Effectiveness of Pediatric Antiretroviral Therapy in Resource-Limited Settings: A Systematic Review

Article (PDF Available)inClinical Infectious Diseases 49(12):1915-27 · November 2009with36 Reads
DOI: 10.1086/648079 · Source: PubMed
Abstract
Responses to antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected children in resource-limited settings have recently been reported, but outcomes vary. We sought to derive pooled estimates of the 12-month rate of virologic suppression (HIV RNA, <400 copies/mL) and gain in CD4 cell percentage (DeltaCD4%) for children initiating ART in resource-limited settings. We conducted a systematic review and meta-analysis of published reports of HIV RNA and CD4 outcomes for treatment-naive children aged 0-17 years old by means of the Medline, EMBASE (Excerpta Medica Database), and LILACS (Latin American and Caribbean Health Sciences Literature) electronic databases and the Cochrane Clinical Trials Register. Pooled estimates of the reported proportion with HIV RNA <400 copies/mL and DeltaCD4% after 12 months of ART were derived using patient-level estimates and fixed- and random-effects models. To approximate intention-to-treat analyses, in sensitivity analyses children with missing 12-month data were assumed to have HIV RNA>400 copies/mL or DeltaCD4% of zero. In patient-level estimates after 12 months of ART, the pooled proportion with virologic suppression was 70% (95% confidence interval [CI], 67%-73%); the pooled DeltaCD4% was 13.7% (95% CI, 11.8%-15.7%). Results from the fixed- and random-effects models were similar. In approximated intention-to-treat analyses, the pooled estimates decreased to 53% with virologic suppression (95% CI, 50%-55%) and to a DeltaCD4% of 8.5% (95% CI, 5.5%-11.4%). Pooled estimates of reported virologic and immunologic benefits after 12 months of ART among HIV-infected children in resource-limited settings are comparable with those observed among children in developed settings. Consistency in reporting on reasons for missing data will aid in the evaluation of ART outcomes in resource-limited settings.
HIV/AIDS CID 2009:49 (15 December) 1915
HIV/AIDSMAJOR ARTICLE
Effectiveness of Pediatric Antiretroviral Therapy
in Resource-Limited Settings: A Systematic Review
and Meta-analysis
Andrea L. Ciaranello,
1
Yuchiao Chang,
2
Andrea V. Margulis,
3
Adam Bernstein,
4
Ingrid V. Bassett,
1,2
Elena Losina,
2,5,7
and Rochelle P. Walensky
1,2,6,8
The Divisions of
1
Infectious Disease and
2
General Medicine, Massachusetts General Hospital, the Departments of
3
Epidemiology and
4
Nutrition,
Harvard School of Public Health, the
5
Department of Orthopedic Surgery and the
6
Division of Infectious Disease, Brigham and Women’s Hospital,
the
7
Department of Biostatistics, Boston University School of Public Health, and the
8
Center for AIDS Research, Harvard Medical School, Boston,
Massachusetts
Background. Responses to antiretroviral therapy (ART) among human immunodeficiency virus (HIV)–infected
children in resource-limited settings have recently been reported, but outcomes vary. We sought to derive pooled
estimates of the 12-month rate of virologic suppression (HIV RNA,
!400 copies/mL) and gain in CD4 cell percentage
(DCD4%) for children initiating ART in resource-limited settings.
Methods. We conducted a systematic review and meta-analysis of published reports of HIV RNA and CD4
outcomes for treatment-naive children aged 0–17 years old by means of the Medline, EMBASE (Excerpta Medica
Database), and LILACS (Latin American and Caribbean Health Sciences Literature) electronic databases and the
Cochrane Clinical Trials Register. Pooled estimates of the reported proportion with HIV RNA
!400 copies/mL
and DCD4% after 12 months of ART were derived using patient-level estimates and fixed- and random-effects
models. To approximate intention-to-treat analyses, in sensitivity analyses children with missing 12-month data
were assumed to have HIV RNA
1400 copies/mL or DCD4% of zero.
Results. In patient-level estimates after 12 months of ART, the pooled proportion with virologic suppression
was 70% (95% confidence interval [CI], 67%–73%); the pooled DCD4% was 13.7% (95% CI, 11.8%–15.7%).
Results from the fixed- and random-effects models were similar. In approximated intention-to-treat analyses, the
pooled estimates decreased to 53% with virologic suppression (95% CI, 50%–55%) and to a DCD4% of 8.5%
(95% CI, 5.5%–11.4%).
Conclusions. Pooled estimates of reported virologic and immunologic benefits after 12 months of ART among
HIV-infected children in resource-limited settings are comparable with those observed among children in developed
settings. Consistency in reporting on reasons for missing data will aid in the evaluation of ART outcomes in
resource-limited settings.
INTRODUCTION
Combination antiretroviral therapy (ART) is effective
in preventing morbidity and mortality in human im-
munodeficiency virus (HIV)-infected children who are
living in developed settings [1–5]. Ninety percent of
Received 25 March 2009; accepted 24 June 2009; electronically published 16
November 2009.
Presented in part: International AIDS Society Meeting, Cape Town, South Africa,
July 2009 (abstract MOPEB081).
Reprints or correspondence: Dr Andrea L. Ciaranello, Division of Infectious
Disease, Massachusetts General Hospital, 50 Staniford St, 9th fl, Boston, MA
02114 (aciaranello@partners.org).
Clinical Infectious Diseases 2009;49:1915–27
2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4912-0023$15.00
DOI: 10.1086/648079
the 2.1 million HIV-infected children worldwide live in
resource-limited settings, where lack of access to ART
for children remains a substantial problem [6]. Re-
cently, government- and donor-funded programs have
expanded access to ART for HIV-infected children in
resource-limited settings [7]. Clinical, virologic, and
immunologic responses to ART among HIV-infected
children have now been described by programs in Af-
rica, Asia, and the Caribbean, but reported outcomes
vary [8–13].
