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PREDICTION OF PLASMODIUM FALCIPARUM RESISTANCE TO SULFADOXINE/ PYRIMETHAMINE IN VIVO BY MUTATIONS IN THE DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHETASE GENES: A COMPARATIVE STUDY BETWEEN SITES OF DIFFERING ENDEMICITY

MICHAEL ALIFRANGISCentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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SONJA ENOSSECentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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INSAF F. KHALILCentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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DONATH S. TARIMOCentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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MARTHA M. LEMNGECentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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RICHARDO THOMPSONCentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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IB C. BYGBJERGCentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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ANITA M. RØNNCentre for Medical Parasitology, Institute of Medical Microbiology and Immunology, and Institute of Public Health, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; National Institute of Health, Ministry of Health, Maputo, Mozambique; Faculty of Medicine, Muhimbili University, Dar es Salaam, Tanzania; National Institute for Medical Research, Amani Research Centre, Amani, Tanzania

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Plasmodium falciparum resistance to sulfadoxine/pyrimethamine (S/P) is due to mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhfr) genes. Large-scale screening of the prevalence of these mutations could facilitate the surveillance of the level of S/P resistance in vivo. The prevalence of mutations in dhfr and dhps in relation to S/P efficacy was studied in four sites of differing endemicity in Sudan, Mozambique, and Tanzania. The sites were organized in order of increasing resistance and a significant increase in the prevalence of triple mutations in codons c51, c59, and c108 of dhfr was observed. A similar trend was observed when dhfr genotypes were combined with c437 of dhps. Since the differences in S/P resistance between the sites were minor, but nevertheless revealed major differences in dhfr genotype prevalence, the role of dhfr as a general molecular marker seems debatable. The differences may reflect variation in the duration and magnitude of S/P usage (or other antifolate drugs) between the sites. Thus, triple dhfr mutations may prove suitable only as a general guideline for detecting emerging S/P resistance in areas where S/P has been introduced recently. However, changes in susceptibility within the same area with moderate levels of resistance may be possible by longitudinal surveillance of a subset of dhfr/dhps mutations that has been associated with S/P resistance in vivo in a defined location.

Author Notes

Reprint requests: Michael Alifrangis, Panum Institute, Institute of Medical Microbiology and Immunology, Building 24.2, Blegdamsvej 3, 2200 Copenhagen N, Denmark, Telephone: 45-3-532-7676, Fax: 45-3-532-7851, E-mail: malif@biobase.dk.
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