title: Amplification of pvmdr1 associated with multidrug-resistant Plasmodium vivax.
abstract: BACKGROUND
  Multidrug-resistant strains of Plasmodium vivax are emerging in Southeast Asia.
  
  
  METHODS
  In vitro drug susceptibility and pvmdr1 genotype were determined in P. vivax field isolates from Indonesia and Thailand.
  
  
  RESULTS
  Increased pvmdr1 copy number was present in 21% of isolates from Thailand (15/71) and none from Indonesia (0/114; P < .001). Compared with Indonesian isolates, the median IC(50) of Thai isolates was lower for chloroquine (36 vs. 114 nmol/L; P < .001) but higher for amodiaquine (34 vs. 13.7 nmol/L; P = .032), artesunate (8.33 vs. 1.58 nmol/L; P < .001), and mefloquine (111 vs. 9.87 nmol/L; P < .001). In 11 cryopreserved Thai isolates, those with increased pvmdr1 copy number had a higher IC(50) for mefloquine (78.6 vs. 38 nmol/L for single-copy isolates; P = .006). Compared with isolates with the wild-type allele, the Y976F mutation of pvmdr1 was associated with reduced susceptibility to chloroquine (154 nmol/L [range, 4.6-3505] vs. 34 nmol/L [range, 6.7-149]; P < .001) but greater susceptibility to artesunate (1.8 vs. 9.5 nmol/L; P = .009) and mefloquine (14 vs. 121 nmol/L; P < .001).
  
  
  CONCLUSIONS
  Amplification of pvmdr1 and single-nucleotide polymorphisms are correlated with susceptibility of P. vivax to multiple antimalarial drugs. Chloroquine and mefloquine appear to exert competitive evolutionary pressure on pvmdr1, similar to that observed with pfmdr1 in Plasmodium falciparum.
authors.affiliation: International Health Division, Menzies School of Health Research, Darwin, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Suwanarusk
authors.forename: M
authors.initials: M
authors.lastname: Chavchich
authors.forename: B
authors.initials: B
authors.lastname: Russell
authors.forename: A
authors.initials: A
authors.lastname: Jaidee
authors.forename: F
authors.initials: F
authors.lastname: Chalfein
authors.forename: M
authors.initials: M
authors.lastname: Barends
authors.forename: B
authors.initials: B
authors.lastname: Prasetyorini
authors.forename: E
authors.initials: E
authors.lastname: Kenangalem
authors.forename: K A
authors.initials: KA
authors.lastname: Piera
authors.forename: U
authors.initials: U
authors.lastname: Lek-Uthai
authors.forename: N M
authors.initials: NM
authors.lastname: Anstey
authors.forename: E
authors.initials: E
authors.lastname: Tjitra
authors.forename: F
authors.initials: F
authors.lastname: Nosten
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
authors.forename: R N
authors.initials: RN
authors.lastname: Price
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics*; D005838:Genotype; D020128:Inhibitory Concentration 50; D016780:Malaria, Vivax / Q000469:parasitology*; D021261:Parasitic Sensitivity Tests; D010966:Plasmodium vivax / Q000187:drug effects* / Q000235:genetics*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials