Update on the in vivo tolerance and in vitro reduced susceptibility to the antimalarial lumefantrine

Coartem(®), the combination of artemether (an artemisinin derivative) and lumefantrine, has been adopted as the first-line treatment for uncomplicated malaria in many countries. The emergence of resistance to artemisinin derivatives has now been proven in South-East Asia, and there is concern that this may spread to other endemic areas. Strategies to contain and control the spread of artemisinin resistance have been proposed. On the other hand, not much attention has been given to lumefantrine. Indeed, for more than 7 years, reports have been emerging that the use of Coartem(®) is associated with rapid selection of lumefantrine-tolerant parasites. These parasites can survive in the presence of sub-therapeutic lumefantrine concentrations, and, interestingly, this in vivo phenotype is translated in vitro into reduced susceptibility to lumefantrine. As a result, such parasites could form the setting in which lumefantrine resistance would emerge. Thus, identifying genetic markers that reflect this phenotype (both in vitro and in vivo) could yield information on the mechanisms of lumefantrine resistance. More interestingly, lumefantrine tolerance is associated with an increase in chloroquine susceptibility, raising the possibility of re-introducing chloroquine. In this work, we have reviewed the current knowledge, and we present existing challenges and gaps with regard to the mechanisms of in vivo tolerance and in vitro reduced susceptibility to lumefantrine. The re-introduction of chloroquine in areas of high lumefantrine resistance is also discussed.