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Molecular studies have demonstrated that mutations in the  Plasmodium falciparum  chloroquine resistance transporter gene ( Pfcrt ) play a major role in chloroquine resistance, while mutations in  P. falciparum  multidrug resistance gene ( Pfmdr-1 ) act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44%) appears disconnected from the overall level of  in vitro  CQ susceptibility (prevalence of CQ-resistant parasites <5%) or  Pfcrt  mutant isolates (<1%), strongly contrasting with sub-Saharan African countries. Previous studies showed a high frequency of  Pfmdr-1  mutant parasites (>60% of isolates), but did not explore their association with  P. falciparum  chloroquine resistance. To document the association of  Pfmdr-1  alleles with chloroquine resistance in Madagascar, 249  P. falciparum  samples collected from patients enrolled in a chloroquine  in vivo  efficacy study were genotyped in  Pfcrt / Pfmdr-1  genes as well as the estimation of the  Pfmdr-1  copy number. Except 2 isolates, all samples displayed a wild-type  Pfcrt  allele without  Pfmdr-1  amplification. Chloroquine treatment failures were significantly associated with  Pfmdr-1  86Y mutant codon (OR = 4.6). The cumulative incidence of recurrence of patients carrying the  Pfmdr-1  86Y mutation at day 0 (21 days) was shorter than patients carrying  Pfmdr-1  86N wild type codon (28 days). In an independent set of 90 selected isolates,  in vitro  susceptibility to chloroquine was not associated with  Pfmdr-1  polymorphisms. Analysis of two microsatellites flanking  Pfmdr-1  allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar,  Pfmdr-1  polymorphism is associated with late chloroquine clinical failures and unrelated with  in vitro  susceptibility or  Pfcrt  genotype. These results highlight the limits of the current  in vitro  tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in  Pfmdr1  remains important, particularly regarding the evolution and spread of  Pfmdr-1  alleles in  P. falciparum  populations under changing drug pressure which may have important consequences in terms of antimalarial use management.

Chloroquine Clinical Failures in P. falciparum Malaria Are Associated with Mutant Pfmdr-1, Not Pfcrt in Madagascar