title: Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in northern Cambodia: an open-label randomized trial.
abstract: BACKGROUND
  Emerging antimalarial drug resistance in mobile populations remains a significant public health concern. We compared two regimens of dihydroartemisinin-piperaquine in military and civilians on the Thai-Cambodian border to evaluate national treatment policy.
  
  
  METHODS
  Efficacy and safety of two and three-day regimens of dihydroartemisinin-piperaquine were compared as a nested open-label evaluation within a malaria cohort study in 222 otherwise healthy volunteers (18% malaria-infected at baseline). The first 80 volunteers with slide-confirmed Plasmodium falciparum or vivax malaria were randomized 1:1 to receive either regimen (total dose 360 mg dihydroartemisinin and 2880 mg piperaquine) and followed weekly for up to 6 months. The primary endpoint was malaria recurrence by day 42. Volunteers with vivax infection received primaquine at study discharge with six months follow-up.
  
  
  RESULTS
  Eighty patients (60 vivax, 15 falciparum, and 5 mixed) were randomized to dihydroartemisinin-piperaquine. Intention-to-treat all-species efficacy at Day 42 was 85% for the two-day regimen (95% CI 69-94) and 90% for the three-day regimen (95% CI 75-97). PCR-adjusted falciparum efficacy was 75% in both groups with nearly half (45%) still parasitemic at Day 3. Plasma piperaquine levels were comparable to prior published reports, but on the day of recrudescence were below measurable in vitro piperaquine IC50 levels in all falciparum treatment failures.
  
  
  CONCLUSIONS
  In the brief period since introduction of dihydroartemisinin-piperaquine, there is early evidence suggesting declining efficacy relative to previous reports. Parasite IC50 levels in excess of plasma piperaquine levels seen only in treatment failures raises concern for clinically significant piperaquine resistance in Cambodia. These findings warrant improved monitoring of clinical outcomes and follow-up, given few available alternative drugs.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01280162.
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand; US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia.
authors.forename: Chanthap
authors.initials: C
authors.lastname: Lon
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Manning
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Pattaraporn
authors.initials: P
authors.lastname: Vanachayangkul
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Mary
authors.initials: M
authors.lastname: So
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Darapiseth
authors.initials: D
authors.lastname: Sea
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand; US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia.
authors.forename: Youry
authors.initials: Y
authors.lastname: Se
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Panita
authors.initials: P
authors.lastname: Gosi
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lanteri
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Suwanna
authors.initials: S
authors.lastname: Chaorattanakawee
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Sabaithip
authors.initials: S
authors.lastname: Sriwichai
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia.
authors.forename: Soklyda
authors.initials: S
authors.lastname: Chann
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Worachet
authors.initials: W
authors.lastname: Kuntawunginn
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Nillawan
authors.initials: N
authors.lastname: Buathong
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia.
authors.forename: Samon
authors.initials: S
authors.lastname: Nou
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Walsh
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Tyner
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Juliano
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lin
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Michele
authors.initials: M
authors.lastname: Spring
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: Delia
authors.initials: D
authors.lastname: Bethell
authors.affiliation: Center of Excellence for Biomedical and Public Health Informatics (BIOPHICS), Mahidol University, Bangkok, Thailand.
authors.forename: Jaranit
authors.initials: J
authors.lastname: Kaewkungwal
authors.affiliation: Fast Track Biologics, Potomac, Maryland, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Tang
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Char Meng
authors.initials: CM
authors.lastname: Chuor
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Prom
authors.initials: P
authors.lastname: Satharath
authors.affiliation: US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology & Medicine, Bangkok, Thailand.
authors.forename: David
authors.initials: D
authors.lastname: Saunders
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002160:Cambodia / Q000453:epidemiology; D004334:Drug Administration Schedule; D018432:Drug Resistance, Multiple; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D008889:Military Personnel; D008954:Models, Biological; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012008:Recurrence; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines