Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age.Cochrane Database Syst Rev. 2012 Jul 11CD
In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiate ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to switch or interrupt therapy. This review aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 2 years of age.
To evaluate 1) when to start ART in young children; 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and PI-based regimens; and 3) whether and when ART should be stopped or switched from a PI-based regimen to an NNRTI-based regimen.
We searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform).
We identified RCTs that recruited perinatally HIV-infected children under 2 years of age without restriction of setting. We rejected trials that did not include children less than 2 years of age, or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy.
DATA COLLECTION AND ANALYSIS
Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes.
Of 1921 records retrieved, 5 studies were eligible for inclusion in the review, addressing when to start treatment (n=2), what to start (n=2) and whether to switch regimen (n=1). Three ongoing studies that address the question of treatment interruption were also identified.Early infant treatment was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller trial,median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure was 2.01 (95%CI 1.47, 2.77) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p<0.0001) with no clear difference in effect by age group. The hazard for virological failure was overall 2.28 (95%CI 1.55, 3.34) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0005) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life. By contrast, increases in weight z-score (MD=0.37, 95%CI 0.08, 0.65, p=0.01) and height z-score (MD=0.23, 95%CI 0.04, 0.42, p=0.02) were larger in the NVP arm compared to the LPV/r arm .Infants starting on a LPV/r regimen but who then switched to a NVP-based regimen after a median time of 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (>1000 copies/mL) was higher among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002).