Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort.

Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy is unclear. The authors estimated the effect of prophylaxis after antiretroviral therapy initiation in adults. Participants in their observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug antiretroviral therapy with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. They estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, body-mass index, and previous WHO stage 3 or 4 events on antiretroviral therapy. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on antiretroviral therapy was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but the authors observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or body-mass index (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68]. These results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination antiretroviral therapy in Africa.

Editors’ note: DART delivers again, this time with data supporting the use of cotrimoxasole (trimethoprim-sulfamethoxasole) at the start of antiretroviral therapy in resource-limited settings, if it hasn’t been started before. Co-trimoxasole is off-patent, low-cost, simple to take (once daily), safe, and tolerable. First-year mortality on antiretroviral treatment in sub-Saharan Africa ranges from 8 to 26%, most in the first 3 to 6 months. Mortality in this large study was halved in the first 72 weeks on antiretroviral treatment with daily cotrimoxasole prophylaxis. The mortality reduction was greatest in the first 12 weeks and then was sustained out to 72 weeks for both patients with CD4 counts under 200 and over 200. The effects on malaria in the Uganda patients was sustained out past 72 weeks. Clearly, starting on antiretroviral treatment is not reason to stop or not to start cotrimoxasole prophylaxis. Whether cotrimoxasole works by helping reduce immune activation before antiretroviral treatment starts to kick in or acts through another mechanism is unknown but these data support the World Health Organisation recommendation to start or continue cotrimoxasole prophylaxis when antiretroviral treatment is started. There is now justification for continuing it for at least 72 weeks.