Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment
Leang R., Taylor WRJ., Bouth DM., Song L., Tarning J., Char MC., Kim S., Witkowski B., Duru V., Domergue A., Khim N., Ringwald P., Menard D.
<jats:title>ABSTRACT</jats:title><jats:p>Western Cambodia is recognized as the epicenter of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for<jats:italic>in vitro</jats:italic>susceptibilities to piperaquine and mefloquine, polymorphisms in the<jats:italic>K13</jats:italic>gene, and the copy number of the<jats:italic>Pfmdr-1</jats:italic>gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (<jats:italic>P</jats:italic><10<jats:sup>−3</jats:sup>). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC<jats:sub>50</jats:sub>) of PP were independent of treatment outcomes, in contrast to median mefloquine IC<jats:sub>50</jats:sub>, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM;<jats:italic>P</jats:italic>= 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the<jats:italic>K13</jats:italic>mutant allele (odds ratio [OR], 17.5; 95% confidence interval [CI], 1 to 308;<jats:italic>P</jats:italic>= 0.04). Our data show evidence of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.)</jats:p>