A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa. C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001). Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.

P. vivax is supposed to be involved in benign tertian fever, responsible for a non-complicated disease that could be easily treated by standard antimalarial drug regimen. This could be considered as a long-standing paradigm of a non-virulent malaria parasite. When a patient exhibits severe malaria with the vivax parasite, the issue is often to find falciparum. However, with the implementation of molecular diagnosis, it has becoming more evident that vivax parasites could be involved in severe disease with probably a different pathogenesis. Mixed infections are frequent in various parts of Southeast Asian endemic areas and it was speculated that drugs used to treat falciparum could be involved in the development of vivax drug resistance. How should primaquine be used today for the treatment and prophylaxis of vivax malaria? Considering the re-emergence of vivax malaria in several areas, improving the treatment for this disease is certainly an important issue to avoid late episodes and transmission potential.