title: Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young Ugandan children: a randomized controlled trial.
abstract: BACKGROUND
  Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.
  
  
  RESULTS
  This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill. Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%-67%, p<0.001) for DP, 28% (95% CI, 7%-44%, p = 0.01) for TS, and 7% for SP (95% CI, -19% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.
  
  
  CONCLUSIONS
  For preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem. Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.
  
  
  BACKGROUND
  www.ClinicalTrials.gov NCT00948896 Please see later in the article for the Editors' Summary.
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Victor
authors.initials: V
authors.lastname: Bigira
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: James
authors.initials: J
authors.lastname: Kapisi
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Clark
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kinara
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Florence
authors.initials: F
authors.lastname: Mwangwa
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Muhindo
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Beth
authors.initials: B
authors.lastname: Osterbauer
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Francesca T
authors.initials: FT
authors.lastname: Aweeka
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Liusheng
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Jane
authors.initials: J
authors.lastname: Achan
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Diane V
authors.initials: DV
authors.lastname: Havlir
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use; D015331:Cohort Studies; D004338:Drug Combinations; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008288:Malaria / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology; D008297:Male; D011739:Pyrimethamine / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use; D014454:Uganda / Q000453:epidemiology; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011739:Pyrimethamine; D011804:Quinolines; D013413:Sulfadoxine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; C001205:fanasil, pyrimethamine drug combination; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
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