinguishable from pyogenic granuloma (lobular capil-
sion, and smaller, papular, or subcutaneous lesions should lary hemangioma) and verruga peruana, the late, chronic
be examined by punch biopsy. Biopsy of the cellulitic pla- phase of infection with B. bacilliformis [3]. A histopatholog-
que that frequently overlies osteolytic lesions may be suffi- ical diagnosis of pyogenic granuloma, angiosarcoma or
cient to yield a diagnosis of BA, but in some patients, open peliosis of the liver or spleen in an HIV-infected patient
excisional bone biopsy is necessary [16]. Fine needle aspi- should prompt further evaluation of the tissue for bacilli
ration of BA lymph nodes has not been useful in diagnosis to determine whether the lesion may actually be due to Bar-
of BA in our center; thus, open excisional or incisional bi- tonella infection. The presence of bacillary organisms is
opsy remains the optimal technique for diagnosis. For BP the diagnostic feature that distinguishes cutaneous BA,
of the liver or spleen, the diagnostic procedure with greatest extracutaneous BA, and parenchymal BP from these other
A B
Figure 33.7 (A) Hematoxylin and eosin staining of a biopsied cutaneous BA lesion demonstrating a dermal vessel. The vessel is lined
with protuberant endothelial cells surrounded by myxoid connective tissue containing neutrophils and amphophilic granular material
in close proximity to the vascular lumen. (B) Transmission electron micrograph of cutaneous tissue showing multiple trilaminar
cell-walled bacillary organisms.
(Reproduced with permission from Koehler JE, LeBoit PE, Egbert BM, Berger TG. Cutaneous vascular lesions and disseminated cat-scratch disease
in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med 1988; 109:449–455.)
425
diagnoses (with the exception of the cutaneous lesions of vial culture assay [53], but these systems are not readily
verruga peruana, which are associated with B. bacilliformis available to most microbiology labs. Because culture of
bacilli). Bartonella species from biopsied cutaneous or hepatic tissue
remains difficult, blood culture represents the most acces-
sible method of isolating Bartonella species; however,
Serological diagnosis bacteremia is not always present in patients with cutaneous
Bartonella antibodies can be detected in patients with CSD BA or BP.
by an indirect fluorescence antibody (IFA) test developed at
the Centers for Disease Control and Prevention [18]. This
test also detects Bartonella antibodies in serum from pa- TREATMENT OF BARTONELLA
tients with BA [50]. Antibodies to Bartonella were detected
INFECTIONS
in seven HIV-infected patients with biopsy-confirmed
cutaneous BA, and no antibodies were detected in seven
HIV-infected patients without BA. For three of the patients Choice of antibiotics
with Bartonella antibodies, examination of banked serum
revealed the presence of Bartonella antibodies as long as 7 There have been no controlled trials for antibiotic treat-
years prior to the development of BA disease, suggesting ment of BA. The first patient diagnosed with BA was treated
infection with this bacterium occurred years before the empirically with erythromycin, with complete resolution
diagnosis of BA. Prior to the diagnosis of BA in these three of subcutaneous nodules [1]. From subsequent reports
patients, a fourfold rise in titer occurred, raising the possi- and our experience at San Francisco General Hospital, it
bility of either relapse or reinfection. Culture-proven re- is evident that doxycycline or erythromycin are the drugs
lapse in another BA patient [16] was also predicted by a of first choice for patients with BA and BP (Fig. 33.8). Oral
rising serum antibody titer [50]. This IFA is useful for the doxycycline (100 mg twice daily) or oral erythromycin
diagnosis of BA and other Bartonella-associated infections (500 mg four times daily) are standard, but intravenous
in HIV-infected patients, as well as in following the therapy should be given to patients with severe disease or
response to antibiotic treatment. those unable to tolerate oral medication. Resolution of
BA due to B. henselae was reported in one HIV-infected pa-
tient following oral tetracycline treatment [16] and two
Culture of Bartonella species from immunocompetent patients with B. henselae bacteremia
[5]; an immunocompetent patient with cutaneous BA
blood and tissue of patients with BA
was successfully treated with minocycline [54]. In several
Slater and co-workers [5] first reported isolation of Barto- retrospective descriptions of patients with cutaneous BA,
nella species from blood using lysis-centrifugation tubes resolution of lesions was noted to be temporally related
(Isostat; Wampole, Cranbury, New Jersey) and plating onto to institution of antimycobacterial therapy [2, 3, 55–57],
chocolate agar or fresh heart infusion agar with 5% rabbit presumably due to the rifampin component.
blood without antibiotics. Blood collection tubes contain- A summary of recommended treatment for patients
ing EDTA also were used to isolate B. henselae from the with Bartonella infection, in the presence or absence of im-
blood of an HIV-infected patient [6]; this standard CBC col- munocompromise, has been published [58]. In addition,
lection tube is much less expensive and more readily avail- treatment recommendations for HIV-infected adults [59]
able. Bartonella bacteremia can be detected using acridine and children [60] with Bartonella infections are available.
orange staining of aliquots removed from Bactec blood cul- Although immunocompetent patients with B. henselae
ture bottles [51]. The use of semi-quantitative cultures dem- infection (CSD) usually do not need to be treated with an-
onstrates that immunocompromised patients can have a tibiotics [58], all immunocompromised patients with Bar-
high-grade bacteremia with Bartonella, with blood cultures tonella infection should be treated with an appropriate
yielding >1,000 colony-forming units/mL of blood [16]. antibiotic for at least 3 months, regardless of the degree
Isolation of Bartonella species directly from cutaneous BA of immunosuppression. Note that some patients develop
lesions is difficult due to the fastidious growth characteris- a Jarisch–Herxheimer reaction after the first several doses
tics of this genus. Both B. quintana or B. henselae can be iso- of antibiotic, with exacerbation of systemic symptoms
lated by mincing a sterilely obtained skin [16], lymph node and fever [16]. This response may be attenuated by pretreat-
[52], splenic [29], or hepatic biopsy specimen in inocula- ment with an antipyretic, but severely ill AIDS patients
tion media [16], and then spreading onto both fresh heart should be monitored closely after the first 48 hours of
infusion agar with 5% rabbit blood and chocolate agar, and treatment.
incubating for 3 weeks in a humid, 5% CO2 environment The clinical response of patients with BA to treatment
[16]. The highest recovery rate of Bartonella species from with erythromycin, doxycycline, and tetracycline usually
cutaneous BA lesions has been accomplished using an en- corresponds to the in vitro susceptibilities of B. quintana
dothelial cell monolayer co-cultivation system [16] or shell and B. henselae to these antibiotics [5, 61–63]. However,
426
Figure 33.8 Algorithm for treatment of Bartonella

infections in HIV-infected individuals. MAC, Diagnosis
Mycobacterium avium complex; TMP-SMX,
trimethoprim-sulfamethoxazole.
First choice doxycycline 100 mg PO bid, or erythromycin 500 mg PO qid

Alternative tetracycline 500 mg PO qid
If patient very ill, especially with If cutaneous, lymphadenitis

osteomyelitis, peliosis hepatis,
endocarditis
Use doxycycline or erythromycin
(as above) for minimum 3 months
Use IV therapy initially and treat
for 4 months minimum
Erythromycin 500 mg IV q6h or Follow closely after antibiotics
doxycycline 100 mg IV q12h (relapse common, and may
Consider addition of rifampin involve different organ)
300 mg IV q12h
Note
• Rx/prophylaxis of MAC may treat BA; rifabutin, clarithromycin, azithromycin
may be active against bartonella species.
• Drugs with questionable efficacy: TMP-SMX, ciprofloxacin.
• Drugs with no efficacy: penicillins, first-generation cephalosporins.
• Watch for Jarisch–Herxheimer reaction.
there is little correlation between the in vivo and in vitro anti-

Table 33.1 Clinical efficacy of antibiotics in the treatment of
biotic susceptibilities for other antibiotics, especially those
BA and BP
that target steps in cell wall synthesis, e.g. penicillins. It is ob-
vious from numerous reports that penicillin, penicillinase-
DEFINITE POSSIBLE INCONCLUSIVE NONE
resistant penicillins, aminopenicillins, and first-generation
cephalosporins have no activity against the B. quintana and Erythromycin Rifampin Ceftriaxone Penicillin
B. henselae bacilli in BA lesions [2, 3, 16, 33, 46, 49, 64]. An
apparent initial response to some antibiotics, e.g. vancomy- Doxycycline Gentamicin Ceftizoxime Ceph [1]
cin [33] or a first-generation cephalosporin [49], likely repre-
Tetracycline Ciprofloxacin PCN-D
sents the treatment of superinfecting skin flora. We pretreated
one patient who had superinfected cutaneous BA lesions with Minocycline TMP/SMX
cephradine to successfully isolate Bartonella organisms selec-
tively from the lesions [16], and B. quintana was isolated from Ceph [1], first-generation cephalosporins; PCN-D, penicillin
the BA lesions of another patient who had received nafcillin derivatives (PCNase-resistant penicillins and aminopenicillins);
TMP-SMX, trimethoprim-sulfamethoxazole.
and gentamicin for several days prior to biopsy [11]. The
discrepancies between in vitro and in vivo sensitivities may oc-
cur because the bacilli present in BA lesions have different
cell wall characteristics from those grown on agar; these in vivo is not recommended due to the rapid development of resis-
changes in composition could alter susceptibility to cell wall- tance. For severely ill patients, we administer rifampin in
active antibiotics. Additionally, the fastidious nature of Barto- addition to a first-line drug (erythromycin or doxycycline)
nella species makes accurate susceptibility testing difficult to during the initial several weeks of therapy. For some other
perform. antibiotics listed in Table 33.1 with possible clinical effi-
Rifampin appears to have clinical efficacy in treating cacy, single case reports have been associated with improve-
Bartonella infections (Table 33.1), but use of this drug alone ment in lesions or symptoms, but the response to these
427
antibiotics is not consistent enough to warrant their recom- perhaps indefinite, oral antimicrobial therapy. Serial tech-
mendation at present. It also is difficult to directly attribute netium-99m methylene diphosphonate bone scans or
improvement of symptoms to treatment with a specific an- radiographs can be used to monitor treatment efficacy, al-
tibiotic when many patients have concomitant infection though resolution of osseous lesions is delayed, as seen
with other pathogens. The clinical efficacy of ciprofloxacin, with other causes of osteomyelitis.
trimethoprim-sulfamethoxazole and third-generation ceph-
alosporins remains inconclusive. One pregnant patient re-
ceived 2 weeks of ceftizoxime treatment for cutaneous BA Treatment of hepatic and splenic
and experienced complete resolution of lesions [42]. Of bacillary peliosis
note, we observed progression of BA lesions in patients trea-
Most patients with BP have severe systemic symptoms, in-
ted with ciprofloxacin in our study of patients with BA [65].
cluding nausea and vomiting that may substantially de-
Although one patient reportedly improved with trimethoprim-
crease absorption of oral antibiotics. Additionally, oral
sulfamethoxazole [34], most patients demonstrated no
erythromycin or doxycycline may not be tolerated by these
improvement or had progression of lesions [14, 17,
patients; thus, initial treatment should be with intravenous
42, 44, 64], and we have isolated B. henselae from the tissue
antibiotics for several weeks, followed by oral therapy for
of two patients taking prophylactic oral trimethoprim-
at least 4 months, possibly indefinitely. For severely ill
sulfamethoxazole[11]. In contrast, no Bartonella isolate was re-
patients, rifampin can be added to the initial treatment
covered from any BA patient treated with a tetracycline or
regimen. Treatment progress can be monitored by follow-
erythromycin (even after a single dose) [66], and prior treat-
ing hepatic transaminases and by serial computed tomog-
ment with a macrolide has been found to be significantly
raphy, if peliotic lesions are visualized at the time of
protective against development of BA [11].
diagnosis (Fig. 33.6).
Treatment of cutaneous bacillary Treatment of Bartonella bacteremia

angiomatosis lesions
If possible, Bartonella blood cultures should be performed
Immunocompromised patients with cutaneous BA should be for patients with all forms of BA, prior to antibiotic treat-
evaluated for parenchymal and osseous disease before begin- ment. For bacteremia, an initial period of intravenous an-
ning treatment, because presence of either of these requires tibiotic therapy with doxycycline 100 mg IV q12h (with or
treatment for a longer duration. For cutaneous disease alone, without oral rifampin 300 mg twice daily) is probably
antibiotic therapy can be given orally. Response of cutaneous appropriate for bacteremia, followed by at least 3 months
lesions is usually rapid, with improvement in 1 week and of oral antibiotic therapy with oral doxycycline 100 mg
complete resolution by 1 month, although hyperpigmenta- twice daily. Fever and constitutional symptoms typically re-
tion may persist at the site of the lesion. As a result of our solve within 1 week of institution of antibiotic treatment,
experience, we treat patients with cutaneous lesions for 3 although one patient did not have permanent remission
months, and if relapse occurs we extend treatment for an of fever until he had received 8 weeks of treatment [5].
additional 4 months and occasionally treat indefinitely. Because endocarditis can develop during infection with
B. quintana [17, 67], B. henselae [68], and rarely other Bar-
tonella species, all patients with Bartonella bacteremia and a
Treatment of osseous bacillary cardiac murmur or relapsing bacteremia should be evalu-
angiomatosis lesions ated with echocardiography. Patients with Bartonella endo-
Duration of antibiotic therapy for patients with Bartonella carditis should receive 6 weeks of intravenous antibiotic
osteomyelitis is not well established. We treated one pa- therapy, probably with two drugs (doxycycline plus rifam-
tient (Fig. 33.2) with oral erythromycin 500 mg six times pin or erythromycin plus rifampin), because neither first-
a day for 2 months, followed by 500 mg four times a day line drug is bactericidal. Although gentamicin has been
for an additional 2 months [2]. This patient experienced shown to be a useful adjunctive antibiotic when added
complete resolution of the osteolytic lesion without relapse to doxycycline in the first 2 weeks of therapy [58], we have
during the subsequent 24 months, when he died of another found that the majority of patients do not tolerate gentami-
opportunistic infection. Relapse occurred in another pa- cin due to the renal insufficiency that frequently accom-
tient with osseous BA [16] despite 4 months of oral treat- panies Bartonella endocarditis.
ment with 500–1,000 mg erythromycin four times a day;
the osseous BA healed but relapse with B. quintana bacter-
Relapse
emia occurred 1 month after stopping erythromycin. For
patients with osseous BA, it may be most appropriate to Both B. quintana [69] and B. henselae [70] produce relaps-
treat initially with several weeks of intravenous antibiotics ing illness in immunocompetent hosts; therefore, it is thus
(erythromycin or doxycycline) followed by prolonged, and not surprising that immunocompromised patients with BA
428
or BP frequently experience relapse despite prolonged anti- [74, 75], providing compelling evidence that the domestic
biotic therapy [5, 6, 16, 33, 46, 49, 64, 71]. It should be cat is the major reservoir for B. henselae.
noted that reinfection remains a possibility in these pa- The cat flea has been established as a vector of B. henselae
tients, but the majority of these cases probably represent re- among cats [76]. Initially, an epidemiological association
lapse. The frequency of relapse appears to be increased between owning a kitten with fleas and development of
when patients are treated with antibiotics for a shorter du- CSD was described [73]. Also, a seroprevalence survey of
ration. Over the years, we have increased the duration of B. henselae antibodies in pet cats throughout regions
treatment for all presentations of BA as the result of our in- of North America revealed that the regions with the highest
creased experience, and we currently recommend that all average prevalence of antibodies coincided with the geo-
patients with BA be treated for a minimum of 3 months, graphic areas predicted to have the highest prevalence of
and those with peliosis hepatis be treated for a minimum the cat flea (e.g. Hawaii, coastal California, the Pacific
of 4 months [58]. If relapse of Bartonella infection occurs Northwest, and south central plains) [77]. Viable B. hense-
after a first or second full course of an appropriate antibi- lae bacilli were isolated from several fleas combed from a
otic, prophylactic treatment with a macrolide or doxycy- bacteremic cat [74], and B. henselae transmission from
cline should be administered as long as the CD4 count cat to cat via the cat flea was demonstrated in 1996 [76].
remains <200 cells/mm3. Finally, Foil and co-workers [78] demonstrated that the fe-
ces of fleas fed on bacteremic cats are infectious and capa-
ble of transmitting B. henselae to uninfected cats.
EPIDEMIOLOGY AND PREVENTION According to the Humane Society, there are 93.6 million
owned cats in the USA. Despite this large number, and the
OF BARTONELLA INFECTIONS high percentage of cats with B. henselae infection, transmis-
sion of B. henselae to humans is relatively rare; thus, the
Arthropods serve as vectors of Bartonella species. Bartonella benefit of these companion animals far outweighs the risk
quintana is known to be transmitted from the human reser- of B. henselae infection [79]. We suggest that several practi-
voir to other humans via the body louse [69], and the cat flea cal measures be followed to reduce the risk of B. henselae
is the vector that transmits B. henselae from cat to cat. How- infection in HIV-infected individuals: (1) wash hands after
ever, at present the vector most strongly implicated in trans- petting and handling pets; (2) wash bites and scratches im-
mission of B. henselae to humans is the domestic cat. Ticks mediately with soap and water; (3) never allow any pet
are also possible vectors of Bartonella species: two patients to lick an open wound; and (4) minimize flea infestation
reported tick bites preceding the diagnosis of B. henselae bac- of pets (keep pets indoors and use flea protection
teremia [7, 70]. However, there are no definitive data sup- products).
porting direct transmission of Bartonella species from ticks Although the domestic cat has been identified as the
to humans. major reservoir and vector for B. henselae, it is evident
Serological studies initially revealed that B. henselae is the that B. quintana, which causes nearly half of the BA in-
principal bacterial agent causing CSD in immunocompe- fections in San Francisco, is not associated with cat con-
tent individuals [18]. Subsequent, corroborating data intact. In a study of 49 patients and 96 matched controls,
cluded the direct culture of B. henselae from lymph nodes patients with BA caused by B. quintana infection were
that had histopathological characteristics suggestive of significantly more likely than controls to be homeless,
CSD [52] and the demonstration of Bartonella DNA (but have low socioeconomic status, and have had recent in-
not A. felis DNA) in the CSD skin test antigen [72]. Simi- festation with head or body lice [11]. Physicians should
larly, an association between cat exposure and the develop- consider B. quintana infection as a cause of fever in
ment of BA was noted in many case reports [20]. The first homeless patients, whether cutaneous lesions are present
systematic evaluation of the relationship between cat con- or absent. Strategies to prevent infection with B. quintana
tact, numerous other environmental exposures, and devel- are currently limited to reducing homelessness and expo-
opment of BA was conducted by Tappero and co-workers sure to body lice.
[65]. This case-control study found a significant epidemio-
logical association between development of BA and trau-
matic cat exposure (cat bite or cat scratch). Both CSD
and BA due to B. henselae are statistically associated with
cat exposure [11, 65, 73]. The association between B. hen- ACKNOWLEDGMENTS
selae-infected cats and development of BA in the cat owners
was demonstrated in 1994, when bacteremia was detected Dr Koehler received funding support from a California HIV/
in all seven cat contacts of four patients with BA due to AIDS Research Program Award, a Burroughs Wellcome
B. henselae [74]. It was further found that about 40% of Fund Clinical Scientist Award in Translational Research,
the domestic cat population sampled in the greater and from NIH R01AI52813 and NIH U54AI065359 from
San Francisco Bay Area was bacteremic with B. henselae the National Institute of Allergy and Infectious Diseases.
429
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432
Chapter | 34 |
Management of herpesvirus infections
(cytomegalovirus, herpes simplex virus,
and varicella-zoster virus)
W. Lawrence Drew, Kim S. Erlich
CYTOMEGALOVIRUS Chorioretinitis
Ocular disease caused by CMV occurs only in patients with
severe immunodeficiency and was especially common in pa-
General comments tients with AIDS prior to the advent of HAART. Clinical ev-
With the advent of highly active antiretroviral therapy idence of CMV retinitis (Fig. 34.1) occurred in as many
(HAART), there has been a marked decline in cytomegalo- as 40% of AIDS patients, and autopsy series revealed
virus (CMV) disease except in the developing world, where that CMV retinitis was present in up to 30% of patients. With
up to 25% of AIDS patients may develop end-organ CMV the routine use of prophylaxis against Pneumocystis pneumo-
disease. Even where antiretroviral therapy (ART) is avail- nia, retinitis became a common presenting manifestation of
able, the syndromes discussed below still occur in the early AIDS, but it occurred more often months to years after the
months of therapy, because the CD4 lymphocytes require diagnosis of AIDS had been established. The incidence of
weeks to months to become fully functional [1]. CMV dis- CMV disease is currently low, primarily because of the effi-
ease is also seen in patients who have eluded medical care cacy of ART in preventing severe immunosuppression.
and in those who fail or are intolerant of ART [2]. Decreased visual acuity, the presence of floaters, or uni-
Serologic evidence of infection with CMV is extremely lateral visual field loss are the most common presenting
common in HIV-infected patients, and the virus can cause complaints. Ophthalmologic examination typically reveals
several clinical illnesses, including chorioretinitis, esoph- large creamy to yellowish white granular areas with perivas-
agitis, colitis, pneumonia, and several neurologic disor- cular exudates and hemorrhages (Fig. 34.1). These lesions
ders in patients with severe immunosuppression. Even initially occur more often at the periphery of the fundus
patients with blood, urine, or tissue cultures positive for and, if left untreated, progress centrally within 2–3 weeks.
CMV may not develop clinical illness related to the infec- Retinitis usually begins unilaterally, but progression to bi-
tion. However, in patients with advanced AIDS (CD4 lateral involvement is common because of associated vire-
counts of <50 cells/mm3), the risk of developing CMV mia. Systemic CMV infection involving other viscera may
disease and death is directly related to the quantity of be present.
CMV nucleic acid in plasma. In a study of over 600 ad- CMV accounts for at least 90% of HIV-related infectious
vanced AIDS patients, each log10 increase in baseline retinopathies. Differentiating suspected CMV retinitis le-
CMV DNA was associated with an approximate three-fold sions from cotton-wool spots is essential. Cotton-wool spots
increase in CMV disease and a twofold increase in mortal- appear as small, fluffy, white lesions with indistinct margins
ity at 1 year [3]. and are not associated with exudates or hemorrhages. They
Diagnosis of CMV disease may require tissue biopsy with are common in AIDS patients, are usually asymptomatic, and
histologic evidence of viral inclusions, antigen or nucleic represent areas of focal ischemia. These lesions do not pro-
acid in tissue. This section reviews the most common clin- gress and often undergo spontaneous regression. Toxoplas-
ical manifestations of CMV and their management mosis is the second most common opportunistic infection
(Table 34.1). of the eye but is characterized by little if any hemorrhage.
433
Table 34.1 Treatment of cytomegalovirus (CMV) infection in AIDS patients
PREFERRED THERAPY ALTERNATIVE THERAPY
CMV retinitisa,b,c
Sight-threatening lesions Ganciclovir implant þ valganciclovir or GCV IV, foscarnet IV,

(induction therapy) valganciclovir cidofovir IV
Peripheral lesions Valganciclovir Same as above
(induction therapy)
Maintenance therapy Valganciclovir Same as above
Relapsing and/or GCV Re-induction with ganciclovir/valganciclovir Cidofovir (if only UL97 mutation); fomivirsen
resistant þ/ ganciclovir implant; foscarnet IV þ/
ganciclovir/valganciclovir
CMV gastrointestinal disease Ganciclovir IV
Foscarnet IV or valganciclovir (if absorbing)
CMV neurological disease Ganciclovir IV þ foscarnet IV
a
If not already begun, ART should be initiated concurrent with anti-CMV therapy, except possibly when treating CNS disease.
b
For retinitis, anti-CMV therapy should be continued until CD4 count has exceeded 100–150 cells/mm3 for 3-6 months and retinitis is inactive. If
anti-CMV therapy is discontinued, regular eye exams should be performed every three months.
c
Early relapses of CMV retinitis in patients treated systemically are usually due to inadequate drug penetration; re-induction with the same drug is
often effective. Drug resistance may occur in patients treated for > 3 months. Therapy of these patients may be guided by antiviral susceptibility
testing.
with pupillary dilation, and ideally, indirect ophthalmos-

copy, may be valuable when cell counts decline to this
level. It is also important to ask about visual abnormalities,
especially increased floaters or visual field defects, and to
examine the fundus carefully when there are visual com-
plaints. Patients with confirmed CMV chorioretinitis
should be treated with ganciclovir, valganciclovir, foscar-
net, or cidofovir [4–6]. These agents are equally effective
in the treatment of CMV retinitis [7]. The toxic effects of
these agents vary widely but the usual drug of choice is gan-
ciclovir/valganciclovir. In resource-poor settings, intravi-
treal treatment may be employed.
Nervous system
CMV commonly involves the central nervous system (CNS)
Figure 34.1 Funduscopic appearance of CMV retinitis, in AIDS patients. The spectrum of neurologic syndromes in
illustrating ‘cottage cheese and catsup’ appearance resulting AIDS patients ranges from polyradiculopathy, encephalitis
from perivascular exudates and hemorrhages. with dementia, and ventriculoencephalitis to mononeuritis
(Courtesy of Dr L Schwartz, San Francisco, California.)
multiplex and painful neuropathy.
It is associated with cerebral toxoplasmosis in the majority of

patients. Syphilis, herpes simplex virus (HSV), varicella- Polyradiculopathy and myelitis
zoster virus (VZV), and tuberculosis are other infections that The clinical syndrome of CMV polyradiculopathy and my-
may rarely involve the retina. elitis usually has an insidious onset with low back pain ra-
Virtually all patients with CMV retinitis have CD4 counts diating to the perianal area and progressive lower extremity
of < 50 cells/mm3. Ophthalmologic screening of patients weakness, hypo- or areflexia, and variable sensory deficit,
434
Chapter | 34 | Management of herpesvirus infections
usually with preserved proprioception and vibratory sensa- avium complex). Psychomotor slowing, primitive reflexes,
tion. Most patients develop urinary retention and fecal and peripheral neuropathy may also be seen in CMVE. Dis-
incontinence due to bladder and/or anal sphincter dys- tal sensory polyneuropathy usually antedates the onset of
function. The disease clinically resembles Guillain–Barré CMVE [11].
syndrome but may be differentiated by lack of sphincter The course of encephalopathic illness in both CMVE and
involvement in the latter. HIVD includes progressive worsening in mental status until
Diagnosis of CMV polyradiculopathy is based on the death. The median survival of CMVE patients is sig-
characteristic neurologic features described above. The cere- nificantly shorter (weeks) compared with that of HIVD
brospinal fluid (CSF) abnormalities are unusual for a viral patients (months). Autopsies reveal a range of neuropa-
infection: pleocytosis with predominant polymorphonu- thology, including ependymal and subependymal necrosis,
clear leukocytosis and hypoglycorrhachia. Culture of CSF areas of demyelination, and microglial nodules that are
is usually positive, but antigen or DNA assays are more sen- more frequently encountered than typical nuclear and
sitive methods of diagnosis. Magnetic resonance imaging cytoplasmic CMV inclusions [12]. Neuropathologic eval-
(MRI) may reveal enhancement of leptomeninges and uations of CMVE and HIV co-infection of single cells sug-
clumping of lumbosacral roots. Characteristic pathologic gests that CMV and HIV increase each other’s replication
changes seen in CMV polyradiculopathy are demyelination in the brain [13].
and destruction of axons. It is difficult to make a definitive diagnosis of CMVE, and
Acute CMV polyradiculopathy should be differentiated laboratory investigations are not helpful in distinguishing
from idiopathic lumbosacral polyradiculopathy, in which CMV from HIVD. Electrolyte abnormality, especially hypo-
CSF pleocytosis is predominantly mononuclear and clini- natremia, is more commonly present in CMVE patients
cal improvement is seen without CMV treatment. Lym- [14]. There are insufficient data to determine whether CMV
phoma, tuberculosis, syphilis, and toxoplasmosis also antigen or DNA is regularly detected in CSF. Conversely, de-
cause similar clinical syndromes. tection of CMV DNA may only reflect latent, but not active,
CMV diseases. MRI scans showing meningeal enhancement
consistent with ventriculitis and periventricular enhance-
Encephalitis with dementia
ment are helpful in differentiating CMVE from HIVD. How-
and ventriculoencephalitis ever, periventricular enhancement may also be seen in
CMV encephalitis (CMVE) with dementia and ventricu- lymphoma, toxoplasmosis, and pyogenic brain abscesses.
loencephalitis are the two syndromes of CMVE described Progressive ventriculomegaly, if seen in serial computed
in AIDS patients. CMVE with dementia, the more common tomography scans, is highly suspicious for CMVE [15, 16].
of the two syndromes, is well described neuropathologi- Combination therapy with ganciclovir and foscarnet is
cally [8] as a multifocal, scattered micronodular encephali- commonly used, especially when disease progression is
tis that resembles HIV encephalitis, the cause of HIV- noted with single-agent therapy but trials of single versus
associated dementia (HIVD) [9]. CMV ventriculoencepha- combined therapy have not been performed.
litis is a late and terminal event with acute onset of enceph-
alitis often associated with cranial nerve involvement and
nystagmus. The significance of differentiating CMVE and
Mononeuritis multiplex
HIVD lies in the different drugs available for treatment. This is the least common of all the neurologic syndromes
CMVE is seen more commonly among men who have sex attributed to CMV. Clinical characteristics of CMV mono-
with men (MSM), which may reflect the increased CMV se- neuritis are more varied than polyradiculopathy/myelitis.
roprevalence in that population [10]. CMVE always occurs Patients may present with multifocal, patchy and/or asym-
in patients with CD4 counts of < 100 cells/mm3 and metrical sensory and motor deficits. Cranial nerve palsies
should be suspected in patients presenting with a subacute caused by CMV, especially in the recurrent laryngeal nerve,
encephalopathy who have had AIDS for more than 1 year. have been reported in the setting of severe immunosup-
Clinicians should suspect a diagnosis of CMVE in patients pression [17]. This symptom may occur with other mani-
who have a history of systemic CMV infection, especially festations of CMV (e.g. polyradiculopathy, encephalitis,
those with CMV retinitis who develop encephalopathic fea- or retinitis). Pathologic findings in peripheral nerve biop-
tures and change in mental status. sies have shown endoneurial necrosis with cellular infil-
Patients with dementia caused by CMVE usually have a trates and Schwann cells showing CMV inclusions.
more acute onset and rapid progression than patients with
HIVD. The encephalopathic symptoms include delirium
and confusion, lethargy and somnolence, apathy and with-
Painful distal neuropathy
drawal, personality changes, and focal neurologic signs A syndrome of painful distal symmetrical neuropathy of
with cranial nerve involvement. During the course of ill- subacute onset limited to the feet and associated with some
ness, recurrent fever episodes may occur that may be attrib- numbness and weakness has been reported with CMV
uted to other opportunistic infections (e.g. Mycobacterium infection [18].
435
Gastrointestinal system CMV treatment for 3–6 weeks and should be considered
for continued maintenance treatment, in part to prevent
CMV colitis may occur in at least 5–10% of untreated AIDS retinitis [20].
patients. Diarrhea, weight loss, anorexia, and fever are of-
ten present. The differential diagnosis includes infection
by other gastrointestinal pathogens, including Cryptosporid-
Pulmonary system
ium, Giardia, Entamoeba, mycobacteria, Shigella, Campylo-
bacter, and Strongyloides stercoralis, and involvement by Isolation of CMV from pulmonary secretions or lung tissue
lymphoma or Kaposi’s sarcoma. Endoscopy usually reveals in AIDS patients with pneumonia who undergo bronchos-
diffuse submucosal hemorrhages and mucosal ulcerations, copy is common, but a true pathogenic role of the virus in
although a grossly normal-appearing mucosa may be en- the disease process may be difficult to establish. Many pa-
countered in up to 10% of those with histologic evidence tients with pulmonary disease and CMV isolation from the
of CMV colitis (Fig. 34.2). Biopsy reveals vasculitis, neutro- lung have concomitant infection with other pathogens, es-
philic infiltration, and non-specific inflammation, but the pecially Pneumocystis jiroveci. Many of the patients respond
diagnosis is confirmed by the presence of characteristic to therapy directed at P. jiroveci pneumonia alone, raising
CMV inclusions, antigen, or nucleic acid and the absence the question of whether CMV is a true pulmonary pathogen
of other pathogens. in patients with AIDS. However, patients with positive
Symptomatic esophagitis in AIDS patients is most often CMV cultures and consistent histologic findings from lung
due to Candida albicans but may also be caused by CMV. Pa- tissue in whom no other pathogens are identified may truly
tients with CMV esophagitis are apt to have pain on have invasive CMV pneumonia.
swallowing and distal ulceration on endoscopy. As in coli- When CMV causes pulmonary disease in AIDS patients,
tis, diagnosis should be established through endoscopic the syndrome is that of an interstitial pneumonitis. Patients
examination and biopsy. Other causes of ulcerative esoph- often complain of gradually worsening shortness of
agitis include HSV and aphthous esophagitis. breath, dyspnea on exertion, and a dry, non-productive
The efficacy of anti-CMV treatment in patients with cough. The heart and respiratory rates are elevated, but aus-
enterocolitis is not dramatic [19]. When compared with cultation of the lungs often reveals minimal findings with
placebo, a significant antiviral effect was observed, but a no evidence of consolidation. Chest radiographs show dif-
clinical benefit was less apparent. Diarrhea and abdominal fuse interstitial infiltrates similar to those in patients with
discomfort were not relieved, but in general, patients P. jiroveci pneumonia. Hypoxemia is invariably present.
seemed to improve with this therapy [19]. Anti-CMV therapy should be considered when a patient
Patients with symptomatic esophagitis or enterocolitis has documented CMV pulmonary infection as the only
who have CMV (and no other pathogens) detected by en- pathogen identified and a progressive, deteriorating clini-
doscopy, histology, or culture should benefit from anti- cal course [21–23].
Figure 34.2 Sigmoidoscopic appearance of CMV colitis (two views), demonstrating diffuse submucosal hemorrhages and mucosal
ulcerations.
(Courtesy of Dr D Dieterich, New York.)
436
Treatment of CMV infection dosage for maintenance therapy is approximately one-half

the induction dose (i.e. 5 mg/kg per day, 7 days/week) or, if
Ganciclovir/valganciclovir oral valganciclovir, 900 mg daily, with food.
Structure and mechanism of action When administered by intravenous infusion over 1 h in
the usual dosage of 5 mg/kg, peak ganciclovir blood levels
Ganciclovir is a nucleoside analog that differs from acyclo- are approximately 8–9 mg/mL, and the serum half-life is
vir by a single carboxyl side chain. This structural change 3.5 h. The absolute bioavailability of oral valganciclovir
confers approximately 50 times greater activity than acyclo- capsules is approximately 60%. When administered orally
vir against CMV. Acyclovir has low activity against CMV be- as 900 mg with food, peak serum levels approach those
cause it is not well phosphorylated in CMV-infected cells. achieved by intravenous administration of 5 mg/kg. Oral
This is due to the absence of the gene for thymidine kinase valganciclovir may be used for induction treatment and
(TK) in CMV. Ganciclovir, however, is active against CMV is the drug of choice for maintenance therapy [25]. Because
because it does not require TK for phosphorylation. Instead, ganciclovir is excreted unchanged through the kidneys,
another viral-encoded phosphorylating enzyme (UL 97) is dosage for intravenous ganciclovir must be reduced in pa-
present in CMV-infected cells [24]. It is capable of phos- tients with renal impairment. Dosage adjustments should
phorylating ganciclovir and converting it to the monopho- also be considered for oral valganciclovir. The appropriate
sphate. Cellular enzymes then convert the monophosphate dose reductions are presented in Table 34.2. Initial response
to the active compound, ganciclovir triphosphate. Ganci- in retinitis (improvement or stabilization in vision or oph-
clovir triphosphate acts to inhibit the viral DNA polymer- thalmoscopic appearance) occurs in approximately 75% of
ase. Valganciclovir is an oral prodrug of ganciclovir, i.e. it is treated patients [6]. By comparison, the disease is relentlessly
converted to ganciclovir after absorption. progressive in 90% of patients if left untreated. Visual-field
defects present at the onset of therapy do not reverse, but a
Pharmacology and dosage decrease in visual acuity caused by edema of the macula
Ganciclovir is available for clinical use in intravenous for- may improve with treatment. Retinal detachment may occur
mulations, as well as a sustained release intraocular im- in later stages as the necrotic retina scars and thins.
plant. The oral form of ganciclovir has been replaced by Prior to the availability of HAART, maintenance therapy
valganciclovir. Intravenous ganciclovir is used for initial in- throughout the life of the patient was critical for CMV ret-
duction therapy, followed by either intravenous ganciclovir initis because the virus is only suppressed by ganciclovir
or oral valganciclovir for maintenance therapy. and is not eliminated. Even with continued maintenance
Initial intravenous induction treatment for CMV disease therapy, CMV retinitis eventually progressed. Why this oc-
consists of 5 mg/kg twice daily for 14–21 days or until there curred is not clearly understood, but it is likely related to
is an adequate clinical response. The standard intravenous suboptimal drug delivery to the retina. This hypothesis is
Table 34.2 Ganciclovir dosage adjustment in patients with impaired renal function
CREATININE IV INDUCTION INDUCTION MAINTENANCE MAINTENANCE ORAL VALGANCICLOVIR

CLEARANCE DOSE (mg/kg) DOSING DOSE (mg/kg) DOSING INDUCTION DOSE
(mL/min)a INTERVAL (h) INTERVAL (h)
>70 5.0 12 5.0 24 900 mg twice daily every

other day
50–69 2.5 1 2.5 24 900 mg twice daily every

other day
25–49 2.5 24 1.25 24 450 mg once daily
10–24 1.25 24 0.625 24 450 mg three-times a week
<10 1.25 3 three times a 3 three times a Do not use

week following week following
hemodialysis hemodialysis
a
Creatinine clearance can be related to serum creatinine by the following formulas:
140 age ðyearsÞ weight ðkgÞ
For males :
72 serum creatinine ðmg=dLÞ
For females: 0.85 male value.
437
supported by the longer times to progression achieved with may occur. Many strains with this mutation are cross-
the ganciclovir intraocular implant, which delivers greater resistant to cidofovir but usually remain sensitive to
concentrations of ganciclovir to the vitreous [26]. Viral re- foscarnet [35, 36].
sistance does not appear to be involved in most progres- The most rapid method for detecting resistance is to ge-
sions of CMV retinitis [27]. notype UL 97 and UL 54, to detect resistance mutations.
With successful ART, it is possible for selected patients This may be done on a viral isolate or on body fluids di-
with CMV retinitis to discontinue maintenance therapy rectly (e.g. plasma) if sufficient CMV DNA copy numbers
but not until CD4 count has exceeded 100 cells/mm3 for are present. Patients with ganciclovir-resistant disease
3–6 months and the retinitis is inactive [28]. should be switched to foscarnet, since cross-resistance to
Intravitreal injection of ganciclovir has been used in these two drugs is rare. Discontinuing ganciclovir may al-
certain special situations, such as in patients in whom low reversion to wild-type virus to occur more rapidly than
neutropenia limited the systemic use of the drug, and if continued.
in one series [29] appeared effective and relatively safe.
Sustained intravitreal release of ganciclovir has been ac-
complished using a surgical implantable device [14, 30, Toxicity
31]. This implant, which is designed to deliver ganciclovir Toxicity may limit therapy with ganciclovir. CBCs, electro-
into the vitreous over several months, has been shown to lytes and renal function should be monitored weekly while
be highly efficacious for local control of retinitis. When on therapy. The following adverse effects may occur.
the implant is used, oral valganciclovir should also be
given at least until CD4 function is restored by ART. This
is needed to treat or prevent contralateral eye or systemic Effects on hematopoiesis
disease. The implant delivers approximately five times as Leukopenia and anemia may occur in up to 40 and 25%, re-
much ganciclovir compared with intravenous therapy and spectively, of patients receiving intravenous ganciclovir or oral
may be useful in treating low-level GCV-resistant CMV valganciclovir for treatment of CMV disease (Table 34.3).
retinitis. Many patients have low white blood cell counts before
therapy, so the contribution of ganciclovir/valganciclovir
to leukopenia is not always clear. Neutropenia may develop
at any time and is usually reversible. Cytokines, such as
Clinical use granulocyte colony-stimulating factor (G-CSF; filgrastim),
Administration of ganciclovir or valganciclovir is indicated are effective in reversing ganciclovir/valganciclovir induced
for the treatment of CMV disease, but other herpesviruses, neutropenia. Severe neutropenia (absolute neutrophil
including HSV-1, HSV-2, VZV, and human herpesvirus count < 500 cells/mm3) requires a ganciclovir/valganciclovir
(HHV)-6, are also susceptible to the drug in vitro. Because dose interruption until evidence of marrow recovery is
HIV-infected patients with severe CMV infection frequently
have illnesses caused by other herpesviruses, a bonus of
ganciclovir/valganciclovir therapy may be prevention or
Table 34.3 Selected laboratory abnormalities in
improvement of these infections.
patients receiving ganciclovir for treatment of CMV retinitis
CMV IV (5 PLACEBO
Resistance RETINITIS mg/kg L/d)
TREATMENT
Erice and co-workers [32] reported three patients whose
clinical course suggested the emergence of resistance and Number of patients 175 234
whose CMV isolates exhibited increases in the concentra-
tion of ganciclovir required to inhibit the virus in tissue cul- Neutropenia (ANC/L)
ture over baseline determinations. In a separate report, after <500 25 6
3 months of continuous intravenous ganciclovir therapy, 500–749 14 7
approximately 10% of patients were excreting resistant 750–1000 26 16
strains of CMV (arbitrarily defined as strains that are only
inhibited by four times or more the median concentration Anemia (hgb, g/dL)
of ganciclovir required to inhibit a group of pretherapy iso- <6.5 5 <1
lates) [33]. In virtually all isolates, there was a mutation in 6.5–7.9 16 3
the phosphorylating gene (UL 97) [34]. These strains re- 8.0–9.5 26 16
main sensitive to foscarnet, which may be used as an alter-
Data are percentages of patients. ANC; absolute neutrophil count;
native therapy. As treatment continues, a polymerase hgb, hemoglobin.
mutation (UL 54) conferring further ganciclovir resistance
438
observed and neutrophil counts have risen, preferably to resistance, because the principal mode of viral resistance
>1,000 cells/mm3. Thrombocytopenia occurs in up to 6% to nucleoside analogs is a mutation that eliminates phos-
of ganciclovir/valganciclovir-treated patients. phorylation of the drug in virus-infected cells. Foscarnet
can be used to treat patients with ganciclovir-resistant
Toxicities in other organ systems CMV; cross-resistance to foscarnet is rare. However, pa-
Gastrointestinal adverse events, most commonly diarrhea, tients treated with foscarnet may develop foscarnet resis-
nausea, anorexia, and vomiting, affect a substantial number tance due to mutations in the viral polymerase UL54 [36].
of patients treated with ganciclovir. When compared to pla-
cebo, events are only modestly higher among ganciclovir- Pharmacology
treated patients; 48% developed diarrhea (versus 42% of The recommended dose for initial therapy is 60 mg/kg by
placebo-treated patients), 19% developed anorexia (pla- intravenous infusion every 8 hours or 90 mg/kg every
cebo, 16%), and 14% developed vomiting (placebo, 12 hours. A dose of 120 mg/kg per day may be superior
11%) [37]. In patients receiving valganciclovir, diarrhea in efficacy to 90 mg/kg/per day [39], but this dose may also
occurred in 41%, nausea in 30%, and vomiting in 24%. be more toxic.
Neuropathy and paresthesia are the most frequent adverse CSF concentrations of foscarnet are approximately 40%
events involving the nervous system, affecting up to 21 and of serum levels. Excretion is entirely renal, without a
10% of patients, respectively, and only neuropathy oc- hepatic component. Oral bioavailability is estimated at
curred more often in ganciclovir-versus placebo-treated 12–22%, but it is poorly tolerated and not used.
patients (21% versus 15%, respectively). Neuropathy oc- Adverse effects include renal impairment, anemia, hypo-
curred in 9% of patients receiving valganciclovir. A minority calcemia (especially ionized calcium), hypomagnesemia,
of ganciclovir-treated patients will experience modest eleva- and hypophosphatemia. It is important to measure renal
tions in serum creatinine (maximum levels of at least 1.5 mg/ function frequently and adjust dosage accordingly to min-
dL, or >25% increases over pretreatment levels). imize toxicity. Daily pre-infusion of 1 L of saline may
reduce nephrotoxicity during maintenance therapy.
Gonadal toxicity Palestine and co-workers [5] reported the results of a ran-
In pre-clinical animal studies, ganciclovir (and therefore domized control trial of foscarnet in the treatment of CMV
valganciclovir) is a potent inhibitor of spermatogenesis retinitis in HIV-infected patients. Patients were assigned to
and may also suppress female fertility. Sperm counts in receive either no therapy or immediate treatment with in-
humans before and during ganciclovir therapy, however, travenous foscarnet. The justification for the design was
have been performed too infrequently to provide meaning- that the lesions were peripheral and not threatening visual
ful information on spermatogenesis. Patients wishing to acuity. The mean time to progression of retinitis was
have children should use ganciclovir/valganciclovir only 3 weeks in the control group versus 13 weeks in the treat-
for the strongest indications. ment group, thereby demonstrating the effectiveness of fos-
carnet. Also, an excellent antiviral effect was achieved in the
Teratogenesis treatment group (i.e. 9 of 13 patients had positive blood
cultures for CMV at entry, and all nine had CMV cleared
Because ganciclovir and valganciclovir are mutagens and
from their blood by the end of the 3-week induction
teratogens in animals, effective contraception should be
period). Adverse effects were seizures, hypomagnesemia,
practiced by men and women with childbearing potential
hypocalcemia, and elevated serum creatinine levels.
during treatment. Ganciclovir/valganciclovir should be
used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Ganciclovir and foscarnet
The results of a Studies of Ocular Complications of AIDS
Foscarnet (SOCA) trial of combination therapy versus monotherapy
Foscarnet is a pyrophosphate that inhibits the DNA poly- for relapsed CMV retinitis were published in early 1996
merase of CMV. Specifically, the drug blocks the pyrophos- [40]. Combination therapy (5 mg/kg per day ganciclovir
phate-binding site of the viral DNA polymerase, preventing and 90 mg/kg per day foscarnet) was significantly superior
cleavage of pyrophosphate from deoxyadenosine triphos- in delaying progression than either ganciclovir alone
phate [38]. This action is relatively selective in that CMV (10 mg per day) or foscarnet alone (120 mg/kg per day).
DNA polymerase is inhibited at concentrations < 1% of This study also found no advantage in switching monother-
that required to inhibit cellular DNA polymerase. Unlike apy. That is, patients in whom monotherapy failed with
such nucleosides as acyclovir and ganciclovir, foscarnet ganciclovir who then switched to high-dose foscarnet did
does not require phosphorylation intracellularly to be an not do better than patients who continued ganciclovir at
active inhibitor of viral DNA polymerases. This biochemi- the higher dose. The median times to progression were: fos-
cal fact becomes especially important with regard to viral carnet group, 1.3 months; ganciclovir group, 2.0 months;
439
and combination group, 4.3 months (p < 0.001). Side ef- throughout the life of the host, and all infected persons
fects were not statistically significantly different in any are at risk for virus shedding and recurrent symptomatic
group, but the quality of life was poorest in the combina- disease. Recurrent HSV mucocutaneous eruptions are com-
tion group as a result of the prolonged daily infusion time mon in patients with HIV infection and can be severe, with
of 3.1 hours. extensive tissue destruction and prolonged viral shedding
[43–45].
Recent studies confirm the high prevalence of both
Cidofovir HSV-1 and HSV-2 in the general population [46–48].
Cidofovir represents a departure from previous nucleoside Type-specific serologic studies conclude that up to 70%
analogs because it appears to the cell as a nucleotide. It of the population are infected with HSV-1, and up to
has a phosphonate moiety attached to a cytosine analog 22% are infected with HSV-2. HSV-2 infection rates are
and does not require phosphorylation by viral-encoded higher in women than in men and higher in African-
enzyme. It is therefore active against the majority of gan- Americans and Mexican-Americans than in Caucasians
ciclovir-resistant CMV strains that only have resistance [46–48]. The presence of underlying HSV infection may in-
mutations in UL97, the phosphorylating gene. When crease the risk of acquiring HIV infection following expo-
polymerase, UL54, mutations occur in ganciclovir UL54 sure to HIV. This increased risk for HIV may occur as a
treated patients, cross-resistance to cidofovir is frequent. result of the presence of susceptible CD4 T cells present
These UL54-resistance mutations also occur in patients in HSV ulcerations [49, 50]. The prevalence of HSV infec-
treated with cidofovir de novo [36]. The drug also has an tion in homosexual AIDS patients exceeds that of the
extremely long half-life, permitting intravenous adminis- general population and likely reflects the common risk
tration as infrequently as every 2 weeks during mainte- factor for transmission of both HSV and HIV (sexual con-
nance treatment [41]. tact). Serologic studies have revealed that up to 77% of
Cidofovir is nephrotoxic, especially to the proximal renal HIV-infected patients have been previously infected with
tubule, but toxicity can be diminished with prehydration HSV. AIDS subgroups who did not acquire HIV infection
and concomitant probenecid therapy. Renal function and through sexual contact, such as hemophiliacs and transfu-
toxicity must be monitored carefully, and proteinuria or sion recipients, have rates of HSV infection that are lower
a rising creatinine level are reasons for dosage reduction, in- than the incidence in patients with AIDS as a whole, and
terruption, or discontinuation. Concurrent administration are likely comparable with those in the general population.
of other nephrotoxic drugs must be avoided and there must The presence of latent HSV infection in this high percentage
be at least a 7-day period of “washout” of these drugs if of patients with HIV infection explains the frequency of clin-
their use precedes administration of cidofovir. ical disease in this population. Clinical observations suggest
that the frequency and severity of HSV recurrences may
increase with advancing immunosuppressions [48, 51–54].
Immune recovery uveitis
Immune recovery uveitis is an immunologic reaction to
CMV characterized by inflammation in the anterior cham- Clinical presentation
ber or vitreous. It occurs after the initiation of ART and typ-
Because most HIV-infected patients have been infected
ically occurs in patients who experience a substantial rise in
with HSV before acquiring HIV, recurrent HSV is much
CD4 count during the 4–12 weeks after initiation of ther-
more common than primary HSV infection in this popula-
apy. Treatment consists of periocular corticosteroids or a
tion. HSV infection in AIDS patients may appear similar to
short course of systemic steroids [42].
the typical HSV lesions observed in the normal host or, al-
ternatively, lesions may appear quite atypical and unusual
because of the immunosuppressed state associated with
HERPES SIMPLEX VIRUS HIV infection. The severity of clinical illness depends on
several factors, including the anatomic site of initial infec-
Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) cause tion, the degree of immunosuppression, and whether the
disease in both normal and immunocompromised hosts clinical episode represents initial primary infection (no pre-
and are responsible for substantial morbidity in patients vious exposure to either HSV type), initial non-primary in-
with AIDS. Most adult patients with AIDS have been fection (previous exposure to the heterologous HSV type),
infected with one or both HSV types before the develop- or recurrent infection [43–45].
ment of AIDS, and these patients are not susceptible to pri- Localized mucocutaneous ulcerative lesions, without vis-
mary HSV infection following new exposure. During initial ceral or cutaneous dissemination, is the most frequent
HSV infection, viral latency develops in the nerve root presentation of HSV infection in HIV-infected patients. Be-
ganglia corresponding to the site of mucocutaneous inocu- cause the lesions may appear atypical, a high index of sus-
lation. Latent virus can then reactivate at any time picion is required by the clinician in evaluating any
440
mucocutaneous lesion in a patient with HIV infection. heterologous HSV type) as compared with patients with
Chronic or persistent HSV infection (ulcerative HSV infec- non-primary initial infection (prior infection with the
tion present for great than one month) is an AIDS-defining heterologous HSV type). When present, signs and symp-
condition. toms include small papules that rapidly evolve into fluid-
filled vesicles. These lesions are usually painful and tender
to palpation. The vesicles ulcerate rapidly and, in the
Orolabial infection normal host, heal over 3–4 weeks by crusting and re-
Orolabial infection in adults with AIDS is usually due to re- epithelialization. Tender inguinal adenopathy is common,
current disease from previously latent infection. Primary and dysuria may be present even if the urethra is not
infection of the mouth or nose may occur, however, in a infected. Systemic symptoms, such as fever, headache, my-
seronegative individual who acquires infection at this site algias, malaise, and meningismus, may be present during
for the first time. Primary infection is more likely to occur primary infection [43–45].
in children with AIDS than in adults, because HIV infection In the normal host, recurrent genital herpes is less severe
in children (especially those infected prenatally) is more than primary infection. Compared with primary infection,
likely to precede initial exposure to HSV. recurrent herpes typically results in fewer external lesions, a
The incubation period of primary HSV infection ranges shorter duration of illness, and the absence of systemic
between 2 and 12 days. In the normal host, primary orola- symptoms [43–45]. As with primary infection, recurrent
bial infection may be asymptomatic or result in clinically genital herpes in patients with AIDS may be more severe
apparent gingivostomatitis [45–48, 55]. Immunocompro- and prolonged compared with that seen in the normal
mised patients are at greater risk than normal hosts of de- host. Prolonged new lesion formation, continued tissue de-
veloping a severe clinical illness during primary HSV-1 struction, persistent virus shedding, and severe local pain
infection, with a painful vesicular eruption occurring along are not uncommon findings in this setting. As with orola-
the lips, tongue, pharynx, or buccal mucosa. The vesicles bial herpes, the frequency and severity of genital recur-
rapidly coalesce and rupture to form large ulcers covered rences may increase with advancing immunosuppression,
by a whitish yellow necrotic film [55, 56]. Fever, pharyngi- and symptoms may last for several weeks if left untreated
tis, and cervical lymphadenopathy are often present in [51, 57].
adults, whereas infants may display poor feeding and per- Asymptomatic genital HSV shedding in non-
sistent drooling. immunocompromised patients occurs on between 1 and
Following initial or primary infection, all infected patients 6% of the days on which cultures are obtained [58, 59].
remain at risk for virus reactivation and recurrent disease. Re- HIV-infected patients infected with HSV shed HSV at even
current HSV gingivostomatitis (“fever blisters”) may occur higher rates, and asymptomatic shedding may increase
spontaneously or as a result of external stimuli, such as a fe- with advancing immunosuppression [60]. All HSV-
brile illness, excessive wind or ultraviolet light exposure to infected individuals (whether HIV infected or not) should
the lips, surgical manipulation of the trigeminal nerve, or be counseled about asymptomatic HSV shedding and the
stress. Prodromal symptoms, consisting of tingling or numb- risk of transmission to sexual partners despite the absence
ness at the site of the impending recurrence, may be present of symptoms or visible lesions [61].
from 12 to 24 hours before the onset of an HSV recurrence.
Instituting antiviral therapy during the prodrome may
shorten the duration of illness or may abort the develop-
ment of visible cutaneous lesions (see Treatment of HSV Anorectal infection
Infection, below). Recurrences may increase in frequency Chronic perianal herpes was among the first reported op-
and severity as immunosuppression worsens, although many portunistic infections associated with AIDS. HSV is the
AIDS patients will have only infrequent, mild, self-limiting re- most frequent cause of non-gonococcal proctitis in sexually
currences throughout the course of their disease [51, 55]. active homosexual men [62, 63]. HSV proctitis usually re-
In the normal host, orolabial herpes lesions usually heal sults from primary HSV-2 infection but may also occur as a
in 7–10 days. By comparison, AIDS patients often have a result of HSV-1 infection or recurrent disease caused by ei-
prolonged illness with markedly delayed healing of mucocu- ther viral type. Severe anorectal pain, perianal ulcerations,
taneous lesions. If left untreated, chronic ulcerative lesions constipation, tenesmus, and neurologic symptoms in the
with persistent viral shedding may last for several weeks [56]. distribution of the sacral plexus (sacral radiculopathy, im-
potence, and neurogenic bladder) are common findings of
HSV proctitis. These signs and symptoms help differentiate
Genital infection HSV proctitis from proctitis from other causes (Fig. 34.3)
After a 2- to 12-day incubation period, many individuals [62]. Anorectal or sigmoidoscopic examination in patients
with primary genital herpes develop local symptoms with HSV proctitis typically reveals a friable mucosa, diffuse
[43–45]. Symptoms will be most apparent in patients with ulcerations, and occasional intact vesicular or pustular
primary genital infection (no prior infection with the lesions [62].
441
Figure 34.3 Perianal ulcerations typical of herpes simplex.
Recurrent perianal lesions caused by HSV in the absence

of true proctitis is a common finding in patients with AIDS.
Local pain, tenderness, itching, and pain on defecation are
prominent symptoms of these lesions. Shallow ulcers in the
perianal region are often visible on external examination,
and ulcerative lesions frequently coalesce and extend along
the gluteal crease to involve the area overlying the sacrum.
These lesions are often atypical in appearance and may be
confused with pressure decubiti (Fig. 34.3). To prevent mis-
diagnosis, perianal ulcerations and anal fissures in patients Figure 34.4 Barium esophagram revealing a cobblestone
appearance of the esophageal mucosa. These findings are
with AIDS should be examined for the presence of HSV by
typical in both HSV esophagitis and Candida esophagitis.
culture, polymerase chain reaction (PCR), or direct antigen
(Reprinted with permission from Farthing CF, Brown SE, Staughton RCD.
detection whenever possible. A Colour Atlas of AIDS and HIV Disease Slide Set. 2nd edn. London:
Mosby; 1989.)
Esophagitis
Symptoms of HSV esophagitis typically include retrosternal patients, and simultaneous brain infections with HSV
pain and odynophagia. Patients may present with acute on- and CMV have been reported [66–68]. In adults with AIDS,
set of dysphagia or with chronic swallowing complaints, HSV encephalitis usually occurs as a complication of pri-
and symptoms may be severe enough to interfere with eat- mary or reactivated orolabial HSV infection. In neonates,
ing and adequate nutrition. Visible herpetic lesions in the the disease may occur as a result of primary HSV infection
oropharynx may not be present, and the clinical picture at the time of birth [45].
may be confused with Candida, CMV, or aphthous esoph- The presentation of HSV encephalitis in adults with AIDS
agitis. Radiographic contrast studies typically reveal a cob- is often highly atypical. A subacute illness with subtle neu-
blestone appearance of the esophageal mucosa, but this rologic abnormalities is common in AIDS patients with
finding is non-specific and is also present with esophagitis HSV encephalitis, suggesting that host immune responses
from other causes (Fig. 34.4) [64]. Definitive diagnosis of contribute to the clinical manifestations of the disease
HSV esophagitis should be made by direct endoscopic [55, 68]. Headache, meningismus, and personality changes
visualization of the esophageal mucosa with positive viral may develop gradually as the illness progresses. Alterna-
studies and histopathologic evidence of invasive viral infec- tively, however, some AIDS patients with HSV encephalitis
tion [65]. present with acute onset of symptoms. Abrupt onset of fe-
ver, headache, nausea, lethargy, and confusion may occur
with temporal lobe abnormalities, cranial nerve defects,
Encephalitis and focal seizures. Grand mal seizures, obtundation, coma,
HSV encephalitis occurs rarely in AIDS but is the most life- and death may eventually ensue.
threatening complication of HSV infection. Both HSV-1 The clinical diagnosis of HSV encephalitis may be ex-
and HSV-2 have been identified in brain tissue of AIDS tremely difficult, because other central nervous system
442
infections (including HIV encephalopathy, Cryptococcus life threatening, and all symptomatic HSV infections
neoformans, and Toxoplasma gondii) may present with simi- should be treated aggressively even if they are reactivations.
lar features. Studies have demonstrated the utility of detect- The prompt administration of antiviral chemotherapy in
ing HSV DNA in CSF by the polymerase chain reaction patients with acute HSV infection reduces morbidity and
technique as a method of non-invasive diagnosis of HSV the risk of serious complications. Currently, several effec-
encephalitis, although false-positive and false-negative tive antiviral drugs are available, and the clinician must
results do occur [69, 70]. CSF usually reveals non-specific choose the appropriate medication and the optimal route
findings, including elevated protein and a lymphocytic of administration (topical, oral, or intravenous).
pleocytosis. Viral CSF cultures are usually negative [70].
Other non-invasive diagnostic studies (such as MRI scan,
CT scan, radionuclide brain scan, or electroencephalography) Acyclovir
are rarely diagnostic but may reveal localized abnormalities Acyclovir, a synthetic purine nucleoside analog, was the
(often in the temporal lobes) to guide diagnostic brain first antiviral agent approved by the FDA for treatment of
biopsy. Definitive diagnosis may require brain biopsy and mucocutaneous HSV infection. Acyclovir has been avail-
the recovery of virus or demonstration of viral DNA or able and widely used since the early 1980s and, until re-
antigens from tissue specimens [71]. The histopathologic cently, has been the undisputed antiviral agent of choice
abnormalities typically observed in normal hosts (hemor- for HSV infections in patients with AIDS and for other im-
rhagic cortical necrosis and lymphocytic infiltration) may munocompromised and non-immunocompromised hosts
be absent in patients with AIDS [66–68, 71]. HIV-infected pa- [77] The drug has significant activity against HSV-1, HSV-2,
tients with suspected HSV encephalitis should be treated with and VZV. Despite excellent in vitro activity against these vi-
high-dose intravenous acyclovir pending results of diagnostic ruses, the bioavailability of oral acyclovir is only about
studies. 20%, resulting in relatively low serum drug levels following
oral administration compared with levels achieved with in-
travenous therapy. Despite these findings, the serum levels
Drug-resistant HSV infection of acyclovir achieved with standard acyclovir dosing
Since the initial description of acyclovir-resistant HSV in- (200 mg five times daily or 400 mg three times daily) ex-
fection in patients with AIDS, numerous additional reports ceed the levels required to inhibit the growth of HSV-1
have appeared in the literature [72, 73]. The incidence of and HSV-2,. Higher oral doses (800 mg five times daily)
acyclovir-resistant HSV infections in immunocompro- are needed to achieve inhibitory serum drug levels to treat
mised hosts had been estimated as 4–5% [72], but the VZV (see below) [77]. Acyclovir has a high therapeutic-to-
incidence has decreased dramatically since the advent of toxic ratio because it undergoes selective activation and
HAART. The most common mechanism of acyclovir resis- phosphorylation by virus-induced TK only in HSV- and
tance in patients with AIDS is the selection and overgrowth VZV-infected cells. Acyclovir triphosphate selectively in-
of HSV strains deficient in the enzyme thymidine kinase. hibits HSV DNA polymerase and results in early termina-
These mutated TK-deficient strains do not phosphorylate tion of DNA chain synthesis. The drug has slightly higher
acyclovir or penciclovir to the active antiviral compounds, activity against HSV-1 than HSV-2.
and these viruses are resistant to standard dosages of acy- Acyclovir distributes into all tissues, including the brain
clovir, valacyclovir, and famciclovir. Although these strains and CSF, and is cleared by renal mechanisms. The serum
have reduced virulence in animal models [74] and only half-life in patients with normal renal function is 2.5–3.3
rarely cause clinical disease in non-immunocompromised hours. The dose of intravenous acyclovir is 15 mg/kg per
hosts [75], they are capable of causing severe clinical illness day in three divided doses for treatment of mucocutaneous
in patients with advanced HIV disease [74]. Other mecha- infection and 30 mg/kg per day for HSV encephalitis. Al-
nisms of drug resistance, including alteration of TK and though oral dosage adjustment is not required because of
DNA polymerase specificity, have been described but occur poor bioavailability, the intravenous dose should be re-
much less frequently. Most reports of drug-resistant HSV duced in patients with impaired renal function (Table 34.4).
have cited localized chronic mucocutaneous infection, High-dose intravenous therapy can be associated with
but cases of disseminated mucocutaneous disease [73], crystalluria, and adequate hydration should be maintained
meningoencephalitis [76], and esophagitis [72] caused in patients on intravenous acyclovir to prevent this compli-
by these strains have been described. cation [77].
Numerous studies have shown acyclovir to be effective
for treatment of primary as well as recurrent HSV infection,
and as suppressive therapy for patients with frequently re-
Treatment of HSV infection
curring HSV. In HIV-infected patients with symptomatic
Mucocutaneous HSV infections in patients with AIDS are HSV infection, treatment is of great benefit in reducing
often symptomatic and can be a source of great discomfort. symptoms, viral shedding, and the duration of illness.
Visceral involvement or disseminated HSV disease can be The drug has an excellent safety record and is usually well
443
administration, valacyclovir is rapidly absorbed from the

