Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial

Abstract

Background Cotrimoxazole (CTX) prophylaxis reduces mortality among HIV-infected children, but no randomized trial has evaluated efficacy in HIV-exposed uninfected (HEU) children in a non-malarial, low-breastfeeding setting. Methods HEU children in Botswana were randomized to CTX or placebo from age 14–34 days through 15 months. Mothers chose infant feeding method. Breastfed children were randomized to breastfeeding for duration of 6 months (Botswana guidelines) or 12 months (World Health Organization guidelines). Primary analysis was modified intent-to-treat, comparing cumulative mortality for CTX versus placebo, and HIV-free survival for breastfeeding duration, from randomization to 18 months. Findings From June 2011–April 2015, 2848 HEU children were randomized (1423 CTX, 1425 placebo); the study was stopped early by the Data Safety Monitoring Board for low likelihood of showing CTX benefit. Only 5% of children were lost to follow-up, and 72% received continuous study drug through 15 months, death or study closure. Post-randomization mortality was similar between CTX/placebo arms: 30 children died in the CTX arm vs. 34 in the placebo arm; estimated mortality at 18 months was 2·4% vs. 2·6%, respectively (difference: −0·2%; 95%CI: −1·5%, 1·0%, p=0·70). At 18 months, no difference by CTX vs. placebo was noted for hospitalization (12·5% vs. 17·4%, p=0·19), grade 3/4 diagnoses (16·5% vs. 18·4%, p=0·18), or grade 3/4 anemia (8·1% vs. 8·3%, p=0·93). More infants in the CTX arm experienced grade 3/4 neutropenia (8·1% vs. 5·8%, p=0·03), and more CTX resistance was detected in commensal E. coli from stool at 3 and 6 months (p=0·001 and p=0·01, respectively). Only 572 (20%) infants breastfed; no significant difference in the composite endpoint of child HIV-infection or mortality was observed by 6 vs. 12 months randomized breastfeeding duration (3.9%% vs. 1.9%, p=0·21). Interpretation Prophylactic CTX did not improve 18-month survival among HEU children in a non-malarial area of Botswana. In non-malarial settings with very low risk for MTCT, prolonged CTX for HIV-exposed children may not be required.

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Similar HIV protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in Botswana

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The impact of health programmes to prevent vertical transmission of HIV. Advances, emerging health challenges and research priorities for children exposed to or living with HIV: Perspectives from South Africa

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