Recovery of Chloroquine Sensitivity and Low Prevalence of the Plasmodium Falciparum Chloroquine Resistance Transporter Gene Mutation K76t Following the Discontinuance of Chloroquine Use in Malawi

Abstract

In 1993, Malawi stopped treating patients with chloroquine for Plasmodium falciparum malaria because of a high treatment failure rate (58%). In 1998, the in vitro resistance rate to chloroquine was 3% in the Salima District of Malawi; in 2000, the in vivo resistance rate was 9%. We assayed two genetic mutations implicated in chloroquine resistance (N86Y in the P. falciparum multiple drug resistance gene 1 and K76T in the P. falciparum chloroquine resistance transporter gene) in 82 P. falciparum isolates collected during studies in 1998 and 2000. The prevalence of N86Y remained similar to that in neighboring African countries that continued to use chloroquine. In contrast, the prevalence of K76T was substantially lower than in neighboring countries, decreasing significantly from 17% in 1998 to 2% in 2000 (P < 0.02). However, neither mutation was significantly associated with in vivo or in vitro resistance (P > 0.29). Withdrawal of the use of chloroquine appears to have resulted in the recovery of chloroquine efficacy and a reduction in the prevalence of K76T. However, other polymorphisms are also expected to contribute to resistance.

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

“…Nevertheless, our observations are consistent with recent findings in parts of China (Liu et al, 1995), Vietnam (Nguyen et al, 2001;Thanh et al, 2001;Nguyen et al, 2003) and Malawi (Kublin et al, 2003;Mita et al, 2003;Mita et al, 2004), where concerted efforts to halt CQ use have resulted in an increase in the in vitro and in vivo sensitivity of field isolates to the drug, and a concomitant decrease in the prevalence of certain mutations in pfmdr1 and pfcrt associated with resistance. It was shown in Malawi (Kublin et al, 2003) that the frequency of the KAET mutation at codon 76 of pfcrt found in most [but not all Rason et al, 2002;Thomas et al, 2002;Vinayak et al, 2003)] strains resistant to CQ in vitro declined sixfold from 1992 to 2000.…”

“…In Vietnam, where artemisinin replaced CQ as the first-line treatment for falciparum malaria in 1992, comparative studies have shown that in vitro and in vivo parasite sensitivity to CQ has increased significantly over time (Nguyen et al ., 2001;Thanh et al ., 2001;Nguyen et al ., 2003). A field survey in Malawi, where sulfadoxinepyrimethamine replaced CQ as the first-line antimalarial in 1993, showed that in vitro chloroquine resistance in the local area had decreased from 47% in 1988 to 3% in 1998, noting this was also accompanied by a significant reduction in the prevalence of one of the key pfcrt mutations associated with resistance (Mita et al ., 2003). This was subsequently shown to be attributed to expansion of the wild-type pfcrt allele in the parasite population, rather than a back mutation in the mutant allele (Mita et al ., 2004).…”

Minority-Variant pfcrt K76T Mutations and Chloroquine Resistance, Malawi

“…This mutation in a putative transporter gene is well-associated with chloroquine resistance in P. falciparum (5). The MSS-HTA was compared with a standard allele-restricted PCR (ARPCR) in clinical samples from Malawi, a country where standard PCR analyses and a recent clinical trial have suggested that chloroquine-resistant malaria has disappeared (6)(7)(8)(9).…”

Alta frecuencia de mutaciones puntuales en pfcrt de Plasmodium falciparum y emergencia de nuevos haplotipos mutantes en Colombia

“…Previous studies have reported the reversal of the wild type (K76) genotype after cessation of CQ use (29,30). Although the current study was not aimed at exploring this phenomenon, the persistence of the T76 mutant phenotype was detected in a geographic region where use of CQ for falciparum malaria (but not vivax malaria) was abolished 21 years ago.…”