Single combined estimates of virologic and immu-
nologic responses to ART for children in a wide range
of resource-limited settings will serve 2 primary func-
tions. First, in the absence of multiple randomized tri-
als, pooled estimates will comprise useful comparators
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1916
Table 1. Studies Included in a Meta-analysis of the Effectiveness of Pediatric Antiretroviral Therapy (ART) in Resource-Limited Settings
Studies Baseline characteristics of study population ART characteristics
Author, year of
publication
Program
dates Location
No. of children
initiating ART
Age,
years
a
Female (%)
HIV RNA
(log10 copies/mL)
a
CD4 cell
percentage
a
CD4 cells/mL
(absolute)
a
Baseline
growth
parameters
b
PMTCT
(Local PMTCT
coverage)
c
First-line
ART regimen
Chearskul, 2005 9/96–3/04 Thailand 66 5.4 (range, 0.3–14.6)
d
48 No VL 3.8 (0.1–35.0)
e
91 (2–2016)
e
CD4 115%,
WAZ -1.3,
HAZ -1.0;
CD4
!15%,
WAZ -2.6,
HAZ -2.5
NR (40% in 2005) PI-based (8%); EFV-based (45%);
NVP-based (47%)
Eley, 2006 8/02–12/04 South Africa 409 1.9 (0.7–4.6) NR 5.4 (5.1–6.1); 5.5
(5.2–6.1)
f
11.7 (7.0–17.3);
12.0 (7.2–17.2)
f
NR WAZ -2.2,
HAZ -2.5,
WHZ -0.6
NR (22% in 2004) PI-based (51%);
NNRTI-based (49%)
Koekkoek, 2006 NR Thailand 16
g
7.1 (range, 4.4–12.0)
d
50 5.3 (range,
5.0–6.0)
d
5.0 (range,
1.0–15.0)
d
NR NR NR (40% in 2005) d4T/3TC/NVP (50%); ZDV/3TC/NVP
(31%); ZDV/3TC/EFV (19%)
O’Brien, 2006 6/01–3/05 8 countries
(MSF)
h
All ages, 1184;
ages 1.5–5, 322
All ages, 7.0 (4.6–9.3);
1.5–5 y, NR
All ages, 48;
1.5–5 y, NR
No VL 1.5–5 y, 9.9
(6.0–13.2)
15 y, 190 (73–339) All ages,
WHZ -0.6,
HAZ -2.0
No prior drug expo-
sure for PMTCT
d4T/3TC/NVP (generic adult FDC)
Rouet, 2006 10/00–9/04 Cote d’Ivoire 78 6.5 (range, 0.7–15.2)
d
44 5.4 (5.1–6.0) 7.5 (2.1–11.1) NR WAZ -2.0,
i
HAZ -2.0
i
,
j
NR (5% in 2004) NFV-based (78%);
EFV-based (22%)
Ble, 2007 2002–2005 Tanzania
k
59 4.5 (2.3) (0.6–10.6)
d
34 No VL 10.3 (SD NR) 310 (SD NR) WAZ -1.9,
i
HAZ- 1.7
i
NR (3% in 2004) NFV-based (44%); NVP-based
(39%); EFV-based (8%);
NFV and NNRTI (8%)
Bolton-Moore,
2007
5/04–6/07 Zambia 2938; 1147
l
6.8 (3.0–10.4) 52 No VL
m
All ages, 12.9
(12.5–13.3)
n
15 y, 284 (270–299)
n
WAZ -2.2
i
NR (15% in 2004;
22% in 2006)
d4T/3TC/NVP (51%); ZDV/3TC/NVP
(38%); d4T/3TC/EFV (7%);
ZDV/3TC/EFV (4%)
George, 2007 5/03–4/06 Haiti 236 6.3 (4.0–11.0) 58 5.3 (IQR, NR) 12.0 (6.0–19.0)
!1.5 y, 1260
(604–1735);
1.5–12 y, 413
(102–724);
113 y: 151 (8–367)
WAZ -2.0 NR; PMTCT pro-
grams were 1 of
2 referral sources
ZDV/3TC/EFV (59%); ZDV/3TC/
NVP(20%); ZDV/3TC/ABC (5%);
ddI/3TC/EFV (9%);
ddI/3TC/NVP(4%)
Janssens, 2007 6/03–3/06 Cambodia 212 6.0 (4.0–7.9) 44 No baseline VL All ages, 6.0
(2.6–13)
15 y, 100 (22–273) WHZ: -1.6
i
NR; Cambodia
PMTCT program
began 2003
d4T/3TC/NVP (69%); d4T/3TC/EFV
(19%); ZDV/3TC/NVP (12%)
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Kamya, 2007 4/04–6/05 Uganda 250 9.2 (4.5) 48 5.3 (0.8) 8.6 (3.5–12.7) 272 (8–516) NR 3.6% received ei-
ther NVP or ZDV
for PMTCT
d4T/3TC/ NVP (26%); ZDV/3TC/EFV
(55%); ZDV/3TC/NVP (13%);
d4T/3TC/EFV (6%)
Myung, 2007 8/02–10/04 Cambodia
o
117
p
5.5 (2.5) (1.0–13.0)
d
43 No VL 6.8 (6.8) 255 (282) WAZ -3.8
i
NR (NR) d4T/3TC/NVP (62%);
d4T/3TC/EFV (38%)
Puthanakit, 2007 8/02–3/05 Thailand 192 7.6 (0.4–14.8)
d
51 5.4 (0.5) 5.2 (4.9) 171 (289) NR NR (40% in 2005) d4T/3TC/NVP (59%); d4T/3TC/EFV
(38%); ZDV/3TC/NVP (3%)
Zhang, 2007 7/05–8/06 China 51 10.0 (7.0–13.0) 33 5.5 (5.2–5.7) NR 117 (24–186) WAZ -1.9 NR (NR) ZDV/3TC/NVP (proportions NR)
Kumarasamy, 2008 2/96–3/08 India 67
q
6.3 (4.2) 39 No VL 12.0 (7.0–18.0) 225 (95–411) WHZ, 0.5
i
NR (NR) d4T/3TC/NVP (42%); ZDV/3TC/NVP
(16%); d4T/3TC/EFV (21%)
Prendergast, 2008
All 7/03–9/05 South Africa 60; 53
r
0.1 (0.0–1.1)
s
47 6.0 (5.3–6.6) 30.0 (17–43) NR NR All received sdNVP ZDV/3TC/NFV/NVP (94%);
ZDV/3TC/NVP (6%)
Immediate ART
arm
r
40 0.1 (0.0–0.5)
s
50 5.8 (5.3–6.5) 36.0 (28–45) NR NR All received sdNVP ZDV/3TC/NFV/NVP (97%);
ZDV/3TC/NVP (3%)
Deferred ART
arm
r
20; 13 0.4 (0.2–0.6)
s
40 6.5 (6.0–6.6) 15.0 (12–18) NR NR All received sdNVP ZDV/3TC/NFV/NVP (85%);
ZDV/3TC/NVP (15%)
NOTE. ABC, abacavir; d4T, stavudine; EFV, efavirenz; FDC, fixed-dose combination; HAZ, height-for-age Z-score; HIV, human immunodeficiency virus; IQR, interquartile range; MSF, Medecins sans Frontieres; NFV,
nelfinavir; NNRTI, nonnucleoside reverse-trancriptase inhibitor; no VL, no viral load (HIV RNA) assay; NR, not reported; NVP, nevirapine; PI, protease inhibitor; PMTCT, prevention of mother-to-child transmission of HIV;
SD, standard deviation; sdNVP, single-dose nevirapine; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score; WHO, World Health Organization; y, year; ZDV, zidovudine; 3TC, lamivudine.
a
Baseline values (age, HIV RNA, CD4 cell count, and CD4 percentage) are reported as median with IQR (or range where marked) or as mean with SD.
b
WAZ, WHZ, and HAZ are reported as median values unless otherwise indicated.
c
PMTCT data are provided for comparison, as receipt of antiretroviral drugs for PMTCT may impact later ART outcomes [16]. Data not in parentheses are rates of receipt of any antiretroviral drug for PMTCT, as
reported in each study. Data in parentheses are WHO estimates of receipt of any antiretroviral drug for PMTCT among antenatal clinic attendees, based on each country and the fiscal year closest to the program dates.
