Two mutations in dihydrofolate reductase combined with one in the dihydropteroate synthase gene predict sulphadoxine-pyrimethamine parasitological failure in Ugandan children with uncomplicated falciparum malaria

The point mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and the dihydropteroate synthase (dhps) genes that are linked to sulphadoxine-pyrimethamine (SP) resistance in vitro have been well characterised. To determine whether a few of these mutations could predict SP treatment failure in vivo, two mutations (Asn-108 and Arg-59) in the dhfr gene and one (Glu-540) in the dhps gene were analysed according to the risk of SP parasitological failure (RI-RIII) at day 28 in pre-treatment isolates in 79 Ugandan children aged 6-59 (mean = 18.4, S.D. = 8.8) months with uncomplicated falciparum malaria. Neither the dhfr-108 (P = 0.3) nor the dhps-540 (P = 0.6) or dhfr-108 + dhps-540 (P = 0.08) mutations were significantly associated with SP parasitological failure. However, the dhfr-108 + dhfr-59 (P = 0.04), the dhfr-59 + dhps-540 (P = 0.04) and the dhfr-108 + dhfr-59 + dhps-540 (P = 0.02) mutations significantly increased the risk for SP parasitological failure. Our findings confirm an earlier report that the dhfr-59 and the dhps-540 mutations could be useful genetic markers for rapid screening of populations at high risk of SP resistance. (C) 2004 Elsevier B. V. All rights reserved.