HIV PREVENTION AND TREATMENT

HIV in mothers and children What’s new?

Melanie M Rosenvinge
C Use of maternal viral load to guide start-time for anti-retroviral
Katja Doerholt therapy (ART) in pregnancy
C If a woman conceives while taking an effective ART regimen, the
balance of risk is generally thought to be in favour of continuing
the successful regimen through the pregnancy rather than
Abstract
changing it
There has been a dramatic fall in the rate of mother-to-child transmissions
C Where the benefits of breastfeeding outweigh the risks of for-
(MTCTs) of human immunodeficiency virus (HIV) since the introduction of
mula feeding, studies show that mother-to-child transmission is
universal HIV testing in antenatal clinics in the UK. Currently in the UK,
reduced if the mother continues to take ART, or ART prophylaxis
less than 1% of infants born to women found to be HIV-positive before
is given to the infant until after breastfeeding has finished
delivery will become infected. Maternal anti-retroviral therapy (ART) is
C ART is now started in children at higher CD4 counts compared
commenced in accordance with the mother’s immune status and viral
to historic guidelines
load, with the aim of achieving an undetectable viral load by delivery.
C Late diagnosis of perinatally HIV-infected adolescents is
Replacement feeding effectively eliminates postnatal MTCT but, where
increasingly reported; they are often clinically well but have low
this is not safe, studies have shown that continuing ART for mothers or
CD4 counts.
their infants until after breastfeeding has ceased can further reduce trans-
mission. Access to effective ARTstrategies in the prevention of MTCT in low-
and middle-income countries has improved but is still only approximately
50%. ART is now initiated earlier in children and has significantly reduced diagnosis is made before delivery, and three-quarters of these are
mortality and morbidity with perinatally HIV-infected children growing up aware of their HIV status before becoming pregnant.1 As a
and transitioning into adult care. Unfortunately, there are still serious diffi- consequence, only 30e40 children are perinatally infected with
culties surrounding access to paediatric formulations and adequate diag- HIV each year in the UK, with fewer than 10 transmissions
nostics for children in resource-poor settings. Hypervigilance for the occurring where the mother was found to have HIV before de-
potential long-term toxicities of ART in children is particularly important, livery. The mother’s HIV status may remain unknown if she de-
as treatment initiated at a young age is currently a lifelong commitment. clines screening, accesses antenatal services late or becomes
infected with HIV during pregnancy/breastfeeding.1 By contrast,
Keywords anti-retroviral therapy; breastfeeding; HIV; mother-to-child in low- and middle-income countries, only an estimated 35% of
transmission (MTCT); perinatal; pregnancy; prevention pregnant women underwent HIV testing and counselling in 2010,
with 48% of HIV-positive pregnant women being treated with the
most effective PMTCT regimens.2 Hence, in 2011, approximately
330,000 children were newly infected with HIV worldwide.
Although this represents a decline of 43% since 2003,3 there is
Prevention of mother-to-child transmission (PMTCT) clearly much more to be achieved in this area.

Introduction
HIV transmission
Universal screening for HIV infection in all antenatal units in the
Without any interventions the risk of MTCT is thought to be
UK, introduced in 2003, has dramatically reduced MTCT. In 2011,
between 20 and 40%, depending on the population. The most
684,510 pregnant women (97%) were screened for HIV in En-
striking risk factor is the maternal viral load (VL). If this is un-
gland. In approximately 95% of HIV-positive pregnant women, the
detectable at delivery the risk of MTCT is 0.1% (Table 1). The
routes of transmission are as follows.

Melanie M Rosenvinge MA MBBS MRCP Dip HIV DTM&H Dip GUM DFFP is a Intrauterine: in utero infection is more common towards the end
Consultant in Genitourinary & HIV Medicine at St George’s Hospital, of pregnancy and may be associated with placental disruption by
London, UK. Conflicts of interest: she has received reimbursement of chorioamnionitis.
expenses incurred whilst attending conferences from Abbott,
Boehringer Ingelheim, Bristol Myers Squibb Pharmaceuticals, Gilead Intrapartum: transmission could occur via direct contact with
Sciences, MSD, Janssen and Viiv. She has also received fees for infectious maternal blood and genital secretions during birth or
speaking from Janssen and two research grants from Gilead Sciences. alternatively maternalefetal micro-transfusion may occur during
contractions. Prolonged labour and rupture of membranes rupture
Katja Doerholt MD MRCPCH MSc Epi is a Consultant in Paediatric Infectious may increase the risk of MTCT. Pre-labour caesarean section
Diseases and HIV at St. George’s Hospital, London, UK. She has mainly (PLCS) alone has been shown to reduce the risk of HIV trans-
trained in the UK, but also worked in other European and central mission by 80%.4 This is usually performed at 38e39 weeks.
African countries. She completed a Masters in Epidemiology at the
London School of Hygiene and Tropical Medicine in 2004. Research During lactation: breastfeeding approximately doubles the
interests are paediatric HIV, pharmacovigilance and antimicrobial use in MTCT rate (36.7% compared to 20.5% who were formula-fed)
children. Conflicts of interest: none declared. (Table 1).5

MEDICINE 41:8 461 Ó 2013 Elsevier Ltd. All rights reserved.

Downloaded for prasandhya astagiri ([email protected]) at Universitas Indonesia from ClinicalKey.com by Elsevier on September 10, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 HIV PREVENTION AND TREATMENT

associated with the development of a high rate of resistance,

Low rates of mother-to-child transmission of HIV: UK & compromising the mother’s future ART options.10
Ireland 2000e2006 (Townsend CL et al. AIDS 2008; 22:
973e981) Infant post-exposure prophylaxis (PEP): all infants should
receive PEP. Where the maternal viral load is under 50 copies/ml
Group Number of transmissions MTCT
at delivery, the infant should receive zidovudine monotherapy
rate (%)
for 4 weeks. Where it is more than 50 copies/ml, then a three-
drug regimen should be initiated. PEP should be given ideally
Overall 61/5151 1.2
within 2 hours of birth (<72 hours) and continued for 4 weeks
More than 14 days of cART 40/4864 0.8
post-partum. Options may be reduced in pre-term neonates
AZT þ PLCS 0/464 0.0
where oral absorption can be difficult, toxicities are more likely
cART þ PLCS 16/2286 0.7
and zidovudine is the only intravenous drug widely available.
cART þ SVD 4/559 0.7
VL <50 copies/ml at 3/2117 (*2 with evidence 0.1
delivery of in utero transmission) Mode of delivery: where a mother’s viral load is under 50
copies/ml at delivery, there is no advantage of PLCS over vaginal
AZT, zidovudine; cART, combination anti-retroviral therapy; CI, confidence in- delivery. If viral load is over 400 copies/ml at 36 weeks, then a
terval; HIV, human immunodeficiency virus; MTCT, mpther-to-child transmis- PLCS is recommended. For low-level viraemia, the decision will
sion; PLCS, planned lower caesarean section; SVD, spontaneous vaginal
delivery; VL, viral load. depend on length of time on treatment, trajectory of viral load
(Copyright of National Study of HIV in Pregnancy and Childhood. Reproduced and maternal adherence to ARVs.
with kind permission. www.ucl.ac.uk/nshpc/slides)

