HIGH PREVALENCE OF MUTATIONS IN THE DIHYDROFOLATE-REDUCTASE GENE OF PLASMODIUM-FALCIPARUM IN ISOLATES FROM TANZANIA WITHOUT EVIDENCE OF AN ASSOCIATION TO CLINICAL SULFADOXINE PYRIMETHAMINE RESISTANCE/

Recently the efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Tanzania has been seriously com promised by the development of resistance. The occurrence of active si te mutations in the Plasmodium falciparum gene sequence coding for dih ydrofolate reductase (DHFR) is known to confer resistance to pyrimetha mine. This study investigates the occurrence of these mutations in inf ected blood samples taken from Tanzanian children before treatment wit h S/P and their relationship to parasite breakthrough by day 7. The re sults confirm the occurrence of one or more DHFR mutations in ail the samples, but no relationship was found with the presence of parasites in the blood at day 7. The results suggest that alterations in the cod ing region for dihydropteroate synthetase (DHPS), the enzyme target fo r sulfadoxine, should be studied in order to predict resistance to the S/P combination. It has been proposed earlier that sulfadoxine could itself act on DHFR, because of a false dihydrofolate produced by drug metabolism through DHPS and dihydrofolate synthase. The results of thi s treatment study suggest that such a possibility is unlikely.