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No formal comparison has been made between the pediatric post–highly active antiretroviral therapy (HAART) outcomes of resource-limited and developed countries.
To systematically quantify and compare major baseline characteristics and clinical end points after HAART between resource-limited and developed settings.
Published articles and abstracts (International AIDS Society 2009, Conference on Retroviruses and Opportunistic Infections 2010) were examined from inception (first available publication for each search engine) to March 2010. Publications that contained data on post-HAART mortality, weight-for-age z score (WAZ), CD4 count, or viral load (VL) changes in pediatric populations were reviewed. Selected studies met the following criteria: (1) patients were younger than 21 years; (2) HAART was given (≥3 antiretroviral medications); and (3) there were >20 patients. Data were extracted for baseline age, CD4 count, VL, WAZ, and mortality, CD4 and virologic suppression over time. Studies were categorized as having been performed in a resource-limited country (RLC) or developed country (DC) on the basis of the United Nations designation. Mean percentage of deaths per cohort and deaths per 100 child-years, baseline CD4 count, VL, WAZ, and age were calculated for RLCs and DCs and compared by using independent samples t tests.
Forty RLC and 28 DC publications were selected (N = 17 875 RLCs; N = 1835 DC). Mean percentage of deaths per cohort and mean deaths per 100 child-years after HAART were significantly higher in RLCs than DCs (7.6 vs 1.6, P < .001, and 8.0 vs 0.9, P < .001, respectively). Mean baseline CD4% was 12% in RLCs and 23% in DCs (P = .01). Mean baseline VLs were 5.5 vs 4.7 log10 copies per mL in RLCs versus DCs (P < .001).
Baseline CD4% and VL differ markedly between DCs and RLCs, as does mortality after pediatric HAART. Earlier diagnosis and treatment of pediatric HIV in RLCs would be expected to result in better HAART outcomes.
Highly active antiretroviral therapy (HAART) results in marked survival benefits for HIV-infected people.1,2 In contrast to adults, who may defer HAART for several years, nearly half of HIV-1 infected children in Africa will die by the age of 2 if they are not treated.3,4 By 2005 in Africa, where ~90% of the world's HIV-infected children reside, children represented 13% of the population in need of antiretroviral treatment (ART) and only ~5% of the population receiving ART.5,6 The number of children receiving ART has since increased; however, children are still less likely than adults to receive therapy.5
Many factors impede the use of HAART in resource-limited settings, particularly in pediatric populations. Lack of infrastructure, health care professionals, and technology to diagnose HIV-1 and monitor treatment have initially delayed treatment of both adults and children.7 The threat of poor adherence and viral resistance continues to be a concern in resource-limited settings.8,9 Children face additional barriers to treatment including dosing, formulations, higher costs for pediatric antiretroviral drugs, and high infant mortality rates.3,10–13
Beginning in 2004, African countries began expanding access to antiretroviral medications as funding became available.14,15 Better descriptions of clinical diagnosis, staging, and management of HIV-infected children facilitated scale-up of treatment.16 A number of publications in which treatment outcomes for pediatric populations in resource-limited settings were described have recently emerged. These studies, including 2 recent reviews by Sutcliffe et al14 and Ciaranello et al,17 reference outcomes from developed-countries (DCs) publications for informal comparison; however, no study has systematically compared outcomes and characteristics of pediatric ART between resource-limited countries (RLCs) and DCs.
The purpose of this study was to review the literature to quantify and compare major clinical end points and baseline characteristics for children receiving HAART in DCs versus RLCs.
A systematic literature search was performed through March 2010 for all studies for which outcomes (mortality, weight-for-age z score [WAZ], CD4%, and viral load [VL]) were reported after initiation of HAART in pediatric patients. The following databases were searched: PubMed, EBSCO, Global Health Host, AIDSLine, and the Cochrane Library. Conference abstracts from the International AIDS Society 2009 and Conference on Retroviruses and Opportunistic Infections 2010 were searched, because these data likely have not had time to be published. Search terms included “pediatric,” “children,” “HIV,” “HAART,” “Africa,” “resource-limited,” “developing country,” “outcomes,” “mortality,” “efficacy,” and “adherence” (or equivalents of these terms [ie, HIV-1, ART, antiretrovirals, ARV, therapy, treatment]). This search strategy was supplemented by searching references in the bibliographies of articles.
