title: Artemisinin resistance in Plasmodium falciparum malaria.
abstract: BACKGROUND
  Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.
  
  
  METHODS
  In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.
  
  
  RESULTS
  We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.
  
  
  CONCLUSIONS
  P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)
authors.affiliation: Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. arjen@tropmedres.ac
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.forename: Poravuth
authors.initials: P
authors.lastname: Yi
authors.forename: Debashish
authors.initials: D
authors.lastname: Das
authors.forename: Aung Phae
authors.initials: AP
authors.lastname: Phyo
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Khin Maung
authors.initials: KM
authors.lastname: Lwin
authors.forename: Frederic
authors.initials: F
authors.lastname: Ariey
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.forename: Kamolrat
authors.initials: K
authors.lastname: Silamut
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.forename: Trent
authors.initials: T
authors.lastname: Herdman
authors.forename: Sen Sam
authors.initials: SS
authors.lastname: An
authors.forename: Shunmay
authors.initials: S
authors.lastname: Yeung
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Duong
authors.initials: D
authors.lastname: Socheat
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077332:Artesunate; D004351:Drug Resistance / Q000235:genetics; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006801:Humans; D019271:Hypoxanthine / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D015767:Mefloquine / Q000008:administration & dosage; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D012008:Recurrence; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D019271:Hypoxanthine; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C039060:artenimol