Selection of Plasmodium falciparum Multidrug Resistance Gene 1 Alleles in Asexual Stages and Gametocytes by Artemether-Lumefantrine in Nigerian Children with Uncomplicated Falciparum Malaria

Abstract

ABSTRACT We assessed Plasmodium falciparum mdr1 (Pf mdr1 ) gene polymorphisms and copy numbers as well as P. falciparum Ca 2+ ATPase (Pf ATPase6 ) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pf mdr1 and Pf ATPase6 genes and the Pf mdr1 copy number variation, respectively, in patients samples collected prior to treatment and at the reoccurrence of parasites during a 42-day follow-up. The Pf mdr1 haplotype 86N-184F-1246D was significantly associated ( P < 0.00001) with treatment failures and was selected for among posttreatment samples obtained from patients with newly acquired or recrudescing infections ( P < 0.00001; χ 2 = 36.5) and in gametocytes (log rank statistic = 5; P = 0.0253) after treatment with AL. All pre- and posttreatment samples as well as gametocytes harbored a single copy of the Pf mdr1 gene and the wild-type allele (L89) at codon 89 of the Pf ATPase6 gene. These findings suggest that polymorphisms in the Pf mdr1 gene are under AL selection pressure. Pf mdr1 polymorphisms may result in reduction in the therapeutic efficacy of this newly adopted combination treatment for uncomplicated falciparum malaria in Saharan countries of Africa.