Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with and without prior nevirapine exposure for the prevention of mother-to-child HIV transmission

Abstract

Background: In a randomized trial comparing nevirapine (NVP)-based versus lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) in HIV-infected children [primary endpoint discontinuation of study treatment for any reason or virologic failure by week 24] aged 2 months to 3 years, we assessed whether clinical, virologic, immunologic and safety outcomes varied by prior single-dose NVP exposure (PrNVP) for prevention of mother-to-child HIV transmission and other covariates.

Methods: Efficacy was assessed by time to ART discontinuation or virologic failure, virologic failure/death and death; safety by time to ART discontinuation because of a protocol-defined toxicity and first ≥ grade 3 adverse event; immunology and growth by changes in CD4%, weight/height World Health Organization z-scores from entry to week 48. Cox proportional hazards and linear regression models were used to test whether treatment differences depended on PrNVP exposure and other covariates.

Results: Over a median follow up of 48 (PrNVP) and 72 (no PrNVP) weeks, there was no evidence of differential treatment effects by PrNVP exposure or any other covariates. LPV/r-based ART was superior to NVP-based ART for efficacy and safety outcomes; however, those on NVP had larger improvements in CD4%, weight and height z-scores. Lower pretreatment CD4% and higher HIV-1 RNA levels were associated with reduced efficacy, lower pretreatment CD4% with shorter time to ART discontinuation because of a protocol-defined toxicity, and no PrNVP with shorter time to first grade ≥ 3 adverse event.

Conclusions: Differences between LPV/r and NVP ART in efficacy, safety, immunologic and growth outcomes did not depend on PrNVP exposure, prior breast-feeding, sex, HIV-1 subtype, age, pretreatment CD4%, HIV-1 RNA or World Health Organization disease stage. This finding should be considered when selecting an ART regimen for young children.

Trial registration: ClinicalTrials.gov NCT00307151.

Figures

Figure 1

Cumulative incidence over time of outcomes by randomized treatment for participants with and without prior single dose NVP exposure PrNVP – trial participants who had received single dose nevirapine (NVP) at least 6 months before enrollment to P1060 (No PrNVP had never received nevirapine); LPV/r – lopinavir/ritonavir

Figure 2

Forest plot of hazard ratios for time to each efficacy and safety endpoint. Adjusted models included sex, HIV-1 subtype, age, prior breastfeeding, WHO category, CD4% and HIV-1 RNA at study entry PrNVP – trial participants who had received single dose nevirapine (NVP) at least 6 months before enrollment to P1060 (No PrNVP had never received nevirapine); LPV/r – lopinavir/ritonavir; TRT – treatment; VF – virologic failure; HR – hazard ratio; CI – confidence interval

Figure 3

Weight and height WHO z-scores and CD4% means (95% confidence intervals) by week (1st column) and changes from baseline (2nd column) PrNVP – trial participants who had received single dose nevirapine (NVP) at least 6 months before enrollment to P1060 (No PrNVP had never received nevirapine); LPV/r – lopinavir/ritonavir; WHO – World Health Organization; Z – age and sex-adjusted z-score