Efficacy of Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010

Abstract

We describe here the results of antimalarial therapeutic efficacy studies conducted in Cambodia from 2008 to 2010. A total of 15 studies in four sentinel sites were conducted using dihydroartemisinin-piperaquine (DP) for the treatment of Plasmodium falciparum infection and chloroquine (CQ) and DP for the treatment of P. vivax infection. All studies were performed according to the standard World Health Organization protocol for the assessment of antimalarial treatment efficacy. Among the studies of DP for the treatment of P. falciparum, an increase in treatment failure was observed in the western provinces. In 2010, the PCRcorrected treatment failure rates for DP on day 42 were 25% (95% confidence interval [CI] ‫؍‬ 10 to 51%) in Pailin and 10.7% (95% CI ‫؍‬ 4 to 23%) in Pursat, while the therapeutic efficacy of DP remained high (100%) in Ratanakiri and Preah Vihear provinces, located in northern and eastern Cambodia. For the studies of P. vivax, the day 28 uncorrected treatment failure rate among patients treated with CQ ranged from 4.4 to 17.4%; DP remained 100% effective in all sites. Further study is required to investigate suspected P. falciparum resistance to piperaquine in western Cambodia; the results of in vitro and molecular studies were not found to support the therapeutic efficacy findings. The emergence of artemisinin resistance in this region has likely put additional pressure on piperaquine. Although DP appears to be an appropriate new first-line treatment for P. vivax in Cambodia, alternative treatments are urgently needed for P. falciparum-infected patients in western Cambodia.

Ex Vivo Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers

“…While DHA-PPQ has shown excellent efficacy in recent clinical trials in Africa (3)(4)(5) and Asia (6-13), a recent report from western Cambodia suggests that this fixed drug combination may be failing. Specifically, the efficacy of DHA-PPQ in Pailin decreased from 92% in 2009-2010 to 75% in 2010-2011; in Pursat Province, it was found to be 89% in 2010-2011 (14). Whether this decreased efficacy results from parasite resistance to artemisinin (ART) derivatives, PPQ, or both has not been determined.…”

“…Whether this decreased efficacy results from parasite resistance to artemisinin (ART) derivatives, PPQ, or both has not been determined. However, similar median 50% inhibitory concentrations (IC 50 s) for PPQ in Pailin, Pursat, Preah Vihear, and Ratanakiri Provinces in 2010 suggest that this decreased efficacy is unlikely due to PPQ resistance (14).…”

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

“…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.…”

“…Cambodia's recent shift to dihydroartemisinin-piperaquine as first-line therapy for vivax malaria in 2012 will result in strong selective pressure on the parasite and may eventually result in selection of mutations in this gene. 11,12 Future surveillance of the K12 gene with NGS techniques is warranted to capture any potential homologous artemisinin resistance-conferring mutations among P. vivax. …”

“…Thus, as ACTs are increasingly used to treat P. vivax, a baseline evaluation of K12 mutations and a means of rapid surveillance for potential resistance mutations is needed. 5,6,11,12 The aim of this study was to develop a rapid method to survey K12 for mutations that might confer artemisinin resistance and conduct a baseline evaluation of the reservoir of genetic diversity in K12. We modified our previously described pooled next-generation sequencing (NGS) approach and validated it using controls and simulations.…”