Tuberculosis in Pregnancy
Tuberculosis in Pregnancy
Tuberculosis in Pregnancy
INVITED ARTICLE
Division of Infectious Diseases, Weill Cornell Medical College, New York, New York; 2Division of Infectious Diseases, Johns Hopkins University
School of Medicine, and 3Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Tuberculosis kills approximately 500 000 women annually, a disproportionate number of them during
their reproductive years [14], yet there are critical research gaps regarding the epidemiological and clinical
features of tuberculosis in pregnant and postpartum
women. In this article, we review the current state of
knowledge, highlighting those gaps.
WHAT IS THE GLOBAL BURDEN OF
TUBERCULOSIS AND LATENT
TUBERCULOSIS AMONG PREGNANT
AND POSTPARTUM WOMEN?
The human immunodeciency virus (HIV) epidemic,
reduced healthcare access, and hormonal changes
likely make tuberculosis a leading cause of morbidity
and mortality in women of reproductive age [57].
1532
HIV/AIDS
Table 1 summarizes the prevalence of active tuberculosis in pregnant and postpartum women from highburden (>60 cases per 100 000 population per year)
and low-burden tuberculosis countries (<20 cases per
100 000 population per year or <10 cases total). Rates
of active tuberculosis ranges from 0.7% to 7.9% among
HIV-positive women in high-burden countries, and is
as high as 11% if they are positive for tuberculin skin
test (TST) [8] (Table 1). High-burden countries may
underestimate prevalence because many women do
not have access to healthcare when pregnant [1]. Few
national programs collect or report pregnancy-specic
tuberculosis data to the World Health Organization
(WHO).
Burden of Latent Tuberculosis
Tuberculosis is most common during a womans reproductive years and is a major cause of maternalchild
mortality. National guidelines for screening and management vary widely owing to insufcient data. In this
article, we review the available data on (1) the global burden of tuberculosis in women of reproductive age;
(2) how pregnancy and the postpartum period affect the course of tuberculosis; (3) how to screen and diagnose pregnant and postpartum women for active and latent tuberculosis; (4) the management of active and
latent tuberculosis in pregnancy and the postpartum period, including the safety of tuberculosis medications;
and (5) infant outcomes. We also include data on HIV/tuberculosis coinfection and drug-resistant tuberculosis. Finally, we highlight research gaps in tuberculosis in pregnant and postpartum women.
Study Site
Author
Low-burden countries
United States
Good et al4
Sample
Size, No.
HIV
Positive, %
Locations of
Tuberculosis
Screening
Site of
Infection
Tuberculosis
Case Definition
Overall %
Drug
Resistant, %
371
Unknowna
Inpatient
PTB
7.20b
59.20
51 983
63 (7/11)c
Inpatient
PTB, EPTB
0.06
NA
United States
Margono et al9
United States
Schulte et al10
207
100
ANC
Unspecified
1.00
NA
United States
Schwartz et al11
3847
ANC
PTB
Symptoms or TST+/CXR+
with sputum AFB+
0.13
NA
United Kingdom
Llewelyn et al12
9069
0 (0/10)d
Inpatient
PTB, EPTB
0.14
United Kingdom
Kothari et al13
12 697
4 (1/24)e
ANC, inpatient,
postpartum clinic
PTB, EPTB
0.25f
NA
3.40
NA
2.80
NA
High-burden countries
HIV/AIDS
Gupta et al14
715
100
ANC, inpatient
PTB, EPTB
Kenya
Jonnalagadda et al15
393
100
ANC
Unspecified
Rwanda
Leroy et al16
431
49
Inpatient
PTB, EPTB
HIV+: 7.90,
HIV : 0.46
NA
Tanzania
Sheriff et al17
396
ANC
PTB
Nachega et al8
120h
100
Postpartum clinic
PTB, EPTB
HIV+: 10.0g,
HIV: 0.53g
11.00
NA
South Africa
South Africa
Pillay et al18
50 518
29
ANC, inpatient
PTB, EPTB
HIV+: 0.77,
HIV: 0.07
1.30
South Africa
Kali et al19
370
100
Unspecified
NA
Gounder et al20
3963
36
2.16
South Africa
ANC, posttest
counseling
ANC pretest
counseling
HIV+: 0.69,
HIV: 0.20
0.00
India
PTB
NA
1533
HIV/AIDS
Abbreviations: AFB, acid-fast bacilli; ANC, antenatal clinic; CSF, cerebrospinal fluid; CXR, chest radiograph; EPTB, extrapulmonary tuberculosis; HIV, human immunodeficiency virus; MGIT, Mycobacteria growth
indicator tube (liquid medium); NA, not applicable; PTB, pulmonary tuberculosis; TST, tuberculin skin test; US, ultrasound.
3.00
2.10
Symptoms with response
to treatment
Unspecified
ANC
100
1536
Toro et al21
HIV
Positive, %
Sample
Size, No.
Author
Study Site
Sub-Saharan
African
countries
Drug
Resistant, %
Overall %
Site of
Infection
Tuberculosis
Case Definition
Prevalence
Locations of
Tuberculosis
Screening
Table 1 continued.
Tuberculosis increases mortality during pregnancy or postpartum, especially in HIV-positive women [14, 3941]. Pregnant
women with pulmonary or extrapulmonary tuberculosis, other
than lymphadenitis, also have increased risk of complications
including antenatal hospitalization and miscarriages (Table 3)
[3, 4, 4248].
Lack of awareness is a barrier to diagnosis in low-burden
countries. In high-burden countries, healthcare workers often
lack diagnostic tests, relying on clinical presentation. Women
are less likely than men to present with symptoms like hemoptysis, fever, and night sweats [49], and pregnancy further
masks these symptoms. In South Africa, 60% of antenatal
women diagnosed with tuberculosis reported cough of 2
weeks, but <30% had fevers or night sweats [20]. In Tanzania,
the most common tuberculosis symptoms were malaise and
anorexia [17].
Many tuberculosis-endemic countries also have a high prevalence of HIV, which further masks symptoms and causes
atypical symptoms. Acid-fast bacilli stains and chest radiographs are less sensitive in HIV-infected patients [50], and
cultures can take 410 weeks to become positive.
The complex symptomatology notwithstanding, WHO recommends screening for symptoms of cough of any duration,
1534
Table 2.
Study Site
Low-burden countries
United States
Sample
Size, No.
Author
Mofenson et al25
HIV Positive, %
Location of Tuberculosis
Screening
TST+, %
IGRA, %
46
100
ANC, inpatient,
postpartum clinic
11
United States
United States
Medchill et al26
Schulte et al10
1497
176
0
100
ANC
ANC
15
26
United States
Schwartz et al11
3847
ANC
50a
27
Chehab et al
Worjoloh et al28
102
199
0
0
ANC
ANC
10
23b
7
14c
India
India
Gupta et al14
Mathad et al24
688
152
100
0
ANC, inpatient
ANC
21
18
34
Kenya
Jonnalagadda et al15
333
100
ANC
36d
318
286
100
14.5
Postpartum clinic
ANC
49
HIV+: 23, HIV : 31
United States
United States
High-burden countries
South Africa
Tanzania
Nachega et al
Sheriff et al29
QuantiFERON-TB In-Tube.
fever, night sweats, and weight loss [51]. The absence of these
symptoms has a negative predictive value of 90%97.7% [52],
even in peripartum women [53], but poor sensitivity and positive predictive value [52, 53].
In symptomatic women and asymptomatic women with a
recent tuberculosis contact, the Centers for Disease Control
and Prevention (CDC) and others recommend a shielded
chest radiograph, which poses minimal risk to the fetus [54
56]. If ndings are abnormal, sputum samples should be submitted for microscopy and culture [56]. The British Health
Protection Agency has similar guidelines, but adds sputum
studies in all women with HIV [57]. Note that chest radiography and sputum examination may miss miliary and extrapulmonary tuberculosis disease. Common extrapulmonary sites
of tuberculosis in pregnancy include lymph nodes, intestines,
and bones [44, 58]. Additional diagnostic testing (eg, biopsy)
should be pursued if clinical suspicion is high.
Some experts advocate integrating active tuberculosis casending into peripartum care, but best approaches are
unknown. Universal antenatal tuberculosis screening in South
Africa found that symptoms of tuberculosis were common
whether or not the patient had tuberculosis, wasting resources
on unnecessary evaluations [19, 20]. Cost-effective tuberculosis
screening approaches are urgently needed.
HIV/AIDS
1535
Abbreviations: ANC, antenatal clinic; HIV, human immunodeficiency virus; IGRA, interferon- release assay; TST, tuberculin skin test.
1536
Table 3. Outcomes for Pregnant Women With and Without Active Tuberculosis Disease and Their Infants
Site
Case-control
Norway
Author
Bjerkedal
et al42
Cases
PTB
Controls/
Comparison
Group
No TB
Maternal
Sample
Size
542
HIV
Positive,
%
Maternal
Mortality,
Case % vs
Control %
RR (95% CI)
Infant
Mortalitya,
Case % vs
Control %
(RR [95%
CI])
NR
NR
1.5 vs 1.1
RR (95% CI)
1.3 (0.62.6)b
Other
Outcomes,
Case % vs
Control %
Vaginal hemorrhage:
4.1 vs 2.2c
HIV/AIDS
Maternal toxemia:
7.4 vs 4.7c
Miscarriage:
2.0 vs 0.2c
Premature:
5.2 vs 5.0
LBW: 3.9 vs 3.7
Congenital defect:
2.9 vs 2.2
Mexico
FigueroaDamin &
ArredondoGarca3
TB
No TB
35
2.8
NR
8.6 vs 0.9c
3.1 (1.14.9)
Maternal medical
complications:
23 vs 3.8c
Premature:
14.3 vs 4.8c
Birthweight (mean):
2.9 kg vs 3.1 kgc
India
Jana et al43
PTB
No TB
79
NR
0.0 vs 0.0
10.1 vs 1.6c
Jana et al44
EPTB
No TB
33
NR
0.0 vs 0.0
10.0 vs 2.0
India
Table 3 continued.
Site
Taiwan
Author
45
Lin et al
Controls/
Comparison
Group
Cases
TB
No TB
Maternal
Sample
Size
761
HIV
Positive,
%
Maternal
Mortality,
Case % vs
Control %
RR (95% CI)
Infant
Mortalitya,
Case % vs
Control %
(RR [95%
CI])
0.0
NR
NR
RR (95% CI)
Other
Outcomes,
Case % vs
Control %
Premature: 8.0 vs 7.9
LBW: 8.5 vs 6.4c
SGA: 19.7 vs 16.7c
Cohort
United States
Ratner et al39
TB and
preterm
infant
TB and full
term infant
55
NR
16.3 vs
3.6c
5.8 (1.324)b
7 vs 0e
11.5
(0.65204)b
Premature: 44.0 vs NA
Birthweight (mean):
4.2 lbs vs 7.0 lbs
United States
Schaefer
et al46
TB from
19521972
TB from
19331951
1565
NR
0.4 vs 0.5
1.4 (0.27.0)b
NR
United
Kingdom
Kothari et al13
Delay in TB
diagnosis
No delay in TB
diagnosis
32
3.1
0 vs 0
0 vs 0
Miscarriage: 6.3
(overall)
Sub- Saharan
Africa
Gupta et al14
HIV+ with TB
HIV+ without
TB
24
100.0
12 vs 1
12.2
(2.053.3)g
17 vs 4f
4.7
(1.113.5)g
HIV/AIDS
Toro et al21
HIV+ on ART
and TB
treatment
HIV+ on ART
treatment
33
100.0
3 vs NR
15.2 vs 5.9c,e
2.6
(1.16.1)b
Pillay et al47
HIV+ with TB
HIV negative
with TB
107
77.0
1.2 vs 0.0
0.93
(0.0322)b
7.3 vs 0
4.0
(0.2369)b
Prospective
case series
South Africa
1537
1538
Table 3 continued.
