title: Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study.
abstract: BACKGROUND
  Artemisinin resistance in Plasmodium falciparum extends across Southeast Asia where it is associated with worsening partner drug resistance and a decline in the efficacy of frontline artemisinin-based combination therapy. Dihydroartemisinin-piperaquine (DP) is an essential component of preventive and curative treatment in the region, but its therapeutic efficacy has fallen in Cambodia.
  
  
  METHODS
  A prospective clinical and parasitological evaluation of DP was conducted at two sites in Upper Myanmar between August 2013 and December 2014, enrolling 116 patients with acute uncomplicated falciparum malaria. Patients received DP orally for 3 days together with primaquine 0.25 mg/kg on admission. Parasite clearance half-lives based on 6 hourly blood smears, and day 42 therapeutic responses were assessed as well as parasite K13 genotypes.
  
  
  RESULTS
  Median parasite clearance half-life was prolonged, and clearance half-life was greater than 5 h in 21% of patients. Delayed parasite clearance was significantly associated with mutations in the propeller region of the parasite k13 gene. The k13 F446I mutation was found in 25.4% of infections and was associated with a median clearance half-life of 4.7 h compared with 2.7 h for infections without k13 mutations (p < 0.001). There were no failures after 42 days of follow-up, although 18% of patients had persistent parasitaemia on day 3.
  
  
  CONCLUSIONS
  The dominant k13 mutation observed in Upper Myanmar, F446I, appears to be associated with an intermediate rate of parasite clearance compared to other common mutations described elsewhere in the Greater Mekong Subregion. Discerning this phenotype requires relatively detailed clearance measurements, highlighting the importance of methodology in assessing artemisinin resistance.
authors.affiliation: Defence Services Medical Research Centre, Naypyitaw, Myanmar.|Myanmar Oxford Clinical Research Unit, Yangon, Myanmar.
authors.forename: Kyaw Myo
authors.initials: KM
authors.lastname: Tun
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand.
authors.forename: Atthanee
authors.initials: A
authors.lastname: Jeeyapant
authors.affiliation: Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.affiliation: Defence Services Medical Research Centre, Naypyitaw, Myanmar.
authors.forename: Min
authors.initials: M
authors.lastname: Thein
authors.affiliation: Defence Services Medical Research Centre, Naypyitaw, Myanmar.
authors.forename: Sai Soe Moe
authors.initials: SS
authors.lastname: Aung
authors.affiliation: Defence Services Medical Research Centre, Naypyitaw, Myanmar.
authors.forename: Tin Maung
authors.initials: TM
authors.lastname: Hlaing
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand.
authors.forename: Prayoon
authors.initials: P
authors.lastname: Yuentrakul
authors.affiliation: Worldwide Antimalarial Resistance Network (WWARN), Bangkok, Thailand.
authors.forename: Cholrawee
authors.initials: C
authors.lastname: Promnarate
authors.affiliation: Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.|Worldwide Antimalarial Resistance Network (WWARN), Bangkok, Thailand.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dhorda
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Woodrow
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.affiliation: Myanmar Oxford Clinical Research Unit, Yangon, Myanmar.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.|Medical Action Myanmar, Yangon, Myanmar.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Smithuis
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Rd., Ratchathewi District, Bangkok, 10400, Thailand. nickd@tropmedres.ac.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. nickd@tropmedres.ac.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D002052:Myanmar; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000235:genetics; D011804:Quinolines / Q000627:therapeutic use; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
keywords: Artemisinin resistance; Kelch 13 propeller; Myanmar; Parasite clearance half-life; Plasmodium falciparum