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Journal of the Pediatric Infectious Diseases Society

ORIGINAL ARTICLE

Prevalence and Factors Associated With Virological


Treatment Failure Among Children and Adolescents on
Antiretroviral Therapy Attending HIV/AIDS Care and
Treatment Clinics in Dodoma Municipality, Central
Tanzania
Niyonziza Z. Bitwale,1 David P. Mnzava,2 Francisca D. Kimaro,1 Theopista Jacob,3 Bonaventura C.T. Mpondo,4 and Shakilu Jumanne1 .

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1
Department of Paediatrics & Child Health, University of Dodoma, Dodoma, Tanzania; 2Department of Paediatrics & Child Health, Dodoma Regional Referral Hospital, Dodoma,
Tanzania; 3Department of Paediatrics & Child Health, Mbeya Zonal Referral Hospital, Mbeya, Tanzania; and 4Department of Internal Medicine, University of Dodoma, Dodoma,
Tanzania

Background.  As the World Health Organization (WHO) and its joint partners such as USAIDS target achieving 90% sus-
tained virological suppression among children and adolescents living with Human Immunodeficience Virus (HIV)/AIDS, it is
imperative to elucidate the current prevalence and factors associated with virological treatment failure for formulation of appro-
priate strategies. This study was conducted determine the prevalence and factors associated with virological treatment failure
among children and adolescents with HIV/AIDS on antiretroviral therapy (ART) attending HIV/AIDS care clinics in Dodoma,
Central Tanzania.
Methods.  This was a cross-sectional study of children aged 1–19 years attending 3 HIV/AIDS care clinics in Dodoma (central
Tanzania) from November 2018 to February 2019. Sociodemographic and clinical factors were documented, HIV viral load and
CD4+ T lymphocytes were evaluated for children on ART for ≥6 months. The primary outcomes were the prevalence and factors
associated with viralogic treatment failure.
Results.  Of 300 children enrolled, 102 (34%) had virological treatment failure. Poor adherence to ART (adjusted odds ratio
[AOR] = 3.221; 95% confidence interval [CI], 1.867–5.558; P = .032), nevirapine regimen (AOR = 3.185; 95% CI, 1.473–6.886; P ≤
.001), not using cotrimoxazole prophylaxis (AOR = 25.56; 95% CI, 3.15–27.55; P = .002) and nondisclosure of HIV status to others
(AOR = 7.741; 95% CI, 2.351–25.489; P = .001) were independently associated with virological treatment failure.
Conclusions.  Current prevalence of virological treatment failure among children and adolescents living with HIV on ART re-
main high. Factors such as ART adherence, nevirapine based regimen, HIV status disclosure to those caring for the child need to be
addressed to achieve sustained virological suppression.
Keywords.  adolescents; antiretroviral therapy; children; HIV/AIDS; virological treatment failure.

Treatment of human immunodeficiency virus (HIV) infection use of ART allows ongoing HIV replication and chronic inflam-
with antiretroviral therapy (ART) aims to maintain suppressed mation. Inappropriate use of ART may lead to treatment failure
plasma HIV RNA below detectable levels using highly sensitive and limit future treatment options for children and adolescents
HIV-RNA polymerase chain reaction (PCR) assays [1]. ART re- living with HIV [2].
duces morbidity and mortality, promotes normal growth and Tanzania ranks third among sub-Saharan countries with
development, and improves the quality of life for children and the highest prevalence of HIV among children and harbors 5%
adolescents living with HIV; however, its effectiveness depends of the world’s adolescents living with HIV [3]. About 62  781
on sustained suppression of viral replication [2]. Inconsistent children aged <14 years were estimated to be living with HIV in
Tanzania in 2019 and only 65% were on ART [4].

To ensure successful treatment with ART, viral load moni-


Received 12 December 2019; editorial decision 27 March 2020; accepted 17 April 2020;
Published online May 28, 2020.
toring is universally recommended for monitoring treatment
Correspondence: Shakilu Jumanne, Department of Paediatrics and Child Health, College failure [5]. Virological monitoring using plasma HIV1 viral load
of Health Sciences, University of Dodoma, Box 395, Dodoma-Tanzania (shakiluj@gmail.com,
shakiluj@udom.ac.tz).
has been shown to be more reliable than immunological and
Journal of the Pediatric Infectious Diseases Society   2021;10(2):131–40 clinical monitoring [6, 7].
© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Different factors in various settings have been associated
Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com.
with virological treatment failure in children and adolescents.
DOI: 10.1093/jpids/piaa030 These include ART drug toxicity, drug resistance, poor drug

HIV Virological Treatment Failure in Tanzanian Children  •  jpids 2021:10 (February) • 131


adherence, nevirapine-based ART, low CD4+  lymphocyte caretaker or assent for children aged >13 years. Children aged
levels  at initiation of ARTs long duration of ART [7–9], and <18  months with a presumptive HIV diagnosis not yet con-
young age [10]. firmed by DNA-PCR were excluded. Ethical clearance was
Children and adolescents on ART are reported to have granted by the University of Dodoma Ethics Review Board.
poor virological outcome compared with adults due to rapid A minimum sample size of 292 children living with HIV
HIV disease progression and behavioral characteristics of ado- was estimated using the Kish and Leslie formula (1965) for
2
lescents that increase the risk of treatment failure, morbidity, cross-sectional studies [7]: n = Z P(1−P)
d2 , where n = sample size,
and mortality [11]. With the recent ART treat-all strategy for Z = score for 95% confidence interval (CIs) set at 1.96, with P
children and adolescents confirmed to be living with HIV, keen as the prevalence of virological treatment failure from a pre-
monitoring of virological treatment failure and assessing the viously reported study of 25.4%, and d = tolerable error set at
associated factors are mandatory for sustained virological sup- 5% [7]. Systematic sampling was used to obtain the minimum
pression, avoidance of drug resistance, and preservation of fu- sample size for the 3 facilities according to the number of cli-
ture ART options [12]. ents attending the respective sites: DRRH, 50%; Makole Health
Few pediatric studies have been published on the prevalence Centre, 30%; and Village of Hope, 20%. The equiprobability

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and factors associated with virological treatment failure among method (k = N/n) was used to obtain the number of partici-
children and adolescents on ART. In this study, our aim was to pants at each site. The first participants to be enrolled in the
determine the extent of virological treatment failure and asso- study at every visit were conveniently obtained followed by the
ciated factors among children living with HIV in Tanzania in sampling interval shown Table 1.
order to identify gaps for improved virologic suppression as set
out in the 90–90–90 World Health Organization (HIV)/United Study Procedures
Nations Programme on HIV and AIDS (UNAIDS) targets. Data were collected from November 2018 to February 2019 at
respective clinics using interviewer-administered structured
questionnaires to record sociodemographic, clinical, and labo-
METHODS
ratory details. Clinical details included duration since HIV di-
This was a cross-sectional hospital-based study to determine agnosis, use of ART, drug regimen (from patients’ ART cards),
the prevalence of and factors associated with virological treat- self-reported medication adherence in the past month, and re-
ment failure among children living with HIV from November call of missed doses since the last clinic visit. Poor adherence was
2018 to February 2019. The study was conducted at the 3 major defined as any missed dose of ART since the last clinic visit [13],
pediatric HIV/AIDs care and treatment clinics in Dodoma thus ART adherence was not assessed as a percentage. Parents/
Municipality: Dodoma Regional Referral Hospital (DRRH), guardians were asked to describe symptoms suggestive of op-
Makole Health Centre, and Village of Hope Health Centre in portunistic infections, such as fever, long-standing cough, dif-
central Tanzania. DRRH is 490-bed public referral and teaching ficulty breathing, oral thrush, or difficulty swallowing. Physical
hospital affiliated with the College of Health Sciences of the examination was then performed.
University of Dodoma. The HIV Care and Treatment Centre Laboratory investigations included CD4+  lymphocyte
at DRRH has 9291 enrolled patients, 930 being children and count/percentage and plasma HIV1 RNA levels. Other investi-
adolescents aged ≤19 years. Makole Health Center is a primary gations were performed as clinically indicated. At each respec-
healthcare public facility that operates the HIV/AIDS Care and tive clinic site, 8 mL of venous blood was collected by aseptic
Treatment Clinic with 2552 clients and 475 pediatric cases. technique into an EDTA bottle. Samples from Makole Health
The Village of Hope Health Centre is a faith-based (Catholic Centre and Village of Hope were stored and transported in cold
church–owned) primary healthcare facility and HIV orphanage boxes maintained at a temperature between 2ºC and 8ºC (as per
center with 1602 clients and 127 pediatric cases enrolled in their national protocol and laboratory standard procedures) to the
HIV/AIDS care and treatment program. The main laboratory
at DRRH is designated as a referral laboratory for plasma HIV1
RNA assays for the central zone of Tanzania. Table 1.  Sampling Interval for Enrollment at Different Study Sites 
We enrolled 300 children living with HIV aged 6  months
to 19  years who attended the 3 care and treatment clinics for Dodoma Regional Makole Village
Study Site Referral Hospital Health Centre of Hope
routine HIV/AIDS care and ART monitoring during the study
period. Inclusion criteria were being aged 6 months to 19 years 2016 quarter registered 9291 5709 1602
number of clients
with confirmed HIV (by HIV antibody positivity for children Proportional percentage 50 30 20
aged ≥18 months or by DNA-PCR for those aged <18 months) Site sample size (N) 150 90 60
who had been on ART for a minimum of 6  months prior to Study sample size (n) 300 300 300
our study, and with verbal and written consent granted by a Sampling interval (k) 2nd 3rd 5th

132 • jpids 2021:10 (February) •  Bitwale et al


DRRH main laboratory for CD4+ lymphocyte and plasma HIV1 for tuberculosis (TB) infection (active disease) by probing their
RNA viral load testing. CD4+ lymphocytes were measured history of exposure to active TB cases and symptoms sugges-
using the fluorescence-activated cell sorter FACSCALIBUR flow tive of TB, such as prolonged cough, fever, and night sweats.
cytometry machine (Beckman, Dickinson, and Co, Franklin Those with a suspicious history underwent further workup that
Lakes, NJ) whereby 3  mL of venous blood kept in an EDTA- included chest X-ray, sputum/gastric aspirate for acid fast ba-
containing tube at room temperature (shelf life of 72 hours) and cilli  (AFB), Mycobacterium tuberculosis/rifampin GeneXpert
50 µL of reagent was added and vortexed for 5–10 seconds and assay, and culture. Those confirmed to have TB were treated per
then incubated for 1–2 hours followed by fixing using 50 µL fix- Tanzania National Tuberculosis and Leprosy Control Program
ative via the Fast-count machine. guidelines; this included rifampicin, isoniazid, pyrazinamide,
Plasma HIV1 RNA levels were tested using the Abbott m2000 and ethambutol for 2 months followed by rifampicin and isoni-
system (Abbott Molecular Inc, Wiesbaden, German). The azid for 4 months. All children living with HIV aged <5 years,
lowest limit for detection of plasma HIV1 RNA by PCR was 40 children aged >5  years with CD4+ lymphocytes <500 cells/µL,
copies/mL for 600-µL samples whereby 5 mL of venous blood and those with WHO HIV/AIDS clinical stage 3 or 4 were sup-
kept in the plasma preparation tube containing EDTA gel (shelf posed to be on cotrimoxazole prophylaxis.

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life of 6 hours) was centrifuged. Plasma was taken to the viral
load testing machine for extraction in 3 hours and amplification Data Analyses
followed by detection for 3 hours to get the RNA measure. Data were analyzed using SPSS version 25. Descriptive data
Per Tanzanian national HIV/AIDS management guidelines, were summarized in frequency percentage distributions and
immunological treatment failure was defined as CD4+ lympho- proportions. Categorical variables were summarized by means
cytes <25% for children aged <5  years and < 500 cells/mm3 for and mode, while continuous variables were summarized by
those aged >5  years. Per Tanzanian national HIV/AIDS man- median and interquartile ranges. Multivariate logistic regres-
agement guidelines, virological treatment failure was defined sion was performed to identify factors independently asso-
as plasma HIV1 RNA ≥1000 copies/mL after being on ART for ciated virological treatment failure, odds ratio and 95%  CI
6 months or more. Results for patients with unsuppressed viral intervals were calculated and factors with a P value < .05
load were reported to the attending clinicians of respective clinics were considered statistically significant. The primary and
for clinical decisions, including enhanced adherence counseling, secondary endpoints were the prevalence of virological treat-
and samples were sent to the national reference laboratory for re- ment failure and factors associated with virological treatment
sistant mutation testing (results not part of this study). failure, respectively.
Children and adolescents were on efavirenz, nevirapine, and
protease inhibitor–based antiretroviral drugs that were the reg-
RESULTS
imen available and recommended in the Tanzanian national
HIV/AIDS management guidelines. Antiretroviral drugs were A total of 638 children and adolescents attended the 3 HIV/
provided for free to all clients. AIDS care and treatment clinics in Dodoma Municipality
Age-appropriate HIV status disclosure to the child was during the study period and were evaluated for study eligi-
measured by asking if the child knew why he/she was taking bility. A total of 368 children were eligible for enrollment; 300
ART. The response of “for HIV” was considered full disclo- children and adolescents were finally enrolled after 68 children
sure, “for bad bugs” was considered partial disclosure, and “I were excluded for various reasons, as shown on Figure 1.
don’t know why” or mention of other diseases was considered
nondisclosure [14]. Children and adolescents were informed Baseline Characteristics of Children Living With HIV on ART
of their HIV-positive status following the Tanzanian national Of the 300 children enrolled, 51.7% (155/300) were female
guideline, with partial disclosure starting at age 6 years and full and 53.7% (161/300) were adolescents. Ages ranged from 1 to
disclosure starting at age 10 years. Disclosure to others was as- 19 years, with a median of 10 years, mean of 10.2 years, standard
sessed by asking if another member of the family/community is deviation of 4.7  years, and interquartile range of 7  years. The
aware of the HIV status of the child/adolescent. mean duration on ART was 3.6 ± 2.5 years.
Nutritional status was evaluated using WHO weight-for- Two-thirds of participants had good ART adherence
height z score for children aged <5 years and body mass index (61.0%), and 48.7% (146/300) were on efavirenz-based ART.
(BMI) for children aged >5 years as per age and sex. The nutri- About half (48.3%) had changed their ART regimen for various
tional status was categorized as normal for those with normal reasons, and 50.3% (151/300) had been on ART for more than
weight-for-height z score and BMI. Mild acute malnutrition was 4 years. More than half (53.0% [159/300]), of the children were
defined as –1 standard deviation (SD), moderate acute malnutri- WHO HIV/AIDS clinical stage 3–4, while two-third (189/300)
tion as –2 SD, and severe acute malnutrition as –3 SD based on the had normal CD4+ lymphocyte count levels. Other notable
WHO z score charts and BMI. All study children were screened findings included 56% (169/300) not being on cotrimoxazole

HIV Virological Treatment Failure in Tanzanian Children  •  jpids 2021:10 (February) • 133


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Figure 1.  Study flow chart of enrolled children living with human immunodeficiency virus attending care and treatment clinics in Dodoma Municipality.
Abbreviations: ART, antiretroviral therapy; DRRH, Dodoma Regional Referral Hospital; HC, Health Centre; HIV, human immunodeficiency virus.

prophylaxis and 8% (24/300) having TB infection. Other base- poor adherence to ART (AOR = 3.409; 95% CI, 1.109–10.476;
line characteristics of the study participants are listed in Table 2. P = .032), and not being on cotrimoxazole prophylactic therapy
(AOR = 25.56; 95% CI, 3.15–27.55; P = .002), as shown in
Prevalence of Virological Treatment Failure Among Children and Table 3.
Adolescent Living With HIV on ART
Overall, 34% (102/300) of children and adolescents met our DISCUSSION
definition of virological treatment failure (viral load ≥1000
copies/mL). Of the 34%, 56.9% (58/102) were from DRRH, Achievement of sustained virological suppression in children
26.5% (27/102) from Makole Health Centre, and 16.6% (17/102) living with HIV is crucial to ensuring long-term survival and
from Village of Hope. The proportion of virological treatment reducing HIV-related morbidity. Attainment of this goal in
failures to the number of children per clinic attended was 39% children compared with adults is affected by several challenges,
(58/150) at DRRH, 30% (27/90) at Makole Health Centre, and including the inherent risk for rapid HIV disease progression,
28% (17/60) at Village of Hope. limited availability of appropriate drug formulations, and drug
palatability that leads to subtherapeutic drug levels. The socio-
Factors Associated With Virological Treatment Failure Among Children cultural environment that surrounds the child, such as parental
and Adolescents Living With HIV health status, primary caretaker, and availability of compre-
On multivariate logistic regression analysis, children and ado- hensive HIV/AIDS care and treatment services, has a signifi-
lescents on a nevirapine-based regimen (34% [102/300]) were cant impact as well. In this cross-sectional study, we report a
more likely to have virological treatment failure compared high prevalence of virological treatment failure, 34% (102/300)
with those on efavirenz (48.7% [146/300]) or protease in- among children living with HIV on ARTs who attended routine
hibitor–based regimens (17.% [52/300]; adjusted odds ratio care clinics.
[AOR] = 3.221; 95% CI, 1.867–5.558; P = <.001). Several other Plasma HIV viral load testing in children living with HIV is the
factors were independently associated with virological treat- recommended gold standard test. Despite this recommenda-
ment failure, including TB infection (AOR = 8.881; 95% CI, tion, plasma HIV virological testing is not widely available in
2.012–39.202; P = .004), nonparent caregiver (AOR = 6.598; most developing countries. Until recently, most HIV/AIDS care
95% CI, 1.146–37.995; P = .035), nondisclosure of HIV status and treatment centers in resource-limited settings have used
to others (AOR = 7.741; 95% CI, 2.351–25.489; P = .001), the CD4 + lymphocyte level (absolute count or percentage) as

134 • jpids 2021:10 (February) •  Bitwale et al


Table 2.  Baseline Characteristics of Children and Adolescents on Table 2.  Continued
Antiretroviral Therapy Attending Care and Treatment Clinics in Dodoma
Variable Frequency (N = 300)
Municipality
CD4 level
Variable Frequency (N = 300)  Normal 189 (63.0%)
Child age, y  Lowa 111 (37.0%)
 <10 139 (46.3%)
Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus. 
 ≥10 161 (53.7%) a
Low CD4+ level defined as <25% for children aged <5 years and <500 cells/mm3 for children aged >5 years.
Sex
 Male 145 (48.3%)
 Female 155 (51.7%) an immunological marker of ART treatment response, though
Education level
this approach is increasingly reported to be less reliable in both
 No schooling 62 (20.7%)
 Primary 190 (63.3%)
children and adults on ART [15, 16]. Children, especially those
 Secondary 48 (16.0%) aged <5  years, have relatively higher CD4+ lymphocyte levels
Residence per body volume, and CD4+ counts can be affected by other

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 Urban 258 (86.0%) factors such as malnutrition and other infections. These factors
 Rural 42 (14.0%) and the emerging evidence imply that a significant proportion
Caregiver relationship
of children living with HIV who are failing on first-line ART are
 Parent 166 (55.3%)
 Non-parent 134 (44.7%)
missed and therefore pose a risk of accumulating drug resist-
Caregiver marital status ance mutations.
 Married 145 (48.3%) The prevalence of virological failure in our study was higher
 Single 155 (51.7%) than that reported by a group from the Ifakara Health Institute
Age of caregiver, y
in eastern Tanzania of 25.4% (54/213). This is possibly due to
 <45 169 (56.3%)
the fact that we enrolled children attending 3 HIV/AIDS care
 ≥45 131 (43.7%)
HIV status disclosure to child and treatment clinics that were independently operated by non-
 Yes 132 (44.0%) specialist clinicians compared with Ifakara, which is a research
 No 168 (56.0%) center [7]. Complex socioeconomic background for some of
HIV status disclosure to others our study participants, especially those who received care at the
 Yes 135 (45.0%)
Village of Hope (an HIV orphanage center), might also have in-
 No 165 (55.0%)
creased the risk for virological treatment failure.
ART adherence
 Good 183 (61.0%) Different rates of virologic treatment failure have been re-
 Poor 117 (39.0%) ported in the literature. This may be attributable to several
Tuberculosis status factors, including variation in settings, HIV prevalence, defi-
 Positive 24 (8.0%) nition of virological treatment failure, and socioeconomic fac-
 Negative 276 (92.0%)
tors related to HIV/AIDS care access and adherence [17, 18].
ART changes
 Yes 145 (48.3%)
In a study conducted in rural Cameroon, Zoufaly et al reported
 No 155 (51.7%) the prevalence of virological treatment failure to be 53% higher
Cotrimoxazole prophylaxis than in our study; however, their definition of virological treat-
 Yes 131 (43.7%) ment failure was a plasma HIV1 viral load of >200 copies/mL
 No 169 (56.3%)
compared to >1000 copies/mL in our study [9].
ART duration, mo
Our study findings and those from neighboring regions in-
 6–24 60 (20.0%)
 25–47 89 (29.7%)
cluding Kenya and Uganda show a high prevalence of virolog-
 ≥48 151 (50.3%) ical treatment failure among children living with HIV on ART
Current ART regimen compared with prevalence from western and southern Africa
 Nevirapine-based 102 (34.0%) of 10.7% (45/421) and 16.7% (15/90), respectively [8, 19–21].
 Efavirenz-based 146 (48.7%)
This might be due to chance variations in study findings. The
 Protease inhibitor–based 52 (17.3%)
possibility of other pertinent factors such as the presence of
Nutritional status
 Normal 211 (70.3%) more virulent and treatment-resistant HIV1 strains or specific
 Mild–moderate malnutrition 79 (26.3%) sociocultural factors in our settings warrant exclusion [22,
 Severe malnutrition 10 (3.4%) 23]. The observed high prevalence of children and adolescents
World Health Organization HIV clinical stage living with HIV with virological treatment failure in our study
 1–2 141 (47.0%)
and other reported studies in our settings underscore the ur-
 3–4 159 (53.0%)
gent need to scale up access to plasma HIV1 viral load testing

HIV Virological Treatment Failure in Tanzanian Children  •  jpids 2021:10 (February) • 135


Table 3.  Factors Associated With Virological Treatment Failure Among Children and Adolescents on Antiretroviral Therapy Attending Care and
Treatment Clinics in Dodoma Municipal

Viral Load
Bivariate Odds Ratio Multivariate Adjusted Odds
Variable Suppressed (N = 198) Unsuppressed (N = 102) (95% CI, P value) Ratio (95% CI, P value)
Age of client, y
 <10 85 (42.9%) 54 (52.9%) 0.669 (0.414–1.081, .100)
 ≥10 113 (57.1%) 48 (47.1%)
Sex
 Male 96 (48.5%) 49 (48.0%) 1.018 (0.631–1.642, .942)
 Female 102 (51.5%) 53 (52.0%)
Education level
 No schooling 36 (18.2%) 25 (24.5%)
 Primary 129 (65.2%) 62 (60.8%) 1.486 (0.672–3.288, .328)
 Secondary 33 (16.7%) 15 (14.7) 1.066 (0.539–2.107, .855)
Residence

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 Urban 178 (89.9%) 80 (78.4%) 2.447 (1.264–4.738, .008) 0.803 (0.132–4.889, .812)
 Rural 20 (10.1%) 22 (21.6%)
Age of caregiver, y
 <45 109 (55.1%) 60 (58.8%) 0.857 (0.529–1.390, .533)
 ≥45 89 (44.9%) 42 (41.2%)
Caregiver employment
 Employed 20 (10.1%) 10 (9.8%) 1.034 (0.465–2.300, .935)
 Self-employed 178 (89.9%) 92 (90.2%)
Mother
 Alive 133 (67.2%) 75 (73.5%) 0.737 (0.433–1.252, .259)
 Dead 65 (32.8%) 27 (26.5%)
Caregiver marital status
 Married 111 (56.1%) 34 (33.3%) 2.552 (1.550–4.200, <.001) 2.656 (0.788–8.954, .115)
 Single 87 (43.9%) 68 (66.7%)
Age of child at diagnosis, y
 ≤5 117 (59.1%) 67 (65.7%) 0.836 (0.599–1.166, .290)
 >5 81 (40.9%) 35 (34.3%)
Caregiver HIV status
 Positive 110 (55.6%) 66 (64.7%) 0.708 (0.477–1.051, .086)
 Negative 88 (44.4%) 36 (35.3%)
Caregiver ART use
 Yes 110 (55.6%) 66 (64.7%) 0.682 (0.416–1.117, .128)
 No 88 (44.4%) 36 (35.3%)
Nevirapine prophylaxis
 Yes 18 (9.1) 13 (12.7%) 0.685 (0.321–1.460, .327)
 No 180 (90.9%) 89 (87.3%)
Disclosure to others
 Yes 117 (59.1%) 18 (17.6%) 6.741 (3.764–12.070, <.001) 7.741 (2.351–25.489, .001)
 No 81 (40.9%) 84 (82.4%)
ART adherence
 Good 136 (68.7%) 47 (46.1%) 2.567 (1.570–4.197, <.001) 3.409 (1.109–10.476, .032)
 Poor 62 (31.3%) 55 (53.9%)
HIV status disclosed to child
 Yes 88 (44.4%) 39 (38.2%) 0.521 (0.247–1.102, .088)
 No 90 (45.5%) 46 (45.1%) 0.601 (0.288–1.257, .177)
Not on criteria 20 (10.1%) 17 (16.7%)
Tuberculosis status
 Positive 3 (1.5%) 21 (20.6%) 16.852 (4.891–58.068, <.001) 8.881 (2.012–39.202, .004)
 Negative 195 (98.5%) 81 (79.4%)
Father
 Alive 131 (66.2%) 65 (63.7%) 1.113 (0.675–1.834, .675)
 Dead 67 (33.8%) 37 (36.3%)

136 • jpids 2021:10 (February) •  Bitwale et al


Table 3.  Continued

Viral Load
Bivariate Odds Ratio Multivariate Adjusted Odds
Variable Suppressed (N = 198) Unsuppressed (N = 102) (95% CI, P value) Ratio (95% CI, P value)
Caregiver relationship
 Parent 123 (62.1%) 43 (42.2%) 2.250 (1.383–3.661, .001) 6.598 (1.146–37.995, .035)
 Non-parent 75 (37.9%) 59 (57.8%)
ART changes
 Yes 85 (42.9%) 60 (58.8%) 1.899 (1.170–3.083, .009) 0.614 (0.163–2.309, .470)
 No 113 (57.1%) 42 (41.2%)
Cotrimoxazole prophylaxis
 Yes 100 (50.5%) 31 (30.4%) 2.337 (1.410–3.875, .001) 25.56 (3.15–27.55, .002)
 No 98 (49.5%) 71 (69.6%)
Isoniazid prophylaxis
 Yes 71 (35.9%) 32 (31.4%) 1.223 (0.735–2.035, .439)
 No 127 (64.1%) 70 (68.6%)

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Caregiver alcohol use
 Yes 26 (13.1%) 13 (12.7%) 1.035 (0.507–2.112, .925)
 No 172 (86.9%) 89 (87.3%)
ART duration
 6–24 months 42 (21.2%) 18 (17.6%) 0.668 (0.352–1.270, .218)
 25–47 months 64 (32.3%) 25 (24.5%)
 ≥48 months 92 (46.5%) 59 (57.8%) 0.609 (0.346–1.073, .086)
ART regimen
 Nevirapine-based 55 (27.8%) 47 (46.1%) 3.185 (1.473–6.886, .003) 3.221 (1.867–5.558, <.001)
 Efavirenz-based 102 (51.5%) 44 (43.1%) 1.608 (0.757–3.416, .217) 1.302 (0.106–1.869, .205)
 Protease inhibitor–based 41 (20.7%) 11 (10.8%)
Current HIV World Health Organization
stage
 1–2 106 (53.5%) 35 (34.3%) 2.206 (1.344–3.618, .002) 0.716 (0.088–5.836, .755)
 3–4 92 (46.5%) 67 (65.7%)
Nutritional status
 Normal 140 (70.7%) 71 (69.6%)
 Mild–moderate malnutrition 54 (27.3%) 25 (24.5%) 0.338 (0.092–1.237, .101)
 Severe malnutrition 4 (2.0%) 6 (5.9%) 1.185 (0.764–1.836, .449)
CD4 level
 Normal 141 (71.2%) 48 (47.1%) 2.783 (1.695–4.569, <.001) 1.298 (0.415–4.055, .654)
 Low 57 (28.8%) 54 (52.9%)

Abbreviations: ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus.

for children living with HIV. This will ensure early detection with other studies, a nevirapine-based regimen was associ-
of those failing treatment and administration of prompt inter- ated with development of virological treatment failure [10, 26,
ventions including enhanced adherence counseling and timely 27]. The increased likelihood for virological treatment failure
ART regimen transitions [24]. for nevirapine-based regimens in children is mainly attributed
When compared with adults living with HIV, children and to the use of this drug as a monotherapy during prevention of
adolescents living with HIV are at significantly higher risk of de- mother-to-child transmission of HIV. Virological treatment
veloping virological treatment failure [25]. Children and adoles- failure has also been reported among children living with
cents depend heavily on a high level of caretaker involvement. HIV on a nevirapine-based regimen with no prior exposure to
In addition, other sociocultural factors influence their situation. nevirapine monotherapy [28, 29].
These unique needs should be taken into consideration when Nevirapine is known to have a low genetic barrier to resist-
planning and implementing treatment to ensure good adherence. ance development, which may partly explain the development
Similar to previous studies in Tanzania, Emmett et al found of virological treatment failure among children not previously
that children on a nevirapine-based regimen were 2 times exposed to this drug [30, 31]. The association of a nevirapine-
more likely to have virological treatment failure than those on based regimen and virological treatment failure among children
efavirenz or protease inhibitor–based regimens [47]. In line living with HIV who attend care clinics could also reflect HIV

