Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta-analysis

Introduction Co-trimoxazole prophylaxis is used to reduce morbidity and mortality in people with HIV. We systematically reviewed three topics related to co-trimoxazole prophylaxis to update WHO guidelines: initiation, discontinuation, and dose. Methods We searched PubMed, Embase, WHO Global Index Medicus, and clinical trial registries in November, 2013, for randomised controlled trials and observational studies including co-trimoxazole prophylaxis and a comparator group. Studies were eligible if they reported death, WHO clinical stage 3 or 4 events, admittance to hospital, severe bacterial infections, tuberculosis, pneumonia, diarrhoea, malaria, or treatment-limiting adverse events. Infant mortality, low birthweight, and placental malaria were additional outcomes for the comparison of co-trimoxazole prophylaxis and intermittent preventive treatment for malaria in pregnant women (IPTp). We compared a dose of 480 mg co-trimoxazole once a day with one of 960 mg co-trimoxazole once a day. We used a 10% margin for non-inferiority and equivalence analyses. We used random-effects models for all meta-analyses. This study is registered with PROSPERO, number CRD42014007163. Findings 19 articles, published from 1995 to 2014 and including 35 328 participants, met the inclusion criteria. Co-trimoxazole prophylaxis reduced rates of death (hazard ratio [HR] 0.40, 95% CI 0.26-0.64) when started at CD4 counts of 350 cells per mu L or lower with antiretroviral therapy (ART) worldwide. Co-trimoxazole prophylaxis started at higher than 350 cells per mu L without ART reduced rates of death (0.50, 0.30-0.83) and malaria (0.25, 0.10-0.57) in Africa. Co-trimoxazole prophylaxis was non-inferior to IPTp with respect to infant mortality (risk difference [RD] -0.05, 95% CI -0.12 to 0.02), low birthweight (0.00, -0.07 to 0.07), and placental malaria (0.00, -0.10 to 0.10). Co-trimoxazole prophylaxis continuation after ART-induced recovery with CD4 counts higher than 350 cells per mu L reduced admittances to hospital (HR 0.42, 95% CI 0.22-0.80), pneumonia (0.73, 0.61-0.88), malaria (0.03, 0.01-0.10), and diarrhoea (0.61, 0.48-0.78) in Africa. A dose of 480 mg co-trimoxazole prophylaxis once a day did not reduce treatment-limiting adverse events compared with 960 mg once a day (RD -0.07, 95% CI -0.52 to 0.39). Interpretation Co-trimoxazole prophylaxis should be given with ART in people with CD4 counts of 350 cells per mu L or lower in low-income and middle-income countries. Co-trimoxazole prophylaxis should be provided irrespective of CD4 count in settings with a high burden of infectious diseases. Pregnant women with HIV in Africa should use co-trimoxazole rather than IPTp to prevent malaria complications in infants. Further research is needed to inform dose optimisation and co-trimoxazole use in the context of expanded ART in different epidemiological settings. Copyright (C) 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved.