title: Chloroquine-treatment failure in northern Ghana: roles of pfcrt T76 and pfmdr1 Y86.
abstract: Although chloroquine (CQ) monotherapy is now generally inadequate for the treatment of Plasmodium falciparum malaria in northern Ghana--recently, 58% of 225 children failed treatment by day 14--use of the drug continues because of its low cost and wide availability. The risk factors associated with CQ-treatment failure in this region of Africa, including the T76 mutation in the chloroquine resistance transporter (pfcrt) gene and the Y86 mutation in the multidrug resistance (pfmdr1) gene of P. falciparum, have now been investigated, and genotype-failure indices (GFI) have been calculated. Treatment failure was found to be associated with young age, poor nutritional status, pfcrt T76 and pfmdr1 Y86, and early treatment failure (ETF) was also associated with high parasitaemia. The presence and concentration of 'residual' CQ in the blood of patients immediately before they were treated with CQ for the present study appeared to have no effect on outcome. Presence at recruitment of pfcrt T76 or pfmdr1 Y86 or both mutations increased the risk of treatment failure by 3.2-, 2.4- and 4.5-fold, and the risk of ETF by 9.8-, 2.7- and 10.2-fold, respectively. The pfcrt T76 GFI for clinical and all treatment failures were 2.8 and 1.4, respectively. These indices were relatively low in the younger children, those with malnutrition, and those with high parasitaemias when treated. Residual CQ did not affect the GFI substantially. Both pfcrt T76 and, to a lesser extent, pfmdr1 Y86 would be useful tools for the surveillance of CQ resistance in northern Ghana. In the current transition phase to alternative first-line treatment for P. falciparum malaria, it should be possible to provide estimates of the level of CQ resistance by monitoring the prevalences of these mutations.
authors.affiliation: Institute of Tropical Medicine, Charité - University Medicine Berlin, Spandauer Damm 130, 14050 Berlin, Germany. frank.mockenhaupt@charite.de
authors.forename: F P
authors.initials: FP
authors.lastname: Mockenhaupt
authors.forename: S
authors.initials: S
authors.lastname: Ehrhardt
authors.forename: T A
authors.initials: TA
authors.lastname: Eggelte
authors.forename: P
authors.initials: P
authors.lastname: Agana-Nsiire
authors.forename: K
authors.initials: K
authors.lastname: Stollberg
authors.forename: A
authors.initials: A
authors.lastname: Mathieu
authors.forename: M
authors.initials: M
authors.lastname: Markert
authors.forename: R N
authors.initials: RN
authors.lastname: Otchwemah
authors.forename: U
authors.initials: U
authors.lastname: Bienzle
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D044342:Malnutrition / Q000150:complications; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009154:Mutation; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D017211:Treatment Failure
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine