title: Rapid selection of dhfr mutant allele in Plasmodium falciparum isolates after the introduction of sulfadoxine/pyrimethamine in combination with 4-aminoquinolines in Papua New Guinea.
abstract: To overcome the declining efficacy of the 4-aminoquinolines in Papua New Guinea, sulfadoxine/pyrimethamine (SP) was combined with the 4-aminoquinolines as the first line treatment for falciparum malaria since 2000. To assess how this change had affected SP resistant gene polymorphisms, we determined allele frequencies of dhfr and dhps in 113 Plasmodium falciparum isolates from Wewak, East Sepik of Papua New Guinea in 2002 and 2003. In dhfr, double mutant (ACNRNVI) was the predominant allele with a prevalence of 91%. We found a significant decrease of wild dhfr allele prevalence (7%) compared with that reported in the adjacent area of East Sepik called the Wosera region (57%), before the drug policy changed in 1990-1993. Between 2002 and 2003, the prevalence of this allele decreased from 15% to 3% (P=0.02). Two distinct microsatellite haplotypes flanking dhfr were found in isolates with dhfr double mutant, suggesting the selection of preexisting SP resistant parasites rather than a frequent occurrence of dhfr mutations. The dhfr/dhps quartet mutations (ACNRNVI in dhfr and SGEAA in dhps) were identified in six of the isolates (8%) from 2003. This genotype, which is associated with in vivo resistance to SP, has not been reported before in Papua New Guinea. These findings suggest that isolates resistant to SP were rapidly selected despite the use of the SP combination therapy, probably because of their preexisting high level of resistance to the 4-aminoquinoline partner drug.
authors.affiliation: Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan. hiro-tm@research.twmu.ac.jp
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Mita
authors.forename: Akira
authors.initials: A
authors.lastname: Kaneko
authors.forename: Ilomo
authors.initials: I
authors.lastname: Hwaihwanje
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Hikota
authors.initials: H
authors.lastname: Osawa
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kobayakawa
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
mesh_terms: D000483:Alleles; D000634:Aminoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000235:genetics; D004359:Drug Therapy, Combination; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology* / Q000469:parasitology; D009154:Mutation; D010219:Papua New Guinea / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics*; D011110:Polymorphism, Genetic; D011739:Pyrimethamine / Q000008:administration & dosage / Q000627:therapeutic use*; D012641:Selection, Genetic; D013413:Sulfadoxine / Q000008:administration & dosage / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D000634:Aminoquinolines; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; C001920:4-aminoquinoline; D011739:Pyrimethamine