Feeding: replacement feeding eliminates postnatal MTCT but it is

Table 1
an option only where it is safe for the infant. Where formula
feeding is not advised, the WHO recommends exclusive breast-
Current interventions to reduce transmission feeding for 6 months, then continued breastfeeding until 12
Anti-retroviral therapy (ART): what ART is chosen and when it is months, stopped gradually over 1 month.11 ART should be
started depends on the mother’s treatment history, whether they continued for the mother or child during the breastfeeding period
have conceived while taking medication, how much is known about as it significantly reduces transmission.12,13 In the UK, if the
the safety of the drug regimen, their baseline viral load and when mother is very keen to breastfeed and has an undetectable viral
they first present. The aim is to prevent transmission whilst also load with high adherence to cART, she should be counselled
avoiding maternal/fetal toxicity and compromising future maternal thoroughly regarding the risks involved. If she decides to
options of therapy. The following advice is based on the UK 2012 breastfeed, she should be closely supported with frequent
British HIV Association (BHIVA) guidelines.6 In low-income set- monitoring of her viral load and additional testing of her baby.
tings, decisions will be more affected by the available resources.
Safety of ARV drugs
When to start ART in pregnancy: women who need ART for their Whilst prospective safety data on the use of ART in pregnancy is
own health should commence cART (combination anti-retroviral limited, it is generally accepted that there is no increase above
therapy) as soon as possible. Women should commence tempo- the expected background prevalence of defects for neonates
rary ART by 24 weeks and ideally by the beginning of the second exposed to the majority of agents. Where possible, new agents
trimester if their viral load is over 30,000 copies/ml. The aim is an are avoided as there are fewer data surrounding their use in
undetectable viral load by delivery, which is less likely with a high pregnancy. Those who conceive while taking effective cART
baseline viral load.7 cART may be started early if pre-term delivery should generally continue, with the exception of PI monotherapy
is likely or amniocentesis is planned. or cART including stavudine or didanosine. There are no routine
dose alterations in pregnancy. Nevirapine should not be started if
Which maternal ART combination? three agents (usually two the woman has a CD4 count of more than 250/ml because of the
nucleoside reverse transcriptase inhibitors (NRTIs) plus a non- risk of serious rash or hepatotoxicity. There are concerns that use
nucleoside reverse transcriptase inhibitor (NNRTI) or protease of PIs is associated with an increased risk of premature birth and
inhibitor (PI)) should be used. The exception is if the mother has more information about this is needed.14
a CD4 count over 350/ml and a viral load of less than 10,000 Short-term toxicities of ART drugs in neonates include
copies/ml, and is happy to have a PLCS when zidovudine anaemia, lactic acidosis and adrenal dysfunction.15 Lopinavir/ri-
monotherapy is an option. Mutations associated with resistance tonavir can cause gastrointestinal disturbance and deaths have
to zidovudine are unusual in this setting.8 been seen in pre-term neonates secondary to its co-formulation
Women who present late or with high baseline viral load with ethanol in combination with overdosing. Long-term effects
should be considered for a regimen including raltegravir, which for neonates exposed to ART drugs are still not fully understood.16
is associated with a rapid decline in viral load.9 Those presenting
with a detectable viral load in labour should also be considered Infant testing
for a stat dose of nevirapine and an infusion of zidovudine. In The UK guidelines recommend testing during first 48 hours, at 6 and
pre-term labour, the mother may be given additional ART that 12 weeks of age, and on other occasions if risks such as breast-
effectively crosses the placenta in order to preload the neonate. feeding are known, with a confirmatory test if the initial test is
Single-dose nevirapine should not be used in isolation as it is positive.6 HIV DNA or RNA can be used for viral testing; clearance

MEDICINE 41:8 462 Ó 2013 Elsevier Ltd. All rights reserved.

Downloaded for prasandhya astagiri ([email protected]) at Universitas Indonesia from ClinicalKey.com by Elsevier on September 10, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 HIV PREVENTION AND TREATMENT

lymphadenopathy, recurrent bacterial infections, diarrhoea and

Pneumocystis jirovecii pneumonia
failure to thrive. Bilateral, persistent parotid enlargement is a
useful sign of HIV infection. Older children can present with a
pattern of disease similar to adult disease, with severe bacterial
or opportunistic infections, or focal organ disease (e.g. isolated
cardiomyopathy, chronic renal failure). A small proportion will
not present until adolescence and often have a low CD4 count at
diagnosis despite being clinically asymptomatic.21