WHO data on type of antiretroviral drug used for PMTCT are not available; however, in most cases where rates of PMTCT coverage are low, the regimen is likely to be single dose [17].
d
Mean value with SD in parentheses if available and range.
e
Not reported whether median or mean or whether IQR or range.
f
The first value represents baseline data for the 409 children initiating ART, but the second value represents baseline values for the 264 children with 12-mo follow-up data only.
g
Cohort defined as children with 12-mo follow-up data, not all ART initiators.
h
Medecins sans Frontieres: Cambodia, Kenya, Malawi, Mozambique, Thailand, Uganda, Burkina Faso, and Zimbabwe.
i
Mean value.
j
Baseline and 12-mo growth parameters are reported in an earlier publication from this cohort [15].
k
Institutionalized orphans.
l
1147 children started ART more than 12 mo before analysis date (and therefore were eligible to have 12-mo data).
m
HIV RNA assay used only for infant diagnosis, not for treatment monitoring.
n
Baseline values are mean (95% confidence interval); they are also reported as median (IQR) for entire cohort (all ages): absolute CD4 count, 300 cells/mL (138–551 cells/mL); CD4 percentage, 11.8% (7.2%–17.4%).
o
Institutionalized and community-living orphans receiving directly observed ART.
p
117 children were started on ART; 22 died in the first 6 mo. Baseline data are for only the 95 children who survived to 6 mo; 12-mo data are for 68 children with follow-up data at 12 mo.
q
Data are reported only on children with complete 18-mo follow-up, not all ART initiators.
r
A total of 63 infants were randomly assigned (43 to immediate, 20 to deferred); 3 infants from the immediate ART arm were lost to the study before initiating ART and were not included in the cohort reported
here. Of 20 infants randomly assigned to the deferred arm, 3 were lost to the study before initiating ART and 4 did not start ART. To be consistent with other cohorts reporting on ART initiators only, these 7 infants
were not included in the cohort reported here (leaving 13 in the deferred arm and 53 total ART initiators).
s
Median with range.
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1918 CID 2009:49 (15 December) HIV/AIDS
Figure 1. Selection of publications for a systematic review and meta-analysis of pediatric combination antiretroviral therapy (ART) effectiveness.
The flowchart describes the results of the literature search, including the source of each publication reviewed and reasons for exclusion of studies
from the final analysis. After the initial search, 546 abstracts were excluded because they reported only on ART-experienced children (1), critically ill
children (1), animals (1), or adults (58); they provided only cross-sectional data (2) or case reports (3); they did not report on human immunodeficiency
virus (HIV) (7); they reported on non–resource-limited settings (RLS) (12); they described diagnostic tests (20) or cohorts not treated with ART (22);
the format was commentary or review rather than original research (119); they primarily addressed prevention of mother-to-child transmission (MTCT)
of HIV (146); or they did not report outcomes related to viral load or CD4 cells (154). Cochrane, Cochrane Clinical Trials Register; EMBASE, Excerpta
Medica Database; LILACS, Latin American and Caribbean Health Sciences Literature.
for outcomes from individual programs and new treatment
strategies. Second, these estimates will allow comparison with
published ART outcomes for children in developed countries.
We therefore performed a systematic review and meta-analysis
to aggregate virologic suppression rates and CD4 cell responses
at 12 months after ART initiation among ART-naive, HIV-
infected children in resource-limited settings.
METHODS
Search Strategy and Selection Criteria
Primary search. We performed a systematic search of peer-
reviewed, published reports by means of the Medline, EMBASE
(Excerpta Medica Database), and LILACS (Latin American and
Caribbean Health Sciences Literature) electronic databases and
the Cochrane Clinical Trials Register. Observational studies and
clinical trials published from 1 January 1997 through 15 Oc-
tober 2008 were included. Search terms referred to HIV infec-
tion, children, and resource-limited settings. Additional reports
were selected for review from discussion with experts and re-
view of bibliographies of published reports.
Abstract review. Publications were selected for review if
study subjects were children (aged 0–17 years) who were living
in a country with an International Monetary Fund designation
of emerging or developing economy [14] and who were treated
with combination ART (defined as 3 drugs, including 2
nucleoside reverse-transcriptase inhibitors and either a non-
nucleoside reverse-transcriptase inhibitor [NNRTI], a protease
inhibitor, or both) and if publications reported on changes in
HIV RNA levels and CD4 cells.
Article review. Publications were included in the final anal-
ysis if they reported the proportion of patients with HIV RNA
level below assay limit of detection (virologic suppression) or
the change in CD4 percentage (DCD4%) at 12 months after
ART initiation or if they reported sufficient information to
perform these calculations.
Citations were limited to reports in which 95% of children
were treatment-naive (having received no prior antiretroviral
drugs, except for prevention of mother-to-child transmission).
Cohorts that comprised both adults and children were included
if pediatric outcomes were reported separately. When more
than one publication reported outcomes from the same cohort,
the most recent publication (or the largest study cohort, if 2
publications occurred within a 1-year period) was used. Studies
were not included if they reported on outcomes among criti-
cally ill children only.
Titles and abstracts were independently reviewed by 3 au-
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HIV/AIDS CID 2009:49 (15 December) 1919
Table 2. Meta-analysis of Viral Suppression Rate (Proportion of Children with HIV RNA!400 copies/mL) 12 Months after
Antiretroviral Therapy (ART) Initiation for Treatment-Naive Children in Resource-Limited Settings
Studies 12-mo HIV RNA outcomes
Author
No. of children
initiating ART
HIV RNA
assay limit
of detection,
copies/mL
HIV RNA
! limit of detection,
% of patients
HIV RNA
! limit of detection,
no. of children
HIV RNA
data at 12 mo,
no. of children
a
Eley 409 !400 70 184 264
Koekkoek 16
!50 83 5 6
Rouet 78 !250 and/or !300 49 33 67
George 236
!50 56 56 100
Janssens 212 !400 81 156 193
Kamya 250
!400 74
b
; 69
c
164 222
Puthanakit 192 !50 68 130 181
Zhang 51
!400 55
d
NR NR
Prendergast
e
All 53 !400 and !50 100 (!400); 94 (!50) 49 (!400); 46 (!50) 49
Immediate ART arm
e
40 !400 and !50 100 (!400); 94 (!50) 36 (!400); 34 (!50) 36
Deferred ART arm
e
13 !400 and !50 100 (!400); 92 (!50) 13 (!400); 12 (!50) 13
NOTE. HIV, human immunodeficiency virus; NR, not reported.
a
None of the 1457 ART initiators included in the pooled HIV RNA analysis were reported to have !12 mo of follow-up time and therefore to be
ineligible for 12-mo data.
b
Percentage with virologic suppression, including only patients for whom HIV RNA data were available.
c
Percentage with virologic suppression if patients lost to follow-up or deceased were assumed to have had detectable HIV RNA.
d
This 55% reported only in abstract and graphically in Figure 2.
e
By design, compared with children in the deferred ART arm and to children in the other included studies, children in the immediate ART arm of
the Prendergast trial were younger and had less advanced HIV infection at ART initiation (Table 1). The immediate ART arm of this trial was therefore
excluded from pooled analyses. A total of 63 infants were randomly assigned (43 to immediate, 20 to deferred). Of 20 infants randomly assigned to
the deferred arm, 3 were lost to the study before initiating ART, and 4 did not start ART. To be consistent with other cohorts reporting only on ART
initiators, these 7 infants were not included in the cohort reported here (leaving 13 in the deferred arm).
