• Chanthap Lon, Jessica E Manning, Pattaraporn Vanachayangkul, Mary So, Darapiseth Sea, Youry Se, Panita Gosi, Charlotte Lanteri, Suwanna Chaorattanakawee, Sabaithip Sriwichai, Soklyda Chann, Worachet Kuntawunginn, Nillawan Buathong, Samon Nou, Douglas S Walsh, Stuart D Tyner, Jonathan J Juliano, Jessica Lin, Michele Spring, Delia Bethell, Jaranit Kaewkungwal, Douglas Tang, Char Meng Chuor, Prom Satharath, and David Saunders.
• 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.
• Plos One. 2014 Jan 1; 9 (3): e93138.

IntroductionEmerging 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.MethodsEfficacy 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.ResultsEighty 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.ConclusionsIn 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.Trial RegistrationClinicalTrials.gov NCT01280162.

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