Controls/
Comparison
Group
Author
Cases
HIV
Positive,
%
Maternal
Mortality,
Case % vs
Control %
RR (95% CI)
RR (95% CI)
Other
Outcomes,
Case % vs
Control %
LBW: 49.0
(overall)
IUGR: 66.0
(overall)
Lowe48
Treated TB
Untreated TB
253
NR
NR
3.6 (overall)f
Good et al4
DR TB
DS TB
27
NR
17 vs 0
3.5 (0.18
67)b
19 vs 9f
2.0 (0.24
17)b
Congenital
defect: 2.7 vs. 4.1
Perinatal TB:
19.0 vs 9.0
United States
Margono
et al9
TB
None
16
64.0h
6.3
NR
Abbreviations: ART, antiretroviral therapy; CI, confidence interval; DR, drug resistant; DS, drug sensitive; EPTB, extrapulmonary tuberculosis; Hb, hemoglobin; HIV, human immunodeficiency virus; IUGR,
intrauterine growth retardation; LBW, low birth weight; NA, not applicable; NR, not reported; PTB, pulmonary tuberculosis; RR, relative risk; SGA, small for gestational age; TB, tuberculosis.
a
Infant mortality defined as stillbirth greater than 28 weeks or death within 7 days of birth.
HIV/AIDS
Site
Maternal
Sample
Size
Infant
Mortalitya,
Case % vs
Control %
(RR [95%
CI])
HIV/AIDS
1539
Table 4.
HIV-negative
HIV-positive
High-Burden Countriesc
Isoniazid 5 mg/kg/d 9 mo
Isoniazid 5 mg/kg/d 6 mo
Rifampin 10 mg/kg/d 9 mo
Ethambutold 2 mo
Rifampicin 10 mg/kg/d 6 mo
Ethambutol 15 mg/kg/d 2 mo
Pyridoxine 25 mg/d 9 mo
Pyrazinamide 25 mg/kg/d 2 mo
Rifampicin 10 mg/kg/d 6 mo
Ethambutold 2 mo
Pyrazinamidee,f 2 mo
Ethambutol 15 mg/kg/d 2 mo
Pyrazinamide 25 mg/kg/d 2 mo
Pyridoxine 25 mg/d 6 mo
Treatment of extrapulmonary tuberculosis involves the same medications as pulmonary tuberculosis, but many experts recommend 912 mo of treatment
for tuberculosis meningitis (plus steroids) or tuberculosis bone/joint infections [70, 71].
Based on recommendations of the Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Diseases Society of America
[70].
Based on recommendations of the World Health Organization and International Union Against Tuberculosis and Lung Disease [71].
Ethambutol weight-based dosing: 800 mg/d for 4055 kg, 1200 mg/d for 5675 kg, 1600 mg/d for 76 kg.
Pyrazinamide weight-based dosing: 1000 mg/d for 5055 kg, 1500 mg/d for 5675 kg, 2000 mg/d for 76 kg.
Pyrazinamide is only recommended in HIV-positive women because the benefit of potent 4-drug therapy in HIV-positive women outweighs the potential risk
of pyrazinamide use during pregnancy [70].
Multidrug-Resistant Tuberculosis
Only case reports provide guidance for management of multidrug-resistant (MDR) tuberculosis in pregnancy [8491]
(Table 7). Most second-line agents are FDA pregnancy class
C, except for aminoglycosides, which are mainly class D
(Table 6).
Some women terminate their pregnancy to avoid teratogenicity of ATT. While there are obstetric, fetal, and infant complications associated with MDR tuberculosis regimens, small
case series suggest that good outcomes are achievable [88, 91],
but close monitoring is essential. Among 38 Peruvian pregnant women treated for MDR tuberculosis, 23 (60%) were
cured, 5 (13%) died (4 from tuberculosis), and 2 experienced
treatment failure. Eight (21%) experienced pregnancy complications, such as spontaneous abortion and vaginal bleeding.
No infants displayed teratogenic effects [91] (Table 7).
Among 5 South African pregnant women with MDR tuberculosis, 3 of whom had HIV, 2 experienced adverse drug
events (deafness and drug-induced hepatitis). The infants
showed no evidence of teratogenicity [89].
1540
HIV/AIDS
Table 5.
HIV-Positive Women
Regimen
High-Burden Countriesb
Pyridoxine 25 mg/d 69 mo
OR
Pyridoxine 25 mg/d 9 mo
Defer treatment for TST+ or IGRA+ until 23 mo
postpartum unless recent known tuberculosis contact
HIV-positive
No recommendations
Immediate treatment for all HIV- positive
without active tuberculosis
Abbreviations: HIV, human immunodeficiency virus; IGRA, interferon- release assay; TST, tuberculin skin test.
a
Based on recommendations of the Centers for Disease Control and Prevention [96].