Table 3. Pooled Estimates of Percentage of Children with Virologic Suppression (HIV RNA !400
copies/mL)
Analysis
Pooled estimate
of % of children with
virologic suppression
(95% CI)
Primary analyses
Patient-level analysis 70 (67–73)
Fixed-effects model (inverse variance) 72 (70–75)
Random-effects model (Dersimonian-Laird) 70 (62–79)
Sensitivity analyses (patient-level estimates)
Exclude studies with
150% missing data or with missing data not
reported (Koekkoek, George, Zhang) 72 (69–75)
Missing 12-mo data: assume HIV RNA 1400 copies/mL 53 (50–55)
NOTE. HIV, human immunodeficiency virus.
thors (A.B., A.L.C., and A.V.M.). If disagreements between au-
thors were encountered, eligibility for inclusion was determined
by consensus.
Data Extraction and Outcomes Definitions
Data were extracted independently by 2 authors (pairs of A.B.,
A.L.C., and A.V.M.), and discrepancies in data extraction were
resolved by repeat manuscript review and consensus. Baseline
data, collected at the time of ART initiation (or, if not available,
at the time of enrollment), are outlined in Table 1.
Primary Outcomes
Virologic suppression. Virologic suppression was defined as
the proportion of children reported to have HIV RNA
!400
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Figure 2. Forest plot of viral suppression rates (proportion of children with human immunodeficiency virus [HIV] RNA !400 copies/mL) 12 months
after antiretroviral therapy (ART) initiation for treatment-naive children in resource-limited settings. Studies included in this pooled analysis are shown
to the left. Reported proportions of children with HIV RNA
!400 copies/mL are depicted as circles, with the size of each circle proportional to the
number of children included in each study; reported estimates and confidence intervals (CIs) are shown to the right. The dashed vertical line indicates
the value of the patient-level pooled estimate (70%). The last column indicates the percentage of total included children contributed by each included
study.
copies/mL after 12 months of ART. When virologic suppression
thresholds were reported as HIV RNA
!50, !100, !250, or
!300 copies/mL, we conservatively analyzed these results as
!400 copies/mL.
DCD4%. When the mean or median DCD4% was reported
for all children with 12-month data, this value was used in the
meta-analysis. When DCD4% was not reported or was reported
for only a subset of children with baseline and 12-month values
[8], the DCD4% was calculated by subtracting the mean (or
median) CD4% at baseline from the mean (or median) 12-
month value. Most of the reported interquartile ranges (IQRs)
of CD4% showed symmetry around the reported medians, sup-
porting the assumption that CD4% or DCD4% might be nearly
normally distributed [18, 19]. Mean and median values were
therefore analyzed together.
Secondary Outcomes
Secondary 12-month outcomes included growth parameters
(weight-for-age, height-for-age, or weight-for-height Z-scores)
[20, 21], mortality and loss-to-follow-up rates, and number of
children with 12-month HIV RNA and CD4 data. Secondary
outcomes were not aggregated into pooled estimates but were
collected to describe the effect of ART on growth and mortality
and to evaluate the impact of missing data.
Data Analysis
Methods for combining estimates. Analyses were performed
using SAS, version 9.1 (SAS). Because all studies included in
the analysis were cohort studies without control arms, we used
a straightforward pooling method of weighting each study by
the number of children with 12-month HIV RNA or CD4 data
(patient-level analysis). For comparison, we also calculated
pooled estimates by means of 2 traditional meta-analytic meth-
odologies: (1) a fixed-effects model approach (weighted by the
inverse of the variance from each study) and (2) a random-ef-
fects model approach (based on the DerSimonian-Laird meth-
od and weighted by the inverse of the sum of between- and
within-study variances) [22].
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HIV/AIDS CID 2009:49 (15 December) 1921
Table 4. Meta-analysis of Gain in CD4 Cell Percentage (CD4%) 12 Months after Antiretroviral Therapy (ART) Initiation for Treatment-
Naive Children in Resource-Limited Settings
Studies Variables
Author
No. of children
initiating ART
Baseline CD4%,
median (IQR) or mean (SD)
12-mo CD4%,
median (IQR) or mean (SD)
a
CD4 data at 12 mo,
no. of children
b
Chearskul 66 3.8 (0.1–35.0)
c
Gain, 15.2 (1.8–29.0)
d
NR
Eley 409 11.7 (7.0–17.3); 12.0 (7.2–17.2)
e
24.0 (18.7–30.0) 261
Koekkoek 16
f
5.0 (1.0–15.0)
d
20.0 (IQR, NR) 16
O’Brien 1.5–5 y: 322
g
1.5–5 y, 9.9 (6.0–13.2) 1.5–5 y, 21.5 (19.4–27.8);
1.5–5 y gain, 14.8 (5.5–17.9)
15 y, 54;
1.5–5 y, 28
Rouet 78 7.5 (2.1–11.1) 18.5 (IQR, NR) 68
Ble 59 10.3 (SD, NR) 25.3 (SD, NR); gain, 15.0 (SD, NR) Absolute, 45; %, 16
Bolton-Moore 2938; 1147
h
All ages, 12.9 (12.5–13.3)
i
All ages, 27.0 (26.3–27.6)
i
862
Janssens 212 6.0 (2.6–13) Gain, 17.0 (16.3–30.7) 193
Myung 117
j
6.8 (6.8) 21.7 (7.5) 68
Puthanakit 192 5.2 (4.9) 17.2 (7.5) 181
Kumarasamy 67
k
12.0 (7.0–18.0) 23.0 (15.0–31.0) 67
Prendergast
l
All
m
53 30.0 (17.0–43.0) NR 49
Immediate ART arm
l
40 36.0 (28.0–45.0) 33.0 36
Deferred ART arm
l
13 15.0 (12.0–18.0) 32.0 13
NOTE. NR, not reported; IQR, interquartile range; SD, standard deviation; y, year
a
Reported values are 12-mo values, unless noted as “gain.”
b
Of the 5329 ART initiators, 2676 were reported to be eligible for 12-mo CD4% data; others were ineligible because they initiated ART !12 mo before data
reporting or because only absolute CD4 count was recorded because of age
15 years.
c
Not reported whether median or mean or whether IQR or range.
d
Range.
e
Baseline value for the 264 children with 12-mo follow-up data, not the 409 children initiating ART.
f
Cohort defined as children with 12-mo follow-up data.
