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

• Main Authors: Profanter Katharina, Greutélaers Katja C, Gabor Julian J, Ord Rosalynn, Oyakhirome Sunny, Mombo-Ngoma Ghyslain, Greutélaers Benedikt, Kurth Florian, Lell Bertrand, Kun Jürgen FJ, Issifou Saadou, Roper Cally, Kremsner Peter G, Grobusch Martin P
• Format: Article
• Language: English
• Published: BMC 2011-05-01
• Series: Malaria Journal
• Online Access: http://www.malariajournal.com/content/10/1/123

<p>Abstract</p> <p>Background</p> <p>Drug resistance contributes to the global malaria burden. <it>Plasmodium </it><it>falciparum </it>dihydrofolate reductase (<it>dhfr</it>) and dihydropteroate synthase (<it>dhps</it>) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP).</p> <p>Methods</p> <p>The study assessed the frequency of SP resistance-conferring polymorphisms in <it>Plasmodium </it><it>falciparum</it>-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.</p> <p>Results</p> <p>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 <it>dhfr </it>haplotype. Three point mutations were found in <it>dhps </it>in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon.</p> <p>Conclusions</p> <p>There is a high prevalence of <it>dhfr </it>triple mutant with some <it>dhps </it>point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00453856">NCT00453856</a></p>