title: Association between mutations in Plasmodium falciparum chloroquine resistance transporter and P. falciparum multidrug resistance 1 genes and in vivo amodiaquine resistance in P. falciparum malaria-infected children in Nigeria.
abstract: This study investigated the association between Plasmodium falciparum chloroquine resistance transporter (pfcrt) T76 and P. falciparum multidrug resistance gene 1 (pfmdr1) Y86 alleles and in vivo amodiaquine (AQ) resistance, as well as the clearance of parasites harboring these two alleles in children treated with AQ in southwest Nigeria. One hundred one children with acute uncomplicated P. falciparum malaria infections were treated with the standard dosage of AQ and followed-up for 28 days. Blood samples were collected on filter paper samples at enrollment and during follow-up for identification of parasite genotypes and pfcrt and pfmdr1 mutations using polymerase chain reaction and restriction fragment length polymorphism approaches. Parasitologic assessment of response to treatment showed that 87% and 13% (RI) of patients were cured and failed treatment, respectively. Although infections in patients were polyclonal (as determined by merozoite surface protein 2 genotyping), the presence of both mutants pfcrtT76 and pfmdr1Y86 alleles in parasites is associated with in vivo AQ resistance (odds ratio = 7.58, 95% confidence interval = 1.58-36.25, P = 0.006) and is selected by the drug in children who failed AQ treatment. Treatment failure with the combination of mutant pfcrtT76 and pfmdr1Y86 alleles as well as the ability of patients to clear these resistant parasites is dependent on age, suggesting a critical role of host immunity in clearing AQ-resistant P. falciparum. The combination of mutant pfcrtT76 and pfmdr1Y86 alleles may be useful markers for monitoring the development and spread of AQ resistance, when combining this drug with other antimalarials for treatment of malaria in Africa.
authors.affiliation: Malaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria. christianhappi@hotmail.com
authors.forename: C T
authors.initials: CT
authors.lastname: Happi
authors.forename: G O
authors.initials: GO
authors.lastname: Gbotosho
authors.forename: O A
authors.initials: OA
authors.lastname: Folarin
authors.forename: O M
authors.initials: OM
authors.lastname: Bolaji
authors.forename: A
authors.initials: A
authors.lastname: Sowunmi
authors.forename: D E
authors.initials: DE
authors.lastname: Kyle
authors.forename: W
authors.initials: W
authors.lastname: Milhous
authors.forename: D F
authors.initials: DF
authors.lastname: Wirth
authors.forename: A M J
authors.initials: AM
authors.lastname: Oduola
mesh_terms: D000367:Age Factors; D000655:Amodiaquine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009549:Nigeria; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C065974:merozoite surface protein 2, Plasmodium; D000655:Amodiaquine