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

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 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.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

Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Two-Day Regimen of Dihydroartemisinin-Piperaquine for Malaria Prevention Halted for Concern over Prolonged Corrected QT Interval

“…While the 3-day regimen was found to be effective in western Thailand, electrocardiogram monitoring was not performed (6). This study also followed a recent study by the Armed Forces Research Institute of Medical Science (AFRIMS), Cambodian National Center for Parasitology, Entomology, and Malaria Control (CNM), and Royal Cambodian Armed Forces (RCAF) in 2010 that found similar efficacy between 2-and 3-day treatment courses of dihydroartemisinin-piperaquine for infection of all species (12). Unfortunately, in the present study, the compressed 2-day regimen resulted in unacceptably high levels of QT interval prolongation, and the trial was halted after only 69 participants were enrolled following prespecified cardiac safety rules.…”

“…Quantification of piperaquine was performed using a previously described method (12), determined by ultraperformance liquid chromatography followed by tandem mass spectrometry (UPLC/MS/ MS), and reported as quantities of piperaquine base (molecular weight [MW] of 535.54). If manual QTc (QTcFm) was greater than 450 ms following the second monthly dose of study drug, drug levels were repeated weekly until the QTcFm intervals normalized.…”

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia

“…In 2010 and 2011, a comparison of a 3-day DP (3DP) regimen and a compressed 2-day DP (2DP) regimen revealed that both had similar efficacies for the treatment of uncomplicated malaria in northern Cambodia. A mean prolongation of the QT interval corrected using Fridericia's formula (QTcF) of 20 to 30 ms between the predose QT interval and the QT interval at the time of the trough piperaquine levels at 24 h postdosing was measured (4). In 2012, a follow-on randomized, double-blind, placebo-controlled study evaluating a 2-day DP regimen as a monthly malaria prevention therapy was halted after 4 out of 69 volunteers met prespecified criteria to stop the study because of individual cardiac safety endpoints with a QTcF prolongation of Ͼ500 ms. An unblind review by the Data Safety Monitoring Board (DSMB) revealed a 46-ms mean QTcF prolongation over that achieved with placebo at the time of the maximum plasma concentration (C max ) of piperaquine on day 2.…”

Longitudinal Pooled Deep Sequencing of the Plasmodium vivax K12 Kelch Gene in Cambodia Reveals a Lack of Selection by Artemisinin

“…[1][2][3][4][5] A molecular correlate of this resistance was recently discovered, and resistance was found to be associated with specific mutations in the BTB/POZ and propeller domains of the P. falciparum kelch protein, K13 (PF3D7_1343700). [6][7][8][9][10] K13 mutations are now being used as molecular markers for surveillance of artemisinin resistance.…”

“…9,10 Artemisinin resistance has not been reported in Plasmodium vivax. 3,11 However, in Cambodia, antimalarial drugs are often dispensed without species-level diagnosis, and coinfections are common, likely resulting in artemisinin exposure to P. vivax. Moreover, dihydroartemisinin-piperaquine replaced chloroquine for treatment of P. vivax malaria in Cambodia in 2012 due to concerns of chloroquine resistance.…”