HIV-exposed uninfected (HEU) children experience higher mortality than HIV-unexposed children. Cotrimoxazole (CTX) reduces mortality among HIV-infected children, but no randomized clinical trials have evaluated its efficacy among HEUs.
We randomized HEU children in a non-malarial region of Botswana to receive either double-blinded CTX or placebo from 14-34 days through 15 months of life. Children were followed every 1-3 months through 18 months; infants diagnosed with HIV after randomization transitioned to open-label CTX. Feeding method was chosen by mothers, with either formula (provided by the Botswana government) or breastfeeding supported with maternal or infant antiretroviral prophylaxis. Breastfed infants were randomized to either 6 or 12 months duration. Primary analysis was intent-to-treat (restricted to infants HIV negative at randomization) and compared mortality at age 18 months using Kaplan-Meier estimates.
From May 2011-April 2015, 2866 HEU children were randomized (1432 CTX, 1434 placebo); the study was then stopped at the recommendation of the Data and Safety Monitoring Board because it was unlikely to show a benefit of CTX. Loss-to-follow-up was low: 95% of infants completed study follow-up; 72% received continuous study drug through 15 months of age, death or study closure. In primary analysis, mortality was similar by randomized arm: 30 deaths in the CTX arm vs. 34 deaths in the placebo arm; estimated mortality at age 18 months was 2.4% vs. 2.6% (difference: 0.2%; 95% CI: -1.0% to 1.5%; Figure 1). The following outcomes did not differ by CTX and placebo arms: hospitalization (10.8% vs. 12.4%, p=0.24), grade 3/4 diagnosis (16.1% vs. 17.8%, p=0.36), or grade 3/4 anemia (8.0% vs. 8.2%, p=0.84). More infants in the CTX vs. placebo arm experienced grade 3/4 neutropenia (7.9% vs. 5.8%, p=0.05). Fewer infants breastfed than expected (20% overall), and few deaths (11, 2.3%) occurred in breastfed children by age 18 months: 8 vs. 3 among those randomized to breastfeed for 6 vs. 12 months, and only 3 vs. 2 deaths after 6 months.
Prophylactic CTX did not improve 18-month survival or other clinical outcomes among HEU children in southern Botswana. In low-mortality, non-malarial settings with low risk for late MTCT, prolonged CTX for HIV-exposed children may not be required.