HIV Virological Treatment Failure in Tanzanian Children  •  jpids 2021:10 (February) • 137


infection by a maternal HIV strain that is already carrying The current study showed that children cared for by nonbi-
drug resistance–related mutations (DRMs). A  previous study ological parents and those whose HIV infection status had not
conducted in Dodoma among ART-naive pregnant women been disclosed to other family members had a higher likelihood
reported primary drug resistance of 11.9% and primary drug of developing virological treatment failure. A study in Uganda
class–specific resistance for nonnucleoside reverse-transcriptase revealed that an individual’s HIV/AIDS status disclosure to
inhibitors (NNRTIs) of 7.5% with the K103S mutation [32]. In family and friends increases support in aspects of life as well as
a study from south–central Tanzania, Muri et al reported 90% behavioral changes [43]. Thus, the finding that nondisclosure of
NNRTI resistance such as K103N/KN mutations that led to HIV status of the child to other family members was linked to
high-level resistance to efavirenz and nevirapine [7]. The fact virological treatment failure is likely related to the lack of these
that efavirenz did not show statistical significance might be due supportive mechanisms.
to chance variations in study findings. Trimethoprim-sulfamethoxazole (cotrimoxazole) is a
HIV/TB coinfection is common among people living with commonly used antibiotic in people living with HIV/AIDS,
HIV, especially in the pediatric population [33]. In our study, especially children and adolescents. It is mainly used as pro-
TB infection was found to be highly associated with the occur- phylaxis for Pneumocystis jirovecii pneumonia, toxoplas-

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rence of virological treatment failure, with 9 times higher odds mosis, malaria, pneumonia, and diarrhea diseases [44]. In
of developing virological treatment failure. These findings are our current study, children not on cotrimoxazole prophylaxis
in accordance with those reported in a study from Kilimanjaro, were much more likely to have virological treatment failure
Tanzania, and rural South Africa [19, 34, 47]. While this was than those on prophylaxis. Cotrimoxazole prophylaxis was
not assessed in our study, drug–drug interactions between an- associated with reduction of morbidity, mortality, and the
tiretroviral and anti-TB medications may have been the reason requirement for an antibiotic prescription among children
for development of virological treatment failure among children living with HIV in a randomized placebo-controlled trial in
treated for TB while on ART without drug and dosage adjust- Zambia. The finding that this drug prevents development of
ments. Rifampicin is known to activate rapid drug metabolism virological treatment failure is quite new and requires fur-
by hepatic enzyme cytochrome CYP-450, causing a decline ther investigation [45, 46].
in the serum nevirapine levels of 30% to 55% and leading to The strength of our study is that it was undertaken in a
subtherapeutic drug levels [35]. pragmatic way; this reflects a setting in which the vast ma-
Children with severely depressed CD4+ lymphocytes are at jority of children and adolescents on ART who attend care
high risk of progression to active TB from latent TB and have and treatment clinics are managed. Thus, results of this study
a high likelihood of acquiring the disease on exposure [36]. could be generalized to other resource-limited settings. A lim-
Conversely, there is a possibility that HIV disease preferentially itation of our study is that the results of ART drug resist-
affects the TB-specific CD4+ lymphocytes before a significant ance testing to identify the prevalence and the most common
decline in general cell-mediated immunity. It has been observed DRMs to use when choosing the best switch regimen for these
that people living with HIV in high TB endemic regions have patients were not included. The cross-sectional nature of our
an elevated risk of acquiring TB disease even with very high study, which was due to time limitations, limited the establish-
CD4+ lymphocyte counts early on after HIV infection [37]. ment of causal relationships of factors such as cotrimoxazole
There are limited data describing how TB infection affects HIV prophylaxis and TB infection with the development of viro-
disease progression and the response to ART, but in vitro evi- logical treatment failure.
dence shows that TB accelerates HIV replication [38].
Poor adherence predisposes individuals to development of
CONCLUSIONS
DRMs and virological treatment failure. A significant propor-
tion of our study participants (39%; 117/300) were found to Despite increased availability and access to highly active ART
have poor adherence to ART, and this increased the likelihood in low- to middle-income countries such as Tanzania, achieve-
of treatment failure 3-fold. Poor adherence to ART is frequently ment of long-term virological suppression to meet the UNAIDS
attributed to virological treatment failure among children and 90–90–90 strategy is threatened by a high prevalence of viro-
adolescents on ART [39, 40]. Maintenance of good adherence logical treatment failure among children and adolescents living
is affected by a complex interaction of factors, including the de- with HIV, as shown in this study. There is a need to scale up the
pendence of children on committed caretakers to ensure daily use of plasma HIV1 viral load testing for ART response moni-
intake of ART, pill burden in dosage and frequency, adolescent toring and to scale up the use of HIV antiretroviral drug resist-
behaviors at this developmental stage, HIV-associated stigma, ance testing for prompt identification and switching of failing
HIV infection status disclosure, and financial and infrastruc- patients. Follow-up studies are required to address the known
tural factors related to accessibility of HIV care and treatment and emerging factors that contribute to virological treatment
[41, 42]. failure in order to prevent virological treatment failure and

138 • jpids 2021:10 (February) •  Bitwale et al


develop ART drug resistance mutations. Strategies are needed 17. Kabago J, Ochwoto M, Omange RW, et al. Risk factors of virologic failure and slow
response to ART among HIV-infected children and adolescents in Nairobi. East
to reduce HIV-associated stigma and promote disclosure, Afr Med J 2017; 94:487–498.
increase ART adherence, and prevent common opportunistic 18. Kadima  J, Patterson  E, Mburu  M, et  al. Adoption of routine virologic testing
and predictors of virologic failure among HIV-infected children on antiretro-
and HIV-associated infections using sustainable provision of viral treatment in western Kenya. PLoS One 2018; 13:1–15. https://doi.org/DOI:
cotrimoxazole prophylaxis. 10.1371/journal.pone.0200242
19. Collier D, Iwuji C, Derache A, et al. virological outcomes of second-line pro-
tease inhibitor-based treatment for human immunodeficiency virus type 1 in
Notes a high-prevalence rural South African setting: a competing-risks prospective
Acknowledgments. We express our sincere gratitude to Dr Nassoro cohort analysis. Clin Infect Dis 2017; 64:1006–16. https://doi.org/10.1093/
David, Joram Timba, Seif Kachemela, and Dr Gabriel Mchonde for their cid/cix015
20. Gidey Brhane, B, Nibret, E, Kahsu Abay, G. HIV/AIDS treatment failure and its
enormous support during dissertation development and the Tanzanian
determinant factors among first line HAART patients at Felege-Hiwot Referral
Ministry of Health for financial support.
Hospital, Bahir Dar, Northwest Ethiopia. J AIDS Clin Res2 2017; 8:1000744.
Potential conflicts of interest. All authors: No reported conflicts of in- https://doi.org/10.4172/2155–6113.1000744
terest. All authors have submitted the ICMJE Form for Disclosure of 21. Owusu M, Mensah E, Enimil A, Mutocheluh M. Prevalence and risk factors of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to virological failure among children on antiretroviral therapy. BMJ Global Health
the content of the manuscript have been disclosed.  2017; 2(Suppl 2):A9.2–A9. https://doi.org/10.1136/bmjgh-2016-000260.20

