Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty

Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models.Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT) for malaria was estimated, and a policy of multiple first-line therapies (MFTs) was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases.At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.Plasmodium falciparum, which causes malaria, is the most important parasite species that infects humans with approximately 2.37 billion people at risk [1,2]. Prompt effective drug treatment can reduce the risk of mortality for those with clinical infections, and is a key component of malaria elimination and eradication plans both past and present [3]. Diminished therapeutic efficacy due to the evolution of resistance to previous first-line drugs, however, contributed to the failure of initial eradication efforts and resulted in increases in infection and mortality [4]. Drug stewardship, combination therapies, and other policies h