The role of gametocytogenesis in the spread of resistance to artemisinin-based combination therapies

OBJECTIVE: In response, to spreading resistance-associated mutations in Plasmodium falciparum, several malaria-endemic countries are evaluating the introduction of triple artemisinin combination therapies (TACTs), and alternative first-line ACTs alongside or in place of existing regimens such as artemether-lumefantrine (AL). Such combinations were associated with higher post treatment gametocyte count and prevalence compared with AL. We aim to mechanistically explain the effects of using ACTs associated with higher gametocytemia and the spread of drug resistance. METHODS: We developed a deterministic model that describes the effects of drugs on idealized dynamics of asexual parasites (merozoites) and early- and late-stage gametocytes. The model incorporates differential drug activity against partially resistant and sensitive merozoites, as well as against early- and late-stage gametocytes. Model inputs are parameters describing the metabolic costs, delayed clearance associated with resistance mutations, and the onset of treatment timing. The model output is the evolutionary fitness, defined as the area under the curve (AUC) of late-stage gametocytes, of resistant and sensitive parasites. These fitness measures are combined with a population-genetic model tailored to the spread of antimalarial resistance to illustrate how differences in gametocyte dynamics influence resistance spread. RESULTS: We compared the evolutionary fitness of three drug regimens with equivalent efficacy against asexual parasites, but varying gametocytocidal activity: (i) no effect, (ii) activity against early-stage gametocytes only, and (iii) activity against both early- and late-stage gametocytes. Early-stage gametocytocidal activity substantially decelerated resistance spread. Late-stage gametocytocidal activity was effective only if sustained beyond asexual parasite clearance. CONCLUSIONS: As our model is mechanistic, these results should be interpreted qualitatively rather than qualitatively. Nevertheless. Our findings highlight that drug-induced gametocyte dynamics play a central role in shaping the evolutionary fitness of resistant parasites. In particular, treatment strategies associated with higher post-treatment gametocyte prevalence may increase the transmission advantage of resistant parasites. These results highlight the importance of considering gametocyte dynamics when evaluating strategies to limit the spread of antimalarial resistance, and suggest that interventions targeting gametocytes, such as 8-aminoquinolines, may help mitigate this effect.