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The use of molecular genotyping to distinguish recrudescence from new infections has become common in antimalarial clinical trials. However, methods used to interpret genotyping results have not been standardized. We analyzed data from 3,000 patients enrolled in clinical trials at seven sites in Uganda. Late treatment failure requiring genotyping occurred in 51% of the patients. Among samples successfully genotyped, 21% were definitive new infections (no recrudescent strains present on day of failure), 35% were definitive recrudescences (only recrudescent strains present), and 44% were mixed (new and recrudescent strains present). The probability of having a mixed genotyping result increased as transmission intensity increased. At the highest transmission site, the estimated risk of treatment failure increased from 34% to 84% for chloroquine plus sulfadoxine-pyrimethamine, from 18% to 45% for amodiaquine plus sulfadoxine-pyrimethamine, and from 12% to 57% for amodiaquine plus artesunate, depending on whether mixed genotyping results were classified as new infections or recrudescences, respectively. The method used to classify treatment outcomes can have a major impact on estimates of drug efficacy, especially in areas of high transmission intensity.
Received November 19, 2004. Accepted for publication March 29, 2005.
Acknowledgments: This work would not have been possible without the establishment of the sentinel site surveillance system and continued support by the East African Network for Monitoring Antimalarial Treatment. We thank the clinical study team of Joy Bossa, Nelson Budaka, Oswald Byaruhanga, Moses Musinguzi, Isaac Kigozi, Felix Jurua, Richard Allen, Fred Kizito, and Grace Musimenta for their participation in the study. We also thank Sam Nsobya, Regina Nakafero, and Dan Kyabayinze for training the laboratory staff and providing laboratory quality control; Adoke Yeka, Kristin Banek, John Patrick Mpindi, and Sarah Staedke for their work on the clinical studies; Sara Kibirango and Kenneth Mwebaze for administrative support; Nuhu Kibampawo, Joshua Sekitoleko and Marx Dongo for logistical support; and all of the district health care workers and study participants for their cooperation.
Financial support: This study was supported by the Centers for Disease Control and Prevention/Association of Schools of Public Health cooperative agreement "Malaria Surveillance and Control in Uganda" (SA3569 and S1932-21/21), the Fogarty International Center/National Institutes of Health (TW00007, TW01506, and AI43301), and the Department for International Development.
* Address correspondence to Dr. Grant Dorsey, Department of Medicine, University of California, Parnassus Avenue, Box 0811, San Francisco, CA 94143. E-mail: grantd{at}itsa.ucsf.edu
Authors’ addresses: Madeline Slater, Chris Dokomajilar, Philip J. Rosenthal, and Grant Dorsey, Department of Medicine, University of California, Parnassus Avenue, Box 0811, San Francisco, CA 94143, Telephone : 415-648-4680, Fax : 415-648-8425, E-mails: mslater{at}itsa.ucsf.edu, cdoko{at}itsa.ucsf.edu, rosnthl{at}itsa.ucsf.edu and grantd{at}itsa.ucsf.edu. Moses Kiggundu and Moses R. Kamya, Makerere University Medical School, PO Box 7072, Kampala, Uganda, Telephone: 256-41-541-188, Fax: 256-41-540-524, E-mails: mosesk_33{at}hotmail.com and mkamya{at}infocom.co.ug. Nathan Bakyaita and Ambrose Talisuna, Ministry of Health/UMSP, PO Box 7475, Kampala, Uganda, Telephone: 256-41-231-563 or 2315-69, Fax: 256-41-540-524, E-mails: natsbach{at}hotmail.com and acesd{at}afsat.com.
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