Management
About 20 different anti-retroviral drugs are currently available for
children. After starting cART, immune reconstitution is faster in
younger children (often less than 1 year in those under 2 years of
age), but can take years in school-aged children. The Children with
HIV Early Anti-retroviral Therapy (CHER) Study showed that
starting cART under 1 year of age regardless of CD4 count signifi-
cantly reduces mortality.22 This practice has been adopted world-
wide.2,20,23 In older age groups, WHO,24 US25 and European23
Figure 1 Chest computed tomography scan of Pneumocystis jirovecii guidance differ in precise recommendations (Table 2) but, overall,
pneumonia in an infant. Note patchy ground-glass shadowing and cystic commencing ART is now advised at higher CD4 counts. Achieving
change. (From Sharland M, Bryant PA. Paediatric HIV infection. Medi- this in low- and middle-income settings is challenging where only
cine 2009; 37(7): 371e373.) 28% of eligible 0e14-year-olds received cART in 2011.3
of maternal antibodies should be confirmed at 18e24 months. The Arrow and DART trials, in children over 4 years and adults in
If virological testing is unavailable, WHO recommends a clinical low-income countries, showed increased mortality, mainly due to
algorithm for infants under 18 months with positive serology.17 bacterial infections, among those with low CD4 values in the first 3
months after starting cART.26 Paediatric data from high-income
Paediatric HIV infection settings have shown that most children on cART remain very
well, and mortality has decreased dramatically by 80%, and
Clinical features morbidity by 50%, since the introduction of cART in 1996.27 Most
Before the advent of ART, the European Collaborative Study affected children will now live well into mid-adult life. As yet, it is
showed that 10e20% of vertically infected children present in unclear how the long-term risks of toxicity (lipodystrophy, hyper-
the first 2 years of life with rapidly progressing HIV disease, and lipidaemia, etc) will affect the children later in life.
50% progress to AIDS or die by the age of 10 years.18 Low CD4 For most paediatric ART, there are major problems with the
percentage and young age are associated with progression to taste and/or size of syrups and tablets, which can impair
AIDS and death.19,20 In low-income settings, if CD4 count is not adherence. Adherence to treatment is a challenge, particularly
available, other predictors such as weight for age or haemoglobin through adolescence, and maintenance of psychological health is
can be used.20 important. Increasingly, children with HIV infection are aware of
In infants, Pneumocystis jirovecii pneumonia (PCP) is the most their diagnosis earlier in life.
common opportunistic infection and can lead to severe respira-
tory failure (Figure 1). Outcomes have improved with earlier The future
diagnosis and improved management in intensive care. Pre- Treatment with cART is a lifelong commitment and therefore
school children commonly present with widespread pharmacovigilance is vital to identify long-term toxicities in children

Criteria for starting ART in children according to WHO, PENTA23 and US guidance26
Age WHO 2010 PENTA 2009 US 2012

<2 years <18 months and presumptive All <1 year

clinical diagnosis of HIV 1e3 years with CD4 <1000/ml or <25%
2e5 years CD4 <750/ml or <25% 3e5 years with CD4 <500/ml or <20% 3e5 years with CD4 <750/ml or <25%
>5 years CD4 <350/ml CD4 <350/ml or CD4 350e500/ml if viral
load >100,000 copies/ml
Clinical criteria Start ART for all children with WHO stage 3 or 4 or CDC stage B or C Start children >1 year who have mild
symptoms with CD4 counts higher than
levels above

ART, anti-retroviral therapy; CDC, US Centers for Disease Control and Prevention (CDC); PENTA, Paediatric European Network for Treatment of AIDS; WHO, World Health
Organization.

Table 2

MEDICINE 41:8 463 Ó 2013 Elsevier Ltd. All rights reserved.