Observational cohorts and clinical trial studies were selected for review on the basis of predefined criteria. Full-length articles published in a language other than English were included if they had an abstract in English. Studies were selected on the basis of the following criteria: (1) patients were younger than 21 years and not limited to a narrow age range such as <24 months or >13 years), (2) patients had received HAART (≥3 antiretroviral medications), (3) the sample size was >20 patients, and (4) patients had at least 6 months' follow-up on HAART. Outcome measures included mortality, weight change, CD4 counts and percentages, and VLs. Two authors reviewed the reports and came to agreement on inclusion or exclusion of the publications.
In addition to the outcome measures, information was extracted on the focus of the study, regimen, previous ART exposure including prevention of mother-to-child transmission, time from presentation to initiation of HAART, disease severity, predictors of mortality, orphan status, hospitalization, follow-up time, percentage of patients lost to follow-up, and intent-to-treat versus as-treated analysis. Articles were separated into 2 categories, RLCs or DCs, according to rankings by the United Nations Statistics Division.18 Articles were then subcategorized according to geographic location. Studies were also grouped on the basis of the cohorts' previous HAART exposure: HAART-naive (previous mono/dual therapy or antiretroviral naive) or HAART-exposed (3-drug regimen including a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor).
Multiple reports were reviewed for the same study, and individual studies were compared for overlap. Overlap was evaluated by reviewing authors, location, date, duration, and specific interventions. When results overlapped, data from the largest cohort, most recent publication, or longest follow-up time were selected. Multiple reports for the same or overlapping cohort were included if they each provided unique outcome data (eg, 1 reported mortality, 1 reported CD4%, or each reported CD4 count at different time points). Unique outcome data were extracted and added so that no overlapping data points were used in calculations. Reports were excluded if data were not used (see Appendix).
The mortality percentage was collected directly or calculated from reported results. Deaths per 100 child-years (DPCY) was calculated by using the number of deaths and time of the mortality measurement, unless reported directly in the article. The total number of child-years was estimated as the sum of years contributed by living patients at the time of mortality measurement and one-half of this follow-up time for deceased patients. These estimations are likely to be less accurate with longer follow-up times.
For articles in which mortality rates at multiple follow-up time points were provided, the mortality measurement nearest 12 months' follow-up was used, because it was the most commonly used follow-up time point.
Mean baseline characteristics and mortality rates were calculated for comparison between RLCs and DCs. All mean calculations were weighted on the basis of cohort size. Hereafter, weighted means will be referred to simply as means. The means, ranges, SDs, and confidence intervals of HAART-naive studies were calculated for both mortality percentage and DPCY for each geographic subregion, RLCs, and DCs. In addition, the RLC and DC means, ranges, SDs, and confidence intervals for baseline characteristics including CD4 T-cell percentage, VL (log10 copies per mL), age, and WAZ were calculated for HAART-naive studies and for all studies that included HAART-experienced cohorts. CD4% and the percentage of patients who achieved virologic suppression were graphed over time, and the mean levels 12 months after HAART were calculated. The RLC and DC baseline values and outcomes were compared by using independent-samples t tests.
The initial literature search produced 723 publications: 313 published articles and 410 conference abstracts. Abstracts, methods, and/or results were reviewed, and 199 reports were found to contain some relevant selection criteria. Of these reports, 131 were excluded for reasons listed in Fig 1 and the Appendix, and the remaining 68 were used for analysis (RLCs = 40, total N = 18 882 and 17 875 approximately correcting for overlap; DCs = 28, total N = 3150 and 1835 approximately correcting for overlap). Characteristics of included studies are summarized in Table 1.
The mean baseline age in RLC studies was 5.4 and 5.7 years in HAART-naive and all studies, respectively (Table 2). In DCs, the mean age of patients in HAART-naive and all studies was 6.5 and 6.7 years, respectively. There was no significant difference in the mean/median age at baseline between RLCs and DCs for HAART-naive cohorts (P = .1) or all studies (P = .2).
The mean WAZ for children who were initiated on HAART in RLCs was −2.2 for both HAART-naive and all studies combined (Table 2). In DCs, the mean WAZ for both HAART-naive and all studies was −0.4. There was a large and statistically significant difference between baseline WAZ in RLCs and DCs (P < .001).
The mortality analysis included 38 cohorts: 30 cohorts from RLCs (N = 9663) and 8 cohorts from DCs (N = 1277). Only outcomes for patients on HAART (≥3 antiretroviral medications) were used in the analysis. Several calendar studies were excluded, because the authors reported mortality rates for birth cohorts without separating outcomes for patients on no ART, mono/dual therapy, or HAART; these studies revealed decreased mortality rates after the introduction of HAART.2,80,83–85 In addition, 11 study reports provided mortality data but were not included in pooled analysis because of overlap with larger or more recent studies.*
Post-HAART mortality data for HAART-naive studies are shown in Fig 2 and Table 3. Geographic subregions used for RLCs were Africa (20 studies), Asia/Eastern Europe (4 studies), and South America/Caribbean (2 studies). The mean mortality rates in Africa, Asia/Eastern Europe, and South America/Caribbean were 7.4%, 8.8%, and 7.6% per cohort and 7.5, 11.9, and 8.4 DPCY, respectively. In US and European HAART-naive studies, the mean mortality rates were 1.6% per cohort and 0.9 DPCY.
Comparisons between RLCs and DCs are listed in Table 2. Post-HAART mortality rates for HAART-naive cohorts in RLCs were ~5 and 9 times greater than in DCs: 7.6% vs 1.6% and 8.0 vs 0.9 for mortality percentage and DPCY, respectively (P = .002 and P < .001, respectively). Mean mortality rates for all studies that included previously mono/dual protease inhibitor– and nonnucleoside reverse transcriptase inhibitor–treated children were 7.5% vs 1.7% mortality percentage and 7.7 vs 1.0 DPCY for RLCs and DCs, respectively.
Forty-two study reports provided unique data for either baseline CD4% or CD4% over time: 25 from RLCs and 17 from DCs. Twenty-three RLC and 13 DC studies were pooled for baseline CD4%, restricting to 1 value from overlapping cohorts (Table 2). HAART-naive studies had mean baseline CD4% values of 12% (range: 5%–20%) and 23% (range: 7%–47%) for RLCs and DCs, respectively (P = .01). Twenty reports from RLCs and 9 reports from DCs described changes in CD4% after HAART initiation (Fig 3). In this graphical presentation, overlap exists between the Pediatric AIDS Clinical Trial Group publications (namely, refs 58, 60, 62, 63, and 65). Mean CD4% 12 months after HAART was significantly different between RLC and DC studies: 24% and 27%, respectively (P = .03).
