Antimalarial efficacy of piperaquine-based antimalarial combination therapies: facts and uncertainties

Piperaquine is a bisquinoline antimalarial drug extensively used as monotherapy in China in the 1980s and subsequently included as one of the components of the artemisinin-based combination therapies (ACTs) in the 1990s. Among them, dihydroartemisinin-piperaquine (DHA-PQP) represents a new and extremely promising fixed combination. Several clinical trials have repeatedly shown that DHA-PQP is a safe and highly efficacious therapy against uncomplicated Plasmodium falciparum and the asexual stages of Plasmodium vivax malaria. Studies conducted with this drug have reported cure rates consistently above 95%, with the only exception being a study carried out in Papua New Guinea which reported a high rate of treatment failures. Although it has been hypothesized that such treatment failures could be related to cross-resistance mechanisms between piperaquine and other quinolines or to a reduced susceptibility of parasites to artemisinin derivatives, a critical review of the studies published so far seems to exclude both of these possibilities. Overall, there is now sufficient evidence on the safety and efficacy of the DHA-PQP therapy. Accordingly, the use of this ACT for the treatment of P. falciparum malaria has been recently approved in the EU via a centralized procedure by the European Medicines Agency. Moreover, it is now recommended globally by the World Health Organization as an option for the first-line treatment of uncomplicated malaria.