Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young Ugandan children: a randomized controlled trial

PLoS Med. 2014 Aug 5;11(8):e1001689. doi: 10.1371/journal.pmed.1001689. eCollection 2014 Aug.

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.

Methods and findings: 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.

Trial registration: www.ClinicalTrials.gov NCT00948896 Please see later in the article for the Editors' Summary.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimalarials / therapeutic use*
  • Artemisinins / therapeutic use
  • Cohort Studies
  • Drug Combinations
  • Female
  • Humans
  • Incidence
  • Infant
  • Malaria / drug therapy*
  • Malaria / epidemiology
  • Malaria / parasitology
  • Male
  • Pyrimethamine / therapeutic use
  • Quinolines / therapeutic use
  • Sulfadoxine / therapeutic use
  • Trimethoprim, Sulfamethoxazole Drug Combination / therapeutic use
  • Uganda / epidemiology

Substances

  • Antimalarials
  • Artemisinins
  • Drug Combinations
  • Quinolines
  • fanasil, pyrimethamine drug combination
  • dihydroartemisinin
  • Trimethoprim, Sulfamethoxazole Drug Combination
  • Sulfadoxine
  • piperaquine
  • Pyrimethamine

Associated data

  • ClinicalTrials.gov/NCT00948896