Table 34.4 Dosage adjustment of intravenous acyclovir in
gastrointestinal tract. The drug is rapidly and extensively
patients with renal dysfunction
converted to acyclovir in vivo, and the resulting acyclovir se-
rum levels are much higher than those achieved with oral
CREATININE STANDARD DOSING
acyclovir. Pharmacokinetic studies reveal that a therapeutic
CLEARANCE (mL/min DOSE (%) INTERVAL
drug level equivalent to acyclovir 800 mg five times daily
per 1.73 m2) (h)
can be achieved with 1000 mg valacyclovir given every
>50 100 8 8 hours [87–89].
Because of the improved bioavailability of valacyclovir
25–50 100 12 compared with acyclovir, studies have evaluated less fre-
quent dosing for patients with HSV infection. Valacyclovir
10–25 100 12
is effective in the treatment of first-episode HSV infection at
0–10 50 24 a dose of 500–1000 mg to twice daily, and in the treatment
of recurrent HSV infection at a dose of 500 mg twice daily if
Usually 5 mg/kg; 10 mg/kg is used for HSV CNS infections and in initiated within the first 24 h of signs or symptoms. Ther-
some instances for VZV infections. apy should be continued until all lesions are dry and
crusted. Additionally, valacyclovir is effective as suppressive
therapy at a dose of 250 mg twice daily, 500 mg once daily
tolerated, although some patients may complain of head- (for patients with fewer than 10 recurrences per year), and
ache or nausea. Acyclovir can be administered orally 1 g once daily (for patients with 10 or more recurrences per
[78–84], intravenously [85, 86], or topically [57, 81], year) [89]. Dosage reduction is recommended in patients
and the optimal route of administration, dosage, and dura- with a creatinine clearance < 50 mL/min (Table 34.5).
tion of therapy depend on the site and severity of the HSV A study evaluating very high valacyclovir dosing (8 g/
infection. Oral acyclovir is usually appropriate for outpa- day) for suppression of CMV in patients with advanced
tients with localized, non-life-threatening mucocutaneous HIV disease suggested a possible association between vala-
HSV infection. Intravenous therapy should be prescribed cyclovir and the syndromes of thrombotic thrombocytope-
for patients with disseminated disease, HSV encephalitis, nic purpura and hemolytic-uremic syndrome (TTP/HUS).
or visceral organ involvement. Additionally, intravenous A cause-and-effect relationship has not been firmly estab-
therapy is indicated for those patients who do not respond lished, however, and these findings have not been observed
adequately to oral treatment, raising concern over issues in patients receiving standard dosages of valacyclovir. In
such as poor drug absorption, poor compliance with oral view of these observations, the standard recommended
therapy, or the development of drug-resistant infection. dosages of valacyclovir should not be exceeded [89].
Topical acyclovir ointment is only minimally effective
and should not be prescribed in the place of systemic anti- Famciclovir
viral therapy.
Famciclovir is the diacetyl 6-deoxy analog of the active anti-
viral compound penciclovir. When taken orally, famciclo-
vir is readily absorbed from the upper gastrointestinal tract,
Valacyclovir and is rapidly converted into penciclovir. In a manner sim-
Valacyclovir hydrochloride is the L-valyl ester of acyclovir, ilar to acyclovir, penciclovir undergoes phosphorylation
and is available and effective in the treatment of HSV to the triphosphate compound by viral-induced TK and
[87] and VZV [88] infections. Following oral cellular enzymes. Penciclovir triphosphate acts as a
Table 34.5 Valacyclovir dosing based on indications for treatment and renal function
CREATININE DOSAGE FOR VARICELLA DOSAGE FOR INITIAL DOSAGE FOR RECURRENT
CLEARANCE ZOSTER INFECTION HERPES SIMPLEX VIRUS HERPES SIMPLEX VIRUS
(mL/min) (CHICKENPOX OR SHINGLES) INFECTION INFECTION
50 1 gm every 8 hours 1 gm every 12 hours 500 mg every 12 hours
30–49 1 gm every 12 hours 1 gm every 12 hours 500 mg every 12 hours
10–29 1 gm every 24 hours 1 gm every 24 hours 500 mg every 24 hours
<10 500 mg every 24 hours 500 mg every 24 hours 500 mg every 24 hours
444
competitive inhibitor of the natural substrate required for Foscarnet must be given intravenously, and side effects
viral DNA replication, but does not irreversibly terminate (including nausea, fever, headache, anemia, and renal fail-
DNA replication. The drug has a very long half-life (10– ure) are common. Because of the potential for nephrotoxic
20 h) in HSV-infected cells, ensuring prolonged antiviral effects and electrolyte imbalances, close monitoring of re-
activity [90–94]. nal function and serum levels of potassium, calcium, phos-
Clinical studies have shown that oral famciclovir is effec- phate, and magnesium is required. Variable penetration
tive in the treatment of first-episode HSV infections at a into the CSF has been reported. Dosage adjustments are
dose of 250 mg three times daily and is effective in the treat- required in patients with renal dysfunction.
ment of recurrent HSV infection at a dose of 125 mg twice
daily if given within the first 6 hours of symptoms or signs. Other antiviral drugs
Therapy should be continued until all lesions are dry and
crusted. Additionally, famciclovir is effective as suppressive Cidofovir is a long-acting antiviral drug approved by
therapy at a dose of 250 mg twice daily [89, 91, 92, 94]. the FDA for the treatment of CMV retinitis, and also ap-
Dosage reduction is recommended in patients with creati- pears to be effective in the treatment of drug-resistant
nine clearance less than 60 mL/min (Table 34.6). HSV [99, 100]. Cidofovir has a prolonged serum half-
Topical penciclovir has been approved by the FDA for the life, allowing for once-weekly intravenous administra-
treatment of recurrent HSV gingivostomatitis. Unlike topi- tion. Nephrotoxicity can occur with therapy, however,
cal acyclovir, penciclovir appears to have a beneficial effect and pretreatment with intravenous fluids and probene-
on recurrent mucocutaneous HSV infection when com- cid is recommended. A gel form of cidofovir for topical
pared with placebo [95]. Topical penciclovir has not been use is effective for mucocutaneous drug-resistant HSV
extensively evaluated in patients with HIV infection, how- infections [101].
ever, and may not be as effective as systemic therapy in this
immunocompromised population. Management of patients with HSV infection
Most HIV-infected patients with primary or recurrent mu-
cocutaneous HSV infections are not ill enough to require
hospitalization and are suitable candidates for outpatient
Foscarnet
treatment. The treatment of choice for most HSV infections
Foscarnet (phosphonoformic acid) is an inorganic pyro- in AIDS is either oral acyclovir, oral valacyclovir, or oral
phosphate with a broad range of antiviral activities against famciclovir (Table 34.7). Because therapy with valacyclovir
herpesviruses as well as HIV [38]. Studies have demon- or famciclovir results in serum antiviral levels comparable
strated foscarnet to be effective in the treatment of CMV dis- to those with intravenous acyclovir, many HIV-infected pa-
ease and in the treatment of drug-resistant HSV and VZV tients with severe HSV infection who can tolerate oral
infections. Unlike acyclovir and famciclovir, foscarnet does therapy can be treated as outpatients.
not require viral enzyme-mediated phosphorylation for Although the bioavailability and resultant serum drug
activity. Hence, foscarnet remains an effective antiviral levels with oral acyclovir are not as favorable as those
agent for treatment of TK-deficient, drug-resistant HSV with valacyclovir or famciclovir, acyclovir remains a safe,
[96–98]. Foscarnet is superior to vidarabine in the treat-
ment of acyclovir-resistant HSV infections in patients with
AIDS, and remains a treatment of choice for this illness at a Table 34.7 Management of HSV infections in AIDS
dose of 40 mg/kg three times daily [96].
Mucocutaneous Acyclovir 400 mg PO three times
infection, mild daily, famciclovir 500 mg PO twice
daily, or valacyclovir 1000 mg PO
Table 34.6 Dosage adjustment of famciclovir in patients twice daily
with zoster and renal dysfunction
Mucocutaneous Acyclovir 5 mg/kg IV three times
infection, severe daily, famciclovir PO 500 mg twice
CREATININE CLEARANCE DOSAGE
daily, or valacyclovir PO 1000 mg
(mL/min) REGIMEN
twice daily
60 500 mg every 8 h Suppression of Acyclovir 400–800 mg PO twice
40–59 500 mg every 12 h mucocutaneous daily or three times daily famciclovir
lesions 500 mg PO twice daily, or
20–39 500 mg every 24 h valacyclovir 500 mg PO twice daily
There are insufficient data to recommend a dosage for patients with Acyclovir-resistant Foscarnet 40 mg/kg IV three
creatinine clearance < 20 mL/min. infection times daily
445
effective, and well-tolerated treatment regimen in HIV- therapy. Topical therapy has little, if any, usefulness in
infected patients with HSV infection. Most HIV-infected pa- the clinical setting [81].
tients respond well to oral acyclovir, although many clini- Systemic antiviral therapy should be continued until all
cians use higher doses of acyclovir in HIV-infected patients mucocutaneous lesions have crusted or re-epithelialized.
than those recommended in non-immunocompromised This may require longer treatment than the usual duration
patients. of therapy prescribed in the non-immunocompromised
The most recent guidelines (December 2010) from the host, because HSV lesions may heal slowly in AIDS patients
Centers for Disease Control and Prevention (CDC) state even with optimal antiviral therapy. If lesions do not heal
that patients with symptomatic HSV disease should be trea- despite standard therapy, repeat viral cultures should be
ted as early as possible with acyclovir 400 mg three times obtained, high-dose oral therapy (e.g. acyclovir 800 mg
daily, valacyclovir 1000 mg twice daily, or famciclovir five times daily, famciclovir 500 mg three times daily, vala-
500 mg twice daily for 5 to 10 days [102]. Ideally, treat- cyclovir 1 g three times daily, or intravenous acyclovir
ment should be continued until all mucocutaneous lesions 30 mg/kg per day) should be given, and the possibility of
are dry and healed. In some individuals, depending on the drug-resistant HSV infection should be considered. If avail-
immune status and clinical features, higher or lower anti- able, antiviral susceptibility testing should be performed in
viral doses and durations may be more appropriate. this setting to determine whether drug-resistant HSV infec-
Patients requiring suppressive therapy because of frequent tion is present. If antiviral testing is not available, patients
or exceptionally severe recurrence can be treated with acyclo- who continue to have positive cultures for HSV and no ev-
vir 400–800 mg two or three times daily, valacyclovir 500 mg idence of clinical response despite high-dose intravenous
twice daily or famciclovir 500 mg twice daily. These doses are acyclovir should be treated presumptively for drug-resistant
higher than those used for non-HIV-infected patients with infection with intravenous foscarnet.
HSV, but are endorsed by the CDC [102]. As mentioned
above, FDA-approved doses of valacyclovir should be used
cautiously in patients with HIV infection because of the
Suppressive antiviral therapy
observation of TTP/HUS with high-dose (8 g/day) therapy.
Intravenous acyclovir should be reserved for patients for HSV infection
with severe or extensive mucocutaneous HSV infection Many HIV-infected patients suffer from frequently recur-
and for patients with viral dissemination, visceral organ in- ring HSV infection or develop new HSV recurrences shortly
fection (e.g. brain, esophagus, eye), or neurologic compli- after antiherpes therapy is discontinued. These patients
cations (atonic bladder, transverse myelitis). Intravenous can often be managed with suppressive antiviral therapy
therapy may also be indicated for patients who require anti- [85–87, 90, 91, 96, 98, 101, 103]. As mentioned above,
viral chemotherapy but are unable to tolerate or absorb the CDC states that patients requiring suppressive therapy
oral antiviral therapy because of nausea, dysphagia, or pro- should initially be treated with a regimen of oral acyclovir
tracted diarrhea. The dose of intravenous acyclovir for pa- 400–800 mg two or three times daily, valacyclovir 1000 mg
tients with mucocutaneous HSV infection and normal twice daily, or famciclovir 500 mg twice daily [102]. In-
renal function is 15 mg/kg per day in three divided doses creased daily dosage may be necessary to control recur-
[85]. Patients with life-threatening HSV infection (encepha- rences, but gastrointestinal intolerance may limit the
litis, neonatal infection, disseminated infection), or visceral amount of drug that can be taken, Breakthrough recur-
organ involvement (esophagitis, proctitis), should receive rences that develop while the patient is receiving suppres-
intravenous acyclovir 30 mg/kg per day in three divided sive therapy may be controlled by increasing the daily
doses [86]. Treatment should last for a minimum of 10 days, suppressive dose. Breakthrough recurrences may or may
but longer therapy may be necessary if response to therapy is not represent the emergence of drug-resistant strains
slow. As noted above, the dose of intravenous acyclovir [104]. Patients who demonstrate a good response to sup-
should be adjusted in patients with impaired renal function pressive therapy at high doses may attempt a reduction
(Table 34.4). Oral treatment with acyclovir, valacyclovir, or in the daily suppressive dose [80, 105]. Some clinicians
famciclovir can be substituted for intravenous acyclovir once and patients choose to continue suppressive therapy longer
the patient is ready for hospital discharge. than FDA recommendations in order to avoid develop-
Because of their limited absorption, topical acyclovir and ment of symptomatic recurrences. Recurrences after dis-
topical penciclovir are much less effective than either oral continuation of antiviral suppression may be more severe
or intravenous therapy in the treatment of HSV infections than those experienced before starting suppression. Sup-
in AIDS. Although topical therapy slightly decreases the du- pressive therapy has been used continuously for over
ration of viral shedding in immunocompromised hosts 15 years without evidence of adverse reactions or cumula-
with mucocutaneous HSV infection, these non-systemic tive toxicity. Studies have shown that the incidence of
therapies do not reduce new lesion formation or the risk asymptomatic virus shedding is decreased while a patient
of dissemination. There is no added benefit to combining is on acyclovir suppression [106]. Individuals maintained
topical therapy with either oral or intravenous antiviral on long-term suppressive therapy should be cautioned,
446
however, that recurrences will likely develop after discon-

tinuation of therapy and that the first recurrence may be VARICELLA ZOSTER VIRUS
more severe than those previously experienced [78, 79,
83, 84]. In a study that evaluated immunocompetent, het-
Prior to widespread vaccination, primary VZV infection was
erosexual, HSV discordant couples, the use of valacyclovir
typically a childhood illness, with attack rates exceeding
500 mg daily as suppression reduced the risk of HSV trans-
90% in susceptible household contacts [116]. Primary
mission from the infected individual to the susceptible part-
VZV is now much less common since many children are
ner [107]. Acyclovir and famciclovir have also been shown
vaccinated against VZV, but primary infection still occurs.
to reduce asymptomatic HSV shedding and may also play a
Most adults with AIDS have either been previously infected
role in preventing transmission to sexual contacts [108]. Re-
or vaccinated with VZV and (as with HSV) are not suscep-
cent studies have shown that suppressive therapy for HSV re-
tible to primary infection.
sults in a reduction in HIV RNA, suggesting a possible
HIV-infected patients develop recurrent VZV infection
adjunctive role of treatment directed at HSV in patients
(zoster) more frequently than do age-matched immuno-
co-infected with both HSV and HIV [109–112].
competent hosts. A retrospective review of 300 HIV-infected
patients with Kaposi’s sarcoma revealed that 8% had at least
Management of drug-resistant HSV infection one prior attack of zoster, an incidence seven times greater
than expected by the age of the study group. Zoster also oc-
Since the wide availability of HAART, drug-resistant HSV
curs with a higher-than-expected frequency in HIV-infected
has become much less common. However, studies of acy-
individuals who appear otherwise healthy. Additionally,
clovir-resistant HSV infections in the pre-HAART era exam-
some HIV-infected patients develop more than one episode
ined the utility of alternate antiviral agents and treatment
of zoster in a relatively short period of time, an uncommon
regimens. Standard doses of intravenous or oral acyclovir
occurrence in immunocompetent hosts [117–121].
have no clinical benefit if the HSV isolate is resistant to
acyclovir (ID50 > 3.0 mg/mL) in vitro. Most acyclovir-
resistant strains isolated from patients with AIDS have Primary infection varicella
been TK-deficient and are therefore also resistant to vala-
cyclovir and famciclovir. These strains remain susceptible Varicella in immunocompetent children is usually a benign
to foscarnet, which does not require phosphorylation illness. However, adults are more likely to develop compli-
for activity. Foscarnet is effective in the treatment of cations during primary VZV infection. Viral dissemination
these TK-deficient, drug-resistant HSV infections, and fos- to visceral organs occurs in up to one-third of immuno-
carnet remains the treatment of choice in this setting competent adults with primary infection [116]. Although
[96–98]. The dosage of foscarnet used for the treatment most HIV-infected adults have been previously infected
of acyclovir-resistant HSV infections in AIDS patients is or vaccinated against VZV and are not susceptible to
40 mg/kg every 8 hours (with reduction in dose for renal primary infection [122], for those who are susceptible, a
dysfunction). protracted and potentially life-threatening illness could
Continuous-infusion acyclovir therapy has been effective follow [117].
in a few AIDS patients with severe acyclovir-resistant HSV
infection. Acyclovir has been administered at a dosage of
Herpes zoster
1.5–2.0 mg/kg/h for 6 weeks, and complete resolution of
acyclovir-resistant HSV proctitis has been reported [113]. Unlike primary VZV infection, herpes zoster is common in
Other investigational agents for possible treatment of drug- HIV-infected patients. The illness usually begins with radic-
resistant HSV infections include topical trifluridine [114], ular pain and is followed by a localized or segmental
topical cidofovir gel [101], and intravenous cidofovir [99]. erythematous rash covering 1–3 dermatomes. Maculopa-
As with many opportunistic infections in AIDS patients, pules develop in the dermatomal area, and the patient
there is a high incidence of recurrent HSV disease after suc- experiences increasing pain. The maculopapules progress
cessful treatment for drug-resistant HSV. Some relapses in to fluid-filled vesicles, and contiguous vesicles may be-
this setting have been due to drug-resistant strains, suggest- come confluent, with true bullae formation. In most
ing that these mutant viruses are capable of causing latency HIV-infected patients, the lesions remain confined to a
in the immunocompromised host. Chronic prophylaxis dermatomal distribution and heal by crusting and re-
with daily acyclovir, valacyclovir, famciclovir, or foscarnet epithelialization. Occasionally, however, widespread cuta-
can be considered in patients who are treated successfully neous or visceral dissemination may occur. Extensive cuta-
for drug-resistant HSV, although there are no data to con- neous dissemination may appear identical to primary
firm efficacy in this setting. Foscarnet-resistant strains of varicella. Visceral dissemination to lung, liver, or the CNS
HSV have been reported, raising concerns over the possible may produce a life-threatening illness [117–120, 123].
selection for multi-drug-resistant HSV with suppressive Reactivated infection involving the ophthalmic division of
therapy [100, 115]. the trigeminal nerve often results in infection of the cornea
447
(zoster ophthalmicus). The presence of vesicles on the tip of

Table 34.8 Management of VZV infections in AIDS
the nose is often associated with involvement of the eye. Al-
though healing without sequelae may occur, untreated
patients are at increased risk of developing anterior uveitis, CLINICAL TREATMENT
PRESENTATION
corneal scarring, and permanent visual loss [104]. Acyclo-
vir-resistant zoster is a rare complication, and has a peculiar Primary infection Acyclovir, 30 mg/kg/day IV, or
dermatomal wart-like, non-healing appearance [124]. (varicella) acyclovir 800 mg PO five times
daily, or valacyclovir 1 g PO three
Complications times daily, or famciclovir
500 mg PO. three times daily
Complications of VZV infection are common in immuno-
compromised patients and may cause prolonged morbidity Recurrent infection Acyclovir 30 mg/kg/day IV, or
and death. Dissemination of virus to the lung, liver, and (localized zoster) acyclovir 800 mg PO five times
CNS has been associated with a mortality rate of 6–17%. daily, or valacyclovir 1 g PO three
times daily, or famciclovir
Varicella pneumonia may occur during primary VZV infec-
500 mg PO three times daily
tion or during reactivated infection with visceral dissem-
ination in immunocompromised patients. Symptoms are Recurrent infection, Acyclovir 30 mg/kg/day IV
variable. Many patients develop only mild respiratory disseminated
symptoms, whereas others suffer from severe hypoxemia
and succumb to respiratory failure. Radiographic abnor- Severe infection caused Foscarnet 40 mg/kg IV three
malities are usually out of proportion to the clinical find- by acyclovir-resistant VZV times daily (not FDA-approved)
ings, with diffuse nodular densities on chest radiograph
Modified with permission from Drew WL, Buhles W, Erlich KS.
and occasional pleural effusions [116, 125]. Herpesvirus infections (cytomegalovirus, herpes simplex virus,
Encephalitis is a rare complication of VZV infection in varicella-zoster virus). How to use ganciclovir (DHPG) and acyclovir.
AIDS patients but may occur with or without visceral dis- Infect Dis Clin North Am 1988; 2:495–509.
semination. The illness begins 3–8 days after the onset of
varicella or 1–2 weeks after the development of zoster,
although occasionally AIDS patients have developed pro- Because VZV is less susceptible to acyclovir, valacyclovir,
gressive neurologic disease caused by VZV up to 3 months and famciclovir than HSV, the dosages of antiviral therapy
after the onset of localized zoster [123]. Headache, vomiting, used for treatment of VZV infections must be higher. Oral
lethargy, and cerebellar symptoms (ataxia, tremors, dizzi- acyclovir in the dosage used to treat HSV does not produce
ness) are prominent findings. Diagnosis based on clinical serum drug levels high enough to inhibit VZV in tissue cul-
criteria alone can be difficult, because other CNS infections ture, and is unlikely to be effective in patients with active
can present in a similar fashion. The diagnosis of VZV en- VZV infection. To treat VZV with oral acyclovir, a dose of
cephalitis is documented by finding VZV DNA by polymer- 800 mg five times daily should be prescribed [125, 129–
ase chain reaction or VZV antibody in CSF. Postherpetic 131]. This higher dose results in serum levels high enough
neuralgia, defined as prolonged pain following resolution to inhibit the growth of VZV in vitro, and this regimen has
of the cutaneous lesions from zoster, can be severe and been shown to modestly decrease the incidence and sever-
disabling [116, 126, 127]. ity of postherpetic neuralgia in non-immunocompromised
Although post-herpetic neuralgia is a more common oc- patients [127, 132].
currence in elderly individuals with zoster, HIV-infected Valacyclovir and famciclovir (discussed in detail above)
patients also may be at risk for this complication. Polyradi- are also effective agents against VZV and are suitable for oral
culopathy similar to that caused by CMV may rarely be due treatment of acute VZV infections. Because of their improved
to VZV. In these cases, VZV may be isolated from CSF. bioavailability, these drugs have the advantage of producing
higher serum drug levels than that achieved with oral acyclo-
vir. Treatment with valacyclovir 1 g three times daily [88], or
Management of VZV infection
famciclovir 500 mg three times daily [93, 133], reduces the
HIV-infected patients who develop primary or VZV infec- severity of acute VZV infection and appears to reduce the se-
tion or herpes zoster should be treated promptly with an verity and duration of postherpetic neuralgia [90, 126].
effective antiviral regimen (Table 34.8) [128]. Acyclovir, Although the favorable pharmacokinetics and higher serum
valacyclovir, and famciclovir are safe and effective in the drug levels achieved with these agents could be expected to
treatment of patients with primary or recurrent VZV infec- offer a therapeutic advantage as compared with oral acyclo-
tion. Treatment should be started as soon as the diagnosis is vir, no comparative trials evaluating clinical outcome in
made (preferably within 72 hours of rash onset), and HIV-infected patients have been reported.
should be continued until all the external lesions are dry As mentioned in the section on treatment of HSV, the
and crusted (usually 7–10 days). possible association between valacyclovir and TTP/HUS in
448
and-effect relationship has not been firmly established, the taken to ensure that an exposed individual is truly suscep-
standard FDA-recommended dosages should not be tible to infection (serologic testing could be performed if
exceeded [89]. there is no history of chickenpox in an exposed individual)
Most HIV-infected patients with dermatomal zoster are prior to administration of VZIG. VZIG is contraindicated in
not ill enough to require hospitalization, and can be treated individuals with a history of prior chickenpox and in those
on an outpatient basis with oral acyclovir, valacyclovir, or who have serologic evidence of previous VZV infection.
famciclovir. Intravenous acyclovir remains an available op- VZIG is not effective as treatment in individuals who pre-
tion, however, and has been shown to be effective in the sent with acute VZV infection.
treatment of patients with VZV infection. Treatment with Effective vaccines are licensed in the USA for prevention
intravenous acyclovir reduces the duration of viral shed- of primary VZV infection (varicella) and recurrent disease
ding, new lesion formation, the incidence of dissemina- (zoster) in non-immunocompromised hosts [138–140].
tion, and mortality rates in immunocompromised hosts Both vaccines contain the live, attenuated OKA strain of
with VZV infection [129, 134]. Intravenous acyclovir VZV, although the zoster vaccine contains higher titers of
should be prescribed to patients with disseminated disease virus than that found in the varicella vaccine. The efficacy
or visceral organ involvement, and for those who are un- and safety of these vaccines in HIV-infected patients has
able to tolerate oral therapy. The dosage for patients not been studied, and current CDC guidelines recommend
with VZV infection is 30 mg/kg per day in three divided the varicella vaccine for HIV-infected children greater than
doses (with dosage adjustments for renal dysfunction; see or equal to 8 years of age who have CD4 count 200 cells/
Table 34.4). Treatment should be continued for at least mm3 (percentage > 15%) and no evidence of varicella im-
7 days or until all external lesions are crusted. The decision munity. Vaccinating younger children is also suggested by
whether to hospitalize a patient for intravenous acyclovir many authorities. Vaccinating HIV-infected adults to pro-
must be based on several factors, including the severity tect against herpes zoster should be done with caution,
of the infection, the immune status of the host, and since the zoster vaccine is not licensed for use in HIV-
whether visceral or cutaneous dissemination has occurred. infected patients and there is the theoretical risk of dissem-
Treatment with steroids to prevent post-herpetic neuralgia ination in immunocompromised hosts. A small number of
remains a controversial topic in a non-immunocompromised patients receiving the varicella vaccine have developed a
population, but recent studies have failed to document the varicella-like rash after administration [141], and this rash
efficacy of this practice [135, 136], although the general qual- contains live virus that is transmissible. HIV-infected pa-
ity of life may be improved. Because of the potential for fur- tients who receive either vaccine and develop a varicella-
ther immunosuppression and increasing the risk of VZV like rash following vaccination should be treated with
dissemination in HIV-infected patients, steroids should not one of the effective antiviral drugs discussed above. Because
be routinely prescribed for this indication in this population. the vaccine strain produces latency after administration,
vaccinated individuals remain at risk to develop zoster later
in life [138, 139, 142].
Treatment of drug-resistant
VZV infection
Drug-resistant VZV has been reported in patients with CONCLUSION
AIDS. These patients may present with atypical-appearing
cutaneous lesions that shed VZV intermittently despite on-
Herpesvirus (CMV, HSV, VZV) infections are common in
going high-dose antiviral therapy. All strains have been iso-
AIDS patients and often exist in a chronic or progressive
lated from patients previously treated with acyclovir for
form. Oral valganciclovir prophylaxis can reduce the risk
recurrent VZV or HSV infection, and these strains may be
of developing CMV disease. CMV retinitis occurs in up to
resistant to acyclovir, valacyclovir, and famciclovir by defi-
40% of AIDS patients and can be treated effectively with
ciency of the enzyme thymidine kinase [137]. Foscarnet has
ganciclovir, valganciclovir, or foscarnet. Perianal ulcers,
been shown to be effective in small studies, but remains in-
proctitis, and other clinical syndromes caused by HSV
vestigational for this purpose [124]. The intravenous dos-
can be treated effectively with acyclovir, valacyclovir, or
age used has been 40 mg/kg three times daily.
famciclovir. These drugs can be administered daily to pre-
vent HSV recurrences. Herpes zoster in a young adult may
be the first indication of immune deficiency resulting from
Prevention of VZV infection
HIV. Because VZV is less susceptible to antiviral drugs than
Varicella-zoster immune globulin (VZIG) is effective in pre- HSV, higher doses of acyclovir, valacyclovir, or famciclovir
venting severe primary VZV infection in susceptible (i.e. se- are required to achieve inhibitory blood levels. HSV and
ronegative) immunocompromised hosts if administered VZV resistant to acyclovir and related drugs are usually
within 96 hours of the time of exposure. Care should be susceptible to foscarnet.
449
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454
Chapter | 35 |
HIV-associated malignancies
Ronald T. Mitsuyasu
INTRODUCTION EPIDEMIOLOGY OF HIV-ASSOCIATED

MALIGNANCIES
Malignancies have been a well-recognized manifestation of
AIDS since the beginning of the epidemic. The increased inci- The introduction of HAART in 1996 has not only extended
dence of aggressive B-cell non-Hodgkin’s lymphoma and life and reduced the incidence of AIDS in HIV but has also
Kaposi’s sarcoma led to one of the first description of this resulted in a change in the spectrum of HIV-associated
new disease in 1981 [1, 2]. Cancers considered to be AIDS- malignancies. Several large epidemiologic studies have
defining by the US Centers for Disease Control and Prevention demonstrated a change in the distribution of cancers
(CDC) are listed in Table 35.1, and include Kaposi’s sarcoma seen in HIV in Western countries with widespread use of
(KS), aggressive B-cell non-Hodgkin’s lymphoma (NHL), pri- ART [3–6]. An assessment by the NCI Cancer Epidemiology
mary CNS lymphoma (PCNSL), and invasive squamous car- and Genetics Branch using data from the US cancer and
cinoma of the cervix. The relative risks of these neoplasms HIV match registry identified 472,378 individuals with
are listed, along with several other malignancies for which HIV and cancer from 1980 to 2006 [7]. Using non-
there appears to be a relationship with HIV disease based parametric competing-risk methods, the cumulative inci-
on the higher relative risk among HIV-infected patients. It is dence of cancer was estimated across 3 calendar periods
important to recognize, however, that while HIV-induced (1980–9, 1990–5, and 1996–2006). Measured at 5 years af-
immunodeficiency clearly plays a role in the development ter AIDS onset, the cumulative incidence of ADC declined
of these cancers, many are also associated with oncogenic from 18% in 1980–9, to 11% in 1990–5, to 4.2% in 1996–
viruses. Some, such as squamous conjunctival cancer and leio- 2006. This decline was seen for both KS and for NHL. The
myosarcoma, are less commonly seen in Western countries or cumulative incidence of NADC increased during this same
are seen in certain subpopulations, such as in children. time, with the incidence of specific cancers such as anal
It has been suggested that loss of immune surveillance cancer, Hodgkin’s lymphoma, and liver cancer increasing
may be the most important factor in the pathogenesis of steadily over this period. The incidence of lung cancer
neoplasms with viral etiologies. The listing of suspected vi- increased initially from 0.14 to 0.32% and has remained
ral pathogens associated with cancers in HIV (Table 35.1) stable in the post-HAART era.
would suggest that this hypothesis is correct, although Possible reasons for this change in cancer distribution
the exact mechanism by which these viruses give rise to may include: the reversal of HIV-induced declines in
neoplasms has not been fully elucidated. CD4 count with ART, resulting in decreased incidence
More recently, the incidence of non-AIDS-defining cancers of KS and NHL, which are more closely associated with
(NADCs) has increased in the HIV-infected population, while immunosuppresion; the enhanced longevity of individ-
the incidence of AIDS-defining cancers (ADCs), specifically KS uals living with immune impairment; the continued ex-
and NHL, has decreased. These NADCs now account for a sig- posure to carcinogenic substances such as tobacco and
nificant proportion of deaths and morbidity in HIV in the era alcohol; decreased immune surveillance and increased
of highly active antiretroviral therapies (HAART, or ART). immune activation; and perhaps increased susceptibility
455
types. About 30% of patients have intermediate-grade,

Table 35.1 Relative risks and viral associations
diffuse, large, B-cell lymphoma (DLBCL), and 10% present
for neoplasms associated with HIV infection
with more unusual form of lymphoma including low-grade
B-cell lymphomas, anaplastic large-cell lymphomas, plasma-
NEOPLASM RELATIVE VIRAL
blastic lymphomas, and rare T-cell lymphomas [9].
RISK ASSOCIATION
The pathogenesis of these lymphomas is not fully under-
Kaposi’s sarcoma >10,000 KSHV stood and may involve a number of different pathogenic
mechanisms. Pathogenesis may involve interactions be-
B-cell NHL 100–400 EBV, KSHV tween host factors, HIV infection, chronic B-cell antigenic
stimulation, and cytokine dysregulation. Between 40 and
Cervical carcinoma 2.9–4 HPV
60% of HIV-associated lymphomas are associated with
Anal carcinoma 14 HPV the Epstein–Barr virus (EBV) [10]. EBV is more commonly
associated with large-cell lymphomas and with Burkitt-type
Hodgkins’ lymphoma 7–11 EBV lymphomas. It is commonly believed that the excessive
B-cell stimulation associated with HIV infection results in
Leiomyosarcoma 10,000 EBV
the proliferation of antigen-selected B-cell clones [9, 11],
Hepatoma 6–9 HBV, HCV with subsequent genetic changes leading to the evolution
of a transformed clonal lymphoma. The molecular patho-
Squamous conjunctiva 13 HPV genesis of AIDS-NHL is characterized by distinct genetic
Oral and head/neck 2–6 HPV
pathways, including chromosomal rearrangements of
squamous carcinoma c-MYC and BCL6 in AIDS-associated Burkitt lymphoma
and AIDS-associated diffuse large B-cell lymphoma, respec-
Merkle cell carcinoma 2.3–13.4 MCV tively [9].
KSHV, Kaposi’s sarcoma-associated herpes virus, also known as

human herpesvirus-8 (HHV-8); EBV, Epstein–Barr virus; HPV, human Clinical management
papilloma virus; HBV, hepatitis B virus; HCV, hepatitis C virus; MCV,
Merkle cell virus. Most patients with HIV-associated lymphoma present with
advanced-stage and extranodal disease. Two-thirds of pa-
tients have stage IV disease at the time of presentation,
and 90% have extranodal lymphoma at the time of diagno-
to cancer-inducing genetic mutations or to environmen- sis [12]. About 80% present with B symptoms, consisting of
tal toxins. fever, drenching night sweats, and/or weight loss. Menin-
geal involvement at the time of diagnosis has been ob-
served in 3–20% of patients. Although in the pre-HAART
era, the median CD4 count at the time of diagnosis had
LYMPHOPROLIFERATIVE DISEASE
been reported to be in the range 100–180 cells/mm3, there
has been a recent trend toward earlier presentation, in
Non-Hodgkin’s lymphoma patients with higher CD4 counts and fewer HIV-related
complications prior to diagnosis.
NHL remains one of the most common AIDS-defining con- Decreased survival is associated with CD4 counts < 100
ditions, occurring in approximately 16% of all new cases cells/mm3, age > 35 years, Karnofsky performance status
of AIDS [8]. All age groups and all groups at risk for HIV < 70%, advanced stage IV disease, elevated lactate dehydro-
infection are equally likely to develop lymphoma. Systemic genase, higher International Prognostic Index (IPI) scores
NHL, PCNSL, and primary effusion lymphoma (PEL) have (2–3), and certain subtypes of lymphoma (e.g. PCNSL,
all been described in patients with HIV infection. PEL, and perhaps subtypes of DLBCL, such as activated
B-cell phenotype) [13–17].
In the pre-HAART era, treatment outcomes were poor
Systemic NHL regardless of treatment choice, with complete response
Although the risk of lymphoma has decreased significantly rates of approximately 50%, and median survivals in the
in patients treated with ART, this decline has been smaller 5- to 8-month range [12, 18].
than that seen with KS or various opportunistic infections, Since the introduction of ART in 1996, several studies
resulting in a relative increase in the occurrence of lym- have demonstrated significant improvement in clinical
phoma as the initial AIDS-defining illness. outcome in ART-treated patients compared to historical
Most AIDS-related lymphomas are of high-grade B-cell type. controls. Furthermore, patients experiencing virologic fail-
Approximately 60% are immunoblastic lymphomas or small ure on ART had poorer outcomes than those being treated
non-cleaved lymphomas, including Burkitt or non-Burkitt with suppressive ART. These findings have made ART a
456
Chapter | 35 | HIV-associated malignancies
critical component of the management of patients with Hematopoietic cell transplantation

HIV-associated NHL; it is now recommended that ART for HIV-NHL
be administered concurrently in patients receiving chemo-
therapy for HIV-NHL [19]. Several reports have suggested the potential value of high-
dose chemotherapy with autologous stem cell transplant.
In the largest of these studies, 20 (subsequently updated
Infusional chemotherapy to 29) patients with HIV-associated lymphoma who either
The use of infusional combination chemotherapy regimens had relapsed or had refractory disease or high-risk first
to increase dose intensity of chemotherapy and to reduce remission received high-dose chemotherapy with autolo-
toxicities has been evaluated in both HIV-infected and gous stem cell infusion [25]. Mobilization and stem cell
HIV-uninfected individuals with NHL. Three different infu- collection were successful in all patients. There was no en-
sional regimens have been studied in the HIV-NHL popula- graftment failure, although one patient who was receiving
tion. Sparano and co-workers. were the first to study the zidovudine had delayed engraftment. Two patients who
infusional regimen CDE, in which cyclophosphamide, were not compliant with prophylaxis developed Pneumo-
doxorubicin, and etoposide are infused over 96 hours every cystis pneumonia. Two developed disseminated herpes
28 days [20]. This trial included patients who were treated zoster, one developed cytomegalovirus (CMV) retinitis,
both in the pre- and post-HAART eras, and demonstrated and two developed asymptomatic CMV viremia. All of
a 2-year overall survival of 47% in the post-HAART group these patients responded to therapy. With a 31.8-month
with no treatment-related mortality compared with 30% median follow-up time, 17 of the patients remained in re-
in the pre-HAART-era patients, who also had a 10% treat- mission. Progression-free survival was 85%, and overall
ment-related mortality. survival was 85% for the entire group. Other small series
However, the regimen that has generated the greatest have demonstrated similarly effective stem cell mobiliza-
interest is EPOCH. In this regimen, doxorubicin, vincris- tion and collection, lack of unexpected toxicities, and sig-
tine, and etoposide are administered as a continuous nificant long-term disease-free survival times [26–29].
96-hour infusion, and cyclophosphamide, dose adjusted A case-control study comparing 53 HIV-infected patients
for initial CD4 count, is administered as a bolus intravenous with lymphoma who underwent stem cell transplantation
infusion on day 5. In a phase II National Cancer Institute to HIV-uninfected matched controls demonstrated an over-
trial using this regimen, the overall complete remission rate all survival of 61.5% (95% CI 47–76%) for HIV-infected
was 74%, and at 53 months of follow-up, the disease-free patients and 70% for controls (p ¼ NS), with a median
survival was 92%, with an overall survival rate of 60%. It follow-up of 30 months [30]. In view of this experience,
should be noted that 59% fell into the intermediate-high high-dose chemotherapy with autologous stem cell trans-
or high of risk groups by the IPI, 41% had CD4 counts plant may be considered the best treatment option for
100 cells/mm3, and none received ART until chemotherapy individuals with refractory or relapsed HIV-NHL [31].
had been completed [21].
Primary CNS lymphoma
Use of rituximab PCNSL usually occurs in severely immunocompromised
Rituximab is a humanized monoclonal anti-CD20 antibody patients with advanced HIV infection, the vast majority
currently in widespread use for treatment of a variety of of whom have CD4 counts < 50 cells/mm3. The incidence
B-cell non-Hodgkin’s lymphomas. Its use in combination of PCNSL has fallen significantly since the introduction of
with CHOP chemotherapy for treatment of diffuse large B- ART [32].
cell lymphoma in HIV-uninfected patients became standard PCNSL in the setting of HIV infection is universally asso-
of care after publication of a randomized study demonstrat- ciated with Epstein–Barr virus [11], which can be useful di-
ing a survival advantage for patients receiving CHOP plus agnostically. EBV is rarely detected in the cerebrospinal
rituximab versus CHOP alone [22]. Initial trials of rituximab fluid (CSF) of HIV-infected patients without PCNSL, but
with CHOP from other groups raised concerns about it is commonly detected in the CSF of patients with this tu-
the risk of treatment-related infectious deaths that occurred mor. In one study EBV DNA was detected by nested poly-
in a higher proportion of rituximab-receiving versus non- merase chain reaction (PCR) in the CSF in 7 of 8 patients
receiving individuals [23]. Most of these deaths occurred with PCNSL diagnosed by brain biopsy (87.5% sensitivity),
in patients with baseline CD4 counts <50 cells/mm3 [23]. and in none of the 11 controls with non-lymphomatous
A larger subsequent study of EPOCH with either concurrent mass lesions (100% specificity). A total of 21 AIDS patients
or sequential rituximab with use of concurrent ART, prophy- with or without neurological disorders but without focal
lactic antibiotics, and white cell growth factor conducted by brain lesions were PCR-negative [32]. In another study,
the AIDS Malignancy Consortium has shown a low inci- EBV DNA was detected in the CSF from 16/20 (80%) pa-
dence of treatment-related infections and high response tients with PCNSL [33]. In combination with imaging stud-
rates and disease-free survivals [24]. ies, EBV PCR may obviate the need for brain biopsy [34].
457
Most HIV-PCNSLs are characterized as diffuse large B-cell Other lymphoproliferative disease
lymphomas and tend to be multifocal in the brain. Confu- in HIV infection
sion, memory loss, lethargy, and focal neurologic findings
are the most frequent presenting symptoms and signs. Primary effusion lymphoma (PEL)
Historically, prognosis for these individuals has been
Primary effusion lymphoma (PEL) accounts for < 5% of
poor. Palliative whole-brain radiotherapy has been used,
all AIDS-related lymphomas. The disease is characterized
with survival of 1–3 months. Most patients died from
by presentation as a body cavity effusion. Almost all of
opportunistic infections. High-dose methotrexate with leu-
these cases are associated with Kaposi’s sarcoma-associated
kovorin is now used alone or in combination with radio-
herpes virus (KSHV), also known as human herpesvirus-8
therapy, especially since the advent of ART, which seems
(HHV-8), and EBV has been identified in the vast majority
to make such therapy more tolerable. A pre-ART study in
of cases. These lymphomas generally lack B- or T-cell
PCNSL patients with a median CD4 count of 30 cells/
markers, although the presence of immunoglobulin gene
mm3 found a 50% complete response rate and a median
rearrangements in most cases suggests a B-cell origin. Most
survival of 10 months [35]. Data suggest that immune re-
patients present with advanced HIV disease and severe im-
covery associated with ART can dramatically improve sur-
munodeficiency [45]. As a result, complete response rates
vival. A retrospective review of 111 patients with PCNSL
using CHOP-like regimens have been <50%, and overall
found that the use of ART and radiotherapy were each as-
survival is in the 3- to 6-month range [45, 46]. More inten-
sociated with significantly improved survival [36].
sive chemotherapy regimens with ART may lead to better
outcomes.
Hodgkin’s lymphoma
Plasmablastic lymphoma
Hodgkin’s lymphoma is not an AIDS-defining condition.
However, multiple cohort studies have demonstrated an Although this disorder has been observed in immunocompe-
increased risk of Hodgkin’s lymphoma in HIV-infected tent individuals, it has been reported predominately in
patients [2, 37]. HIV-associated Hodgkin’s lymphoma patients with HIV disease [47]. These lymphomas are typi-
has largely been associated with a predominance of two cally negative for B- and T-cell markers and generally have a
unfavorable subtypes: lymphocyte-depleted and mixed- phenotype more typical of mature plasma cells. Morpholog-
cellularity, although nodular sclerosing and lymphocyte ically, the malignant cells appear most like plasmablasts but
predominant subtypes also occur [38–40]. Clonal EBV carry a phenotype more typical of mature plasma cells. Mono-
is identified in 80–100% of cases associated with HIV clonal gammopathy is not commonly noted, helping to dis-
infection [11]. tinguish this entity from solitary plasmacytoma. Historically,
Early clinical trials of standard chemotherapy regimens these lymphomas have been associated with a poor prognosis
for HIV-associated Hodgkin’s lymphoma showed poor and a median survival of approximately 9 months, although
long-term survival, with treatment being frequently com- use of ART has extended life expectancy [48, 49].
plicated by severe and prolonged myelosuppression [41].
Significant improvement in tolerability and clinical out-
come in patients with HIV-associated Hodgkin’s lym-
Multicentric Castleman’s disease
phoma have been documented since the advent of ART This lymphoproliferative disorder characteristically presents
[38]. Retrospective evaluation of 108 patients from a single with polyclonal hypergammaglobulinemia, generalized
institution demonstrated improvement in complete re- lymphadenopathy, hepatosplenomegaly, constitutional sym-
sponse rate from 64.5 to 74.5% and improvement in 2-year ptoms, and often autoimmunehemolytic anemia [50]. Lymph
disease-free survival from 45 to 62% (p ¼ 0.03) in the years node histologic findings include perifollicular vascular prolif-
following introduction of ART [42]. eration and germinal center angiosclerosis. Overexpression of
The best chemotherapy option for patients with HIV-HL IL-6 appears to be the hallmark of this disease [51]. The disease
has not yet been established. With the use of ART, it does ap- is associated with HHV-8 infection of the B-cells in the mantle
pear that standard full-dose chemotherapy regimens such as zone of the lymph node [52]. Natural history can vary from an
ABVD and BEACOPP can be given and are well tolerated indolent, waxing and waning course to one that is extremely
in this patient population [43, 44]. It is currently recom- aggressive and may transform to non-Hodgkin’s lymphoma
mended that individuals with HIV-HL receive the same treat- in some cases. Based on several small series, rituximab with/or
ments that are used in the general population based on without etoposide seems to give the best responses [53–55].
the staging of disease and other prognostic factors. An inter- Although some transient responses to anti-herpesvirus agents
group study of ABVD, with randomization to continue ther- have been reported, overall results with these agents have been
apy or intensify to BEACOPP in those with persistent disease disappointing [54]. Standard lymphoma chemotherapy regi-
after 2 cycles of therapy, is currently being conducted in mens have generally been associated with relatively transient
HIV-infected and HIV-uninfected patients with HL. responses and poor long-term outcome [56, 57].
458
alone. In patients who have never taken ART before, the

KAPOSI’S SARCOMA overall response rate of KS to ART alone is approximately
60% after 6 months (11% complete remission) and in-
creases to 75% at 24 months, with 60% achieving complete
Pathogenesis remissions [61]. Multivariate analysis demonstrated that
KS was one of the first opportunistic disorders recognized reduction of KSHV viral load to undetectable levels and
as an AIDS-defining condition. AIDS-related KS is seen in improvement in CD4 count correlated with KS response
all HIV risk groups worldwide, although most cases in [62, 63].
the United States have occurred in gay or bisexual men. It is most important, however, to note that while ART
The epidemiology of KS has always suggested a sexually alone may be sufficient therapy for individuals with limited
transmissible etiology and KSHV (HHV-8) has been iden- cutaneous or mucocutaneous disease, it is not adequate for
tified in virtually all tissue specimens from individuals with those with more advanced or symptomatic disease. In a
KS, whether HIV-infected or not [58]. study of moderate to advanced KS, those receiving liposo-
The pathogenesis of KS is believed to involve interactions mal doxorubicin in addition to ART had a markedly better
between KSHV/HHV-8, HIV, and immune dysregulation response rate at 48 months than did those on ART alone
[59]. KSHV is a lymphotropic gamma-2 herpesvirus whose (76 versus 20%) [64].
seroprevalence correlates with the incidence rates of clinical While ART is recommended for all HIV-infected patients
KS in various populations. The viral genome encodes a va- with KS, individuals with advanced and/or symptomatic KS
riety of genes that are homologs of normal human cell cycle should receive some form of local or systemic therapy.
regulatory and angiogenesis proteins such as vCyclin D, Standard therapeutic approaches are summarized below.
vbcl-2, basic fibroblast growth factor (bFGF), vascular en-
dothelial growth factor (VEGF), and a G protein-coupled
receptor that are capable of inducing angiogenesis in vitro Local therapies
[60]. HIV may directly induce production of Tat protein, These are generally appropriate for treating unsightly or
which in combination with bFGF can induce KS-like le- locally symptomatic lesions. They may be used in those
sions. There is also evidence that platelet-derived growth individuals with limited disease as an adjunct to ART. Surgical
factor receptor (PDGFR) may play a role in inducing KS removal, cryotherapy, laser, local radiation therapy, local
spindle cell growth and inducing angiogenesis by upregu- low-dose intralesional chemotherapy or topical 9-cis-retinoic
lating production of VEGF [60]. acid gel (aliretinoin 1%) have all been use with good local
The clear association of KS with immunodeficiency in responses.
HIV, in old age, and in transplant recipients, and its regres-
sion with restoration of better immune function, provide
evidence of the close association of this tumor with under- Radiotherapy
lying immunodeficiency.
At one time radiotherapy was the mainstay of local therapy.
Used as a single 80 Gy or equivalent fractionated dose, it is
Clinical presentation an active treatment modality. It is less commonly used now
due to local toxicities when administered over large cutane-
AIDS-KS typically presents at multiple mucocutaneous sites. ous areas, resulting in loss of skin elasticity, discomfort, and
Lymphatic and visceral sites of disease have been common occasionally contractures. When used, it should be admin-
historically, with up to 40% of ART-untreated individuals istered only to small fields for treating localized mucocuta-
having gastrointestinal involvement at diagnosis. GI KS is neous lesions. Lower fractionated doses are associated with
usually asymptomatic but occasionally may cause vague ab- less-significant long-term toxicities. Doses of 15 Gy for oral
dominal pain, bleeding, or obstruction. Pleuropulmonary lesions, 20 Gy for lesions involving eyelids, conjunctiva,
disease is seen in some patients and is usually associated and genitals, and 30 Gy for cutaneous lesions have been
with cough, bronchospasm, dyspnea and eventually hypox- shown to be sufficient to produce shrinkage of the tumor
emia. The dramatic decline in the incidence of epidemic KS and good palliation of the symptoms [65].
since the introduction of ART has resulted in fewer individ-
uals presenting with advanced, symptomatic disease.
Alitretinoin gel
Alitretinoin gel (1%): a randomized phase III vehicle-
Clinical management
controlled study of topical administration of this agent
In addition to reducing the incidence of KS, there is strong demonstrated a 37% response rate compared with 7% in
evidence for an antitumor effect of ART in those with estab- vehicle control patients [66]. It was particularly useful for
lished disease. Multiple case reports and small series have facial lesions, although often associated with excessive local
documented significant regression of KS after ART therapy irritation.
459
Intralesional vinblastine associated with response rates as high as 70% in previously

treated patients with advanced KS [68]. The use of oral etopo-
Generally used as dilute injected solution, this cytotoxic
side has been recommended by some due to its ease of admin-
agent is a vesicant useful for treating small cosmetically
istration. In a study from Brazil, 21 patients received daily oral
unsightly mucocutaneous lesions. There is pain associated
etoposide at a dose of 20 mg/m2 every 8 hours for 7 days every
with injection and several injections may be required.
21 days. This was associated with an objective response rate of
It often results in residual hyperpigmentation.
83% [69]. Paclitaxel is associated with a 44% incidence of al-
opecia, making it less favorable than liposomal doxorubicin
Cryotherapy as first-line therapy. It is also associated with significant mye-
Liquid nitrogen cryotherapy is commonly used by derma- losuppression. In a randomized study of oral etoposide com-
tologists for local treatment of small lesions. Multiple ther- pared to radiotherapy or 3-drug combination chemotherapy
apies may also be required with this modality, which tends in Zimbabwe, oral etoposide had better improvement in qual-
to leave a hypopigmented area following therapy. ity of life scores, although there were no differences in tumor
responses or survival [70]. Vinorelbine has also been evalu-
ated for KS treatment and was associated with a 43% response
Systemic therapy rate in a group of 35 individuals with KS refractory to a variety
Chemotherapy of prior chemotherapy regimens [71]. A small retrospective
study of gemcitabine therapy in previously treated patients
Cytotoxic therapy is still the most effective treatment for with Kaposi’s sarcoma in Kenya demonstrated good clinical
advanced, symptomatic and visceral disease (Table 35.2). responses with minimal toxicities [72].
First-line standard of care is liposomal doxorubicin (Doxil),
which had a higher response rate than a standard three-drug
combination (ABV) in a randomized phase III trial [67]. Ex-
Interferon-a
cept for some myelosuppression and occasional skin rash Interferon-a was documented to have activity in HIV-KS early
and desquamation, it is a well-tolerated agent with a low inci- in the AIDS epidemic. The debilitating constitutional toxic-
dence of gastrointestinal toxicity and rare alopecia. For pa- ities associated with high-dose interferon limited its use. How-
tients who are poorly responsive to or relapse after lipsomal ever, it may be effective at lower doses (1 million units daily by
doxorubicin (Doxil) therapy, paclitaxel (Taxol) has been subcutaneous injection) when combined with ART [73]. This
Table 35.2 Cytotoxic therapy for Kaposi’s sarcoma
AGENT DOSE RESPONSE (%) TOXICITY

2
Liposomal 10–20 mg/m every 21 days 46–59 Neutropenia; cardiomyopathy;
doxorubicin hand–foot rashes
Paclitaxel 100 mg/m2 every 14 days 59–79 Neutropenia; myalgias; neuropathy; alopecia
Vinorelbine 30 mg/m2 every 14 days 43 Neutropenia; neuropathy
Etoposide 50 mg every day for 7 days, 83 Neutropenia; alopecia

every 21 days
Bleomycin 15 mg/m2 23 Pulmonary fibrosis; peripheral neuropathy

every 21 days
Vincristine 2 mg
Doxorubicin 20 mg/m2 25 Neutropenia; pulmonary fibrosis,

neuropathy; cardiomyopathy
Bleomycin 10 mg/m2 every 14 days
Vincristine 1 mg
Gemcitabine 1 g/m2 every 14 days 48 Neutropenia, alopecia
460
may be an option for patients who have limited disease that is Screening and diagnosis
unresponsive to ART and who do not require chemotherapy.
Responses to this agent are associated with higher CD4 Because the majority of women with cervical dysplasia and
counts. Those with a CD4 count of < 100 cells/mm3 are early invasive cervical cancer are asymptomatic, cytologic
unlikely to respond. screening should be performed frequently. The role of newly
developed HPV vaccines in preventing HPV infection or dis-
ease progression in HIV-infected women is currently under in-
vestigation, although its clear efficacy in non-HIV-infected girls
Investigational agents and young women suggests that its use in the HPV-uninfected,
Several approaches to therapy based upon the pathogenesis HIV-infected population may be important [79, 80].
of the disease have also been studied in recent years. The Current screening recommendations call for women
AIDS Malignancy Consortium is actively investigating a with HIV to undergo pelvic examinations and cytologic
number of these agents, and referral to local network trials screening every 6 months during the first year after HIV di-
sites is encouraged (http://www.aidscancer.org) [74, 75]. agnosis and annually thereafter if the test results are normal
[81]. Pap smears demonstrating cervical SIL should be fol-
lowed by colposcopy and biopsy. Although abnormalities
are sometimes missed by relying solely on cytologic screen-
CERVICAL CANCER ing, the routine use of colposcopy has not yet been estab-
lished for this population. For women who have a history
Cervical cancer has been recognized as an AIDS-defining of cervical SIL, more frequent evaluations and screening are
malignancy since 1993. In some women cervical cancer indicated. Since these women are at high risk for recurrence
may be the first indication of HIV infection. Women consti- or development of lesions in other areas of the genital tract,
tute the fastest-growing group of new AIDS cases in much of post-therapy monitoring with repeat colposcopy is war-
the world. The primary risk factor for HIV infection in these ranted. In resource-limited settings, visual inspection with
individuals is heterosexual transmission, often from a part- acetic acid (VIA) has been shown to be a practical and ef-
ner whose HIV status was unknown to the woman. fective way of screening for high-grade cervical neoplasia,
Cervical intraepithelial neoplasia (CIN) is also seen with on a par with or better than cervical cytology [82, 83].
increased frequency in HIV infection. These premalignant For women with invasive carcinoma, complete staging
lesions, also known as squamous intraepithelial lesions should be undertaken, including pelvic examination, CT
(SILs), have been associated with human papillomavirus and possibly PET scanning of the pelvis and abdomen,
(HPV) infection, particularly those subtypes with high chest X-ray, and screening laboratory testing for hepatic
oncogenic potential, e.g. serotypes 16, 18, 31, 32, and 35. and bone disease.
Epidemiology Treatment
In high-prevalence areas for HIV, among women younger The staging classification for cervical carcinoma as adopted
than age 50 with cervical cancer, up to 19% were found to by the American Joint Committee on Cancer (AJCC) or the
be HIV-infected [76]. Similarly, HIV-infected women have International Federation of Gynecology and Obstetrics
up a 10-fold higher risk of abnormal cervical cytology on (FIGO) also applies to AIDS patients.
Pap testing. Prevalence of abnormal cytology among HIV- Cervical dysplasia in HIV-infected women is often of
infected women in some parts of the world has ranged from higher histologic grade (CIN 2–3), and should be treated
30 to 60%, and cervical dysplasia incidence increases with with ablative therapy. Cryotherapy, laser, cone biopsy, and
declining CD4 count. In the USA, invasive cervical cancer and loop electrosurgical excision procedures (LEEP) have
was found in 1.3% of women with AIDS; this cancer consti- all been used successfully to treat preinvasive disease
tutes up to 4% of AIDS-defining illnesses in women [77]. in HIV-infected patients. Short-term recurrence rates of
40–60% have been reported. In resource-limited settings
use of cryoablation at the time of screening allows for local
treatment of abnormal-appearing lesions and helps reduce
Etiology
loss to follow-up when it is difficult to refer such women
There is abundant evidence that HPV infection is related to for more extensive colposcopy and biopsy [84].
malignant and premalignant lesions in the genital tract. Im- For invasive cervical carcinoma, the same principles that
munosuppression may allow more rapid development of guide the management of the immunocompetent patient
both in situ and invasive disease in the setting of infection with cancer should be utilized in HIV-infected women. De-
with oncogenic HPV strains. Infection with more than one cisions about surgical intervention should be based on on-
serotype of HPV and lower CD4 counts have been associated cologic appropriateness rather than HIV status. As most
with a higher incidence of cervical cancer and CIN [78]. HIV-infected women with cervical cancer present with
461
advanced disease, radiation therapy is often indicated. For antibody, cetuximab, are being conducted to determine if
patients with advanced, stage III–IV disease, a combination the addition of this agent to standard chemoradiotherapy
of irradiation and concurrent cisplatinum-based chemo- may result in longer disease-free survival in HIV-infected
therapy is often used. At this time there is no evidence and HIV-uninfected individuals.
to suggest that treatment of cervical carcinoma in HIV-
infected women is less effective than HIV-uninfected
women with similar stage disease [76]. NON-AIDS-DEFINING MALIGNANCIES
With improved HIV therapy, patients are living longer and