Downloaded for prasandhya astagiri ([email protected]) at Universitas Indonesia from ClinicalKey.com by Elsevier on September 10, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 HIV PREVENTION AND TREATMENT

and young adults. There remain serious issues about equality of 16 Shepherd J. FDA Drug Safety Podcast for Healthcare Professionals:
access for both first- and second-line ART drugs and adequate di- Serious health problems seen in premature babies given Kaletra
agnostics for infants and children in the resource-poor setting. A (lopinavir/ritonavir) oral solution. http://www.fda.gov/Drugs/
DrugSafety/DrugSafetyPodcasts/ucm246459.htm.
17 WHO recommendations on the diagnosis of HIV in infants and chil-
dren, 2010. Available at: http://whqlibdoc.who.int/publications/2010/
REFERENCES 9789241599085_eng.pdf.
1 National Study of HIV infection in Pregnancy and Childhood [data- 18 Gray L, Newell ML, Thorne C, Peckham C, Levy J. Fluctuations in
base on the Internet] [cited 01/03/13]. Available from: http://www. symptoms in human immunodeficiency virus-infected children: the
nshpc.ucl.ac.uk. first 10 years of life. Pediatrics 2001; 108: 116e22.
2 WHO/UNAIDS. GLOBAL HIV/AIDS RESPONSE: eEpidemic update and 19 Dunn D. Short-term risk of disease progression in HIV-1-infected
health sector progress towards Universal Access, Progress Report children receiving no antiretroviral therapy or zidovudine mono-
2011. Available at: http://www.who.int/hiv/pub/progress_ therapy: a meta-analysis. Lancet 2003; 362: 1605e11.
report20011/summary_en.pdf. 20 Panel on Antiretroviral Therapy and Medical Management of HIV
3 UNAIDS. Global Report: UNAIDS report on global AIDS epidemic Infected Children. Guidelines of the Use of Antiretroviral Agents in
2012. Available at: http://unaids.org/en/media/unaids/contentassets/ Pediatric HIV Infection. Available at: http://aidsinfo.nih.gov/
docments/epidemiology/2012/gr2012/20121120_UNAIDS_Global_ contentfiles/lvguidelines/pediatricguidelines.pdf.
Report_2012_en_pdf. 21 Judd A, Ferrand RA, Jungmann E, et al. Vertically acquired HIV diagnosed
4 The European Mode of Delivery Collaboration. Elective caesarian in adolescence and early adulthood in the United Kingdom and Ireland:
section versus vaginal delivery in prevention of vertical HIV-1 trans- findings from national surveillance. HIV Med 2009; 10: 253e6.
mission: a randomized controlled trial. Lancet 1999; 353: 1035e9. 22 Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and
5 Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and mortality among HIV-infected infants. N Engl J Med 2008; 359: 2233e44.
formula feeding on transmission of HIV-1: a randomized clinical trial. 23 Welch S, Sharland M, Lyall EG, et al. PENTA 2009 guidelines for the
J Am Med Assoc 2000; 283: 1167e74. use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med
6 Taylor GP, Clayden P, Dhar J, et al. British HIV Association guidelines 2009; 10: 591e613.
for the management of HIV infection in pregnant women 2012. HIV 24 Antiretroviral therapy for HIV infection in infants and children: to-
Med 2012; 13(suppl 2): 87e157. wards universal access. Recommendations for a public health
7 Read PJ, Mandalia S, Khan P, et al. When should HAART be initiated in approach 2010. Available at: http://whqlibdoc.who.int/publications/
pregnancy to achieve an undetectable HIV viral load by delivery? 2010/9789241599801_eng.pdf.
AIDS 2012; 26: 1095e103. 25 Panel on Antiretroviral Therapy and Medical Management of HIV-
8 Read P, Costelloe S, Mullen J, et al. New mutations associated with Infected Children. Guidelines for the Use of Antiretroviral Agents in
resistance not detected following zidovudine monotherapy in preg- Pediatric HIV Infection. Available at: http://aidsinfo.nih.gov/
nancy when used in accordance with British HIV Association guide- contentfiles/lvguidelines/pediatricguidelines.pdf (accessed 06 March
lines. HIV Med 2008; 9: 448e51. 17 2013).
9 Murray JM, Emery S, Kelleher AD, et al. Antiretroviral therapy with the 26 Walker AS, Prendergast AJ, Mugyenyi P, et al. Mortality in the year
integrase inhibitor raltegravir alters decay kinetics of HIV, signifi- following antiretroviral therapy initiation in HIV-infected adults and
cantly reducing the second phase. AIDS 2007; 21: 2315e21. children in Uganda and Zimbabwe. Clin Infect Dis 2012; 55: 1707e18.
10 Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral 27 Judd A, Doerholt K, Tookey PA, et al. Morbidity, mortality, and
therapy after a single, peripartum dose of nevirapine. N Engl J Med response to treatment by children in the United Kingdom and Ireland
2007; 356: 135e47. with perinatally acquired HIV infection during 1996e2006: planning
11 WHO. Guidelines on HIV and infant feeding 2010. Principles and for teenage and adult care. Clin Infect Dis 2007; 45: 918e24.
recommendations for infant feeding in the context of HIV and a
summary of evidence. Available at: http://www.who.int/maternal_
child_adolescent/documents/9789241599535/en/. Practice points
12 Kesho Boro Study Group, de Vincenzi I. Triple antiretroviral compared
with zidovudine and single-dose nevirapine prophylaxis during preg- Prevention of mother-to-child transmission
nancy and breastfeeding for prevention of mother-to-child transmission C Consider repeat testing for HIV in the third trimester of preg-

of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect nancy in those at higher risk of HIV
Dis 2011; 11: 171e80. C Initiate anti-retroviral therapy (ART) in all pregnant women by

13 Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant an- 24 weeks’ gestation. Those with baseline viral load >30,000
tiretroviral drugs to reduce HIV-1 transmission. N Engl J Med 2010; copies/ml should commence combination anti-retroviral therapy
362: 2271e81. (cART) at the beginning of the second trimester and those who
14 Sibiude J, Warszawski J, Tubiana R, et al. Premature delivery in HIV- need it for their own health should start as soon as possible
infected women starting protease inhibitor therapy during pregnancy: C Vaginal delivery is advocated for women who have an unde-

role of the ritonavir boost? Clin Infect Dis 2012; 54: 1348e60. tectable viral load at delivery
15 Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal C Administer post-exposure prophylaxis immediately after de-

and postnatal exposure to lopinavir-ritonavir and adrenal dysfunc- livery to all neonates born to HIV-positive mothers. Continue for
tion among uninfected infants of HIV-infected mothers. J Am Med 4 weeks post-partum
Assoc 2011; 306: 70e8.

MEDICINE 41:8 464 Ó 2013 Elsevier Ltd. All rights reserved.

Downloaded for prasandhya astagiri ([email protected]) at Universitas Indonesia from ClinicalKey.com by Elsevier on September 10, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 HIV PREVENTION AND TREATMENT

C Recommend replacement feeding where safe

C Where replacement feeding is not safe, continue the mother/
infant’s ART until 1 week after exposure to breast milk has
ended

Paediatric HIV
C Test infants born to women with HIV for HIV DNA or RNA in the

first 2 days, and at 6 and 12 weeks, with an antibody test at 18

months and additional testing if breastfed
C Start co-trimoxazole in newly diagnosed infants and those at

high risk of infection

C Start cART in all infants <1 year of age

C Start cART in children >1 year according to guidelines (Table 2)

C Continue education, and adherence and psychological support

throughout treatment, with close monitoring of toxicities such

as lipids, lipodystrophy, and bone metabolism

MEDICINE 41:8 465 Ó 2013 Elsevier Ltd. All rights reserved.

Downloaded for prasandhya astagiri ([email protected]) at Universitas Indonesia from ClinicalKey.com by Elsevier on September 10, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.