Abstract
BackgroundCotrimoxazole (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.Methods and FindingsBetween 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.ConclusionsCTX 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.Trial registrationClinicalTrials.gov NCT01425073
Highlights
Cotrimoxazole (CTX), fixed-dose trimethoprim-sulfamethoxazole, is a low-cost and widely utilized broad spectrum antibiotic used to prevent opportunistic infections in patients with human immunodeficiency virus type 1 (HIV-1)
CTX discontinuation among antiretroviral therapy (ART)-treated, immune-reconstituted adults in a malariaendemic 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
Summary
Cotrimoxazole (CTX), fixed-dose trimethoprim-sulfamethoxazole, is a low-cost and widely utilized broad spectrum antibiotic used to prevent opportunistic infections in patients with human immunodeficiency virus type 1 (HIV-1). Following antiretroviral therapy (ART), CTX can be discontinued once immune reconstitution is documented (CD4 count > 200 cells/mm3) [13,15,16,17]. The 2006 World Health Organization (WHO) guidelines recommend CTX prophylaxis for HIV-1-infected patients with a CD4 cell count of 350 cells/mm3 [14]. For settings with a high prevalence of HIV-1 and limited health infrastructure, WHO guidelines recommend that all HIV-1-infected adults take CTX prophylaxis [14]. These guidelines were developed prior to the scale-up of ART. Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. At least a third of people living with HIV have access to ART, and the global mortality (death) rate from HIV/AIDS is falling
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