ABSTRACT
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.
Subject(s)
Antimalarials/therapeutic use , Dihydropteroate Synthase/genetics , Folic Acid Antagonists/pharmacology , Malaria, Falciparum/prevention & control , Plasmodium falciparum/drug effects , Tetrahydrofolate Dehydrogenase/genetics , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Dihydropteroate Synthase/metabolism , Drug Combinations , Drug Resistance/genetics , Female , Follow-Up Studies , HIV Infections/complications , HIV Infections/epidemiology , Humans , Incidence , Infant , Insecticide-Treated Bednets , Malaria, Falciparum/complications , Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Male , Mutation/drug effects , Mutation/genetics , Plasmodium falciparum/genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Prevalence , Risk Factors , Tetrahydrofolate Dehydrogenase/metabolism , Treatment Outcome , Uganda/epidemiologyABSTRACT
Amodiaquine, a 4-aminoquinoline compound, is being considered as an alternative to chloroquine and pyrimethamine/sulfadoxine where resistance in Plasmodium falciparum to both drugs has been selected. Although amodiaquine is more potent than chloroquine, its effectiveness is reduced in areas where chloroquine resistance is high. We report an association of the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multiple drug resistance 1 (pfmdr1) gene, two chloroquine resistance markers, with chloroquine and amodiaquine efficacy in vivo in southern Sudan. The data show that the allele of the pfcrt gene with a lysine to threonine change at codon 76 is strongly associated with both chloroquine and amodiaquine resistance. No such association was observed with the pfmdr1 gene.