Forty-three study reports provided unique data for either baseline VL or percent virologic suppression: 21 from RLCs and 22 from DCs. Fourteen RLC and 14 DC studies reported baseline VL (Table 2). Baseline VLs in HAART-naive studies were 5.5 log10 copies per mL in RLCs and 4.7 log10 copies per mL in DCs (P < .001). Nineteen RLC and 20 DC reports described the percentage of patients who achieved virologic suppression (Fig 4). Viral suppression was defined as <400 copies per mL. Six study reports only defined viral suppression as <50 copies per mL.26,39,43,51,60,72 Overlap exists between refs 11, 58, 64, 65, and 68; the Paediatric European Network for Treatment of AIDS overlaps with ref 81 but not with ref 80, because data from this reference were extracted for the 2003–2006 birth cohort. Twelve months after HAART, the mean percentage of children who achieved viral suppression was 65% in RLC and 49% in DC studies, and there was no significant difference between the 2 groups (P = .4). Eleven of the DC and 7 of the RLC studies reported using an intention-to-treat approach when evaluating the rate of virologic suppression.†
Weighted least-squares regression was used to determine if differences in mortality between RLCs and DCs diminished after controlling for baseline WAZ, CD4%, or VL. Adjusting for baseline CD4 level, the mortality difference between RLCs and DCs persisted (6.7% mortality difference; P = .01), and there was negligible evidence of confounding. There were fewer studies for which VL and WAZ were reported; however, the mortality difference between RLCs and DCs seemed to be confounded by baseline WAZ and VL.
Studies from both RLCs and DCs revealed associations between mortality rate, baseline CD4%, and VL.11,12,13,36,42,61,63,68 Low WAZ was a risk factor for mortality.12,26,27,40,44,77 Several RLC studies revealed that younger age was associated with mortality, whereas DC studies revealed conflicting findings regarding age and mortality.12,22,36,51,73,80 Finally, 2 RLC studies revealed that orphans had a higher mortality rate, although programs with >50% orphans achieved relatively low mortality rates overall.22,23,45
Information was also collected surrounding initiation of HAART. RLC studies referenced various World Health Organization (WHO) pediatric ART guidelines that recommend initiation of HAART at WHO stage 3 or 4 or at a CD4% of <15%, <20%, <15%, or <20%, depending on age, or <200 cells per μL. The authors of ref 45 (Cambodia) noted that 37% of evaluated children did not meet initiation criteria, and 10% of eligible children died before initiation. DC studies often did not report specific initiation criteria. Between 61% and 99% of children in RLC studies initiated HAART at WHO stage 3 or 4 disease.27,36 Between 10% and 62% of children in DC studies had Centers for Disease Control and Prevention class C disease.78,82 Only 1 RLC study42 (Zambia) reported median age at diagnosis: 5.5 years. The authors of ref 69 (Denmark) reported median age of diagnosis at 1.5 years; median age of initiation was 6.7 years. Another study80 found that between 2004 and 2006 foreign-born children presented later than UK-born children: 7.6 versus 0.8 years, respectively. Four RLC studies reported time between diagnosis and HAART initiation ranging from a median of 53 days to 26 months.20,33,40,44 RLC studies reported that <10% of subjects received antiretroviral medications in attempt to prevent vertical transmission (<1%–12%); however, it is possible that perinatal nevirapine exposure was not systematically ascertained or was underreported.16,20,25,26,27,33,38,41 Prevention of mother-to-child transmission was reported as being widely available in DCs, but rates of utilization were not specified.11,61,67,80
In this study, we determined and compared baseline status and outcomes of children who initiated HAART in RLCs and DCs. As anticipated, mortality rates were dramatically lower with HAART than in studies before HAART and <10% in both settings. Mortality rates were higher in RLCs than in DCs, but the mortality difference observed was less than would have been expected on the basis of general childhood mortality estimates from those regions, which suggests that the added contact with care providers enhances survival beyond baseline, likely by prevention of common infectious diseases. RLC cohorts involved children with significantly lower baseline CD4 counts and WAZ and higher VLs, all of which would be expected to also contribute to increased mortality rates. Efforts to initiate HAART earlier would be expected to identify children before substantial immunosuppression, which should translate into improved survival rates.
Comparisons between observational studies have inherent limitations; nonetheless, these comparisons are important for the evaluation of programs and to guide future treatment. Although authors of recent reviews have described post-HAART outcomes in Africa, none has systematically compared outcomes between regions.14 RLC outcomes have been compared informally to DC outcomes without careful consideration of the cohort selection criteria or treatment regimens. Informal comparisons have been made to DC study reports that provided outcomes according to calendar years, including patients not on ART and those on HAART for years, infant studies, overlapping studies, and cohorts of < 20 patients.2,14,17,80–85,89–91 Publications included in this study were systematically screened on the basis of age, cohort size, and regimens. Outcome data were extracted to avoid analysis of data from overlapping cohorts, and standardized outcomes were compared.
