title: Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria.
abstract: The artemisinin-based combination therapies artemether-lumefantrine (AL) and amodiaquine (AQ) plus artesunate have been adopted for treatment of Plasmodium falciparum malaria in many African countries. Molecular markers of parasite resistance suitable for surveillance have not been established for any of the component drugs in either of these combinations. We assessed P. falciparum mdr1 (Pfmdr1) alleles present in 300 Tanzanian children presenting with uncomplicated falciparum malaria, who were enrolled in a clinical trial of antimalarial therapy. Pfmdr1 genotype analysis was also performed with isolates from 182 children who failed AQ monotherapy and 54 children who failed AL treatment. Pfmdr1 alleles 86Y, 184Y, and 1246Y were more common among treatment failures in the AQ group than among pretreatment infections. The converse was found in the AL-treated group. Children presenting with the 86Y/184Y/1246Y Pfmdr1 haplotype and treated with AQ were significantly more likely to retain this haplotype if they were parasite positive during posttreatment follow-up than were children treated with AL (odds ratio, 33.25; 95% confidence interval, 4.17 to 1441; P, <0.001). We conclude that AL and AQ exert opposite within-host selective effects on the Pfmdr1 gene of P. falciparum.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
authors.forename: G S
authors.initials: GS
authors.lastname: Humphreys
authors.forename: I
authors.initials: I
authors.lastname: Merinopoulos
authors.forename: J
authors.initials: J
authors.lastname: Ahmed
authors.forename: C J M
authors.initials: CJ
authors.lastname: Whitty
authors.forename: T K
authors.initials: TK
authors.lastname: Mutabingwa
authors.forename: C J
authors.initials: CJ
authors.lastname: Sutherland
authors.forename: R L
authors.initials: RL
authors.lastname: Hallett
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000235:genetics*; D000483:Alleles; D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology*; D002675:Child, Preschool; D004351:Drug Resistance; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D005449:Fluorenes / Q000494:pharmacology*; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013636:Tanzania; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000655:Amodiaquine; D000077549:Artemether; D000078102:Lumefantrine