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Open Access Research

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

Ghyslain Mombo-Ngoma123, Sunny Oyakhirome128, Rosalynn Ord1045, Julian J Gabor12, Katja C Greutélaers12, Katharina Profanter12, Benedikt Greutélaers12, Florian Kurth129, Bertrand Lell12, Jürgen FJ Kun2, Saadou Issifou12, Cally Roper5, Peter G Kremsner12 and Martin P Grobusch1267*

Author Affiliations

1 Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon

2 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany

3 Département de Parasitologie, Université des Sciences de la Santé, Libreville, Gabon

4 Medical Parasitology, New York University School of Medicine, New York, NY, USA

5 London School of Hygiene & Tropical Medicine, Department of Infectious Tropical Diseases, London, UK

6 Infectious Diseases, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

7 Infectious Diseases, Tropical Medicine and AIDS, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands

8 Glaxo Smith Kline Biologicals, Rixensart, Belgium

9 Department of Neonatology and Pediatric Intensive Care, University Hospital Carl Gustav Carus, Dresden, Germany

10 Lindsay F. Kimball Research Institute, New York Blood Center, New York, NY, USA

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Malaria Journal 2011, 10:123  doi:10.1186/1475-2875-10-123

Published: 14 May 2011

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