Abstract
BackgroundThe evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty.MethodsHere, 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.ResultsUsing 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.ConclusionsAt 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.
Highlights
The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs
Reducing parasite fitness To illustrate how multiple first-line therapies would reduce resistant parasite fitness, the reductions in drug pressure achieved using an Multiple first-line therapies (MFTs) policy was compared to a drug rationing policy
The expected waiting time to appearance was exactly twice as long when drug pressure was cut in half (Figure 5, top)
Summary
The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty. Combination therapies, and other policies have been advocated to slow the evolution of resistance to anti-malarial drugs, to be effective, a policy must delay emergence or at least slow the spread of resistant parasites. Multiple first-line therapies (MFTs) on the other hand, reduce pressure on each drug, defined as the proportion of clinical episodes that are treated, and slow spread while avoiding the ethical problem of leaving some patients untreated [7,8]
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