g
1184 children initiated ART. CD4% data were collected only for children aged !5 years, and baseline and 12-mo CD4% data are reported only for children
aged 1.5–5 years. Only children aged 1.5–5 years are therefore included in the analysis.
h
1147 children started ART more than 12 mo before analysis date (and therefore were eligible to have 12-mo data).
i
Values are mean (95% confidence interval [CI]).
j
Baseline data are only for the 95 children who survived to 6 mo; 12-mo data are for 68 children with follow-up data at 12 mo.
k
Data are reported only for children with complete 18-mo follow-up, not all ART initiators.
l
By design, compared with children in the deferred ART arm and to children in the other included studies, children in the immediate ART arm of thePrendergast
trial were younger and had less advanced human immunodeficiency virus (HIV) infection at ART initiation (Table 1). The immediate ART arm of this trial was
therefore excluded from pooled analyses. A total of 63 infants were randomly assigned (43 to immediate, 20 to deferred). Of 20 infants randomly assigned to
the deferred arm, 3 were lost to the study before initiating ART, and 4 did not start ART. To be consistent with other cohorts reporting only on ART initiators,
these 7 infants were not included in the cohort reported here (leaving 13 in the deferred arm).
m
CD4% at 12 mo not statistically significantly different between study arms.
Methods for examining heterogeneity, bias, and study quality.
Statistical heterogeneity was assessed using Q statistics with x
2
tests [22] and was summarized by the I
2
statistic [23], which
reflects the proportion of total variation across studies that is
due to heterogeneity rather than to chance. The presence of
publication bias was assessed using the Begg test and the Egger
test [22]. We also examined the relationship between several
clinical and programmatic factors and the primary outcomes
to better understand sources of anticipated statistical hetero-
geneity. Information with regard to study quality and com-
parability was collected in accordance with published guidelines
[24, 25].
Sensitivity analyses—effects of missing data. The majority
of reported viral suppression and DCD4% results were derived
from on-treatment analyses; children who initiated ART but
for whom 12-month HIV RNA and CD4% data were missing
were excluded. To examine the effects of missing data on the
patient-level estimates, we conducted 2 sensitivity analyses.
First, we excluded studies in which 12-month data were avail-
able for
!50% of children initiating ART, in which data to
calculate this proportion were not reported, or in which missing
data could not be assessed because cohorts were limited to
children with complete follow-up data. Second, we calculated
a proxy for intention-to-treat outcomes for each study. For the
viral suppression outcome, we used as the denominator all
children who began ART
112 months before the date of analysis
(or all children in the cohort when entry dates were not spec-
ified). The numerator remained the number of children known
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1922 CID 2009:49 (15 December) HIV/AIDS
Table 5. Pooled Estimates of Gain in CD4 Cell Percentage (CD4%) at 12 Months
Analysis
Pooled estimate
of gain in CD4%
at 12 mo (95% CI)
Primary analyses:
Patient-level analysis 13.7 (11.8–15.7)
Fixed-effects model (inverse variance) 14.3 (11.3–17.3)
Random-effects model (Dersimonian-Laird) 14.3 (11.3–17.3)
Sensitivity analyses (patient-level estimates)
Exclude studies with
150% missing data or missing data not reported
(Koekkoek, O’Brien, Ble, Kumarasamy, Chearskul) 14.0 (8.8–19.1)
Missing 12-mo data: assume CD4% gain p 0 8.5 (5.5–11.4)
NOTE. CI, confidence interval.
Figure 3. Forest plot of absolute gain in CD4 percentage (CD4%) 12 months after antiretroviral therapy (ART) initiation for treatment-naive children
in resource-limited settings. Studies included in this pooled analysis are shown to the left. Reported absolute gains in CD4% are depicted as circles,
with the size of each circle proportional to the number of children included in each study; reported estimates and confidence intervals (CIs) are shown
to the right. The dashed vertical line indicates the value of the patient-level pooled estimate (13.7%). The last column indicates the percentage of
total included children contributed by each included study. CD4%, defined as the percentage of total lymphocytes that are CD4+ cells, is a more
useful representation of immune function in children
!5 years of age than absolute CD4 cell count (total number of CD4 cells/mL of serum), because
CD4% maintains a more constant value during normal immune system maturation [35]. As a result, CD4% is often reported for children of any age,
while absolute CD4 is usually reported only for adults and children
15 years old.
to have HIV RNA !400 copies/mL. This analysis assumed that
children who died or lacked HIV RNA data at 12 months in
fact had HIV RNA levels
1400 copies/mL. For the DCD4%
outcome, we assumed that all patients who initiated ART but
lacked 12-month follow-up data had zero DCD4%.
Supplementary information. Additional details regard-
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Table 6. Secondary Outcomes: Mortality and Loss to Follow-up 12 Months after Antiretroviral Therapy (ART) Initiation for Treat-
ment-Naive Children in Resource-Limited Settings
Author
No. of children
initiating ART
Mortality of children
Growth
Patient disposition and completeness
of available data
% reported dead
at 12 mo
12-mo
Kaplan-Meier
survival (95% CI)
12-mo
increase in
growth parameters
a
Proportion (%)
reported lost
to follow-up
Proportion (%)
with CD4%
data at 12 mo
b
Proportion (%)
with HIV RNA
data at 12 mo
b
Chearskul 66 3.0%
c
93%
d
WAZ, 0.7; HAZ, 0.3 2/66 (3.0)
c
NR No VL
Eley 409 15.4% 84% (80–87%) WAZ, 1.2; HAZ, 0.6;
WHZ, 1.1
19/409 (4.6) 261/409 (63.8) 264/409 (64.5)
Koekkoek 16
e
NR NR NR NR
e
16/16 (100)
e
6/16 (37.5)
O’Brien All ages, 1,184;
1.5–5 y, 322
All ages, 3.0%
f
;
1.5–5 y, 0.6%
f
95% (93%–97%);
87% (84%–89%)
g
NR All ages, 89/
1184 (7.5)
f
;
1.5–5 y, 27/
322 (8.4)
f
15 y, 54/1184
(4.6); 1.5–5
y, 28/322
(8.7)
No VL
Rouet 78 10.3% NR WAZ, 0.6
h
; HAZ, 0.2
h
,
i
4/78 (5.1)
j
68/78 (87.1) 67/78 (85.9)
Ble 59 0.0% NR WAZ, 1.1
h
; HAZ, 1.0
h
0 (0) 16/59 (27.1) No VL
Bolton-Moore 2938; 1147
k
6.7%
l
NR WAZ, 0.6
h
382/2938
(13.0)
l
862/1147
(75.1)
No VL
George
m
236 9.0%
n
NR WAZ, 0.7 24/236
(10.2)
n
,
o
100/236 (42.4)
Janssens 212 6.1%
p
92%
q
(CI, NR) WHZ, 0.8 4/212 (1.9)
p
193/212 (91.0) 193/212 (91.0)
Prendergast
r
All 53
s
7.5%
t
NR NR 1/54 (1.9)
r
49/53 (92.4) 49/53 (92.4)
Immediate ART arm 40 10.0% NR NR 0 (0) 36/40 (90.0) 36/40 (90.0)
Deferred ART arm 13 0.0% NR NR 1/14 (7.1)
r
13/13 (100.0) 13/13 (100)
Kamya
m
250 5.2% NR NR 3/250 (1.2) 222/250 (88.8)
Myung 117
u
18.8% NR WAZ, 1.4 NR
u
68/117 (58.1) No VL
Puthanakit 192 6.3% NR NR 0 (0) 181/192 (94.2) 181/192 (94.2)
Zhang
m
51 0.0–3.9%
v
NR WAZ, 0.3
w
0–1/51
(0%–2%)
v
NR
Kumarasamy 67
x
NR NR WHZ, 0.1
h
NR
x
67/67 (100.0)
x
No VL
NOTE. CI, confidence interval; HAZ, height-for-age Z-score; no VL, no viral load (human immunodeficiency virus [HIV] RNA) assay available; NR, not
reported; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score.
a
Increases in WAZ, WHZ, and HAZ are reported as difference in median values from baseline to 12 mo.
b
Note that it is not clear if missing data are because of death, loss to follow-up, or lack of resources to measure CD4 and HIV RNA, or because some
children started ART
!12 mo prior to the analysis date (and therefore would not have been able to contribute to 12-mo data).
c
Over entire duration of follow-up (median follow-up, 26 mo).
d
Kaplan-Meier mortality estimated from figure.
e
Cohort defined as children with 12-mo follow-up data.
f
Over entire duration of follow-up (median follow-up, 6 mo; range, 2–12 mo). In addition to 7.5% of patients reported lost to follow-up, 3% had “unknown
outcomes.”
g
When end point is defined as loss to follow-up or death.
h
Difference in mean values.
i
Final growth parameters are not at 12 mo but over median follow-up of 620 days and are reported in an earlier publication from this cohort [15].
j
Over entire duration of follow-up (median follow-up, 36 mo).
k
There were 1147 children who started ART 112 mo before analysis date (and therefore were eligible to have 12-mo data).
l
Over entire duration of follow-up (median follow-up, 378 days).
m
These studies were not included in the pooled CD4% analysis.
n
Over entire duration of follow-up (median follow-up, 20 mo; range, 0–36 mo).
o
171 children were “in follow-up 11 year.” Over a median of 20 mo of follow-up, 24 children were reported lost to follow-up and 21 (9%) deceased. It
was not reported if those remaining (not dead or lost to follow-up at 12 mo) had initiated ART
!12 mo earlier, and therefore they were ineligible for 12 mo
data. It is reported that 98% of the children in care at 12 mo had absolute CD4 cell count data (not included in meta-analysis), and 58% had HIV RNA data.
p
Over entire duration of follow-up (median follow-up, 16.8 mo).
q
This is the Kaplan-Meier estimate for number of children alive and in care at 12 mo.
r
One infant from the immediate arm reached criteria to start ART but was either lost to follow-up or died (not reported which) before 12 mo. As it is
not reported whether this infant initiated ART, this infant was not included in the pooled HIV RNA and CD4 analyses but is considered lost to follow-up,
raising the number of children in the cohort to 54 (total) and 14 (deferred ART).
s
A total of 63 infants were randomly assigned (43 to immediate, 20 to deferred); 3 infants from the immediate ART arm were lost to the study before
initiating ART and were not included in the cohort reported here. Three infants from the deferred ART arm were lost to the study before initiating ART, and
4 did not start ART; these 7 were not included in the cohort reported here (leaving 53 ART initiators: 13 in the deferred arm and 40 in the immediate arm).
t
Proportion reported is among children who initiated ART (13 in deferred group, 40 in immediate group), rather than among children randomly assigned
to each strategy, in order to achieve consistency with other included studies.
u
117 children were started on ART; 22 died in the first 6 mo. 95 children contributed baseline data; 68 children had follow-up data at 12 mo.
v
Not reported if both children who died and 1 child who was lost to follow-up were among the 51 ART-naive children included in this analysis; the
possible range is reported here.
w
Median difference reported.
x
Data are reported only for children with complete 18-mo follow-up, not all ART initiators.
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1924 CID 2009:49 (15 December) HIV/AIDS
ing the literature search, data extraction, and data analysis are
available from the authors upon request.
RESULTS
Literature Search
Primary search and abstract review. We retrieved 436 cita-
tions from Medline, 168 from EMBASE, 16 from the Cochrane
Clinical Trials registry, 52 from LILACS, and 10 from expert
discussion and bibliography review. After duplicate citations
were eliminated, 591 citations remained; 546 abstracts were
excluded for the reasons outlined in Figure 1.
Article review. Forty-five published abstracts were selected
for full article review. Thirty articles were excluded (Figure 1),
leaving 15 articles [8–10, 26–37] eligible for at least one of the
primary analyses (Table 1).
Characteristics of Included Cohorts
Table 1 describes characteristics of the included cohorts, from
15 countries in Asia, Africa, and the Caribbean. Numbers of
children initiating ART in each program ranged widely (16–
2938; total, 5928), as did age at ART initiation (mean and/or
median, 0.1–10.0 years; range, 0.0–15.2 years). Overall, children
initiated ART with low immune function: mean and/or median
baseline CD4% ranged from 3.8% to 30.0% (mean, 8.1%).
First-line ART was NNRTI-based in 81% of children for whom
regimens were described. All but one of the studies were ob-
servational. The single trial randomly assigned infants to initiate
ART before 3 months of age or to defer ART until World Health
Organization 2006 criteria for ART initiation were met [26].
To remain consistent with other included studies that reflect
ART initiation in accordance with pre-2008 guidelines [38, 39],
we included data from only the deferred ART arm of this study
in the pooled analyses. Eleven studies [8, 10, 27–34, 37] re-
ported baseline growth parameters. In 5 of these studies [28–
30, 32, 33], mean or median values indicated at least moderate
underweight (weight-for-age), stunting (height-for-age), or
wasting (weight-for-height), defined as Z-scores less than 2.
Only 3 manuscripts [8, 26, 35] specifically reported on prior
receipt of antiretroviral drugs for prevention of mother-to-child
transmission.
Primary Outcomes 12 Months after ART Initiation
Virologic suppression. Nine papers reported proportion of
children with HIV RNA
!400 copies/mL at 12 months [9, 10,
26–29, 35–37], representing 1457 children initiating ART (Table
2). Twelve-month HIV RNA data were available for 1097 chil-
dren (75%). The patient-level pooled estimate of the proportion
with virologic suppression was 70% (95% confidence interval
[CI], 67%–73%) (see primary analyses in Table 3 and Figure
2). Estimates from the fixed-effects (72%; 95% CI, 70%–75%)
and random-effects (70%; 95% CI, 62%–79%) models were
similar.
