Abstract
BackgroundToday, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014–2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)–piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria.MethodsBlood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes.ResultsValidated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%).ConclusionsThese findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa.Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist=. FSFV: 23-Jul-2014; LSLV: 09-Oct-2015
Highlights
Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emer‐ gence of Plasmodium falciparum resistance
Artemisininbased combination therapy (ACT) which are currently recommended as first-line treatment of uncomplicated falciparum malaria, is less effective in Southeast Asia, in Cambodia, where high rates of treatment failure associated with artemisinin and piperaquine resistance are currently reported [4,5,6,7,8,9,10,11,12,13,14,15,16]
In Asia, seven isolates (10.8%, 7/65, 95% CI 4.3–22.2%) had genotypes associated with both artemisinin and PPQ resistance (Fig. 2a)
Summary
The development of new and well-tolerated anti-malarial drugs is strongly justified by the emer‐ gence of Plasmodium falciparum resistance. Artemisininbased combination therapy (ACT) which are currently recommended as first-line treatment of uncomplicated falciparum malaria, is less effective in Southeast Asia, in Cambodia, where high rates of treatment failure associated with artemisinin and piperaquine resistance are currently reported [4,5,6,7,8,9,10,11,12,13,14,15,16]. The containment and the elimination of these multidrug resistant parasites in Southeast Asia are a priority for the WHO to avoid their spread to Africa as was the case with previous generations of anti-malarial drugs (e.g. chloroquine, sulfadoxine–pyrimethamine) [17]. Mutations in the propeller domain of a kelch gene located on the chromosome 13 (kelch13), and amplification of a cluster of genes encoding both plasmepsin 2 (Pfpm2) and plasmepsin 3 proteins, have been recently shown to be associated with artemisinin and PPQ resistance, respectively [18,19,20]
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