Abstract
There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4 percentage (CD4%) <25%. ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping. The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm(3) (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1-6.5) (no ART) to 2.1% (95% CI: 1.3%-3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%-3.5%) and 2.2% (95% CI: 1.4%-3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data. The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm(3) or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values. Please see later in the article for the Editors' Summary.
Highlights
HIV infection continues to contribute substantially to the burden of disease in children, with an estimated 330,000 new paediatric infections worldwide in 2011
The results indicate no mortality difference for up to 3 y between antiretroviral therapy (ART) initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count,750 cells/mm3 or CD4%,25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values
The primary comparison we considered was (i) giving ART immediately irrespective of CD4 criteria or (ii) deferring ART until a child’s CD4 cell count falls below 750 cells/mm3 or CD4% falls below 25%; further strategies we considered were (iii) deferring ART until the threshold of CD4 count,500 cells/mm3 or CD4%,20% is reached, (iv) deferring ART until the threshold of CD4 count,250 cells/mm3 or CD4%,15% is reached, and (v) no ART is given
Summary
HIV infection continues to contribute substantially to the burden of disease in children, with an estimated 330,000 new paediatric infections worldwide in 2011. The Pediatric Randomized to Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) trial [7,8,9] enrolled children aged 1–12 y with initial CD4 percentage (CD4%) values of 15%–24% without US Centers for Disease Control and Prevention (CDC) category C disease. These children were randomly assigned to start ART immediately or defer therapy until their CD4% dropped below 15% or a CDC category C event occurred. ART is very effective in children but is expensive, and despite concerted international efforts over the past decade to provide universal access to ART, in 2011, less than a third of children who needed ART were receiving it
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