At a global scale, because of uncertainty about the time to the emergence of artemisinin combination therapy (ACT) resistance, there was a strong case for multiple first-line therapies (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.
Malaria is a widespread parasitic disease that affects humans, with approximately 2.37 billion people at risk. New strategies are needed to delay the emergence of anti-malarial drug resistance, a phenomenon that will negatively impact eradication efforts and lead to greater mortality worldwide.
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords
ACTs,
drug resistance,
MFTs,
multiple first-line therapies