ANAL CANCER are developing other cancers that are not AIDS-defining.
A number of reports from around the world now show that
other cancers are occurring with greater frequency in HIV-
Although anal cancer is not currently an AIDS-defining ill-
infected individuals [5, 89, 90]. These include: Hodgkin’s lym-
ness, the incidence of this cancer is increasing in the popu-
phoma, anal cancer, liver cancer, head and neck cancers, lung
lation at risk for HIV infection [84]. The incidence of anal
cancer, non-melanomatous skin cancers, germ cell tumors,
cancer in homosexual men in a San Francisco study was es-
myeloid and lymphoid leukemias, squamous cell cancers of
timated at between 25 and 87 cases per 100,000, compared
various organs, and leiomyosarcoma in pediatric patients.
to 0.7 per 100,000 in the general male population.
Rates of these NADCs suggest that these cancers are now occur-
ring at a higher frequency overall than the ADCs in the devel-
Etiology oped world. Interestingly, the rates of some of the more
common cancers, such as breast, prostate, and colon cancer,
Anal intraepithelial neoplasia (AIN), also known as anal
do not appear to be higher in the HIV-infected population.
squamous intraepithelial lesion (SIL), is generally associated
with oncogenic serotypes of HPV, especially 16, 18, 31, 32,
33, and 35. Cytologic abnormalities have been noted in as Clinical features
many as 40% of patients with HIV, especially those with In general, in HIV-infected individuals NADC seem to pre-
CD4 counts < 200 cells/mm3 [85]. sent at a younger age, with more advanced-stage disease at
diagnosis and with a higher likelihood of relapse after defin-
Screening itive therapy. Unusual locations and presentations of some
of these tumors have been reported. A high index of suspi-
Studies evaluating the usefulness of yearly Pap cytologic cion for cancer needs to be maintained in the HIV-infected
screening with subsequent high-resolution anoscopy population, and more frequent screening for the more com-
(HRA) and biopsy have found a high incidence of false- mon cancers may also be required. The routine use of screen-
negative Pap tests, even in some individuals with high- ing biomarkers has not yet been evaluated in HIV-infected
grade AIN [86]. Guidelines for frequency of screening have patients; however, periodic screening tests such as screening
not yet been established, but many HIV practitioners rec- mammography, alpha fetoprotein, prostate-specific antigen,
ommend 2 initial baseline Pap tests or HRAs 6 months and routine skin exam may be warranted.
apart, followed by yearly screening if no abnormalities
are seen. Findings of low-grade SIL (AIN 1) are generally
followed closely with repeat HRA and biopsies. Patients
Treatment
with high-grade AIN 2–3 undergo ablative therapy, either In the absence of prospective clinical trials data for many of
surgically or with infrared or electrocauterization [87]. these cancers in HIV-infected patients, treatment strategies
have generally followed the same stage-adjusted approaches
as used in individuals not infected with HIV. Appreciation
Treatment for the greater likelihood and/or severity of drug toxicities,
Treatment for invasive cancer requires coordinated concur- the potential for drug interactions between anticancer agents
rent chemoradiotherapy and in some cases surgical resec- and antiretroviral drugs, and the need to provide supportive
tion followed by radiation or chemoradiotherapy. For treatment and prophylactic antibiotics should be incorporated
most patients with squamous cell carcinoma of the anus, into the management of HIV-infected patients with cancer.
chemotherapy consists of mitomycin (10 mg/m2 on day
1) and fluorouracil (5-FU; 1,000 mg/m2 by continuous in-
fusion on days 1–4) combined with radiation therapy. Al- ACKNOWLEDGMENTS
ternatively, some clinicians prefer substituting cisplatin for
mitomycin in patients with HIV [88]. Despite high re- Supported in part by grants from the California HIV/AIDS
sponse rates to this combined therapy, patients with HIV Research Program (MC08-LA-710) and USPHS, NIH
have a higher risk of relapse and studies including the EGFR grants, AI-69424, AI-28697, CA-121947, and RR-00865.
462
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466
Chapter | 36 |
STDs and syphilis
Elysia Larson, Jeffrey D. Klausner
cases, respectively, in 1999) [2]. Every year over 2 million

INTRODUCTION pregnant women are diagnosed with syphilis [3]. In North
America, Western Europe, and Australia, a majority of new
Sexually transmitted infections like syphilis, herpes, gonor- syphilis cases are among men, particularly men who have
rhea, chlamydia and trichomoniasis have circulated for sex with men [4, 5].
thousands of years, long before the emergence of HIV. The Because syphilis may facilitate HIV acquisition and trans-
areas currently most affected by STDs are South and South- mission, and because syphilis and HIV have similar modes
east Asia and sub-Saharan Africa. Infections can lead to acute of transmission, co-infection is common. In the United
symptoms ranging from ulcers and abrasions to painful States approximately 10-20% of syphilis patients are co-
urination. Long-term outcomes are more severe, including infected with HIV; in Rwanda the prevalence of syphilis
infertility, ectopic pregnancy, and other adverse pregnancy in HIV-infected women was almost twice as high as in
outcomes. Because some sexually transmitted diseases (such HIV-uninfected women [6]. All patients with syphilis
as chlamydia and herpes) may be asymptomatic during should therefore be tested for HIV infection, and HIV-
acute infection, they are unknowingly spread and may lead infected patients should be screened at their initial visit
to serious complications if they remain undetected. and regularly thereafter with the frequency dependent on
As sexual transmission is the primary mode for the spread risk behavior.
of HIV infection, individuals at risk for STDs are also at risk
for HIV infection. Approximately one in five HIV-infected in-
dividuals worldwide is co-infected with a second sexually Natural history, pathogenesis,
transmitted infection [1]. Additionally, the presence of and pathology
untreated STDs has been shown to increase the acquisition Syphilis is caused by infection with Treponema pallidum pal-
and transmission of HIV. Therefore, all individuals infected lidum. The primary mode of transmission is through sexual
with STDs should be treated and tested for HIV infection. contact. Syphilis is readily transmissible by oral sex and
Furthermore, recognition of a new STD in an HIV-infected through vaginal and anal intercourse. Syphilis can also
patient is an indication of unprotected sex with the potential be transmitted vertically (in utero and at delivery) and less
for HIV transmission in the community. frequently by blood transfusion [5].
Syphilis occurs in three distinct stages: primary, secondary,
and tertiary. Once infected, there is an approximately three-
SYPHILIS week incubation period before the initial lesion of primary
syphilis develops. Primary syphilis lasts from a few days to
several months and may overlap with the signs and symp-
Epidemiology
toms of secondary syphilis in about one-third of patients (this
About 90% of syphilis cases worldwide are in low-income increases to up to three-fourths among HIV co-infected pa-
countries, with sub-Saharan Africa and South and South- tients.) Secondary syphilis presents between 1 to 3 months
east Asia carrying most of the burden (9.6 and 9.2 million after infection and is followed by latent syphilis. Without
467
therapeutic cure, approximately a third of patients will pro-

gress to tertiary syphilis [7].
Because syphilis is readily treatable with antibiotics, the
natural history has not been well-studied. However, the
Oslo syphilis natural history study conducted from 1891
to 1951 found a mortality rate of 15% for men and 8%
for women [8].
Clinical features
Syphilis is a systemic disease that has symptomatic periods
that alternate with periods of clinical latency. Primary syph-
ilis is characterized by an ulcer or chancre at the site of in-
oculation (see Fig. 36.1). Usually the lesion is solitary, but Figure 36.2 Palmar rash.
HIV co-infected patients are more likely to have several le- Courtesy of San Francisco City Clinic.
sions that may be larger and deeper than those in HIV-
uninfected patients. Approximately 80% of patients also widespread use of antibiotics. The most common complica-
develop unilateral lymphadenopathy near the site of the tion is disease of the aorta resulting in aortic regurgitation or
lesion [5, 7]. aortic aneurysm, usually of the ascending arch. Gummatous
Secondary syphilis typically presents as a diffuse non-pru- syphilis is named for the granulomatous-like lesion most
ritic rash consisting of many 3- to 10-mm pink, red, or copper- commonly found in the skin, bone, and liver. Although
colored flat lesions or macules. The rash most often affects the rarely physically debilitating, those lesions can present in
trunk and limbs, and raised circular lesions (papulosqua- any organ and can therefore cause complications. Incidence
mous) with fine circumferential scaling are found on the peaks approximately 15 years post infection [5, 7, 9].
palms and soles in some cases (see Fig. 36.2). In addition Neurosyphilis is caused by invasion of the cerebrospinal
to the rash, 5–10% of patients may experience patchy hair fluid (CSF) by T. pallidum and can occur at any stage of dis-
loss. Some patients may experience diffuse lymphadenopa- ease. Most patients who experience early treponemal inva-
thy, pharyngitis, or fever [5, 7]. sion of CSF will have spontaneous resolution. For others,
Although the symptoms of secondary syphilis will abate early neurosyphilis is characterized by meningovascular
even in the absence of treatment, up to 25% of patients will disease, acute and subacute myelopathy, brainstem or
experience a recurrence of secondary syphilis, usually cranial nerve abnormalities, or vestibular and ocular abnor-
within the first year. The period during which no symptoms malities [10]. Partial loss of movement and muscle weakness
are present is termed latent syphilis, and although sexual and abnormal physical sensations are classic late-stage
transmission during latency is unlikely, the possibility of neurosyphilis syndromes as well as dementia [5, 7].
mother-to-child transmission remains [7].
Up to a third of patients with untreated syphilis will
develop tertiary syphilis. Characterized by a broad range Patient evaluation, diagnosis, and
of long-term complications, tertiary syphilisis generally
divided into three sub categories: cardiovascular syphilis,
gummatous (late benign) syphilis, and late neurosyphilis. The diagnosis of a patient with suspected syphilis must
Cardiovascular syphilis is the most common manifestation, begin with a detailed history (including sexual behavior,
although it is on the decline, probably as a result of the a risk assessment for HIV and other STDs and questioning
regarding symptoms) and a physical examination (includ-
ing examination of the skin, scalp, oropharynx, genital and
anal area and a targeted neurological examination). In cer-
tain settings, direct darkfield microscopy or fluorescent
antibody testing of lesion exudates can be performed. Sero-
logical testing is used to confirm the diagnosis in those with
signs and symptoms or as a screening test in those who are
asymptomatic. Non-treponemal testing (rapid plasma re-
agin [RPR], venereal disease research laboratory [VDRL],
toluidine red unheated serum test [TRUST]) is used as
the initial screen followed by a treponemal test (trepone-
mal pallidum particle agglutination [TP-PA]) to confirm
Figure 36.1 Penile chancre. an initial reactive non-treponemal test. Increasingly in
Courtesy of San Francisco City Clinic. the United States and in other countries, due to the
468
Chapter | 36 | STDs and syphilis
automation of treponemal testing using enzyme immuno- of disease. Male partners of pregnant women with syphilis
assays, a treponemal antibody test is used as the initial should be treated presumptively to reduce the risk of
syphilis screening test. Since treponemal antibodies persist maternal re-infection. Routine and frequent testing of
for life in most patients with syphilis, the clinician cannot syphilis in high-risk populations has been shown to be as-
determine based on a positive treponemal test the duration sociated with a reduction in syphilis incidence in the target
of infection. A second non-treponemal test is then used and, population [4].
if positive, the patient is diagnosed with recent syphilis in- Patients with signs or symptoms of neurologic involve-
fection. In some cases, however, the initial treponemal test ment (e.g. cranial nerve palsies, motor or sensory defects)
will be reactive and the second non-treponemal test will be should undergo lumbar puncture and CSF examination
negative, making the determination of active infection dif- to exclude neurosyphilis. Neurosyphilis is diagnosed on
ficult. If a patient has no history of syphilis treatment, most the basis of elevated cerebrospinal fluid total white cell
national guidelines recommend treatment in that setting for count ([5-10] 10 cells/mm3 for HIV-uninfected patients
latent infection. Interpretation of all serological tests should and [10-20] 20 cells/mm3 for HIV-infected), abnormal pro-
be the same for both HIV-infected and HIV-uninfected tein or reactive VDRL or flourescent treponemal antibody-
patients [11]. In low-resource settings rapid treponemal absorption test. Other indications for CSF analysis in
tests are often used as the single assay. Persons with a reac- patients with syphilis are suspected treatment failure or
tive test are treated without determination of the serologi- evidence of tertiary syphilis. HIV co-infection is not an
cal titer and staged by history and clinical findings. Those indication for CSF analysis [11]. Because intramuscular
with symptoms are categorized as early syphilis (primary penicillin G benzathine does not reach adequate levels in
or secondary) and those without symptoms as latent syph- the brain to be treponemocidal, patients with neurosyphi-
ilis. If syphilis exposure is likely to have occurred within the lis must be treated with intravenous penicillin G.
past 12 months, the patient is managed as early syphilis; if
the exposure was more than 12 months or unknown, the
patient is managed as late syphilis.
Treatment
In patients with genital ulcerative lesions consistent with
syphilis, other causes might include herpes simplex virus Both HIV-infected and HIV-uninfected patients should un-
infection and chancroid. Rarely granuloma inguinale dergo the same treatment: intramuscular benzathine peni-
(Klebsiella granulomatis) is a cause of genital ulcer disease. cillin G (see Table 36.1). The efficacy of benzathine
Raised genital lesions of secondary syphilis (see Fig. penicillin G in the treatment of syphilis has been support
36.3) might also be confused with external genital warts by decades of clinical experience and numerous case series,
Drug reactions, trauma, pyogenic bacterial infections, observational studies, and clinical trials. Patients should
and malignancy might also be included in the differential be informed about the Jarisch–Herxheimer reaction—fe-
diagnosis of early symptomatic syphilis. Because syphilis is ver, headache, chills, and rigors—which is an acute fe-
curable, all patients with such genital lesions should be brile reaction that usually occurs within the first 24
tested for syphilis [12, 13]. hours after syphilis treatment. It most often occurs
As congenital syphilis can be almost entirely avoided among patients who have early syphilis and is more fre-
by early detection and treatment of maternal infections, quent among HIV-infected patients [7]. Pretreatment
all pregnant women should undergo syphilis screening at with acetaminophen (paracetamol) can reduce the sever-
the first antenatal care visit [3]. Pregnant women with a ity of that reaction. In many countries, it is recom-
reactive serology should be treated for latent syphilis if mended that the treatment of pregnant women occurs
asymptomatic and early syphilis if there are clinical signs in a hospital setting because the Jarisch–Herxheimer re-
action is associated with premature labor and fetal loss.
Some efficacy has been demonstrated with other antibi-
otics in patients who have true penicillin allergies; for exam-
ple, doxycycline, 100 mg orally twice a day for 14 days.
However, tetracyclines are contraindicated in pregnant
women and children < 8 years of age. Pregnant women with
penicillin allergies should be desensitized and treated with
penicillin [11]. A series of congenital syphilis cases was
reported among pregnant women with syphilis in China
treated with azithromycin [14]. A randomized controlled
trial comparing intravenous ceftriaxone to intravenous pen-
icillin G in HIV-infected patients with neurosyphilis found
similar improvements clinically and in laboratory measures
Figure 36.3 Anal condylomata lata of syphilis. such as the CSF VDRL titer, CSF white blood cell count, and
Courtesy of San Francisco City Clinic. CSF protein concentration for the two groups [15].
469
Table 36.1 Recommended treatment regimens for syphilis patients [11, 12]
POPULATION RECOMMENDED REGIMENS COMMENTS
Primary, secondary, and early Benzathine penicillin G 2.4 million units Routine penicillin allergy screening with
latent syphilis (first year of administered intramuscularly (IM) as a single injectable penicillin in or under the skin
latent syphilis) dose prior to treatment administration is not
recommended
Late latent syphilis, latent syphilis Benzathine penicillin G 2.4 million units Pregnant women who miss any dose must
of unknown duration, or administered IM at 1-week intervals for three repeat the full course of therapy. In the
tertiary syphilis without CNS weeks for a total of 7.2 million units general population if more than 14 days
involvement lapse between doses then the full course of
therapy should be repeated [3]
Neurosyphilis or syphilitic eye Intraveneous aqueous crystalline penicillin

disease G 3–4 million units every 4 hours or continuous
infusion for 10–14 days (total 18–24 million
units per day) followed by at least one dose of
benzathine penicillin G IM, 2.4 million units
Childrena with primary, Benzathine penicillin G 50,000 units/kg IM, For children 1 month with acquired
secondary, or early up to the adult dose of 2.4 million units primary or secondary syphilis conduct an
latent syphilis evaluation through consultation with child-
protection services and a CSF examination
for detection of asymptomatic
neurosyphilis
Children with late latent syphilis Benzathine penicillin G 50,000 units/kg IM,
or latent syphilis of unknown up to the adult dose of 2.4 million units,
duration administered at -week intervals for three
weeks (3 doses in total)
a
Treatment for congenital syphilis is more complex and beyond the scope of this chapter.
Treatment success for both HIV-uninfected and HIV- those of other sexually transmitted diseases: the number
infected persons is defined as a four fold decrease in non- of lifetime sex partners, young age at sexual debut, and pre-
treponemal titers at 6 to 12 months post treatment in early vious history of STDs [16]. HSV-1 seroprevalence in adults
syphilis and 12 to 24 months post treatment in late syph- approaches 70% in developed countries and 100% in de-
ilis. HIV-infected patients should be re-evaluated every veloping countries. Sub-Saharan Africa has the highest bur-
3 months for a year after initial treatment [11]. When con- den of HSV-2 infection, ranging from 20–80% in low-risk
sidering treatment failure, the possibility of re-infection adults and about 40–90% in high-risk adults, with slightly
should be considered, as this simply requires retreatment. lower prevalence in West Africa than the other regions. Sim-
In the absence of evidence of re-infection, CSF analysis ilar prevalence of HSV-2 infection is found in Central and
should be performed to rule out neurosyphilis, and a South America and the Middle East, ranging from about
3-week course of treatment should be initiated [4, 7]. If 30% to 50%. Although data are sparse from countries in
neurosyphilis cannot be excluded, the patient must be Asia, available data suggest a lower HSV-2 prevalence [17].
treated for neurosyphlis with intravenous penicillin G. Across the globe HSV-2 infection is more prevalent
among women than men, and prevalence increases with
age [17]. The burden of HSV-2 infection is consistently
GENITAL HERPES higher in HIV-infected individuals than in HIV-uninfected
individuals. There is a wealth of epidemiologic evidence
demonstrating that prevalent HSV-2 is associated with a
Epidemiology two- to eight-fold increase in incident HIV-1 infection, even
Both herpes simplex virus type 1 (HSV-1) and type 2 (HSV- when adjusted for sexual behavior [18, 19]. Because HSV-2
2) are prevalent worldwide. Most persons are infected with infection leads to the disruption of the genital mucosa and
HSV-1 in childhood; however, HSV-2 infection is usually an influx of CD4-bearing T cell lymphocytes, it is biologi-
transmitted sexually and risk factors are thus similar to cally plausible that HSV-2 infection could lead to increased
470
risk of HIV-1 acquisition [18]. It has also been suggested small, painful, itchy ulcers (see Figs. 36.4A and 4B) [9].
that persons co-infected with HSV-2 and HIV-1 are more Although lesions primarily arise on the external genitalia,
likely to transmit HIV-1; however, recent studies have they can also appear in the vagina and on the cervix, in
found similar rates of HIV-1 transmission between HSV-2 the anus and rectum, in the perianal region, on the but-
infected and uninfected individuals [18]. Several clinical tocks or on the upper thighs. When the lesions are present
trials to treat HSV-2 infection were recently completed that approximately 80% of women report dysuria, and 40% of
demonstrated no impact of HSV-2 treatment on HIV acqui- men and 70% of women report flu-like symptoms, includ-
sition or transmission [20, 21]. Treatment of HSV-2 infec- ing headache and fever [16]. In about 10% of newly
tion in HSV-2/HIV co-infected patients, however, was infected patients, clinical symptoms and signs consistent
associated with a delay in HIV disease progression [22]. with aseptic meningitis may develop [16, 24]. Primary
HSV infection should always be included in the differential
Natural history, pathogenesis, and diagnosis of meningitis. The lesions take about 1–2 weeks
to heal. During that period most patients develop new le-
pathology sions. In the first year after a symptomatic first episode of
A person becomes infected with HSV after exposure to virus genital herpes, 70–90% of HSV-2 -infected individuals
that is shed from the genital tract or skin of an HSV-infected and 20–50% of HSV-1-infected individuals will have a re-
individual. While most HSV-1 infection usually occurs current episode [16]. Recurrences, which occur approxi-
from oral contact (kissing) in childhood, in many countries mately four times per year, decrease in frequency and
HSV-1 is increasingly being acquired from oral-genital con- severity over time. Some patients have prodromal symp-
tact in adolescence [23]. HSV-2 acquisition almost always toms, such as tingling, itching, and pain, which occur
occurs through sexual contact. Once infected, the virus rep- 6-24 hours before the lesions develop [9].
licates at the site of infection. The virus then spreads HIV-infected individuals are more likely to have HSV-2
through the lymphatic system to the sensory nervous sys- reactivation than HIV-uninfected individuals; however,
tem, where it persists. HSV is cleared from the cells at the most reactivation is subclinical in both groups. Antiretrovi-
site of infection; however, recurrences at this and other sites ral therapy with immune restoration can reduce the fre-
can occur after HSV reactivation and transport back down quency of recurrent outbreaks in HIV/HSV-2 co-infected
the nerves to the dermis, skin, or mucous membranes. individuals [18].
Reactivation of HSV leads to viral shedding, even in the
absence of symptoms. Because most infections are asymp- Patient evaluation, diagnosis, and
tomatic, sexual transmission of herpes usually occurs from differential diagnosis
persons who are unaware they are infected [9, 16].
Because most patients are asymptomatic, and those with
lesions have varying symptoms, clinical diagnosis is neither
Clinical features
sensitive nor specific. Clinical diagnosis should ideally
HSV infection is often asymptomatic. In a true primary first be confirmed by laboratory tests. Those tests should be
episode (a first episode in a person who was previously not type-specific, as the frequency of clinical recurrences is
infected with either HSV-1 or HSV-2), small fluid-filled er- dependent on viral type.
ythematous papules or vesicles will usually appear after an When there are vesicles or ulcers, it is possible to diag-
incubation period of 1–14 days and quickly evolve into nose infection and viral type with viral antigen assays,
A B
Figure 36.4 (A) Penile vesicles and (B) labial ulcerations.

Collection of Dr. Jeffrey Klausner.
471
including PCR and culture [11]. However, as the lesions be- infection acquired during the third trimester before the
gin to heal, viral detection becomes more difficult. The best development of protective maternal antibodies, most cases
means to detect virus during infection is to unroof the ves- of neonatal herpes occur from asymptomatic genital HSV-
icle and swab the base of the ulcer. If the patient is asymp- 2 reactivation and viral- shedding. Neonatal herpes is a
tomatic or if the lesions have begun to crust over, it is devastating disease, with about 50% mortality and long
necessary to perform serum antibody testing [16]. Type- term neurologic morbidity in those who survive [26].
specific HSV-1 or HSV-2 IgG antibody testing is readily Unfortunately there is limited experience with strategies
available in many countries. However, antibody testing is to prevent neonatal herpes when HSV-2 infection is not
limited as it is not a marker of disease and cannot be used identified in the mother [26].
to determine the duration of infection. Persons with prior
history of infection may have a positive antibody assay, but
the current genital lesion may or may not be related to HSV
infection.
GONORRHEA
Treatment Epidemiology
Although treatment for genital herpes cannot eliminate The global burden of gonorrhea was estimated at 62 mil-
latent virus or affect the frequency of recurrence once dis- lion cases in 1999, with the highest incidence in South
continued, antiviral treatment can reduce the symptoms and Southeast Asia, at an estimated 27.2 million new cases.
of a recurrence, and if taken early enough during the pro- Sub-Saharan Africa and Latin America/Caribbean have the
drome (described above), can even abort the recurrence next highest burden. Asymptomatic gonorrhea is common,
completely. Treatment depends on the type of clinical ranging between 67% and 100% of those with infection in
episode, the frequency of previous episodes, and the indi- the general population and 9–40% of those reporting to a
vidual’s HIV serostatus. Multiple clinical trials have demon- genitourinary medicine clinic [2, 27].
strated that acyclovir, valacyclovir, and famciclovir provide Gonorrhea is more prevalent among women than men,
clinical benefit (see Table 36.2 for treatment guidelines). As among youth (aged 18–24 years old), persons who have
symptoms are often systemic, currently available topical never married, and persons who have had more than
creams or ointments are not effective and thus not recom- one partner in the previous 3 months [28].
mended. Chronic daily suppressive treatment with valacy- Quinolone-resistant Neisseria gonorrhoeae is common
clovir has been shown to reduce the transmission of HSV-2 among many populations worldwide and affects treat-
infection to susceptible partners [25]. ment decisions (see Treatment section). The prevalence
The transmission of herpes from mother to infant of quinolone-resistant N. gonorrhoeae has been reported
occurs most often around the time of delivery. While the as greater than 40%, even reaching 98%, in South Africa
likelihood of HSV transmission is greatest from an as well as many countries in the Middle East, Asia,
Table 36.2 Recommended treatment for herpes simplex virus infection [11, 12]
POPULATION ACYCLOVIR FAMCICLOVIR VALACYCLOVIR
First clinical 400 mg orally 3 times daily 250 mg orally 3 times daily 1 g orally twice daily for
episode of for 7–10 days OR 200 mg orally for 7–10 days 7–10 days
genital herpes 5 times a day for 7–10 days
Recurrent 400 mg orally 3 times daily for 5 days 125 mg orally twice daily for 500 mg orally twice daily
episode OR 800 mg orally twice daily for 5 days 5 days OR 1000 mg orally for 3 days OR 1.0 g orally
OR 800 mg orally three times daily for 2 days twice daily for 1 day once a day for 5 days
Suppressive 400 mg orally twice daily 250 mg orally twice daily 500 mg orally once daily
therapy OR 1.0 g orally once daily
HIV-infected persons
Recurrent 400 mg orally 3 times daily 500 mg orally twice daily for 1.0 g orally twice daily for
episode for 5–10 days 5–10 days 5–10 days
Suppressive 400–800 mg orally twice or 500 mg orally twice daily 500 mg orally twice daily
therapy 3 times daily
472
Central Asia, and the South Pacific [29]. Surveillance for

antimicrobial resistance is essential to continue making
informed treatment decisions.
Natural history, pathogenesis, and

pathology
Gonorrhea is caused by infection with the bacterium N.
gonorrhoeae. Once exposed, the gonococci colonize muco-
sal cells. Due to anatomical differences between men and
women, infection is more easily transmitted from an
infected man to a woman (50–73% probability) than from
an infected woman to a man (20–35% probability) [30].
After infection there is an incubation period lasting approx- Figure 36.5 Gram stain of urethral exudate from patient with
imately 1–2 days in men and 5–10 days in women before gonorrhea.
Courtesy of San Francisco City Clinic.
the onset of clinical symptoms [30]. Untreated infection
may resolve within 6 months in men, whereas untreated
infection in women may result in upper genital tract infec- requirements, culture may not be the best choice in some
tion in about 15% of women [31]. low-resource settings. NAATs are becoming a popular choice
Re-infection is common in both women and men (about for diagnosis, as they can be used with urine and endocervi-
10–15% and 5–10%, respectively). Re-infection is more cal or urethral swabs, vaginal swabs (self-collected), and
common in younger individuals. Treating partners or rectal and pharyngeal swabs. NAATs are more sensitive
providing medications for infected patients to deliver to and as specific as culture [11]. Some NAATs can be used to
their partners significantly decreases the risk of reinfection diagnose co-infection with chlamydia, but as NAATs differ
[31, 32]. by manufacturer, it is important that clinicians be aware of
the performance characteristics of the particular NAAT
Clinical features being used. While culture is still the gold standard for anti-
microbial susceptibility testing, novel methods have been
In men with symptomatic gonococcal infection, pain with
used to describe specific gene mutations in N. gonorrhoeae
urination usually precedes urethral discharge. Symptoms in
associated with antimicrobial resistance and may soon
women include pain during urination or intercourse, vag-
replace culture in the monitoring of resistance [9, 11, 33].
inal discharge, abnormal menstrual bleeding, and genital
Because asymptomatic infection is common, high-risk indi-
discomfort. If left untreated, local infection can ascend,
viduals, especially young women, should be screened for
causing pelvic inflammatory disease or upper reproductive
gonorrhea. Because re-infection is common, infected indi-
tract infection that may lead to chronic pelvic pain, ectopic
viduals should be re-screened 3 months after treatment
pregnancy or infertility [9, 30].
[31, 32].
With rectal infections symptoms may range from mild
The differential diagnosis of urethral or cervico-vaginal
rectal itchiness and discharge to frank proctitis with rectal
discharge usually includes gonorrhea, chlamydia, and
bleeding and pain. Although oral infection is asymptom-
trichomoniasis, along with bacterial vaginosis and candidi-
atic in a majority of cases, it may cause pharyngitis and
asis in females. Other pathogens, such as Mycoplasma
rarely tonsillar abscess [9].
species, HSV, and oral bacterial flora or respiratory viruses
(adenoviruses) may also cause urethral infection [12].
Patient evaluation, diagnosis and
Treatment
Definitive diagnosis can be made by Gram stain, culture,
nucleic acid hybridization tests, or nucleic acid amplifica- With an increase in quinolone-resistant N. gonorrhoeae in-
tion tests (NAATs) of a clinical specimen (urethral, cervical, fections, treatment decisions for gonorrhea must be made
vaginal, rectal or pharyngeal swab) depending on the site of within the context of local rates of antimicrobial resistance
infection and resources available. A Gram stain to identify (see Table 36.3). If resistance to a drug is greater than 5% in
Gram-negative intracellular diplococci can be used with a population, then that drug should no longer be used in
male urethral specimens (see Fig. 36.5). In asymptomatic that population. Infected individuals should also be asked
cases culture or nucleic acid tests are required to increase about their recent travel history to exclude possible expo-
sensitivity. Culture and nucleic acid tests are highly specific sure to antimicrobial resistant infections elsewhere [29].
and can be used with various clinical specimens. However, Because of the frequency of gonococcal and chlamydial
because of the rigorous collection, storage, and transport co-infection, patients with gonorrhea should be co-treated
473
Table 36.3 Recommended treatment for gonorrhea [11, 12, 29]
POPULATION RECOMMENDED REGIMENS
Uncomplicated infections of the cervix, urethra, and rectum Ceftriaxone 250 mg IM as a single dose
OR
Cefixime 400 mg orally as a single dose
OR
Ciprofloxacin* 500 mg orally as a single dose
PLUS
azithromycin 1 g orally as a single dose
OR
doxycycline 100 mg orally twice a day for 7 days
Uncomplicated infections of the pharynx Ceftriaxone 250 mg IM as a single dose

PLUS
Azithromycin 1 g orally as a single dose
OR
Doxycycline 100 mg orally twice a day for 7 days
Pregnant women Ceftriaxone 250 mg IM as a

single dose
PLUS
Azithromycin 1 g orally as a single dose
OR if cannot tolerate cephalosporin,
azithromycin 2 g orally as a single dose
Gonococcal conjunctivitis Ceftriaxone 1 g IM as a single dose
Disseminated gonococcal infection Recommended: Ceftriaxone 1 g IM or IV every 24 h

All regimens should be continued for 24-48 hours after OR Alternative Regimens:
improvement begins, then switched to one of the Cefotaxime 1 g IV every 8 hours
following oral antimicrobial regimens for at least an OR
additional week Ceftizoxime 1 g every 8 hours
Cefixime 400 mg orally twice daily
For prophylaxis in infants born to mothers with gonococcal Ceftriaxone 25–50 mg/kg IV or IM as a single dose, not to
infection or for infants with ophthalmia neonatorum exceed 125 mg
Ophthalmia neonatorum prophylaxis Erythromycin (0.5%) ophthalmic ointment in each eye in a

single application
For infants with disseminated gonococcal infection and Ceftriaxone 25–50 mg/kg/day IV or IM as a single daily dose,
scalp abscesses not to exceed 125 mg a day for 7 days; treat for 10–14 days
if meningitis is documented
OR
Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days; treat
for 10–14 days if meningitis is documented
*Ciprofloxacin in geographic areas where surveillance data show quinolone resistance is < 5%.
474
for uncomplicated genital chlamydial infection. Co-treatment period is about 7 to 21 days. It is likely that chlamydia is
might also slow the development of drug resistance in more readily transmitted from men to women than from
gonorrhea and is increasingly recommended. HIV-infected women to men [35]. Studies have shown that re-infection
patients should receive the same treatment for gonorrhea as is common in both women and men (approximately
HIV-uninfected patients [11]. 10–20%) [31, 32]. Providing medications for infected
patients’ partners (expedited partner therapy) significantly
decreases the risk of re-infection.
CHLAMYDIA
Epidemiology Clinical features

Chlamydia is the most commonly reported sexually trans- Men with clinical symptoms may present with painful urina-
mitted disease worldwide, with an estimated 92 million tion, increased frequency of urination, thin mucoid urethral
new cases in 1999. Following a similar geographic distribu- discharge, and penile itching or discomfort (see Fig. 36.6).
tion as gonorrhea, the area with the most incident cases Symptoms in women may include painful urination, in-
in 1999 was South and Southeast Asia (42.9 million creased frequency of urination, vaginal discharge, abnormal
cases) followed by sub-Saharan Africa and Latin America/ menstrual bleeding, lower abdominal pain, and/or pain
Caribbean (15.9 and 9.3 million cases, respectively) [2]. during intercourse [9]. If infection is left untreated in women,
Despite education and awareness campaigns, recent trends more serious complications may include pelvic inflammatory
have shown increases in the prevalence of chlamydia. disease, chronic pelvic pain, and ectopic pregnancy. In both
However, it is not clear if those increases are due at least men and women infertility may result [9]. Increasingly C. tra-
in part to increased screening [34, 35]. chomatis has been recognized as a cause of rectal infection and
Chlamydia is generally more prevalent among women proctitis. Patients may be asymptomatic or have symptoms
and younger individuals (18–24 years), as well as persons ranging from mild rectal itching to discharge and proctitis with
who have multiple sex partners [28]. Asymptomatic infec- rectal bleeding. Some proportion of rectal chlamydial infec-
tion is common among both women and men, accounting tion may be due to the C. trachomatis serovars L1–L3 tradition-
for over 75% of infections in many populations [2, 28]. ally associated with lymphogranuloma venereum.
Natural history, pathogenesis, Patient evaluation, diagnosis,

and pathology and differential diagnosis
Chlamydia is caused by infection with the bacterium Chla- Even in persons with symptomatic chlamydial infection,
mydia trachomatis. The bacteria infect epithelial cells and the symptoms are not specific enough for a diagnosis, so
undergo intracellular replication. The clinical incubation it is necessary to perform diagnostic assays. Diagnosis
Figure 36.6 Non-gonococcal urethritis.

Courtesy of Dr Kenneth Katz.
475
can be made from urine or swabs collected from the endo- with a multi-day regimen is uncertain. Patients remain in-
cervix or vagina (in women), the urethra (in men), or the fectious for 7 days after the start of treatment and should
rectum (to detect rectal infection in persons with a history be advised to abstain from sex for that period. To prevent
of receptive anal intercourse). Culture, direct fluorescent re-infection patients should be advised to ensure all their
antibody tests, enzyme immunoassays, nucleic acid hy- sex partners have been treated; providing patients addi-
bridization tests, and NAATs can all be used for testing tional treatment to give to sex partners should be considered.
swab specimens, but only NAATs can be used with urine. Retesting of pregnant women, infants, and children three
NAATs provide the most sensitive results, and because they weeks after treatment completion is recommended to
can be used with urine samples, they can be used in non- confirm cure [11].
clinical settings. NAATs are therefore recommended for The optimal treatment of rectal chlamydial infection
use when available [11, 35]. Because co-infection with is unknown. For non-lymphogranuloma venereum sub-type
N. gonorrhoeae is common, patients should undergo testing or asymptomatic rectal chlamydial infection the recom-
for both chlamydia and gonorrhea. mended treatment is azithromycin 1 g once or doxycycline
The differential diagnosis of urethral or cervico-vaginal 100 mg orally twice daily for 7 days. Because in most sett-
discharge usually includes gonorrhea, chlamydia and tricho- ings the bacterial sub-type of rectal chlamydial infection
moniasis, along with bacterial vaginosis and candidiasis cannot be determined, in symptomatic patients some ex-
in females. Other pathogens like Mycoplasma species, HSV, perts recommend a 3-week course of treatment (doxycycline
and oral bacterial flora or respiratory viruses (adenoviruses) 100 mg orally twice daily for 21 days or azithromycin 1 g
may also cause urethral infection [12]. orally weekly for 3 weeks) [11].
Treatment TRICHOMONIASIS
Treatment of patients with chlamydia not only cures
the infection and relieves symptoms, but also is import-
Epidemiology
ant to prevent the further transmission to sex partners
(Table 36.4). In pregnant women treatment generally Although it is not a reportable infectious disease, tricho-
prevents mother-to-child transmission of C. trachomatis. moniasis is the most common STD worldwide, with the
HIV-infected patients should receive the same treatment highest incidence in South and Southeast Asia, followed
for chlamydia as HIV-uninfected patients [11]. by sub-Saharan Africa. Prevalence of Trichomonas vaginalis
Although doxycycline costs less than azithromycin, azi- infection increases with age. While trichomoniasis is a com-
thromycin should be used in patients for whom compliance mon cause of vaginal and urethral discharge, up to one-third
Table 36.4 Recommended treatment for chlamydia [11, 12]
POPULATION RECOMMENDED REGIMENS ALTERNATIVE REGIMENS
Adults Azithromycin 1 g orally as a single Erythromycin base 500 mg orally

dose four times a day for 7 days
OR OR
Doxycycline 100 mg orally twice daily Ofloxacin 300 mg orally twice daily for
for 7 days 7 days
Women who are pregnant Amoxicillin 500 mg orally three times Erythromycin base 500 mg orally
or lactating daily for 7 days four times daily for 7 days
OR
Erythromycin base 250 mg orally
four times daily for 14 days
Neonatal chlamydial conjunctivitis, Erythromycin base 50 mg/kg orally

neonatal pneumonia, or children per day, divided into four doses daily
< 45 kg for 14 daysa
Children 45 kg Azithromycin 1 g orally in a single For children 8 years old doxycycline

dose 100 mg orally twice daily for 7 days
a
Infants should be watched for signs of infantile hypertrophic pyloric stenosis.
476
of infected women and a majority of men are asympto- Treatment

matic [36]. Asymptomatic infection results in long-standing
chronic infection and continued transmission of infection. Both the WHO and CDC recommend treating trichomoni-
Trichomonas infection has been associated with increased asis with either 2 g metronidazole orally in a single dose
acquisition of HIV due to vaginal inflammation, increased or 2 g tinidazole orally in a single dose. Pregnant women
genital HIV viral replication in men and women, and vaginal should be treated with metronidazole. If symptoms persist
mucosal micro-ulcerations [37]. after 7 days and re-infection has been excluded, patients
can be treated with 500 mg metronidazole orally twice
daily for 7 days. HIV-infected patients should be treated
with the same regimens as HIV-uninfected patients. Sex
Natural history, pathogenesis, partners should also be treated in order to prevent re-
and pathology infection [11, 12, 36]. There have been rare cases of me-
tronidazole-resistant trichomoniasis. Usually treatment
Trichomoniasis is caused when the parasite T. vaginalis in- failure may be overcome with higher doses of metronida-
fects the squamous epithelium of the vagina or urethra. The zole for a longer duration (e.g. 500 mg orally twice daily
infection causes an inflammatory response, resulting in for 7 days or 2 g orally a day for 5–7 days). Persistent treat-
symptoms in about half of all women and a somewhat ment failure in which re-infection has been excluded
lower proportion of men [9]. Infection may persist asymp- should be treated in consultation with an infectious disease
tomatically for years. specialist [11].
Clinical features SYNDROMIC MANAGEMENT

Symptomatic women generally present with vaginal dis-
charge (frothy and yellowish-green in appearance), irrita- Introduction
tion, itching, and sometimes lower abdominal pain and Unfortunately, the diagnostic tests described in the previous
pain during urination. Those symptoms might be more sections are not available in many settings, making defini-
common in HIV co-infected women than HIV-uninfected tive, specific diagnosis of symptomatic individuals impossi-
women [9, 36]. Long-term complications of untreated in- ble. In those instances it is necessary to provide individuals
fection in women can include pelvic inflammatory disease with treatment based on their symptoms. In addition to the
and adverse birth outcomes [38]. Men may present with benefits in individuals, syndromic management can lead to
symptoms of urethritis and rarely chronic prostatitis [36]. a reduction in the prevalence of curable sexually transmitted
diseases that tend to become symptomatic [39].
When providing syndromic management clinicians
should take into account the patient’s sexual history and
Patient evaluation, diagnosis,
the local epidemiology of sexually transmitted diseases.
and differential diagnosis All patients treated for sexually transmitted disease should
Where tests are available, women presenting with vaginal undergo counseling and testing for HIV infection as well as
discharge should be tested for trichomonas infection. Cul- counseling for safe sex practices.
ture is the most sensitive and specific diagnostic technique
for T. vaginalis, but wet mount microscopy of vaginal secre-
Genital ulcers (Fig. 36.7A)
tions (sensitivity of about 60–70%) is commonly used.
Point-of-care antigen detection tests have recently been de- Because HSV-2 has become the leading cause of genital
veloped. The sensitivity and specificity of those assays com- ulcer disease globally and syphilis is highly curable, when
pared with culture are about 83 and 97%, respectively. an ulcer is present (with no clear vesicles), the patient
Testing of oral and rectal specimens is not recommended, should be treated with acyclovir for 7 days for HSV infec-
as rectal infection in men who have sex with men is rare, tion and penicillin for syphilis [13]. If clear vesicles are pre-
and T. vaginalis is not known to infect the oropharynx [11]. sent, treatment for HSV infection alone is recommended,
The differential diagnosis of vaginal discharge in women unless the patient is RPR positive and has not been treated
includes Candida vaginitis and bacterial vaginosis. If there for syphilis recently. The WHO recommends treatment for
is cervicitis, then chlamydia and gonorrhea should be chancroid as well (e.g. azithromycin 1 g orally as a single
considered. In men the differential diagnosis of urethral dose), but given the rarity of chancroid many national
discharge includes gonorrhea and chlamydia along with programs do not include that recommendation. If the ulcer
other bacterial pathogens like Mycoplasma species, HSV, has not healed after 7 days of treatment, treatments for
and oral bacterial flora or respiratory viruses (adenovi- other causes of genital ulcers, such as chancroid, should
ruses) [12]. be considered [12].
477
Patient complains of a
genital sore or ulcer
Take history
and examine
No Sore or ulcer No Educate and counsel

Only vesicles
present? present? Promote condom use
and provide condoms
Yes Yes Offer HIV counseling
and testing if both
facilities are available Patient complains of
Treat for HSV-2 Treat for syphilis
Treat for syphilis and chancroid urethral discharge
if indicated1 Treat for HSV-22 or dysuria
Educate and counsel Take history and examine

Promote condom use and provide condoms Milk urethra if necessary
Offer HIV counseling and testing if both facilities are available
No Any other No Educate and counsel
Discharge
No No confirmed? genital disease? Promote condom use
Ulcer(s) healed? Refer and provide condoms
Ulcer(s) improving?
Yes Yes Offer HIV counseling
and testing if both
Yes Yes
Treat for gonococcal Use appropriate facilities are available
infections and flowchart Review if symptoms
Educate and counsel Continue treatment for Chlamydia trachomatis persist
on risk reduction a further 7 days
Promote condom use Educate and counsel
and provide condoms on risk reduction
Manage and treat Promote condom use
partner and provide condoms
Offer HIV counseling Manage and treat
and testing if both partner
facilities are available Offer HIV counseling
and testing if both
facilities are available
1 Ask patient to return
Indications for syphilis treatment:
in 7 days if symptoms
RPR positive; and
patient has not been treated for syphilis recently persist
2 Treat for HSV-2 where prevalence is 30% or higher, or adapt to local conditions
A B
Figure 36.7 Adapted from the WHO guidelines for the management of sexually transmitted infection. (A) Genital ulcers, (B) urethral
discharge,
Continued
Urethral discharge (Figs. 36.7B causes of male urethral discharge, accounting for 98% of
and 36.7C) cases in one recent South African study [40]. Whenever pos-
sible, single-dose regimens are preferred to encourage ad-
For men who present with complaints of pain on urination herence. In the case of persistent or recurrent discharge, a
or urethral discharge, clinicians should investigate for medical and sexual history should be taken to rule out
evidence of discharge. If none is observed, the penis should non-adherence with the treatment regimen or re-infection
be milked or massaged from the base to the tip in an before other pathogens or drug resistance is considered.
attempt to produce discharge. If there is still none, and Other causes of urethral discharge include Mycoplasma
there is no other evidence of discharge (stained underwear spp., T. vaginalis, and HSV infections [9, 12]. Given
or tissue) the patient should be counseled about safer sex the frequency of T. vaginalis in some settings, the WHO
and asked to return if symptoms persist. If there is evidence recommends treatment for trichomoniasis as part of
of discharge, then patients should be treated for both chla- the urethral discharge management algorithm. National
mydia and gonorrhea as these conditions are the primary guidelines vary.
478
Patient complains of
persistent/recurrent
urethral discharge
or dysuria
Patient complains of
vaginal discharge,
vulval itching
Take history and examine
or burning
Milk urethra if necessary
No No Take history and examine

Discharge Any other Educate and counsel
Assess risk
confirmed? genital disease? Promote condom use
and provide condoms
Yes Offer HIV counseling No No
Abnormal discharge Any other Educate and counsel
and testing if both
or vulval erythema? genital disease? Promote condom use
Use appropriate facilities are available
Yes and provide condoms
flowchart Yes Offer HIV counseling
and testing if both
Use appropriate facilities are available
Yes Yes
Does history confirm Repeat urethral flowchart for
re-infection or poor discharge additional
compliance? treatment treatment
No Yes
Lower abdominal Use flowchart
tenderness? for lower
Treat for
abdominal pain
Trichomonas vaginalis
No
Educate and counsel
on risk reduction High GC/CT or risk Yes Treat for gonoccocal
Promote condom use assessment positive? infection, Chlamydia
and provide condoms trachomatis, bacterial
Manage and treat No vaginosis
partner and Trichomonas
Ask patient to return Treat for vaginalis
in 7 days if symptoms bacterial vaginosis
persist and
Educate and counsel Trichomonas Vulval edema/ Yes Treat for
vaginalis curd-like discharge, Candida albicans
Yes Promote condom use
Improved? and provide condoms erythema,
Offer HIV counseling excoriations
and testing if both present?
No facilities are available
No
Refer
Educate and counsel
Promote condom use and provide condoms
Offer HIV counseling and testing if both
facilities are available
C D
Figure 36.7, cont’d (C) persistent/recurrent urethral discharge, (D) vaginal discharge.
From Guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2003.
OR 150 mg fluconazole orally as a single dose) to treat can-

Vaginal discharge (Fig. 36.7D)
didiasis [12]. In the absence of laboratory testing, treatment
Complaints of vaginal discharge are highly indicative of for chlamydia or gonorrhea should be given only if the in-
vaginal infection as opposed to cervical infection. In women fection appears to be cervical, if the woman has a high risk
of reproductive age, vaginal discharge is most often caused profile, or if the epidemiologic profile of the region suggests
by T. vaginalis, Candida albicans, or bacterial vaginosis. The high incidence of chlamydia or gonorrhea in women pre-
WHO recommends that patients be treated for all three con- senting with vaginal discharge. Although symptoms may ap-
ditions: metronidazole 400 or 500 mg orally twice daily for pear minor, it is important to properly treat women, as
7 days to treat T. vaginalis and bacterial vaginosis, AND mi- cervico-vaginal infections and abnormal vaginal flora are as-
conazole or clotrimazole 200 mg intravaginally daily for 3 sociated with adverse pregnancy outcomes and increased
days (OR clotrimazole 500 mg intravaginally as a single dose risk of HIV acquisition [41].
479
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481
Chapter | 37 |
Prevention of mother-to-child
transmission of HIV-1
Lynne M. Mofenson
limited maternal–child healthcare infrastructure has had

INTRODUCTION difficulty supporting the addition of antenatal HIV-1 test-
ing and antiretroviral programs [3]. Postnatal transmission
Globally, mother-to-child transmission (MTCT) is the remains a significant problem in these settings, where
primary mode of HIV-1 acquisition in children. Prior breastfeeding is a cornerstone of infant survival [4]. Recent
to the development of effective interventions to reduce clinical trials have demonstrated that antiretroviral prophy-
MTCT, estimated transmission rates ranged from 15–25% laxis of the breastfeeding infant or the lactating mother can
in non-breastfeeding populations in the USA and Europe significantly decrease postnatal HIV-1 acquisition, offering
to 25–40% in breastfeeding populations in resource- new hope for prevention in these settings [5].
constrained countries. This chapter will discuss risk factors for MTCT; review
An estimated 370,000 children were infected with HIV-1 progress in prevention of MTCT, concentrating on antire-
worldwide in 2009 [1]. Although this represents a 24% de- troviral interventions; and discuss guidelines related to pre-
crease from 2001, over 1,000 infections continue to occur vention of MTCT in resource-rich and resource-constrained
in children daily. Over 90% of these infections occurred settings.
in sub-Saharan Africa, where HIV-1 acquisition through
breast milk accounts for at least 40% of infections. RISK FACTORS FOR HIV-1 MTCT
In well-resourced health systems in the USA and Europe,
virtual elimination of perinatal HIV-1 infection is within
reach. Early identification of infection among pregnant HIV-1 can be transmitted during pregnancy, labor, and
women through routine, opt-out antenatal HIV-1 testing, through breast milk. While different risk factors may influ-
immediate assessment of infected pregnant women to deter- ence transmission during each of these periods, maternal
mine their need for treatment, and provision of antiretroviral HIV-1 viral load has consistently been a strong indepen-
therapy when needed or antiretroviral prophylaxis if therapy dent predictor of transmission, regardless of timing of
is not yet required has substantially reduced the risk of infant transmission [6, 7]. Hence, interventions that reduce viral
infection during pregnancy and delivery. When combined load might be expected to influence transmission during
with elective cesarean delivery and complete avoidance of each of these periods.
breastfeeding, these interventions have reduced MTCT rates
to 1–2% [2]. In utero and intrapartum
However, in resource-constrained countries, where most
transmission
HIV-1-infected women reside, control of the perinatal epi-
demic continues to be challenging. Clinical trials have In the absence of breastfeeding and antiretroviral prophy-
identified simple, less expensive, effective antiretroviral laxis, in utero transmission proportionally accounts for 25–
prophylaxis regimens more relevant to these countries that 30% and intrapartum transmission 65–70% of MTCT.
can reduce transmission during pregnancy and delivery. During pregnancy the placenta provides a physical and im-
However, implementation has been slow, as the existing mune barrier between maternal and fetal circulations and
485
Section | 4 | Prevention and management
also against in utero HIV-1 infection, as the absolute rate of Babies (ZVITAMBO) trial, which enrolled infants born to
in utero transmission is only 5–10%. Although the exact 4,495 women with chronic HIV-1 infection [17].
mechanisms of in utero transmission have not been eluci- Although the risk of HIV-1 transmission through breast
dated, factors that disrupt placental integrity, such as chor- milk persists for the duration of breastfeeding, the early
ioamnionitis, might be expected to play a role. Genetic breastfeeding period (first 1–2 months) may be the period
factors (e.g. HLA type, CCR5 genotype) and viral character- of highest risk. This is illustrated by the SAINT trial, in
istics, such as viral subtype, have been reported to influence which all women and infants received effective prophylaxis
in utero transmission. against intrapartum transmission (zidovudine [AZT]/lami-
Intrapartum transmission can occur through access of cell- vudine [3TC] or single-dose nevirapine [NVP]) [18]. The
free or cell-associated virus to the infant systemic circulation trial included formula and breastfed infants; breastfeeding
by maternal–fetal transfusions during uterine contractions in was the most significant risk factor for MTCT. By age
labor, or through the infant swallowing HIV-1 present in 8 weeks, breastfeeding accounted for an absolute 6% in-
genital fluids during delivery, with resultant viral passage crease in MTCT compared to formula-feeding. Postnatal
through the gastrointestinal mucosa to underlying lymphoid transmission was also highest in the first few weeks of life
cells, followed by systemic dissemination. The proven effi- in the control arm of the Breastfeeding and Nutrition
cacy of interventions restricted to the peripartum period, such (BAN) study (receiving single-dose NVP and 1 week post-
as elective cesarean section performed prior to labor and rup- natal AZT/3TC): postnatal transmission was 0.5%/week
ture of membranes or antiretroviral prophylaxis adminis- between 2 and 6 weeks, 0.3%/week between 7 and 12
tered only around the time of delivery, illustrates the weeks, and 0.1%/week thereafter [5, 19].
importance of the intrapartum period in MTCT [8–12]. In addition to duration of breastfeeding, postnatal trans-
Risk factors for transmission during the antepartum and mission risk factors include high plasma and maternal viral
peripartum periods were examined in 3,396 infants with load; low CD4 count; breast milk immunologic factors;
known infection status born between 2002 and 2006 in breast pathology including clinical and subclinical mastitis,
New York State [13]. On multivariable analysis, maternal nipple bleeding, cracked nipples, or breast abscess; and in-
HIV diagnosis at or after delivery, maternal acquisition of fant pathology that disrupts mucosal integrity, such as
HIV during pregnancy, illicit substance use during preg- thrush [7, 20]. Several studies have suggested that exclusive
nancy, having 0–2 prenatal care visits, and neonatal birth breastfeeding is associated with lower risk of transmission
weight <2,500 g were associated with MTCT. than mixed feeding including breast milk and non-human
milk, fluids, or other foods [20–22]. In the Zambia Exclu-
sive Breastfeeding Study, early postnatal transmission
before age 4 months was 2.7-fold higher in infants who
Postnatal transmission
did not exclusively breastfeed compared to those who
Breastfeeding substantially increases MTCT and can ac- did, adjusted for maternal CD4 count and viral load, syph-
count for 30–50% of all transmission in breastfeeding ilis, and low birth weight [23]. Finally, primary infection
populations. Postnatal transmission results in a significant during breastfeeding has been shown to substantially in-
diminution of the efficacy of antiretroviral interventions crease the risk of postnatal transmission [17, 24, 25].
that prevent in utero and intrapartum transmission [11,
14, 15]. Thus, for optimal prevention of MTCT in a breast-
feeding setting, additional interventions are needed to ANTIRETROVIRAL INTERVENTIONS
reduce postnatal transmission.
Determining the timing of breast milk transmission has TO PREVENT HIV-1 MTCT
been complicated by the difficulty in distinguishing be-
tween intrapartum and early breast milk transmission; In 1994, the PACTG 076 clinical trial first demonstrated
thus, most studies have focused on postnatal transmission that an antiretroviral drug, AZT, given during pregnancy,
occurring after age 1 month. The Breastfeeding and HIV In- intravenously during labor, and to the newborn for 6 weeks
ternational Transmission Study was an individual patient significantly reduces in utero and intrapartum HIV-1 trans-
meta-analysis involving 4,085 children in 9 clinical trials mission [26]. In resource-rich countries, this relatively
in breastfeeding populations [16]. Of 539 children with complex regimen was rapidly adopted as standard of care
known timing of infection, 225 (42%) had late postnatal for HIV-infected pregnant women and their infants, with
transmission (occurring after age 1 month). Overall, late subsequent decline in overall population-based MTCT
postnatal transmission risk was 8.9 infections per 100 rates [27]. As new antiretroviral drugs became available,
child-years of breastfeeding, with a generally constant risk treatment with combination drug regimens (initially dual
throughout the breastfeeding period (0.17%/week); the and then triple regimens) became standard of care, includ-
cumulative probability of late postnatal infection at age ing for treatment of pregnant women. Although there were
18 months was 9.3%. Almost identical results were no randomized clinical trials, observational data suggested
reported from the Zimbabwe Vitamin A for Mothers and that use of combination regimens during pregnancy further
486
Chapter | 37 | Prevention of mother-to-child transmission of HIV-1
reduced MTCT compared to AZT alone, at least in women delivery and receipt of antenatal antiretroviral drugs are
requiring therapy for their own health [2, 27]. Thus, in each independently associated with transmission, suggest-
resource-rich countries, combination regimens that include ing that antiretroviral prophylaxis does not work solely
3 or more antiretroviral drugs are currently given during through viral load reduction [27].
pregnancy to HIV-infected women. In women who meet Studies have demonstrated that the quantity of cell-free
treatment criteria, these drugs are continued postpartum; and cell-associated virus in cervico-vaginal secretions is
in women who do not yet require treatment for their associated with MTCT, independent of plasma viral load
own health, the drugs may be discontinued postpartum. [29]. Thus, providing prophylaxis to the infant immedi-
However, in resource-constrained countries, the PACTG ately before and after extensive viral exposure during labor
076 regimen was considered too complex and expensive and delivery is an additional important mechanism of effi-
to implement following the 1994 trial, and researchers cacy and results of clinical trials (discussed below) have
explored the development of shorter, less expensive pro- demonstrated that intrapartum/postpartum antiretroviral
phylactic regimens more applicable to these settings. Stud- regimens, without any maternal antenatal drug compo-
ies initially focused on shortened AZT-alone prophylaxis nent, can significantly decrease MTCT [10–12].
regimens, and moved to evaluating whether combination
regimens, such as short-course AZT plus 3TC, might have
better efficacy than AZT alone. Studies also evaluated Clinical trials for prevention
whether even simpler, less expensive, single-drug regimens,
such as single-dose intrapartum/neonatal NVP, would be
of HIV-1 MTCT
effective, and whether combining single-dose NVP with Early international trials to prevent MTCT largely focused
other short-course regimens might result in improved on antiretroviral drug use solely for prevention of transmis-
efficacy. sion, without consideration of maternal treatment, because
The overall results from these international trials, as well antiretroviral therapy was not generally available in re-
as open-label and observational studies, demonstrate that a source-constrained countries at the time the studies were
number of different regimens have efficacy in preventing in performed. However, treatment is now available in these
utero and intrapartum transmission, but that efficacy is di- settings; a key issue in decisions on which antiretroviral
minished in breastfeeding populations due to postnatal regimen to choose for an HIV-infected pregnant woman
HIV acquisition through breast milk. More recent trials (or a postpartum lactating woman) is whether the drugs
have demonstrated that antiretroviral prophylaxis of the are being provided for treatment (in which case combina-
lactating woman or her breastfeeding infant is a safe and tion antiretroviral therapy should be provided and contin-
effective way to reduce postnatal transmission in settings ued for life) or solely for MTCT prophylaxis (in which case
where feeding with breast milk alternatives is not safe, less intensive regimens may be equally effective and antire-
acceptable, feasible, affordable, and sustainable. troviral drugs could stop when transmission risk has
ceased). In resource-constrained countries, guidelines rec-
ommend that pregnant women with CD4 <350 cells/
Mechanisms of action of mm3 or World Health Organization (WHO) stage III or IV
disease should start on life-long combination antiretroviral
antiretroviral prophylaxis
therapy [30]. In a study of 3,736 HIV-1-infected pregnant
Antiretroviral drugs can reduce in utero and intrapartum women in 13 clinical programs in 8 African countries and
MTCT by several different mechanisms, including: decreas- Thailand, 52% met WHO treatment criteria and 48% did
ing maternal viral load in blood and genital secretions; pro- not [31]. Current research is focused on what prophylactic
vision of pre-exposure prophylaxis to the infant through regimen would be most efficacious and cost-effective for
drug administration to the mother during labor, resulting the subgroup of women who don’t require therapy.
in systemic drug levels in the infant at a time of intensive Tables 37.1–37.3 summarize results of randomized clin-
exposure of the infant to HIV-1 during delivery; and provi- ical trials of antiretroviral interventions for prevention of
sion of post-exposure prophylaxis through drug adminis- MTCT. Table 37.1 summarizes early trials of AZT, AZT/
tration to the infant after birth to protect against cell-free 3TC, and single-dose NVP; Table 37.2 summarizes trials
or cell-associated virus that entered the circulation during combining single-dose NVP with various antepartum regi-
uterine contractions or is passed through the mucosa of mens; and Table 37.3 summarizes more recent trials eval-
the infant during delivery. uating regimens to prevent postnatal transmission. These
Efficacy is likely multifactorial. In women with high viral trials have built sequentially on each other and identified a
loads, it is likely that lowering viral levels with antenatal an- number of simple regimens effective in reducing MTCT. Di-
tiretroviral drugs is a critical component of protection. rect comparison between trials is difficult, as they enrolled pa-
However, antiretroviral drugs have been shown to reduce tient populations from different geographic areas, infected
the risk of transmission even among women with very with different viral subtypes, and having different infant
low viral levels [28]. The HIV RNA level (viral load) at feeding practices. However, some general conclusions can
487
Section | 4 |
488
Table 37.1 Clinical trials of antiretroviral drugs for prevention of mother-to-child HIV-1 transmission—zidovudine, zidovudine/lamivudine, single-dose nevirapine
STUDY/ INFANT REGIMEN ANTENATAL/ POSTPARTUM EFFICACY

LOCATION FEEDING INTRAPARTUM
PACTG 076 Formula AZT vs placebo Long (from Long (6 weeks) MTCT at 18 months, 7.6% AZT vs 22.6%
USA, France [26] 14 weeks), (Infant only) placebo (68% efficacy)
Intravenous IP
Prevention and management