The post-HAART mortality rates for HAART-naive children were fivefold to ninefold greater in RLCs than in DCs. Although not directly comparable, this difference was less than the difference between overall mortality rates for children between the ages of 1 and 5 years in RLCs and DCs (exceptions included Brazil and Thailand).92 Six studies from Zambia, Kenya, Rwanda, and Tanzania found that post-HAART mortality rates fell below 3.5 DPCY despite higher regional child mortality rates (range: 37–56 deaths per 1000 live births between the ages of 1 and 5 years, as estimated by subtracting infant mortality rates from mortality rates of children <5 years old).22–24,33,40,44,92 Although HIV contributes to overall child mortality rates in high HIV-prevalence areas, HAART seems to provide some survival benefits to patients, perhaps by simply bringing children in contact with medical services.93,94
The CD4 and VL data provide important contextual information for interpretation of the mortality results by demonstrating that HAART programs in RLCs have reported efficient and comparable increases in CD4% and declines in VLs as DC programs. Significantly lower CD4 levels observed in RLCs 12 months after HAART are likely a result of markedly lower baseline CD4 levels. In contrast, post-HAART VL-suppression rates were not significantly different between DCs and RLCs after HAART despite significantly higher baseline VL in RLCs.
Strengths of this analysis include the large number of studies evaluated, the study-selection process, and the standardized comparisons of mortality rates, baseline CD4 percentage, and baseline VLs. This comprehensive comparison spanned 11 years of publications, during which drug regimens, guidelines, and patient populations evolved, particularly in DCs. Although later publications from DCs would be expected to use more potent medications, earlier study reports described larger HAART-naive cohorts, which provides better comparison of baseline characteristics and perhaps slightly underestimates the difference between DCs and RLCs.74 A limitation of the study is that outcomes were likely biased toward better outcomes, because children lost to follow-up could include unreported deaths or immunologic and virologic nonresponders. We excluded cohorts that had only included children with a minimum amount of follow-up for the same reason. The studies we included had survivor bias (mean baseline age: >5 years); in RLCs, untreated HIV-infected children have only 50% survival rates below 2 years. As-treated analysis also results in overestimation of virologic suppression, because the proportion of children who achieved virologic suppression has been reported within the denominator of patients with VL data rather than the total number of patients who initiated treatment.
Low baseline CD4, WAZ, and high VL levels were identified by individual studies as strong predictors of mortality in both RLCs and DCs. In multivariate analysis, mortality-rate differences between RLCs and DCs persisted even after adjusting for baseline CD4 count. However, we found that at least a portion of the mortality-rate difference was attributable to differences in WAZ or VL in these different settings. In RLCs, children were older at the time of diagnosis and had more advanced disease, and the majority of deaths occurred in the first 6 months of treatment.‡ Earlier identification of children could improve post-HAART outcomes by identifying children with less advanced disease.95,96 Revised 2010 WHO treatment guidelines recommend treatment for all children younger than 24 months and a new CD4 threshold of 25% or 750 cells per μL for children aged 2 to 5 years. Additional studies are needed to evaluate the effect of these new guidelines on post-HAART outcomes.97
Pediatric HAART programs in RLCs are successfully achieving a reduction in HIV- related mortality; however, post-HAART mortality rates remain higher than the rates in DCs. Currently, children in RLCs begin HAART at higher baseline VLs and lower baseline CD4 levels. Continuing to improve child health with interventions including nutritional support and prevention and treatment of coinfections may additionally improve survival rates. With increased availability of treatment and earlier treatment, regions with high HIV prevalence should realize marked declines in HIV-related child mortality.