DCD4%. Twelve studies reported on 12-month CD4% out-
comes [8, 9, 26–34, 36], representing 5329 children initiating
ART (Table 4). Of these, 2676 were reported to be eligible for
12-month CD4% data, and 12-month CD4% data were avail-
able for 1839 children (35% of total, 69% of “eligible”). The
patient-level pooled estimate of DCD4% at 12 months was an
absolute increase of 13.7% (95% CI, 11.8%–15.7%; see prima-
ry analyses in Table 5 and Figure 3), which was similar to the
estimate generated by both the fixed- and random-effects mod-
els (14.3%; 95% CI, 11.3%–17.3%).
Heterogeneity and bias. There was no statistically signifi-
cant heterogeneity in either the HIV RNA ( ) or DCD4%
P p .26
( ) outcome. The percentage of variation due to het-
P p .99
erogeneity (I
2
) was 20.4% for the HIV RNA outcome and 0%
for the DCD4% outcome. There was no evidence of publication
bias for the HIV RNA (Begg test, ; Egger test,
P p .40 P p
) or DCD4% (Begg test, ; Egger test, ) out-
.53 P p .78 P p .12
come. Graphical visualization of scatter plots did not reveal
any association between the primary outcomes and geographic
region, study size, year of program initiation, type of ART
(protease inhibitor– vs. NNRTI-based), or stage of disease or
age at ART initiation.
Sensitivity analyses—effects of missing data. The first sen-
sitivity analysis addressed the exclusion of studies with a high
proportion of missing data (Tables 3 and 5, bottom). In 3
studies,
150% of children initiating ART lacked 12-month data
[8, 10, 34]; in 2 studies, data to calculate the proportion of
children with missing data were not reported [32, 37]; and in
2 studies, cohorts were limited to children with complete data
[31, 36] (Table 6). When these studies were excluded, the
pooled estimate of viral suppression was 72% (95% CI, 69%–
75%), and the pooled estimate of DCD4% was 14.0% (95%
CI, 8.9%–19.1%).
The second sensitivity analysis represented a proxy for inten-
tion-to-treat analyses (Tables 3 and 5, bottom). When we as-
sumed that children without 12-month HIV RNA data had HIV
RNA levels
1400 copies/mL, the pooled estimate for viral sup-
pression was 53% (95% CI, 50%–55%). When we assumed that
children without 12-month CD4 data experienced a DCD4% of
zero, the pooled estimate for DCD4% was 8.5% (95% CI, 5.5%–
11.4%).
Secondary Outcomes
As shown in Table 6, reported mortality after 12 months of
ART ranged from 0.0% to 18.8% [8, 9, 26–29, 32–35, 37].
Gains in weight-for-age Z-score ranged from 0.3 to 1.4 [28–
30, 32–34, 37]; gains in height-for-age Z-score ranged from 0.2
to 1.0 [28, 29, 32, 34]; and gains in weight-for-height Z-score
ranged from 0.1 to 1.1 [27, 29, 31]. Loss to follow-up was
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HIV/AIDS CID 2009:49 (15 December) 1925
defined in only 3 studies: children 30 days [30], 12 months
[8], or
13 months [27] late for appointments and not known
to have died or transferred care. Rates of loss to follow-up at
12 months after ART initiation were reported in 6 studies
(range, 0.0%–7.1%) [9, 26, 29, 34, 35, 37], with others reporting
loss to follow-up at time points other than 12 months [8, 10,
27, 30, 32], not reporting loss to follow-up [36], or limiting
cohorts to children with complete follow-up data [31, 33, 34].
DISCUSSION
We performed a systematic review and meta-analysis of 12-
month virologic and immunologic outcomes for treatment-
naive, HIV-infected children who were initiating ART in re-
source-limited settings. Data from 9 studies, representing 1097
children with complete follow-up data, contributed to a pooled
estimate of 70% virologic suppression (HIV RNA,
!400 copies/
mL); data from 12 studies and 1839 children with complete
data contributed to a pooled estimate of 13.7% absolute
DCD4%. These findings are similar to reported ART outcomes
for treatment-naive children in the United States and Europe,
which include 12-month virologic suppression rates (HIV RNA,
!400 copies/mL) of 53%–84% [2, 5, 11, 40–46] and median
DCD4% of 10%–13% [5, 41–43]. As has been reported for
adults [47], our study highlights that comparable outcomes in
children are observed in resource-limited and developed set-
tings, despite advanced stages of disease at ART initiation, pre-
dominantly NNRTI-based ART, and substantial barriers to ART
delivery in resource-limited settings. In addition, clinically sig-
nificant improvements in growth parameters are noted after 12
months of ART [48]. However, missing data remain an im-
portant concern, and a proxy for an intention-to-treat analysis
generates much lower estimates: 53% virologic suppression and
8.5% DCD4% at 12 months.
Two recent systematic reviews without meta-analysis sum-
marized responses to pediatric ART in Africa [11] and in a
variety of resource-limited settings [12]. A pooled patient-level
analysis from 16 African sites also provided mortality and loss-
to-follow-up estimates for children who were receiving ART
[13]. The current study reinforces the findings of these analyses,
including similar ranges of 12-month viral suppression rates
[11], DCD4% [11], and mortality [12]; advanced stage of dis-
ease and large proportion of children aged
15 years at ART
initiation [11–13]; wide variation in study size [11]; and notable
inconsistency in data reporting [11].
Our analyses suggest that the pooled estimates were not sig-
nificantly affected by statistical heterogeneity. However, we an-
ticipated that variation in clinical and programmatic factors
(clinical heterogeneity) would contribute to differences in the
primary outcomes. Although we found no association between
HIV RNA or DCD4% outcomes and many such factors, in-
cluding age at ART initiation and protease inhibitor– versus
NNRTI-based ART, our ability to formally assess such associ-
ations was limited because of the relatively small number of
included studies. Additionally, incomplete data precluded ex-
amination of the effects of receipt of medications for prevention
of mother-to-child transmission, nutritional status, resource-
related factors (pharmacy stockouts and free provision of med-
ications), and prevalence or incidence of tuberculosis, malaria,
anemia, and diarrheal disease.
This analysis has several limitations. First, because conference
proceedings may be of more variable quality than published
reports and did not change study results when added to pub-
lished reports in a previous review [11], we included only pub-
lished reports. This may have omitted very recent reports of
ART outcomes. Second, we included only 12-month treatment
outcomes, because 12-month data were provided in the greatest
number of reports. Third, programs made use of HIV RNA
assays with varying limits of detection. We conservatively des-
ignated all children with HIV RNA
!50, !250, or !300 copies/
mL as having HIV RNA levels
!400 copies/mL, thus under-
estimating true rates of suppression to
!400 copies/mL. Finally,
consistent with most reports from both developed and re-
source-limited settings [9, 49, 50], the included studies did not
report clinical correlations between DCD4% or HIV RNA sup-
pression and the risks of AIDS-related morbidity. However,
DCD4% and HIV RNA suppression are likely to serve as reliable
surrogate outcomes for these events [51]. Analyses that use
individual patient data from a large pediatric cohort are an-
ticipated, and these will avoid many of the limitations of meta-
analysis [13, 52].
Our study also has several notable strengths. First, we expand
upon the previous literature by reviewing studies from re-
source-limited settings outside Africa and by analyzing 10 new
reports not included in the prior published review [11]. Next,
in addition to narrative review, we use recommended tech-
niques for meta-analyses of observational studies [24] to pro-
vide, to our knowledge, the first pooled estimates of the vi-
rologic suppression rate and DCD4% for children who are
receiving ART in resource-limited settings. Finally, we conduct
2 sensitivity analyses that demonstrate the impact of missing
data.
Data were incomplete for many children who initiated ART.
Of 5928 children initiating ART, 81% lacked 12-month HIV
RNA data and 69% lacked 12-month CD4% data. Children
who lack follow-up data may be more likely to have died than
those who were followed up, as has been observed in adults
[53, 54], and thus may be assumed to have inferior virologic
and immunologic outcomes. If true, this would lead our pooled
estimates to overestimate the benefit of ART. However, lack of
CD4% or HIV RNA data may not reflect true loss to follow-
up to programs. Instead, ART initiation may have occurred
!12 months before data reporting, absolute CD4 cell count
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1926 CID 2009:49 (15 December) HIV/AIDS
may have been obtained in preference to CD4% for children
15 years old, or laboratory testing may have been unavailable
on the occasions on which children were seen (in the single
study reporting this outcome, 25% of children still in care at
12 months lacked CD4% data [30]).
In sensitivity analyses, virologic suppression rates and
DCD4% did not change substantially when we excluded studies
with a high proportion of missing data. However, when we
assumed that all children who died or lacked 12-month data
had HIV RNA
1400 copies/mL, the pooled estimate of viral
suppression decreased to 53%. This estimate likely comprises
the lower bound of expected 12-month viral suppression rates.
Similarly, when we assumed that children with missing CD4%
data had true DCD4% of zero, the pooled estimate of DCD4%
decreased to 8.5%. Because children who die or are lost to
follow-up may have a decrease rather than a zero change in
CD4%, it is possible that the true DCD4% may be even lower
than 8.5%. However, because of some expected decrease in
CD4% with increasing age [19, 38], small gains in CD4% may
represent true improvements in immune function.
Definition and reporting of loss to follow-up and clear de-
scriptions of reasons for missing data are therefore important
considerations in interpreting reports of pediatric ART effec-
tiveness and the success of ART programs. Given the high
mortality in the first 3–6 months after ART initiation that is
observed in children as well as adults [9, 11, 30, 55], program-
matic efforts to retain children in care will be crucial to im-
proving clinical outcomes during the first year on ART.
CONCLUSIONS
This systematic review and meta-analysis demonstrates that the
pooled 12-month HIV RNA suppression rate (70%) and
DCD4% (13.7%) for children initiating ART in resource-lim-
ited settings are comparable with those seen in developed coun-
tries. This work also highlights important inconsistencies in the
reporting of data that may guide the interpretation of clinical
and programmatic outcomes, such as definitions of loss to
follow-up and descriptions of patient disposition. As pediatric
ART programs are expanded worldwide, clear and compre-
hensive reporting of these data will be crucial to interpreting
and comparing the effectiveness of ART in resource-limited
settings.
Acknowledgments
We gratefully acknowledge Paul Bain, Wendy Brown, and Carol Mita at
the Countway Medical Library of Harvard Medical School, for assistance
with electronic database searches and document retrieval, and Jennifer Chu
and Ji-Eun Park, for assistance with document procurement and manu-
script preparation.
Financial support. National Institute of Allergy and Infectious Disease
(T32 AI07433 to A.L.C.; R01 AI058736 to A.L.C., E.L., and R.P.W.; R37
AI420061 to A.L.C., E.L., and R.P.W.; K23 AI068458 to I.V.B.; and P30 AI
60354 to A.L.C., Y.C., and E.L.); the National Institute of Diabetes and
Digestive and Kidney Diseases (T32 DK07703 to A. B.); the Harvard School
of Public Health Pharmacoepidemiology Program Training Fund (to
A.V.M.); the Doris Duke Charitable Foundation (Clinical Scientist Devel-
opment Award to R. P. W.); and the Elizabeth Glaser Pediatric AIDS Foun-
dation (to A.L.C. and R.P.W.).
Potential conflicts of interest. All authors: no conflicts.
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    • "The equations used to generate these age-specific weight distributions rely on the Lambda-Mu-Sigma parameters: the median (M) weight, the generalized coefficient of variation (S), and the power in the Box-Cox transformation (L) [32,34]. To account for lower weights among HIV-infected children relative to the general population of same age, the age-specific weight distributions for HIV-infected children were shifted to the -1.5 z-score of the general population distributions [33]. The HIV-infected median weight-for-age values (MHIV) were calculated at half-year intervals, where MHIV was equal to the value M*(1 + LSZ)(1/L). "
    [Show abstract] [Hide abstract] ABSTRACT: Background Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. Methods We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0–13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. Results The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. Conclusions The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments.
    Full-text · Article · May 2014
    • "Antiretroviral therapy (ART) has been shown to reduce human immunodeficiency virus (HIV) associated morbidity and mortality by restoring and preserving the immunological function [1-6]. Globally, there has been a pronounced increase in scaling up ART services notably in sub-Saharan Africa [7,8], with Uganda being among the pioneering countries [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: Early recognition of antiretroviral therapy (ART) failure in resource limited settings is a challenge given the limited laboratory facilities and trained personnel. This study aimed at describing the incidence, risk factors and the resistance associated mutations (RAMs) of first line treatment failure among HIV-1-infected children attending the Joint Clinical Research Centre (JCRC), Kampala, Uganda. A retrospective cohort of 701 children who had been initiated on ART between January 2004 and September 2009 at the JCRC was studied. Data of children aged 6 months up to 18 years who had been started on ART for at least 6 months was extracted from the clinic charts. The children who failed the first-line ART were taken as cases and those who did not fail as the controls. Data was analysed using STATA version10. Of 701 children, 240(34%) failed on first line ART (cases) and 461(66%) did not fail (controls). The overall median time (IQR) to first line ART failure was 26.4 (18.9 -- 39.1) months. The factors associated with treatment failure were poor adherence [(OR = 10, 95 CI: 6.4 -- 16.7) p < 0.001], exposure to single dose nevirapine (sdNVP) [(OR = 4.2, 95%CI:1.8-9.4), p = 0.005] and a NVP containing regimen [(OR = 2.2,95%CI:1.4-3.6), p < 0.001]. Of 109 genotypic resistance profiles analyzed, the commonest non nucleoside reverse transcriptase inhibitor (NNRTI) resistance associated mutations (RAM) were: K103N (59; 54%)), Y181C (36; 27%)) and G190A (26; 24%)) while the commonest nucleoside reverse transcriptase inhibitor (NRTI) RAM was the M184V (89; 81%). Thymidine analogue- mutations (TAMs) were detected in 20% of patients. One in three children on first-line ART are likely to develop virological treatment failure after the first 24 months of therapy. . Poor adherence to ART, a NVP based first-line regimen, prior exposure to sdNVP were associated with treatment failure.
    Full-text · Article · Nov 2013