Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in-vivo drug resistance in West Papua, Indonesia

This study (conducted in 1996-99) examines the association of mutations in pfmdr1, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum with in-vivo drug resistance in West Papua, Indonesia. Initially, 85 patients infected with P. falciparum were treated with chloroquine, of whom 21 were cleared of parasites, 49 had parasitaemia s classified as RI, RII or RIII resistance and 1 patient had recrudescent p arasitaemia. Fansidar(R) (pyrimethamine-sulfadoxine) was the second-line tr eatment and 18 patients were cleared of parasites and 31 had continuing inf ections classified as RI, RII or RIII resistance and 1 patient had recrudes cent parasitaemia. The pfmdr1, dhfr and dhps genes were examined for mutati ons previously shown to be associated with resistance to these drugs. In th is study, mutations in pfmdr1 were associated with chloroquine resistance a nd mutations in both dhfr and dhps were associated with Fansidar resistance in vivo. Interestingly, Gly-437 in dhps along with Arg-59/Asn-108 in dhfr were associated with RI, RII and RIII resistance whereas Glu-540 was highly associated with only RII and RIII Fansidar resistance. This finding suppor ts the hypothesis that the molecular basis of RI, RII and RIII Fansidar res istance involves an accumulation of mutations in both dhfr and dhps. These results suggest that mutations in both dhfr and dhps genes are a good predi ctor of potential Fansidar treatment failure.