title: 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: Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear.
  
  
  
  HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14-34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761.
  
  
  
  From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference -0·2%, 95% CI -1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3-4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3-4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3-4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21).
  
  
  
  Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV.
  
  
  
  US National Institutes of Health.
authors.affiliation: Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA, USA; Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Lockman
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hughes
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana; Division of Global Health, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Powis
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana.
authors.forename: Gbolahan
authors.initials: G
authors.lastname: Ajibola
authors.affiliation: Bennett Statistical Consulting Inc, Ballston Lake, NY, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Bennett
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana.
authors.forename: Sikhulile
authors.initials: S
authors.lastname: Moyo
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana.
authors.forename: Erik
authors.initials: E
authors.lastname: van Widenfelt
authors.affiliation: Goodtables Consulting, Norman, OK, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Leidner
authors.affiliation: Division of Infectious Disease, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McIntosh
authors.affiliation: Department of Paediatrics, University of Botswana School of Medicine, Gaborone, Botswana.
authors.forename: Loeto
authors.initials: L
authors.lastname: Mazhani
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana.
authors.forename: Joseph
authors.initials: J
authors.lastname: Makhema
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Essex
authors.affiliation: Botswana Harvard AIDS Institute Partnership for HIV Research and Education, Gaborone, Botswana; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA; Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: rshapiro@hsph.harvard.edu.
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001902:Botswana / Q000453:epidemiology; D001942:Breast Feeding; D004311:Double-Blind Method; D004352:Drug Resistance, Microbial; D004926:Escherichia coli; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D006760:Hospitalization; D006801:Humans; D007223:Infant; D066088:Infant Death; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D009503:Neutropenia / Q000209:etiology; D066087:Perinatal Death; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy* / Q000517:prevention & control; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination