Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial

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

Assessment of the Impact of Cotrimoxazole Prophylaxis on Key Outcomes Among HIV-Infected Adults in Low- and Middle-Income Countries

“…Nine were randomized control trials (RCTs), 18,19,23,24,27,29,33,35,38 26 were observational studies (OS), 8–17,20–22,25,26,28,30–32,34,36,37,42–45 2 were SRM, 39,41 1 was another SR, 40 and 4 addressed CE. 46–49 …”

“…Of the 35 individual studies (excluding the SRs and CE studies), 20 (including 4 of the 9 RCTs and 16 of the 26 OS) included participants either already on or initiating ART. 8,9,11,13,15,16,20,23–28,31,32,35,36,42,43,45 Fourteen studies (including 5 RCTs and 9 OS) included persons who had not received ART (“non-ART” participants). 10,12,14,17–19,21,29,30,33,34,37,38,44 One study did not report whether patients received ART.…”

“…Of the 4 RCTs that enrolled ART patients, 2 addressed CTX discontinuation 23,35 and the other 2 compared CTX prophylaxis with intermittent preventive treatment of malaria with either sulfadoxine–pyrimethamine (SP) or mefloquine (MQ) in HIV-infected pregnant women. 24,27 …”

“…Eleven articles that addressed mortality in patients on ART were assessed, including 1 RCT, 35 9 OS, 9,11,13,15,16,20,31,32,36 and 1 SRM. 39 Patients enrolled in these studies initiated CTX prophylaxis before, at the same time as, or after ART initiation.…”

“…Polyak et al 35 assessed a “composite” primary end-point of morbidity and mortality among ART patients who discontinued vs. those who continued CTX in Kenya. This combined morbidity/ mortality end-point was significantly more frequent in the CTX discontinuation arm than in the continuation arm (IRR = 2.27; 95% CI: 1.52 to 3.38; P < 0.001) and was mainly driven by malaria morbidity.…”