title: Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty.
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.
authors.affiliation: Emerging Pathogens Institute and Department of Biology, University of Florida, Gainesville, 32611, USA. davesmith@ufl.edu
authors.forename: David L
authors.initials: DL
authors.lastname: Smith
authors.forename: Eili Y
authors.initials: EY
authors.lastname: Klein
authors.forename: F Ellis
authors.initials: FE
authors.lastname: McKenzie
authors.forename: Ramanan
authors.initials: R
authors.lastname: Laxminarayan
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D004359:Drug Therapy, Combination; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology; D008954:Models, Biological; D010961:Plasmodium / Q000187:drug effects* / Q000235:genetics; D013269:Stochastic Processes; D013997:Time Factors; D035501:Uncertainty
chemical_list: D000962:Antimalarials; D037621:Artemisinins