title: Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial.
abstract: BACKGROUND
  Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.
  
  
  RESULTS
  Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥ 18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression. Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52-3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52-241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82-2.27, and IRR = 1.43, 95% CI 0.54-3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.
  
  
  CONCLUSIONS
  CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01425073.
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Bethesda, Maryland, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Polyak
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Krista
authors.initials: K
authors.lastname: Yuhas
authors.affiliation: Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Benson
authors.initials: B
authors.lastname: Singa
authors.affiliation: Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Monica
authors.initials: M
authors.lastname: Khaemba
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Global Health, University of Washington, Seattle, Washington, United States of America.|Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Judd
authors.initials: J
authors.lastname: Walson
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Global Health, University of Washington, Seattle, Washington, United States of America.|Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Barbra A
authors.initials: BA
authors.lastname: Richardson
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Global Health, University of Washington, Seattle, Washington, United States of America.|Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: John-Stewart
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D015497:HIV-1; D006801:Humans; D007630:Kenya / Q000453:epidemiology; D008288:Malaria / Q000175:diagnosis / Q000453:epidemiology* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D056990:Post-Exposure Prophylaxis / Q000379:methods; D013413:Sulfadoxine / Q000008:administration & dosage*; D014295:Trimethoprim / Q000008:administration & dosage*
chemical_list: D044966:Anti-Retroviral Agents; D000962:Antimalarials; D004338:Drug Combinations; C000301:trimethoprim, sulfadoxine drug combination; D013413:Sulfadoxine; D014295:Trimethoprim