Downloaded from https://academic.oup.com/jpids/article/10/2/131/5848104 by guest on 17 April 2023


22. Easterbrook PJ, Smith M, Mullen J, et al. Impact of HIV-1 viral subtype on disease
progression and response to antiretroviral therapy. J Int AIDS Soc 2010; 13:4–4.
References https://doi.org/10.1186/1758-2652-13-4
1. Geretti  AM, Conibear  T, Hill  A, et  al. Sensitive testing of plasma HIV-1 RNA 23. Spira S, Wainberg MA, Loemba H, et al. Impact of clade diversity on HIV-1 viru-
and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resist- lence, antiretroviral drug sensitivity and drug resistance. J Antimicrob Chemother
ance prior to starting first-line antiretroviral therapy with etravirine or efavirenz. 2003; 51:229–40. https://doi.org/10.1093/jac/dkg079
J Antimicrob Chemother 2014; 69:1090–7. https://doi.org/10.1093/jac/dkt474 24. Peter T, Ellenberger D, Kim AA, et al. Early antiretroviral therapy initiation: ac-
2. Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect cess and equity of viral load testing for HIV treatment monitoring. Lancet Infect
Med 2012; 2:a007161, 1–23. https://doi.org/doi: 10.1101/cshperspect.a007161 Dis 2017; 17:e26–9. https://doi.org/10.1016/S1473-3099(16)30212-2
3. United Nations Programme on HIV and AIDS. Global HIV & AIDS statistics — 25. Wadunde  I, Tuhebwe  D, Ediau  M, et  al. Factors associated with adherence to
2019 fact sheet. UNAIDS [Internet]. 2019. Retrieved from: https://www.unaids. antiretroviral therapy among HIV infected children in Kabale district, Uganda:
org/en/resources/fact-sheet a cross sectional study. BMC Res Notes 2018; 11:466. https://doi.org/10.1186/
4. AVERT. HIV and AIDS In Tanzania. 2019. Retrieved from https://www.avert.org/ s13104-018-3575-3
printpdf/node/406 26. Chouraya  C, Ashburn  K, Khumalo  P, et  al. Association of antiretroviral drug
5. World Health Organization. What’s new in treatment monitoring: viral load regimen with viral suppression in HIV-positive children on antiretroviral
and CD4 testing. HIV Treatment and Care Information Note (July) 2017:1–2. therapy in Eswatini. Pediatr Infect Dis J 2019; 38:835–9. https://doi.org/10.1097/
Retrieved from www.who.int/hiv. Accessed January 4, 2018. INF.0000000000002347
6. Mgelea  EM, Kisenge  R, Aboud  S. Detecting virological failure in HIV-infected 27. Judd  A, Lodwick  R, Noguera-Julian  A, et  al. Higher rates of triple-class viro-
Tanzanian children. S Afr Med J 2014; 104:696–9. https://doi.org/10.7196/ logical failure in perinatally HIV-infected teenagers compared with heterosexu-
samj.7807 ally infected young adults in Europe. HIV Med 2017; 18:171–80. https://doi.
7. American Political Science Review. Survey Sampling. By Leslie Kish. (New York: org/10.1111/hiv.12411
John Wiley & Sons, Inc., 1965. Pp. xvi, 643. $10.95.). 1965; 59:1025. https://doi. 28. Chohan BH, Tapia K, Benki-Nugent S, et al. Nevirapine resistance in previously
org/10.1017/S0003055400132113 nevirapine-unexposed HIV-1-infected Kenyan infants initiating early anti-
8. Moolasart V, Chottanapund S, Ausavapipit J, et al. The effect of detectable HIV viral retroviral therapy. AIDS Res Hum Retroviruses 2015; 31:783–91. https://doi.
load among HIV-infected children during antiretroviral treatment: a cross-sec- org/10.1089/AID.2014.0370
tional study. Children 2018; 5:6. https://doi.org/10.3390/children5010006 29. Lehman DA, Chung MH, Mabuka JM, et al. Lower risk of resistance after short-
9. Zoufaly A, Fillekes Q, Hammerl R, et al. Prevalence and determinants of virolog- course HAART compared with zidovudine/single-dose nevirapine used for pre-
ical failure in HIV-infected children on antiretroviral therapy in rural Cameroon: vention of HIV-1 mother-to-child transmission. J Acquir Immune Defic Syndr
a cross-sectional study. Antivir Ther 2013; 18:681–90. https://doi.org/10.3851/ 2009; 51:522–9. https://doi.org/10.1097/QAI.0b013e3181aa8a22
IMP2562 30. Delaugerre  C. Barrière génétique à la résistance des antirétroviraux.
10. Makadzange  AT, Higgins-Biddle  M, Chimukangara  B, et  al. Clinical, virologic, Médecine et Maladies Infectieuses 2010; 40:S1–S10. https://doi.org/10.1016/
immunologic outcomes and emerging HIV drug resistance patterns in children S0399-077X(10)70001–9
and adolescents in public ART care in Zimbabwe. PLoS One 2015; 10:e0144057. 31. Zazzi  M. High genetic barrier antiretroviral drugs in human immunodefi-
https://doi.org/10.1371/journal.pone.0144057 ciency virus–positive pregnancy. Clin Infect Dis 2010; 50:895–897. https://doi.
11. Boerma  RS, Boender  TS, Bussink  AP, et  al. Suboptimal viral suppression rates org/10.1086/650748
among HIV-infected children in low- and middle-income countries : a meta- 32. Vairo  F, Nicastri  E, Liuzzi  G, et  al.; AMANI Study Group. HIV-1 drug resist-
analysis. Clin Infect Dis 2016; 63:1645–1654. https://doi.org/10.1093/cid/ciw645 ance in recently HIV-infected pregnant mother’s naïve to antiretroviral therapy
12. Estill  J, Aubrière  C, Egger  M, et  al. Viral load monitoring of antiretroviral in Dodoma urban, Tanzania. BMC Infect Dis 2013; 13(1), 1. https://doi.
therapy, cohort viral load and HIV transmission in southern Africa: a math- org/10.1186/1471-2334-13-439
ematical modelling analysis. AIDS 2012; 26:1403–13. https://doi.org/10.1097/ 33. Venturini  E, Turkova  A, Chiappini  E, Galli  L, Martino  MD, Thorne  C.
QAD.0b013e3283536988 Tuberculosis and HIV co-infection in children. BMC Infectious Diseases 2014;
13. Intasan  J, Bunupuradah  T, Vonthanak  S, et  al. Comparison of adherence 14(Suppl 1):S5. https://doi.org/10.1186/1471-2334-14-S1-S5
monitoring tools and correlation to virologic failure in a pediatric HIV clin- 34. Bulage  L, Ssewanyana  I, Nankabirwa  V, et  al. Factors associated with viro-
ical trial. AIDS Patient Care STDS 2014; 28:296–302. https://doi.org/10.1089/ logical non-suppression among HIV-positive patients on antiretroviral therapy
apc.2013.0276 in Uganda, August 2014-July 2015. BMC Infect Dis 2017; 17:326. https://doi.
14. Naeem-Sheik A, Gray G. HIV disclosure in children. South Afr J HIV Med 2005; org/10.1186/s12879-017-2428-3
6:46–48. https://doi.org/DOI: 10.4102/hivmed.v6i4.578 35. Padmapriyadarsini  C, Narendran  G, Swaminathan  S. Diagnosis treatment of
15. Moore DM, Awor A, Downing R, et al. CD4+ T-cell count monitoring does not tuberculosis in HIV co-infected patients. Indian J Med Res 2011; 134:850–65.
accurately identify HIV-infected adults with virologic failure receiving anti- https://doi.org/10.4103/0971-5916.92630
retroviral therapy. J Acquir Immune Defic Syndr 2008; 49:477–84. https://doi. 36. Sonnenberg P, Glynn JR, Fielding K, et al. How soon after infection with HIV does
org/10.1097/QAI.0b013e318186eb18 the risk of tuberculosis start to increase? A retrospective cohort study in South
16. Rawizza  HE, Chaplin  B, Meloni  ST, et  al.; APIN PEPFAR Team. Immunologic African gold miners. J Infect Dis 2005; 191:150–8. https://doi.org/10.1086/426827
criteria are poor predictors of virologic outcome: implications for HIV treat- 37. Geldmacher  C, Zumla  A, Hoelscher  M. Interaction between HIV and
ment monitoring in resource-limited settings. Clin Infect Dis 2011; 53:1283–90. Mycobacterium tuberculosis. Curr Opin HIV AIDS 2012; 7:268–75. https://doi.
https://doi.org/10.1093/cid/cir729 org/10.1097/COH.0b013e3283524e32