HIV/AIDS
1541
1542
Table 6. Pregnancy Safety and Breast Milk Information for Tuberculosis Medications
FDA
Categorya
Drug
First-line medications
Crosses Placenta
(Cord:Maternal Ratio)
Fetal Toxicity
AAP Compatible
With Breastfeeding
Present in
Breast Milk (%
of Infant Dose)
Yes
Yes
Yes (6.425)
Yes (0.577.3)
Other Information
CNS defectsc
Hemorrhage
C
C
Yes (0.73)
Yes (0.120.33)
EMB
Yes (0.75)
Unknown
Jaundice
Yes (<0.5)72
Ototoxicity,
thrush, diarrhea
INH
RIFd
Yes
Yes (2.86.9)
Unknown
Yes (0.751.5)
Yes
Yes (0.9522.5)
Aminoglycosidesf
Streptomycin
Capreomycin
Yes (Unknown)
Kanamycin
Yes (Unknown)
Ototoxicity
Unknown
Amikacin
Ethionamide/
prothionamidef
D
C
Yes (<0.5)73
Unknown
Ototoxicity likely
Developmental
anomalies
Unknown
Unknown
Unknown
Unknown
PAS
Unknown
Diarrhea
Unknown
Yes (0.050.95)
Cycloserine
Unknown
Yes
Levofloxacin
Moxifloxacin
C
C
Yes (0.66)
Yes (0.74)
Yes
Unknown
Yes (0.9518)
Monitor LFTs if on PZA, INH, RIF,
EMB, or PAS; avoid use with
cycloserine if seizure disorder
Monitor LFTs if on ethionamide
and INH toxicity
Yes (1128)
Unknown
Unknown
Yes
Unknown
Unknown
Unknown
Unknown
Unknown
Fluoroquinolones
Gatifloxacin
Unknown
Other
Thioacetazone
N/A
Unknown
Clofazimine
Unknown
Clarithromycin
Yes (0.15)
Reversible skin
pigmentation
No
Unknown
HIV/AIDS
PZA
Second-line medications
Yes
Unknown
Table 6 continued.
Drug
FDA
Categorya
Amoxicillinclavulanic acid
Crosses Placenta
(Cord:Maternal Ratio)
Fetal Toxicity
Yes
Present in
Breast Milk (%
of Infant Dose)
Yes (0.56)
Unknown
Unknown
Unknown
Rifapentine
Unknown
Unknown
Unknown
Linezolidg
Unknown
Unknown
Unknown
Rifabutinf
Necrotizing
enterocolitis,
transaminitis
AAP Compatible
With Breastfeeding
Other Information
Yes
Abbreviations: AAP, American Academy of Pediatrics; AZT, zidovudine, antiretroviral; CNS, central nervous system; ddI, didanosine, antiretroviral; EMB, ethambutol; FDA, Food and Drug Administration; LFT, liver
function test; HIV, human immunodeficiency virus; INH, isoniazid; NNRTI, nonnucleoside reverse transcriptase inhibitor, antiretroviral; PI, protease inhibitor, antiretroviral; PAS, para-aminosalicylic acid; PZA,
pyrazinamide; RIF, rifampin.
Sources: AAP Statement (2001); Micromedex 2.0; www.fda.gov.
a
A.
Adequate and well controlled (AWC) studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy;
B. Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no AWC studies in humans AND the benefits from the use of the drug in pregnant women may be acceptable
despite its potential risks;
HIV/AIDS
C. Animal reproduction studies have shown an adverse effect on the fetus, there are no AWC studies in humans AND the benefits from the use of the drug in pregnant women may be acceptable despite its
potential risks;
D. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans BUT the potential benefits from the use of the drug in
pregnant women may be acceptable despite its potential risks.
b
Doses for first-line therapy for pregnant women are: INH 5 mg/kg (max: 300 mg orally daily), RIF 10 mg/kg (max: 600 mg orally daily), EMB 15 mg/kg, and PZA 25 mg/kg (max: 2 g orally daily). Treatment of
MDR tuberculosis in pregnancy should be individualized but there are no established dosage adjustments for pregnancy.
Earlier studies found increased frequency of mental retardation and seizures but more recent studies have not.
