TY - JOUR
T1 - Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in Northern Cambodia
T2 - An open-label randomized trial
AU - Lon, Chanthap
AU - Manning, Jessica E.
AU - Vanachayangkul, Pattaraporn
AU - So, Mary
AU - Sea, Darapiseth
AU - Se, Youry
AU - Gosi, Panita
AU - Lanteri, Charlotte
AU - Chaorattanakawee, Suwanna
AU - Sriwichai, Sabaithip
AU - Chann, Soklyda
AU - Kuntawunginn, Worachet
AU - Buathong, Nillawan
AU - Nou, Samon
AU - Walsh, Douglas S.
AU - Tyner, Stuart D.
AU - Juliano, Jonathan J.
AU - Lin, Jessica
AU - Spring, Michele
AU - Bethell, Delia
AU - Kaewkungwal, Jaranit
AU - Tang, Douglas
AU - Chuor, Char Meng
AU - Satharath, Prom
AU - Saunders, David
PY - 2014/3/25
Y1 - 2014/3/25
N2 - Introduction: 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 360mg dihydroartemisinin and 2880mg 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. Trial Registration: ClinicalTrials.gov NCT01280162.
AB - Introduction: 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 360mg dihydroartemisinin and 2880mg 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. Trial Registration: ClinicalTrials.gov NCT01280162.
UR - http://www.scopus.com/inward/record.url?scp=84899754743&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0093138
DO - 10.1371/journal.pone.0093138
M3 - Article
C2 - 24667662
AN - SCOPUS:84899754743
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e93138
ER -