Effectiveness of pediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis

Abstract

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 (DeltaCD4%) 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 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.

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 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%).

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.

Figure 1. Selection of publications for a systematic review and meta-analysis of pediatric ART effectiveness

Flowchart describing 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 only adults (58); they provided only cross-sectional data (2) or case reports (3); they did not report on HIV (7); they reported on non-resource-limited settings (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 (146); or they did not report outcomes related to viral load or CD4 cells (154). Abbreviations: ART: combination antiretroviral therapy, RLS: resource-limited setting, MTCT: mother-to-child transmission of HIV.

Figure 2. Forest plot of viral suppression rates (proportion of children with HIV RNA<400 copies/ml) 12 months after ART initiation for treatment-naïve children in resource-limited settings

Studies included in the pooled analysis of the proportion of children with HIV RNA <400 copies/ml 12 months after initiating ART are shown on the left of the figure. Reported proportions of children with 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 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.

Figure 3. Forest plot of absolute gain in CD4% 12 months after ART initiation for treatment-naïve children in resource-limited settings

Studies included in the pooled analysis of the absolute gain in CD4% 12 months after initiating ART are shown on the left of the figure. 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 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 percent 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/µL of serum), because CD4% maintains a more constant value during normal immune system maturation. As a result, CD4% is often reported for children of any age, while absolute CD4 is usually reported only for adults and children >5 years old.