title: Spread of artemisinin resistance in Plasmodium falciparum malaria.
abstract: BACKGROUND
  Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.
  
  
  METHODS
  Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.
  
  
  RESULTS
  The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.
  
  
  CONCLUSIONS
  Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
authors: The authors' affiliations are listed in the Appendix.
authors: Elizabeth A
authors: EA
authors: Ashley
authors: Mehul
authors: M
authors: Dhorda
authors: Rick M
authors: RM
authors: Fairhurst
authors: Chanaki
authors: C
authors: Amaratunga
authors: Parath
authors: P
authors: Lim
authors: Seila
authors: S
authors: Suon
authors: Sokunthea
authors: S
authors: Sreng
authors: Jennifer M
authors: JM
authors: Anderson
authors: Sivanna
authors: S
authors: Mao
authors: Baramey
authors: B
authors: Sam
authors: Chantha
authors: C
authors: Sopha
authors: Char Meng
authors: CM
authors: Chuor
authors: Chea
authors: C
authors: Nguon
authors: Siv
authors: S
authors: Sovannaroth
authors: Sasithon
authors: S
authors: Pukrittayakamee
authors: Podjanee
authors: P
authors: Jittamala
authors: Kesinee
authors: K
authors: Chotivanich
authors: Kitipumi
authors: K
authors: Chutasmit
authors: Chaiyaporn
authors: C
authors: Suchatsoonthorn
authors: Ratchadaporn
authors: R
authors: Runcharoen
authors: Tran Tinh
authors: TT
authors: Hien
authors: Nguyen Thanh
authors: NT
authors: Thuy-Nhien
authors: Ngo Viet
authors: NV
authors: Thanh
authors: Nguyen Hoan
authors: NH
authors: Phu
authors: Ye
authors: Y
authors: Htut
authors: Kay-Thwe
authors: KT
authors: Han
authors: Kyin Hla
authors: KH
authors: Aye
authors: Olugbenga A
authors: OA
authors: Mokuolu
authors: Rasaq R
authors: RR
authors: Olaosebikan
authors: Olaleke O
authors: OO
authors: Folaranmi
authors: Mayfong
authors: M
authors: Mayxay
authors: Maniphone
authors: M
authors: Khanthavong
authors: Bouasy
authors: B
authors: Hongvanthong
authors: Paul N
authors: PN
authors: Newton
authors: Marie A
authors: MA
authors: Onyamboko
authors: Caterina I
authors: CI
authors: Fanello
authors: Antoinette K
authors: AK
authors: Tshefu
authors: Neelima
authors: N
authors: Mishra
authors: Neena
authors: N
authors: Valecha
authors: Aung Pyae
authors: AP
authors: Phyo
authors: Francois
authors: F
authors: Nosten
authors: Poravuth
authors: P
authors: Yi
authors: Rupam
authors: R
authors: Tripura
authors: Steffen
authors: S
authors: Borrmann
authors: Mahfudh
authors: M
authors: Bashraheil
authors: Judy
authors: J
authors: Peshu
authors: M Abul
authors: MA
authors: Faiz
authors: Aniruddha
authors: A
authors: Ghose
authors: M Amir
authors: MA
authors: Hossain
authors: Rasheda
authors: R
authors: Samad
authors: M Ridwanur
authors: MR
authors: Rahman
authors: M Mahtabuddin
authors: MM
authors: Hasan
authors: Akhterul
authors: A
authors: Islam
authors: Olivo
authors: O
authors: Miotto
authors: Roberto
authors: R
authors: Amato
authors: Bronwyn
authors: B
authors: MacInnis
authors: Jim
authors: J
authors: Stalker
authors: Dominic P
authors: DP
authors: Kwiatkowski
authors: Zbynek
authors: Z
authors: Bozdech
authors: Atthanee
authors: A
authors: Jeeyapant
authors: Phaik Yeong
authors: PY
authors: Cheah
authors: Tharisara
authors: T
authors: Sakulthaew
authors: Jeremy
authors: J
authors: Chalk
authors: Benjamas
authors: B
authors: Intharabut
authors: Kamolrat
authors: K
authors: Silamut
authors: Sue J
authors: SJ
authors: Lee
authors: Benchawan
authors: B
authors: Vihokhern
authors: Chanon
authors: C
authors: Kunasol
authors: Mallika
authors: M
authors: Imwong
authors: Joel
authors: J
authors: Tarning
authors: Walter J
authors: WJ
authors: Taylor
authors: Shunmay
authors: S
authors: Yeung
authors: Charles J
authors: CJ
authors: Woodrow
authors: Jennifer A
authors: JA
authors: Flegg
authors: Debashish
authors: D
authors: Das
authors: Jeffery
authors: J
authors: Smith
authors: Meera
authors: M
authors: Venkatesan
authors: Christopher V
authors: CV
authors: Plowe
authors: Kasia
authors: K
authors: Stepniewska
authors: Philippe J
authors: PJ
authors: Guerin
authors: Arjen M
authors: AM
authors: Dondorp
authors: Nicholas P
authors: NP
authors: Day
authors: Nicholas J
authors: NJ
authors: White
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use*; D001210:Asia, Southeastern; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008875:Middle Aged; D015999:Multivariate Analysis; D059208:Parasite Load; D018512:Parasitemia / Q000188:drug therapy / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D017354:Point Mutation; D015800:Protozoan Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins