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

Abstract

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 parasitaemias classified as RI, RII or RIII resistance and 1 patient had recrudescent parasitaemia. Fansidar (pyrimethamine-sulfadoxine) was the second-line treatment and 18 patients were cleared of parasites and 31 had continuing infections classified as RI, RII or RIII resistance and 1 patient had recrudescent parasitaemia. The pfmdr1, dhfr and dhps genes were examined for mutations previously shown to be associated with resistance to these drugs. In this study, mutations in pfmdr1 were associated with chloroquine resistance and 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 supports the hypothesis that the molecular basis of RI, RII and RIII Fansidar resistance involves an accumulation of mutations in both dhfr and dhps. These results suggest that mutations in both dhfr and dhps genes are a good predictor of potential Fansidar treatment failure.

Lack of multiple copies of pfmdr1 gene in Papua New Guinea

“…Studies that have tested different P. falciparum isolates from PNG for mefloquine resistance showed full in vitro susceptibility (Hombhanje, 1998). By contrast, other authors previously have shown a high frequency of pfmdr1 sequence polymorphisms, confirming that chloroquine selects for polymorphisms (Nagesha et al, 2001).…”

Short Report: Polymorphisms in the Chloroquine Resistance Transporter Gene in Plasmodium Falciparum Isolates From Lombok, Indonesia

“…In previous studies in Irian Jaya and West Papua, N86Y was found to show a correlation with CQ-resistant P. falciparum parasites. 11,12 The mutation K76T in the pfcrt gene was found in all but one (47 of 48, 97.9%) of the isolates studied. A previous report showed that the K76T mutation showed a correlation with clinical resistance to CQ and as a molecular marker had a sensitivity of 93% and a specificity of 82%.…”

Analysis of Pfcrt, Pfmdr1, Dhfr, and DHPS Mutations and Drug Sensitivities in Plasmodium Falciparum Isolates From Patients in Vietnam Before and After Treatment With Artemisinin

“…14,15 Ten mutant genotypes for DHFR have been reported from a large number of field samples. 4,[16][17][18] Resistance to sulfonamide and sulfones has been shown to result from mutations within dihydropteroate synthetase (DHPS). 19,[20][21][22] The amino acid changes at four positions (Ser-436, Gly-437, Ala-581, and Ala-613) have been shown to confer resistance to sulfadoxine and also cross-resistance to sulfones and sulfonamides.…”

“…21,22 Distribution of mutations in the dhfr and dhps genes and their association with Fansidar resistance have been assessed in different geographic areas, and it has been found that a greater number of mutations in both dhfr and dhps is a good predictor of likely drug failure. 4,17,18,23 Vietnam has well-developed systems for malaria surveillance, with recent data showing that more than half the population lives in forests and mountainous areas where they may be at risk of malaria infection. Drug-resistant malaria has been an increasing problem in the last two decades, and although alternative drugs such as artemisinin and its derivatives have become widely used as first-line therapy for malaria, they have been associated with a high frequency of recrudescence.…”