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

摘要

Background Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposedudbut uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-childudtransmission of HIV is unclear.udMethods HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily untiludage 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14–34 days to age 15 months. Mothersudchose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeedingudfor 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modifiedudintention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We alsoudassessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov,udnumber NCT01229761.udFindings From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazoleud(n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihoodudof benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 inudthe placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure.udMortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazoleudgroup, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference –0·2%,ud95% CI –1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the cotrimoxazoleudgroup vs 17·4% in the placebo group, p=0·19) or grade 3–4 clinical adverse events (16·5% vs 18·4%,udp=0·18). Grade 3–4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3–4 neutropenia wasudmore frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazoleudresistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in theudco-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children wereudbreastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vsud1·9% for 12 months, p=0·21).udInterpretation Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial,udlow-breastfeeding areas with a low risk of mother-to-child transmission of HIV.