HIV Virological Treatment Failure in Tanzanian Children  •  jpids 2021:10 (February) • 139


38. Del  Amo  J, Pérez-Hoyos  S, Hernández  Aguado  I, et  al.; Concerted Action on 43. Atuyambe  LM, Ssegujja  E, Ssali  S, et  al. HIV/AIDS status disclosure increases
Seroconversion to AIDS and Death in Europe Collaboration. Impact of tuber- support, behavioural change and, HIV prevention in the long term : a case for an
culosis on HIV disease progression in persons with well-documented time of urban clinic, Kampala, Uganda. Bio Medical Central 2014; 14:1–11. https://doi.
HIV seroconversion. J Acquir Immune Defic Syndr 2003; 33:184–90. https://doi. org/doi:10.1186/1472-6963-14-276
org/10.1097/00126334-200306010-00011 44. Bwakura-dangarembizi M, Kendall L, Bakeera-kitaka S, et al. A randomized trial
39. Haberer J, Mellins C. Pediatric adherence to HIV antiretroviral therapy. Current of prolonged co-trimoxazole in HIV-infected children in Africa. 2014; 370:41–
HIV/AIDS Rep 2010; 6:194–200. https://doi.org/10.1007/s11904-009-0026-8 53. https://doi.org/10.1056/NEJMoa1214901
40. Mutwa PR, Boer KR, Asiimwe-Kateera B, et al. Safety and effectiveness of com- 45. Boti N, Hebo S. Nutritional status and its effect on treatment outcome among HIV-
bination antiretroviral therapy during the first year of treatment in HIV-1 in- infected children receiving first-line antiretroviral therapy in Arba Minch General
fected Rwandan children: a prospective study. PLoS One 2014; 9:1–12. https:// Hospital and Arba Minch Health Center, Gamo Zone, southern Ethiopia: retrospective
doi.org/10.1371/journal.pone.0111948 cohort study. IntechOpen 2019:1–15. https://doi.org/10.5772/intechopen.85851
41. Mutwa  PR, Van  Nuil  JI, Asiimwe-Kateera  B, et  al. Living situation affects ad- 46. Mulenga V, Ford D, Walker AS, et al.; CHAP Trial Team. Effect of cotrimoxazole
herence to combination antiretroviral therapy in HIV-infected adolescents in on causes of death, hospital admissions and antibiotic use in HIV-infected chil-
Rwanda: a qualitative study. PLoS One 2013; 8:e60073. https://doi.org/10.1371/ dren. AIDS 2007; 21:77–84. https://doi.org/10.1097/QAD.0b013e3280114ed7
journal.pone.0060073 47. Emmett  SD, Cunningham  CK, Mmbaga  BT, et  al. Predicting virologic failure
42. Vervoort  SC, Borleffs  JC, Hoepelman  AI, Grypdonck  MH. Adherence in anti- among HIV-1-infected children receiving antiretroviral therapy in Tanzania: a
retroviral therapy: a review of qualitative studies. AIDS 2007; 21:271–81. https:// cross-sectional study. J Acquir Immune Defic Syndr 2010; 54:368–75. https://doi.
doi.org/10.1097/QAD.0b013e328011cb20 org/10.1097/QAI.0b013e3181cf4882.Predicting

Downloaded from https://academic.oup.com/jpids/article/10/2/131/5848104 by guest on 17 April 2023

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