title: A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.
abstract: BACKGROUND
  Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole.
  
  
  METHODS
  We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolescents in Uganda and Zimbabwe. Eligible participants were older than 3 years of age, had been receiving ART for more than 96 weeks, were using insecticide-treated bed nets (in malaria-endemic areas), and had not had Pneumocystis jirovecii pneumonia. Coprimary end points were hospitalization or death and adverse events of grade 3 or 4.
  
  
  RESULTS
  A total of 758 participants were randomly assigned to stop or continue co-trimoxazole (382 and 376 participants, respectively), after receiving ART for a median of 2.1 years (interquartile range, 1.8 to 2.3). The median age was 7.9 years (interquartile range, 4.6 to 11.1), and the median CD4 T-cell percentage was 33% (interquartile range, 26 to 39). Participants who stopped co-trimoxazole had higher rates of hospitalization or death than those who continued (72 participants [19%] vs. 48 [13%]; hazard ratio, 1.64; 95% confidence interval [CI], 1.14 to 2.37; P = 0.007; noninferiority not shown). There was no evidence of variation across ages (P=0.93 for interaction). A total of 2 participants in the prophylaxis-stopped group (1%) died, as did 3 in the prophylaxis-continued group (1%). Most hospitalizations in the prophylaxis-stopped group were for malaria (49 events, vs. 21 in the prophylaxis-continued group) or infections other than malaria (53 vs. 25), particularly pneumonia, sepsis, and meningitis. Rates of adverse events of grade 3 or 4 were similar in the two groups (hazard ratio, 1.20; 95% CI, 0.83 to 1.72; P=0.33), but more grade 4 adverse events occurred in the prophylaxis-stopped group (hazard ratio, 2.04; 95% CI, 0.99 to 4.22; P=0.05), with anemia accounting for the largest number of events (12, vs. 2 with continued prophylaxis).
  
  
  CONCLUSIONS
  Continuing co-trimoxazole prophylaxis after 96 weeks of ART was beneficial, as compared with stopping prophylaxis, with fewer hospitalizations for both malaria and infection not related to malaria. (Funded by the United Kingdom Medical Research Council and others; ARROW Current Controlled Trials number, ISRCTN24791884.).
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Mutsawashe
authors.initials: M
authors.lastname: Bwakura-Dangarembizi
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kendall
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bakeera-Kitaka
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Patricia
authors.initials: P
authors.lastname: Nahirya-Ntege
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Rosette
authors.initials: R
authors.lastname: Keishanyu
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Kusum
authors.initials: K
authors.lastname: Nathoo
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Moira J
authors.initials: MJ
authors.lastname: Spyer
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Adeodata
authors.initials: A
authors.lastname: Kekitiinwa
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lutaakome
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Mhute
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Philip
authors.initials: P
authors.lastname: Kasirye
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Paula
authors.initials: P
authors.lastname: Munderi
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Victor
authors.initials: V
authors.lastname: Musiime
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: University of Zimbabwe, College of Health Sciences, Harare (M.B.-D., K.N., T.M.); the Medical Research Council Clinical Trials Unit at University College London (L.K., M.J.S., D.M.G., A.S.W., A.J.P.) and Centre for Paediatrics, Blizard Institute, Queen Mary, University of London (A.J.P.), London; and the Paediatric Infectious Diseases Clinic of Baylor Uganda, Mulago Hospital (S.B.-K., A.K., P.K.), and Joint Clinical Research Center (R.K., V.M.), Kampala, and the Medical Research Council and Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe (P.N.-N., J.L., P.M.) - all in Uganda.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Prendergast
mesh_terms: D000293:Adolescent; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D053208:Kaplan-Meier Estimate; D008288:Malaria / Q000150:complications / Q000517:prevention & control*; D008297:Male; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects / Q000627:therapeutic use*; D014454:Uganda; D028761:Withholding Treatment; D015030:Zimbabwe
chemical_list: D000890:Anti-Infective Agents; D044966:Anti-Retroviral Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination