| Title | Molecular correlates of high level antifolate resistance in Rwandan children with Plasmodium falciparum malaria. | | Author(s) | Corine K, Imwong M, Fanello CI, Stepniewska K, Uwimana A, Nakeesathit S, Dondorp A, Day NP, White NJ | | Institution | National Malaria Control Program, Kigali, Rwanda; Centre for Tropical Medicine, Nuffield Department of Medicine, Oxford University, UK; Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. | | Source | Antimicrob Agents Chemother 2009 Oct 19. | | Abstract | Background: Antifolate drugs have an important role in the treatment of malaria. Polymorphisms in the genes encoding dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) enzymes cause resistance to the antifol and sulpha drugs, respectively. Rwanda has the highest levels of antimalarial drug resistance in Africa.
Methods: We correlated the efficacy of chlorproguanil-dapsone+artesunate (CPG-DDS+A) and amodiaquine+sulphadoxine-pyrimethamine (AQ+SP) in children with uncomplicated P. falciparum malaria with Pfdhfr and Pfdhps mutations, known to confer reduced drug susceptibility, in two areas of Rwanda.
Results: In the Eastern Province, where cure rates were low, over 75% of isolates had >/=3 Pfdhfr mutations and 2 or 3 Pfdhps mutations and 11% had the Pfdhfr 164-Leu polymorphism. In the Western province, where cure rates were significantly higher (p<0.001), the prevalence of multiple resistance mutations was lower and the Pfdhfr I164L polymorphism was not found. The risk of treatment failure following AQ+SP more than doubled for each additional Pfdhfr resistance mutation (OR=2.4; 95% CI 1.01 to 5.55; p=0.048) and each Pfdhps mutation (OR=2.1; 95% CI 1.21 to 3.54; p=0.008). The risk of failure following CPG-DDS+A treatment was 2.2 times higher (95% CI 1.34 to 3.7) for each additional Pfdhfr mutation, whereas there was no association with mutations in the Pfdhps gene (p=0.13).
Conclusion: The Pfdhfr 164-Leu polymorphism is prevalent in Eastern Rwanda. Antimalarial treatments with currently available antifol-sulpha combinations are no longer effective in Rwanda because of high level resistance. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19841150 |
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