High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children

• Published in: Malaria journal 2011-05, Vol.10 (1), p.123-123, Article 123
• Main Authors: Mombo-Ngoma, Ghyslain, Oyakhirome, Sunny, Ord, Rosalynn, Gabor, Julian J, Greutélaers, Katja C, Profanter, Katharina, Greutélaers, Benedikt, Kurth, Florian, Lell, Bertrand, Kun, Jürgen F J, Issifou, Saadou, Roper, Cally, Kremsner, Peter G, Grobusch, Martin P
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution - genetics; Antimalarials - administration & dosage; Asexuality; Blood; Care and treatment; Child, Preschool; Children; Clinical outcomes; Dihydrofolate reductase; Dihydropteroate Synthase; DNA; Drug Combinations; Drug Resistance; Drug therapy; Enzymes; Failure; Failures; Female; Gabon; Gene mutations; Genes; Genotype; Genotype & phenotype; Haplotypes; Health aspects; Human diseases; Humans; Infant; Infections; Laboratories; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Male; Mutants; Mutation; Mutation, Missense; Nucleotide sequence; Parasites; PCR; Plasmodium falciparum; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Plasmodium falciparum - isolation & purification; Polymerase chain reaction; Polymorphism; Polymorphism, Genetic; Prevalence; Prevalence studies (Epidemiology); Pyrimethamine; Pyrimethamine - administration & dosage; Schweitzer, Albert; Studies; Sulfadoxine - administration & dosage; Tetrahydrofolate Dehydrogenase - genetics; Treatment Failure; Vector-borne diseases
• ISSN: 1475-2875; 1475-2875
• DOI: 10.1186/1475-2875-10-123

Drug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP). The study assessed the frequency of SP resistance-conferring polymorphisms in Plasmodium falciparum-positive samples from two clinical studies in Lambaréné. Their role on treatment responses and transmission potential was studied in an efficacy open-label clinical trial with a 28-day follow-up in 29 children under five with uncomplicated malaria. SP was well tolerated by all subjects in vivo. Three subjects were excluded from per-protocol analysis. PCR-corrected, 12/26 (46%) achieved an adequate clinical and parasitological response, 13/26 (50%) were late parasitological failures, while 1/26 (4%) had an early treatment failure, resulting in early trial discontinuation. Of 106 isolates, 98 (92%) carried the triple mutant dhfr haplotype. Three point mutations were found in dhps in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon. There is a high prevalence of dhfr triple mutant with some dhps point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored.