High proportion of multiple copies of Plasmodium falciparum Plasmepsin-2 gene in African isolates: Is piperaquine resistance emerging in Africa?

Emergence of Plasmodium falciparum resistance to antimalarial drugs is currently the primary rationale supporting the development of new and well-tolerated drugs. 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. Blood 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 plasmepsin2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. Validated 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 to PPQ resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (>30%).\n\nOur findings sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to decipher the genetic background associated with PPQ resistance in Africa by investigating in vitro susceptibilities to PPQ of isolates with multiple copies of the Pfpm2 gene and the urgent need to assess the risk of development of PPQ resistance, along with the efficacy of both current frontline therapies and new antimalarial combinations.