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.


Knight, GM; Colijn, C; Shrestha, S; Fofana, M; Cobelens, F; White, RG; Dowdy, DW; Cohen, T; (2015) 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. Clinical infectious diseases , 61 (suppl 3). S147-S154. ISSN 1058-4838 DOI: 10.1093/cid/civ579

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Abstract

 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.  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.  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.  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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Research Centre: Antimicrobial Resistance Centre (AMR)
PubMed ID: 26409276
Web of Science ID: 362952900007
URI: http://researchonline.lshtm.ac.uk/id/eprint/2312482

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