Bangkok Short- Formula AZT vs placebo Short (from None MTCT at 6 months, 9.4% AZT vs 18.9%
Course AZT 36 weeks) placebo (50.1% efficacy)
Trial Oral IP
Thailand [32]
Thai Perinatal Formula AZT different length AP and Long (from Long (for 6 weeks) Short-Short stopped early due to
HIV Prevention infant PP regimens, no 28 weeks) Short (for 3 days) significantly higher MTCT (10.5%).
Trial (PHPT-1) placebo Short (from (Infant only) MTCT at 6 months, 6.5% Long-Long vs
Thailand [33] 36 weeks) 4.7% Long-Short vs 8.6% Short-Long
Oral IP (statistical equivalence).
However, in utero transmission
significantly lower with Long vs Short
maternal AP AZT (1.6% vs 5.1%)
Ivory Coast Breastfeeding AZT vs placebo Short (from None MTCT at 3 months, 15.7% AZT vs 24.9%
Short-Course 36 weeks) placebo (37% efficacy)
AZT Oral IP
Trial
Ivory Coast [14]
DITRAME / Breastfeeding AZT vs placebo Short (from Short (1 week) MTCT at 6 months, 18.0% AZT vs 27.5%
ANRS 049a 36 weeks) (Mother only) placebo (38% efficacy); MTCT at 15 months,
Ivory Coast / Oral IP 21.5% vs 30.6% (30% efficacy).
Burkina Faso MTCT at 24 months (pooled analysis with
[15] other Ivory Coast trial), 22.5% vs 30.2%
(26% efficacy)
PETRA Breastfeeding AZTþ3TC in 3 regimens Short (from Short (7 days) MTCT at 6 weeks, 5.7% 3-part (63%
South Africa, (3-part AP/IP/PP; 2-part IP/ 36 weeks) (Mother and Infant) efficacy) vs 8.9% 2-part (42% efficacy) vs
Tanzania, and PP; IP alone) vs placebo Oral IP 14.2% IP alone vs 15.3% placebo.
Uganda [10] MTCT at 18 months, 14.9% 3-part vs 18.1%
2-part vs 20% IP alone vs 22.2% placebo
Chapter | 37 |
HIVNET 012 Breastfeeding IP/PP NVP vs AZT No AP ARV Single-dose NVP 2 mg/ MTCT 15.7% in NVP arm versus 25.8% in
Uganda [11] Oral IP: Single- kg within 72 h of birth AZT arm (41% efficacy) at 18 months
dose oral NVP vs
200 mg vs AZT short AZT (7 days)
(Infant only)
SAINT Breastfeeding IP/PP NVP versus No AP ARV Single-NVP dose MTCT at 8 weeks, 12.3% NVP vs 9.3%
South Africa [18] (42%) and AZTþ3TC Oral IP: Single- within AZTþ3TC
Prevention of mother-to-child transmission of HIV-1

formula dose NVP 200 mg 48 h of birth vs short
feeding vs AZTþ3TC AZTþ3TC (7 days)
(Mother and Infant)
3TC ¼ lamivudine; ARV ¼ antiretroviral; AP ¼ antepartum; AZT ¼ zidovudine; IP ¼ intrapartum; MTCT ¼ mother-to-child transmission; NVP ¼ nevirapine; PP¼ postpartum.
Table 37.2 Clinical trials of antiretroviral drugs for prevention of mother-to-child HIV-1 transmission—zidovudine or zidovudine/lamivudine combined
with single-dose nevirapine

Thai Perinatal Formula AZT vs AZT þ maternal/infant Long (AZT from 1 week AZT alone AZT alone arm stopped early due to
HIV Prevention single-dose NVP vs AZTþ 28 weeks) vs 1 week AZT þ significantly higher MTCT: MTCT at 6
Trial-2 (PHPT-2) maternal single-dose NVP only IP: Oral AZT þ single-dose NVP months, 6.3% AZT alone vs 1.1%
Thailand [34] single-dose NVP (infant only) with AZT plus maternal/infant NVP vs
or placebo 2.1% with AZT plus maternal NVP
alone
Final analysis, MTCT at 6 months,
2.8% with AZT plus maternal NVP
only vs 1.9% with AZT plus maternal/
infant NVP
DITRAME PLUS / Breastfeeding Open label, AZTþ maternal/ Short (from 36 Single-dose NVP þ MTCT at 6 weeks, 6.5% (95% CI,
ANRS 1201.0 (54%) and infant single-dose NVP weeks) 1 week AZT 3.9–9.1%)
Abidjan, Cote formula Oral IP: Single- (Infant only) Compared to MTCT in historical
d’Ivoire [36] feeding dose NVP 200 mg control AZT alone (1995–2000)
þ AZT 12.8% (in AZT alone group,
breastfeeding rate was 97.6%)
Continued
489
Section | 4 |
490
Table 37.2 Clinical trials of antiretroviral drugs for prevention of mother-to-child HIV-1 transmission—zidovudine or zidovudine/lamivudine combined
with single-dose nevirapine—cont’d

DITRAME PLUS / Breastfeeding Open label, AZTþ3TC boosted Short (from 32 AZTþ3TC for 3 MTCT at 6 weeks, 4.7% (95% CI,
ANRS 1201.1 (66%) and by IP/PP NVP weeks) days 2.4–7.0%)

Abidjan, Cote formula Oral IP: Single- (Mother only) MTCT not significantly different than
d’Ivoire [36] feeding dose NVP 200 mg Single-dose NVP þ observed with DITRAME 1201.0
þ AZTþ3TC one week AZT regimen AZT þ single dose NVP (p ¼
(Infant only) 0.34)
PACTG 316 Formula IP/PP NVP vs placebo in Non-study AP Single-dose NVP Trial stopped early due to very low
USA, Europe, Brazil, women already receiving AZT ARV 2 mg/kg within MTCT in both arms. MTCT at 6
Bahamas [37] or AZT plus other ARV Oral IP: Single- 72 h of birth þ 6 months, 1.4% NVP versus 1.6%
(77% on combination drugs) dose NVP 200 mg weeks AZT placebo
þ intravenous AZT (Infant only)
NVAZ-1 Breastfeeding Neonatal single-dose NVP No ARV AP or IP Single-dose NVP Overall MTCT at 6–8 weeks, 15.3%
Malawi [12] only vs NVPþAZT (late presenters) immediately after NVPþAZT vs 20.9% NVP only
birth þ AZT twice MTCT at 6–8 weeks in babies who
daily for one week were uninfected at birth, 7.7%
(Infant only) NVPþAZT vs 12.1% NVP only (36%
efficacy)
NVAZ-2 Breastfeeding Neonatal single-dose NVP No ARV AP Single-dose NVP Overall MTCT at 6–8 weeks, 16.3%
Malawi [38] only vs NVPþAZT Oral IP: Single- immediately after NVPþAZT vs 14.1% NVP only
dose NVP to birth þ AZT twice MTCT at 6–8 weeks in babies who
mother daily for one week were uninfected at birth, 6.9%
(Infant only) NVPþAZT vs 6.5% NVP only
Mashi Breastfeeding Factorial design, randomized to Short (AZT from Single-dose NVP þ Original study (maternal/infant NVP
Botswana [35] and formula mode of infant feeding and 34 weeks) 1 month AZT if vs placebo): NVP provides added
feeding maternal/infant single-dose NVP Oral IP: AZT þ formula feeding efficacy in formula-fed but not
(randomized) vs placebo single-dose NVP Single-dose NVP þ breastfed infants. MTCT at 1 month,
Infant placebo discontinued 08/ or placebo (infant 6 months AZT if formula-fed infants, 2.4% NVP/NVP
02 (after PHPT-2 results), study only) breastfeeding vs 8.3% placebo/placebo; breastfed
modified to maternal NVP vs (infant only) infants, 8.4% NVP/NVP vs 4.1%
placebo, with all infants receiving placebo/placebo
single-dose NVP Revised study (maternal NVP vs
placebo, all infant NVP): No added
efficacy from maternal NVP
Chapter | 37 |
regardless of infant feeding mode.
MTCT at 1 month, 4.3% NVP/NVP vs
3.7% placebo/NVP
Infant feeding: Breastfeeding þ AZT
higher transmission than formula.
MTCT at 7 months, 9.1%
breastfeeding þ AZT vs 5.6%
formula. However, higher infant

mortality with formula at 7 months,
9.3% formula vs 4.9% breastfeeding
þ AZT
Incremental risk of postnatal MTCT
between 1 and 7 months, 4.5%
(comparable to postnatal MTCT in
BHITS meta-analysis between 1 and 6
months, 4.2%, with no infant
prophylaxis)
HIV-free survival at 18 months did
not differ between arms. MTCT or
death at 18 months, 14.2% formula
(33 infected, 46 deaths) vs 15.6%
breastfed þ AZT (54 infected, 34
deaths)
NICHD/HPTN 040 Formula Compares 3 different infant No AP drugs Arm 1 (control): Total in utero transmission was
USA, Brazil, South feeding prophylaxis regimens IP regimen (if Infant AZT for 6 5.7%, and not significantly different
Africa [39] when mothers do not receive presents early weeks between arms
AP drugs enough): Arm 2: Control as Total intrapartum transmission rate
Intravenous AZT above þ 3 doses of was 3.2%: 4.9% (95% CI: 3.3–7.2)
NVP in first week in control Arm 1; 2.2% (95% CI: 1.2–
Arm 3: Control as 4.0) in Arm 2 (p ¼ 0.045 compared to
above þ daily 3TC control); AZT þ NVP 2.2%, (95% CI:
and nelfinavir for 1.2–4.0, p ¼ 0.045 compared to
first 2 weeks control); 2..5% (95% CI: 1.4–4.3) in
(infants only) Arm 3 (p ¼ 0.045 compared to
control)
More neutropenia seen in Arm 3.
3TC ¼ lamivudine; ARV ¼ antiretroviral; AP ¼ antepartum; AZT ¼ zidovudine; IP ¼ intrapartum; MTCT ¼ mother-to-child transmission; NVP ¼ nevirapine; PP¼ postpartum.
491
Section | 4 |
492
Table 37.3 Clinical trials of antiretroviral drugs for prevention of postnatal breast milk mother-to-child HIV-1 transmission

SWEN Breastfeeding Infant prophyalxis: No ARV AP Single-dose NVP vs single-dose Postnatal infection in infants

(Six Week Single-dose maternal/infant Oral IP: Single- NVP þ 6 weeks daily NVP uninfected at birth:
Extended-Dose NVP vs extended 6 weeks dose NVP to (infant only) • MTCT at 6 weeks was 5.3% in
Nevirapine) infant NVP mother single-dose NVP arm vs 2.5% in
Uganda, Ethiopia, extended NVP arm (risk ratio 0.54,
India [56] p ¼ 0.009)
• MTCT at 6 months was 9.0% in
single-dose NVP arm vs 6.9% in
extended NVP arm (risk ratio 0.80,
p ¼ 0.16)
• HIV-free survival significantly
better in extended NVP arm at
both 6 weeks and 6 months
PEPI trial Breastfeeding Infant prophylaxis: No ARV AP Infant single-dose NVP þ AZT for Postnatal infection in infants
Malawi [55] Single-dose NVP vs 14 weeks Oral IP: Single- 1 week (control) vs control þ NVP uninfected at birth:
extended infant regimen dose NVP to for 14 weeks vs control þ NVP/ • MTCT at 6 weeks was 5.1% in
mother AZT for 14 weeks (infant only) control vs 1.7% in extended NVP
(if presents in (67% efficacy) and 1.6% in
time to receive) extended NVP/AZT arms (69%
efficacy)
• MTCT at 9 months was 10.6% in
control vs 5.2% in extended NVP
(51% efficacy) and 6.4% in
extended NVP/AZT arms (40%
efficacy)
• No significant difference in MTCT
between the extended
prophylaxis arms; however, more
hematologic toxicity with
NVP/AZT
HPTN 046 Breastfeeding Infant prophylaxis: AP: Provided All infants receive 6 weeks of daily Postnatal infection at 6 months in
Uganda, Compares 6 months and 6 outside of study infant NVP starting at birth infants uninfected at age 6 weeks:
Zimbabwe, weeks daily infant NVP to Randomized at 6 weeks:
prevent postnatal infection Arm 1 (control): Daily placebo
Chapter | 37 |
Tanzania, South from 6 weeks to 6 months • Overall MTCT was 2.4% (95% CI,
Africa [57] Arm 2: Daily NVP from 6 weeks to 1.3–3.6) in placebo Arm 1 and
6 months (infant only) 1.1% (95% CI, 0.3–1.8%) in NVP
Arm 2 (p ¼ 0.048)
• In mothers on ART at
randomization, overall MTCT was
0.2% (0% placebo Arm 1 and
0.5% NVP Arm 2); in women not

on ARV treatment, overall MTCT
was 2.4% (3.4% placebo Arm 1
and 1.4% NVP Arm 2, p ¼ 0.027)
• In mothers not on ARV treatment,
if CD4 was < 350, MTCT not
significantly different between
arms (8.1% placebo Arm 1 and
4.8% NVP Arm 2, p ¼ 0.44);
however, if CD4 was 350,
MTCT significantly less with
extended NVP and similar to that
seen in women on ARV treatment
(2.8% placebo Arm 1 and 0.7%
NVP Arm 2, p ¼ 0.014)
Mma Bana Breastfeeding Maternal prophylaxis: Arm 1: AZT/ Arm 1: Maternal AZT/3TC/ABC MTCT at 6 months overall was 1.3%:
Botswana [47] Maternal triple-drug 3TC/ABC for 6 months; infant single-dose 2.1% in AZT/3TC/ABC Arm 1 and
prophylaxis (compares 2 Arm 2: AZT/ NVP þ AZT for 4 weeks 0.4% in AZT/3TC/LPV/r Arm 2 (p ¼
regimens) in women with CD4 3TC/LPV/r Arm 2: Maternal AZT/3TC/LPV/r 0.53)
>200 From 26 weeks for 6 months; infant single-dose
through labor NVP þ AZT for 4 weeks
Kesho Bora Breastfeeding Maternal prophylaxis: Arm 1: AZT/ Arm 1: Maternal AZT/3TC/LPV/r MTCT at birth was 1.8% with
Multi-African [63] and formula AP AZT/single-dose NVP with 3TC/LPV/r for 6 months; infant single-dose maternal triple-drug prophylaxis Arm
feeding no postnatal prophylaxis vs Arm 2: NVP þ AZT for 1 week 1 and 2.5% with AZT/single-dose
maternal triple-drug AZT þ single- Arm 2: Maternal AZT/3TC for NVP Arm 2, not significantly different
prophylaxis in women with dose NVP 1 week (no further postnatal MTCT at 12 months was 5.4% with
CD4 between 200 and 500 From 28 weeks prophylaxis); infant single-dose maternal triple-drug prophylaxis Arm
through labor NVP þ AZT for 1 week (no further 1 and 9.5% with AZT/single-dose
postnatal prophylaxis) NVP (with no further postnatal
prophylaxis after 1 week) Arm 2
(p ¼ 0.029).
Continued
493
Section | 4 |
494
Table 37.3 Clinical trials of antiretroviral drugs for prevention of postnatal breast milk mother-to-child HIV-1 transmission—cont’d

BAN Breastfeeding Infant vs maternal No AP drugs Arm 1 (control): Maternal AZT/ Postnatal infection in infants
Malawi [5] prophylaxis: Oral IP regimens: 3TC for 1 week; infant single- uninfected at 2 weeks:
Postpartum maternal triple- Arm 1 (control): dose NVP þ AZT/3TC for 1 week • MTCT at 28 weeks was 5.7% in
AZT/3TC þ

drug prophylaxis vs infant NVP Arm 2: Control as above, then control Arm 1; 2.9% in maternal
in women with CD4 250 single-dose NVP maternal AZT/3TC/LPV/r for 6 triple-drug prophylaxis Arm 2 (p ¼
Arm 2: AZT/3TC months 0.009 vs control); 1.7% in infant
þ single-dose Arm 3: Control as above, then NVP Arm 3 (<0.001 vs control)
NVP infant NVP for 6 months No significant difference between
Arm 3: AZT/3TC maternal triple-drug prophylaxis
þ single-dose Arm 2 and infant NVP Arm 3 (p ¼ 0.12)
NVP
3TC ¼ lamivudine; ABC ¼ abacavir; ARV ¼ antiretroviral; AP ¼ antepartum; AZT ¼ zidovudine; ddI ¼ didanosine; IP ¼ intrapartum; LPV/r ¼ lopinavir/ritonavir; MTCT ¼ mother-to-child transmission;
NVP ¼ nevirapine; PP¼ postpartum.
be drawn regarding antiretroviral drug use for prevention of remains unclear. The Thailand PHPT-2 study suggested that
MTCT that are relevant to both resource-constrained and re- the infant NVP dose may not be necessary when maternal
source-rich countries. NVP is provided, and the Botswana Mashi study suggested
Short-term efficacy has been demonstrated for regimens that maternal NVP may not be necessary when infant
with AZT alone; AZT plus 3TC; single-dose NVP; and com- single-dose NVP is provided at birth [34, 35].
bining single-dose NVP with either short-course AZT or In some countries, a significant proportion of women
AZT/3TC. Combination regimens, such as short-course lack antenatal care and present to the healthcare system
AZT plus single-dose NVP, are more effective than single- during labor. A trial was conducted in a breastfeeding pop-
drug regimens in reducing MTCT, and a longer antenatal/ ulation in Malawi to define the optimal infant prophylaxis
intrapartum/postpartum regimen is superior in preventing regimen in resource-constrained settings when no antena-
MTCT than a shorter 2-part antepartum/intrapartum or tal maternal therapy was received (Table 37.2). The addi-
intrapartum/postpartum regimen. tion of one week of AZT to infant single-dose NVP
Almost all trials have included an intrapartum prophy- reduced the risk of transmission by 36% compared to
laxis component, with varying durations of maternal ante- infant single-dose NVP alone (12). However, when mater-
natal and/or infant (and sometimes maternal) postpartum nal intrapartum NVP was received, thereby providing pre-
prophylaxis. Regimens with antenatal components starting exposure in addition to post-exposure prophylaxis, infant
as late as 36 weeks’ gestation and lacking infant prophylaxis single-dose NVP alone was as effective as the combined
can reduce transmission [32]; however, longer duration of NVP/AZT infant post-exposure prophylaxis regimen (38).
antenatal therapy starting at 28 weeks is more effective than In resource-rich countries, standard infant prophylaxis in
shorter [33]. Observational data from the European Na- the absence of maternal antenatal antiretroviral drugs is
tional Study of HIV in Pregnancy and Childhood have 6 weeks of AZT. NICHD/HPTN 040 was designed to deter-
shown even longer antenatal drug duration (starting before mine the optimal infant prophylaxis regimen in formula-
28 weeks’ gestation) further reduces MTCT; each additional fed infants born to women who did not receive antepartum
week of drug corresponded to a 10% reduction in transmis- therapy (Table 37.2). The trial compared standard 6-week in-
sion after adjusting for viral load, mode of delivery, and infant AZT prophylaxis to 6 weeks of AZT combined with either
fant sex [2]. More prolonged post-exposure prophylaxis 3 NVP doses during the first week of life or 2 weeks of nelfi-
of the infant does not substitute for longer duration of navir and 3TC. Both combination regimens reduced intrapar-
maternal therapy [33]. tum MTCT compared to AZT alone by approximately 50%:
Regimens that include no antenatal prophylaxis but in- intrapartum MTCT was 4.9% with AZT alone versus 2.2%
clude intrapartum and postpartum drug administration with AZT/NVP and 2.5% with AZT/3TC/nelfinavir [39].
are also effective (Table 37.1) [10, 11]. However, the PETRA In breastfeeding populations, the impact of short-course
study demonstrated that intrapartum pre-exposure prophy- antiretroviral prophylaxis regimens on long-term risk of in-
laxis alone, without continued post-exposure prophylaxis fant infection is diminished due to the continued transmis-
of the infant, is not effective [10]. The SAINT trial demon- sion during the breastfeeding period. Several trials have
strated that the two proven effective intrapartum/postpar- assessed the effect of antiretroviral prophylaxis provided
tum regimens (AZT/3TC or single-dose NVP) were similar to the mother during lactation or to the breastfeeding in-
in efficacy and safety [18]. fant (Table 37.3) and are reviewed in detail elsewhere
In an attempt to improve the efficacy of short-course regi- [40]. It is not possible to directly compare MTCT rates in
mens but retain a regimen that remains appropriate to the these studies. The patient populations significantly differ;
cost limitations in resource-constrained countries, researchers all the infant prophylaxis studies except one (BAN)
evaluated whether the addition of a potent intrapartum enrolled women regardless of CD4 count, whereas the
intervention—the single-dose NVP regimen—to short-course 3 randomized trials of maternal prophylaxis restricted
antepartum regimens might increase efficacy (Table 37.2). In enrollment to women with CD4 counts > 200–250 cells/
the setting of short-course AZT alone or AZT/3TC regimens, mm3 (Table 37.3). Antepartum antiretroviral drug admin-
the Perinatal HIV Prevention Trial (PHPT)-2 study in non- istration and duration significantly differ: the infant pro-
breastfeeding women in Thailand, the Mashi study in Bot- phylaxis studies enrolled women who had not received
swana (in the formula-fed strata), and the DITRAME studies any antepartum drugs while all the maternal prophylaxis
in a partly breastfeeding population in the Cote d’Ivoire, dem- studies except one (BAN) provided antepartum drugs (of
onstrated that the addition of single-dose NVP did signifi- different durations, starting at 25 to 36 weeks’ gestation).
cantly increase efficacy [34–36]. However, a clinical trial Additionally, the postnatal prophylaxis duration differs be-
conducted in resource-rich countries, PACTG 316, demon- tween studies, with 2 infant prophylaxis studies providing
strated that the addition of single-dose NVP did not appear only 6 to 14 weeks of postnatal prophylaxis while all of the
to offer significant benefit in the setting of potent combination maternal prophylaxis studies provided 6 months of postna-
antiretroviral therapy throughout pregnancy and very low vital prophylaxis.
ral load at the time of delivery [37]. The relative importance of Despite these differences, currently available data suggest
the maternal and infant components of single-dose NVP that both infant and maternal prophylaxis are effective in
495
reducing postnatal infection in women who don’t require Data are conflicting on whether combination antiretro-
therapy for their own health, and may have similar efficacy viral drug use during pregnancy is associated with preterm
when compared during similar periods of prophylaxis delivery. A pooled analysis of 19,585 singleton births from
[5, 40]. This is best illustrated by the BAN study, the only 4 European and US observational cohorts concluded that a
trial that included both infant and maternal prophylaxis 3-drug regimen conferred a 1.5-fold increased adjusted
arms (Table 37.3) [5]. Given two presumably similarly odds of preterm delivery compared with a 2-drug regimen
effective interventions, the choice of intervention to pre- [46]. A randomized trial comparing two different combina-
vent MTCT for breastfeeding women who do not require tion regimens found a higher preterm delivery rate in
treatment for their own health will involve weighing a women receiving a protease inhibitor-based compared
number of different considerations, including relative to a triple nucleoside regimen [47]. In contrast, a US study
costs, feasibility, and risks and benefits of the interventions. of 777 HIV-1-infected pregnant women who were not
receiving antiretroviral drugs at conception found no asso-
ciation of combination drugs with preterm delivery [48].
However, only 21% had received drugs during the first
SHORT- AND LONG-TERM SAFETY trimester; some studies suggest that preterm delivery is
more likely to be associated with drug use early in preg-
OF ANTIRETROVIRAL EXPOSURE nancy (e.g. first trimester or at conception) [49].
FOR INFANTS AND WOMEN Some data suggest that short-term toxicity may be greater
with combination regimens than single-drug regimens.
Higher rates of anemia and neutropenia in the first few
Infant
months of life were observed in uninfected infants born
The short-course antiretroviral regimens studied in clinical to mothers receiving 3-drug regimens during pregnancy
trials in resource-constrained settings have been associated compared to those exposed only to single or dual drugs,
with minimal short-term infant toxicity; antiretroviral expo- but this resolved by age 6 months [50, 51]. Additionally,
sure is associated with transient, mild hematologic abnor- uninfected infants exposed to maternal 3-drug regimens
malities that resolve following completion of prophylaxis had lower birth weight and length than those exposed only
[41, 42]. However, longer-term outcome data in infants to AZT, although this difference resolved (weight) or nar-
exposed to the more complex and prolonged maternal anti- rowed (height) by age 6 months [52].
retroviral prophylaxis regimens used in resource-rich coun- Longer-term data are limited. Pre-clinical data indicate
tries are still limited. that some nucleoside analogue reverse transcriptase inhib-
Current data indicate no increase in congenital abnor- itor (NRTI) drugs are carcinogenic in vitro and can be asso-
malities among offspring of women with first trimester ciated with mitochondrial toxicity. No increase in overall
use of most antiretroviral drugs [43]. However, there re- cancer risk has been observed in > 9,000 uninfected
main concerns related to efavirenz (EFV). In a primate NRTI-exposed children followed to median age 5.4 years
study, prenatal EFV exposure was associated with central [53]. However, French researchers have reported rare occur-
nervous system defects in infant monkeys and the Antire- rence of mitochondrial dysfunction in uninfected infants
troviral Pregnancy Registry has received six retrospective with in utero antiretroviral exposure, with higher risk
reports of central nervous system defects (e.g. meningo- among those exposed to combination regimens. In a co-
myelocoele) in human infants after first trimester exposure hort of 4,392 uninfected HIV-1-exposed children, evidence
[43]. However, a meta-analysis of observational data from of mitochondrial dysfunction was identified in 12 children
1,132 women with first trimester EFV exposure from 9 pro- (with 2 deaths), yielding an 18-month incidence of 0.26%
spective cohorts (including the Antiretroviral Pregnancy [54]. All children presented with neurologic symptoms, of-
Registry) found no increased risk of overall birth defects ten with abnormal magnetic resonance imaging and/or a
compared with exposure to other antiretroviral drugs significant episode of hyperlactatemia, and all had an iden-
[44]. Across 11 cohorts including 1,256 live births with tified deficit in one of the mitochondrial respiratory chain
first trimester EFV exposure, one neural tube defect was ob- complexes and/or abnormal muscle biopsy histology.
served, giving a prevalence of 0.08% [44]. Although these While continued follow-up of infants exposed to antire-
data are reassuring, the low neural tube defect incidence troviral drugs for potential adverse long-term effects is crit-
in the general population means that larger exposure num- ical, current data indicate that if such toxicity is observed, it
bers are needed to definitively rule out an increased risk of is relatively rare, and potential risks of antiretroviral expo-
this specific defect. EFV should be avoided in the first tri- sure for the infant need to be placed in perspective with the
mester of pregnancy (although second/third trimester use proven benefit of antiretroviral therapy for the health of the
may be considered). Women of childbearing potential mother and in reducing HIV-1 MTCT by up to 70%.
should undergo pregnancy testing before initiating EFV Extended daily infant NVP prophylaxis can prevent
therapy, and be counseled about the potential risk to the breast milk MTCT [5, 55–57]. Extended NVP used for up
fetus and provided with adequate contraception [45]. to 6 months has been studied in over 4,500 infants in
496
the SWEN, PEPI—Malawi, HPTN 046, and BAN trials trial (Promoting Maternal Child Health Everywhere,
(Table 37.3); the regimen appears safe compared to control PROMISE—Clinical trial NCT00955968).
interventions, with the exception of higher number of
rashes in the BAN study (however, grade 3 or 4 rash in
BAN was <2%) [5]. Daily AZT/NVP infant prophylaxis
was associated with higher rates of hematologic toxicity ANTIRETROVIRAL DRUG RESISTANCE
than daily NVP [55].
Short-course antiretroviral drug regimens used to prevent
MTCT that do not fully suppress viral replication may be
associated with antiretroviral drug resistance. This is most
Pregnant woman
likely to occur with prophylaxis regimens using drugs for
Minimal toxicity has been seen in women receiving the which a single point mutation can confer drug resistance,
short-course regimens studied in trials in resource- such as NVP or 3TC.
constrained settings. Toxicity has been primarily confined Genotypic resistance to 3TC was observed in pregnant
to women receiving longer, more complex, combination women receiving 3TC with AZT as a dual NRTI regimen
regimens; primary toxicity concerns include lactic acidosis to prevent MTCT. In a study in France, 3TC was added to
with NRTI drugs; rash and hepatic toxicity with NVP; and AZT after 32 weeks’ gestation; 39% of 132 women had de-
potential for hyperglycemia with protease inhibitors [45]. tectable high-level resistance (M184V) to 3TC at 6 weeks,
It is unclear if pregnancy augments the incidence of the postpartum [66]. Resistance was only detected in women
lactic acidosis/hepatic steatosis syndrome reported in non- who had received 3TC for 4 weeks during pregnancy. De-
pregnant individuals receiving NRTI drugs. Cases of lactic spite the high prevalence of 3TC resistance, the MTCT rate
acidosis, including maternal and fetal fatalities, have been was low, 1.6%. Whether the presence of 3TC drug resis-
reported in HIV-1-infected pregnant women receiving pro- tance following prophylaxis is associated with diminished
longed therapy with NRTIs, with symptoms presenting virologic response to subsequent 3TC-based therapy is
in late pregnancy. Physicians caring for HIV-infected preg- unknown.
nant women receiving NRTIs need to be alert for the early Resistance mutation selection in infected women and in-
diagnosis of this syndrome [45]. fants following single-dose NVP is well documented. NVP
Severe symptomatic, and rarely fatal, hepatic toxicity as- has a long half-life, and hence persists for a prolonged pe-
sociated with chronic NVP therapy is more frequent in fe- riod, and a single mutation in the viral codon confers drug
males. Some but not all studies suggest increased risk in resistance. Resistance rates vary by maternal CD4 count and
pregnant women with CD4 count > 250/mm3 or elevated viral load at the time of exposure, viral subtype, whether
transaminases at the start of treatment [58, 59]. Hepatic other antiretroviral drugs were given, the type of resistance
toxicity has not been observed in women receiving sin- assay, and for infants, whether the mother received single-
gle-dose NVP. Women who experience clinical hepatotox- dose NVP [67, 68]. Women who require treatment for their
icity or rash while receiving NVP should have the drug own health are also those at greatest risk for resistance fol-
discontinued and should not receive NVP in the future. lowing single-dose NVP; identification of such women and
Protease inhibitors can be associated with metabolic ab- initiation of lifelong combination antiretroviral therapy
normalities, including hyperglycemia and new-onset dia- during pregnancy will avoid the development of resistance
betes. Data are conflicting regarding whether there is an in this high-risk group [68].
increase in gestational hyperglycemia in HIV-1-infected While resistance is frequent in the first few weeks–
pregnant women and its association with protease inhibi- months following exposure, detection decreases with time,
tor use [60, 61]. This complication may be increased in although low levels of virus with resistance mutations can
HIV-1-infected pregnant women co-infected with hepatitis persist for prolonged periods and in some cases can remain
C virus [62]. present in latently infected cells. Current data suggest that
The use of antepartum and extended postpartum mater- protease inhibitor-based therapy is superior to NNRTI-based
nal 3-drug prophylaxis to prevent breast milk MTCT, stud- therapy in women starting treatment within 12–24 months
ied in over 1,800 mother/infant pairs in the Kesho Bora, of single-dose NVP exposure and in infants infected despite
BAN and Mma Bana trials (Table 37.3), appears safe for use of single-dose NVP [69, 70].
the mother compared to control interventions, with the Antiretroviral drug administration for a short period fol-
exception of maternal neutropenia; in the BAN trial sig- lowing single-dose NVP (use of a “tail”) can reduce resis-
nificantly more neutropenia was observed in women tance incidence to very low levels. Regimens studied for
receiving triple drugs [5, 47, 63]. prevention of resistance include AZT/3TC given for 4 to 7
There are only limited data on the safety of stopping days following single-dose NVP; tenofovir/emtricitabine
3-drug regimens used solely for prevention of MTCT in as a single-dose during labor or for 7 days postpartum;
women who do not need therapy for their own health AZT/didanosine (ddI)/lopinavir-ritonavir for 7 or 30 days;
[64, 65]. This is being assessed in a large randomized and administration of AZT/ddI for 30 days [67]. NNRTI
497
resistance rates of 0 to 7% at 2 to 6 weeks’ postpartum using randomized clinical trial [8, 9]. Non-elective cesarean de-
ultrasensitive assays have been reported with some of these livery performed after onset of labor or rupture of mem-
tail regimens. Thus, administration of a minimum 7-day branes did not reduce MTCT compared with vaginal
tail following use of single-dose NVP as MTCT prophylaxis delivery.
is recommended to reduce resistance in women. It is unclear if benefit would be observed in women on
Very high NVP resistance rates are observed in infants receiving potent combination drugs who have undetect-
infected despite extended infant NVP prophylaxis of breast able virus [78, 79]; in this situation, the risk of MTCT is very
milk transmission. In the SWEN study of 6 weeks of infant low and the risk of operative delivery to the mother may
NVP prophylaxis, 92% of infants infected during the first 6 outweigh the potential benefit in reducing MTCT.
weeks of life (the period of NVP prophylaxis) had NNRTI
resistance compared to 38% in the control single-dose NVP
arm [71]. However, NNRTI resistance among infants who CURRENT GUIDELINES FOR
became infected after prophylaxis had ceased (after age 6
PREVENTION OF MTCT FOR THE
weeks) was similar, 15%, to the single-dose NVP control.
Co-administration of NVP and AZT in PEPI—Malawi trial UNITED STATES
decreased NVP resistance but resistance was still frequent
(62%) [72]. Current guidelines for antiretroviral therapy and elective ce-
Antiretroviral drug resistance has also been observed in sarean delivery for the USA [45] are shown in Table 37.4
infants infected despite maternal triple-drug prophylaxis. (see http://AIDSInfo.nih.gov for more details). Based on ob-
Some antiretroviral drugs are known to enter breast milk. servational studies indicating that MTCT rates are extremely
3TC appears to concentrate in breast milk, and is present low in women receiving antiretroviral drugs who have very
at levels 3–5 times that in maternal plasma, while AZT ap- low or undetectable HIV RNA levels, combination antiretro-
pears to be present at levels similar to or somewhat less viral drug regimens are recommended for all pregnant
than maternal plasma [73]. NVP levels are only about women. Additionally, elective cesarean delivery is recom-
60–75% of maternal plasma, and the protease inhibitors mended if HIV RNA levels remain 1,000 copies/mL near
that have been studied have had very limited penetration delivery.
into milk [74]. Thus, breastfeeding infants of mothers re- Based on efficacy studies in preventing transmission and
ceiving triple-drug prophylaxis who become infected may large safety experience with use in pregnancy, the preferred
be ingesting sub-therapeutic levels of antiretroviral drugs NRTI combination for antiretroviral-naı̈ve pregnant women
present in breast milk and therefore develop drug-resistant is AZT/3TC. The alternative NRTI combination regimen if
virus. Three studies have now identified multi-class drug re- AZT/3TC is not tolerated (e.g. anemia) is tenofovir with
sistance (mutations conferring resistance to NRTIs as well 3TC or emtricitabine. There is less experience with tenofovir
as to NNRTIs) in breastfeeding infants who have become in pregnancy. The Antiretroviral Pregnancy Registry has not
infected despite maternal triple-drug prophylaxis [75–77]. reported an increase in overall birth defects in 879 pregnan-
cies with first trimester exposure, but a primate study has
suggested the potential for decreased fetal growth and reduc-
NON-ANTIRETROVIRAL tion in fetal bone porosity with in utero exposure, and studies
INTERVENTIONS in infected children on chronic tenofovir-based therapy has
shown bone demineralization in some children. Therefore,
tenofovir is considered an alternative NRTI during preg-
In general, with the exception of elective cesarean delivery, nancy for naı̈ve women. However, for pregnant women with
the results of non-antiretroviral interventions to prevent HIV/hepatitis B co-infection, tenofovir with 3TC or emtrici-
MTCT have been disappointing. Approaches have included tabine would be the preferred NRTI combination. In addi-
treatment/prophylaxis of chorioamnionitis, vaginal viru- tion to the two NRTIs, either an NNRTI or PI would be
cidal cleansing, and nutritional supplementation, none preferred for combination regimens in antiretroviral-naı̈ve
of which have proven effective for prevention of MTCT pregnant women. Efavirenz is not recommended for use
and hence will not be discussed here. in the first trimester of pregnancy due to concerns related
to birth defects, as discussed earlier. Use of efavirenz after
the first trimester of pregnancy may be considered based
Elective cesarean delivery
on clinical indication, although current data are limited. Ne-
Prolonged duration of membrane rupture is associated virapine would be the preferred NNRTI for antiretroviral na-
with MTCT; elective cesarean delivery (performed prior ı̈ve pregnant women with CD4 count less than 250 cells/
to labor and membrane rupture) has been shown to reduce mm3, and may be continued in an antiretroviral experienced
MTCT in an individual patient data meta-analysis includ- woman already receiving a nevirapine-based regimen re-
ing 8,533 non-breastfeeding mother–child pairs from 15 gardless of CD4 count. Lopinavir/ritonavir is the preferred
prospective US and international cohort studies, and a protease inhibitor for antiretroviral-naı̈ve pregnant women
498
Table 37.4 Recommendations for antiretroviral drug use by pregnant HIV-1-infected women and prevention of mother-to-child
transmission in the USAa
CLINICAL SITUATION RECOMMENDATION
HIV-1-infected women of childbearing potential and • Combination treatment as per adult treatment guidelines. Use
indications for initiating antiretroviral therapy one or more NRTI with good placental passage as a component
of the antiretroviral regimen when feasible.
• Avoid drugs with teratogenic potential (e.g. efavirenz) if the
woman is trying to conceive or is not using adequate
contraception. Exclude pregnancy before starting treatment
with efavirenz and assure access to effective contraception.
HIV-infected women with indications for antiretroviral Woman:

therapy, are receiving treatment, and become pregnant • In general, if woman requires treatment, antiretroviral drugs
should not be stopped during the first trimester or during
pregnancy.
• Continue current combination antiretroviral therapy regimen if
successfully suppressing viremia; however, avoid use of
efavirenz or other potentially teratogenic drugs in the first
trimester and drugs with known adverse potential for mother
throughout the pregnancy.
• Perform HIV antiretroviral drug resistance testing if the woman
has detectable viremia on therapy.
• Continue combination antiretroviral therapy regimen during
intrapartum period (AZT given as continuous infusion during
labor while other antiretroviral agents are continued orally) and
postpartum.
• Schedule cesarean delivery at 38 weeks’ gestation if plasma HIV
RNA remains >1,000 copies/mL near the time of delivery.
Infant:
• AZT for six weeks.
HIV-infected pregnant women who are antiretroviral Woman:

naı̈ve and have indications for therapy • Perform HIV antiretroviral drug resistance testing prior to
initiating combination antiretroviral drug therapy and repeat
after initiating therapy if viral suppression is suboptimal.
• Initiate combination antiretroviral regimen.
- Avoid use of efavirenz or other potentially teratogenic drugs
in the first trimester and drugs with known adverse potential
for mother (e.g. combination stavudine/didanosine).
- Use one or more NRTI with good placental passage as a
component of the antiretroviral regimen when feasible.
- Use NVP as a component of the antiretroviral regimen only if
the woman has CD4 count 250 cells/mm3. If the woman
has CD4 count >250 cells/mm3, use NVP as a component of
therapy only if the benefit clearly outweighs the risk due to an
increased risk of severe hepatic toxicity.
• If woman requires initiation of therapy for her own health,
initiate treatment as soon as possible, including in the first
trimester.
• Continue combination antiretroviral therapy regimen during
intrapartum period (AZT given as continuous infusion during
labor while other antiretroviral agents are continued orally) and
postpartum.
Infant:
• AZT for 6 weeks.
Continued
Table 37.4 Recommendations for antiretroviral drug use by pregnant HIV-1-infected women and prevention of mother-to-
child transmission in the USA—cont’d
HIV-infected pregnant women who are antiretroviral Woman:

naı̈ve and do not require treatment for their own health • Perform HIV antiretroviral drug resistance testing prior to
initiating combination antiretroviral drug therapy and repeat
after initiation of therapy if viral suppression is suboptimal.
• Prescribe a combination antiretroviral drug prophylaxis regimen
(i.e. at least 3 drugs) for prophylaxis of perinatal transmission.
- For women who are receiving antiretroviral drugs solely for
prevention of perinatal transmission, delaying initiation of
prophylaxis until after the first trimester of pregnancy may be
considered, but earlier initiation of prophylaxis may be more
effective in reducing perinatal transmission of HIV.
- Avoid use of efavirenz or other potentially teratogenic drugs
in the first trimester and drugs with known adverse potential
for mother (e.g. combination stavudine/didanosine).
- Use one or more NRTIs with good placental passage as a
component of the antiretroviral regimen when feasible.
- If the woman has CD4 count >250 cells/mm3 use NVP as a
component of therapy only if the benefit clearly outweighs
the risk due to an increased risk of severe hepatic toxicity.
• Continue antiretroviral prophylaxis regimen during intrapartum
period (AZT given as continuous infusion during labor while
other antiretroviral agents are continued orally).
• Evaluate need for continuing the combination regimen postpartum;
following delivery, considerations regarding continuation of the
antiretroviral regimen for maternal therapeutic indications are the
same as for other non-pregnant individuals. If stopping and the
regimen includes drug with long half-life like NNRTI, consider
stopping NRTIs at least 7 days after stopping NNRTI.
Infant:
• AZT for six weeks.
HIV-infected women who have received no antiretroviral Woman:

therapy prior to labor • Give AZT as continuous infusion during labor.
Infant:
• AZT given for 6 weeks, þ 3 doses of NVP: first dose by 48 h of
age; second dose 48 h after first dose; third dose 96 h after
second dose (e.g. 2, 4, and 7 days of age).
OR
• AZT given for 6 weeks, þ 3TC and nelfinavir daily from birth to
14 days of age.
Infant born to HIV-infected woman who has Infant:

received no antiretroviral therapy prior to or during • AZT given for 6 weeks, þ 3 doses of NVP: first dose by 48 h of
labor age; second dose 48 h after first dose; third dose 96 h after
second dose (e.g. 2, 4, and 7 days of age).
OR
• AZT given for 6 weeks, þ 3TC and nelfinavir twice daily from
birth to 14 days of age.
a
Adapted from Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission [45].
3TC ¼ lamivudine; AZT ¼ Zidovudine; NRTI ¼ nucleoside analogue reverse transcriptase inhibitor; NNRTI ¼ non-nucleoside reverse transcriptase
inhibitor; NVP ¼ nevirapine.
because of efficacy studies in adults and experience with use in for initiation therapy for their own health (CD4 count
pregnancy [45]. The alternative protease inhibitor if lopinavir/ < 350 cells/mm3 or WHO stage III or IV disease), starting
ritonavir is not tolerated would be atazanavir/ritonavir. Data a standard combination therapy regimen is recommended,
on use in pregnancy for darunavir, fosamprenavir, and tipra- which should be continued postpartum for life. For women
navir are too limited to recommend routine use in pregnancy, who lack indications for therapy for their own health, two
although these drugs can be used in antiretroviral-experienced options are available, started as early as 14 weeks, gestation.
women when resistance or intolerance prevents use of a pre- Option A includes maternal antepartum AZT with intrapar-
ferred regimen. When pregnancy is identified in HIV-infected tum single-dose NVP and AZT/3TC continued for 7 days
women already receiving antiretroviral therapy for their own postpartum, plus daily infant NVP from birth until the
health, continuation of therapy is recommended, with the ex- end of the breastfeeding period. Option B includes a
ception being if a woman is receiving efavirenz and her preg- three-drug regimen given to the mother during pregnancy
nancy is recognized during the first trimester, an alternative until the end of the breastfeeding period; the infant then
antiretroviral drug should be substituted when possible. More receives 6 weeks of infant prophylaxis (either AZT or
detailed discussion can be found in Recommendations for Use of NVP). If the infant is not breastfeeding, then 6 weeks of in-
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Ma- fant prophylaxis (either AZT or NVP) would be given for
ternal Health and Interventions to Reduce Perinatal HIV Transmis- either Option A or B (see Table 37.5).
sion in the United States [45]. Infant feeding guidelines have also been revised to rec-
Because antiretroviral prophylaxis is beneficial in reduc- ommend that national public health authorities should de-
ing perinatal transmission even among infected pregnant cide whether health services will principally counsel
women with HIV RNA < 1,000 copies/mL, use of prophy- mothers to either breastfeed and receive maternal or infant
laxis is recommended for all pregnant women regardless antiretroviral interventions or avoid all breastfeeding, as
of antenatal HIV RNA level. Following delivery, consider- the strategy that will most likely give infants the greatest
ations regarding continuation of the antiretroviral regimen chance of HIV-free survival [80]. If breastfeeding, exclusive
for maternal therapeutic indications are the same as for breastfeeding for the first 6 months of life with continued
non-pregnant individuals. When used solely to prevent breastfeeding through age 12 months with introduction of
perinatal transmission, it is not known what impact dis- complementary foods is recommended. Breastfeeding
continuing combination antiretroviral drug regimens should stop only once a nutritionally adequate and safe
postpartum will have on the short- and long-term health diet without breast milk can be provided. Gradual weaning
of the mother. However, so far, studies of pregnant over the course of 1 month is recommended, with infant or
women with relatively high CD4 counts who stop therapy maternal antiretroviral prophylaxis continued until 1 week
after delivery have not shown a risk for increased disease after breastfeeding is fully stopped.
progression. As noted earlier, the risks versus benefits of
stopping therapy postpartum in women with high CD4
counts is being evaluated in an ongoing trial. Breastfeed-
ing is not recommended for HIV-1-infected women in SUMMARY
the USA because breast milk transmission can occur even
in women receiving combination antiretroviral regimens There has been dramatic progress in reducing HIV MTCT
and safe and affordable infant formula is available. When in both resource-rich and resource-constrained settings in
no antenatal drugs are received, intravenous intrapartum recent years. In resource-rich countries, new pediatric infec-
AZT is recommended for the mother if there is adequate tions are nearly eliminated. In resource-constrained set-
time. Given the recent results of the NICHD/HPTN 040 tings, when services are available and accessible, MTCT
study (Table 37.2) [39], when the mother has not received can be reduced to less than 5% in breastfeeding popula-
antepartum drugs, combining the standard 6-week infant tions with current interventions. However, while there
AZT regimen with NVP given at birth and days 3 and 7 of has been impressive improvement in access to services in
life or with 2 weeks of 3TC/nelfinavir is recommended low- and middle-income countries since 2004, only 26%
(Table 37.4). of pregnant women were tested for HIV, and 53% of preg-
nant women living with HIV received any antiretroviral
drugs to prevent MTCT in 2009 (up from 7 and 10%,
CURRENT GUIDELINES FOR respectively, in 2004–2005). In 2010, UNAIDS called for
PREVENTION OF MTCT FOR the virtual elimination of mother-to-child transmission
globally by 2015, promoting a comprehensive approach
RESOURCE-CONSTRAINED SETTINGS including primary prevention of HIV infection among,
women of childbearing age; preventing unintended preg-
WHO guidelines for antiretroviral therapy for pregnant nancies among women living with HIV; preventing trans-
women and preventing MTCT were updated in July 2010 mission from an HIV-positive woman to her infant;
(Table 37.5) [30]. For women who meet WHO criteria and providing appropriate treatment, care, and support
501
Table 37.5 World Health Organization recommendations for antiretroviral drug use in HIV-1-infected pregnant women in
resource-limited settingsa
HIV-1-infected women with childbearing potential • Treatment regimen choice should follow WHO
and indications for starting therapy recommendations (all women with CD4 350 cell/mm3
irrespective of clinical staging or WHO clinical stage III or IV,
irrespective of CD4 count)
First-line regimens for childbearing-age women:b
- AZT þ 3TC þ NVP or
- AZT þ 3TC þ EFV or
- TDF þ 3TC (or FTC) þ NVP
- TDF þ 3TC (or FTC) þ EFV
• Exclude pregnancy before starting treatment with efavirenz
and provide adequate contraception
HIV-1-infected women with indications for antiretroviral Woman:

therapy, are receiving treatment, and become pregnant • Continue current regimen except discontinue drugs during the
first trimester that have teratogenic potential (efavirenz)
(women who are receiving efavirenz and are in the second or
third trimester can continue the current regimen).
• Continue combination regimen during intrapartum period and
postpartum
Infant:
• Once-daily NVP or twice-daily AZT from birth until 4–6 weeks of
age (irrespective of mode of infant feeding)
Women first diagnosed with HIV-1 infection during Woman:

pregnancy with clinical indications for antiretroviral • Treatment should be provided to:
therapy ○ All women with CD4 350 cell/mm3, irrespective of clinical
staging, and all women with clinical stage III or IV,
irrespective of CD4 count
• Treatment regimen choice should follow WHO
recommendations
○ First-line regimens for childbearing-age women:b
- AZT þ 3TC þ NVP or
- AZT þ 3TC þ EFV or
- TDF þ 3TC (or FTC) þ NVP
- TDF þ 3TC (or FTC) þ EFV
• Avoid drugs with teratogenic potential in women of
childbearing age (efavirenz) the first trimester
• Start treatment as soon as possible, including the first trimester.
• Continue combination regimen during intrapartum period and
postpartum
Infant:
• Once-daily NVP or twice-daily AZT from birth until 4–6 weeks of
age (irrespective of mode of infant feeding)
Pregnant HIV-1-infected women without indication for Woman:

treatment for their own health • Start antiretroviral prophylaxis as early as 14 weeks’ gestation.
Option A: maternal AZT

• AZT during pregnancy plus
• Single-dose NVP þ AZT/3TC during labor and delivery plus
• AZT/3TC x 7 days postpartum
502
resource-limited settings—cont’d
OR
Option B: triple antiretroviral drug prophylaxis until one week
after all exposure to breast milk has ended
• AZT þ 3TC þ LPV/r or
• AZT þ 3TC þ ABC or
• AZT þ 3TC þ EFV
• TDF þ 3TC (or FTC) þ EFV
Infant:
Option A
Breastfeeding infants:
• Once-daily NVP from birth till 1 week after all exposure to
breastfeeding
Non-breastfeeding infants:
• Once-daily NVP or single-dose NVP þ twice-daily AZT from birth
until 4–6 weeks of age
OR
Option B
• Once-daily NVP or twice-daily AZT from birth until 4–6 weeks of age
Pregnant women of unknown HIV infection status at • If there is time, counsel and offer HIV-1 rapid test; if positive,
time of labor or HIV-infected pregnant women who have initiate intrapartum prophylaxis. If insufficient time to
not received antepartum antiretroviral drugs obtain HIV-1 test result while in labor, offer HIV-1 test as soon
as possible after delivery, and follow the recommendations in
next scenario
Option A (infant antiretroviral drug prophylaxis):c

• Mother: single-dose NVP at start of labor and AZT/3TC twice
daily for 1 week
• Infant (if breastfeeding): Once-daily NVP from birth until 1 week
after all exposure to breast milk has ended, or for 4–6 weeks if
breastfeeding ceases prior to 6 weeks.
• Infant (not breastfeeding): Single-dose NVP plus twice-daily
AZT or once-daily NVP from birth until 4–6 weeks of age.
Option B (maternal triple antiretroviral drug prophylaxis,

relevant only if breastfeeding)d:
• Mother: Triple-drug prophylaxis during labor until one week
after all exposure to breast milk has ended.
• Infant: Daily NVP from birth until 6 weeks of age (since infant is
breastfeeding and immediate protection is desirable, NVP
would be the preferred infant prophylaxis and given for a full
6 weeks)
Infants born to HIV-infected women who have not Option A (infant antiretroviral drug prophylaxis):c
received antepartum and intrapartum antiretroviral drugs • Infant (if breastfeeding): Daily NVP from birth until 1 week after
all exposure to breast milk has ended, or for 4–6 weeks if
breastfeeding ceases prior to 6 weeks
• Infant (not breastfeeding): single-dose NVP þ twice-daily AZT
or once-daily NVP from birth until 4 to 6 weeks of age.
Continued
503
resource-limited settings—cont’d
Option B (maternal triple antiretroviral drug prophylaxis, relevant

only if breastfeeding):d
• Mother: Triple-drug prophylaxis until 1 week after all exposure
to breast milk has ended, or for 4–6 weeks if breastfeeding
ceases prior to 6 weeks
• Infant: Daily NVP from birth until 4–6 weeks of age
Related infant feeding recommendation for breastfeeding National authorities should decide whether health services will
HIV-infected women principally counsel mothers to either breastfeed and receive ARV
interventions or avoid all breastfeeding, as the strategy that will
most likely give infants the greatest chance of HIV-free survival. If
breastfeeding recommended:
• Exclusively breastfeed for the first 6 months, introduce
appropriate complementary food thereafter, and continue
breastfeeding for 12 months
• Wean gradually within 1 month
a
Adapted from World Health Organization [30].
b
If exposed to single-dose NVP within past 12 months, then AZT þ 3TC þ LPV/r recommended for first-line.
c
A clinical assessment should be done postpartum and CD4 count drawn. Women who are found to require treatment for their own health should
be started on an appropriate lifelong treatment regimen.
d
A clinical assessment should be done postpartum and CD4 count drawn. Women who are found to require treatment for their own health should
not discontinue their triple-drug regimen but continue on an appropriate lifelong treatment regimen.
3TC ¼ lamivudine; ABC ¼ abacavir; AZT ¼ zidovudine; EFV ¼ efavirenz; FTC ¼ emtricitabine; LPV/r ¼ lopinavir/ritonavir; NVP ¼ nevirapine.
to mothers living with HIV and their children and families awaited, tools are now available that will have a significant im-
(WHOPMTCT10). pact on the HIV epidemic in children globally. The ability to
Although debate continues over the optimal intervention to implement such programs is now tied less to the choice of reg-
reduce MTCT in women who don’t require treatment for their imen or regimen cost than to the development and support of
own health, and results from new clinical trials are eagerly the required maternal–child health infrastructure.
REFERENCES
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507
Chapter | 38 |
Managing HIV infection in children
and adolescents
Elizabeth H. Doby, Andrew T. Pavia
children may represent a significant portion of HIV-

EPIDEMIOLOGY infected children entering care, and they may face unique
challenges.
The epidemiology of HIV disease in children in developed Thus, a large number of children are living with HIV/
countries has changed substantially. These changes have AIDS, but few new infections are occurring. Many older
been driven by the evolving epidemiology of HIV infection children have been infected for years, and usually have
in women, the ability to prevent mother-to-child transmis- received prolonged antiretroviral therapy and may have
sion, the dramatic increases in survival for children treated complex resistance patterns. Many are, or soon will be, ad-
with combination antiretroviral therapy (CART) [1–3], and olescents. The major challenges of treatment now revolve
the evolution of drug resistance. Women constitute a signif- around managing viral resistance, complications of ther-
icant proportion of AIDS cases and new HIV infections. apy, and the psychological and social impact of HIV infec-
Women account for 27% of new HIV infections in the tion rather than when to start therapy.
United States [4]; this has remained stable over the last 5
years. However, women account for 25% of the estimated
1 million people living with HIV in the United States, sug- NATURAL HISTORY
gesting that 250,000 women are infected [4, 5]. In 2005,
the Centers for Disease Control (CDC) estimated that
Timing of infection
6,000–7,000 infants were born to HIV-infected women
each year in the USA [6]; however, only 141 new perinatal HIV progresses more rapidly in children with perinatal in-
infections were reported in 2008 [5]. fection than among children infected at an older age or
Since 1992, the number of children younger than 13 among adults. It has long been recognized that there was
years diagnosed with AIDS in developed countries has de- a bimodal distribution of clinical progression following
creased dramatically, representing one of the remarkable perinatal infection [7–9]. About 20% of children had early
successes in the fight against HIV. In the USA, the estimated onset of symptoms before the advent of effective therapy.
number of children younger than 13 diagnosed with AIDS These children have a rapid downhill course in the first
decreased from 952 in 1992, to 34 in 2008 [5]. This likely 12 months of life, marked by rapid decline in CD4 count,
represents improvements in clinical care and survival, and development of category C disease, often with pneu-
but this has led to a larger population of surviving children. monia due to Pneumocystis jiroveci (formerly P. carinii
By the end of 2008, an estimated 908 children were living pneumonia), or death.
with AIDS in the USA and its territories, and an additional There appear to be a number of predictors of rapid pro-
2,919 children were reported to be living with HIV infec- gression, including severe maternal disease [10], evidence
tion (not AIDS) from the 37 states with name-based report- of in utero transmission (positive PCR at birth), early hepa-
ing [5]. No accurate data are available regarding the tosplenomegaly [11], and higher viral loads after 1 month
number of HIV-infected immigrants, refugees, and adopted of life [12, 13]. CD4 and CD8 counts below the fifth per-
children living in the United States. However, foreign-born centile in infancy were associated with rapid progression
509
it has been difficult to establish specific levels that are sen-

Table 38.1 1994 revised human immunodeficiency virus
sitive and specific for high risk [20]. These differences may
pediatric classification system: Immune categories based on
reflect a greater number of target cells and a limited ability
age-specific CD4 count and percentage
to mount an immune response by the immature immune
system. Children infected in utero tend to have modest viral
IMMUNE <12 1–5 6–12
loads at birth, but the peak value at 1–2 months is higher
CATEGORY MONTHS YEARS YEARS
than those with presumed intrapartum infection.
No./mL No./mL No./mL
(%) (%) (%)
A pivotal meta-analysis of survival data on 3,941 European
and American children with HIV infection in the pre-HAART
Category 1: No >1,500 >1,000 >500 era demonstrated that CD4% and viral load were indepen-
suppression (>25%) (> 25%) (>25%) dent predictors of progression to AIDS or death over the
next 12 months. CD4% was the strongest short-term predic-
Category 2: 750–1499 500–999 200–499 tor (Fig. 38.1) [20]. The risk of progression at a given CD4
Moderate (15–24%) (15–24%) (15–24%) level of viral load varied by age. Importantly, among
suppression
children <12 months, the risk of progression remained mod-
Category 3: <750 <500 <200 erately elevated even when the CD4% was high or the viral
Severe (<15%) (< 15%) (<15%) load was low. A recent analysis of the same cohorts
suppression concluded that CD4 count may be more useful than
CD4% in determining treatment initiation, particularly if
From Centers for Disease Control and Prevention; 1994 revised only one has crossed a threshold [17].
classification system for human immunodeficiency virus infection in With the advent of three-drug combination ART for chil-
children less than 13 years of age. MMWR 1994; 43 (RR-12):1–10.
dren, survival has increased dramatically. In a cohort of
1,000 children in the UK, there was an 80% decline in mor-
tality and a 50% decline in progression to AIDS between
1997 and 2002, along with a 80% decline in hospital
among babies infected in utero in one study [14], perhaps admission rates between 1996 and 2002 [21].
reflecting early destruction of the thymus.
The natural history of HIV among adolescents who have
acquired infection through adult behaviors generally paral- EARLY DIAGNOSIS AND
lels adults. However, younger age at infection for those MANAGEMENT OF THE
with non-perinatally acquired HIV is associated with signif-
icantly slower progression in the absence of antiretroviral EXPOSED INFANT
therapy (ART) [15, 16].
Declining CD4 count and CD4% are the hallmarks of Diagnosis of HIV infection
HIV disease progression in children. CD4 count normally
declines with age in young children, making interpretation Currently, the diagnosis of HIV infection in children born
somewhat difficult. CD4% is less age-dependent and is also to HIV-infected mothers can be made in most infants by 2–
useful in disease staging (Table 38.1) [17]. The revised 4 weeks of age using methods that directly detect virus. De-
CDC, PENTA, and WHO classifications use both immuno- tection of virus by HIV DNA PCR of the infants’ peripheral
logic status and clinical status for staging. Growth failure is blood mononuclear cells (PBMCs) or HIV RNA in plasma
a sensitive indicator of disease activity, and improved is presumptive evidence of infection but must be confirmed
growth is a marker of successful ART. by repeat testing.
Viral culture is no longer used for diagnosis of HIV in in-
fants. Currently, either detection of DNA or RNA by PCR is
the test of choice. HIV DNA PCR is only moderately sensi-
Predicting progression
tive in the first 48 hours of life (38%; 90% confidence in-
Quantitative measurement of plasma viral RNA revolution- terval [CI], 29–46%). Sensitivity rises rapidly during the
ized the management of HIV in adults; similar data in chil- second week; 93% of infected children (90% CI, 76–
dren required a few more years to accumulate [13, 18, 19]. 97%) were PCR positive by 14 days of age. Quantitative
The kinetics of plasma HIV RNA in children differs from RNA PCR is at least as sensitive and specific as DNA
adults in several ways. First, children tend to have higher PCR, and offers the advantages of using smaller blood vol-
viral loads, with median peak values between 100,000 umes, providing important prognostic data [22, 23], and
and 1,000,000 copies. Second, after primary infection, being more sensitive for detecting non-clade B strains
the viral load slowly declines during the first year of life, [24]. False positives can occur; levels <5,000 copies/mL
in contrast to the rapid 2–3 log drop in adults. Third, al- should be considered suspect. Measurement of p24 anti-
though viral load is consistently associated with prognosis, gen, either conventionally or with immune dissociation,
510
Chapter | 38 | Managing HIV infection in children and adolescents
Figure 38.1 Probability of developing AIDS in

the next 12 months by age group. (A) By CD4%;
age groups (top to bottom) ¼ 6 months, 1 year,
80
2 years, 5 years, 10 years.
Adapted from Dunn [20]. (B) By CD4 count; age
within 12 months (%)

Probability of AIDS
groups ¼ 6 months, 1 year, 2 years, 3 years, 4 60
years, 10 years.
Adapted from HIV Paediatric Prognostic Markers
40
Collaborative Study [35].
20
0
0 5 10 15 20 25 30 35 40 45 50
A CD4%
80
70
within 12 months (%)

