Gametocytogenesis-enhancing drug combinations can facilitate artemisinin resistance despite better clinical outcomes

Abstract Background: Malaria eradication goals are threatened by the spread of artemisinin resistance, which is an evolutionary process. The selective advantage of mutations in Plasmodium falciparum conferring tolerance or even resistance is determined as the probability of their successful transmission. The drug’s efficacy in clearing merozoites is the main determinant for the clinical pathogenesis, but only one of many factors determining successful transmission. The actual steps in the transmission cycles contribute as “fitness components”. The abundance of gametocytes is crucial in mediating how the selective advantage at the merozoite level is translated into evolutionary fitness. In this context it is important to recognize that some drugs are associated with higher gametocytaemia. Method: A mechanistic model, which quantitatively describes how evolutionary fitness is determined by the parasite's life history in interaction with antimalarial drugs is formulated. The hypothetical effect of a gametocytogenesis-enhancing drug action on the evolutionary fitness is included. Once fitness is determined, an evolutionary-genetic model is used to describe the resulting trajectory of drug resistance evolution. Results: Assuming intuitive model parameters, the evolutionary fitness of two alternative drug treatments with the same effectiveness on asexual parasites, with and without a gametocytogenesis-enhancing effect are contrasted. The gametocytogenesis-enhancing effect leads to a substantially faster spread of drug resistance. This result changes quantitatively, but not qualitatively, if a threshold gametocytaemia is assumed for successful malaria transmission. Isolating infections in quarantine in order to prevent transmission, can substantially accelerate the dispersion of resistance if antimalarials delay gametocyte development. Conclusions: Gametocytogenesis-enhancing drug treatments can excel the spread of resistance. Initially it might appear that such a treatment leads to improved clinical outcomes, because drug resistance is difficult to detect on a population-level as long as resistance-conferring mutations have low prevalence. Hence, partnering artemisinin with drugs such as sulfadoxine-pyrimethamine of amodiaquine, which have been associated with higher gametocytaemia, might facilitate the spread of resistance.