title: Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa.
abstract: Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensure mutual prevention against a selection and spread of drug-resistant parasites. We have studied if mutations in the pfcrt and pfmdr1 genes selected in recurrent infections after AQ monotherapy are also selected after AQ plus ART combination therapy. Samples for molecular analysis were derived from three clinical trials on children<5 years old with uncomplicated Plasmodium falciparum malaria; one AQ monotherapy study conducted in Kenya 2003 and two AQ plus ART combination therapy studies conducted in Zanzibar 2002-2003 and 2005, respectively. The PCR-adjusted treatment failure rates in the three studies were 19%, 8% and 9%, respectively. After monotherapy there was a significant selection of pfcrt 76T in re-infections (OR not calculable; p=0.048) and of pfmdr1 86Y in recrudescent infections (OR 8.0; p=0.048). No such selection was found after combination therapy. A selection of pfmdr1 1246Y and the pfmdr1 haplotype (a.a 86, 184, 1246) YYY was found in recrudescent infections both after monotherapy (OR 7.6; p=0.009 and OR 3.1; p=0.029) and combination therapy in 2005 (OR 3.6; p=0.017 and OR 5.4; p<0.001). Hence, pfmdr1 1246Y with synergistic or compensatory addition of pfmdr1 86Y and 184Y appears to be involved in AQ/DEAQ resistance and treatment failure. Our results suggest that ART may protect against a selection of these SNPs initially, but maybe not after continuous drug pressure in a population. However, treatment failure rate and spread of pfmdr1 SNPs may remain at a low level because of the suggested opposite selection by ART and the pharmacodynamic advantages with ACT.
authors.affiliation: Malaria Research Laboratory, Unit of Infectious Diseases, Division of Medicine, Karolinska Institute, Stockholm, Sweden. gabrielle.holmgren@karolinska.se
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Holmgren
authors.forename: Johan
authors.initials: J
authors.lastname: Hamrin
authors.forename: Jenny
authors.initials: J
authors.lastname: Svärd
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Gil
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D037621:Artemisinins / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D006801:Humans; D007630:Kenya; D026901:Membrane Transport Proteins / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D016017:Odds Ratio; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics; D012641:Selection, Genetic; D013636:Tanzania
chemical_list: D000655:Amodiaquine; D037621:Artemisinins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C031327:artemisinin