title: Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y.
abstract: The choice of partner drug is critical for artemisinine-based combination therapy (ACT) to remain effective and amodiaquine (AQ) is one important candidate to evaluate. We treated 81 children <5 years with uncomplicated Plasmodium falciparum malaria with AQ alone and related the treatment outcome to the possible selection of pfcrt 76T, 152T, 163S, 326S, pfmdr1 86Y and pfmrp 191H, 437S in recurrent infections (recrudescenses and re-infections) and to the blood concentration of desethylamodiaquine (DEAQ). During 21 days follow-up 28 children had a recurrent infection (9 recrudescenses, 13 re-infections and 6 mixed). Neither genotyping of the polymorphisms before treatment nor DEAQ blood concentrations could predict treatment outcome. pfcrt 76T was however significantly selected for in recurrent infections (p=0.020). pfmdr1 86Y was also selected for, but only in recrudescent infections (p=0.048). The study showed high prevalence of AQ resistant parasites in vivo, which appeared to be associated to pfcrt 76T and pfmdr1 86Y.
authors.affiliation: Malaria Research Laboratory, Unit of Infectious diseases, Department of Medicine, Karolinska Institute, Karolinska University Hospital, M9:02, 17176 Stockholm, Sweden. gabrielle.holmgren@karolinska.se
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Holmgren
authors.forename: José P
authors.initials: JP
authors.lastname: Gil
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Ferreira
authors.forename: Maria I
authors.initials: MI
authors.lastname: Veiga
authors.forename: Charles O
authors.initials: CO
authors.lastname: Obonyo
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019943:Amino Acid Substitution; D000655:Amodiaquine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000953:Antigens, Protozoan; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy*; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000953:Antigens, Protozoan; D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; C065974:merozoite surface protein 2, Plasmodium; D000655:Amodiaquine; C047386:desethylamodiaquine