We thank Romel D. Mackelprang, Neil S. Geisler, Patrick Danaher, and Enrique Peacock-Lopez for their contributions to the creation of the figures.
|Country||Author||Reason for Exclusion|
|1. Cote d'Ivoire||Adje-Toure et al98||Overlap with Fassinou et al20, subset analysis excluded patients who died|
|2. Ethiopia||Biadgilign et al99||Adherence study, cross-sectional|
|3. Nigeria||Onankpa et al100||Epidemiology study, no post-HAART outcomes reported|
|4. South Africa||Cowburn et al101||Mortality not reported, hospitalization study|
|5. South Africa 2004||Eley102||Overlap with Eley,36 data not used in analysis|
|6. South Africa||Prendergast et al103||Limited to infants followed from birth|
|7. South Africa||van Kooten et al104||Cohort too small (17 patients)|
|8. South Africa||Violari et al95||Age limited to 6–12 wk, early vs delayed antiretroviral medication|
|9. Togo||Atakouma et al105||Cross-sectional study|
|10. Togo||Polisset et al106||Adherence study, no post-HAART outcomes reported|
|11. Argentina||Fallo et al107||Calendar-year comparisons|
|12. Brazil||Matida et al108||Calendar surveillance|
|13. Brazil||Candiani et al109||No. on HAART not specified|
|14. Guatemala||Samayoa et al110||Results combine HAART and non-HAART|
|15. Jamaica||Evans-Gilbert et al111||Mortality not reported, hospitalization|
|16. Cambodia||Madec et al112||Age limited to >13 y|
|17. India||Kumarasamy et al113||Excluded patients with follow-up at <18 mo|
|18. India||Lodha et al114||Excluded patients with follow-up at <3 mo|
|19. India||Natu et al115||Mortality not reported|
|20. India||Pensi et al116||Cohort too small (13 patients)|
|21. Romania||Ferris et al117||Overlap with Kline et al,48 focus on disclosure|
|22. Romania 2004||Kline et al88||Overlap with Kline et al,48 data not used in analysis|
|23. Thailand||Chearskul et al118||Overlap with Lapphra et al40, data not used in analysis|
|24. Thailand||Koekkoek et al119||Cohorts too small (16 patients)|
|25. Thailand||Plipat et al120||Cohort too small (19 patients)|
|26. Multiple||O'Brien et al10||Overlap with multiple studies|
|27. Multiple||Arrive et al121||Overlap with multiple studies|
|28. Multiple||KIDS ART-LINC122||Overlap with multiple studies|
|29. Multiple||Saez-Llorens et al123||Did not isolate data from RLCs and DCs|
|30. Africa/Romania||Weidle et al124||Mortality not reported, dosing study|
|31. Lat. America||Hazra et al125||Results combined HAART- and non–HAART-treated patients|
|32. Belgium||Hainaut et al126||Cohort too small (4 patients), age limited to <2 mo|
|33. France||Aboulker et al127||Age limited to <3 mo|
|34. France||Faye et al128||Age limited to <1 y|
|35. Germany||Funk et al90||Cohort too small (16 patients)|
|36. Germany 1998||Wintergerst et al129||Cohort too small (15 patients)|
|37. Italy||Canani et al130||Cohort too small (10 patients)|
|38. Italy||Chiappini et al131||Overlap with de Martino et al87, calendar study|
|39. Italy||de Martino et al87||Overlap with PENTA,82 data not used in analysis|
|40. Italy||Vigano et al132||Cohort too small (11 patients), heavily pretreated|
|41. Netherlands 1998||Cohen et al133||Cohort too small (13 patients)|
|42. Spain||Larru et al134||Limited to patients whose conditions failed to respond HAART|
|43. Spain 2006, 2004||Resino et al135,85||Calendar study|
|44. Spain 2003||Sanchez et al136||Overlap with Larru et al134, Kaplan-Meier survival|
|45. Spain||Guillen Martin et al137||Epidemiology/immigrant study, no post-HAART outcomes reported|
