1. High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children
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Jürgen F. J. Kun, Florian Kurth, Katja C. Greutélaers, Saadou Issifou, Julian J. Gabor, Katharina Profanter, Rosalynn Ord, Sunny Oyakhirome, Martin P. Grobusch, Peter G. Kremsner, Ghyslain Mombo-Ngoma, Bertrand Lell, Cally Roper, Benedikt Greutelaers, Faculteit der Geneeskunde, Amsterdam institute for Infection and Immunity, Amsterdam Public Health, and Infectious diseases
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Male ,lcsh:Arctic medicine. Tropical medicine ,Genotype ,lcsh:RC955-962 ,Plasmodium falciparum ,Drug Resistance ,Mutation, Missense ,DHPS ,Drug resistance ,Pharmacology ,lcsh:Infectious and parasitic diseases ,Antimalarials ,Dihydrofolate reductase ,Sulfadoxine ,parasitic diseases ,medicine ,Prevalence ,Humans ,lcsh:RC109-216 ,Gabon ,Treatment Failure ,Malaria, Falciparum ,Dihydropteroate Synthase ,Polymorphism, Genetic ,biology ,Research ,Haplotype ,Infant ,medicine.disease ,biology.organism_classification ,Virology ,Drug Combinations ,Tetrahydrofolate Dehydrogenase ,Pyrimethamine ,Infectious Diseases ,Parasitology ,Amino Acid Substitution ,Child, Preschool ,biology.protein ,Female ,Dihydropteroate synthase ,Malaria - Abstract
Background Drug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP). Methods 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. Results 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. Conclusions 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. Trial Registration ClinicalTrials.gov: NCT00453856
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