Background: The tolerance of antiretroviral drugs in infants must be carefully evaluated. In previous studies of children with HIV type 1 (HIV-1) less weight gain was observed in children given lopinavir-ritonavir-based combinations than those given nevirapine. We aimed to compare the effects of lopinavir-ritonavir and lamivudine on growth in HIV-exposed uninfected infants included in the ANRS 12174 trial.
Methods: ANRS 12174 was a multicentre, randomised, controlled trial of infant prophylaxis to prevent HIV-1 transmission by breastfeeding done at four antenatal clinics in Burkina Faso, South Africa, Uganda, and Zambia. HIV-exposed uninfected infants born to asymptomatic mothers not eligible for antiretroviral therapy (CD4 count >350 cells per μL) were randomly assigned (1:1) to receive lopinavir-ritonavir or lamivudine 7 days after birth, with stratification by country. In a prespecified secondary analysis, we assessed the effect of lopinavir-ritonavir and lamivudine on the growth of these infants from day 7 until cessation of breastfeeding (maximum treatment time 12 months) in the modified intention-to-treat population, which included all children correctly enrolled with at least one follow-up anthropometric measurement. We compared the growth of infants, defined as children's WHO-defined length-for-age Z score (LAZ), weight-for-length Z score (WAZ), and weight-for-age Z score (WLZ). We used linear mixed effect and β spline-regression models to compare growth between the treatment groups. The trial is registered with ClinicalTrials.gov, number NCT00640263.
Findings: 1273 HIV-exposed uninfected infants and their mothers were enrolled between Nov 16, 2009, and May 7, 2013, of whom 1266 (99%) infants were included in the modified intention-to-treat analysis (630 assigned to lopinavir-ritonavir, 636 assigned to lamivudine). Baseline characteristics of the infants and mothers were similar across the two treatment groups. No differences in least-squares (LS) mean LAZ were identified between the treatment groups at any timepoint. LS mean WLZ was significantly lower in the lopinavir-ritonavir group than the lamivudine group at 26 weeks (difference -0·22 [95% CI -0·34 to -0·09], p=0·0006) and 50 weeks (-0·25 [-0·47 to -0·04], p=0·02). LS mean WAZ was also significantly lower in the lopinavir-ritonavir group than the lamivudine group at 26 weeks (difference -0·18 [95% CI -0·30 to -0·05], p=0·01) and 50 weeks (-0·24 [-0·45 to -0·05], p=0·02). Linear mixed models showed that lopinavir-ritonavir was associated with decreases in WLZ and WAZ over time (p<0·0001 and p=0·002), whereas spline regression models indicated that these reductions occurred early and remained constant thereafter (p<0·0001 with a knot at 44 days for WLZ; p=0·02 with a knot at 118 days for WAZ). The difference in LS mean WLZ at 50 weeks between the treatment groups was higher among girls than boys (difference -0·29 [95% CI -0·58 to 0·01], p=0·05 for girls; -0·22 [-0·53 to 0·09], p=0·18 for boys).
Interpretation: Less weight gain was observed in infants given lopinavir-ritonavir than those given lamivudine, which is indicative of a persistent effect that could have long-term deleterious effects. This finding merits attention considering the recommendations for early and lifelong treatment of infants with HIV.
Funding: French National Agency for Research on AIDS and Viral Hepatitis, the Total Foundation, the European Developing Countries Clinical Trials Partnership, and the Research Council of Norway.
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