|46. Switzerland||Steiner et al138||Overlap with Nadal et al78/Rudin et al79 excludes patients with <72 wk follow-up, growth study,|
|47. UK, Ireland||Gibb et al91||Overlap with PENTA,82 calendar study|
|48. UK, Ireland||Doerholt et al89||Age limited to <12 mo|
|49. 9 countries||Newell et al139||Overlap with PENTA82/Scherpbier et al74, results combined HAART- and non–HAART-treated patients|
|50. Europe 2009||Goetghebuer et al140||Limited to infants followed from birth|
|51. US 2001||Abrams et al141||Calendar study|
|52. US 2003||Benjamin et al142||PACTG 300 mono/dual treatment, growth study|
|53. US 2004||Berrien et al143||Adherence study, post-HAART outcomes not reported|
|54. US 2001||Blazevic et al144||Cohort too small (11 patients)|
|55. US 2000||Borkowsky et al145||Overlap with PACTG 338 reports, data not used in analysis|
|56. US 2010||Brady et al146||Calendar/birth-cohort study|
|57. US 2005||Brogly et al147||Overlap with PACTG 219C reports, calendar study, <24 y of age|
|58. US 2004||Brundage et al148||Overlap with PACTG 382 reports, data not used in analysis|
|59. US 2001||Buchacz et al149||Overlap with PACTG 219 reports, growth measures not comparable|
|60. US 2003||Caudill et al83||Results combined HAART- and non–HAART-treated patients|
|61. US 2005||Chadwick et al150||Age limited between 4 wk and 24 mo|
|62. US 2008||Chadwick et al151||Age limited to <6 mo|
|63. US 2001||Chougnet et al152||Overlap with Mueller et al168,169, excluded patients with clinical/immune decline|
|64. US 2002, 2004||Church et al153,9||Cohort too small (14 patients), Enfuvirtide study|
|65. US 1999||Essajee et al154||Limited to severely immunocompromised patients|
|66. US 2004, 2007||Flynn et al155||Age limited to 8–22 y|
|67. US 2007||Glikman et al157||Cohort too small (9 patients), adherence study|
|68. US 2006||Gona et al158||Overlap with PACTG 219, calendar comparison, opportunistic-infection study|
|69. US 2001||Gortmaker et al2||Overlap with PACTG 219, calendar study|
|70. US 2001||Jankelevich et al159||Excluded patients with follow up at <96 wk|
|71. US 2001||Johnston et al160||Immune-reconstitution study|
|72. US 2009||King et al161||Age limited to 10–18 y, pharmacokinetic study|
|73. US 1998||Kline et al162||Cohort too small (12 patients)|
|74. US 2006||Lee et al163||Overlap with PACTG 219, quality-of-life study|
|75. US 2000||Lindsey et al84||Meta-analysis included mono/dual/HAART|
|76. US 1997, 2004||Luzuriaga et al164,165||Age limited between 2 wk and 24 mo|
|77. US 2005||McConnell et al166||Calendar study|
|78. US 1997||Melvin et al167||Cohort too small (9 patients)|
|79. US 1998, 1998||Mueller et al168,169||Follow-up included 16 wk of monotherapy and only 12 wk on HAART, overlap with Jankelevich et al159|
|80. US 2000||Nachman et al170||Overlap with PACTG 338, data not used in analysis|
|81. US 1999||Palumbo et al171||Mono and dual therapy study|
|82. US 2008||Patel et al172||Overlap with PACTG 219, CD4% comparison between patients with and without HAART initiation|
|83. US 1999||Pelton et al86||Results combined HAART- and non–HAART-treated patients|
|84. US 2005||Pelton et al173||Overlap with PACTG 338, data not used in analysis|
|85. US 2001||Polis et al174||Overlap with Mueller et al168,169, monotherapy|
|86. US 2000||Reddington et al175||Overlap with PACTG 219 is unclear, adherence study|
|87. US 2008||Robbins et al176||Limited to patients whose conditions failed to respond to HAART therapy, pharmacokinetic study|