Potent inducer of cytochrome P450. It is critical to check drug interactions with all medications patient is taking.
1543
1544
Table 7. Outcomes for Pregnant Women With Drug-Resistant Tuberculosis and Their Infants
Study
Average Time to
Sputum Conversion,
mo (Range)
2 dead (miliary TB
and TB meningitis)
3 pulmonary
insufficiency
2 TST positive
1 deaf from
streptomycin
3 LTF
1 pulmonary TB
healthy
Healthy
Unknowna
INH, PZAb
United
Nitta
States
and Milligan83
United
Lessnau and
States
Qarah84
Peru
Shin et al85
RIF/EMB in
C-section
pregnancy,
at 35 wk
Stm postpartum
Variable (incl. Clof,
1 abortion
Cpm, Cyse, Ofx,
(elective)
PAS, Ami,
Eth, high-dose INH)
4.3 (112)
Infant Outcome
2 dead
Signorini
et al82
1 spontaneous
abortion
Maternal
Outcome
11 healthy
Italy
Variable
Pregnancy
Outcome
HIV/AIDS
16
Treatment
Regimen
7 healthy
United
Good
States
et al4
16
Resistance
Profile, No.
Site
History of
Sample Tuberculosis,
Size, No.
No.
2.75
4 (35)
Healthy, completed
3 healthy
1724 mo treatment
2 TST positive
Cpm, Cyse, Levo,
PAS, PZA
Variable (incl Stm,
PAS, Cyse, Cpm,
Ofx, Cipro,
Eth, Amox-CA)
Spontaneous
@ 35 wk
Normal term
deliveries
NR
1.8 (13)
Drobac
et al86
healthy, completed
18 mo treatment
3 healthy
LBW
1 death
2 reversible skin
bronzing
from Clof
1 MDR TB
7 healthy
1 speech delay
South
Africa
Khan
et al87
5 (3
HIV+)
NR
3 drug-related
complications
13 (1014)
1 elective abortion
(HIV pos)
Tabarsi
et al88
INH, RIF,
EMB, Stm
Iran
1 preterm delivery
@34 wk (HIV neg)
Normal term
delivery
HIV-exposed:
HIV+: 1 healthy,
1 discharged
2 growth
to other clinic, 1 LTF
restricted; tx
for TB
HIV: 2 healthy
HIV-unexposed:
2 healthy
Healthy,
completed
18 mo treatment
Healthy, empirically
given EMB/
PZA 2 mo
Table 7 continued.
Site
Peru
Study
Palacios
et al89
History of
Sample Tuberculosis,
Size, No.
No.
38 (3
HIV+)
34
Resistance
Profile, No.
Treatment
Regimen
Pregnancy
Outcome
Average Time to
Sputum Conversion,
mo (Range)
NR
Maternal
Outcome
23 cured
5 dead
Infant Outcome
25 healthy
5 spontaneous
abortions
4 worsened TB
3 LBW
5 LTF
2 latent TB
2 vaginal bleeding
2 treatment failure
2 premature rupture
of membranes
2 still on treatment
2 meconium
aspiration
1 active TB
1 stillborn
1 fetal distress
1 dead
HIV/AIDS
Abbreviations: DR, drug resistant; HIV, human immunodeficiency virus; LBW, low birth weight; LTF, lost to follow-up; MDR, multidrug resistant; NR, not reported; TB, tuberculosis; TST, tuberculin skin test; XDR,
extremely drug resistant.
Drugs: Ami, amikacin; Amox-CA, amoxicillin-clavulanic acid; Cipro, ciprofloxacin; Clarithro, clarithromycin; Clof, clofazimine; Cpm, capreomycin; Cyse, cycloserine; EMB, ethambutol; Eth, ethionamide; INH, isoniazid;
Levo, levofloxacin; Ofx, ofloxacin; PAS, para-amino salicylic acid; Pth, prothionamide; PZA, pyrazinamide; Stm, streptomycin; Thia, thiacetazone.
Patient had received ceftriaxone, Ami, and Clarithro for bacterial pneumonia.
1545
1546
HIV/AIDS
Interventions affecting pregnant women also affect neonates. There is an urgent need for research in pregnant and
postpartum women, including those who are HIV-positive, in
these areas:
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