Probability of AIDS
60
50
40
30
20
10
0
0 1000 2000 3000
B CD4 cell count (cells/mm ) 3
is not recommended for the diagnosis of neonatal HIV Any positive test should be confirmed immediately by
infection because it is less sensitive and specific than PCR. testing of a separate blood sample. Two positive tests
Many experts recommend obtaining a first sample for should be considered diagnostic of infection. Many experts
DNA or RNA PCR during the first 48 hours of life, especially recommend checking HIV antibody at 12 months to docu-
if the infant is at higher risk of infection. Cord blood should ment the clearance of maternal antibody. If antibody is still
not be used because of the possibility of contamination detectable, testing should be repeated until antibody
with maternal blood. A positive viral test in the first 48 becomes undetectable.
hours of life presumptively identifies children infected in
utero who may have a more rapid disease course. However,
plasma RNA measurement after the first month of life may Monitoring in the HIV-exposed or
be more prognostic than time of first positive test.
HIV-infected infant
For infants with an initial negative test or who are not
tested at birth, testing should be repeated at 14–21 days Infants born to HIV-infected women should receive oral
of life. Testing at 14 days offers the potential to stop zido- AZT during the first 6 weeks of life, based on the PACTG
vudine monotherapy for patients with presumed infection 076 protocol. Myelosuppression is common with both
and begin combination therapy during the period of acute AZT and trimethoprim-sulfamethoxazole, and the com-
infection. For infants with initial negative tests, testing plete blood count should be monitored. Plasma viral
should be repeated again at 1–2 months of age. An infant RNA and CD4 count and percentage should be monitored
with two negative virologic tests, one at 14 days and one immediately once the diagnosis of HIV is established, and
at 1 month of age, can be viewed as presumptively unin- followed every 3–4 months. When starting ART, plasma
fected. Thus, one does not need to initiate PCP prophylaxis. viral RNA and CD4 count should be measured at baseline,
Testing should be repeated at 4–6 months of age for after 1 and 2 months, and every 3–4 months thereafter.
definitive exclusion of HIV infection. A suggested monitoring scheme is shown in (Table 38.2).
511
Table 38.2 Suggested schedule for routine monitoring of HIV-exposed and infected infants
INTERVENTION BIRTH 14–21 DAYS 1–2 MONTHS 4–6 MONTHS 1 YEAR
AZT X X Through week 6
PCP prophylaxisa Xa
CBC with differential X X X X

b
HIV plasma RNA or HIV DNA PCR X X X X
CD4 absolute and %c
HIV antibody X
a
PCP prophylaxis is continued until HIV is excluded or for the first 12 months of life in children who are infected or whose infection status is
unknown.
b
See text for use of HIV plasma RNA PCR or HIV DNA PCR. HIV plasma RNA should be measured immediately if infection is detected based on
a positive HIV DNA PCR. If no treatment is initiated, plasma RNA should be monitored every 3–4 months in infected children. If treatment is initiated
or changed, plasma RNA should be monitored 4 and 8 weeks after changing therapy and every 3–4 months thereafter.
c
CD4 counts should be repeated every 3–4 months in children who are infected.
Vaccination Vaccination is also important for HIV-infected adoles-

cents. They should receive pneumococcal and annual influ-
Timely vaccination is important for HIV-infected children. enza vaccinations. Their immunization status to hepatitis A,
Guidelines are available [25]. Inactivated vaccines (hepatitis hepatitis B, and measles should be reviewed and updated.
B, Haemophilus influenzae type B, diphtheria-tetanus-pertus- Meningococcal conjugate vaccine and tetanus diphtheria
sis, IPV) are given according to the schedule recommended acellular pertussis (Tdap) are recommended for all adoles-
for all children. Measles, mumps, and rubella (MMR) and cents. Human papillomavirus vaccine is licensed for use in
varicella vaccines are live-attenuated, which pose a theoret- both females and males; however, no specific recommenda-
ical risk to severely immunocompromised children. The vac- tions exist regarding its use in HIV-infected children and ad-
cines should not be given to those with CD4% less than olescents [4, 27]. Given the increased risk of HPV-related
15%. HIV-infected children without immunosuppression disease among HIV-infected persons, HPV vaccine (HPV4)
should receive their first dose of MMR as soon as possible should be strongly considered for both female and male
after the first birthday. The second dose does not need to HIV-infected adolescents.
be delayed until school entry; it can be given as soon as 1
month after the first dose. Annual immunization against
influenza is recommended for all HIV-infected children. Ini-
tially, two doses are given, separated by at least 1 month. ANTIVIRAL THERAPY
Since infections with encapsulated bacteria are prominent
among HIV-infected children, the potential benefit of pneu-
mococcal vaccine is large. Unfortunately, children < 2 years
Principles of therapy
old respond poorly to polysaccharide vaccines. In February The goal of ART in children, as in adults, is to suppress viral
2010, a new 13-valent pneumococcal conjugate vaccine replication to extremely low levels to prevent loss of CD4
(PCV-13) was approved by the FDA, which offers expanded cells and to allow immune reconstitution. If viral replica-
coverage of the serotypes causing the majority of invasive tion continues in the face of antiretroviral agents, ongoing
pneumococcal disease (IPD) in children. PCV-13 is recom- mutation will lead to drug resistance. Combination therapy
mended for all children younger than 72 months with an with three or more agents offers the greatest opportunity to
underlying medical condition, including HIV. In addition, achieve maximal suppression. The ability to adhere to a reg-
children aged 6–18 years may receive one dose of PCV-13. imen is a key determinant of continued viral suppression.
A single dose of PCV-13 should be given to children younger The complexity of HIV therapy in children and adolescents
than 6 years who were previously vaccinated with PCV-7. Af- and the rapidly changing evidence base suggest that chil-
ter completion of the PCV-13 series, the 23-valent pneumo- dren with HIV should receive care from physicians with
coccal vaccine (PPSV23) should also be given after 24 substantial expertise in HIV and in conjunction with multi-
months of age. Re-vaccination should be offered 5 years after disciplinary teams. Whenever possible, children should be
the first dose of PPSV23 [26]. offered the opportunity to participate in clinical trials.
512
It is important, however, to appreciate ways in which children in 17 cohort studies and randomized trials from
children differ from adults. The majority of HIV-infected 1983 to 2002 showed that CD4 percentage had little or
children are infected around the time of delivery, and ther- no additional prognostic value over CD4 cell count, regard-
apy can potentially be started during primary infection. less of age [17]. These data are reflected in the new treat-
Theoretically, this offers children an advantage that is rare ment guidelines: both the European and WHO no longer
in adults. Intact thymic architecture offers the potential for use CD4 percentages for treatment initiation decisions.
greater immune reconstitution, and in one study, thymic The US guidelines continue to use CD4 percentage thresh-
volume on CT scan correlated with completeness of im- olds for children < 5 years of age.
mune reconstitution [28]. Prompt initiation of ART for all HIV-infected infants < 12
However, many of the differences lead to challenges. In months of age is now universally recommended. The Chil-
general, clinical trial data in children are limited and pharma- dren with HIV Early Antiretroviral Therapy (CHER) random-
cokinetic studies may be inadequate. The disposition of drugs ized trial in South Africa showed a 76% reduction in early
changes during growth and development, changing from in- infant mortality and a 75% reduction in HIV progression
fancy into childhood, and again during adolescence. In gen- in those infants receiving immediate ART with a lopinavir-ri-
eral, volume of distribution is larger, and clearance is faster, tonavir-based regimen, as compared to infants randomized
which may require more frequent dosing. In general, rates to defer therapy until they met clinical or immunologic cri-
of viral suppression below the limits of quantification have teria [30]. The benefits of early initiation of ART for infants
been lower in trials among children and adolescents than were confirmed in a resource-rich setting by the European
among adults. The developing central nervous system of chil- Infant Collaboration (EIC) cohort study [31]. Even with de-
dren appears to be more vulnerable to damage by HIV. Reg- monstrable improvements in mortality and morbidity, early
imens, therefore, should be highly active in the CNS. Young initiation of ART can be challenging. Complete virologic sup-
children usually require liquid formulations, which may be pression often is not achieved or takes longer in younger chil-
unpalatable or unavailable. Young children are dependent dren and likely is associated with higher rates of genotypic
on the caregiver’s ability to give medications consistently, resistance mutations [32]. In addition, administering drugs
on schedule, and despite protests. Older children may be con- and ensuring adherence can be challenging in infants.
cerned about taking antiviral therapy in public, at school, or In children with category C and most category B disease,
at friends’ houses. The social problems which are common in treatment always should be started, as well as in those with
families with HIV-infected children (poverty, homelessness, severe immunosuppression, as defined by age-related CD4
parents who may be ill or absent, substance abuse, mental ill- markers (Table 38.1). Treatment for children older than 1
ness, isolation, fear of disclosure) compound the problems of year with limited or no symptoms is more problematic. For
complex regimens, unpleasant tasting medicine, and some- those with preserved immune function, one approach would
times resistance from the child or adolescent. Thus, problems be to treat all children. This is consistent with evolving data
with adherence can be daunting. favoring earlier treatment in adults [33]. The aggressive ap-
proach can be considered when the family or caregivers are
committed to therapy, there is adequate medical and social
support, and there is a high likelihood of good adherence.
When to start
An alternative approach is to defer therapy in older chil-
Recommendations on starting therapy and preferred regi- dren who have limited symptoms, have no evidence of im-
mens have been formulated by the Panel on Antiretroviral mune dysfunction, and are at low risk of rapid progression
Therapy and Medical Management of HIV-Infected Chil- based on HIV RNA. However, the optimal thresholds
dren in the US and the Paediatric European Network for remain unknown. The risk of progression increases when
Treatment of AIDS (PENTA) (Table 38.3) [24, 29]. These the CD4% is < 25%, especially in younger children. In these
guidelines are generally concordant but have subtle differ- cases, therapy should be considered. Viral loads >100,000
ences. The decision to start therapy balances the probability copies/mL are associated with higher rates of progression or
of developing severe clinical disease in the near term and death [18, 20, 34, 35], and treatment is recommended.
the risk of irreversible damage to the immune system or de- Patients in whom deferral of therapy might be preferred
veloping organs with the known difficulties of maintaining are older children with minimal symptoms, well-preserved
suppression in children, short-term side effects, the risk of CD4 levels, and low viral loads. Perhaps the most important
developing drug resistance, and the possibility of running consideration, and one which requires thoughtful clinical
out of effective agents. In addition, uncertainty remains judgment, is whether to defer therapy in low- and interme-
about the importance and frequency of long-term toxicities diate-risk patients in whom the risk of poor adherence and
in children, including abnormalities of lipid, glucose, and development of resistance is felt to be very high and might
bone metabolism. outweigh the benefit of immediate therapy. If ART is de-
Historically, the decision to initiate ART in children was ferred, close monitoring is essential. Therapy should be ini-
based on myriad factors, including age, clinical status, CD4 tiated if new symptoms develop, or if the CD4 cell count is
count, and CD4 percentage. A meta-analysis of 3,345 falling rapidly (confirmed by repeated measures).
513
Table 38.3 When to start therapy: Comparison of DHHS 2011, PENTA 2009, and WHO 2010 recommendations
AGE GROUP DHHS 2011 PENTA 2009 WHO 2010
< 12 months Treat Treat Treat

All (AI) All All
12–<24 months Treat Treat

• CDC stage B* or C (AI) • CDC stage B or C
• CD4 <25% (AII) • WHO stage 3 or 4
• Asymptomatic or mild • CD4 < 1000 cells/mm3
symptoms and • CD4 < 25%
• CD4 25% and Consider
• HIV RNA 100,000 • HIV RNA 100,000 copies/
copies /mL (BII) mL
Consider or defer
• Asymptomatic or mild symptoms
and
• CD4 25% and
• HIV RNA <100,000
copies/mL (CIII)
24–<36 months Treat Treat

36 months–<5 • CDC stage B or C • WHO stage 3 or 4
years • WHO stage 3 or 4 • CD4 < 750 cells/
• CD4 < 500 cells/mm3 mm3
• CD4% < 20% • CD4% < 25%
Consider
• HIV RNA 100,000
copies/mL
> 5 years Treat Treat Treat

• CDC stage Ba or C (A1) • CDC stage B or C • WHO stage 3 or 4
• CD4 < 350 cells/mm3 (A1) • WHO stage 3 or 4 • CD4 < 350 cells/
• CD4 350–500 cells/mm3 (B11) • CD4 < 350 cells/mm3 mm3
• Asymptomatic or mild symptoms Consider
and • HIV RNA 100,000
• CD4 350 cells/mm3 and copies/mL
• HIV RNA 100,000
copies/mL (BII)
Consider or defer
• Asymptomatic or mild symptoms
and
• CD4 350 cells/mm3 and
• HIV RNA <100,000
copies/mL (CIII)
DHHS: Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in
Pediatric HIV Infection. August 11, 2011. Available at http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf
PENTA: PENTA Steering Committee. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine (2009),
10, 591–613
WHO: WHO. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health
approach — 2010 revision. Available at http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html
(The strength of the recommendation [A–C] and the strength of the evidence (I–III] is shown for the DHHS recommendations)
a
Excludes LIP or single episode of serious bacterial infection.
514
Initial therapy When therapy appears to be failing, the issues are more
complex. When the initial regimen is failing in a child over
When therapy is begun for children, combination therapy 6 years, there may be several acceptable treatment options.
with at least three drugs, including two nucleoside reverse In children younger than 6 and those with extensive drug
transcriptase inhibitors and either a non-nucleoside reverse resistance mutations, there may be limited opportunities
transcriptase inhibitor or a potent protease inhibitor, is pre- to design an effective regimen.
ferred. Monotherapy or the use of two nucleoside analogs is Before changing therapy, it is essential to carefully assess
no longer considered adequate therapy. potential problems with dosing, absorption, and adherence
Selection of appropriate drugs is complicated by the lim- and to try and solve adherence problems. Otherwise, the
ited availability of adequate pharmacokinetic data to allow new regimen is doomed to fail.
appropriate drug exposure, the availability and palatability There are three broad indicators of drug failure: virologic,
of liquid formulations or smaller pills, and the availability immunologic, and clinical [24] Virologic indicators have
of clinical efficacy data. In the US Guidelines, the combina- the advantage of being easily quantifiable and often corre-
tion of two nucleoside analogs plus either lopinavir/ritona- late with the emergence of drug-resistant virus. RNA mea-
vir, atazanavir with low dose ritanavir (for children 6) surements should be repeated before deciding to change
efavirenz (or nevirapine for children < 3 or who cannot therapy. Failure to achieve 1.0 log decrease in viral load af-
swallow capsules) is designated as preferred (Table 38.4). ter 8–12 weeks should prompt a change. The repeated detec-
NNRTI-based regimens should not be used in infants ex- tion of viral RNA (especially levels > 1000 copies/mL) after a
posed to perinatal nevirapine, even if baseline resistance test- period falling below limits of quantification indicates fail-
ing does not show significant NNRTI resistance mutations ure. Failure to achieve a viral load of < 400 copies/mL 6
[36–38]. A recent pediatric trial, PENPACT-1, suggests that months after beginning an aggressive initial regimen is an
among children without perinatal exposure to nevirapine, inadequate response. Recent data suggest that therapy switch
long-term outcomes are similar for children initiating ther- should be considered at lower viral loads (1,000 copies/mL)
apy with PI compared with NNRTI-containing regimens with NNRTI-based regimens because more major NRTI mu-
[39]. Preferred dual-NRTI backbones include either lamivu- tations developed when therapy switch was triggered at
dine or emtricitabine in combination with abacavir (after higher viral loads among children compared to PI-based
testing for HLA B*5701), zidovudine, or tenofovir (in post- regimens [39].
pubertal adolescents). Because the data from the PENTA-5 Virologic failure may not predict immediate clinical or im-
trial show improved viral suppression and growth [40], munologic failure. The decision to change therapy should
the European guidelines recommend abacavir and lamivu- weigh the ability to achieve adherence, available options,
dine as the initial dual-NRTI backbone in HLA-B 5701 neg- and the CD4 response. Stable or increasing CD4 counts in
ative children [29]. Alternative ritonavir-boosted PI-based the face of continued viral replication among children
regimens include darunavir, and fosamprenavir for children who remain on therapy are common, as in adults [42].
aged 6 years and older. Regimens are designated as alterna- Immunologic progression is an indicator of increased
tive regimens either because data are limited or suggest lower risk of death. Therefore, therapy should be changed in
efficacy or because of toxicity. Data were insufficient to make the face of immunologic progression and detectable virus.
recommendations for several drugs and regimens that have CD4% is less affected by age, but absolute CD4 counts may
important potential roles, including raltegravir, etravirine, be used in children at 5 years of age and older. A change to a
rilpivirine maraviroc, enfuvirtide, and triple-class regimens. new immunologic category, a sustained decline in CD4%
Initial studies demonstrated that rates of viral suppression by 5 percentiles at any age, or decline to below pre-therapy
to < 400 copies/mL were substantially lower than among CD4 counts in children 5 years of age and older are clear
adults. However, more recent trials show rates of suppression indicators of immunologic progression. However, rate of
among antiretroviral-naı̈ve children of 65–84% [39, 41]. change should also be considered.
Certain types of clinical progression are ominous and
should prompt change in therapy. Growth failure, severe
or recurrent infections, and progressive neurodevelopmental
When to change
decline are clear indicators of disease progression. Although
In children, the decision to change therapy must balance definitive data on the clinical efficacy are lacking, agents that
the need to better control viral replication and the higher achieve good antiretroviral activity in the CSF should be
likelihood of control with earlier switching against the used. These include AZT, d4T, 3TC, FTC, and nevirapine.
limited number of active drugs and the problems of The choice of agents for ‘salvage’ therapy is difficult, and
cross-resistance. In children who may need therapy for de- there are few clear guidelines. Strategies recommended in
cades, it is important not to exhaust the limited options. adults also make sense for children. However, fewer antire-
When there is major toxicity, the regimen must be changed. trovirals are available for children due to limited pharma-
For minor clinical or laboratory toxicities, it is worth trying cokinetic data and pediatric formulations. The availability
to manage the symptoms. of additional agents in the future must be considered. For
515
Table 38.4 Options for initial antiretroviral therapy in children with HIV infection (DHHS 2011)
Protease inhibitor-based regimens

Preferred regimen Two NRTIsa plus lopinavir/ritonavir or atazanavir plus low dose ritonavir (children
6 years)
Alternative regimen Two NRTIsa plus fosamprenavir with low-dose ritonavir, or darunavir with low-dose
ritonavir (children 6 years)
Non-nucleoside reverse transcriptase inhibitor-based regimens

Preferred regimen Two NRTIsa plus efavirenzb (children 3 years)
Alternative regimen Two NRTIsa plus nevirapineb,c
Use in special circumstances Two NRTIsa plus atazanavir unboosted (for treatment-naı̈ve adolescents 13 years
of age and >39 kg; not for use with tenofovir)
Two NRTIsa plus fosamprenavir unboosted (children 2 years of age)
Two NRTIsa plus nelfinavir (children >2 years of age)
Zidovudine plus lamivudine plus abacavir
Regimens that are not recommended Etravirine-containing regimens

as initial therapy for children Raltegravir-containing regimens
Efavirenz-containing regimens for children <3 years of age
Tipranavir-, saquinavir-, or indinavir-containing regimens
Dual (full-dose) PI regimens
Full-dose ritonavir or use of ritonavir as the sole PI
Unboosted atazanavir-containing regimens in children <13 years of age
and/or <39 kg
Nelfinavir-containing regimens for children <2 years old
Triple-NRTI regimens other than abacavir plus zidovudine plus lamivudine
Triple-class regimens, including NRTI plus NNRTI plus PI
Regimens with dual-NRTI backbones of abacavir plus didanosine, abacavir plus
tenofovir, didanosine plus tenofovir, and didanosine plus stavudine
Tenofovir-containing regimens in children in Tanner stages 1–3
Enfuvirtide (T-20)- or maraviroc-containing regimens
Regimens that should never be used in Monotherapy

children Two NRTIs alone
Certain two-NRTI combinations as part of a regimen (lamivudine plus emtricitabine
due to similar resistance pattern and no additive benefit; and zidovudine plus
stavudine due to virologic antagonism)
Dual-NNRTI combinations
Unboosted saquinavir, darunavir, or tiprinavir
Atazanavir plus indinavir
Certain NRTI-only regimens (tenofovir plus didanosine plus lamivudine or
emtricitabine; or tenofovir plus abacavir plus lamivudine or emtricitabine)
a
Dual NRTI combinations:
• Preferred choices: abacavir (screen for HLA-B*5701) plus lamivudine or emtricitabine; tenofovir plus lamivudine or emtricitabine (for Tanner
stage 4 or postpubertal adolescents only); zidovudine plus lamivudine or emtricitabine. Of note, the 2009 PENTA guidelines recommend
abacavir plus lamivudine (if HLA-B*5701 negative), and zidovudine plus lamivudine (if HLA-B*5701 positive)
• Alternative choices: zidovudine plus abacavir; zidovudine plus didanosine; didanosine plus lamivudine or emtricitabine
• Use in special circumstances: stavudine plus lamivudine or emtricitabine
• Not recommended: abacavir plus didanosine; abacavir plus tenofovir; didanosine plus tenofovir; and didanosine plus stavudine.
b
Efavirenz currently available only in capsule form, although liquid formulation is under study. Nevirapine is preferred NNRTI for children <3 years
because of liquid formulation and well. established PK.
c
Nevirapine-based therapy should not be used in infants exposed to peripartum nevirapine for prevention of maternal-to-child transmission.
516
example, additional active agents may be available for use infants. After that age, prophylaxis is recommended for all
when a child reaches 6 years of age. When available, enroll- children with severe immunosuppression (CDC category
ment in clinical trials can provide more options. Prior to 3). Trimethoprim-sulfamethoxazole is the preferred drug.
changing therapy, barriers to adherence must be addressed, The recommended dose is 150 mg/m2 per day in divided
and resistance testing should be performed. Ideally, all doses on three consecutive days each week, but there are
drugs should be changed in a failing first-line regimen. several acceptable alternatives [25].
At least two fully active antiretroviral agents (preferably
three) should be used. The addition or substitution of a
single new drug should be avoided. Prophylaxis of other opportunistic
infections
Resistance testing The primary prevention of specific opportunistic infections
is extremely important for children with advanced immu-
Recent data demonstrate that the prevalence of resistance nosuppression. Guidelines are available which categorize
among newly diagnosed HIV-infected children is similar the advisability of prophylaxis, the CD4 levels, and the
to the 12–24% prevalence among recently infected adults agents of choice [47].
[24, 43–45]. In children born in countries where single- The safety of stopping primary prophylaxis in adults after
dose nevirapine is used for prevention of peripartum trans- immune reconstitution has been clearly established. Re-
mission, the prevalence of NNRTI resistance may be high. cently, the PACTG 1008 clinical trial established the safety
Resistance testing should be obtained before beginning of discontinuing Pneumocystis jiroveci (PJP) and Mycobacte-
therapy in all treatment-naı̈ve children. In addition, resis- rium avium complex (MAC) prophylaxis in children with
tance testing is necessary to guide selection of new regimens stable immune reconstitution [48].
for children with virologic failure. Of note, the absence of Lifelong suppression (secondary prevention) has been the
resistance mutations in a child who is failing therapy likely standard of care for children with many opportunistic infec-
indicates poor adherence. tions, including PJP, Toxoplasma gondii infection, and Myco-
bacterium avium complex. However, secondary prevention
can, in some cases, be discontinued once stable immune re-
Therapeutic drug monitoring constitution has occurred, based upon adult data and the
The patient-to-patient variability of bioavailability, drug PACTG 1008 trial. This issue merits further study in children.
metabolism, and drug levels is generally larger for children
than adults. Complex drug interactions may make it diffi-
cult to predict drug levels. To date, however, there are no MANAGEMENT
prospective data that demonstrate that therapeutic drug
monitoring improves treatment outcomes in children. In Comprehensive management of the HIV-infected child is
the absence of prospective data, it is reasonable to consider beyond the scope of this chapter. Optimal care requires a
therapeutic drug monitoring for children in certain circum- multidisciplinary approach, and if possible, a dedicated
stances. These circumstances might include children on team. Careful attention must be given to nutrition, devel-
regimens for which dosing recommendations are based opmental assessment, psychosocial issues, and education.
on limited data, children on unusual combinations or with Teaching about HIV and multiple strategies to support ad-
complex drug–drug interactions, those who might have herence are critical. Medical care of the mother is important
difficulty with drug absorption, or those whose clinical to the child’s health as well as the mother’s. If possible, HIV
response varies from that which is expected [24, 46]. services for mother and child should be available at the
same site and should be coordinated. Periodic case man-
agement meetings to coordinate issues among providers
USE OF PCP PROPHYLAXIS and agencies are extremely useful.
Pneumocystis jiroveci pneumonia occurs most often between

3 and 6 months of age in perinatally infected children. Dis- ADOLESCENTS
ease may develop before HIV infection is confirmed or be-
fore a drop in CD4 counts has been documented. Because Adolescents infected with HIV pose unique challenges. The
of continuing mortality with CD4-based guidelines for pro- needs of perinatally infected children who have survived
phylaxis, the CDC published revised guidelines in 1999 into adolescence are different from those infected during ad-
that recommended that PCP prophylaxis should be consid- olescence. They have demonstrated slow disease progres-
ered at 4–6 weeks of life in HIV-exposed infants if HIV sion, but often have advanced disease and may have been
infection cannot be excluded (see above) [25]. Prophylaxis extensively pre-treated. They have often outlived their par-
should be continued until 12 months of age in all infected ents. Most adolescents who are recently infected were
517
infected through sexual activity. HIV infection through sex- and medications may make the adolescent feel different and,
ual abuse occurs, and can be recognized only if there is at times, vulnerable. Multidisciplinary teams, including
awareness and careful investigation. Adolescent behavior mental health, social work, educators, and peer-to-peer
problems, including drug use or having run away, are rela- counseling, may be helpful. In some adolescents at moder-
tively common, and there is a high prevalence of mental ill- ate risk of progression or with treatment failure due to adher-
ness among adolescents living with HIV [49]. Screening ence, it may be wise to delay ART until adherence is more
instruments for depression may be helpful. The clinical likely.
course of disease for adolescents infected sexually or through
drug use is more similar to adults; adult treatment guidelines
are appropriate. UNANSWERED QUESTIONS
Some issues are common among adolescents. Disclosure
of infection status is a difficult issue. Ideally, disclosure is Despite the important gains in antiviral therapy and the
a progressive process that should begin well before adoles- promise of further improvement, frustrating gaps remain
cence. Rapid growth, changes in metabolism, and increases in our knowledge and our ability to deliver antiviral ther-
in muscle mass in males and in fat for women affect drug me- apy to children. Early diagnosis of HIV-infected children
tabolism. Adolescents in early puberty (Tanner stage I and II) and early treatment with fully suppressive regimens hold
should be dosed as children. Those in late puberty (Tanner V) enormous promise. However, we need to learn much more
should be dosed as adults. There are no clear guidelines for about the pharmacology of antiretroviral drugs in all stages
those at intermediate stages. Puberty may be delayed in those of growth. Delays in the availability of newer drugs can be
with long-standing HIV infection, and delayed growth may life threatening; agents must be studied in infants and chil-
be an additional stressor. Contraception is extremely impor- dren during the early phase of development. The optimal
tant, both to prevent HIV transmission and unintended preg- combinations and sequences of drugs and the best way
nancies. However, oral contraceptives and antiretrovirals to ensure adherence to difficult and complex regimens re-
have potential interactions, which can result in less effective main unknown. The long-term consequences of changes in
contraception or increased hormone-related side effects. Hor- lipid, glucose, and bone metabolism may be more complex
monal contraception is optimally managed by an obstetri- and potentially more serious in children over decades of
cian/gynecologist with expertise in the care of HIV-affected treatment [50].
women; condom use remains essential. The prevention of perinatal transmission is the ultimate
Adherence with medical care and ART is particularly diffi- answer to controlling pediatric AIDS. In developed coun-
cult for adolescents. Autonomy, distrust of authority, embar- tries, it is possible to virtually eliminate perinatal transmis-
rassment, lack of support, chaotic lives, and low self-esteem sion of HIV through universal screening of pregnant
may contribute to poor adherence. Adolescents are often un- women, use of effective antiviral regimens during preg-
able to grasp long-term risks and consequences. Medical care nancy and delivery, and optimal obstetrical management.
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520
Chapter | 39 |
Special issues regarding women with HIV infection
Ruth M. Greenblatt, Monica Gandhi
to those in US men as of the latest CDC surveillance report

NATURE OF THE HIV EPIDEMIC
[3]. Although HIV/AIDS does affect racial and ethnic minor-
AMONG WOMEN ities disproportionally in men as well, this disparity is even
more stark among US women.
Globally, about half the cases of HIV infection (or roughly AIDS is among the 10 most frequently reported causes of
16.8 million) occur in women and girls, with the majority death among African American and Hispanic adolescent
(12 million) occurring in females in sub-Saharan Africa and adult women (Fig. 39.2) [5]; this figure is likely to un-
[1]. Indeed, a recent report released by the World Health Or- derestimate the contribution of HIV to mortality among
ganization lists the most common cause of death and dis- these groups because it is limited to cases in which HIV in-
ability in women of reproductive age worldwide to be fection was recognized, and only includes cases in which
HIV/AIDS [2]. Although HIV infection among women is AIDS was reported to be a cause of death. Not only is HIV
not as common in the developed world, rates have increased infection more common among African American women
in this group over the last 30 years. Currently, the number of at all age ranges but also rates of death in this community
cases of HIV infection among women in developed coun- from HIV/AIDS are disproportionately higher than mortal-
tries is comparable to those of many other chronic diseases. ity rates from the infection in other groups of American
As of the last UNAIDS global update on the epidemic in women. Moreover, although the most common causes of
2009, 240,000 women were reported to be living with death at all ranges are malignancy and cardiovascular dis-
HIV in Western and Central Europe and 390,000 in North ease or strokes, undiagnosed HIV infection could contribute
America [1]. In the USA, as reported in the 2009 surveillance to any of these causes of death. Indeed, HIV infection, even
report, 75% of HIV cases were in males and 25% in females when treated, is associated with excess deaths due to cancer,
[3]. The number of cases among males increased 10% be- pneumonia, cardiovascular and neurovascular disease, dia-
tween 2005 and 2008, but case numbers among women betes, liver disease, and renal dysfunction. Therefore, HIV,
remained flat; these data contrast with expectations that whether undiagnosed or treated, could contribute to excess
the number of recognized HIV infections among US women death and to morbidity in minority women that may not be
would substantially increase if testing became more routine. registered in mortality statistics. Even when treated, the con-
Regardless of the sex ratio, the average rate of HIV infections tribution of HIV to other forms of chronic morbidity and to
among US women is currently 179 cases per 100,000 mortality is expected to only increase as HIV-infected indi-
women, with some states reporting rates up to 460 per viduals on combination antiretroviral therapies (cART) sur-
100,000. Racial disparities in rates of HIV infection among vive for longer periods of time. Women living with HIV
US women are prominent: although only 14% of US infection, therefore, require careful clinical assessment
women are African American [4], this group comprises and treatment, including special attention to these chronic
67% of all cases. Figure 39.1 shows the percentages of conditions that result directly from HIV-mediated immune
HIV/AIDS cases in US women by race/ethnicity compared activation.
521
Figure 39.1 US epidemic affects minorities

Women Men disproportionally in women.
White 18% Other 4% White 31% Other 4%
Hispanic 13% Hispanic 21%

African American 67% African American 45%
HIV
Diabetes
Pregnancy
Sepsis
180 Trauma
CV/NV
160 Cancers
140
120
100
80
60
40
20
0
an
ic
an
ic
an
ic
sia
sia
sia
an
an
an
ric
ric
ric
ca
isp
ca
isp
ca
isp
e
e
Am
Am
Am
au
au
au
4H
4H
4H
4C
4C
4C
an
an
an
–3
–4
–5
–3
–4
–5
fric
fric
fric
25
35
45
25
35
45
4A
4A
4A
–3
–4
–5
25
35
45
Figure 39.2 Causes of mortality among different racial/ethnic groups in USA, categorized by age. CV/NV ¼ cardiovascular/neurovascular.
partners is frequently unknown), women with HIV infection

TRANSMISSION OF HIV TO WOMEN may deny any known risk factor. For large populations,
the predominance of heterosexual transmission is imputed,
Most transmission of HIV to women occurs during sexual and likely to be correct. The key concept here is that risk
contact and sexual risk may coincide with risks from injection factors for HIV acquisition are frequently not recognized
needle use, making the precise determination of the mode among women, so that assessment of risk is not a sensitive
of transmission in women with dual risk factors difficult. or useful means of triggering testing in women. Routine
Because exposure events are frequently not recognized screening for HIV infection in medical settings is now recom-
(the presence of HIV infection in sexual or needle-sharing mended for all individuals aged 13 to 64 years in the USA;
522
Chapter | 39 | Special issues regarding women with HIV infection
this strategy is likely to be cost-effective [6] and may be of par- transmission rates [10, 11]. Indeed, the HIV Prevention
ticular value to case identification in women. Trials Network (HPTN) 052 trial, terminated early
Transmission rates per heterosexual coital act are very low due to positive results, showed that the risk of
but likely to be highly variable within sexual pairs (discussed transmission from HIV-infected to HIV-uninfected
in Chapter 36) [7]. Estimates of the rates of transmission for partners is reduced by 96% with the early use of
single male-to-female sexual acts range from 0.02 to 0.43 cART, regardless of CD4 cell count [12]. In individual
depending on geographic location (rates are higher in couples, consistent use of cART may not completely
low-income countries), and whether the sex was transac- eliminate transmission, but massively reduces the
tional (transmission rates are lower with commercial sex) risk [13].
[8]. Even though single sex acts confer minimal risk, sex is • Acute HIV infection: The period of time surrounding
a common behavior, so the ongoing sexual transmission acquisition of new HIV infection is an important
of HIV to women on a global basis has been sustained. Sev- window of increased infectivity likely related to
eral factors are known to influence infectiousness or suscep- relatively uncontrolled viral replication with minimal
tibility to HIV infection, and other factors are biologically host immune responses leading to high levels of
plausible but unproven. Table 39.1 summarizes the factors viremia and genital shedding [14]. Non-specific
that may modify the susceptibility of women to HIV acqui- symptoms of the acute seroconversion syndrome limit
sition during heterosexual sex and further detail on how the efficacy of strategies that involve counseling
these factors influence risk is provided below: individuals to avoid sexual contact with acutely
• HIV viral load in partner: Greater HIV RNA copy infected persons. If the substantial challenge of
numbers (viral load) in blood or genital secretions is an improving the detection of cases of early HIV infection
important predictor of infectivity from males to was paired with safer sex or treatment interventions, a
females [3]. Factors that reduce viremia, such as receipt significant reduction in the incidence of HIV infection
of cART, are associated with decreases in HIV could be achieved [15]. The risk of transmission is also
transmission [9]. Consistent use of cART on the heightened in late-stage untreated HIV infection when
population level should result in decreased HIV HIV viral loads rise.
Table 39.1 Factors that modify the susceptibility to HIV acquisition in women
FACTOR AFFECT IMPACT REFERENCE
High viral load in partner’s blood Increase Major [9–13]
Viral shedding in partner’s genital fluids Increase Major [9]
Acute HIV Infection in partners Increase Major [14, 15]
Number of male partners Variable Moderate [16]
Commercial sex work Variable Minor [17]
Genital tract infections in partner Increase Minor–moderate [18]
Genital tract infections in woman Increase Minor–moderate [18]
Pregnancy Possibly increase Minor–moderate [21–23]
Hormonal contraceptives Possible increase Moderate [25–29]
Male or female condoms Decrease Major
Use of vaginal irritants Increase Moderate [39]
Pre-exposure prophylaxis Decrease, presumably Major [30–38]
Tenofovir vaginal gel Decrease Major [43]
Male circumcision No effect Moderate [44]
Disempowerment of women Increase Major [45]
523
• Number of sex partners: A larger number of male Therefore, the CDC routine testing guidelines
sexual partners is consistently associated with increased recommend repeat HIV testing during the third
rates of infection [16], but infections are also trimester if risk factors are present or if the prevalence of
commonplace in women with a single sexual partner. HIV infection in the surrounding community is high.
• Commercial sex work: Exchanging sex for money, drugs Finally, since acute infection with HIV late in
or other items is associated with increased risk of HIV pregnancy could be missed prior to delivery with an
infection, though commercial sex workers in developing HIV antibody test alone, testing should be extended to
regions have demonstrated a lower per sexual contact the postpartum period in high-risk individuals.
risk than other women, perhaps due to greater use of • Hormonal contraceptives: Several studies have found
condoms in this high-risk population over time [17]. that the use of hormonal contraceptives increases
• Genital tract infections: Genital infections have been susceptibility to HIV infection [25, 26], but not all
found to be associated with HIV transmission in studies support this association [27, 29]. A variety of
numerous studies [18]. The findings are based on hormonal contraceptive formulations are commonly
studies of a wide variety of pathogens ranging from used, and the existing studies have often grouped them
viruses to protozoans, and clinical manifestations in assessing their effect on susceptibility to HIV. Since
including cervicitis/urethritis, vaginitis, genital warts, the specific sex steroid composition of these drugs may
and ulcers. Each of the implicated diseases produces influence immunologic and genital tissue effects,
localized inflammation and/or immune activation, mixing of formulations in studies may tend to
which could increase susceptibility to HIV. Genital obfuscate underlying associations. Current studies
ulcerative diseases are of particular import, having the indicate that of the contraceptive sex steroids, depo
most consistent association with an increased medroxyprogesterone acetate (depo MPA) has the
prevalence of HIV infection. Of these conditions, genital closest association with HIV transmission, but further
herpes is a key pathogen due to its high prevalence and study is needed to confirm this given the tremendous
recurrence rate. Another important pathogen implicated utility of this injectable contraceptive in resource-rich
in the spread of HIV infection in developing world and resource-poor settings.
settings is Haemophilus ducreyi, the agent of chancroid, a • Pre-exposure prophylaxis (PrEP) in the form of daily
bacterial infection that is prevalent in regions with high- use of tenofovir/emtricitabine (TFV/FTC) has been
intensity HIV epidemics. Genital ulcers result in loss of recently demonstrated to reduce rates of HIV acquisition
epidermal or mucosal barrier functions in addition to among men who have sex with men (MSM)[30]. Two
producing local inflammation, which may be a other recent studies (Partners-PrEP and the Botswana
particularly potent combination in terms of augmenting TDF2 HIV Prevention Study [31, 32]) demonstrated the
HIV transmission. However, the extent of the efficacy of TFV/FTC as pre-exposure prophylaxis in both
interactions between sexually transmitted diseases men and women in stable serodiscordant heterosexual
(STDs) and HIV transmission is, for the most part, couples. The FEM-PrEP trial, however, designed to assess
relatively modest, and intervention studies designed to the efficacy of TFV/FTC in high-risk African women for
control STDs as a means of preventing HIV infection PrEP, was terminated early (on April 18, 2011) after
have not been consistently successful [19, 20]. interim analysis showed equal rates of infection in each
Regardless of the precise biological interaction between group [33]. The ongoing VOICE study (Vaginal and Oral
STDs and HIV, the occurrence of STDs is an indicator of Interventions to Control the Epidemic) is a 5-arm
the risk of HIV, and the prevalence of STDs in a given placebo-controlled trial assessing the effectiveness and
population is a good predictor of the intensity of the HIV safety of daily oral TFV-based products or vaginal TFV gel
epidemic in that setting. in preventing HIV acquisition in African women. The
• Pregnancy: Overall research findings indicate that five arms of the trial were originally established to
pregnancy increases susceptibility to sexual HIV compare daily oral TFV, oral TFV/FTC, vaginal 1% TFV
transmission [21, 22]; however, study results are not gel to the appropriate placebo products in preventing
entirely consistent [23]. Findings from studies in HIV acquisition on women. On September 16, 2011, the
sub-Saharan African women are most consistent, TFV-only arm of VOICE was closed for futility, although
perhaps because the large number of transmission the arm evaluating the efficacy of TFV/FTC is continuing.
events supports adequate study power. Pregnancy Although data are not yet available on the reasons for
could influence susceptibility to HIV infection in these disparate efficacy results for PrEP in MSM,
several ways, including increased fragility of genital heterosexual women in stable serodiscordant
tract tissues and alteration in host immunity during partnerships, and high-risk African women, postulated
pregnancy, increasing the susceptibility to some reasons include differences in adherence to study
infections. Incident infection with HIV during product, differences in trial designs in terms of the use of
pregnancy is associated with an increased risk of hormonal contraceptives, and differences in the degree
mother-to-child transmission [24] and may be missed of penetration of oral tenofovir into the rectal mucosa
if HIV testing is only performed in the first trimester. versus the vaginal mucosa (i.e. rectal penetration higher
524
than vaginal). Ongoing data analyses of these trials and

ongoing arms of PrEP trials in heterosexual women THE NATURAL HISTORY OF HIV
should further refine the utility, frequency, timing, route IN WOMEN
of administration, and specific populations who will
benefit most from TFV-based prevention.
While the similarities in the course of HIV infection among
• Topical spermicides and genital preparations have
been proposed as prevention interventions for HIV that women and men outnumber the differences [46, 47], the
would have special relevance for HIV-infected women. differences are important to understand. Women have
Nonoxynol-9, a commonly used detergent that serves as higher rates of many autoimmune diseases than men,
a spermicide, is virucidal in the test tube, but resulted in reflecting, in part, a pattern of more robust immune re-
paradoxical increases in HIV transmission in humans sponses in females. Women also tend to respond more vig-
[39]. Follow-up studies demonstrated that nonokynol-9 orously to vaccination and to clear some infections more
produced inflammation of the vaginal mucosa, a frequently than men. Females have higher absolute CD4
finding that may explain this apparent promotion of cell counts than males (approximately 100 cells/mm3), a
HIV transmission. Several other topic vaginal difference that is found across age and racial groups, and
microbicides demonstrated no efficacy in preventing a difference that persists in HIV infection [48, 49].
HIV transmission [40–42]. A recent trial demonstrated Women have viral loads approximately 0.2 to 0.8 log10
that vaginal application of 1% tenofovir gel twelve hours lower than men during early HIV infection, when CD4
before and after each coital episode was effective in cell counts are greater than 400 cells/mm3 (Fig. 39.3)
reducing the incidence of HIV infection among women [48, 50–63]. As CD4 cell counts decline, the sex discor-
in South Africa. The CAPRISA 004 trial found that dancy in viral load lessens and disappears. Since viral load
vaginal 1% TFV gel reduced HIV infection rates by 39%, is predictive of the rate of disease progression, longer
with a 54% reduction in “high adherers” (>80%) disease-free survival might be expected for women, but this
defined by self-report or applicator counts [43]. has not been observed. Time to clinical progression is equal
However, the vaginal 1% tenofovir gel arm of the VOICE between the sexes, so women actually progress more
trial was recently halted (on November 17, 2011) when rapidly to AIDS per a given viral load. Recent research
the data safety and monitoring board concluded that the has provided some clues to this seeming paradox. Women
gel applied daily was ineffective in preventing HIV pay a price in heightened immune activation for their early
acquisition in VOICE trial participants. Ongoing studies control of viral replication, and this heightened immune
of strategies to administer vaginal 1% TFV gel in women activation may eventually lead to more rapid loss of CD4
as an HIV prevention measure will hopefully clarify the cells [64]. Additionally, women produce more IL-7, a reg-
utility of this product. Moreover, additional HIV-specific ulator of CD4 cell production, at a given CD4 cell count
products formulated as microbicides to prevent HIV than men [49]. IL-7 also stimulates HIV replication, so
acquisition in women are currently under study. the greater response to CD4 depletion that females demon-
strate could also result in the generation of more HIV viral
• Male and female condom use is highly effective in the
prevention of HIV transmission to and from women. particles.
CD4 cell counts and immune functions in general are
• Male circumcision: While male circumcision is highly
effective in reducing the risk of sexual acquisition of HIV influenced by sex steroids. Women in the third trimester
infection in men, it has little effect on transmission from of pregnancy, when estrogen and progestin levels are very
an infected male to his female sexual partner [44]. high, demonstrate transiently reduced peripheral blood
However, population effects by which male circumcision CD4 cell counts. Menopause, which is characterized by sig-
will promote reduced prevalence of HIV infection among nificant and permanent decreases in estrogen and progestin
sexually active males will eventually lead to reduced levels, may also influence immune function, and interact
exposure to the infection among female partners. with other immune perturbations of aging. As HIV infec-
tion or antiretroviral therapy results in increased aging in
While biological factors are undoubtedly important deter- the HIV population, information regarding the effects of
minates of HIV transmission in populations, additional menopause on the course of HIV infection and related con-
characteristics likely influence the chances that an individ- ditions of aging will be useful.
ual woman will acquire HIV infection, including many so- In the USA the chances of progression to clinical AIDS
cial factors that may determine whether she encounters an among HIV seroconverting women is heavily influenced
infected male partner and is capable of effectively engaging by race and geographic location, with the highest rates of
in risk-reduction behaviors. These social factors include in- clinical AIDS occurring among African American and
come, education, employment, family size, mental health, Southern women [48]. Women with HIV infection have
cognitive function, and the presence of substance use. The lower blood hemoglobin and albumin levels, which are in-
social factors may produce vulnerabilities in individual dicators of overall and non-AIDS-related survival, but
women that are ultimately mediated through a loss of women experience similar increases in these values to
sexual autonomy [45]. men after initiation of cART [65].
525
Viral load lower in women Viral load higher in women
–1.0 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0
Reference
34* (VI)
36 750
37*
675
38
34 (V)
600
28 (I) 525
30 (IV)
32
450
35
31
CD4 count
30 (III) 375
34 (IV)
27 300
29* (H)
29* (IDU)
30 (II)
34 (III) 225
33*
30 (I) 150
34 (II)
34 (I) 75
39
0
Estimated differences in mean log10 HIV-1 RNA level between women and men, with 95% confidence intervals. Studies are in ascending order
of median CD4 count, with multiple strata indicated in parentheses for studies 30 (I–IV) and 34 (I–IV). Two different groups of subjects are shown for study 29:
heterosexual transmission (H) and injection drug use (IDU).
* Assumes difference in mean log(RNA) would equal reported difference in median log(RNA), and t-test p-value would equal Mann-Whitney p-value.
Figure 39.3 Comparisons of HIV viral loads by sex and CD4 count.
Adapted from Gandhi et al. [50].
In terms of clinical progression rates of chronically Acute infection

infected individuals on therapy (see Antiretroviral
Treatment of Women section), earlier studies showed that A recent paper evaluated race and sex differences in out-
women seemed to have higher rates of progression to AIDS comes of primary HIV infection in the Acute Infection
or death than men [66], likely due to differential access to and Early Disease Research Program (AIEDRP), a multicen-
care or ART, or increased rates of substance abuse. Later ter, observational cohort of more than 2,000 patients diag-
studies that correct for these factors show no differences nosed with acute and recent HIV infection during the cART
in rates of progression by sex [67], with some more recent era [48]. At enrollment into AIEDRP, women averaged
studies suggesting better clinical outcomes in women ver- 0.40 log10 fewer copies/mL of HIV-1 RNA (p < 0.001)
sus men when adjusting for other relevant factors [68]. Hy- and 66 more CD4 cells (cells/mm3) (p ¼ 0.006) than
potheses around these sex disparities are presented below. men, consistent with reports from chronically infected in-
dividuals [49, 50]. In terms of differences unrelated to bi-
ology, initiation of cART was less likely at any time point
by nonwhite women and men compared to white men
CLINICAL MANIFESTATIONS OF HIV (p < 0.005). Sex (and race) did not affect responses to
ART after 6 months on therapy, but women were 2.17-fold
IN WOMEN more likely than men to experience more than one
HIV/AIDS-related event (p < 0.001). Therefore, despite
The symptoms of HIV, either acute or chronic infection, more favorable clinical parameters initially, female HIV-
among women are comparable to those in men, and in gen- 1-seroconverters had worse outcomes than did male
eral fairly non-specific. Sex differences in the occurrence or seroconverters and these differences were exacerbated in
course of certain conditions exist and are summarized below. non-white individuals.
526
Cancer Osteopenia and osteoporosis

In the cART era, HIV-infected men and women both Inadequate bone mineralization is a significant concern
continue to experience cancer rates that are on an average for women (and men) with HIV infection [78], both in
3–4 times that of the general population, although one re- the pre- or postmenopausal periods [79]. HIV-infected
cent analysis of cancer cases among HIV patients in France postmenopausal women have significantly lower T scores
indicates that peak age of the highest relative risk of cancer on dual-energy X-ray absorptiometry (DXA) scanning in
is lower among women than men (under 40 versus under the spine, hip, and femoral neck and greater levels of bone
50 years) [69]. These data likely reflect the small number of turnover markers, which could lead to an increased risk of
cases of malignancy in older individuals; more precise esti- serious fracture [80]. However, current data, which tends
mates of the cancer rate in older groups of HIV-infected per- to be focused on premenopausal women, do not indicate
sons will become available with increasing survival rates that HIV infection is independently associated with in-
due to treatment and subsequently larger populations of creased fracture rates in women [81]. Nonetheless, as the
older HIV-infected adults. In a large study of cancer cases HIV-infected population continues to age and, as cART is
among HIV-infected individuals in Belgium, rates of non- increasingly linked with higher rates of bone loss in the
AIDS-defining malignancies were comparable between treated population [82, 83], careful attention to screening
men and women, but survival of the women, many of for osteopenia and osteoporosis in HIV-infected women
whom were immigrants from sub-Saharan Africa, was sig- (especially after menopause) is warranted [79].
nificantly shorter than for the men (an average of 14 versus
32 months) [70]. The section below on women-specific
conditions discusses cancers (e.g. breast, cervical, anal) that Thyroid dysfunction
are more likely to demonstrate disparities by sex.
Autoimmune thyroiditis (including Hashimoto’s thyroid-
itis and Graves disease) and hypothyroidism are sig-
Hepatitis C nificantly more common in women than men [84, 85].
Recurrences of clinical thyroiditis, hyperthyroidism, or
Hepatitis C virus (HCV) infection is common among HIV- new-onset hypothyroidism have all been reported after ini-
infected women. Clinicians should be aware that spontane- tiation of cART, likely as a late manifestation of immune
ous clearance of this co-infection occurs more frequently reconstitution [86, 87]. Follow-up thyroid function testing
among women than men [71]. Furthermore, women with should be performed after cART initiation in individuals
HCV are less likely to be viremic and tend to have lower he- with a history of previous thyroid dysfunction, particularly
patic transaminase levels with higher platelet counts than in patients with clinical AIDS or if nadir CD4 cell counts
men at similar stages of HCV infection [71, 72]. However, were < 350 cells/mm3. Clinicians should also be aware
data on sex differences in HCV infection mainly exist for that new-onset thyroiditis can occur after the initiation of
the mono-infected population and further studies on the im- cART. Thyroid tenderness and the presence of antithyroid
pact of sex on HCV progression in HIV-infected individuals peroxidase and antithyroid stimulating hormone receptor
are indicated [73]. antibodies can provide clues to this diagnosis [88].
Body habitus and metabolic changes

Cardiovascular and cerebrovascular
Sex differences in the distribution of body fat in HIV-
disease
uninfected adults are quite evident, and these differences
persist in HIV-infected men and women. However, Women have longer QT intervals than men on electro-
although HIV-infected women have smaller amounts of cardiograms (EKGs), and are therefore more susceptible
subcutaneous fat and total body fat than uninfected to drug-induced torsade de pointes [89, 90], though less
women [74], both HIV-infected and HIV-uninfected frequently experience arrhythmias in the setting of myocar-
women have higher measurements of body fat than men dial ischemia. The disparity in duration of the intervals
[75]. The decreases in body fat (most prominent in the recorded on EKGs is related to the relatively lower levels
limbs) associated with HIV infection are smaller among of testosterone in women, and, to a lesser extent, cyclic
women than men [75]. HIV infection in women is associ- variability in progestin and estrogen levels [90]. This
ated with higher blood levels of triglycerides and insulin, difference is pertinent to HIV since some antiretrovirals, in-
as well as lower levels of HDL, than observed in HIV- cluding ritonavir, can prolong the QT interval, as does meth-
uninfected women [76]. Menopause influences blood adone, potentially increasing the risk of torsades in women
lipids and triglycerides, such that LDL and triglyceride being treated for HIV and/or opioid addiction [91, 92].
levels increase after menopause in HIV-uninfected women The incidence of coronary artery disease (CAD) is much
[77]. Therefore, careful evaluation of lipids in HIV-infected lower among women under the age of 60 than among
women, with greater attention in the postmenopausal men. After age 60 the incidence of CAD in women increases
period, is warranted. steadily until it reaches that of men around the age of 80 [93].
527
The incidence of cerebrovascular incidents follows the screening of HIV-uninfected women stipulate that the
same pattern. Sex steroids influence cardiovascular (and Pap test should be repeated every 3 years if normal cytology
likely cerebrovascular) risk in a sex-dependent manner is seen. Current recommendations for HIV-infected women
[94]. The role of exogenous estrogen treatment to reduce call for cervical cytologic screening twice in the first year af-
rates of vascular disease is controversial, and given the pro- ter HIV infection is diagnosed, and then annually thereafter
thromotic and inflammatory milieu that is associated with if the Pap smear is normal. Consensus recommendations
HIV infection, the potentially adverse effects of estrogen for tissue assessment and treatment following abnormal cy-
treatment may be increased even more in this population. tology do not currently differ by HIV status [103]. Milder
The cardiovascular effects of androgens are influenced by forms of dysplasia (either low-grade squamous intraepithe-
sex and concomitant levels of other sex steroids [95]. lial lesions [LSIL] or atypical squamous cells of undeter-
Higher androgen levels in both premenopausal women mined significance [ASCUS] are the most common types
with polycystic ovary syndrome and in postmenopausal of lesions reported. The optimal clinical management of
women are associated with increased LDL levels and these milder levels of dysplasia is unclear. The US Centers
increased rates of cardiovascular disease. However, the for Disease Control currently recommends magnified ex-
cardiovascular effects of androgen supplementation are cur- amination of the cervix or colposcopy in HIV-infected
rently not clear, and likely depend on other sex steroids and women with ASC-US or any higher grade cytologic abnor-
underlying host genetic traits [96]. Until more definitive mality with the goal of identifying other higher-grade
studies can be done, the potentially adverse effects lesions. HIV infection may not influence the risk of progres-
of androgen supplementation in women with HIV infec- sion of low-grade lesions to higher-grade lesions. However,
tion must be carefully considered. The impact of the pro- HIV infection is associated with reduced disease-free
inflammatory state that is present in treated and untreated survival when invasive cervical cancer occurs, arguing for
HIV infection on CAD and cerebrovascular disease rates in the role of circumspect preventive care.
younger women is currently not known, but actively under Since the sensitivity of HPV testing as a means of detecting
investigation. Clinicians should follow ongoing observa- or predicting dysplasia is variable, the benefits of more costly
tional and interventional research studies that will eventu- HPV detection testing remains to be established. Fortunately,
ally determine diagnostic and preventive strategies for HIV-infected women who receive regular cytological screen-
CAD in premenopausal and postmenopausal HIV-infected ing and recommended treatment are not at increased risk for
women. invasive cervical cancer when compared to HIV-uninfected
women [103]. Recurrence after excisional or ablative treat-
ment of cervical lesions is associated with persistent HPV
detection [104]. Moreover, even after hysterectomy, HIV-
WOMAN-SPECIFIC CONDITIONS infected women with high-grade cervical lesions experience
AND HIV increased rates of vaginal and vulvar abnormalities com-
pared with HIV-uninfected women [105, 106]. Therefore,
Cervical cancer and genital epithelial the current guidelines for the prevention and treatment of
opportunistic infections in HIV-infected adults and adoles-
dysplasia cents stress the importance of careful inspection of the
HIV infection is associated with the detection of human pap- vaginal and vulvar areas during examinations [107].
illomavirus (HPV) and epithelial dysplasia in cervical and Adherent cART use is associated with reductions in detec-
anal tissues in women. HIV infection is also associated with tion and quantity of oncogenic HPV types in cervical cells
the detection of a wider range of HPV types than is found in [108] and the clearance of oncogenic HPV-related cervical
HIV-uninfected women; although HPV type 16 predomi- lesions [109]. However, the risk of dysplasia and response
nates in high-grade cervical dysplasia in HIV-uninfected to treatment remain diminished in the context of HIV infec-
women, HIV-infected women often have multiple HPV tion, despite antiretroviral therapy [102]. HIV-infected
types contributing to the dysplastic lesions [97]. Greater women, whether on or off cART, are at high risk for cervical
CD4 cell depletion results in more HPV replication and in- dysplasia and incomplete responses to treatment, so rou-
tegration of oncogenic HPV DNA (e.g. from HPV types 16 tine cytologic testing is crucial.
and 18) into cervical cells, an event that is closely associated
with the occurrence of epithelial dysplasia [12, 98]. Cervical
Anal cancer
HPV infection also tends to persist longer in HIV-infected
versus HIV-uninfected women [99]. Finally, the presence The anal canal has a transitional zone between keratinized
of HIV proteins themselves may also contribute to the devel- and columnar epithelium that is roughly analogous to that
opment of dysplasia beyond the effect of HPV [100]. of the cervix. The anus is susceptible to infections with ongo-
The severity of cervical dysplasia and rate of recurrence genic HPV types which are linked to anal epithelial dysplasia
after excisional treatment are both greater in HIV-infected and anal cancer. HIV infection is associated with abnormal
women and are proportionate to the extent of immunolog- anal cytology in women with HPV infections. Depletion of
ical injury [101, 102]. Current recommendations for CD4 cells and higher levels of HIV viremia are both linked
528
to shedding of HPV and the occurrence of dysplasia [110]. for breast cancer care, HIV-infected women should receive
Cytologic screening can detect significant dysplasia before the same diagnostic surveillance frequency for breast cancer
invasive disease occurs. However, anal cancer is rare, and as HIV-uninfected women.
since cytologic screening of the anus is an imperfect tool,
screening of HIV-infected women for anal cancer, as currently Menopause
practiced in many centers, may not be cost-effective [111].
No national recommendations exist for routine screen- As noted previously, the menopausal transition is likely to
ing for anal cancer. The 2010 STD treatment guidelines be particularly important for the care of HIV-infected
from the CDC have determined that evidence is still limited women because menopause is associated with:
concerning the natural history of anal intraepithelial neo- • Significant immunologic changes that may have a bearing
plasias, the reliability of screening methods, and the safety on HIV disease progression and treatment responses
and efficacy of treatment. Therefore, specialists at large HIV (more research is needed to define these effects).
treatment centers vary in their approach to screening for • Changes in lipid metabolism and vascular endothelial
dysplasia in the anal canal. Some centers recommend just function that can influence risks for vascular,
an annual digital rectal examination to evaluate for masses cardiovascular, renal, and cerebrovascular diseases,
and others have instituted routine anal cytologic screening which may then interact with the proinflammatory and
for HIV-seropositive men and women along the lines of the prothrombotic milieu of HIV infection.
cervical cancer screening guidelines above. • Acceleration of loss of bone mineral density that can
then result in fracture and disability that may also
Other gynecological conditions interact with other morbidities of HIV infection.
Menopause is clinically defined as the cessation of menses
Candidal vaginitis occurs more frequently among HIV-
for 12 months when no underlying etiology is present. This
infected women in relation to the extent of CD4 cell deple-
definition has limited applicability to the setting of chronic
tion; this condition is therefore similar to other mucosal
illness in which a variety of factors may lead to menstrual
candidal infections in immuno compromised individuals.
irregularity and amenorrhea (including weight loss, use of
Among women with CD4 counts of 350 cells/mm3 and
a range of medications, co-infections, and central nervous
above, topical or oral therapies can be used for candidal vag-
system conditions). Irregular menses and amenorrhea are
initis similar to the HIV-uninfected population. For women
common in both HIV-infected and HIV-uninfected women
who are significantly immunocompromised, oral flucona-
[116], but overall amenorrhea is associated with HIV infec-
zole in two 150 mg doses 3 days apart [103], or a short course
tion [117]. Greater rates of viremia and CD4 cell depletion
of daily 100 mg treatment, may be more effective than topical
are associated with cycle irregularity [118]. Self-reporting
treatment. Suppressive prophylactic azole treatment has been
menopause, followed by a resumption of regular menses
advocated by some, but it is of unproven benefit, and may risk
after cART initiation, is not uncommon. Irregular men-
the development of azole-resistant C. albicans strains or other
strual cycles are associated with the use of medications
Candida species.
and recreational drugs [119], which is an important consid-
While certain sexually transmitted infections, such as
eration in the evaluation of an HIV-infected woman.
genital herpes and syphilis, can have altered manifestations
While the effects of menopause on the course of HIV infec-
in the setting of HIV infection, these are not female specific.
tion and related conditions are still an open question, a range
Current guidelines for the diagnosis and treatment of
of studies have focused on whether HIV influences the course
these infections are available from the Centers for Disease
of menopause. The average age at menopause in the United
Control [112].
States is 51 years. Several studies cite menopause occurring at
a younger age among HIV-infected women [120], with the av-
Breast cancer
erage age reported as below 50 years [120, 121]. More defin-
Breast cancer was less frequently reported among HIV- itive determination of whether HIV infection affects the
infected women than HIV-uninfected women prior to the timing of menopause awaits studies that enroll a broader
availability of cART [113]. Since the advent of cART, breast age range of women, and an optimally matched HIV-
cancer rates rose to meet those of HIV-uninfected women, uninfected group. Since aging is a strong predictor of more
but have not exceeded baseline rates [114]. This increase in rapid HIV progression, it will be important to dissect out
breast cancer rates among HIV-infected women may be at- the effects of somatic aging from gonadal aging on HIV pro-
tributable to increased survival related to effective antiretro- gression in women.
viral treatment. Recently an interesting interaction between Many symptoms are attributed to menopause, but re-
the HIV virus and possible protection from some breast search findings consistently demonstrate that vasomotor
cancers was reported [115]. Women who had detectable symptoms (including facial flushing and night sweats),
X4-tropic HIV in their blood were significantly less likely vaginal dryness and irritation, and sleep disruptions are as-
to develop breast cancer, a finding that may be explained sociated with the menopausal transition. Night sweats and
by the expression of the CXCR4 receptor in some breast sleep disruptions are common in HIV infection regardless
cancer cells. While this finding may provide new directions of menopausal status, however. Some studies have found
529
that HIV-infected women are more likely to have meno- age 50 and particularly in the context of cART initiation,
pausal symptoms than HIV-uninfected women, but this should be cautioned that their menses and consequent fer-
disparity could be explained by differences in demo- tility may resume once they regain health.
graphics between the two groups [120]. Furthermore, men-
opausal symptoms can be more pronounced in women
who experience social stress, a factor that is highly prevalent ANTIRETROVIRAL TREATMENT
among HIV-infected women living in resource-rich envi-
ronments. Thus it can be difficult to determine whether OF WOMEN
symptoms often attributed to menstrual irregularities are
related or not related to menopause. While most studies of the efficacy of cART regimens are under-
Menopause coincides with depletion of ovarian follicles, powered for the detection of sex differences [67], the aggregate
and result in characteristic patterns in gonadotropins data suggest that men and women experience comparable re-
that are related to ovarian depletion. Levels of sex steroids sponses to cART in terms of CD4 cell gain, rates of virologic
and gonadotropins are often used as biomarkers of meno- suppression, and gains in survival [122]. The studies that do
pause. However, ovarian cycling occurs during early show sex differences often feature male and female groups
perimenopause when gonadotropic follicular stimulation with significant differences in timing of treatment initiation,
can produce elevated levels of estradiol. Blood levels of adherence, concurrent conditions, and drug use [123]. For ex-
the most commonly used biomarkers of ovarian aging, ample, one European/Canadian multicohort assessment of
estradiol, follicle stimulating hormone (FSH), and inhibin seroconverters found that since the introduction of cART,
B, all vary significantly with the ovarian cycle phase. women have lower rates of progression to AIDS, death without
Optimal interpretation of levels requires collection during AIDS, dementia, tuberculosis, Kaposi’s sarcoma, and lym-
the early follicular phase, which occurs during days 2–5 of phoma than men; injection drug use was significantly more
the menstrual cycle. However, determining the phase prevalent among the male versus female seroconverters [68].
of the cycle in women with irregular menses can be However, despite this apparent improvement in rates of
difficult. Moreover, FSH levels themselves are influenced clinical progression to AIDS or death seen in women com-
by medications and tobacco smoking. Therefore, the most pared to men across studies over time (Fig. 39.4), women
commonly used laboratory tests to detect ovarian aging have higher rates of discontinuation of cART therapy than
in clinical practice all have limitations, particularly for men [124], a phenomenon observed with even newer
women with chronic illness. Measurement of anti- ART components [125, 126] and multiple different regimen
Müllerian hormone (AMH) may provide a better measure types that include protease inhibitors (PI) [127] or
of menopausal status and studies of this test in the context non-nucleoside reverse transcriptase inhibitors (NNRTIs)
of HIV infection are underway in large observational stud- [128]. Moreover, in a meta-analysis comparing the frequen-
ies. Until then, HIV-infected women, particularly if under cy of adverse effects on cART in women compared to men,
Figure 39.4 Clinical progression or mortality:

1987 2009 trends of observational studies across time.
Higher uptake of ARVs (e.g.

