title: Gambian children successfully treated with chloroquine can harbor and transmit Plasmodium falciparum gametocytes carrying resistance genes.
abstract: Polymorphisms in two genes of Plasmodium falciparum (P. falciparum multidrug resistance 1 [pfmdr1] and P. falciparum chloroquine [CQ] resistance transporter [pfcrt]) are associated with CQ treatment failure. We found significant linkage disequilibrium between these loci among isolates from symptomatic Gambian children (P = 0.026) and strong selection for the resistance-associated alleles pfmdr1-86Tyr and pfcrt-76Thr in children with persistent or re-emerging P. falciparum trophozoites during post-treatment follow-up (P = 1.9 x 10(-7)). Therefore, this genotype is characteristic of resistant infections among our study population. Since the long-term public health impact of parasites carrying such resistant genotypes depends upon their transmissibility, we examined the prevalence of pfmdr1-86Tyr and pfcrt-76Thr among Gambian children harboring sexual stage parasites during post-treatment follow-up. Gametocytes that emerged after successful treatment with CQ were significantly more likely to be of this genotype than were those emerging after other treatments (P = 4.83 x 10(-4)), and were infective to Anopheles mosquitoes. Therapeutic success may thus be accompanied by public health failure as cured children pass resistance genes on to mosquitoes at an enhanced rate.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom. colin.sutherland@lshtm.ac.uk
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Sutherland
authors.forename: Ali
authors.initials: A
authors.lastname: Alloueche
authors.forename: Jill
authors.initials: J
authors.lastname: Curtis
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Drakeley
authors.forename: Rosalynn
authors.initials: R
authors.lastname: Ord
authors.forename: Manoj
authors.initials: M
authors.lastname: Duraisingh
authors.forename: Brian M
authors.initials: BM
authors.lastname: Greenwood
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: David
authors.initials: D
authors.lastname: Warhurst
authors.forename: Geoffrey A T
authors.initials: GA
authors.lastname: Targett
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D016054:DNA, Protozoan / Q000032:analysis; D004351:Drug Resistance / Q000235:genetics*; D005714:Gambia; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D016054:DNA, Protozoan; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine