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Surveillance of molecular markers for key mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) has been proposed as a means of predicting sulfadoxine/ pyrimethamine (SP) treatment outcomes in Africa. This study assessed the association between DHFR and DHPS mutations and standardized clinical outcomes in children treated with SP for uncomplicated malaria in Kampala, Uganda. Two mutations (DHFR Asn-108 and Ile-51) were too common to be useful predictors. Three other mutations (DHFR Arg-59, DHPS Gly-437, and DHPS Glu-540) were associated with clinical treatment failure after 14 days, although associations were not significant. When follow-up was extended to 28 days and genotyping was used to distinguish recrudescence from new infections, associations were significantly strengthened. The presence of both the DHFR Arg-59 and DHPS Glu-540 mutations had the strongest association with clinical treatment failure (odds ratio = 10.7, P = 0.009). These results support a previously proposed method of predicting clinical outcomes based on the prevalence of these two mutations.
Received December 23, 2002. Accepted for publication April 26, 2003.
Acknowledgments: We thank the clinical study team of Moses Kamya, Denise Njama, Sarah Staedke, Bridget K. Nzarubara, Pauline Byakika, Hakim Sendagire, B.M. Karakire, Marx Dongo, Sam Nsobya, Moses Kiggundu, Christopher Bongole, Regina Nakafero, and Sarah Kibirango for their assistance; the community leaders from the Kawempe Division of Kampala for their cooperation; and the study participants and their parents/guardians.
Financial support: this study was supported by the Fogarty International Center/National Institutes of Health (TW00007, TW01506, and AI43301) and the UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR).
Authors’ addresses: Daniel Kyabayinze, Department of Biochemistry, Makerere University Medical School, PO Box 7072, Kampala, Uganda. Adithya Cattamanchi, Philip J. Rosenthal, and Grant Dorsey, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, Telephone: 415-206-8845, Fax: 415-648-8425, E-mail: rosnthl{at}itsa.ucsf.edu. Moses R. Kamya, Department of Medicine, Makerere University Medical School, PO Box 7072, Kampala, Uganda.
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