|88. US 1997||Rutstein et al177||Results combined HAART- and non–HAART-treated patients|
|89. US 2005||Storm et al178||PACTG 219, cross-sectional quality-of-life study|
|90. US 2002||Van Dyke et al179||Overlap with PACTG 377, adherence subset, data not used in analysis|
|91. US 2004||Viani et al180||Calendar comparison|
|92. US 2007||Wiznia et al181||Required HAART for 4 mo before study initiation, Enfuvirtide study|
|IAS Abstracts 2009|
|93. Kenya||Ayaya et al182||Results combined HAART- and non–HAART-treated patients|
|94. Kenya||McGrath et al183||Growth study comparison of children <3 y/>3-y patient outcomes|
|95. Kenya||Owiso et al184||Calendar-study comparison|
|96. Kenya||Wamalwa et al185||Overlap with published study, data not used in analysis|
|97. KwaZulu Natal||Ndirangu et al186||Overlap with Reddi et al,26 growth study|
|98. Malawi||Braun et al187||Limited to “infant” cohort, age not specified|
|99. Malawi||Dow et al188||Age limited to <6 wk|
|100. Malawi||Kabue et al189||Limited to patients failing first line HAART|
|101. Malawi||Kabue et al190||Limited to “infant” cohort age not specified|
|102. Swaziland||Chouraya et al191||Age limited to <12 mo|
|103. South Africa||Colvin et al192||Mortality not reported|
|104. South Africa||Coovadia et al193||Post-PMTCT study|
|105. South Africa||Fatti et al194||Overlap with Eley,36 data not used in analysis|
|106. South Africa||Fenner et al195||Comparison of <5 y/>5-y patient outcomes|
|107. South Africa||Kaplan et al196||Overlap unclear, hospital not listed|
|108. Uganda||Kekitiinwa et al197||Limited to malnourished children|
|109. Cambodia||Augustinova et al198||Age limited to <18 mo|
|110. Cambodia||Isaakidis et al199||Cross-sectional survey|
|111. Cambodia||Sophan et al200||Limited to patients whose conditions failed to respond to first-line HAART|
|112. Indian||Pandian et al201||Overlap with published study, data not used in analysis|
|113. Thailand||McConnel et al202||Overlap with Puthanakit et al51|
|114. Brazil||Rezende et al203||Overlap with Romanelli et al52, limited to patients with follow-up at >48 wk|
|115. Multiple||Carter et al204||Comparison of children <12 mo/>12 mo|
|116. Multiple||Hansudewechakul et al205||Overlap multiple studies|
|117. Southern Africa||Davies et al206||IeDEA, virologic failure study, does not report virologic suppression|
|118. US||Palumbo et al207||IMPAACT trial, age limited to <36 mo|
|119. Unspecified||Bognon et al208||Results combined HAART- and non–HAART-treated patients|
|120. South Africa||Venkatesh et al209||Limited to infants followed from birth|
|121. Uganda||Achan et al210||Outcomes reported virologic failure|
|122. Southern Africa||Becquet et al211||Survival study, not HAART-focused|
|123. India||Pandian et al212||Overlap with Rajasekaran et al47|
|124. Thailand||Sudjaritruk et al213||No mortality reported, hospitalization study|
|125. Spain||Palladino et al214||Fosamprenavir study, experimental|
|126. US||Nachman et al215||Cohort too small (10 patients)|
PENTA indicates Paediatric European Network for Treatment of AIDS; PACTG, Pediatric AIDS Clinical Trial Group; IAS, International AIDS Society; PMTCT, prevention of mother-to-child transmission; IeDEA, International Epidemiologic Databases to Evaluate AIDS; IMPAACT, International Maternal Pediatric Adolescent AIDS Clinical Trials Group; CROI, Conference on Retroviruses and Opportunistic Infections.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
Funded by the National Institutes of Health (NIH).