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Combined Molecular and Clinical Assessment of Plasmodium falciparum Antimalarial Drug Resistance in the Lao People’s Democratic Republic (Laos)

Molecular markers provide a rapid and relatively inexpensive approach for assessing antimalarial drug susceptibility. We collected 884 Plasmodium falciparum–infected blood samples from 17 Lao provinces. Each sample was genotyped for 11 codons in the chloroquine resistance transporter (pfcrt), dihydrofolate reductase (pfdhfr), and dihydropteroate synthase (pfdhps) genes. The samples included 227 collected from patients recruited to clinical trials. The pfcrt K76T mutation was an excellent predictor of treatment failure for both chloroquine and chloroquine plus sulfadoxine-pyrimethamine, and mutations in both pfdhfr and pfdhps were predictive of sulfadoxine-pyrimethamine treatment failure. In multivariate analysis, the presence of the pfdhfr triple mutation (51 + 59 + 108) was strongly and independently correlated with sulfadoxine-pyrimethamine failure (odds ratio = 9.1, 95% confidence interval = 1.4–60.2, P = 0.017). Considerable geographic heterogeneity in allele frequencies occurred at all three loci with lower frequencies of mutant alleles in southern than in northern Laos. These findings suggest that chloroquine and sulfadoxine-pyrimethamine are no longer viable therapy in this country.

Received January 7, 2007. Accepted for publication March 5, 2007.

Acknowledgments: We are grateful to all the patients, the medical staff from malaria clinics and hospitals across Laos, and the directors of all Provincial Malaria Stations for participating in the study, and Maniphone Khanthavong, Bouakham Vannachone, Vonthalom Thongpraseuth, Siamphay Keola, Somphane Sengphinthong, Manisack Phommasansack, Bounpone Phimphalat, Pitta Sengkeomahavong, Bounmy Syphachanh, Ammala Phomsimone, Vilayphone Phan-Anon, Kaiamphone Phonkeopaseuth, Chanthala Vilaihong, and Julie Simpson for technical help. We are also grateful to the staff of the Mahidol Oxford Research Unit, Bangkok, for their vital logistic support, and to Professor Nick Day, Drs. Pranom Phongmany, Odai Xaysitthideth, and Phomma Phengvilaysouk for valuable advice, and the Minister of Health, Dr. Ponmek Dalaloy, the Directors of Hygiene and Preventive Medicine, Drs. Douangchanh Keo-Asa and Bounlay Phommasack, the Director of Mahosot Hospital, Professor Chanpheng Thammavong, and Professor Sasithon Pukrittayakamee (Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand) for support.

Financial support: This study was supported by the Wellcome Trust of Great Britain. Shalini Nair, Dan Sudimack, and Tim J. C. Anderson are supported by National Institutes of Health grant RO1 AI48071. The molecular work at the Southwest Foundation for Biomedical Research was conducted in facilities constructed with support from Research Facilities Improvement Program grant C06 RR013556 from the National Center for Research Resources, National Institutes of Health.

^* Address correspondence to Paul N. Newton, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People’s Democratic Republic. E-mail: paul{at}tropmedres.ac

Authors’ addresses: Mayfong Mayxay, Wellcome Trust–Mahosot Hospital–Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Mahosot Road, Vientiane, Lao People’s Democratic Republic, Telephone: 85-621-250-752, Fax: 85-621-242-168. E-mail: mmayxay{at}yahoo.com and Department of Post Graduate and Research, Faculty of Medical Science, National University of Laos, Vientiane, Lao People’s Democratic Republic. Shalini Nair, Dan Sudimack, and Tim J. C. Anderson, Southwest Foundation for Biomedical Research. San Antonio, TX, Telephone: 210-258-9596. Mallika Imwong and Naowarat Tanomsing, Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, 420/6 Rajvithi Road, Bangkok, 10400, Thailand, Telephone: 66-2-354-9172, Fax: 66-2-354-9169. Tiengkham Pongvongsa, Savannakhet Provincial Malaria Station, Savannakhet Province, Savannakhet, Lao People’s Democratic Republic. Samlane Phompida and Rattanaxay Phetsouvanh, Centre of Malariology, Parasitology and Entomology, Vientiane, Lao People’s Democratic Republic, Telephone: 85-621-214-040, Fax: 85-621-218-131. Nicholas J. White, Wellcome Trust–Mahosot Hospital–Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Mahosot Road, Vientiane, Lao People’s Democratic Republic, Telephone: 85-621-250-752, Fax: 85-621-242-168, E-mail: nickw{at}tropmedres.ac, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford OX3 7LJ, United Kingdom, and Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, 420/6 Rajvithi Road, Bangkok, 10400, Thailand, Telephone: 66-2-354-9172, Fax: 66-2-354-9169. Paul N. Newton, Wellcome Trust–Mahosot Hospital–Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Mahosot Road, Vientiane, Lao People’s Democratic Republic, Telephone: 85-621-250-752, Fax: 85-621-242-168; E-mail: paul{at}tropmedres.ac and Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.

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