LAUSR

The global need for new antimalarial drugs and new combinations is enormous and urgent, but their successful delivery needs resilience to overcome the barriers imposed by expensive and lengthy clinical development plans. Attention is often directed to areas such as southeast Asia, where some antimalarial combinations are failing but transmission intensities are much lower than in sub-Saharan African countries. Children in Africa have frequent and life-threatening malaria infections as they grow up, and these need to be treated safely. Pyronaridine–artesunate and dihydroartemisinin– piperaquine are two artemisinin combination therapies (ACTs) that exemplify the challenges that arise in the pathway towards licensure and wider implementation. These two drug combinations have a good track record of efficacy and are approved by the European Medicines Agency (EMA). However, their introduction into first-line therapies in malaria-endemic countries, particularly in sub-Saharan Africa where the global malaria problem is worst, has been sporadic and slow. Questions about the safety of ACTS (ie, hepatotoxicity for pyronaridine–artesunate and cardiotoxicity for dihydroartemisinin–piperaquine) might have delayed their endorsement by WHO, thereby obstructing adoption into national malaria-control programmes. They are also needed in southeast Asia where other antimalarial treatments are no longer effective when used in conventional doses. Adequate assessment of antimalarial drugs should not be restricted to investigating their ability to cure a single infection safely, but to rather account for their overall efficacy in decreasing the long-term cumulative incidence of disease and their prolonged safety when used repeatedly. In high-transmission, malaria-endemic areas, repeated symptomatic malaria infections are common until the acquisition of a degree of immunity against the disease. In highly endemic vivax transmission areas, relapses caused by hypno zoites frequently contribute to repeated clinical episodes of malaria. In The Lancet, Issaka Sagara and colleagues from the West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) provide reassuring results on the safety and efficacy of pyronaridine–artesunate and dihydroartemisinin–piperaquine in a large, randomised, controlled trial undertaken in Mali, Burkina Faso, and Guinea. For 2 years they followed up a longitudinal cohort of 4710 adult and paediatric patients aged 6 months and older with microscopically confirmed Plasmodium spp malaria to assess the safety and efficacy of pyronaridine–artesunate and dihydroartemisinin– piperaquine to treat recurrent malaria versus current recommended first-line (re)treatments with artemether– lumefantrine or artesunate–amodiaquine. All treatments were once-daily or twice-daily tablets or granules given orally over 3 days at the study centres, and patients were followed up as outpatients up to day 42. The results of this large and complex trial confirmed the non-inferiority of both pyronaridine–artesunate and dihydroartemisinin–piperaquine against the comparators for the primary endpoints of (1) 2-year malaria incidence rate in the intention-to-treat population (pyronaridine–artesunate vs artemether– lume fantrine [1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio (RR) 1·05, 95% CI 0·94–1·17] and vs artesunate–amodiaquine [1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07]; dihydroartemisinin– piperaquine vs artemether–lumefantrine [1·16, 95% CI 1·01–1·34 vs 1·42, 1·25–1·62; RR 1·22, 95% CI 1·06–1·41] and vs artesunate–amodiaquine [1·35, 1·21–1·51 vs 1·68, 1·51–1·88; RR 1·25, 1·02–1·50]); and (2) adequate clinical and parasitological response in uncomplicated malaria across all episodes assessed in the per-protocol population on days 28 and 42 (for P falciparum malaria, PCR-adjusted adequate clinical and parasitological response was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs). These findings highlight that all four ACTs are robust in some of the highest pockets of malaria transmission globally and they exemplify the cumulative advantages of using drug combinations that include partner drugs with longer elimination half-lives, such as piperaquine (around 4 weeks in dihydroartemisinin–piperaquine) or pyronaridine (10–13 days in pyro naridine–artesunate). Indeed, the crude effects of dihydroartemisinin–piperaquine on the 2-year incidence of malaria compared with artemether–lumefantrine or artesunate–amodiaquine probably reflect the better long-term and cumulative effects of post-treatment prophylaxis with piperaquine Published Online March 29, 2018 http://dx.doi.org/10.1016/ S0140-6736(18)30630-5