title: Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta-analysis.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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 μL or lower with antiretroviral therapy (ART) worldwide. Co-trimoxazole prophylaxis started at higher than 350 cells per μL 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 μL 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).
  
  
  CONCLUSIONS
  Co-trimoxazole prophylaxis should be given with ART in people with CD4 counts of 350 cells per μL 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.
  
  
  BACKGROUND
  None.
authors.affiliation: Department of HIV/AIDS, World Health Organization, Geneva, Switzerland. Electronic address: amitabh.suthar@gmail.com.
authors.forename: Amitabh B
authors.initials: AB
authors.lastname: Suthar
authors.affiliation: Department of HIV/AIDS, World Health Organization, Geneva, Switzerland.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Vitoria
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Nagata
authors.affiliation: INSERM Centre 897, Université Victor Segalen, Bordeaux, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Anglaret
authors.affiliation: Eastern and Southern Africa Regional Office, United Nations Children's Fund, Pretoria, South Africa.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Mbori-Ngacha
authors.affiliation: Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.
authors.forename: Omar
authors.initials: O
authors.lastname: Sued
authors.affiliation: Division of Global HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kaplan
authors.affiliation: Department of HIV/AIDS, World Health Organization, Geneva, Switzerland.
authors.forename: Meg C
authors.initials: MC
authors.lastname: Doherty
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control / Q000635:transmission; D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D003362:Cost-Benefit Analysis; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control / Q000635:transmission; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D056990:Post-Exposure Prophylaxis; D065129:Pre-Exposure Prophylaxis; D011247:Pregnancy; D016032:Randomized Controlled Trials as Topic; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage*
chemical_list: D019380:Anti-HIV Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination