Effect of trimethoprim-sulphamethoxazole on the risk of malaria in HIV-infected Ugandan children living in an area of widespread antifolate resistance

Malar J. 2010 Jun 23;9:177. doi: 10.1186/1475-2875-9-177.


Background: Daily trimethoprim-sulfamethoxazole (TS) protects against malaria, but efficacy may be diminished as anti-folate resistance increases. This study assessed the incidence of falciparum malaria and the prevalence of resistance-conferring Plasmodium falciparum mutations in HIV-infected children receiving daily TS and HIV-uninfected children not taking TS.

Materials and methods: Subjects were 292 HIV-infected and 517 uninfected children from two cohort studies in Kampala, Uganda observed from August 2006 to December 2008. Daily TS was given to HIV-infected, but not HIV-uninfected children and all participants were provided an insecticide-treated bed net. Standardized protocols were used to measure the incidence of malaria and identify markers of antifolate resistance.

Results: Sixty-five episodes of falciparum malaria occurred in HIV-infected and 491 episodes in uninfected children during the observation period. TS was associated with a protective efficacy of 80% (0.10 vs. 0.45 episodes per person year, p < 0.001), and efficacy did not vary over three consecutive 9.5 month periods (81%, 74%, 80% respectively, p = 0.506). The prevalences of dhfr 51I, 108N, and 59R and dhps 437G and 540E mutations were each over 90% among parasites infecting both HIV-infected and uninfected children. Prevalence of the dhfr 164L mutation, which is associated with high-level resistance, was significantly higher in parasites from HIV-infected compared to uninfected children (8% vs. 1%, p = 0.001). Sequencing of the dhfr and dhps genes identified only one additional polymorphism, dhps 581G, in 2 of 30 samples from HIV-infected and 0 of 54 samples from uninfected children.

Conclusion: Despite high prevalence of known anti-folate resistance-mediating mutations, TS prophylaxis was highly effective against malaria, but was associated with presence of dhfr 164L mutation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimalarials / therapeutic use*
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cohort Studies
  • Dihydropteroate Synthase / genetics*
  • Dihydropteroate Synthase / metabolism
  • Drug Combinations
  • Drug Resistance / genetics
  • Female
  • Folic Acid Antagonists / pharmacology*
  • Follow-Up Studies
  • HIV Infections / complications
  • HIV Infections / epidemiology
  • Humans
  • Incidence
  • Infant
  • Insecticide-Treated Bednets
  • Malaria, Falciparum / complications
  • Malaria, Falciparum / epidemiology
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / prevention & control*
  • Male
  • Mutation / drug effects
  • Mutation / genetics
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Prevalence
  • Risk Factors
  • Tetrahydrofolate Dehydrogenase / genetics*
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Treatment Outcome
  • Trimethoprim, Sulfamethoxazole Drug Combination / therapeutic use*
  • Uganda / epidemiology


  • Antimalarials
  • Drug Combinations
  • Folic Acid Antagonists
  • Trimethoprim, Sulfamethoxazole Drug Combination
  • Tetrahydrofolate Dehydrogenase
  • Dihydropteroate Synthase