title: The Distribution of Fitness Costs of Resistance-Conferring Mutations Is a Key Determinant for the Future Burden of Drug-Resistant Tuberculosis: A Model-Based Analysis.
abstract: BACKGROUND
  Drug resistance poses a serious challenge for the control of tuberculosis in many settings. It is well established that the expected future trend in resistance depends on the reproductive fitness of drug-resistant Mycobacterium tuberculosis. However, the variability in fitness between strains with different resistance-conferring mutations has been largely ignored when making these predictions.
  
  
  METHODS
  We developed a novel approach for incorporating the variable fitness costs of drug resistance-conferring mutations and for tracking this distribution of fitness costs over time within a transmission model. We used this approach to describe the effects of realistic fitness cost distributions on the future prevalence of drug-resistant tuberculosis.
  
  
  RESULTS
  The shape of the distribution of fitness costs was a strong predictor of the long-term prevalence of resistance. While, as expected, lower average fitness costs of drug resistance-conferring mutations were associated with more severe epidemics of drug-resistant tuberculosis, fitness distributions with greater variance also led to higher levels of drug resistance. For example, compared to simulations in which the fitness cost of resistance was fixed, introducing a realistic amount of variance resulted in a 40% increase in prevalence of drug-resistant tuberculosis after 20 years.
  
  
  CONCLUSIONS
  The differences in the fitness costs associated with drug resistance-conferring mutations are a key determinant of the future burden of drug-resistant tuberculosis. Future studies that can better establish the range of fitness costs associated with drug resistance-conferring mutations will improve projections and thus facilitate better public health planning efforts.
authors.affiliation: Tuberculosis Modelling Group, Centre for the Mathematical Modelling of Infectious Diseases, Tuberculosis Centre, Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine.
authors.forename: Gwenan M
authors.initials: GM
authors.lastname: Knight
authors.affiliation: Department of Mathematics, Imperial College London, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Colijn
authors.affiliation: Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland.
authors.forename: Sourya
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland.
authors.forename: Mariam
authors.initials: M
authors.lastname: Fofana
authors.affiliation: Amsterdam Institute for Global Health and Development, Academic Medical Center KNCV Tuberculosis Foundation, The Hague, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Cobelens
authors.affiliation: Tuberculosis Modelling Group, Centre for the Mathematical Modelling of Infectious Diseases, Tuberculosis Centre, Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine.
authors.forename: Richard G
authors.initials: RG
authors.lastname: White
authors.affiliation: Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland.
authors.forename: David W
authors.initials: DW
authors.lastname: Dowdy
authors.affiliation: Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, Connecticut.
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D056084:Genetic Fitness; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D015995:Prevalence; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology* / Q000382:microbiology; D014481:United States
chemical_list: D000995:Antitubercular Agents
keywords: antibiotic resistance; fitness costs; mathematical modeling; tuberculosis