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Am. J. Trop. Med. Hyg., 71(6), 2004, pp. 758-763
Copyright © 2004 by The American Society of Tropical Medicine and Hygiene

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PRINCIPAL ROLE OF DIHYDROPTEROATE SYNTHASE MUTATIONS IN MEDIATING RESISTANCE TO SULFADOXINE-PYRIMETHAMINE IN SINGLE-DRUG AND COMBINATION THERAPY OF UNCOMPLICATED MALARIA IN UGANDA

GRANT DORSEY, CHRISTIAN DOKOMAJILAR, MOSES KIGGUNDU, SARAH G. STAEDKE, MOSES R. KAMYA, AND PHILIP J. ROSENTHAL
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California; Makerere University Medical School, Kampala, Uganda

Antimalarial resistance to sulfadoxine-pyrimethamine (SP) is mediated by mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes. However, the relative importance of different mutations is incompletely understood and has not been studied with combination therapy. Samples from 812 patients treated for uncomplicated malaria in Kampala, Uganda were tested for the presence of mutations commonly found in Africa. The dhps Glu-540 mutation was the strongest independent predictor of treatment failure. The dhfr Arg-59 mutation was only predictive of treatment failure in the presence of the dhps Glu-540 mutation. Comparing combination regimens with SP monotherapy, the addition of chloroquine to SP did not improve efficacy, the addition of artesunate lowered the risk of treatment failure only for infections with both the dhfr Arg-59 and dhps Glu-540 mutations, and the addition of amodiaquine lowered this risk for all dhfr/dhps mutation patterns. The dhps Glu-540 mutation played a principal role and the dhfr Arg-59 mutation a secondary role in mediating resistance to SP alone and in combination.

Received May 5, 2004. Accepted for publication July 15, 2004.

Acknowledgments: We thank the clinical study team (B. M. Karakire, Marx Dongo, Sam Nsobya, Christopher Bongole, Regina Nakafero, Denise Njama, Anne Gasasira, Arthur Mpimbaza, Bridget K. Nzarubara, Pauline Byakika, and Sarah Kibirango); the community leaders from the Kawempe Division of Kampala; and the study participants and their parents/guardians for their support.

Financial support: This study was supported by the Fogarty International Center/National Institutes of Health (TW00007, TW01506, and AI43301) and the United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases (TDR).

Authors’ addresses: Grant Dorsey, Christian Dokomajilar, Sarah G. Staedke, and Philip J. Rosenthal. University of California at San Francisco, Parnassus Avenue, Box 0811 San Francisco, CA, 94143 Telephone: 415-206-4680 Fax: 415-648-8425, E-mail: grantd{at}itsa.ucsf.edu. Moses Kiggundu and Moses R. Kamya, Makerere University Medical School, Anatomy Building, Room C-443, Kampala, Uganda, Telephone: 256-41-251-387 Fax: 256-41-540-524.




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