IVDU Spain)
? Lower viral load and higher CD4
? Higher drug levels
Higher baseline life expectancies
Differential use of ARVs ? Better cardiovascular outcomes
Unknown infection rate ? Lower rates of viral resistance
Differential access to care
Differential provider treatment Better outcomes in women
Social factors
Higher rates of IVDU
Same in men and women
Worse outcomes in women
530
Figure 39.5 Sex differences in antiretroviral

pharmacokinetics.
Pharmacokinetics
Bioavailability Distribution Metabolism Elimination
• F>M trend • Women weigh less • In vitro: F>M • M>F

• Women ↓ acid, • More proportional • Progesterone — • Smaller organs
slower gastric fat variable effects • Sex disparities
emptying time • Varying plasma on CYP3A4 in hepatitis C
(oral contraceptives, volumes activity and liver status
pregnancy) • Less organ flow • Hepatic p-gp
• Diet differences • Estrogen has concentrations
• No consistent effects on vary by sex
differences in gut plasma binding
CYP or p-gp proteins (↑AAG)
CYP, cytochrome p450, p-gp, p-glycoprotein, AAG, alpha-1-acid glycoprotein
women were consistently more likely to experience tox-

icities of antiretroviral therapy at higher rates than men [67]. CONCLUSIONS
The most likely explanation of these discrepancies—where
women experience improved clinical outcomes on cART with Although significant similarities in the progression and
a higher frequency of adverse effects—is pharmacokinetic dif- pathogenesis of HIV infection exist among HIV-infected
ferences in antiretroviral drug levels by sex [129]. Although women and men, some key differences in transmission risk
women may have higher drug levels of the antiretrovirals factors, co-infections, and complications, and women-
(ARVs) than men for a number of different reasons related specific conditions are outlined in this chapter. Moreover,
to absorption, metabolism, distribution, and elimination although combination antiretroviral treatment is the
(Fig. 39.5), ARV dosing does not typically take sex differences defining component of improved morbidity and mortality
into account. Many experts in the research and care of HIV- outcomes in patients living with HIV disease, differences
infected women are advocating for larger studies that stratify in pharmacokinetics by sex may lead to early and frequent
outcomes by sex, examine sex-based differences in the phar- discontinuation of regimens in women compared to men.
macokinetic and pharmacodynamic differences of ARVs, The 30th year commemoration of HIV/AIDS mandates
and explore dose adjustment as a means to maintain good greater attention to sex differences in HIV disease to accom-
treatment outcomes for women on ARVs while minimizing modate the growing impact of this infection in women
the development of adverse effects. worldwide.
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536
Chapter | 40 |
HIV disease among substance
users: treatment issues
R. Douglas Bruce, Frederick L. Altice, Gerald Friedland
EPIDEMIOLOGY HIV DISEASE IN DRUG USERS
HIV/AIDS and illicit drug use adversely impact tens of The natural history of HIV disease among drug users has
millions of people, with explosive epidemics of both de- been demonstrated to be similar to that in other transmis-
scribed worldwide. Non-injection drug use such as alcohol sion risk categories [6]. Drug users are, however, at an in-
and stimulant use (e.g. cocaine and methamphetamines) creased risk for a number of other infections compared
contribute to risky sexual behaviors leading to HIV acqui- with other risk categories. Although most of these infec-
sition [1]. Injection drug use (IDU), largely of opioids, tions and other complications were common among drug
has been reported in 136 countries and 114 of these have users prior to the HIV epidemic, their incidence and sever-
reported HIV cases [2]. The link between drug use, particu- ity have been accentuated, and clinical presentation af-
larly IDU, and HIV has been well described since the begin- fected by HIV infection. In both inpatient and outpatient
ning of the HIV pandemic [3]. The world’s most volatile settings, these are more common than the designated AIDS
and emerging HIV epidemics are in areas that are fueled indicator diseases or specific HIV-related complications
by illicit drug use, particularly heroin. New IDU epidemics and often confound both diagnosis and treatment [5].
continue to emerge with some of the newest in Kenya and Multiple features of injection drug use that contribute to
Tanzania. Recently, HIV seroprevalence of 42% has been the increased risk of infection are summarized in Box 40.1,
reported among 534 male and female injectors in Dar es A detailed discussion of these infections and their manage-
Salaam, Tanzania [4]. Particularly troubling is that many ment is beyond the focus of this chapter. Table 40.1 offers a
of these epidemics are among individuals younger than summary of substance use-related complications in HIV-
30 and within the most densely populated regions of the infected injection drug users. This chapter will address spe-
world. Injection drug use is especially important in the cific issues for co-managing and treating HIV infection itself
HIV/AIDS epidemic among women and children. among users of illicit drugs.
In light of the increasingly central role of drug use, par-
ticularly IDU, in the global HIV/AIDS epidemic, issues of
HIV clinical care and therapeutics in this population are TREATMENT OF HIV INFECTION
of great importance. Of particular relevance are the special
clinical features of HIV disease in drug-dependent patients, IN DRUG USERS
the treatment of HIV disease itself in this population, the
special difficulties in providing care to drug users and the Combination antiretroviral therapy (cART) has resulted in
treatment of drug addiction and special issues of HIV impressive benefit for people living with HIV/AIDS, includ-
prevention [5]. ing decreasing morbidity, mortality, and hospitalization,
537
and has been demonstrated from a societal perspective to be

Box 40.1 Features of injection drug use (IDU) cost-effective [7]. Despite the widespread availability of anti-
contributing to the infectious diseases listed retroviral medications in resource-rich settings, IDUs have
in Table 40.1 derived less benefit than other populations. This disparity
in benefit among IDUs has been and will likely continue
1. Increased rates of skin, mucous membrane, and
nasopharyngeal carriage of pathogenic organisms.
to be experienced in resource-limited settings even as cART
becomes increasingly available for adults and children with
2. Unsterile injection techniques.
HIV disease. The reasons for the disparity are multifactorial.
3. Contamination of injection equipment or drugs with
In many societies worldwide, both HIV and illicit drug use
microorganisms that may be present in residual blood
are stigmatized such that either or both conditions are often
in shared injection equipment.
cloaked in secrecy and may result in a lack of detection and
4. Humoral, cell-mediated, and phagocyte defects
treatment [8]. Drug users are among the most socially mar-
induced by HIV infection and/or drug use.
ginalized populations and often hidden by circumstances
5. Poor dental hygiene.
and/or choice from mainstream medical care. Even when
6. Impairment of gag and cough reflexes due to available, healthcare services are often constructed in ways
intoxication resulting in increased risk for pneumonia. that are difficult for many drug users to access, either by their
7. Alteration of the normal microbial flora by self- absence in communities with high prevalence of drug use
administered antibiotic use. or by their organization that does not accommodate the
8. Increased prevalence of exposure to certain pathogens chaotic and sometimes unpredictable use of services charac-
(notably Mycobacterium tuberculosis). teristic of drug-using populations. In addition, clinical care
9. Concomitant behaviors such as cigarette smoking for drug users with HIV disease is often challenging and
(i.e. increased susceptibility to pulmonary infections), stressful for clinicians and other healthcare workers as a re-
alcohol use (i.e. increased progression of hepatic sult of the complex array of substance misuse-related med-
fibrosis for HCV-infected drug users), or exchange of ical, psychological and social problems. The frequent co-
sex for drugs or money (i.e. exposure to sexually morbid underlying psychiatric disease often contributes
transmitted infections).
to these difficulties. Substance misusers may also have in-
10. Decreased access to and/or lack of appropriate use of creased difficulties with adherence to cART, which may
preventive and primary healthcare services. be compounded by their underlying co-morbid diseases,
increased side effects, and drug interactions.
Table 40.1 A summary of drug use-related complications in HIV-infected injection drug users
LOCATION DISEASE ORGANISMS TREATMENT COMMENTS
Skin and soft Cellulitis Group A and other Anti-staphylococcal Consider hospitalization
tissue streptococci, agents Consider MRSA
Staphylococcus Same as for cellulitis
aureus Parenteral antibiotics
Same as for to cover both Gram
Abscess cellulitis (þ) and () Incision and drainage
Necrotizing Polymicrobial organisms Consider if crepitus noted; immediate
fasciitis Staphylococcus Anti-staphylococcal surgical consultation required
Septic aureus agents Surgical exploration and vein ligation
thrombophlebitis
Cardiovascular Endocarditis Staphylococcus Anti-staphylococcal Consider if (a) regurgitant murmur,

aureus, agents until cultures (b) presence of peripheral or pulmonary
streptococci, grow emboli, (c) blood culture (þ),
enteric Treat for 4–6 weeks (d) echocardiogram
Gram () rods Consider MRSA
Pulmonary Community- S. pneumoniae, PCN, cephalosporin, Consider even with normal chest X-ray
acquired H. influenzae, macrolide
pneumonia atypical organisms Isoniazid, rifampin,
Septic emboli Tuberculosis pryzinamide, Consider rifabutin due to PI interactions.
Opportunistic ethambutol Rifampin has strong methadone
interaction
538
Chapter | 40 | HIV disease among substance users: treatment issues
Table 40.1 A summary of drug use-related complications in HIV-infected injection drug users—cont’d
LOCATION DISEASE ORGANISMS TREATMENT COMMENTS
infection PCP Bactrim Common complication, consider with

Staphylococcus Anti-staphylococcal pleuritic chest pain
aureus, agents until cultures
streptococci, grow
enteric Gram ()
rods
Liver Hepatitis Hepatitis B Interferon, HBsAg positive

lamivudine, adefovir, HCV antibody positive with
entecavir, detectable RNA
telbivudine
Hepatitis C Pegylated interferon
(PEG) þ ribavirin (RBV)
Telaprevir þ PEG þ
RBV
Boceprevir þ PEG þ
RBV
Neurology Altered mental Substance-induced, Amitriptyline, Consider urine toxicology

status dementia head Gabapentin Consider pattern and tempo of event
Neuropathy trauma Same as for (slowly progressive or sudden onset)
Cerebrovascular Metabolic, endocarditis
accident opportunistic
infection
Substance-induced
(cocaine or
amphetamines)
brain abscess
Hemorrhage due to
emboli
Renal Heroin or HIV Both present with Renal biopsy to Focal and segmental glomerular sclerosis
nephropathy nephritic syndrome establish diagnosis. (FSGS) with progression to renal failure
Electron microscopy in weeks to months
distinguishes
diagnosis
There is often mutual suspicion between drug users and previous difficult encounters with the healthcare system. In
healthcare providers. Clinicians tend to have stereotypic turn, clinicians are sometimes reluctant to confront patients
views of drug users and may harbor negative feelings about with their suspicions about ongoing drug use, fearing that
their social worth. As with other “difficult” patients, physi- the confrontation will compromise their relationship. The fail-
cians may come to view drug users as manipulative, unmo- ure to acknowledge ongoing drug use itself, however, can com-
tivated, and undeserving of care. The chronic relapsing promise the clinician–patient relationship since one of the
nature of addiction as a medical disease is often not appre- most important aspects of the patient’s health is off-limits
ciated by clinicians, nor is the fact that drug users may be for discussion.
quite diverse and heterogeneous. Many physicians assume Because the life of a patient struggling with substance
that drug users’ antisocial behavior and drug use indicate a use disorders (SUDs) is often chaotically organized around
lifelong lack of concern for others and indifference to their their substance use needs, successful programs for this
own well-being, rather than a consequence of addiction. population have developed some or all of the following
Conversely, drug users often are mistrustful of the healthcare characteristics: (1) pharmacologic (e.g. methadone and
system and harbor expectations that they will be treated puni- buprenorphine programs) and/or non-pharmacological
tively. Drug users often conceal their continuing drug use from treatment (e.g. 12 steps) for SUDs; (2) flexible outpatient
healthcare professionals out of fear of rejection prompted by and community care settings (e.g. walk-in clinics, mobile
539
healthcare programs); (3) low-threshold sites to engage active (12) Work consistently as a team. Do not make agreements
users (e.g. syringe exchange sites); (4) modified directly ob- about treatment decisions until the entire team has become
served therapy; (5) intensive outreach and case management involved. This will avoid ‘splitting’ behaviors that often un-
services; or (6) treatment during incarceration [5]. ravel the fabric of a multidisciplinary team. (13) Consider in-
Clinicians involved in the care of drug users with HIV, tegrating drug treatment into the HIV clinical care settings or
should be aware of several key principles, which include HIV clinical care into a drug treatment setting (e.g., a metha-
the following: (1) Become educated about substance abuse done program). While there are no specific recommen-
and its wide array of treatment options. (2) Establish a multi- dations for accomplishing this goal, a number of key
disciplinary team of individuals with expertise in managing approaches have been described. These include complete
HIV, substance abuse, and mental illness, and broadened integration where all clinicians are stakeholders in the treat-
to include social work, nursing, case management, and comment of both conditions, the integration of a specialized
munity outreach. Identify a single provider to maximize addiction specialist team or a hybrid model where both are
consistency. (3) Obtain a thorough history of the patient’s implemented [9].
substance abuse history, practices, needle and syringe source,
drug abuse complications, and treatment history. Non-judg-
mental, clinical assessment of this information is essential. COMMONLY USED DRUGS
Non-judgmental discussion of the adverse health and social
consequences of drug use and the benefits of abstinence may
The illicit drugs most closely associated with the acquisition
increase the patient’s understanding of his or her disease and
of HIV infection globally are heroin, cocaine, and metham-
interest in change. (4) Be aware of pharmacological drug in- phetamine use. Each of these can be administered by a vari-
teractions between HIV therapies and substance abuse thera-
ety of routes. Injection with shared contaminated needles
pies and provide simplified, low pill burden regimens to and syringes or other injection paraphernalia carry the great-
improve treatment adherence. (5) Link HIV and substance
est risk for HIV transmission and other complications. Non-
abuse treatment goals such that success in one arena is linked injection use of cocaine and methamphetamine, however,
to improved outcomes in the other. (6) Establish a relation-
increasingly facilitates HIV transmission through its associ-
ship of mutual respect. Avoid moral condemnation or attri- ation with the exchange of drugs for sex or money or as a re-
bution of addiction to moral or behavioral weakness.
sult of intoxication. It is important to be aware of local
Acknowledge that SUDs are medical diseases, compounded patterns of drug availability and routes of use.
by psychological and social circumstances. As such, they
should be treated using evidence-based guidelines with a
combination of pharmacological and behavioral interven- Heroin
tions. Reducing or stopping drug use is difficult, as is sustain-
ing abstinence. Success may require several attempts and There are a number of illicit opioid and prescribed medica-
relapse is common. Complete abstinence may not be a tions with abuse potential. Heroin is a short-acting,
realistic goal for many substance-misusing patients. Rather, semisynthetic opioid produced from opium. It may be
increasing the proportion of days, weeks, and months smoked, inhaled, or injected; peak heroin euphoria begins
free from mind-altering substances is an acceptable goal. shortly after injection and lasts approximately 1 h,
(7) Work closely with a drug treatment program. (8) Define followed by 1–4 h of sedation. Withdrawal symptoms
and agree on the roles and responsibilities of both the health- commence several hours later. As a consequence, most her-
care team and the patient. Establish a formal treatment con- oin-dependent individuals inject 2–4 times per day. Many
tract that specifies the services to be provided to the patient, heroin users will mediate the sedating effects of heroin by
the caregiver’s expectations about the patient’s behavior, injecting a small amount of cocaine, or other stimulant,
and periodic urine toxicology for substances, and delineate with heroin, a mixture known as a “speedball.” In some
the consequences of behaviors that violates the contract. areas, smoking a heat-stable form of cocaine (“crack”) pro-
Such a contract should be agreeable to both parties, and duces the same rapid effect as injecting cocaine and is, in
not simply a contract of the physician’s expectations. (9) effect, a more modern version of a speedball. The unsterile
Set appropriate limits and respond consistently to behavior method of use, unpredictable concentrations in street
that violates those limits. These should be imposed in a pro- samples, adulterants in the injection mixture, and the life-
fessional manner that reflects the aim of enhancing patients’ style necessary to procure drugs are responsible for most
well-being, and not in an atmosphere of blame or judgment. heroin-associated medical complications.
(10) Carefully evaluate pain syndromes and provide suffi-
cient analgesia as medically indicated. (11) Always consider
acute substance ingestion when evaluating behavior change
Cocaine
and neurologic disease. Use urine toxicology testing to eval- Cocaine is available as a water-soluble hydrochloride salt
uate behavioral changes and to discourage illicit drug use that is injected or taken by nasal inhalation, “snorted.” Al-
by HIV-infected injection drug users during hospital stay. though cocaine hydrochloride is heat labile, it may be
540
chemically converted to a heat-stable basic form (crack),

which can be smoked. Pulmonary absorption of crack is MEDICATION-ASSISTED THERAPIES
as rapid as intravenous injection. Cocaine’s half-life is
short, resulting in the need for frequent administration.
Drug dependence is a chronic, relapsing, and treatable dis-
Active cocaine users may inject or inhale cocaine as many
ease, characterized by compulsive drug-seeking and drug
as 20 times a day. Cocaine induces feelings of elation, om-
use. Although exposure to addictive substances is wide-
nipotence and invincibility and with rapid development of
spread in society, high vulnerability to addiction is more
psychological dependence. The multiple psychological and
limited and is the product of biologic, psychological, and
physical effects of cocaine can increase HIV transmission
environmental influences. Thus, identification of addictive
and acquisition risk and markedly disrupt clinical care.
disease and referral to appropriate treatment services is an
As such, programs that are non-judgmental are essential
essential part of the clinical care of HIV-infected patients. In-
to continue to engage these patients in care rather than risk
deed, successful treatment of HIV disease in drug users often
losing them to follow-up and diminish the likelihood of
requires attention to and treatment of SUDs. Recent data
risk-reduction interventions.
confirm that effective and sustained treatment of SUDs im-
proves HIV treatment outcomes [15]. There is a wide variety
of treatment modalities. Selection of the appropriate pro-
Methamphetamine gram is an individual decision based in part upon the drug
Methamphetamine is a psychostimulant that is similar in used, the length and pattern of the patient’s drug use, per-
chemical structure to amphetamine but has more profound sonal psychosocial characteristics, and local availability
effects on the central nervous system. It can be smoked, (Table 40.2) [16]. Resources are limited in many communi-
snorted, injected or administered rectally. Like cocaine, ties, substantially limiting options for referral.
methamphetamine ingestion produces stimulation and The most effective treatment for opioid dependence for
similar feelings of euphoria; however, methamphetamine patients with long-standing dependence, particularly injec-
has a longer duration of action (6–8 h after a single dose). tion drug users, is pharmacological therapy with metha-
Tolerance develops rapidly and escalation of dose and done or buprenorphine [17, 18].
frequency is required. As is the case with cocaine, metham-
phetamine use is associated with high-risk sexual behavior
and subsequent HIV acquisition [10].
Medically supervised opioid
withdrawal
Alcohol Withdrawal from opioids involves the gradual reduction of
Although not illicit in most societies, the widespread use dosage over a period of time. A hallmark of drug depen-
and medical and psychological importance of alcohol is dence is the patient’s inability to reduce consumption of
associated with many adverse HIV effects. HIV-infected the drug over time without any external assistance. Al-
patients have a higher prevalence of alcohol consumption though patients can be withdrawn using the drug to which
than the general population [11]. Alcohol use ranges from they are addicted, in most instances it is easier to use meth-
hazardous drinking (i.e. drinking at a level that could be adone or buprenorphine. It is usually not possible to know
hazardous to the individual’s health) to alcoholism. Alco- with certainty how much drug the patient has been taking,
hol use can result in ongoing risky sexual behaviors that though self-reports can be reliable. Regardless of the
can lead to the transmission of HIV [12, 13]. Alcohol amount, myalgias, diarrhea, and insomnia and irritability
use, in addition, can compromise cART by influencing associated with withdrawal can be reduced with a daily oral
both access and adherence to ARVs. In addition to HIV, dose of 25–30 mg of methadone or 16 mg of buprenor-
alcohol has well-known negative effects upon the course phine. This dose of methadone, however, will not fully
of hepatitis C (HCV) treatment and HIV/HCV co-infected eliminate drug craving, whereas 16 mg of buprenorphine
patients with hazardous drinking are of special concern will often eliminate craving [19]. Decreasing the metha-
[14]. As in all chemical dependencies, a comprehensive done dose by 10–20% every few days after the withdrawal
approach to the treatment of alcoholism integrates psy- syndrome is suppressed should maintain patient comfort.
chosocial treatment with pharmacologic treatments [5]. Buprenorphine, due to its longer half-life, can be tapered
In the physiologically dependent patient, a structured more rapidly. The decision to medically supervise opioid
withdrawal utilizing benzodiazepines or barbiturates is withdrawal or to recommend chronic maintenance therapy
also necessary and typically occurs on an inpatient unit. depends on a number of factors. In general, supervised opi-
Afterwards, a combination of pharmacological and psy- oid withdrawal should be reserved for short-term opioid
chosocial treatments (e.g. 12 steps) should be utilized users (< 6 months), young adults, and non-injectors.
to maintain abstinence and can be prescribed by a primary Otherwise, relapse to drug use among chronic opioid
care provider. users exceeds 85% when patients undergo supervised
541
Table 40.2 Modalities of substance abuse treatment
TREATMENT BENEFITS LIMITATIONS APPROPRIATE INAPPROPRIATE LOCATION

FOR WHOM? FOR WHOM?
Therapeutic Can address Low retention Highly motivated Individuals with Community settings
community polysubstance rates individuals family/work
abuse commitments
Methadone Reduces crime, Does not address Heavy use of Non-opioid- Requires a more
transmission of other drug use; opioids dependent patients; restrictive
infectious potential for individuals abusing infrastructure
diseases, high diversion other sedatives (e.g.
retention rates benzodiazepines)
Buprenorphine Reduces crime, Does not address Opioid- Non-opioid- Due to improved
transmission of other drug use; dependent dependent patients; safety profile, may be
infectious possibly less patients. individuals abusing more widely
diseases, high potential for Improved safety other sedatives (e.g. accessible and
retention rates diversion than profile compared benzodiazepines) available in primary
methadone with methadone care settings
Naltrexone Effective Lacking high Individuals with Individuals with low Not a narcotic and so
among very motivation, high levels of social support and/ less regulation
motivated treatment is social support or motivation
individuals ineffective and motivation
Adapted with permission from Smith-Rohrberg et al. [16]
withdrawal without chronic maintenance therapy with and therefore to moderate this HIV risk-taking behavior
buprenorphine or methadone [20]. [17, 18]. Chronic maintenance with methadone prevents
relapse to opioid injection-related behavior and maintains
patients in treatment [20]. Methadone maintenance has
Treatment of opioid dependence
been shown to be effective in decreasing psychosocial
The treatment of choice for the patient who is opioid- and medical morbidity associated with opioid addiction,
dependent and has HIV disease is chronic maintenance including increasing access to and retention on ARV and
with an opioid agonist such as methadone or buprenor- other therapies. Furthermore, in addition to its benefit in de-
phine. In addition to agonist therapy, the patient should creasing the spread of HIV among injection drug users, it im-
be enrolled in a comprehensive drug treatment program proves overall health status, and is associated with decreased
designed to prevent the abuse of other drugs and promote criminal activity and improved social functioning. Metha-
rehabilitation [21]. Agonist treatment of opioid addiction done, therefore, is effective for primary and secondary HIV
is particularly important for the patient with co-morbid prevention [25] and is cost-effective to society [26].
HIV infection because effective treatment enhances HIV There is no optimal dose of methadone for treatment of
treatment and may decrease risk-taking behaviors [22]. opioid-dependent patients who must be assessed individu-
Methadone, a semisynthetic, long-acting opioid analgesic, ally for treatment response. Generally, doses of 30–60 mg
is particularly valuable for its oral bioavailability, long half- daily will block opioid withdrawal symptoms, but higher
life of 24–36 h, and the consistent plasma levels that are doses in the 100–150 mg daily range are needed to reduce
obtained with regular administration. A single daily dose opioid craving and decrease illicit drug use. These higher
is given to maintain stable plasma levels. As a result, toler- doses are also associated with greater retention in treatment
ance develops and regular methadone users do not experi- [27]. In the first 6 months of treatment, however, some pa-
ence the euphoria of the heroin cycle [23]. Drug-seeking tients may experience side effects common to other opi-
behavior decreases, creating the possibility for the develop- oids, but tolerance to the majority of these effects
ment of more constructive behaviors and relationships. develops rapidly. Persistent side effects include diaphore-
Methadone maintenance remains a well-validated, evi- sis, constipation, and amenorrhea (the majority of women
denced-based treatment for opioid addiction [24]. Metha- experience the return of menses after 12–18 months of
done has been shown to decrease the injection of opioids therapy).
542
Buprenorphine, unlike methadone, which is a full ago- therapy for cocaine is to relieve the craving for dopamine
nist, is a partial m-receptor agonist. As a partial agonist, by maintaining stable, elevated levels. Taking cocaine
there is a plateau of its agonist effects at higher doses which in addition to disulfiram frequently results in a less reward-
improves its safety profile compared with methadone and ing, dysphoric response caused by excessive amounts of
may reduce its likelihood for medication diversion. The dopamine.
plateau includes an upper limit on the severity of sideeffects Pharmacological interactions are possible with HIV ther-
associated with overdose, such as respiratory depression apies as disulfiram is bioactivated by CYP3A4 [36]. As with
[28]. Buprenorphine has a higher binding affinity for the many treatments in addiction medicine, adherence re-
m-receptor than heroin or methadone [29]. Because bupre- mains a problem with disulfiram. Treatment works well
norphine dissociates slowly from the m-receptor, alternate for motivated patients and for patients receiving disulfiram
day dosing is possible [30]. Buprenorphine has been pre- as directly observed therapy with methadone maintenance.
scribed in France since 1996 and resulted in dramatic im-
provements in the treatment of opioid addiction there.
Buprenorphine was approved for use in the USA in 2002
and population outcome data have recently been reported Treatment for methamphetamine
among HIV-infected patients [15]. Worldwide, it is becom- dependence
ing increasingly more available [31]. Integration of bupre-
Unlike the case of opioid addiction, studies seeking an ef-
norphine is now being incorporated into HIV clinical care
fective and evidence-based pharmacological treatment for
settings for HIV prevention and stabilization to initiate
methamphetamine addiction have been disappointing
cART and using various different models of care prevention
[37]. The lack of successful, standardized treatment strate-
[32]. Unlike methadone, which typically is limited to spe-
gies for methamphetamine users is a significant problem as
cialized treatment settings, buprenorphine, due to its en-
the epidemic of methamphetamine use grows and is now
hanced safety profile, can be utilized in primary and HIV
an international problem. In the absence of effective phar-
clinical care in some countries. Buprenorphine’s cost, how-
macological treatments for methamphetamine use, HIV
ever, limits its availability worldwide. Methadone remains,
care providers may feel helpless and frustrated. Counseling
gram for gram, the cheapest and most effective pharmaco-
is the only treatment modality shown to decrease use of
logical treatment for any opioid addiction [24]. Although
methamphetamine [38]. Referral to a substance abuse
buprenorphine and methadone are comparable in many
treatment program, if available, is essential.
ways, methadone tends to retain patients in treatment lon-
ger than buprenorphine [27].
Naltrexone, an opioid receptor antagonist, can also be
used in the treatment of opioid addiction. Naltrexone Treatment for alcohol use disorders
has demonstrated efficacy in highly motivated populations
[33]. Its use among HIV-infected drug users is discouraged,
and alcoholism
as methadone and buprenorphine have higher retention Naltrexone, the opioid receptor antagonist discussed earlier,
rates and allow for engagement when less motivation remains the most studied and consistently most effective
for treatment exists. In the primary care setting where meth- pharmacotherapy for alcohol dependence [39]. The ex-
adone cannot currently be prescribed for opioid addiction, tended release formulation is the most effective treatment
buprenorphine remains the best option for the treatment currently available. Alcohol stimulates receptor-mediated
of opioid addiction as it has been shown to be superior dopamine release through a complex mechanism involving
to oral naltrexone in a recent randomized controlled gamma-aminobutyric acid activation and the opioid recep-
trial [34]. tor system [40]. By blocking the mu-opioid receptor, naltrex-
HIV-infected drug users must have as their treatment one acts to decrease the dopamine reward. Patients consume
plan an evidence-based approach to provide appropriate less alcohol while receiving naltrexone and those who are so-
and adequate treatment for substance abuse in order to im- ber while receiving treatment tend to have relapses of re-
prove the psychological and physiological disruptions that duced severity [41]. The currently recommended dosage is
perpetuate the often unstable life of a person struggling 100 mg/day, and vigilance for hepatotoxicity must be main-
with addiction. tained (as indicated by the drug’s black box warning).
Expert opinion suggests that even lower doses of naltrexone
may be effective in the treatment of alcohol dependence;
therefore, medical providers should consider starting pa-
Treatment for cocaine dependence
tients at even lower doses (e.g. 25 mg/day) and titrating to
Disulfiram remains the most promising therapeutic agent effect. Although acamprosate and disulfiram are also ap-
for cocaine addiction to date. Six randomized controlled proved for treatment of alcohol dependence, both have been
trials have now shown the efficacy of disulfiram in treating demonstrated to be inferior to naltrexone and should be
cocaine addiction [35]. The goal of pharmacological considered in those who are unable to take naltrexone [39].
543
MENTAL ILLNESS AND ILLICIT DRUG INTERACTIONS WITH HIV

DRUG USE THERAPEUTICS
A thorough discussion of mental illness as it relates to sub- With the proliferation of medications to treat HIV and
stance misuse and HIV is outside the scope of this chapter other medical conditions, drug–drug interactions are be-
and the reader is referred to the literature for more on this coming more common and more complicated. It is essen-
topic [42]. It must be noted, however, that substance misuse tial to be familiar with the current state-of-the-art data on
and mental illness are closely interrelated with HIV. Individ- drug metabolism and expected or actual pharmacokinetic
uals with all three diagnoses are likely to engage in high-risk interactions between HIV therapeutics and the pharma-
behaviors [43], and when untreated, they continue to cological treatment for addiction (Table 40.3 summarizes
fuel the HIV epidemic by engaging in risk behaviors and on- the key interactions for the practitioner) [44]. This under-
going transmission of HIV. These three diagnoses should be standing is critical as medication-assisted treatment with
viewed as overlapping spheres of influence, with each diag- methadone or buprenorphine may alter metabolism of an-
nosis affecting the others. Conceptually, this is important tiretroviral medications, resulting in increased toxicity or
because successful therapy requires screening, diagnosis, reduced efficacy. Alternatively, antiretroviral medications
and treatment of all three spheres of influence rather than may alter the levels of medication-assisted treatment,
ignoring any one single area. For this reason, it is essential resulting in clinical opioid withdrawal or overdose.
to ensure a comprehensive and integrated approach to man- The currently approved nucleoside reverse transcriptase
aging these three co-morbid conditions [42]. inhibitors (NRTIs) do not affect methadone levels in a
Table 40.3 Interactions between antiretrovirals and methadone, and buprenorphine
MEDICATION EFFECT ON EFFECT ARV COMMENTS

METHADONE ON BUP
NRTI
Abacavir " clearance Not # Cmax No dose change required
(ABC)a studied for METH
Didanosine No clinical No clinical METH # ddI AUC by 57% No dose adjustments necessary
(ddI) effect effect for buffered tablet, when EC capsule used with
partially corrected by EC METH patients
capsule. No BUP effect on ddI
Emtriva (FTC) Not studied Not Not studied

studied
Festinavir Not studied Not Not studied

studied
Lamivudine No clinical No clinical No effect of BUP on 3TC AZT/3TC co-formulation studied

(3TC) effect effect only with METH.
No dose adjustments necessary
Stavudine No clinical Not # d4T AUC12h by No dose adjustments necessary

(d4T) effect studied 23% and Cmax by 44%
Tenofovir (TDF) No clinical No clinical No significant effect No dose adjustments necessary

effect effect on TDF by BUP
Zalcitabine Not studied Not Not studied

(ddC) studied
Zidovudine No clinical No clinical " AZT AUC by 40% Watch for AZT-related toxicity
(AZT) effect effect (symptoms and laboratory).
Dose reductions of AZT may be
required
544
Table 40.3 Interactions between antiretrovirals and methadone, and buprenorphine—cont’d

METHADONE ON BUP
NNRTI
Delavirdine " AUC by 19%; " AUC by No clinical effect No dose adjustments necessary;
(DLV) "Cmax by 10% 400%, however, should be used with
without caution as long-term effects
clinical (>7 days) are unknown
effect
Efavirenz (EFV) # AUC by 57% No clinical No clinical effect Opioid withdrawal from METH
effect common. METH dose increase
likely to be necessary
Etravirine (ETV) No clinical Not No clinical effect No dose adjustments necessary

effect (only studied
100 b.i.d. of
etravirine
studied)
Lersivirine No clinical Not Not studied No dose adjustments necessary

effect studied
Nevirapine # AUC by 46% No clinical No clinical effect Opioid withdrawal from METH
(NVP) effect common. METH dose increase
likely to be necessary
Rilpivirine # AUC by 22% Not No clinical effect Monitoring for symptoms of METH
(TMC278) studied withdrawal is recommended
PI
Amprenavir # AUC of Not # AUC by 30% No dose adjustments necessary
(AMP) R-METH studied
by 13%
Atazanavir No effect " AUC by No effect Some individuals may experience

(ATV) 167% oversedation.
Slower titration upwards of BUP
may be advisable
Darunavir # S-METH AUC " norBUP No clinical effect No ARV dose change when
by 36% and # AUC by combined with METH or BUP. Four
R-METH AUC 46% subjects out of 16 in METH study
by 15% reported mild opioid withdrawal,
but no dose adjustments were
needed.
Fosamprenavir # AUC R-METH Not No clinical effect No dose adjustments necessary

(fAMP) by 18% studied
Indinavir (IND) No clinical Not # Cmax between 16% Differences do not appear to be
effect studied and 28% and " Cmin between clinically significant.
50% and 100%
Lopinavir/ # AUC by No clinical Not studied # AUC of METH caused by

ritonavir (LPV/r) 26–36% effect lopinavir.
One study reported opioid
withdrawal symptoms in 27%
of patients.
METH dose increase may be
necessary in some patients
Continued
545
Table 40.3 Interactions between antiretrovirals and methadone, and buprenorphine—cont’d

METHADONE ON BUP
PI—cont’d
Nelfinavir # AUC by 40% No clinical # AUC of active M8 Despite # METH AUC, clinical
effect metabolite by 48% withdrawal is usually absent and
a priori dosage adjustments are
not needed. Decrease in AUC
of M8 unlikely to be clinically
significant.
Ritonavir (RTV) # AUC by 37% in " AUC by Not studied No dosage adjustments necessary
one study and no 157%
effect in another
(see text)
Saquinavir # AUC by Not Not studied Saquinavir boosted with ritonavir

(SQV) 20–32% studied studied. Despite # METH AUC,
clinical withdrawal was not
reported
Tipranavir # by 50%a # norBUP No ARV dose change when METH dose may need to be
(TPV) ACU by combined with METH. increased. TPV may be less
80% TPV/r AUC and Cmax decreased effective with BUP, but no dosage
19% and 25%, respectively, adjustments necessary in BUP
compared to historical controls
in the presence of BUP
Integrase
Elvitegravir Not studied Not Not studied
studied
Raltegravir No clinical No clinical No ARV dose

(RAL) effect effect adjustments necessary
Entry Inhibitors
Maraviroc Not studied Not Not studied
studied
Enfurvitide Not studied Not Not studied

studied
a
Decrease in methadone not specified as AUC or Cmax.
NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; AUC, area under curve;
METH, methadone; BUP, buprenorphine; norBUP, norbuprenorphine.
Adapted with permission from Bruce et al. [45].
clinically significant manner. Methadone, however, affects Zidovudine, lamivudine, didanosine, and tenofovir are the
zidovudine significantly. Methadone increased zidovudine NRTIs that have been studied in combination with buprenor-
drug levels by approximately 40%. As a result, patients may phine. Buprenorphine did not alter the pharmacokinetics of
experience symptoms associated with excessive zidovudine these NRTI in any clinically meaningful manner [45].
plasma levels that may be confused with symptoms of Nevirapine and efavirenz markedly reduce methadone
opioid withdrawal. levels and precipitate clinical opioid withdrawal [46].
546
Although efavirenz and nevirapine significantly reduce bupre- increases methadone exposure, and methadone dosage
norphine levels, this reduction is not associated with symp- may need to be reduced [57].
toms of opioid withdrawal [47, 48]. Newer NNRTIs
have been recently studied and are summarized in Table 40.3.
Most protease inhibitors (PIs) studied do not appear
to have clinically meaningful effects upon methadone SPECIAL ISSUES IN PREVENTION
levels with the following exceptions: One study of the
co-formulated capsule of lopinavir/ritonavir administration
Risk reduction
with methadone reported that 27% of subjects co-
administered lopinavir/ritonavir and methadone experi- The relapsing pattern of drug use and the wide array of seri-
enced clinical opioid withdrawal symptoms [49]. The pack- ous infectious and other medical consequences require the
age insert for tipranavir reports that standard dosing of development of preventive risk-reduction strategies. Risk re-
tipranavir/ritonavir (500/200 mg b.i.d.) may result in a de- duction does not promote injection drug use, but seeks to
crease in methadone levels requiring an increase in metha- decrease the frequency of adverse events that are related to
done dose. Darunavir has also been reported to this practice. Risk reduction is based on the underlying prin-
potentially lead to opioid withdrawal in the methadone- ciple that injection drug use is a chronic and relapsing dis-
maintained patient [51]. ease which may not be cured in the individual or
Most PIs studied do not appear to have clinically mean- eliminated from society but can be conducted in a way that
ingful effects upon buprenorphine levels with the follow- minimizes harm to the user and others. While complete ces-
ing exceptions: Buprenorphine, appears to have a sation of drug use remains a laudable goal, reduction in drug
potential pharmacodynamic interaction with atazanavir use frequency and safer injection practices is more realistic
that can lead to oversedation in some individuals [52]. for many drug users until abstinence can be achieved.
Buprenorphine can be used with atazanavir, but slower up- Risk-reduction strategies have been effectively incorporated
ward titration of dosing is advised with monitoring. In a re- into some drug treatment programs, syringe exchange pro-
cent study, however, a lack of a pharamcodynamic effect grams and safe injection rooms [58]. There are several prac-
was seen in a prospective cohort of HIV-infected opioid- tical components inherent to risk-reduction strategies.
dependent patients on buprenorphine [53]. This study, Education about and provision of drug use paraphernalia
however, occurred after the previous publications caution- (e.g. needles and syringes) for more hygienic injection prac-
ing providers on the rate of build-up and it is unclear if the tices for the prevention of infectious complications of injec-
lack of a pharmacodynamic effect was the result of a slower tion are essential. In addition to the distribution or exchange
upward titration. Tipranavir alters the disposition of bupre- of injection equipment, these programs typically include
norphine without producing a pharmacodyamic effect. HIV/AIDS education, condom distribution, and referral or
More importantly, buprenorphine has been shown to re- enrollment in a variety of drug treatment, medical, and so-
duce the AUC of tipranavir. The clinical significance of this cial services [59]. Specifically, some programs provide onsite
is unknown; however, providers are cautioned to follow medical and drug treatment, resulting in reductions in emer-
patients closely if the two are co-administered [54]. gency department use by IDUs.
Raltegravir, the first available integrase inhibitor, Provision of primary medical care services linked to drug-
has been studied in methadone- and buprenorphine- abuse treatment is a way to promote preventive therapies to
maintained patients with the finding that no dose modifi- enhance harm reduction. In this and all other clinical set-
cation of the methadone was necessary. tings, in addition to the treatment of HIV disease and pre-
Several medications used to treat or prevent opportunistic vention of complications, injection drug users should be
infections in HIV-infected individuals deserve brief com- routinely screened for hepatitis B and C, latent M. tuberculosis
ment. Rifampin, a potent inducer of cytochrome P450, pro- infection, syphilis, and other sexually transmitted disease.
duces rapid and profound reductions in methadone levels They should be offered pneumococcal, influenza, tetanus,
and development of opioid withdrawal; as such, rifampin and hepatitis A and B immunization and, if lately infected
should be changed to rifabutin or methadone doses increased with M. tuberculosis, chemoprophylaxis with isoniazid.
rapidly and dramatically to avoid opioid withdrawal and The ultimate goal of risk-reduction strategies should be
discontinuation of all medications [55]. A recent study the reduction or prevention of illicit drug use itself, the de-
of buprenorphine and rifampin has demonstrated that velopment of strategies that will minimize the serious med-
rifampin precipitates opioid withdrawal in buprenorphine- ical consequences of drug misuse, and the development of
maintained patients [56]. Patients receiving both medica- strategies that will eliminate drug misuse and its root
tions should be observed closely for opioid withdrawal and causes. Until we are successful in this arena, we stand little
increases in buprenorphine may be required. Fluconazole, chance of limiting the spread and consequences of HIV
a known inhibitor of cytochrome P450 metabolism, disease in this and related populations.
547
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549
Chapter | 41 |
The HIV-infected international traveler
Malcolm John
There has also been increasing numbers of immigrants to

INTRODUCTION developed countries who visit their countries of origin and
return that are a population at high risk for tropical infec-
The advent of (ART) has led to significant decreases in tions including tuberculosis (TB), malaria, food- and wa-
human immunodeficiency virus type 1 (HIV-1)-related ter-borne illnesses, hepatitis A, and sexually transmitted
morbidity and mortality, with concomitant improved im- infections (STIs) [11]. It is therefore important that persons
munocompetence [1–5]. Despite this, the HIV-infected living with HIV/AIDS and their pre-travel providers stay in-
traveler is still at increased risk for opportunistic infections formed about preparations and precautions that should be
and other complications compared with HIV-uninfected taken by the HIV-infected person when traveling interna-
travelers. This is especially true for those with low CD4 tionally today.
T-cell counts and those traveling to developing countries.
Nonetheless, pre-travel health advice is often underutilized
[6, 7]. GENERAL CONSIDERATIONS
One study of patients at an HIV clinic in a North Amer-
ican tertiary care hospital found that 46% of 290 surveyed The quality of pre-travel health advice can vary greatly; thus,
individuals had traveled internationally within the previ- consultation with a travel medicine specialist is advisable.
ous 5 years. Yet, only 44% sought health advice before trav- A study from the United Kingdom (UK) of 215 clinicians
eling [7]. Of those seeking pre-travel advice, only half told serving higher education establishments in the UK showed
the provider that they were HIV-infected. International that practitioners often gave good advice with respect to im-
travel was associated with poor adherence to antiretrovirals munizations and malaria prophylaxis, but little on HIV and
(ARVs) and to risky sexual activity in these patients. A total other risks [12]. Training in travel medicine was associated
of 93% of the 75 individuals not seeking pre-travel health with more appropriate pre-travel health advice.
advice believed such consultations were unnecessary. Such Pre-travel health advice for the HIV-infected interna-
data are disturbing, given that international travel increased tional traveler should be sought as soon as possible.
steadily throughout the 1990s and early twenty-first century Consultation at least 6–8 weeks before travel is recom-
[8]. Indeed, outbound overseas travel from the USA climbed mended to allow time for development of adequate
to a high of almost 27 million by 2000 with travel to Asia, responses to any necessary vaccinations. Use of resources
South America, and the Middle East growing by 93, 130, such as travel clinics and travel-related websites before
and 159%, respectively [7]. During this period, incident traveling is appropriate. Detailed counseling and evalua-
infections in returning international travelers continued to tion of the risks and benefits of preventive prophylaxis
rise [9]. Post-9/11, US-international overseas travel in- and vaccinations are essential.
creased to a new high of 47.7 million bidirectional visits Pre-travel advice should include a discussion of immuni-
in 2004. Countries within Eastern Europe and the Caribbean zations, malaria prophylaxis, traveler’s diarrhea manage-
experienced the fastest growth from 2000 to 2004 (25 and ment, supplemental health insurance, accidents and
15%, respectively) [10]. injuries, motion sickness, jet lag, extremes of temperature
551
and sun exposure, food and water safety, use of an emer- while traveling and what to do while traveling that should
gency medical bracelet, list of medical services abroad, be part of a pre-travel consultation.
and possible arrangement of visits with physicians who It is wise to reassess the stage of HIV prior to travel as low
speak the traveler’s language [13]. The last issue is especially CD4 counts are the biggest predictor of risk of opportunis-
important for extended visits, so that adequate medical fol- tic infections (OIs) when traveling. However, changing
low-up and medication supplies are maintained. Emphasis antiretroviral medications just prior to travel is not encour-
on maintaining adherence to ARV regimens is important as aged in order to avoid complications from the ARVs occur-
there is evidence that adherence is more difficult abroad ring while traveling. The Centers for Disease Control and
[14]. Strategies such as keeping antiretroviral medications Prevention (CDC) suggest that to minimize the risk of in-
in carry-on baggage should be reviewed. A discussion of be- fection, treatment naı̈ve HIV-infected individuals with CD4
havioral risk reduction while traveling is also essential. cell counts below 200/mm3 should delay travel if possible
Boxes 41.1 and 41.2 summarize advice on items to take until CD4 T-cell reconstitution with ART occurs.
Box 41.1 What to take when traveling
• Adequate supply of medications (1–2 weeks’ extra supply is • Insect repellent that contains <30% DEET
advisable) and prophylactic agents (e.g. for malaria) for (N,N-diethylmetatoluamide).
shorter trips, along with copies of prescriptions; attention • Medications for sinusitis and jet lag.
should be given to any need for refrigeration of • Condoms and other safe-sex items.
medications.
• First-aid kit, including topical antibiotics.
• Documentation of vaccinations.
• Consider bringing own equipment for boiling water,
• Medications for traveler’s diarrhea, e.g. ciprofloxacin for purifying water by iodine treatment, and/or filtration of
3- to 7-day courses of treatment or daily prophylaxis up to water using commercial filters with 1 mm or smaller filters.
3 weeks’ duration; trimethoprim-sulfamethoxazole (TMP-
• Consider need for fluconazole, itraconazole, and isoniazid
SMX) recommended for children and pregnant women.
prophylaxis if CD4 count <100 cells/mm3.
• Mosquito netting (preferably treated with permethrin).
Box 41.2 What to do when traveling
• Take steps to maintain adherence to medication regimen. – Avoid walking barefoot in areas with high risk of soil
• Carry securely basic medical information, e.g. medical pathogens.
conditions, medications, allergies. – Avoid swimming in bodies of water that may be
• Know how to access local health care (general care and contaminated by other people and from sewage, animal
HIV-specific care) wastes, and wastewater run-off; avoid swallowing water
• Avoid behaviors that increase risk of new infections or when swimming, even chlorinated water, which may
complications: contain live organisms (e.g. Cryptosporidium, Giardia,
hepatitis A virus, and Norwalk virus), and which have
– “Boil it, peel it, cook it, or forget it”, and WASH HANDS.
moderate to very high resistance to chlorine; avoid
– Avoid raw vegetables, fruit you have not peeled yourself,
swimming in areas of endemic schistosomiasis or water at
unpasteurized dairy products, cooked food not served
risk of contamination from animals carrying Leptospira.
steaming hot, and tap water, including ice; meat should
– Use safe-sex practices to avoid risks from acquiring
be well-cooked, as undercooked beef, pork, or fish can
sexually transmitted diseases. These risks include
be a source of tapeworms.
increased severity and complications (e.g. herpes
– Purify water in high-risk areas—boiling water is the best
outbreaks more prolonged and severe), risks related to
method of purification; tincture of iodine or tetraglycine
acquiring new HIV strains (e.g. non-nucleoside reverse
hydroperiodide tablets is an alternative but the water
transcriptase inhibitors are not active against HIV-2).
must be used within a few weeks and the method
– Avoid blood exposures (e.g. acupuncture, tattoos,
cannot be relied on to kill Cryptosporidium unless the
injections with possibly unsterile needles, sharing razors,
water is allowed to sit for 15 h before it is drunk; filtering
manicures and pedicures) that can lead to acquiring
water produces variable results, especially for small
hepatitis C as hepatitis C-related cirrhosis is accelerated
bacteria or viruses, and proper selection, operation, care,
in those co-infected with HIV.
and maintenance of water filters are essential.
552
Chapter | 41 | The HIV-infected international traveler
Vaccinations
Box 41.3 Useful travel resources
Concerns over vaccinating HIV-infected persons because
• CDC Travelers’ Health site: http://www.cdc.gov/travel/ of documented elevations in HIV viral loads have not
index.htm
borne out. Such viral load elevations are transient, resolving
• CDC Malaria webpage: http://www.cdc.gov/ within 4–6 weeks and sooner if on ART without any docu-
malaria mented long-term deleterious effects [15]. All HIV-infected
• CDC Information Line: 1-877-CDC-INFO or 1-800-232- travelers should therefore be uptodate on routinely recom-
4636, toll free. Choose international travel option at the mended vaccines and those routinely recommended for
prompt HIV-infected individuals. Additional vaccines should be
• World Health Organization (WHO) homepage: http:// given based on the specific travel risk exposures to endemic
www.who.int/en infections. It should be noted that vaccine responses are gener-
• WHO International Travel and Health page: http:// ally inadequate if the patient’s CD4 count is < 100 cells/mm3;
www.who.int/ith/en best results are obtained if the CD4 count is >350 cells/mm3
• US State Department Travel Warnings and Consular [16]. The CDC’s Yellow Book states that antiretroviral drug-
Information: http://travel.state.gov/travel/cis_pa_tw/tw/ induced increased CD4 counts, and not nadir counts, should
tw_1764.html be used to categorize HIV-infected persons and that waiting
3 months post-immune reconstitution before immunization
is advisable.
In general, inactivated vaccines are safe to administer and
The CDC also warns that some countries screen for HIV should be initiated 6–8 weeks before travel. Live vaccines,
and deny entry to those who have AIDS or test positive for including BCG, should be avoided with two exceptions
HIV (usually those entering for extended periods, e.g. for (Table 41.1):
work or study). Some countries further deny entry to those • Live measles vaccine is recommended for non-
carrying antiretroviral medications. Placing ARVs in an immune travelers whose CD4 counts are > 200 cells/
empty vitamin or other medication container is one means mm3 as the clinical course of the disease is worse
of avoiding problems in such situations. More specific in- in those with HIV. Non-immune travelers with
formation is best obtained from the consular officials of CD4 counts < 200 cells/mm3 should receive the
the individual nations. See Box 41.3 for a list of travel immune globulin if traveling to endemic areas (CDC,
resources. Yellow Book).
Table 41.1 Summary of vaccination recommendations
ROUTINELY GIVEN GIVEN IF TRAVEL INDICATES CONTRAINDICATED
• Tetanus–diphtheria (Td or Tdap vaccines) • Japanese B encephalitis (many side effects • BCG
• Hepatitis A not unique to HIV-infected persons; use if • Polio, live
• Hepatitis B at high risk, e.g. >1 month in rural • Typhoid, live
• Influenza (inactivated) endemic area) • Influenza, live
• Pneumococcal polysaccharide vaccine • Measles (live vaccine should not be given if attenuated (LAIV)
(H. influenzae B generally not severe immunosuppression; use • Varicella-zoster virus
recommended as HIV-infected adults are immunoglobulin if needed) (VZV; can consider if CD4
generally infected with non-typeable • Meningococcal (consider either the count >200 cells/mm3)
strains; children should be vaccinated) polysaccharide or conjugate vaccine) (cholera vaccine no longer
• Polio, inactivated (IPV) recommended or required)
• Rabies (safe; pre-exposure prophylaxis
generally not indicated)
• Tick-borne encephalitis (only if high risk,
e.g. forested endemic areas and drinking
unpasteurized milk products)
• Typhoid Vi (inactivated, Vi)
• Yellow fever (live vaccine should not be
given if severe immunosuppression,
instruct how to avoid mosquito bites and
provide a vaccination waiver letter)
553
• Yellow fever vaccine is of unknown risk and benefit to mortality. HIV-infected persons with Salmonella septicemia
HIV-infected individuals; however, it should be offered require chronic maintenance therapy to prevent recurrence.
to asymptomatic HIV-infected individuals with Other common bacterial enteric infections in the HIV-
minimal immunosuppression (avoid if CD4 counts infected traveler include enterotoxigenic E. coli, enteroag-
< 200 cells/mm3) who cannot avoid potential gregative E. coli, Shigella, and Campylobacter, especially
exposure to the yellow fever virus. Those at risk who among men who have sex with men. Other causes of TD
defer immunization should be instructed in methods include parasites, e.g. Giardia, Isospora, CRYPTOSPORID-
to avoid mosquito bites and provided a vaccination IUM, and Cyclospora, especially in Central America. Despite
waiver letter understanding that such a letter may not the fact that parasitic diarrheal diseases occur in the HIV-
be accepted by some countries (CDC, http://www.cdc. infected traveler, there appears to be little evidence that
gov/travel/hivtrav.htm). HIV infection increases the risk of intestinal helminth infec-
tions [18, 19]. More rarely, one sees TD related to Yersinia,
Plesiomonas, Aeromonas (more commonly in Southeast
Prophylaxis considerations Asia), Entamoeba, and non-cholera Vibrio species. Rarely,
Prophylaxis should be given for malaria to those at risk. cholera or polio is found. Viruses can cause TD in HIV-
Empiric treatment for traveler’s diarrhea (TD) rather than infected travelers as in HIV-uninfected persons although
primary prophylaxis is generally recommended. However, this may reflect infection prior to travel; rotavirus and Nor-
primary prophylaxis for TD can be considered for those walk viruses are common agents in this group and have
who cannot afford to get ill, e.g. those with severely de- been implicated in outbreaks on cruise ships in the Carib-
pressed CD4 counts (see sections below on Malaria and bean. TD due to infection with hepatitis A can be avoided
Enteric Infections for details). with proper immunization.
Consider prophylaxis for those with severe immunosup-
pression (e.g. CD4 counts <100 cells/mm3) at risk for TB Prevention of TD in HIV-infected travelers
or disseminated infections from endemic mycoses such as
Penicillium marneffei, Coccidioides immitis, Histoplasma cap- Some recommend empiric daily prophylaxis (e.g. ciproflox-
sulatum, and Paracoccidioides brasiliensis as well as Cryptococ- acin 500 mg daily) for up to 3 weeks for those who must
cus neoformans (see below). avoid TD [16, 18, 20]. This may include those with severely
depressed CD4 counts and may be desired even if such trav-
elers are already on trimethoprim-sulfamethoxazole (TMP/
SELECTED DISEASE-SPECIFIC ISSUES SMX) for Pneumocystis carinii pneumonia (PCP) prophylaxis
given the high rates of TMP/SMX resistance in enteric path-
ogens worldwide. Antibiotics recommended by the Infec-
HIV-infected travelers and their healthcare providers tious Disease Society of America include ciprofloxacin,
should review the risks of the following disorders and op- norfloxacin, rifaximin, and bismuth subsalicylate. Care
portunistic infections to travelers to the developing world, should be taken to avoid contact with reptiles (e.g. snakes,
especially to those with low CD4 counts: lizards, iguanas, and turtles) as well as chicks and ducklings
• Enteric infections (e.g. salmonella) and wasting. because of the risk for salmonellosis [20]. Travelers should
• TB, bacterial respiratory infections (e.g. S. pneumoniae). avoid swallowing water during swimming and should not
• Malaria, leishmaniasis, Chagas disease, and other swim in water that might be contaminated with sewage or
parasitic infections. animal waste to avoid getting illnesses like cryptosporidiosis
• Penicilliosis and other disseminated endemic mycoses. and giardiasis.
• Other, e.g. new HIV infections, fevers. Prevention of enteric infections in the HIV-infected trav-
eler is best accomplished by ensuring safe water for drinking,
brushing teeth, and making ice cubes. Bottled beverages, hot
Enteric infections coffee and tea, beer, and wine, are considered safe for drink-
ing. All fruits and vegetables must be washed and peeled,
Etiologies of traveler’s diarrhea (TD)
preferably by the travelers themselves; all meats and other
in HIV-infected travelers foods should be cooked thoroughly to steaming hot. Boiling
The main enteric bacterial pathogen to which HIV-infected water is the best method of water purification and should be
individuals are at increased risk of acquiring is Salmonella done until at least 1 min (3 min at > 2000 m altitude) of vig-
typhimurium and other non-typhoidal Salmonella (NTS). orous boiling has been achieved. Tincture of iodine or tetra-
HIV-infected patients have up to a 100-fold risk of infection glycine hydroperiodide tablets is an alternative, but the
compared with HIV-uninfected individuals in developing water must be used within a few weeks and the method can-
countries where NTS is the leading cause of diarrhea with not be relied on to kill Cryptosporidium unless the water is
fever [17]. Disease often relapses and can be difficult to allowed to sit for 15 h before it is drunk. Filtering water pro-
treat effectively, leading to significant morbidity and duces variable results, especially for small bacteria or viruses.
554
Proper selection, operation, care, and maintenance of water TD is Campylobacter rather than enterotoxigenic E. coli
filters is essential. Commercial filters should be labeled ei- until further studies are done. Note that trimethoprim-
ther “reverse osmosis,” “absolute pore size of 1 micron or sulfamethoxazole is no longer a first-line treatment due to
smaller,” “tested and certified by NSF Standard 53 or NSF increased resistance worldwide.
Standard 58 for cyst removal,” or “tested and certified by
NSF Standard 53 or NSF Standard 58 for cyst reduction.” Respiratory infections
Reverse-osmosis filters provide broad protection but they
are expensive, relatively large, and have small pores that Bacterial pneumonia
are easily plugged by dirty water. Microstrainer filters with
Bacterial infections are increased in HIV-infected individ-
pore sizes in the range 0.1–0.3 mm do not remove viruses,
uals and bacterial pneumonias may be acquired during
so disinfection with iodine or chlorine is still necessary.
travel [18]. Streptococcus pneumoniae infections in particu-
The importance of preventing diarrheal disease in the
lar may be problematic given the increased rates of peni-
HIV-infected traveler is underscored by the fact that wasting
cillin/b-lactam-resistant S. pneumoniae worldwide (often
syndrome (“slim disease”) has been associated with inter-
also resistant to TMP-SMX and macrolides). All travelers
national travel in a study carried out among 4,549 partici-
should be immunized with the 23-valent polysaccharide
pants of the SWISS HIV Cohort Study [21]. Slim disease has
pneumococcal vaccine as part of their routine care. This
been a major health problem in developing nations con-
may be repeated if not vaccinated within the previous
sisting of chronic diarrhea associated with wasting in
5 years [20].
HIV-infected patients. There is also evidence that chronic
parasitic infections of the intestines may negatively influ-
ence the natural history of HIV infection and chronically Tuberculosis
increase HIV viral loads [22, 23]. Additional concerns HIV-infected travelers are at increased risk for primary TB or
include the risk of post TD irritable bowel syndrome which reactivation upon return from developing countries or other
can occur in up to 14% of those with TD [24]. areas with a high prevalence of TB. Care should be taken to
avoid conditions that promote TB transmission such as
crowded situations and contact with hospital, prison, or
Treatment of TD in HIV-infected travelers
homeless shelter populations. TB skin testing should be
Empiric treatment for TD should be given at the onset of di- assessed prior to travel as part of routine care and again
arrhea. This consists of antiperistaltic agents (e.g. lopera- 3 months after returning from developing countries [26].
mide) for mild diarrhea (< 2 loose stools/day), which Travelers with negative TB skin tests prior to travel to high-
should not be used if there is high fever, blood in the stool, risk areas are at increased risk for primary infection but
or symptoms persisting > 48 h on antiperistaltics. Antibiotics efficacy of treatment among this group has not been demon-
should be combined with antiperistaltic agents for more se- strated. Decisions concerning the use of chemoprophylaxis
vere diarrhea or diarrhea with fevers or constitutional symp- in these situations must be considered individually and
toms. Medical attention should be sought for fevers lasting latent TB infections treated according to treatment guidelines
beyond 10–14 days, high fevers, abdominal pain, bloody di- [20].
arrhea, vomiting, or dehydration. Recommended antibiotics
include ciprofloxacin 500 mg twice daily (or equivalent quin-
olone) for 3–7 days. Azithromycin 500 mg once daily for Other respiratory infections
3 days can be given for pregnant women, those in areas of PCP is not more common during travel and the incidence is
increasing fluoroquinolone resistance (e.g. Thailand and lower in tropical areas than in North America. However, all
Nepal), and children (5–10 mg/kg 1). Single-dose regi- at risk should be on appropriate chemoprophylaxis. HIV-
mens such as azithromycin 1000 mg once can be attempted infected travelers should note that the common cold and
when taken early in the course of infection and with milder sinusitis are some of the more common health issues to
symptoms. Rifaximin is a poorly absorbed rifamycin FDA ap- affect all travelers and should bring along medications
proved for diarrhea from non-invasive strains of E. coli in for symptomatic relief.
persons 12 years old. It is a reasonable alternative to cipro-
floxacin for afebrile, non-dysenteric TD. It may be useful in
pregnant women and children as there is less interaction with Emerging and re-emerging
ARVs than with the macrolides, but there are little data to sup- infections in HIV
port this. Rifaximin has been shown to be as effective as cip-
rofloxacin in the management of TD in Mexico and Jamaica, Malaria
perhaps attributable to its activity against a wide range of Despite mixed data in the past, it now appears that malaria
enteric bacteria [25]. The usual dose of rifaximin is 200 mg interacts with HIV especially in advanced HIV disease
three times per day for 3 days. Its use should be limited and pregnancy, which has long been associated with
to areas outside of Asia where the predominant cause of more severe disease independent of HIV serostatus [22].
555
Malaria presentation changes with decreasing CD4 counts, from visualization of parasites in peripheral blood mono-
with increased episodes of symptomatic parasitemia, in- cytes may be possible given the high parasite burden in
creased density and duration of parasitemia, and pro- HIV-infected patients [20, 22]. Polymerase chain reaction
longed fever and malaria can be more severe in areas of of the buffy coat of blood can yield the diagnosis in up
unstable disease transmission [27–29]. In addition, there to 100% of patients [22]. Treatment consists of stibo-
is increased activation and replication of HIV during gluconate or amphotericin B with 50–100% of patients
infection with malaria [27]. Changes in host–parasite responding. However, long-term suppressive treatment
interactions occur that may worsen malarial disease in will be required, e.g. ART with intermittent liposomal
HIV-infected persons on ART [22]. amphotericin B every 21 days until CD4 >350 cells/mm3
Prophylaxis for malaria should be given to those travel- for 3–6 months [32].
ing to endemic areas. Some caution may be warranted as
mefloquine has been shown to decrease ritonavir levels,
a component of most protease-based ART regimens, in
Chagas disease
healthy volunteers [30]. The clinical relevance of this is
unclear. There is also concern that ARVs with central ner- Trypanosoma cruzi infection (Chagas disease) is accelerated
vous system effects such as efavirenz may worsen the and more severe in HIV infection [22]. The chronic phase
neuropsychiatric effects of mefloquine. For this reason, of infection is characterized by persistent reactivation of
doxycycline, chloroquine, atovaquones, and proguanil Chagas disease with high levels of parasitemia in co-
may be the preferred prophylaxis in travelers on ART, but infected individuals in contrast with low-level parasitemia
there is no contraindication to mefloquine. Those on in HIV-uninfected persons [33]. Fever, cutaneous erup-
TMP-SMX for PCP prophylaxis will have some protection tions, and myocarditis similar to that seen in acute Chagas
against malaria. Malaria prophylaxis should be started disease is often seen in contrast to the cardiac and GI in-
prior to travel to monitor for any side effects and to achieve volvement characteristic of disease in HIV-uninfected per-
adequate drug levels in the body before being exposed to sons. CNS involvement such as meningoencephalitis that
infected mosquitoes. Use of the CDC’s hotline (1-800- can be fatal, CNS abscesses, and granulomatous encepha-
CDC-INFO/1-800-232-4636) or malaria website (http:// litis is usually present in co-infected patients while it is
www.cdc.gov/malaria) can help in assessing the risk of rarely seen in HIV-uninfected patients [22, 34]. Diagnosis
acquiring malaria and drug-resistant P. falciparum malaria. in co-infected persons can be made by examination of the
Despite many pharmacological interactions, there ap- peripheral blood for spirochetes, PCR of the blood or
pear to be little clinically significant interactions between tissue, or examination of tissue biopsies. Treatment for
antimalarials and HIV ARVs with two possible exceptions. T. cruzi should be initiated earlier than usually done in
Lumefantrine and halofantrine are extensively metabo- HIV-uninfected persons, preferably in the asymptomatic
lized by CYP3A4; use with CYP3A4 inhibitors such as pro- phase of the disease. Lifelong treatment with benznida-
tease inhibitors is contraindicated in the manufacturer’s zole or nifurtimox may be needed [34].
documentation of halofantrine and should be used with Precautions should be taken to avoid infection if travel-
caution with lumefantrine. Quinine and quinidine are ing in the Americas where the infection exists and is spread
also extensively metabolized by CYP3A4 and should be by the bite of the reduviid bug. The risk of infection is sig-
used with caution, if at all, with ritonavir-containing nificant for those with extended stays; infections of tourists
regimens. are uncommon. To minimize risk of infection, avoid sleep-
ing in substandard houses, use mosquito nets, and use in-
sect repellents at night.
Leishmaniasis
Visceral leishmaniasis (Kala-Azar) remains an emerging
opportunistic infection among HIV-infected individuals.
Other parasitic infections
Co-infections with HIV and Leishmania have occurred
at significant rates in Eastern Africa, India, Brazil, and Few major interactions exist between HIV and other emerg-
Europe and have been reported in 35 countries [22]. ing parasitic infections in travelers. The propensity for dis-
In Brazil and southwestern Europe, HIV–Leishmania seminated strongyloidiasis is associated with HTLV-1 not
co-infection is promoted by the sharing of needles in in- HIV-1 infection. The egg burden in schistosomiasis may
travenous drug use rather than the usual case of transmis- be higher in HIV-infected persons and the time until
sion by sandflies. When CD4 counts fall below 200–300 re-infection may be shorter [22]. Onchocerciasis does not
cells/mL, parasites spread to atypical sites, especially appear to be significantly affected by HIV infection, al-
the gastrointestinal site. Only 50% of patients have fever though cellular immune responses may be depressed in
and hepatosplenomegaly; cytopenias are very severe [31]. HIV–Onchocerca volvulus co-infected individuals [22, 35].
Diagnosis may be difficult as 50% of patients do not There are little data on the impact of HIV on filariasis
develop characteristic antibodies. Ultimately, diagnosis and loiasis [22].
556
Penicilliosis Cryptococcus neoformans causes disseminated cryptococ-

cosis, a common opportunistic infection worldwide in
Penicilliosis, disseminated infection with the fungus Penicil-
AIDS patients with CD4 counts < 50 cells/mm3. Cryp-
lium marneffei, has become an important opportunistic infec-
tococcus neoformans has been found in soil samples from
tion in AIDS patients in southeast Asia (especially northern
around the world in areas frequented by birds, especially
Thailand) and southern China. The disease usually occurs
pigeons and chickens, but there has been no evidence link-
when CD4 counts fall below 50 cells/mm3 [36]. Common
ing exposure to pigeon droppings with an increased risk for
presenting symptoms include fever, sweats, wasting, and skin
acquiring cryptococcosis. Little can be done to avoid expo-
lesions—often papules with central umbilication or nodules,
sure to C. neoformans. Prophylaxis for those at risk is not
but a wide range of skin eruptions are possible—in associa-
commonly recommended but can be considered in the
tion with anemia, lymphadenopathy, and hepatomegaly.
context of prophylaxis for other mycoses.
Diagnosis is often made by bone marrow examination or
skin biopsy, and less reliably from blood cultures. Treatment
consists of amphotericin B followed by itraconazole. Chronic
maintenance therapy with itraconazole is needed as post-
TRAVEL-RELATED SKIN DISORDERS
treatment relapse is common [37]. Untreated, mortality is
over 75% [37]. Penicilliosis can occur in AIDS patients with Dermatologic lesions in the returning traveler are common
a remote history of only brief travel to endemic areas. Soil in the HIV-infected and HIV-uninfected traveler alike. One
exposure is a known risk factor and should be avoided in prospective study of 269 returning travelers with skin disor-
endemic areas, especially during the rainy season. Prophylac- der found that the most common skin lesions were cutane-
tic itraconazole at 200 mg/day for AIDS patients traveling ous larva migrans (25%); pyodermas (18%); pruritic
in high-risk parts of endemic areas may be considered, arthropod-reactive dermatitis (10%); myiasis (9%); tungia-
especially for those with CD4 counts < 100 cells/mm3. sis (6%); urticaria (5%); fever and rash (4%); and cutane-
ous leishmaniasis (3%) [38].
The appearance of skin lesions can give clues to their
Other endemic mycoses etiology [9]:
HIV-infected travelers with low CD4 counts are at risk for • Papules, usually pruritic: consider insect bites, scabies,
diseases from other endemic fungal infections. These in- seabather’s eruption for rashes confined to skin covered
clude coccidioidomycosis in southwest USA, northern by bathing suits, cercarial dermatitis for rashes
Mexico, and South America, histoplasmosis with a world- involving exposed skin, onchocerciasis in long-term
wide distribution but primarily in the Americas and Africa, travelers, and drug eruptions.
and paracoccidioidomycosis in Central America. These dis- • Nodules: consider myiasis if painful boil-like lesions
seminated diseases are more common in the immunocom- with central opening with intermittently visible fly
promised host with decreased cell-mediated immunity larva, tungiasis (jiggers) especially if lesions mainly on
such as HIV-infected travelers with low CD4 counts. Dis- soles of the feet and around toenails, loiasis if
ease can reflect new infection, re-infection, or reactivation migratory areas of angioedema (Calabar swellings),
of previous infections. acute East African trypanosomiasis and furuncles.
Prophylaxis with itraconazole at 100 mg/day can be • Ulcers: consider pyoderma if lesions painful (frequently
considered for travelers with CD4 counts < 100 cells/mm3, bite-related with secondary infection from S. aureus or
who are at high risk for acquiring histoplasmosis because group A streptococci), leishmaniasis if lesions painless,
of occupational exposure or who travel to a community with and rickettsial diseases if an eschar is present.
a hyperendemic rate of histoplasmosis (>10 cases/100 • Linear and migratory lesions: consider cutaneous larva
patient-years) although there has not been demonstrated migrans, larva currens due to strongyloidiasis if
survival benefit in doing this [20]. Severely immunocom- perianal cutaneous track present, and photodermatitis
promised travelers should avoid activities known to be asso- if painless, non-pruritic fixed linear streaks (from skin
ciated with increased risk such as creating dust when working exposure to psoralen-containing products, e.g. limes).
with surface soil; cleaning chicken coops that are heavily
contaminated with droppings; disturbing soil beneath bird
roosting sites; cleaning, remodeling, or demolishing old OTHER ISSUES IN THE HIV-INFECTED
buildings; and exploring caves [20]. Prophylaxis for the other TRAVELER
endemic mycoses is generally not recommended. Avoiding
the agents of coccidioidomycosis and paracoccidioidomyco-
New HIV infections
sis is not entirely possible, but at-risk travelers should avoid
activities associated with increased risk including those In Western countries, where the B-subtype is predominant,
involving extensive exposure to disturbed native soil, e.g. dust there is a steep increase in non-B-subtypes and circulating
storms [20]. recombinant forms, while new recombinants emerge
557
worldwide. Travelers contribute to the spread of HIV-1 ge- (e.g. RMSF, scrub typhus), leptospirosis, typhoid fever, tu-
netic diversity worldwide; in the developing world, migra- berculosis, acute schistosomiasis, East African trypanoso-
tion of rural populations and civil war are additional miasis, viral hepatitis, and traveler’s diarrhea [9].
contributing factors. The spreading of HIV-1 variants has
implications for diagnostic, treatment (unknown clinical
relevance at this time), and vaccine development [39].
CONCLUSION
Fever in the returning HIV-infected
As individuals with HIV/AIDS continue to live longer in the
traveler
era of ART, we can expect increased rates of international
The evaluation of fever in the returning HIV-infected trav- travel in this population, including those with depressed
eler should focus on the same etiologies as those in the CD4 counts. Careful medical evaluation and appropriate
HIV-uninfected traveler. Common causes are still most pre-travel health advice will be increasingly important.
likely, such as sinusitis, pneumonia, urinary tract infection, Simple precautions and the use of a travel health expert
and drug fever. Important infectious causes of non-specific can help minimize risks, enabling all HIV-infected travelers
fevers include malaria, dengue, rickettsial diseases to have safer and more enjoyable international travel.
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Acknowledgments
We would like to thank Terry O’Donnell at the University of California, San Francisco and Poppy
Garraway at Elsevier for their help in making this book a reality.
xv
Contributors
Frederick L. Altice, MD, MA David B. Clifford, MD

Professor of Medicine Melba and Forest Seay Professor of
Epidemiology and Public Health Neuropharmacology in Neurology
Divisions of Infectious Diseases and Epidemiology Departments of Neurology and Medicine
of Microbial Diseases Washington University in St Louis
Yale University St Louis, MO, USA
New Haven, CT, USA
Susa Coffey, MD
Andrew F. Angelino, MD Associate Professor
Associate Professor Department of Medicine, Positive Health Program
Department of Psychiatry and Behavioral Sciences University of California, San Francisco
Johns Hopkins University School of Medicine San Francisco, CA, USA
Baltimore, MD, USA
David A. Cooper, MD, DSc
Director, The Kirby Institute for infection and immunity in society
Leyla Azis, MD University of New South Wales
Fellow
Director, St Vincent’s Centre for Applied Medical Research
Section of Infectious Diseases St Vincent’s Hospital
Boston Medical Center Sydney, NSW, Australia
Boston, MA, USA
Suzanne M. Crowe, MBBS, FRACP, MD
John G. Bartlett, MD Head, Centre for Virology and Professor of Medicine
Professor of Medicine Burnet Institute and Monash University
Division of Infectious Diseases Melbourne, Victoria, Australia
Johns Hopkins University School of Medicine
Baltimore, MD, USA J. Lucian Davis, MD, MAS
Assistant Professor
Robert J. Blount, MD Division of Pulmonary and Critical Care Medicine
Fellow, Pulmonary and Critical Care Medicine University of California, San Francisco
Division of Pulmonary Medicine San Francisco General Hospital
University of California, San Francisco San Francisco, CA, USA
San Francisco, CA, USA
Kevin M. De Cock, MD, FRCP (UK), DTM&H
Director
R. Douglas Bruce, MD, MA, MSc
Center for Global Health
Assistant Professor of Medicine and Epidemiology
Centers for Disease Control and Prevention
Divisions of Infectious Diseases and Epidemiology
Atlanta, GA, USA
of Microbial Diseases
Yale University Douglas T. Dieterich
New Haven, CT, USA Professor of Medicine
Director of Continuing Medical Education,
Richard Chaisson, MD Department of Medicine
Professor of Medicine, Epidemiology Director of Outpatient Hepatology
and International Health Division of Liver Diseases
Johns Hopkins University School of Medicine Mount Sinai School of Medicine
Baltimore, MD, USA New York, NY, USA
ix
Contributors
Elizabeth H. Doby, MD Trevor E. Gerntholtz, MD

Pediatric Infectious Diseases Fellow Nephrologist and Director of Research
Department of Pediatrics, University of Utah Chris Hani Baragwanath Hospital
School of Medicine, Soweto, Johannesburg, South Africa
Salt Lake City, UT, USA
Clive M. Gray, MSc, PhD
W. Lawrence Drew, MD, PhD Professor and Chair, Division of Immunology
Professor Emeritus Institute of Infectious Disease and Molecular Medicine
Departments of Laboratory Medicine and Medicine University of Cape Town
University of California, San Francisco South Africa
UCSF Medical Center at Mount Zion
San Francisco, CA, USA Ruth M. Greenblatt, MD
Professor
James P. Dunn, MD Departments of Clinical Pharmacy, Medicine
Associate Professor Epidemiology and Biostatistics
The Wilmer Eye Institute University of California, San Francisco, Schools of
Johns Hopkins University School of Medicine Pharmacy and Medicine
Baltimore, MD, USA San Francisco, CA, USA
Jerrold J. Ellner, MD Warner C. Greene, MD, PhD

Professor and Chief of Infectious DIseasee Director, Gladstone Institute of Virology and Immunology,
Department of Medicine President, Accordia Global Health Foundation
Boston University and Boston Medical Center Nick and Sue Hellmann Distinguished Professor
Boston, MA, USA of Translational Medicine
Professor of Medicine, Microbiology and Immunology,
Kim S. Erlich, MD University of California, San Francisco
Consultant in Infectious Diseases San Francisco, CA, USA
Associate Clinical Professor of Medicine
University of California, San Francisco Deborah Greenspan, BDS, DSc
Daly City, CA, USA Leland A. and Gladys K. Barber Distinguished
Professor in Dentistry
Charles W. Flexner, MD Chair, Orofacial Sciences, School of Dentistry
Professor, Medicine, and Pharmacology and Molecular Sciences, University of California, San Francisco
and International Health San Francisco, CA, USA
Bloomberg School of Public Health
Johns Hopkins University School of Medicine John S. Greenspan, BSc, BDS, PhD, FRCPath,
Baltimore, MD, USA FDS(RCSEng)
Distinguished Professor of Oral Pathology
Gerald Friedland, MD Orofacial Sciences, School of Dentistry
Professor of Medicine and Epidemiology Distinguished Professor
Departments of Medicine and Epidemiology of Pathology, School of Medicine
Microbial Diseases Associate Dean for Global Oral Health
Yale University School of Medicine School of Dentistry
New Haven CT, USA Director, AIDS Research Institute
Adjunct Professor University of California, San Francisco
Mailman School of Public Health San Francisco, CA, USA
Columbia University
New York City, NY Carl Grunfeld, MD, PhD
Professor, Department of Medicine
Monica Gandhi, MD, MPH University of California, San Francisco
Associate Professor Associate Chief of Staff for Research and Development, and
Department of Medicine, Division of HIV/AIDS Chief, Division of Metabolism and Endocrinology
University of California, San Francisco San Francisco Veterans Affairs Medical Center
San Francisco, CA, USA San Francisco, CA, USA
x
Contributors
Pamela Gumbi, PhD Anthony D. Kelleher, MBBS, PhD

Research Scientist Clinical Academic
Division of Virology, Institute of Infectious Disease and Molecular HIV, Immunology and Infectious Diseases Clinical Services Unit
Medicine, University of Cape Town St Vincent’s Hospital
Cape Town, South Africa Head, Immunovirology Laboratory
St Vincent’s Centre for Applied Medical Research
Guan-Zhu Han, BS St Vincent’s Hospital
Graduate Student Head, Immunovirology and Pathogenesis Program
Department of Ecology and Evolutionary Biology The Kirby Institute for infection and immunity in society
University of Arizona University of New South Wales
Tucson, AZ, USA Sydney, NSW, Australia
Jerome H. Kim, MD
Laurence Huang, MD Project Manager, HIV Vaccines and
Professor of Medicine Chief, Laboratory of Molecular Virology and Pathogenesis
Department of Medicine US Military HIV Research Program
University of California, San Francisco School of Medicine Walter Reed Army Institute of Research
Chief, HIV/AIDS Chest Clinic
Silver Spring, MD, USA
San Francisco General Hospital
San Francisco, CA, USA Jeffrey D. Klausner, MD, MPH
Professor of Medicine and Global Health
Jula K. Inrig, MD, MHS Division of Infectious Diseases
Assistant Professor of Medicine Department of Medicine
Division of Nephrology University of California, Los Angeles
UT Southwestern Medical Center Los Angeles, CA, USA
Adjunct Associate of Medicine
Duke University Medical Center Paul E. Klotman, BS MD
Durham, NC, USA President and CEO
Baylor College of Medicine
Mark A. Jacobson, MD Houston, TX USA
Professor of Medicine
Positive Health Program Jane E. Koehler, MA, MD
University of California, San Francisco Professor of Medicine
Medical Director Division of Infectious Diseases
UCSF CTSI Clinical Research Center at San Francisco University of California, San Francisco
General Hospital San Francisco, CA, USA
Oliver Laeyendecker, MS, MBA
Sr. Research Associate
Malcolm John
Laboratory of Immunoregulation
Associate Professor
National Institute of Allegy and Infectious Diseases,
UCSF School of Medicine
National Insitutes of Health
University of California, San Francisco
Instructor
Division of Infectious Diseases
Department of Medicine
Edward C. Jones-López, MD, MS Johns Hopkins University School of Medicine
Assistant Professor of Medicine Baltimore, MD, USA
Section of Infectious Diseases
Boston University School of Medicine and Boston Medical Center Elysia Larson
Boston, MA, USA Epidemiologist
Department of Epidemiology
Salim S. Abdool Karim, MBChB, PhD Boston University
Director Boston, MA, USA
Centre for the AIDS Programme of Research
in South Africa (CAPRISA) Simon Mallal, MBBS, FRACP, FRCPA
University of KwaZulu-Natal Director
Doris Duke Medical Research Institute Institute for Immunology and Infectious Diseases
Nelson R Mandela School of Medicine Murdoch University
Congella, South Africa Murdoch, WA, Australia
xi
Contributors
Toby Maurer, MD David Nolan, MBBS, FRACP, PhD

Professor of Clinical Dermatology Consultant Physician and Associated Professor
Department of Dermatology Department of Clinical Immunology (Royal Perth Hospital), and,
University of California, San Francisco Institute of Immunology and Infectious Disease
San Francisco, CA, USA (Murdoch University)
Royal Perth Hospital and Murdoch University
Concepta Merry, FRCPI, PhD Perth, WA, Australia
Senior Lecturer, Global Health Trinity College
Dublin, Ireland Chiadi U. Onyike, MD, MHS
Infectious Diseases Institute Makerere University Assistant Professor
Kampala, Uganda Department of Psychiatry and Behavioral Sciences
Johns Hopkins University
Nelson L. Michael, MD, PhD Baltimore, MD, USA
Director
US Military HIV Research Program Julie Overbaugh, PhD
Walter Reed Army Institute of Research Member
Division of Human Biology
Silver Spring, MD, USA
Fred Hutchinson Cancer Research Center
Seattle, WA, USA
Rakesh K. Mishra, MD
Assistant Clinical Professor Kathleen R. Page, MD
Division of Cardiology, Department of Medicine Assistant Professor
San Francisco Veterans Affairs Medical Center and Division of Infectious Diseases
University of California, San Francisco Johns Hopkins University School of Medicine
San Francisco, CA, USA Baltimore, MD, USA
Ronald T. Mitsuyasu, MD Andrew T. Pavia, MD

Professor of Medicine and Director George and Esther Gross Presidential
UCLA Center for Clinical AIDS Research and Education Professor and Chief
Group Chair, AIDS Malignancy Consortium Division of Pediatric Infectious Diseases
Department of Medicine Department of Pediatrics
University of California, Los Angeles University of Utah School of Medicine
Los Angeles, CA, USA Salt Lake City, UT, USA
Lynne M. Mofenson, MD B. Matija Peterlin, MD

Chief, Pediatric, Adolescent and Maternal AIDS Branch Professor, Departments of Medicine and
Center for Research for Mothers and Children Microbiology/Immunology
Eunice Kennedy Shriver National Institute of Child Health University of California, San Francisco
and Human Development National Institutes of Health San Francisco, CA, USA
Rockville, MD, USA
Marion G. Peters, MD
Pablo A. Moncado, MD
Chief of Hepatology Research
Postdoctoral Fellow, Internal Medicine
Division of Gastroenterology
Infectious Diseases and Geographic Medicine
University of California, San Francisco
Stanford School of Medicine
Stanford, CA, USA
Departamento Medicina Interna, Division Infectologia William G. Powderly, MD
Fundación Valle del Lili Dean of Medicine
Cali, Colombia Professor of Medicine and Therapeutics
School of Medicine and Medical Sciences
Jose G. Montoya, MD University College Dublin
Associate Professor of Medicine Dublin, Ireland
Department of Medicine and Division of Infectious
Diseases and Geographic Medicine Thomas C. Quinn, MD, MSc
Stanford University School of Medicine Associate Director for International Research, NIAID
Stanford, CA Director, Johns Hopkins Center for Global Health
Director, Toxoplasma Serology Laboratory Professor of Medicine and Pathology
Palo Alto Medical Foundation Johns Hopkins University School of Medicine
Palo Alto, CA, USA Baltimore, MD, USA
xii
Contributors
Mopo Radebe, BTech, MTech Khuanchai Supparatpinyo, MD

PhD Candidate Professor of Medicine
Department of Paediatrics and Child Health Department of Medicine, Faculty of Medicine
Nelson R. Mandela School of Medicine Chiang Mai University
University of KwaZulu-Natal Chiang Mai, Thailand
Durban, South Africa
Lynda A. Szczech, MD
Peter Reiss, MD, PhD Associate Professor of Medicine
Professor of Medicine Department of Medicine
Department of Global Health and Division Duke University School of Medicine
of Infectious Diseases Durham, NC, USA
Amsterdam Institute for Global Health and Development
Academic Medical Center, University of Amsterdam
Steven A. Taylor, MD
Amsterdam, The Netherlands
Assistant Professor of Medicine
The Late Merle A. Sande, MD University of Texas Southwestern School of Medicine
Formerly Professor of Medicine Austin, TX, USA
University of Washington School of Medicine
Formerly President, Academic Alliance for AIDS
Care and Prevention in Africa Mengesha A. Teshome, MD
Seattle, WA, USA Research Patient Coordinator/Professional
Department of Neurology
Washington University in St Louis
Monika Sarkar, MD St Louis, MI, USA
Gastroenterology Fellow
Department of Medicine, Division of Gastroenterology
University of California, San Francisco Glenn J. Treisman, MD, PhD
San Francisco, CA, USA Professor of Psychiatry and Behavioral Sciences
Professor of Internal Medicine
Morris Schambelan, MD Johns Hopkins University School of Medicine
Baltimore, MD, USA
Professor Emeritus of Medicine
University of California, San Francisco Marie-Louise Vachon, MD, MSc
San Francisco, CA, USA Division of Infectious Diseases
Centre Hospitalier de l’Université Laval
Hanneke Schuitemaker, PhD Quebec, Canada
Professor in Virology
Department of Experimental Immunology
Daniëlle van Manen
Academic Medical Center of the
Post-Doctoral Fellow
University of Amsterdam
Academica Medical Center of the University of Amsterdam
James C. Shepherd, MD PhD
Associate Director
CDC Botswana Angélique B. van ’t Wout
Gaborone, Botswana Principal Investigator
Academica Medical Center of the University of Amsterdam
Thira Sirisanthana, MD
National Research University Program
Chiang Mai University Paul A. Volberding, MD
Chiang Mai, Thailand Professor, Department of Medicine
University of California San Francisco
Matthew Stremlau, PhD Director, UCSF AIDS Research Institute
Postdoctoral Fellow Director of Research, UCSF Global Health Sciences
The Broad Institute Co-Director, UCSF-GIVI Center for AIDS Research
Cambridge, MA, USA San Francisco, CA, USA
xiii
Contributors
Mark A. Wainberg, PhD Irum Zaidi, MPH

Professor and Director Epidemiologist
McGill University AIDS Centre Division of Global HIV/AIDS
Lady Davis Institute Centers for Disease Control and Prevention
Jewish General Hospital Atlanta, GA, USA
Montreal, Quebec, Canada
Lycias Zembe, BSc, MSc, Med
Bruce Walker, MD PhD student
Director Clinical Laboratory Science, Division of Medical Virology
Ragon Institute of MGH, MIT and Harvard Institute of Infectious Diseases and Molecular Medicine
Charlestown, MA, USA University of Cape Town
Cape Town, South Africa
Michael Worobey, BS, DPhil
Professor
Department of Ecology and Evolutionary Biology
University of Arizona
Tucson, AZ, USA
Gerasimos J. Zaharatos, MD, CM

Assistant Professor
Division of Infectious Diseases
McGill University AIDS Centre
Jewish General Hospital
Montreal, Quebec, Canada
xiv
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ISBN: 9781455706952
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Last digit is the print number: 9 8 7 6 5 4 3 2 1

Index
Note: Page numbers followed by b indicate boxes, f indicate figures and t indicate tables.
3TC see lamivudine adefovir 538t psychiatric problems 257–259, 260

dipivoxil 414–415 renal complications 287, 288–289,
adenosylmethionine, S- 307–308 293, 294
A
adenovirus (ADV) 241, 269–270 travel, international 556, 557, 558
abacavir (ABC) 227, 253 adolescents 517–518 tuberculosis 325–327, 329, 331
antiretroviral therapy 135–144, 136t, adrenal women and special issues 521, 524
146 alterations in function 277 see also Middle East and North Africa
children and adolescents 516t antiretroviral and other therapies ageing, neuropathy 254
drug abuse 544t 277–278 AIDS dementia complex (ADC) 261
hypersensitivity reactions 178–180, DHEA in HIV infection 277 AIDSVAX protein vaccines 101
179f insufficiency 270b, 277 AITD (autoimmune thyroid diseases)
mother-to-child transmission pathology 277 276
prevention 492t treatment considerations 278 albendazole 243
pharmacology 170t Adult AIDS Clinical Trials Group albumin, low 378
resistance to 158 268 alcohol consumption/alcoholism 282,
tuberculosis 341 Aeromonas 554 412–413, 541
absolute lymphocyte count (ALC) 317 affect, flattened 251 treatment 543
abstinence 113–114 Africa (mainly sub-Saharan) 53, 124, alendronate 281
ABVD 458 355 alitretinoin gel 459
acamprosate 543 biology of transmission 89, 91 alphavirus-based vaccines 103–107
acquired immunity to viral infections cardiovascular complications ALVAC see canarypox
46–48 270–271 amenorrhea 282–283
acute infection 77–87 dermatology 220, 221, 222, 223, amikacin 340t, 351–352
clinical manifestation 80–81 224–225, 226, 227 aminoglycosides 318t, 336
diagnosis 81–82 drug abuse 537 see also amikacin; kanamycin;
laboratory testing and diagnosis 82–85 drug resistance 160 streptomycin
management 85 fungal infections 369–370, 374–375, aminoketones 262t
pathogenesis 98 376, 377 aminosalicylic acid 340t
pathophysiology 77–80 global epidemiology 3, 6–8 amitriptyline 538t
see also laboratory testing hepatitis 397, 411 amoxicillin 314, 315t, 317, 318t
acute retinal necrosis (ARN) 212 mother-to-child transmission 485, amoxicillin-clavulanate 315t, 318t
acute retroviral syndrome (ARS) 219 486, 487, 488t, 489t, 492t amphotericin B
acyclovir (Zovirax) origins and diversification of HIV candida 362t, 363t, 364
gastrointestinal disorders 238 15–16, 17–18 cardiovascular complications 270
herpes simplex virus 472, 472t pharmacology of antiretroviral drugs dermatology 224–225
management of infections 443–444, 174–175 endocrine complications 280–281
444t, 445–446, 445t, 448t pneumonias 297, 298t, 314 fungal infections 373, 374–375, 374t,
mouth ulcers 360 pregnancy 524 376, 378–379, 379t, 382t
ocular manifestations 208, 210–212 primary neurological manifestations histoplasmosis 321
ADC see AIDS dementia complex 249, 250, 254 liposomal 556
561
Index
amphotericin B (Continued) aphthous stomatitis, recurrent 227 Mycobacterium avium complex 349, 355
Penicillium marneffei infection aphthous ulcers 360 neuropathy 254
393–394 recurrent (RAU) 196t, 202f Penicillium marneffei infection 389,
pneumonias 317–320, 319t, 320t APOBEC3G 34–35, 35f 391t, 393t
travel, international 556, 557 appendicitis 241 Pneumocystis pneumonia 297, 298t
ampicillin-sulbactam 318t aprivus see tipranavir prevention 117–118
amprenavir 227 APV see amprenavir psychiatric problems 257–258, 260,
drug abuse 544t ARGs (AIDS-restricting genes) 53 261
pharmacology 170, 170t see also IRIS travel, international 551, 554,
see also fosamprenavir ARN (acute retinal necrosis) 212 555, 557
anabolic steroids 279–280, 282, 284 ART/ARV (antiretroviral therapy/ tuberculosis 325
anal cancer 462 treatment) 133–152 aspergilloma 331
women 528–529 adrenal 277–278 aspergillosis 196t, 314t, 317–320, 320t
anal carcinoma 243–244, 456t adverse effects during long-term aspergillus/Aspergillus fumigatus 225,
anal condyloma 243–244 therapy 181–185 275, 319t
in syphilis 469f adverse effects in early phase, asymptomatic neurocognitive
anal fissures and fistulas 243–244 177–181 impairment 261
anal intrepithelial neoplasia (AIN) 462 -associated hepatotoxicity 417–418 atazanavir (ATZ/ATV) 180–181, 185,
anal sphincter dysfunction 434–435 bone 280–281 353t
anal squamous intraepithelial lesion clinical application 146–147 antiretroviral therapy 136t, 145
(SIL) 462 cornerstone agents 144–146 children and adolescents 515, 516t
anemia 281, 282, 317, 378, 422, 438t dermatology 220, 222, 223, 224, 225 drug abuse 544t, 547
anerobes 314t drug abuse 537–538 pharmacology 170t
angiomatosis see bacillary angiomatosis gastrointestinal disorders 237 tuberculosis 341, 342
angiosarcoma 425–426 ‘late’ salvage 148 atherosclerosis 267–268, 270
angiotensin-converting enzyme in life cycle of HIV 134–135 ATN (antiretroviral toxic neuropathy)
inhibitors 291–293 infection 133–134 254
anidulafungin 363–364 mechanisms of action 487 atopic dermatitis 227
animal models, vaccine design and monitoring 147 atorvastatin 280
99–100 Mycobacterium avium complex, drug atovaquone 309t, 310t, 403, 403t,
anorectal disorders 243–244 interactions and 354 404, 404t
anorectal herpes infection 441–442 pancreas 278–279 ATV/ATZ see atazanavir
anorexia 275–276, 436, 439 pituitary 283 Australia 259, 349, 389
antenatal HIV 3, 8 pretreatment assessment 146 fungal infections 377
mother-to-child transmission prevention of HIV 115–116 autoimmune thyroid diseases (AITD)
prevention 489t regimen design 146 276
see also pregnancy renal complications 291 autoimmunity 270b
antibodies 25, 26–27, 79 reproductive health in men 282 axonal degeneration 254
antidepressants 262t reproductive health in women 283 azido-thymidine see AZT
antihistamines 220, 227 in resource-constrained settings 149 azithromycin
antimony 223–224 susceptibility 155, 158–159, 160 chlamydia 476, 476t
antipsychotics 262t thyroid 275 dermatology 219–220, 222
antiretroviral therapy/treatment see ART; timing, optimal 146–147 gonorrhea 472t
HAART; pharmacology toxic neuropathy (ATN) 254 Mycobacterium avium complex 351,
antiviral host factors and molecular toxicity 148 352, 353, 355
biology of HIV 34–36 tuberculosis 327, 341, 342, 343 pneumonias 314, 315t, 317, 318t
antiviral therapy/treatment women 530–531, 531f syphilis 469
breast-feeding 485, 486, 487, 488t, virologic failure 147–148 toxoplasmic encephalitis 403t, 404t
489t, 492t, 495, 496–497, 498 see also complications; drug resistance travel, international 555
changing 515–517 development; HAART; azoles 362–363
children 512–517 pharmacology; regimens azoospermia 282
initial therapy 515 arthragias 284 azotemia 288
principles of 512–513 ARV see ART/ARV AZT (azido-thymidine)
resistance 497–498 Asia 160 children and adolescents 511, 512t
resistance 517 dermatology 220, 225 mother-to-child transmission
therapeutic drug monitoring 517 fungal infections 369–371, 376, 377 486–495, 488t, 489t, 492t
timing start 513–514, 514t global epidemiology 3, 11 pharmacology 170t, 171
anxiolytics 262t hepatitis viral infection 405 aztreonam 318t
562
Index
B C
blastomycosis 371t
B-cell receptors 46 bleomycin 460t calcipotriene 226
bacillary angiomatosis (BA) 196t, blepharitis 209 Cambodia 11
221–222 blood transfusions/blood-borne Cameroon 293
Bartonella infections 421–425, 428 transmission epidemiology 8, 18, 19
bacillary peliosis 421, 423, 428 avoiding 552b Campylobacter 241, 243, 436, 554
bacteremia 421, 424, 428 harm reduction programs 117–118 Canada see North America
fever of unknown origin 424–425 see also drug abuse; non-sterile cancer see malignancy
see also Bartonella infections injections cancrum oris 222
bacterial infections 91, 271b blood-borne transmission 114b, Candida albicans 238, 360, 361, 362,
anorectal 243–244 117–119 365, 436, 479
oral 196t, 199, 200 harm reduction for injection drug Candida dubliniensis 360
bacterial pneumonias 313–317 users 117–118 Candida glabrata 360, 361, 362
pneumococcal 313–314 nosocomial transmission 118 Candida krusei 360, 361, 362, 363
see also Haemophilus influenzae; post-exposure prophylaxis 118–119 Candida tropicalis 360
Pseudomonas aeruginosa; prevention 114b, 117–119 candidemia 361, 363t, 365
Staphylococcus aureus screening of blood supply for candidiasis 319t, 359–366
bactrim 538t transfusions 118 clinical manifestations 360–361
Bahamas 489t universal precautions 118 diagnosis 361–362
Bartonella infections 421–431 BMD (bone marrow density) disseminated 361
clinical presentation 421–425 280–281 epidemiology 359–360
diagnosis 425–426 BMS488043 inhibitor 25 erythematous 196t
epidemiology and prevention 429 bone esophageal 237–238, 359–361,
history 421 antiretroviral and other therapies 363t, 364
relapse 428–429 280–281 gastrointestinal disorders 237, 238,
treatment 426–428 density 188 239f, 240–241, 243
Bartonella bacilliformis 425–426 infection, Bartonella 422, 423f oral 195–199, 196t
Bartonella henselae 425–426 metabolism alterations 280 oropharyngeal 359–360, 363t, 364
Bartonella quintana 425–426 pathology 280 prevention 365
basal ganglia impairment 251–252 treatment considerations 281 treatment 362–365
BCG vaccination 344–345 boric acid 363t vaginitis 529
behavioral change with HAD 251b Botswana 8, 341 Cannomys badius 390
programs and sexual transmission mother-to-child transmission 489t, capreomycin 340t
117 492t carcinoma see malignancy
behavioral prevention programs 117 Pneumocystis pneumonia 298t cardiomyopathy 269–270
benzathine penicillin 222 brain see cerebral; encephalitis; cardiovascular complications 267–273
benznidazole 556 encephalopathy cardiomyopathy and congestive heart
benzodiazepine 262t, 263 Brazil 126, 290f, 460, 489t, 556 failure 269–270
benzthine penicillin in syphilis 470t dermatology 220, 223 coronary artery disease 267–268
benzyl benzoate 220–221 Mycobacterium avium complex endocarditis 271–272
beta-lactam and beta-lactamase 314, 349–350 neoplasms 272
316, 318t Pneumocystis pneumonia 298t pericardial disease 270–271, 271b
biological phenotype and disease breast cancer 529 pulmonary hypertension 271
progression 61–63 breastfeeding in women 527–528
biology of HIV-1 transmission 89–93, biology of HIV-1 transmission 89 cardiovascular risk 187–188
97–98 mother-to-child transmission Caribbean/Central America 298t
early target cells and virus-host prevention 485, 486, 487, 488t, dermatology 221
dynamics 92 489t, 492t, 495, 496–497, 498 global epidemiology 10–11
endogenous host factors 91 risks 6, 90, 117, 501 travel, international 554, 555
exogenous host factors 91–92 tuberculosis treatment and 338 carnitine deficiency 270b
infecting partner 89–90 broadly neutralizing antibody 100 carpal tunnel compression 284
prevention 93 bronchopneumonia 314, 315t casereporting 4
superinfection 92–93 buprenorphine 264 caspofungin 225
viral selection 90 drug abuse 539–540, 542, 542t, 543, candida 238, 319t, 363–364,
bipolar disorder 259 544t, 547 363t, 365
bisphosphonates 281 Burkina Faso 488t Castleman’s disease, multicentric 458
bladder dysfunction 434–435 Burkitt’s lymphoma 456 cats and diseases 397
Blastomyces 378 butoconazole 363t see also Bartonella infections
563
Index
CCLs (chemokine ligands) 64t, 91 ceftizoxime 427t vertical transmission to 89

CCR2 64t ceftriaxone 427t see also adolescents; antenatal HIV;
CCR5 79, 80, 134 gonorrhea 472t breast-feeding; infants;
antagonists 146 pneumonias 314, 315t, 317, 318t mother-to-child; pregnancy
biology of HIV-1 transmission 90, 91, syphilis 469 Chile 298t
92 cefuroxime 315t, 318t chimpanzee 16–17, 16f, 18, 19
inhibitors 26–27, 29f, 250 cellulitis 538t China 125, 225, 261, 557
viral and host determinants of disease Central African Republic 18 global epidemiology 11
progression 61–62, 64t Central and Eastern Europe 125 penicillium marneffei infection
CD4 T-cells, numbers of 90, 149, 349 epidemiology 9 389–390
acute infection 77–80, 78f prevention 117–118 tuberculosis 325
antiretroviral therapy 146–147 central nervous system and bartonella Chlamydia 475–476
Bartonella infections 422, 424–425, infections 424 clinical features 475
428–429 cephalosporin 427t, 538t epidemiology 475
biology of HIV-1 transmission 90, 91, pneumonias 314, 315t, 317, 318t natural history, pathogenesis, and
92 cephalosporin-cefpodoxime 318t pathology 475
cardiovascular complications 268 Cercocebus (torquatous) atys see patient evaluation, diagnosis, and
children and adolescents 509–510, mangabey differential diagnosis 475–476
512t, 513 cerebral treatment 476, 476t
fungal infections 369, 370 cryptococcomas 375 Chlamydia trachomatis 243–244, 475, 476
gastrointestinal disorders 237–238, internal reward circuitry 261 Chlamydophila pneumoniae 313, 316,
240–242 see also PML; toxoplasmic encephalitis 318t
hepatitis 412–413, 414 cerebrovascular accident 538t cholesterol levels 187, 268b
immune response to HIV 48–50 cerebrovascular disease 527–528 CHOP regime (cyclophosphamide,
laboratory testing 126, 127t cervical cancer 461–462 doxorubicin, vincristine,
loss 60–61, 133–134 epidemiology 461 prednisone) 457
lymphocyte counts 146, 249–250 etiology 461 chorioamnionitis prevention 498
molecular biology of HIV and screening and diagnosis 461 chorioretinitis 433–434
implications for new therapies treatment 461–462 chronic mental illness 258, 259–260
26–27, 29f cervical disorders cidofovir (vistide) 225–226
neoplasia 456 cancer 528 management of infections 434, 434t,
NRTIs 144 carcinoma 456t 438, 440, 445
ocular manifestations 212 dysplasia 528 ocular manifestations 210, 214
pneumocystis 297–305, 305f, 306f, cervical intraepithelial neoplasia (CIN) ciprofloxacin 554
309–310 461 gonorrhea 472t
pneumonias 314, 316, 319t cesarean birth, elective 498 Mycobacterium avium complex
receptors 25, 134, 250 cesarean delivery, elective 498 351–352, 353–354
renal complications 289 Chagas disease 556 pneumonias 315t, 316, 318t
toxoplasmic encephalitis 398, chancroid 477 travel, international 552b, 555
401, 403 cheilitis 198, 198f tuberculosis 339
travel, international 552 chemical prevention see microbicides circulating recombinant forms (CRFs)
women 525, 526f chemokine receptor 250 18, 20
CD8 T-cells 125–126 complex 134 circumcision 91–92
acute infection 78f, 79–80 ligands affecting viral load 64t lack of/need for 525
escape from control 51–52 chemotherapy, neoplasia 460 medical male 115
CDC (Centers for Disease Control and chest radiography 305–306, 305f, cirrhosis 411–414
Prevention) 552 313–314, 317, 321, 370–371 clarithromycin 240t
CDE infusional regime 457 chicken pox 196t Mycobacterium avium complex 352,
CEE see Central and Eastern Europe children 509–519 353, 353t, 354–355
cefazolin 318t antiviral therapy 512–517 pneumonias 317, 318t
cefdinir 315t, 318t cardiovascular complications 270 toxoplasmic encephalitis 403t, 404t
cefditoren 318t epidemiology 509 clindamycin
cefepime 318t management 517 dermatology 221, 227
cefixime in gonorrhea 472t natural history 509–510 pneumonia 309, 309t, 315t, 316, 318t
cefotaxime 314, 315t, 317, 318t prophylaxis of other infections toxoplasmic encephalitis 403, 403t,
cefpodoxime 315t 517 404t
cefprozil 315t, 318t HIV prevalence in 5t, 6, 9–10 clinical trials for prevention of MTCT
ceftazidime 318t therapeutic drugs and 175 485, 486–496, 488t, 489t, 492t
564
Index
clofazimine 351–352, 353 pancreatitis 182 epidemiology 369–370

Clostridium difficile 241, 243, see also cardiovascular complications; extraneural 376–377
244–245, 244f endocrine complications; fungal infections 319t
clotrimazole 227, 363t, 364 neuropathy; ocular gastrointestinal disorders 240–241
CMV see cytomegalovirus complications; oral microbiology 369
CNS disease complications; renal natural history 370
antiretroviral drugs compartment, complications non-meningeal disease 381
253 computed tomography, high-resolution, ocular complications 212–213
HAD 249–250, 250b of chest 306f oral complications 196t
opportunistic 255 condoms 114 pathogenesis 370
primary lymphoma 457–458 condyloma, anal 243–244 pathology 370
co-infection 80 congestive heart failure 269–270 pneumonias 314t, 320–321, 320t
co-receptors and biological phenotype Congo 8, 298t see also cryptococcal meningitis;
62 origins and diversification of HIV 18, Cryptococcus
cobicistat 172 19–21, 21f, 22 Cryptococcus 271b
cocaine 540–541 conjunctivitis 208 Cryptococcus neoformans 275, 277,
Coccidioides 378, 381 contraception 283, 524 320–321, 369, 370, 371–372,
Coccidioides immitis 319t, 380, 380f, see also condoms 373f, 394, 442–443, 554, 557
390–391, 554 cornerstone agents in ARV 144–146 Cryptosporidium/cryptosporidiosis 237,
coccidiomycosis 314t, 380–382 coronary artery disease 267–268, 268b 240–242, 243, 436, 552b
clinical features 380–381 cortical atrophy 252f CSF 250, 252, 515
diagnosis 381 corticosteroids 280–281, 293, 309t CSWs see commercial sex workers
differential diagnosis 381 gastrointestinal disorders 238 CT scans 252, 400
epidemiology 380 toxoplasmic encephalitis 402–403 CTLs (cytotoxic T-cell lymphocytes),
natural history, pathogenesis and corticosterone 277 response to infection 48f, 50, 60
pathology 380 corticotrophin-releasing hormone CTX see cotrimoxazole
patient evaluation 381 (CRH) 277 Cushing’s syndrome 277
travel, international 557 costs of medicines 149 cutaneous bacillary angiomatosis 422,
treatment 381–382, 382t cosyntropin 278 423f, 428
cognitive changes with HAD 251b Côte d’Ivoire 293 cutaneous tuberculosis 223
colitis 241, 243, 244f cotrimoxazole (CTX) 360 CX3CR1 64t
cytomegalovirus 436, 436f counseling 114, 147 CXCL12 64t, 91
see also ulcerative colitis Coxsackie virus 270b CXCR4 (X4) receptors 134, 250
commercial sex workers 3, 4, 6, 9, CRAG (cryptococcal antigen) test 371, biology of HIV-1 transmission 90, 91,
523t, 524 372, 376 92
complement receptors (CR) 329 creatinine, elevated serum 293 molecular biology and implications
complications from antiretroviral CRFs (circulating recombinant forms) 25–27, 29f
therapy 177–190 18, 20 for new therapies 25–27, 29f
adverse effects. in early phase Crohn’s disease 237 viral and host determinants of HIV-1
177–181 CRs (complement receptors) 329 disease progression 61–62
adverse effects in long-term therapy cryotherapy 460 cyclophosphamide 457
181–185 cryptococcal meningitis 213, 249, 261, cycloserine 340t, 351
ART impact on ageing diseases 186 319t, 320–321, 391, 392 Cyclospora 554
bone density 188 primary neurological manifestations Cyclospora cayetanensis 241–242
caridiovascular risk 187–188 249 CYP (cytochrome P450 enzymes) 172
abacavir hypersensitivity reactions cryptococcal meningoencephalitis cytochrome P450 enzymes 172
178–180, 179f 369–376 cytokines 438–439
efavirenz toxicity profile 185 elevated intracranial pressure adrenal function 277
hematological 183 375–376 production 250, 269–270
lactic acidosis and hyperlactatemia patient evaluation, diagnosis, and proinflammatory 254
182 differential diagnosis 370–372 cytomegalovirus infections 81, 433–440
lipoatrophy 183–184, 184f prognosis 372 candida 360–361
liver function and enzyme relapse 376 cardiovascular complications
abnormalities 185 treatment 373–376, 374t 269–270, 270b
monitoring and managing 187–188 cryptococcomas, cerebral 375 chorioretinitis 433–434
nevirapene toxicity 180 cryptococcosis 81, 224, 369–370 colitis 436, 436f
non-cirrhotic portal hypertension, clinical features 370 encephalitis 249, 250b, 261,
182 disseminated 557 434, 435
565
Index
cytomegalovirus infections (Continued) diarrhea 185, 241–243, 321 epidemiology 537

endocrine complications 275, 277, drug-induced 237, 241–242 interactions of drugs 544–547, 544t
278, 280 infections 436, 439 medically supervised withdrawal
gastrointestinal 237–238, 239f, traveller’s (TD) 552b, 554, 558 541–543
240–242, 243, 436 diarylquinolines 340 mental illness 544
nervous system 434–435 didanosine (DDL/DDI) parenteral transmission
oophoritis 282 antiretroviral therapy 135, 136t, 144 (contaminated needles) 89
oral complications 196t children and adolescents 515 psychopharmacology 262–264, 262t
pulmonary system 436 complications 182 renal complications 287
radiculomyelitis 250b drug abuse 544t risk reduction 547
retinitis 207, 209–210, 209f, 436, hepatitis viral infection 416–417 treatment/therapy 537–540
437–438 hyperlactatemia 182 see also cocaine; heroin;
treatment 437–440 mother-to-child transmission methamphetamine
ulcers 200 prevention 497–498, 499t drug eruptions, dermatologic 227
ventriculitis 399 pancreatitis 182 drug resistance development 85,
cytoplasmic events, early 27–28 pharmacology 170t, 171, 173 155–166, 443
cytotoxic T-cell lymphocytes see CTLs primary neurological manifestations fusion and entry inhibitors 159–160
cytovene see ganciclovir 254 generated 156–157
resistance to 158 management of infections 438
tuberculosis 341 non-B subtypes of HIV-1 group M 160
D
dideoxycytidine 170t, 279 protease inhibitors 159
D30N 159 dideoxynucleoside drugs 254 reverse transcriptase, inhibitors of
D4T see stavudine see also didanosine; stavudine; 157–159
dapsone 219–220 zalcitabine transmission of 160–162
pneumocystis pneumonia 309t, 310t diffuse infiltrative lymphocytosis DRV see darunavir
toxoplasmic encephalitis 403t, 404t, syndrome (DILS) 203, 203f dry eye 209
405t diphtheria vaccination 512, 553t DSN (distal sensory polyneuropathy)
darunavir 136t, 145, 170t, 544t direct fluorescent antibody 238 254
DC see dendritic cells distal neuropathy 435 dyslipidemia 183, 185, 268, 268b, 284
DDC see dideoxycytidine distal sensory polyneuropathy (DSN) dyspepsia 240–241
see also zalcitabine 254 dysphagia 237–238
DDI see didanosine disulfiram 543
dehydroepiandrosterone (DHEA) 277 DLV see delavirdine
E
delavirdine (DLV) 159, 160, 170t DNA
drug abuse 544t PCR diagnosis 511 Eastern Europe see Central and Eastern
delirium 260, 260b, 261 viral vectors and 102 Europe
dementia 257–258 DNA detection of toxoplasmic EBV see Epstein-Barr virus
global 251–252 encephalitis 400 echocardiography 269
subcortical 251–252 flap 28 echovirus 270b
ventriculoencephalitis 435 pro-viral 82 edema 284
see also AIDS dementia complex; HAD synthesis, interference with 254 education to avoid risk 93
dendritic cells testing 126–128 efavirenz (EFV) 219–220, 227, 253,
DC-SIGN receptor 27 dopamine transporters, loss of, 264, 279, 353t
impairment 52 251–252 antiretroviral therapy 135, 136t, 144,
dengue 558 dorsal column sensory deficits 255 185–186, 219–220
deoxycorticosterone 277 doxorubicin 270, 457, 459, 460, 460t children and adolescents 516t
depression 257, 517–518 doxycycline 469 CNS side effects 185
dermatitis bartonella infections 424, 426, drug abuse 170t, 544t
atopic 227 427–429, 427t endocrine complications 282
seborrheic 220, 226–227 chlamydia 476, 476t hepatitis viral infection 416, 418
dermatology and global HIV 219–234 dermatology 222 mother-to-child transmission
detection of virus 82–84 gonorrhea 472t prevention 496, 498–501, 499t
DFA (direct fluorescent antibody) 238 pneumonias 315t, 316, 318t mutations 144, 159
DHEA (dehydroepiandrosterone) 277 dronabinol (Marinol) 284 pharmacology 170t, 174t, 175
diabetes drug abuse, intravenous 113, 261, resistance to 159, 160
endocrine complications 277, 278–279 537–548 toxicity profiles 185–186
renal complications 288 complications 538t travel, international 556
dialysis 293 epidemiology 6 tuberculosis 341, 342
566
Index
Egypt 289 see also acute infection; biology of

F
EIA (enzyme immunoassay) 82, 414 HIV-1 transmission; global
ELISA (enzyme-linked immunosorbent epidemiology; immune failure of treatment see drug resistant
assay) 123–125, 126 response; molecular biology; HIV
elvitegravir 544t origins and diversification; viral famciclovir 444–445, 445t
emtricitabine (FTC) and host determinants in genital herpes 472, 472t
antiretroviral therapy 135–144, 136t epituberculosis 330 fat distribution, abnormal body
children and adolescents 515, 516t EPOCH regimen 457 183–184, 184f
hepatitis viral infection 414, 416 Epstein-Barr virus (EBV) 270b, 399 fertility see reproductive health
pharmacology 170, 170t, 173t neoplasia 456t, 457, 458 festinavir 544t
emtriva 544t Equatorial Guinea 18 fetal loss, spontaneous 283
encephalitis 261, 361 ertapenem 318t fever 558
with dementia and erythema 422, 423f fidelity 114
ventriculoencephalitis 435 erythematous candidiasis 197f fitness see replication, viral
herpes simplex virus 442–443 erythromycin 316 fluconazole
primary neurological manifestations Bartonella infections 421, 424, candida 362, 362t, 363t, 364–365
249, 250b 426–428, 427t coccidioidomycosis 380–382
vaccination 553t Chlamydia 476t cryptococcal 369–370
see also toxoplasmic encephalitis dermatology 221, 222, 241 dermatology 224
Encephalitozoon 208–209 gonorrhea 472t drug abuse 547
Encephalitozoon intestinalis 241–242, Escherichia coli 237, 241, 243, 554 fungal infections 369–387
243 esophageal disorders 237–238 gastrointestinal disorders 238
endocarditis 268b, 271–272, 361, 378, candidiasis 237–238, 239f, 240–241, histoplasmosis 377–380
421, 424–425, 538t 243, 359–361, 363t, 364 pneumonias 319t, 320t
endocrine complications 275–285 esophagitis 436, 442 travel, international 552b
endocytosis 27 ethambutol (myambutol) 214, 538t flucytosine 224, 374–375, 374t
endogenous host factors 91 Mycobacterium avium complex fluoroquinolone
endophthalmitis 214, 361 351–352, 353–354, 353t pneumonias 314, 315t, 316,
end-stage renal disease 287, 288, tuberculosis 338, 339, 339t, 341 317, 318t
291–293, 294 ethinyl estradiol 283 resistance 555
enfuvirtide 134, 136t, 146, 170t, 544t ethionamide 340t, 351 tuberculosis 339
Entamoeba 436, 554 Ethiopia 160, 293, 298t fluoxetine 284
Entamoeba histolytica 243 ethnic variations 175 fluticasone 277
entecavir 538t ethylenediamines 340–341 folinic acid (leucovorin calcium) 403t,
hepatitis viral infection 414, 416 etoposide 457, 458, 460, 460t 404t
enteric infections 554–555 etravirine 145 food
enteritis 241, 243 Europe 17–18, 123 drug interaction with 173–174
enterocolitis 243, 436 dermatology 220–221, 222, 223–225 insecurity see malnutrition
Enterocytozoon bieneusi 241–242, 243 drug abuse 543 fosamprenavir (Fos-An) 170, 173, 353t,
entry inhibitors 159–160 fungal infections 369 544t
Env (envelope protein, gp120 25, global epidemiology 8–9 antiretroviral therapy 136t, 145
62, 123 hepatitis viral infection 411, 413 children and infants 515, 516t
design of global AIDS vaccine 97, 98, mother-to-child transmission 489t foscarnet (foscavir)
99–100, 101, 102 Mycobacterium avium complex 349–350 cardiovascular complications 270
enzyme Penicillium marneffei infection 389 gastrointestinal disorders 243
abnormalities 185 pneumocystis pneumonia 297 hepatitis viral infection 445
drug interactions 172–173 prevention 117–118 management of infections 434t, 435,
immunoassays see EIA psychiatric problems 257–258, 261 438, 439–440, 448t
see also Elisa renal complications 287, 288, 293 ocular manifestations 210–212
induction 173 travel, international 551, 555, 556 fosinopril 291–292
inhibition 172–173 see also Central and Eastern Europe France 223, 288
epidemiology and biology of HIV EVR 415 mother-to-child transmission,
infection 125, 509 exogenous host factors 91–92 488t, 497
bartonella infections 429 extraneural cryptococcosis 376–377 FSGS (glomerulosclerosis) 289
fungal 359–360, 369–370, 377, 380 diagnosis 376 FTC see emtricitabine
hepatitis viral infection 411–412 treatment 376–377 fungal infections 369–387, 557
renal complications 287–289 primary fungal prophylaxis 377 deep (systemic), dermatologic
tuberculosis 325–327, 326f eyes see ocular manifestations 224–225
567
Index
fungal infections (Continued) genetics gonadotropin-releasing hormone 281

pneumonias 307–308, 317–321, AIDS-restricting genes (ARGs) 53 gonorrhea 472–475
318t, 319t biology of transmission 91 clinical features 473
primary prophylaxis 373 diversity 20–21 epidemiology 472–473
superficial, dermatologic 224 genome of HIV provirus 26f natural history, pathogenesis, and
see also candida; coccidiomycosis; of innate immunity 16–17 pathology 473
cryptococcosis; histoplasmosis primary neurological manifestations patient evaluation, diagnosis, and
fungal pneumonias of HIV/AIDS 250–251 differential diagnosis 473
aspergillosis 317–320, 319t renal complications 289 treatment 473–475, 474t
cryptococcosis 320–321, 320t viral genes, expression of 31–32 gp120 binding 25, 27, 29f, 134
histoplasmosis 320t, 321 see also genes gp41 27, 29f, 134
fungal/protozoan infection 271b genital herpes 441, 470–472 gram-negative bacilli 315t
deep systemic 224–225 epidemiology 470–471 granuloma inguinale 469
see also cryptococcus; histoplasma; natural history, pathogenesis, and Grave’s disease (GD) 276
toxoplasma pathology 471 griseofulvin 224
fusion inhibitors 134, 136t, 146, clinical features 471 growth hormone (GH) 270b, 279,
159–160, 170t patient evaluation, diagnosis, and 283–284
differential diagnosis 471–472 gut associated lymphatic tissues 61, 98,
penile vesicles 471f 237
G
labial ulcerations 471f gynecomastia 281, 282
gabapentin 254, 538t treatment 472, 472t
Gabon 18 herpes simplex virus type 1 (HSV-1)
H
Gag 26f, 123, 134–135 470
design of global AIDS vaccine 101, 102 herpes simplex virus type 2 (HSV-2) HAART (highly active antiretroviral
viral and host determinants of disease 470–471 therapy) 551
progression 62 genital ulcerative disease 524 complications of antiretroviral
galactorrhea 284 syndromic management 477, 478f therapy 177
gallium scanning 306 genital warts 469, 524 endocrine complications 275, 276,
GALT (gut associated lymphoid tissues) genome-wide association studies 67–68 278–279, 280, 281, 283
61, 98, 237 gentamicin 221, 222 fungal infections 377
gamma-benzene hexachloride see geotrichosis 196t candida 359, 361, 365
lindane GERD (gastroesophageal reflux disease) cryptococcal 369, 376
ganciclovir (cytovene) 237 hepatitis viral infection 411
cytomegalovirus 437–439, 437t, 438t GFATM see Global Fund management of infections 433,
gastrointestinal disorders 238, 243 Ghana 8 437–438, 443
management of infections 434, 434t, Giardia lamblia 243 Mycobacterium avium complex
435, 437–440, 437t, 438t giardiasis 241, 436, 552b, 554 349–350, 354
ocular manifestations 210, 212, 250 gingival erythema, linear 196t pneumonias 313, 320–321
gastritis and gastroenteritis 238–239, gingivitis 196t, 199, 360 travel, international 553
240–241 gliosis 252 see also ART/ARV
gastroesophageal reflux disease (GERD) global epidemiology of HIV/AIDS 1–12 HAD (HIV-associated dementia)
237–238 Asia 11 249–250, 251, 261
gastrointestinal disorders 237–246 Caribbean and Latin America 10–11 primary neurological manifestations
anorectal disease 243–244 Central and South America 10–11 249–250, 250b
bacillary angiomatosis 424 Europe 8–9 Haemophilus influenzae 275, 538t
esophageal 237–238 measurement 3–5 pneumonias 313, 315t, 317, 318t
GALT 61, 98, 237 North America 9–10 hair, tinea infections of 224
gastric 238–241 Sub-Saharan Africa 6–8 Haiti 10, 126, 220
gastrointestinal intolerance 185 transmission 5–6 half-life of drugs 171
management of infections 436 Global Summary of HIV and AIDS harm reduction programs
see also colitis; diarrhea; enteric epidemic 257–258 117–118
infections glomerulonephritis 288, 289 Hashimoto’s thyroiditis 276
gastrointestinal, tuberculosis 333 glomerulosclerosis (FSGS) 289 HBV see hepatitis B
gaticloxacin 340t glucocorticoid 277 HCV see hepatitis C
gemcitabine 460t replacement therapy 278 Helicobacter pylori 237–239, 240t
gene-expression screens 68 glucose homeostasis alterations hematopoiesis 438–439
genes, viral accessory 62–63 278–279 hematopoietic cell transplantation 457
see also ARGs; Nef; Vif; Vpn; Vpr gonadal toxicity 439 hemophiliacs 411–412
568
Index
hepatic bacillary peliosis 421, 423, 423f, management of infections 433–434, HIV-associated neurocognitive disorder
425, 428 436, 440–447, 442f (HAND) 251–253
hepatic impairment 174, 185 ocular 208 clinical features 251–252, 251b
cholesterol, increased 268b treatment 443–447 diagnosis 252
liver function test 378 women 524 treatment 252–253
tuberculosis treatment and 338 herpes simplex/herpes zoster 91 HIV-associated sensory neuropathy
hepatic steatosis 182 acute infection 81 (HIV-SN) 254
hepatitis A 290–291, 293, 554 oral 196t, 200 HIVAN (HIV-associated nephropathy)
epidemiology 411 see also Kaposi’s sarcoma see renal complications
natural history 412 herpes zoster ophthalmicus 208 HLA (human leukocyte antigen) 46, 53,
diagnosis 414 heterosexual contact see sexual 63–67, 64t, 91
patient evaluation 413–414 transmission Hodgkin’s lymphoma 196t, 455,
treatment 415 HHE (human haplotype E) 64t 456t, 458
vaccination 512 high density lipoprotein (HDL) homosexuality see male-to-male sex
hepatitis B 81, 135, 290–291, 279–280 Hong Kong 389
538t, 551 highly active antiretroviral therapy see hormone-binding globulin 275–276,
diagnosis 414 HAART 281
epidemiology 411 histopathology hormones 524
natural history 412 Bartonella infection 425–426, 425f host, biology of HIV-1 transmission
patient evaluation 413 toxoplasmic encephalitis 400–401 from 89, 91
travel, international 552b, 553t, Histoplasma 271b HPA see hypothalamic-pituitary-adrenal
558 Histoplasma capsulatum 243, 275, 321, axis
treatment 414–415, 417t 377, 377f, 378–379, 390–391, HPG see hypothalamic-pituitary-
vaccination 512 394, 554 gonadal axis
hepatitis C 81, 276, 293 histoplasmosis 377–380 HPMPC see cidofovir
epidemiology 411–412 clinical features 378 HPV (human papillomavirus) 243–244,
natural history 412–413 dermatology 224–225 528
diagnosis 414 diagnosis 378 cervical cancer 461
treatment 415, 417t differential diagnosis 378 HSV see herpes simplex virus
women 527 epidemiology 377 human efficacy trials 101–102
hepatitis D fungal infections 371t, 373t, human leukocyte antigen 46, 53,
epidemiology 412 377–380 63–67, 64t, 91
natural history 413 gastrointestinal 240–241 human papillomavirus 225–226,
treatment 417 microbiology 377 243–244, 456t, 528
hepatitis E natural history 377–378 warts 201
epidemiology 412 oral complications 196t hydroxyurea 182
natural history 413 pathogenesis 377–378 hyperandrogenemia 283
treatment 417 pathology 377–378 hyperbilirubinemia 180–181
hepatitis virus infections 411–419 patient evaluation 378 hypercortisolism 277
antiretroviral-associated penicillium marneffei infection hypergammaglobulinemia 270
hepatotoxicity 417–418 390–391, 393 hyperglycemia 145, 278–279
diagnosis 414 pneumonias 314t, 320t hyperinsulinemia 270b, 283
epidemiology 411–412 travel, international 557 hyperinsulinism 270
liver transplantation 418 treatment 378–380, 379t hyperkalemia 278
natural history 412–413 see also Histoplasma hyperlactatemia 182
patient evaluation 413–414 HIV-1 associated vacuolar myelopathy hyperlipidemia 145, 272
treatment 414–417 255 hyperpigmentation 219
hepatosplenomegaly 321, 378, 423f, groups N and O 17–18 hyperprolactinemia 284
424 origins in cross-species 16–17, 18, 20 hypertension, pulmonary 271
herbal medicin 174 transmission see chimpanzees hyperthyroidism 275, 276–277
heroin 537, 540 HIV-1 group M subtypes 17–18, 19 hypertriglyceridemia 279
see also drug abuse drug resistance in 160 hypoadrenalism 270
herpes simplex virus genetic diversity in 20–21 hypoalbuminemia 314t, 317
candida 360–361 pandemic 15 hypoandrogenism 282–283
clinical presentation 440–443 phylogenetic tree 20, 21f hypoglycemia 278, 279
dermatology 225 HIV-associated asymptomatic hypoglycorrhachia 435
gastrointestinal disorders 237–238, neurocognitive impairment 261 hypogonadism 280–281, 282
239f HIV-associated dementia see HAD hyponatremia 278, 283
569
Index
hypophosphatemia 181 indinavir (IDV) IRU (immune recovery uveitis) 210

hypopigmentation 219 antiretroviral therapy 136t, 145 isolation studies 399
hypopituitarism 283 children and adolescents 516t isoniazid 355, 538t
hypospermatogenesis 281 dermatology 219–220 travel, international 552b
hypothalamic-pituitary axis drug abuse 544t tuberculosis 338, 338t, 339, 339t,
adrenal 277–278 endocrine complications 278–279 340–341
gonadal 277–278 hepatitis viral infection 417 Isospora belli 241–242, 243, 554
hypothyroidism 271b, 275–277 Mycobacterium avium complex 353t Italy 288
pharmacology 170t, 173t, 174t itching and skin disorders 220–221
primary neurological manifestations itraconazole 220, 224–225
253 candida 362, 362t, 363t, 364–365
I
tuberculosis 342 dermatology 224–225
idiopathic AIDS enteropathy 243 Indonesia 11 fungal infections 376, 377, 378–380,
idiopathic esophageal ulcers (IEU) infants 510–512 379t, 381
237–238, 239f diagnosis 510–511 gastrointestinal disorders 238
IDU (injection drug use) see drug abuse monitoring 511 histoplasmosis 321
IDV see indinavir PCP prophylaxis 512t penicillium marneffei infection
IEU see idiopathic esophageal ulcers vaccination 512 393–394
IFN see interferon see also breast-feeding; children; pneumonias 319t, 320t
IGF-1 binding protein mother-to-child transmission; travel, international 552b, 557
283–284 pregnancy ivermectin 220–221
IgG and IgM antibodies 25, 82, Infectious Disease Society of America 268 Ivory Coast 298t
123–124 infective endocarditis (IE) 272 mother-to-child transmission
imidazoles 224, 227 inflammatory bowel disease (IBD), prevention 488t
imipenem 318t 237, 243
imiquimod 225–226 influenza vaccine 512, 553t
J
immune reconstitution disease/ see also Haemophilus influenzae
syndrome 370, 378, 382 infusional chemotherapy 457 Japan 349, 389
immune reconstitution inflammatory injections see drug abuse; non-sterile Jarisch-Herxheimer reaction 469
syndrome see IRIS injections JC virus 213
immune recovery uveitis (IRU), innate immune responses 79
210, 440 insulin
K
immune response to HIV 45–56 disorders 270
acquired immunity to viral infections -like growth factor-1 283–284 K103N (EFV mutation) 144, 159
46–48 resistance 183, 185, 278–279 K65R 158–159
correlates of protection to infection integrase 27–28 kanamycin 340t
53 inhibitors 134, 145–146 Kaposi’s sarcoma 401, 422, 456t
protective 100 interferon 223–224, 414, 415, 538t -associated herpes virus (KSHV),
reasons for failure to control HIV -alpha 214, 270, 276, 414, 460–461 456t, 458
50–53 gamma 220 candida 360
specific antiviral 59–60 interferon-gamma releasing assays cardiovascular complications 270,
vaccines, prospects for 53–54 (IGRAs) 334–335 271, 271b, 272
immune thrombocytopenic purpura interleukins 64t, 271 clinical management 459
196t, 202 intertriginous infections 220–221 clinical presentation 459
immunoassays, enzyme see EIA; Elisa intestine see enteric infections cytotoxic therapy 460t
immunoblotting 82 intracranial toxoplasmosis 212–213 endocrine complications 275
immunoglobulins 46, 252 intralesional vinblastine 460 gastrointestinal disorders 238,
in utero transmission 485–486 intrapartum period, mother-to-child 240–241, 244f
index case, biology of transmission transmission prevention 488t, investigational agents 461
from 89–90 489t, 492t local therapies 459–460
India 11, 17–18, 556 intrapartum transmission 485–486 management of infections 436
dermatology 220, 221, 223 investigational agents for neoplasia 461 neoplasia 459–461
penicillium marneffei infection iodine 554–555 ocular manifestations 209,
389–390 IRD (immune reconstitution disease) 213–214
pneumocystis pneumonia 298t 369, 370, 378, 382 oral complications 196t,
psychiatric problems 261 IRIS (immune reconstitution 201–202, 201f
renal complications 289 inflammatory syndrome) pathogenesis 459
tuberculosis 325, 327 342–343 pneumonias 314t
570
Index
relative risks 456t leiomyosarcoma 456t structure degeneration 52

systemic therapy 460–461 Leishmania/leishmaniasis 223–224, see also CTLs; lymphocyte counts;
thyroidism 275 314t, 378, 556 T lymphocytes
Kenya 298t leprosy 223 lymphogranuloma venereum 243–244
dermatology 223 leptospirosis 558 lymphoid interstitial pneumonitis 314t
global epidemiology 8 lersivirine 544t lymphoma 202, 271b, 314t, 369
keratitis 208 Lesotho 8 EBV-associated central nervous
ketoconazole 238, 379 leucovorin calcium 403t, 404t system 399
dermatology 219–220, 227 leukocyte antigens, human 64t endocrine complications 275,
endocrine complications 276, leukocytosis 435 278, 283
279–281, 282 leukoencephalopathy, progressive see gastrointestinal disorders 238,
Penicillium marneffei infection PML 240–241, 243
393–394 leukopenia 378 plasmablastic 458
kidney disease see renal complications leukoplakia, hairy 196t, 200–201, 200f primary effusion 458
Klebsiella 314t levofloxacin 316, 318t, 340t toxoplasmic encephalitis 401
stomatitis 196t levothyroxine 276–277 see also Hodgkin’s lymphoma;
Klebisiella granulomatis 469 lindane 220–221 non-Hodgkin’s lymphoma
linezolid 221, 318t, 341 lymphoproliferative disease 456–458
lip cancer 196t Castleman’s disease, multicentric 458
L
lipid associated AmB 363t plasmablastic lymphoma 458
laboratory testing 82–85, 123–130 lipid metabolism, absnormalities primary effusion lymphoma 458
acute infection 82–85 279–280 see also Hodgkin’s lymphoma; non-
detection of virus 84 lipid signalling rafts 27 Hodgkin’s lymphoma
diagnostic 123–125 lipoatrophy 183–184, 184f, 279, 283
drug resistance 85 lipodystrophy 183–184, 184f
M
monitoring patient health 125–126 complications of antiretroviral
monitoring viral replication 126–129 therapy 183–184, 184f, 187 M184V 161
quality assurance and control 129 endocrine complications 283 MAC see Mycobacterium avium
serology 82–84 lipomatosis 275 MAC-IRIS see Mycobacterium avium
viral load during primary infection lipoprotein clearance, impaired 268b complex
84–85 liposomal doxorubicin 459, 460, 460t macrolide 315t, 318t, 538t
lactate dehydrogenase 305 liver transplantation 418 macrophages 250, 254
lactic acidosis 182 see also hepatic; hepatitis maculopapular rash 180f
lamivudine (3TC) local therapies for neoplasia 459–460 magnetic resonance imaging 255, 399,
antiretroviral therapy 135–144, loperamide 555 423f, 435
136t, 141t lopinavir (LPV) 241, 342 malaria 551, 554, 555–556, 558
children and adolescents 515, 516t antiretroviral therapy 136t, 145 Malawi 298t
drug abuse 538t, 544t children and adolescents 515, 516t mother-to-child transmission
hepatitis viral infection 414, 416 drug abuse 544t, 547 prevention 489t, 492t,
mother-to-child transmission endocrine complications 278–279 495, 499t
prevention 486, 488t, 489t, 492t pharmacology 170t, 174t Mycobacterium avium complex 355
pharmacology 170, 170t, 171, 173t lovastatin 280 Pneumocystis pneumonia 298t
resistance to 158 low density lipoprotein (LDL) 279–280 Malaysia 219
lamotrigine 254 LPV see lopinavir male-to-male sex (MSM) 89
language impairment 251–252 Ltr (long terminal repeat) 29 gastrointestinal disorders 241–242,
late targets in HIV life cycle 134–135 luteinizing hormone (LH) 281 243–244
Latin America 489t lymph node bacillary angiomatosis 424 global epidemiology 5–6, 9–10
fungal infections 370–371 lymph nodes 46, 421 hepatitis 411–412, 414
global epidemiology 10–11 lymphadenitis, tuberculosis 325 management of infections 435
pneumocystis pneumonia 297, 298t lymphadenopathy 81, 278, 321, 370, male-to-male transmission, prevention
prevention 117–118 378, 421, 422 116
psychiatric problems 261 lymphocyte counts 146, 309–310, 317 Mali 221
travel, international 555, 557 primary neurological manifestations malignancy/carcinoma 455–465
see also Brazil; Caribbean 249–250, 252 anorectal 243–244
LDH (lactate dehydrogenase) 305 see also CD4 T-cells esophagea 240–241
lean body mass (LBM) 284 lymphocytosis ocular (SCC) 213–214
Legionella 313, 314t, 315t, 316, 318t diffuse infiltrative syndrome (DILS) oral 196t, 202
legionnaires’ disease 316 203, 203f skin 226
571
Index
malignancy/carcinoma (Continued) miconazole 363t, 393–394 resource-constrained guidelines 501

squamous cell 196t, 213–214, microbial translocation 237 risk factors 485–486
243–244 microbicides 115–116 short and long-term safety 496–497
thyroid 275 microsporidiosis/Microsporidia see also prophylactic antiretroviral
women 527 241–242, 243, 275 intervention
see also Kaposi’s sarcoma; lymphoma; ocular 208–209 mouth ulcers 360
neoplasia Middle East and North Africa 551 moxifloxacin 339, 340t
management of herpesvirus infections epidemiology 11 MR spectroscopy 252, 252f
433–453 hepatitis 411 MRCA (most recent common ancestor)
cytomegalovirus 433–440 pneumocystis pneumonia 298t 17
herpes simplex virus 440–447 renal complications 289, 293 MRI (magnetic resonance imaging) 255,
varicella-zoster virus 447–449 mild neurocognitive disorder (MND) 399, 423f, 435
see also diarrhea 261 MTCT see mother-to-child transmission
mangabey, sooty, HIV-2 from 17, miltefosine 223–224 mucocutaneous infection 445t
18, 20 minocycline 424, 426, 427t Mucor sp 243
mania 260 mitochondrial myopathy 255 multicentric Castleman’s disease 458
marantic endocarditis 271 MMR vaccine, avoiding 512 Multi-Country AIDS Program see MAP
Maraviroc inhibitor 26–27, 146, 544t MND 251 multidrug resistance 158–159
Marionol (dronabinol) 284 molecular biology of HIV and mumps vaccine, avoiding 512
MCV see molluscum contagiosum implications for new therapies mupirocin 221
measles 512, 553t 25–42 mutations see drug resistance
measurement of disease 3–5 antiviral host factors 34–36 mutism, akinetic 251–252
medical practice, unsafe 19–20 assembly and budding of HIV virions myalgias 284
mefloquine 556 32f, 33f, 34 myambutol see ethambutol
megestrol acetate 277–278, 279, early cytoplasmic events 27–28 Myanmar 298t
280–281, 282, 284 expression of viral genes 31–32 mycobacterium 436
membranoproliferative GN 289–290, HIV entry 25–27 Mycobacterium abscessus 355
290b integration 28–29 Mycobacterium avium complex (MAC)
memory loss 251–252 nuclear pore, crossing 28 241–242, 349–356, 435, 517
men, reproductive health 281–282 replicating new virus 32–34 endocrine complications 275
see also male-to-male sex transcriptional events 29–31, 30f oral complications 196t
meningitis 249, 361 molluscum contagiosum virus (MCV) see also Mycobacterium avium complex,
aseptic 424 208, 370 disseminated
tuberculous 333 monitoring Mycobacterium avium complex,
vaccination 553t complications 187–188 disseminated 196t, 314t,
see also cryptococcal meningitis infant 512t 349–356
meningococcal conjugate vaccine 512 medication 187, 517 atypical infections 355–356
menopause 529–530 patient health 125–126 clinical manifestations 350–351
mental illness, drug abuse, illicit 544 viral replication 126–129 diagnosis 351
meropenem 318t monkey epidemiology 349–350
mesangioproliferative GN 289–290, HIV from 15–16, 16f, 18, 20 pathogenesis 350
290b vaccines design and 100–101 prophylaxis 349–350, 354–355
metabolic syndrome 187 see also SIV therapy 351–353
metformin 279 monocytes, infected 250 treatment failure 353–354
methadone 264, 539–540, 542–543, mononeuritis multiplex 434 Mycobacterium avium intracellulare (MAI)
542t, 544, 544t, 547 mood disorders 260 275, 281
methamphetamine 541, 543 mortality Mycobacterium bovis 333
methicillin 221 total numbers 45 Mycobacterium celatum 355
methotrexate 226 toxoplasmic encephalitis 398 Mycobacterium chelonae 355
metronidazole 240t, 243 mother-to-child transmission, Mycobacterium fortuitum 355
in trichomoniasis 477 prevention of (MTCT/PMTCT) 6, Mycobacterium genavense 355–356
metyrapone test 278 483–506 Mycobacteriumgordonae 355
Mexico 224–225, 298t guidelines for prevention for the USA Mycobacterium haemophilum 355, 356
fungal infections 377, 380 498–501 Mycobacterium kansasii 314t, 355
travel, international 555, 557 nevirapine, single dose 486, 488t, Mycobacterium malmoense 355
MHC (major histocompatibility 489t, 492t, 498–501 Mycobacterium marinum 355
complex) 67 non-antiretroviral intervention 498 Mycobacterium scofulaceum 355
micafungin 363–364 prevention 114b, 117 Mycobacterium simiae 355
572
Index
Mycobacterium simiae-avium 355 ocular manifestations 213–214 non-antiretroviral intervention and

Mycobacterium terrae 355 oral diseases 196t, 201–202, mother-to-child transmission
Mycobacterium triplex 355 213–214 prevention 498
Mycobacterium tuberculosis (Mtb) 275, risks and viral associations 456t non-bacterial thrombotic endocarditis
277, 307f, 314t, 325, 538b systemic therapy 460–461 271
diagnosis 334–337 see also Kaposi’s sarcoma; non-benzodiazephines 262t
immunology 329 lymphoproliferative disease non-Hodgkin’s lymphoma 196t, 272,
impact on HIV 329 Nepal 555 456–458, 456t
latent infection (LTBI) 325, 334–335 neuroimaging studies of toxoplasmic B-cell 455, 456t
pathogenesis 327–329 encephalitis 400 candida 360
primary infection 328 neurology, cytomegalovirus infections clinical management 456–457
secondary or post-primary disease 434–435 hematopoietic cell transplantation
327 neuromuscular weakness syndrome 255 457
transmission 327–328 neuroophthalmic disorders 212–213 infusional chemotherapy 457
treatment 354 neuropathy 182–183, 249, ocular 213
see also tuberculosis 254–255, 538t primary CNS lymphoma 457–458
Mycobacterium xenopi 355 neurosyphilis 250b rituximab 457
Mycoplasma 473, 476, 477, 478 neutropenia 361, 438t, 460t systemic 456
Mycoplasma pneumonia 313, 316, 318t nevirapine (NVP) 117, 227, 279 non-infectious retinal
myelitis 434–435 antiretroviral therapy 136t, 144–145 microvasculopathy 207–208
myelopathy, HIV-associated 249, 250b drug abuse 544t non-nucleoside reverse transcriptase
vacuolar 255 endocrine complications 283 inhibitors see NNRTIs
myocardial infarction 267–268 hepatitis viral infection 417–418 non-sterile injections and pandemic 20
myocarditis 269, 270b hypersensitivity reactions 180, 180f non-steroidal anti-inflammatory
mother-to-child transmission drugs 375–376
prevention 486, 488t, 489t, non-thyroidal illness (NTI) 275–276
N
492t, 498–501 nonoxynol 9 525
nafcillin 315t, 318t Mycobacterium avium complex 353t North Africa see Middle East and North
nails, tinea infections of 224 pharmacology 170t, 171, 173t, Africa
naltrexone 542t, 543 174, 175 North America (mainly USA)
narcotics see drug abuse resistance to 159, 160 antiretroviral therapy 135
natural killer cells 79 toxicity profile 185–186 children and adolescents 509, 514t
nausea/vomiting 238, 240–241 tuberculosis 341, 342 dermatology 220–221, 222, 223,
necrotizing infections 421 NFV see nelfinavir 224–225
herpetic retinopathy 210–212 NHL see non-Hodgkin’s lymphoma drug abuse 543
retinitis 212 nifurtimox 556 Food and Drug Administration 180
stomatitis 196t Nigeria 18 fungal infections 369, 371, 374,
ulcerative periodontitis 196t renal complications 288, 289 377, 380
Nef (negative effector) 27, 29, 62 nitazoxanide 243 global epidemiology 9–10
negative imaging, MRI 255 nitroimidazoles 340 hepatitis viral infection 411–412
Neisseria gonorrhea 243–244 NK (natural killer) cell receptor 64t laboratory testing 123–130
Neisseria gonorrhoeae 472–473, 475–476 NNRTIs (non-nucleoside reverse mother-to-child transmission and
nelfinavir (NFV) 136t, 145, 353t transcriptase inhibitors) 135, 227 prevention guidelines 488t, 489t,
children and adolescents 516t antiretroviral therapy 134, 144–145 498–501, 499t
drug abuse 544t children and adolescents 516t Mycobacterium avium complex
drug resistance 159 complications 185–186 349–350, 354
endocrine complications 279 hepatitis viral infection 417–418 Penicillium marneffei infection 389
pharmacology 170, 170t mother-to-child transmission pneumonias 297, 313, 314, 316, 317
neonatal herpes 472 prevention 497–501, 499t prevention 114
neoplasia 461 pharmacology 169, 170t psychiatric problems 259, 260
cardiovascular complications, primary neurological manifestations renal complications 287–288,
268b, 272 253 289–290, 290f, 293, 294
chemotherapy 460 resistance to 155, 156f, 157, travel, international 551, 555, 557
epidemiology of malignancies 158–159 tuberculosis 325
455–456 tuberculosis 342 women and special issues 521,
interferon-alpha 460–461 see also efavirenz; nevirapine 522–523, 522f, 525
investigational agents 461 Nocardia 223, 313, 314t, 315t see also Bartonella infections;
local therapies 459–460 non-AIDS-defining malignancies 462 toxoplasmic encephalitis
573
Index
Norwalk virus 241, 552b neoplastic disease 201–202 parasitic infections 555–557
NRTIs see nucleoside reverse oral hairy leukoplakia 360 Parkinson’s disease 251–252
transcriptase inhibitors other bacterial lesions 200 pathophysiology of primary
NSAIDS (non-steroidal antiinfl other lesions 202–203 neurological manifestations
ammatory drugs 375–376 ulcers 196t, 202f, 360 250–251
NTI (non-thyroidal illness) 275–276 origins and diversification of HIV PCNSL (primary central nervous system
nuclear pore, crossing 28 123–130 lymphoma) 455, 456, 457, 458
nucleic acid amplification tests (NAATs) deep roots 15–17 PCP see pneumocystis pneumonia
in chlamydia 475–476 genetic diversity in HIV-1 group M Pediatric AIDS Clinical Trials Group
in gonorrhea 473 subtypes 20–21 486–487
nucleic acid testing 125 geography of 18–19 pediatric treatment see children
nucleoside reverse transcriptase HIV/SIV nomenclature 17–18 PEL (primary effusion lymphoma) 458
inhibitors (NRTI) medical practice, unsafe 19–20 peliosis, bacillary 421, 423, 428
antiretroviral therapy 135, 136t, 141t timing 19 penciclovir 444–445
children and adolescents 515, 516t orolabial infection 441 penicillin 222, 240t, 555
complications of antiretroviral oropharyngeal candidiasis 359–360, Bartonella infections 426–427, 427t
therapy 181–184 363t, 364 pneumonias 314, 317, 318t
drug abuse 544–546 osseous bacillary angiomatosis 422, penicillin G in syphilis 469
drug resistance 155, 156–157, 156f 422f, 428 penicilliosis 196t
endocrine complications 279 osteomyelitis, vertebral 334 Penicillium 225, 378
hematological complications 183 osteonecrosis 280 Penicillium marneffei infection 225, 370,
hepatitis viral infection 417–418 osteopenia 280, 281, 527 389–394, 554
pharmacology 170t, 171 osteoporosis 277, 280–281, 527 clinical features 260–261, 391t, 392f
primary neurological manifestations ovarian function 282–283 diagnosis 392–393
253 oxacillin 315t, 318t differential diagnosis 392–393
see also abacavir; didanosine; oxazolidinones 341 epidemiology 389–390, 390f
emtricitabine; lamivudine; natural history 390–391
stavudine; tenofovir; zidovudine pathogenesis 390–391
P
NVP see nevirapine patient evaluation 392–393
nystatin 363t, 364 p24 antigen detection 84 treatment 393–394
paclitaxel 278, 460t PENTA (Paediatric European Network
PACTG (Pediatric AIDS Clinical Trials for Treatment of AIDS) 514t
O
Group) 486–487 pentamidine 223–224
obesity 283–284 Pan troglodytes see chimpanzee endocrine complications 275, 279,
ocular manifestations 207–216 Panama 224–225, 298t 280–281
anterior segment 208–209 pancreas 278–279 isethionate 309, 309t
drug-induced 214 antiretroviral and other therapies pneumocystis pneumonia 306, 310t,
epidemiology 207 278–279 314t, 436
neoplastic 213–214 glucose homeostasis alterations PEP see post-exposure prevention
neuroophthalmic 212–213 278–279 pericardial disease/pericarditis 267,
non-infectious retinal vasculopathy pathology 278 268b, 270–271, 378
207–208 treatment considerations 279 pericarditis, tuberculosis 333–334
posterior segment 209–212 pancreatic tuberculosis 278 periodontitis/periodontal disease 196t,
restricted movement 255 pancreatitis 182, 378 199, 360
toxoplasmosis 212–213, 398 pancytopenia 321 peripheral neuropathy, HIV-associated
odynophagia 237–238 pandemic 16f 250b, 255
ofloxacin 339 see also epidemiology; non-sterile perirectal abscess 243–244
OHL (oral hairy leukoplakia) 360 injections peritonitis, tuberculosus 333
oligospermia 282 panhypopituitarism 283 permethrin 220–221
onychomycosis 224 papillomavirus see human personality 261–262
oophoritis 282 papillomavirus pertussis vaccination 512
oral complications of HIV infection Paracoccidioides 378 PET (position emission tomography)
193–205 Paracoccidioides braziliense 243, 252, 400
bacterial 196t, 199, 200 275, 554 pharmacology of antiretroviral drugs
candidiasis 195–199 paracoccidiomycosis 557 169–175, 439
diagnosis and management 196t paradoxical inflammatory response see drug metabolism 171
gingivitis and periodontitis 199 IRIS pharmacokinetic definitions
lesions 196t paraplegia (spastic diplegia) 255 170–171, 170f
574
Index
drug transport proteins 171 frequency 313 fidelity 114

major drugs 169–170, 170t pneumococcal 313–314 oral ARV pre-exposure prophylaxis
optimaldosage 169 see also bacterial pneumonias; fungal 116
special populations 174–175 pneumonias; Pneumocystis sexual transmission 113–117,
traditional medicines 174 pneumonia; streptoccus 114b
see also antiretrovirals; ART/ARV; drug pneumonia STD screening and treatment 115
resistance; HAART pneumonitis 370, 380 toxoplasmic encephalitis 405–406
PHI (primary HIV-1 infection), pneumothorax 306 ‘treatment for prevention’ strategy
160–161 PNP (purine nucleoside phosphorylase) 116–117
phosphonoformic acid see foscarnet 171 vaccines 119
phosphorylation, intracellular 171 polio 553t see also mother-to-child transmission
phylogenetic tree 16f polycystic ovary syndrome 283 prevention
pigmentation disorders 219–220 polyenes 364 primaquine 309, 309t
pioglitazone 279 polymerase/polymerase chain reaction primary central nervous system
piperacillin 318t (PCR) 125, 126–128 lymphoma 457, 458
PIs see protease inhibitors polyradiculopathy 434–435 primary effusion lymphoma (PEL) 458
pituitary 283–284 PORN (progressive outer retinal primary HIV 219
antiretroviral therapy 284 necrosis) 210–212 primary infection 161
function changes 283 portal hypertension, non-cirrhotic 182 viral loads during 84–85
pathology 283 position emission tomography, see also acute infection
somatotropic axis 283–284 252, 400 primary neurological manifestations
placenta 485–486 posoconazole 363, 378–379 249–255
plasmablastic lymphoma 458 post-exposure prevention 118–119 epidemiology 250
pleocytosis 435 postnatal transmission prevention 486 HIV-1 associated vacuolar
Plesiomonas 554 postpartum period, mother-to-child myelopathy 255
pleural, tuberculosis 333 transmission prevention 488t, HIV-associated neurocognitive
PMBC (peripheral blood mononuclear 489t, 492t disorder (HAND) 251–253
cell) 510 potassium iodide 225 HIV neuropathy 254–255
PML (progressive multifocal PPIs (proton-pump inhibitors) pathophysiology, pathogenesis and
leukoencephalopathy) 261, 399 238–239 genetics 250–251
ocular manifestations 213 pravastatin 280 prime-boost concept 102
primary neurological manifestations pre-exposure prophylaxis 116, 524 PRO 140 antibody 26–27
249, 250b prednisone 293 PRO 542 inhibitor 25
PMTCT see mother-to-child pregnancy 175, 485–487, 495, 524 proctitis 243–244
transmission, prevention ART 141t, 144, 145 progressive multifocal
pneumococcal pneumonia 313–314 bacillary angiomatosis in 424 leukoencephalopathy see PML
Pneumocystis pneumonia (Pneumonia syphilis screening in 469 progressive outer retinal necrosis
jiroveci/carinii) 81, 297–311, toxoplasmic encephalitis 398, 210–212
298t, 314t, 380, 398 404–405 progressive resistance training 284
chest radiograph 305–306, 305f tuberculosis treatment and 338 proinflammatory cytokines 254
children and adolescents 509, 517 see also antenatal; children; mother- prolactin 283
choroidopathy (PCC) 212 to-child transmission prophylactic antiretroviral intervention
clinical presentation 298t, 305 preintegration complex (PIC) 28 and mother-to-child transmission
diagnosis 306–308, 317 premature birth infection 90 prevention 486–496
endocrine complications 283 prevalence of HIV infection 3–5 clinical trials 487–496, 488t,
epidemiology 297 prevention 113–120 489t, 492t
gastrointestinal disorders 243 abstinence 113–114 mechanisms of action 487
laboratory tests 305 Africa 113, 114, 115, 116–118 resistance to 497–498
management 433, 436 antiviral microbiocides 115–116 short and long-term safety of
prophylaxis 309–311, 310t, 517 Bartonella infections 429 496–497
risk factors for 297–305 behavioral prevention programs 117 prophylaxis
symptoms and signs 305 blood-borne transmission 114b, disseminated Mycobacterium avium
tests 306 117–119 complex 354–355
travel, international 554 candida 365 post-exposure 118–119
treatment 308–309, 309t circumcision, medical male 115 travel, international 554
pneumonia 313–322, 538t, 558 combination 119 see also condoms
bacterial 555 condoms 114 prostatitis 378
pneumococcal 553t, 554 counseling and testing 114 prostitution see commercial sex
575
Index
protease inhibitors 253 R resource-poor settings 149

antiretroviral therapy 134–135, respiratory distress syndrome 398
136t, 145 R5 viruses 90 respiratory tract infections 558
-associated dyslipidemia 268b R5-tropic virions 25–26 travel, international 555
drug resistance 155, 159 rabies 553t see also bacillary angiomatosis
endocrine complications 278–279 radiculomyelitis 249, 250b retina
gastrointestinal disorders 238–239 radiography detachment 210–212
hepatitis viral infection 417 chest 127t, 313–314, 317, necrosis, acute 212
pharmacology 169, 170t, 172 320–321, 378 microvasculopathy, non-infectious
therapy 172 pneumocystis pneumonia 305–306, 207–208
tuberculosis 342 305f retinitis 207, 209–210, 209f, 378, 436,
proteinuria 287, 288, 289, tuberculosis 325, 332f 437–438
290–291, 290b radiotherapy/radiology 400, 459 Rev (regulator of viral gene expression)
prothionamide 340t raltegravir (RAL) 145–146, 544t, 547 26f
proton-pump inhibitors 238–239 RANTES cehmokine 26–27 reverse transcriptase inhibitors 134,
PRT (progressive resistance training) Rasmussen’s aneurysm 331 136t, 157–159
284 RAU (recurrent aphthous ulcers 196t, 202f see also nucleoside reverse
pseudomembranous candidiasis, recombinants/recombination transcriptase inhibitors
196t, 197f alpha-interferons 414 Reverse Transcriptase Polymerase Chain
Pseudomonas aeruginosa 313, 314t genetic 17 reaction (RT-PCR) 126–128
pneumonia 313 recrudescence of infection see IRIS Rhodococcus equi 275, 314t
psoriasis 220, 226 recurrent aphthous ulcers 196t, 202f ribavirin 415, 416–417, 538t
psychiatric barriers and international regimens of antiretroviral therapy 141t rickettsia 558
AIDS epidemic 257–265 components 135 rifabutin 214, 339t
chronic mental illness 258, clinical applications 146–147 drug abuse 547
259–260 overview of 135–146 endocrine complications 283
mood disorders 260 re-infection by other partner 93 Mycobacterium avium complex 351,
neurocognitive disorders 260–261 renal complications 287–294 352, 353, 353t, 355
personality and temperament clinical features 290–291 tuberculosis 339t, 341, 342
261–262 course and outcome 293–294 rifampicin/rifampin 221, 341, 342, 555
psychopharmacology 262–264, diagnosis and differential diagnosis Bartonella infections 427–428, 427t
262t 290b, 290f, 291 drug abuse 538t, 547
substance abuse 261 epidemiology 287–289 endocrine complications 276, 283
psychomotor slowing/retardation global health care/delivery 287 Mycobacterium avium complex
251–252 impairment 174 351–352, 353
psychopharmacology 262–264, 262t insufficiency 378 tuberculosis 336, 337, 338, 339, 339t,
psychosis 251 management 292b 340–341, 342, 343
psychotherapy 264 natural history 289 rifapentine 341
pulmonary disease nephritis, interstitial 289 rifaximin 555
cytomegalovirus infections 436 nephrolithiasis 185 rilpivirine 145, 544t
function tests 306 nephropathy 538t risk
hypertension 268b, 271 nephrosclerosis 289 drug abuse 547
and toxoplasmic encephalitis 398 pathology 289–290 education to avoid 93
pyogenic granuloma 425–426 pathogenesis 289 per exposure, low 89
pyrazinamide 336, 337–338, 338t, 339, replacement therapy 293 ritonavir (RTV) 185, 243–244, 264,
339t, 538t safety 181 279, 353t
pyridoxine in tuberculosis 339 screening 292f antiretroviral therapy 136t, 141t, 145
pyrimethamine treatment 291–293 children and adolescents 515, 516t
sulfadoxine-pyrimethamine 405t renal tuberculosis 334 drug abuse 544t
toxoplasmic encephalitis 403, 403t, replacement therapy 276–277 endocrine complications 276, 277,
404, 404t replication, viral 126–129 278–279, 280, 283
pyrimidine 416–417 reproductive health hepatitis 417
antiretroviral therapy 282, 283 pharmacology 170, 170t, 171,
fertility 282, 283 172–173
Q
men 281–282 travel, international 556
quality assurance/control 129 sex hormone changes 281, 282–283 tuberculosis 341, 342
quantitative plasma RNA 511 treatment considerations 282, 283 women 527
quinolone in gonorrhea 472–473 women 282–283 rituximab 457, 458
576
Index
RNA sexually transmitted diseases/infections sparfloxacin 351

flavovirus see hepatitis C (STDs/STIs) 467–480 spastic diplegia see paraplegia
genome-wide scanning 68 acute infection 81 spermicides 525
pro-viral 82 biology of HIV-1 transmission 89–90, spinothalamic sensory deficits 255
testing 126–128 91–92 splenic bacillary peliosis 423, 428
rotavirus 241 test for 127t splenomegaly 422
RRT (renal replacement therapy) 293 screening and treatment 115 sporotrichosis 225
RTIs see reverse transcriptase inhibitors travel, international 551 squamous carcinoma 196t, 213–214,
RTV see ritonavir women and special issues 523t, 524 243–244, 456t
rubella vaccine, avoiding 512 SHBG (sex hormone-binding globulin) squamous intraepithelial lesions (SILs)
Russia and Russian Federation/former 281 461
Soviet Union 9 Shigella 241, 243, 436 squamous intraepithelial neoplasia
Rwanda 298t shingles see varicella zoster 243–244
sildenafil (viagra) 282 SQV see saquinavir
simian origins see origins SSKI (potassium iodide) 225
S
see also SIV SSRI 262t
safety simian-human immunodeficiency SNRI 262t
blood 118 viruses (SHIV) 99 Staphylococcus aureus 272
mother-to-child transmission simvastatin 280 drug abuse 538t
prevention 496–497 single nucleotide polymorphisms, pneumonia 313, 314t, 315t, 316,
renal 181 63, 91 318t, 538t
salivary gland disease 196t, 203 sinusitis 558 skin infections 221
Salmonella and salmonellosis 241, 243, SIV (simian immunodeficiency virus) STARHS technique 126
554 15–16, 16f, 17, 52, 92, 99 statins 187–188, 280
SAM (S-adenosylmethionine) 307–308 skin disorders 219–234, 557 stavudine (D4T)
saps (secreted aspartic proteinases) sleep disturbance 251 antiretroviral therapy 136t, 144, 149
365 SMX see trimethoprim(TMP)- children and adolescents 516t
saquinavir (SQV) 240t, 342, 353t sulfamethoxazole drug abuse 544t
antiretroviral therapy 136t, 145, SNPs (single nucleotide hepatitis viral infection 416–418
219–220 polymorphisms) 63, 91 hyperlactatemia 182
children and adolescents 516t somatotropic axis, pituitary 283–284 low cost 149
drug abuse 544t source partner see host mother-to-child transmission
pharmacology 170t, 172, 173t, South Africa 17–18, 226, 355 prevention 499t
174, 174t adherence to therapy 298t pancreatitis 182
schistosomiasis 558 mother-to-child transmission pharmacology 170t, 171, 173t,
screening 118 prevention 488t, 489t 174–175
seborrheic dermatitis 220, 226–227 renal complications 288, 289–290, primary neurological manifestations
secreted aspartic proteinases 365 292–294 253, 254
seizures 251 tuberculosis 329, 343 resistance to 158, 162
selenium 270b South America see Latin America STDs see sexually-transmitted diseases
Senegal, adherence to therapy 298t South and Southeast Asia 298t sterilization, inadequate see non-sterile
septic shock syndrome 321 dermatology 220, 225 injections
serology 82–84, 127t fungal infections 369–371, 376 steroids 293, 369, 375–376
Bartonella infections 426 global epidemiology 11 Stevens-Johnson syndrome 360
toxoplasmic encephalitis 399 mother-to-child transmission stibogluconate 556
sex hormone changes 281, 282–283 prevention 488t, 489t, 495 stomatitis
sex hormone-binding globulin 281 Mycobacterium avium complex 355 recurrent aphthous 223
sex workers see commercial sex workers penicillium marneffei infection necrotizing 196t
sexual abuse 517–518 389–390 streptoccus/streptoccal pneumonia 272,
sexual dysfunction 281 prevention 117–118 313, 314, 315t, 317, 555
sexual transmission 6, 113–117, 114b psychiatric problems 257–258, Streptococcus pneumoniae 272, 313, 314,
antiretroviral therapy 149 260, 261 315t, 317
behaviour change programs 117 travel, international 557 Streptococcus viridans 272
biology of 89–90 tuberculosis 327, 330–331 streptomycin 336, 338, 338t, 339, 339t
heterosexual 461, 518 see also India; Thailand Soviet Union, Strongyloides stercoralis 436
safe 552b former see Russia sub-Saharan Africa see Africa
sex workers, immune 53 SP (sulfadoxine-pyrimethamine) 405t substance users see drug abuse
see also male-to-male Spain 223–224 subtype diversity 99
577
Index
subunit vaccines 102 tenesmus 241 TMC114 see darunavir

Subutex/Suboxone see buprenorphine tenofovir (viread/TDF) 115, 279, 414 TMP see trimethoprim
sulfadiazine 403, 403t, 404t antiretroviral therap 135, 136t, 141t TNX-355 inhibitor 25
sulfamethoxazole see trimethoprim children and adolescents 515, 516t tobramycin 316
sulfiram 220–221 complications 182, 183 toll-like receptors (TLRs) 64t, 328
sulfonamide 315t, 403 drug abuse 544t toxicity
superinfection 80, 99 pharmacology 170t, 173t, 174t management of infections 438–439
Switzerland 288, 555 renal safety 181 to selected drugs 185–186
syndromic management 477–479, 478f resistance to 158–159 Toxoplasma 271b
genital ulcers 477 terbinafine 224 Toxoplasma gondii 270b, 277,
urethral discharge 478 testicular pathology 281 442–443, 517
vaginal discharge 479 testosterone 281, 282, 283 diagnosis 399–400, 399b
syphilis 81, 210, 212, 433–434, 435, tetanus vaccination 512 differential diagnosis 401
467–470 tetherin 36 endocrine complications 277, 281
anal condylomata 469f tetracyclic antidepressants 262t histopathology 400–401
clinical features 468 tetracycline 318t management 401–406, 402f
epidemiology 467 Bartonella infections 426–428, 427t see also toxoplasmic encephalitis;
gastrointestinal disorders 240–241 dermatology 221, 222 toxoplasmosis
gummatous 468 tetragenesis 439 toxoplasmic encephalitis 249, 397–409
natural history, pathogenesis and tetraglycine hydroperiodide 554–555 clinical presentation 397–398
pathology 467 Thailand 18, 97, 298t diagnosis 399–400
neurosyphilis 250b, 468, 469 dermatology 220, 223, 225 differential diagnosis 401
palmar rash 468, 468f fungal infections 355, 374 histopathology 400–401
patient evaluation, diagnosis and global epidemiology 11 discontinuation of prophylaxis 406
differential diagnosis 468–469 mother-to-child transmission maintenance 403t, 404
penile chancre 468, 468f prevention 487, 488t, 489t, 495 management 401–406, 402f
skin disorders 222–223 Penicillium marneffei infection 389, prevention 405–406
treatment 469–470, 470t 390–391, 391t, 393–394, 393t primary therapy 403, 403t
systemic therapy for neoplasia 460–461 travel, international 555, 557 toxoplasmosis 127t, 240–241, 261,
vaccine trial 99–100, 101 314t, 397–409, 433–434, 435
thalidomide 220, 223, 227, 238, 375–376 clinical presentation 397–398
T
thiaxetazone 341 congenital, women and 398
T-cells thrombocytopenia 424, 438–439 diagnosis 399–400, 399b
central memory (TCM) cells 47–48 thrush see candidiasis differential diagnosis 401
effector memory (TEM) cells 47–48 thymidine analog mutation 156–157, discontinuation of prophylaxis 406
escape from control 51–52 158–159, 162 endocrine complications 278, 283
loss mechanism 60–61 thyroglobulin antibody 276 epidemiology 397
see also CD4 T-cells; CD8 T-cells thyroid 275–277 fungal infections 369, 370–371
T-helper cell dysfunction 270 alterations in function 275–276, histopathology 400–401
T lymphocytes 91, 92, 125–126 276t maintenance 404, 404t
see also CTLs antiretroviral and other therapies 276 management 401–406, 402f
T20 inhibitor 27 autoimmune diseases 276 ocular 212, 213, 398
Taiwan 298t, 389 hormone 270b see also Toxoplasma gondii;
TAK 220 small-molecule antagonist hormone-binding globulin (TBG) 276 toxoplasmic encephalitis
26–27 pathology 275 TPV see tipranavir
TAMs (thymidine analog mutation) peroxidase antibody 276 traditional remedies 174
156–157, 158–159, 162 -stimulating hormone (TSH) 276–277 transcriptional events, molecular
Tanzania 293 treatment considerations 276–277 biology of HIV 29–31, 30f
mother-to-child transmission women, dysfunction 527 transmission of HIV
prevention 489t thyrotropin-releasing hormones (GnRH global epidemiology 5–6
Pneumocystis pneumonia 298t and TRH) 283 to women 522–525
target cells and virus-host dynamics 92 ticarcillin 318t see also biology; blood transfusions;
Tat (transcriptional activator) 26f ticonazole 363t drug abuse, intravenous; drug
TD (traveller’s diarrhea) 554, 558 tinea infection 224 resistance; mother-to-child;
TDF see tenofovir tinidazole in trichomoniasis 477 sexual transmission and under
telbivudine 414, 538t tipranavir (aprivus/TPV) 136t, 145, 170t Africa, Asia and Eastern Europe
telithromycin 318t children and adolescents 516t transplants, kidney 292b, 293
temperament 261–262 drug abuse 544t, 547 travel, international 551–558
578
Index
emerging and re-emerging infections clinical aspects 329–334 United States see North America
555–556 control 345 urethral discharge, syndromic
endemic mycoses 557 cutaneous 223 management 478, 478f
enteric infections 554–555 diagnosis 317, 334–337 urethritis, non-gonoccocal 475f
fever 558 epidemiology 325–327, 326f uveitis 208, 209, 210, 211f, 212, 214
general considerations 551–554 extrapulmonary 331–334
new HIV infections 557–558 gastrointestinal 333
V
parasitic infections 556–557 lymphadenitis 325
prophylaxis 554 meningitis 333 V106M 160
respiratory infections 555 miliary 331–333 vaccination 313, 344–345
skin disorders 557 mortality 343–344 infants 512
vaccinations 553–554 ocular manifestations 212 prospects for 45, 53–54, 93
‘treatment for prevention’ strategy oral lesions 196t travel, international 553–554, 553t
116–117 pancreatic 278 under development 119
Treponema pallidum 243 pathogenesis 327–329 see also vaccine design
Treponema pallidum pallidum 467 pericarditis 333–334 vaccine design 45–56
Trichomonas vaginalis 476–477, 478, 479 peritonitis 333 challenges 98–101
trichomoniasis 476–477 pleural 333 DNA and viral vectors 102
clinical features 477 prevention 344–345 human trials 101–107, 103t
epidemiology 476–477 primary 329–330 pathogenesis of infection 98
natural history, pathogenesis, and with complications 330 transmitted viruses 98
pathology 477 occult 329–330 vaccine concepts 102
patient evaluation, diagnosis, and uncomplicated 330 vaccinia virus 102
differential diagnosis 477 pulmonary 330–331 vacuolar myelopathy, HIV-1
treatment 476t, 477 renal 334 associated 255
tricyclic antidepressants 262t secondary 330–334 vaginal discharge, syndromic
triglyceride synthesis, increased 268b timing of ART initiation 343 management 478f, 479
TRIM (tripartite motif) protein 35–36, travel, international 551, 555, 558 vaginal infections see vulvovaginal
35f, 64t treatment 327–329, 338t, 339t, 340t valacyclovir (Valtrex) 212
trimethoprim (TMP) 279, 280–281, see also Mycobacterium tuberculosis hepatitis viral infection 444, 444t
283, 309t Tunisia 298t in herpes simplex virus 472, 472t
trimethoprim (TMP)-sulfamethoxazole typhoid 553t, 558 management of infections 443, 444,
(SMX) 212, 279, 297, 427–428, 444t
427t, 511 valganciclovir
U
dermatology 219–220, 221, 223 in cytomegalovirus infection 434t
gastrointestinal disorders 243 Uganda 250, 289 gastrointestinal disorders 238, 243
pneumonias 309t, 310t, 314, 315t, dermatology 220 management of infections 437–439,
316, 318t fungal infections 370, 371, 372 449
toxoplasmic encephalitis 403, 403t, 405 global epidemiology 8, 298t ocular manifestations 210
travel, international 554 mother-to-child transmission Valtrex see valacyclovir
Trinidad 223 prevention 488t, 492t vancomycin 221, 243, 315t, 316, 318t
trypanosomiasis 558 psychiatric problems 258–259, 260 varicella zoster virus (shingles) 249,
TSH see thyroid-stimulating hormone tuberculosis 327, 332f 250b, 433–434
TST (tuberculin skin test) 334 ulcers/ulcerative colitis complications 448
tuberculosis 52–53, 325–346, 435 cytomegalovirus 200 dermatology 225
active disease 328–329, 335–337 esophageal 237–238, 239f drug-resistant infection 449
antigen detection tests 337 gastric 237–238 encephalitis 261
chest radiography 335 genital 524 management of infections 448–449,
diagnosis 335–337 idiopathic esophageal (IEU) 448t
line probe assays (LPAs) 336 237–238, 239f ocular manifestations 208
mycobacterial culture 336 mouth/aphthous/oral 196t, 202f, 360 prevention 449
nuclei acid amplification tests periodontitis, necrotizing 199 primary infections 447
(NAATs) 336 ultrasound 283, 290–291 recurrent 447–448
phage-based assays 337 UNAIDS (Joint United Nations vaccine 512
serological antibody detection tests Programme on HIV/AIDS) 3–4, vascular proliferative lesions 421
337 119, 249 vasculitis 436
serum biomarkers 337 map of global prevalence 7f ventricular enlargement 252f
sputum microscopy 335–336 United Kingdom 220–221 ventriculoencephalitis 434, 435
579
Index
vertebral osteomyelitis 334 voluntary counselling and testingsee mother-to-child transmission

vertical transmission see mother-to-child VCT prevention 499t, 501
transmission voriconazole and fungal infections 375, pneumocystis pneumonia 297, 308f
viagra see sildenafil 378–379, 381–382 psychiatric problems 257, 264
Vibrio 554 hypoglycemia 279 tuberculosis 326f, 327, 338t
Vietnam 389 candida 363, 363t, 364 WT see wild-type infections
Vif (viral infectivity factor) 26f, 62, Vpr (viral protein R) 26f, 27–28, 63
134–135 Vpu (viral protein U) 26f, 63
X
vinblasine, intralesiona 460 vulvovaginal infections
vincristine 460t candidiasis 361, 363t, 364–365, 529 xerosis 227
vinorelbine 460, 460t VZV see varicella zoster virus x-rays see radiography
viral and host determinants of HIV-1
biological phenotype 61–63
W Y
CD4 T-cell loss mechanism 60–61
disease progression 59–74 warts 196t, 201, 201f, 524 Y181C/I (EFV mutation) 144
genome-wide association studies wasting syndrome 284 see malnutrition yellow fever 553t, 554
67–68 weight loss 174–175, 241, 317, 436 Yersinia 554
genome-wide scanning 68 West Indies see Caribbean basin
host factors affecting 64t Western blot test 124–125
host factors influencing viral load 63–67
Z
WHO see World Health Organization
immune response, specific antiviral wild-type (WT) infections 160–162 Zaire 288
59–60 window period 77, 82 zalcitabine (ddC) 158–159, 170t, 254
viral diseases and infections 271b women 521–535 drug abuse 544t
anorectal 243–244 antiretroviral treatment 530–531 hepatitis viral infection 416–417
oral 196t body habitus and metabolic changes Zambia 298t, 486
see also cytomegalovirus; herpes 527 zidovudine (ZDV)
viral load clinical manifestations 526–528 adverse reactions to 148
during primary infection 84–85 epidemiology 521 antiretroviral therapy 136t, 141t, 144
testing 126–128 hepatitis viral infection 413 cardiovascular complications 270
viral vectors, vaccines and 102 HIV prevalence in 89 children and adolescents 512, 516t
viread see tenofovir HIV transmission 522–525 dermatology 219–220, 226
viremia 133–134, 135–144, 147, 413, hormones 91–92 drug abuse 544t
414, 457 natural history 525–526 endocrine complications 282
virions 27 reproductive health 282–283 HAD 252–253
fusion 27 women-specific conditions 528–530 hepatitis viral infection 416–417
new, assembly and budding of 32f, see also breast-feeding; cervical mother-to-child transmission
33f, 34 disorders; children; commercial prevention 486, 488t, 489t, 492t
virus-like particles (VLP) 103–107 sex workers; mother-to-child; mutations and drug resistance
vistide see cidofovir pregnancy; vulvovaginal 158–159, 160
visual inspection with acetic acid (VIA) infections pharmacology 170t, 171
461 World Health Organization renal complications 289, 291, 293
vitamin D deficiencyt, bone health and ARV therapy 149 tuberculosis 341
188 case definition 5t Zimbabwe 8, 160, 289
vitamins children and adolescents 514t mother-to-child transmission
D analogs 226 classification of established infection prevention 486, 492t
B12 270b 5t pneumocystis pneumonia 298t
deficiency 255 clinical staging 4, 4t zovirax see acyclovir
vitreitis/vitritis 212 laboratory testing 124, 128–129 ZR59 HIV-1 sequence 19
580
Preface
The rapid pace of change in HIV/AIDS management is an appropriate challenge to the ongoing
revolution in medical publishing and information exchange. Sande’s HIV/AIDS Medicine: Medical
Management of AIDS 2013 is a thorough revision of its predecessor, Global AIDS Management, pub-
lished in 2007, now named in perpetual recognition of the pioneering efforts of Merle Sande,
MD, one of the first edition’s co-editors and a champion of AIDS care worldwide. The current book
similarly addresses HIV management in the resource-rich “North” and that in the resource-
constrained “South”. Appreciating the challenge of medical care in both settings and the differing
available resources, Sande’s HIV/AIDS Medicine is now being offered in two overlapping but distinct
versions. Each has content focused on the regional nature of disease and available resources and on an
appropriate format of content, delivery mechanism, and cost.
This version of Sande’s HIV/AIDS Medicine aimed at practitioners in settings with more abundant
care resources is published in an ebook format operable across all common devices, and as a soft-
bound book that is printed on demand to reduce environmental impact, reduce costs, and facilitate
rapid updating. This version will be revised annually, allowing an unprecedented currency needed
given the rapid developments in our scientific understanding of HIV pathogenesis and in our treat-
ment options. We are particularly hoping that the ebook format will be widely used to move the very
current and practical content of the book as close to the bedside as possible, increasing the impact of
the book in improving HIV/AIDS care regardless of the multiple sites in which that care takes place.
Electronic publishing combined with frequent revisions and a modest cost should help to ensure con-
tinuing wide use of this important textbook and day-to-day application in direct patient care.
While excited at the innovations in publication format, the editors of Sande’s HIV/AIDS Medicine are
equally proud of the book’s content. Each editor has worked directly with chapter authors deeply ex-
pert in their field and focused on providing an authoritative yet clinically directed and practical review
of a wide range of topics. The book begins with the fundamental underpinnings of HIV pathogenesis
and epidemiology. It moves on to consider the treatment of HIV infection itself as well as the diag-
nosis and management of common co-morbidities, including the opportunistic diseases well known
to be HIV induced, as well as conditions such as cardiovascular disease arising from the chronic dis-
ease that HIV infection has increasingly become in settings where early and continuous antiretroviral
therapy is possible.
The editors applaud the vision of our publisher, Elsevier, in embracing this ground-breaking project
and our authors in eagerly accepting the task of updating their contributions and adjusting them to
the new publication format. We believe this will become the standard way textbooks will be distrib-
uted in the future and are excited that, once again, HIV and AIDS will lead the way.
Paul Volberding
Warner Greene
Joep Lange
Joel Gallant
Nelson Sewankambo
2012
vii
Sande’s HIV/AIDS Medicine
Commissioning Editor: Sue Hodgson/Belinda Kuhn
Development Editor: Poppy Garraway
Editorial Assistant: Sam Crowe
Project Manager: Andrew Riley
Design: Charles Gray/Miles Hitchen
Illustration Manager: Bruce Hogarth
Illustrator: Antbits Ltd
Marketing Manager (UK/USA): Carla Holloway
Sande’s HIV/AIDS
Medicine
Medical Management of AIDS 2013
Second Edition
Paul A. Volberding MD
Professor, Department of Medicine, University of California San Francisco, Director, UCSF AIDS Research
Institute, Director of Research, UCSF Global Health Sciences, Co-Director, UCSF-GIVI Center for AIDS
Research, San Francisco, CA, USA
Warner C. Greene MD, PhD

Director, Gladstone Institute of Virology and Immunology, President, Accordia Global Health Foundation,
Nick and Sue Hellmann Distinguished Professor of Translational Medicine, Professor of Medicine,
Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA
Joep M. A. Lange MD, PhD

Professor of Medicine, Department of Global Health, Academic Medical Center, University of Amsterdam,
Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
Joel E. Gallant MD, MPH

Professor of Medicine and Epidemiology, Associate Director, Johns Hopkins AIDS Service, Division of Infectious
Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Nelson Sewankambo MBChB, M.Med FRCP

Principal, College of Health Sciences, Makerere University, Mulago Hospital, Kampala, Uganda

Sande's HIV - AIDS Medicine (PDFDrive)

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Chapter |1|

The global epidemiology of HIV/AIDS

global epidemic and shows great genetic diversity with nine

Table 1.1b WHO immunological classification for established HIV infection

HIV-ASSOCIATED AGE-RELATED CD4 VALUES

< 11 mo 12–35 mo 36–59 mo  5 yrs

None/not significant > 35 > 30 > 25 > 500

Mild 30–35 25–30 20–25 350–499

Advanced 25–30 20–25 15–20 200–349

Severe < 25 < 20 < 15 < 200 or < 15%

Countries with established national HIV case surveil-

No reports of injecting drug use identified

Figure 1.1 Global prevalence of injection drug use.

Figure 1.2 Global prevalence of HIV, 2009.

recognition is that sub-Saharan Africa also has an epidemic West

East North America

Central and South America

virus (SIV). The genealogical patterns that emerge from

HIV-1,SIVgor, and SIVcpz

SIVgsn SIVIst SIVsun

SIVmon SIVreg SIVbcm SIVolc

by SIV and HIV. A more difficult challenge still confronts

Ltr Vif Vpu Env Nef

Gag Pol Vpr Rev Tat

Once inside the nucleus, the viral PIC establishes a func-

Integrase (IN) Envelope

CD4 receptor LEDGF/p75

Tat Nef (?)

characteristic marks of silent heterochromatin, such as ly-

CTD endogenous retroelements. Thus, the benefits of reactivat-

Rev Tat AP-2

Endophilin Lipid raft

Myristylation AIP-1 Alix

Gag EAP20 CHMP6 CHMP2A,B

SCF-Iike EloB Cul5 Rbx

of viral transcripts are under study [188]. As a proof of prin-

infection. Immunity 2002;16 immunodeficiency virus type Acad Sci U S A 1994;91

of acute viral infections (such as influenza, rotavirus, or

Genital epidermaI Genital T cell B cell zone

Time from infection (months to years)

Epithelial Paneth cell

macaques by B cell depletion [3–5], albeit not in all studies

macaques generally leads to high virus loads, declining

Vpr individuals, as uninfected individuals without CCR5 func-

Vpu Human leukocyte antigens

Epidemiology and biology of HIV infection

m303 Truncation, no Protection from HIV-1 infection Strong [153]

CCR5P1 Increased expression Accelerated disease progression Strong [154]

Delayed disease progression Controversial [160–164]

CXCR6 Secondary rs2234358 Delayed disease progression Weak [165]

CXCR1 Il 8 receptor Haplotype Ha Delayed disease progression Weak [166]

CX3CR1 Secondary V249I Accelerated or delayed disease Controversial [167–170]

T280M Accelerated disease progression Controversial [167–172]

Accelerated disease progression Controversial [179–182]

CXCL12 CXCR4 ligand 3’A Accelerated or delayed disease Controversial [183–186]

Delayed disease progression Controversial [187–189]

Viral and host determinants of HIV-1 disease progression

TLR7 PAMP Gln11Leu Accelerated disease progression Weak [192]

HIV dependency factors

< 11 mo 12–35 mo 36–59 mo 5 yrs