Diagnostic value of molecular markers in chloroquine-resistant falciparum malaria in Southern Mauritania.

Abstract

Despite its diminishing efficacy because of increased resistance, chloroquine remains the primary antimalarial agent in many endemic areas. Evidence is mounting that point mutations on the Pfcrt and possibly the Pfmdr1 genes are conferring plasmodial resistance to chloroquine. In 1998, atypically strong rainfalls led to an increased activity of falciparum malaria in Mauritania that affected non-endemic regions bordering the Saharan desert. An in vivo study on chloroqine resistance was combined with studies for molecular markers of drug resistance. Detection of Pfmdr1-76-tyrosine showed an increased odds ratio (2.91) for resistance (P ‫ס‬ 0.0195). However, by use of this codon alone, sensitivity for detection of resistance was 60.6%, and specificity was 65.3%. In comparison, detection of the K76T mutation at Pfcrt showed a very high sensitivity (100%) while specificity remained relatively low (65.4%). For the combination of mutations on both genes, the odds ratio for detection of resistance increased to 5.31 (P ‫ס‬ 0.0005). Here, sensitivity was again decreased to 60.6% while specificity increased to 76.9%. The results of this study suggest that detection of Pfcrt T76 can be applied for predicting chloroquine resistance in epidemiologic settings with sufficiently high sensitivity to make it an attractive alternative to time-and labor-consuming in vivo trials. Additional testing for Pfmdr Y76 provides increased specificity to this approach.

Characterization of Plasmodium falciparum genes associated with drug resistance in Hodh Elgharbi, a malaria hotspot near Malian–Mauritanian border

“…A high prevalence of mutant K76T Pfcrt allele was observed in the present study. This finding is in agreement with the previous clinical and molecular studies, confirming that Pfcrt is useful for the detection and surveillance of chloroquine-resistant P. falciparum in Hodh Elgharbi region [13]. …”

“…Several studies have shown that P. falciparum is the predominant malaria species in this region and that 30–83% of febrile patients are infected with malaria parasites during the transmission season [2, 13–16]. In Hodh Elgharbi region, the northern Saharo–Sahelian area that borders the Saharan desert has been considered as malaria-free while the southern Sahelian part of the region is classified as holo-endemic [13]. The Malian–Mauritanian border is particularly vulnerable to the spread of malaria parasites with the influx of war refugees from the Malian side of the frontier.…”

Reemergence of Chloroquine‐SensitivePlasmodium falciparumMalaria after Cessation of Chloroquine Use in Malawi

“…Although genetic transformation experiments have found that pfmdr1 mutations can modulate the level of chloroquine resistance once it has been conferred by mutations in pfcrt, mutations in pfmdr1 are by themselves insufficient to confer chloroquine resistance [20]. Recent studies have reported that pfmdr1 mutations, in addition to pfcrt mutations, are no more strongly associated with chloroquine treatment failure than pfcrt mutations alone [7] and that pfmdr1 mutations do not add to the predictive value of pfcrt mutations for chloroquine treatment failure [21]. Even if pfmdr1 mutations do contribute to treatment failure, they require pfcrt mutations to exert an effect on the response to chloroquine.…”

Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

“…24 Furthermore, reports exist that this pfmdr1 mutation is not required for CQ resistance, but rather, seems to exert an added effect on the CQ response in the presence of the K76T mutation in the pfcrt gene. 30 The 100% prevalence of the pfcrtK76T mutation in Suriname throughout geographically different endemic regions provided molecular validation of CQ resistance in Suriname. The reduced CQ use did not successively result in a decrease in the pfcrtK76T prevalence, thus ruling out the possibility of reintroduction of CQ in the near future.…”