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Modeling the emergence of the 'hot zones': tuberculosis and the amplification dynamics of drug resistance

Nature Medicine volume 10, pages 1111–1116 (2004)Cite this article

Abstract

'Hot zones' are areas that have >5% prevalence (or incidence) of multidrug-resistant tuberculosis (MDRTB). We present a new mathematical model (the amplifier model) that tracks the emergence and evolution of multiple (pre-MDR, MDR and post-MDR) strains of drug-resistant Mycobacterium tuberculosis. We reconstruct possible evolutionary trajectories that generated hot zones over the past three decades, and identify the key causal factors. Results are consistent with recently reported World Health Organization (WHO) data. Our analyses yield three important insights. First, paradoxically we found that areas with programs that successfully reduced wild-type pansensitive strains often evolved into hot zones. Second, some hot zones emerged even when MDR strains were substantially less fit (and thus less transmissible) than wild-type pansensitive strains. Third, levels of MDR are driven by case-finding rates, cure rates and amplification probabilities. To effectively control MDRTB in the hot zones, it is essential that the WHO specify a goal for minimizing the amplification probability.

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Figure 1: Reconstructed evolutionary trajectories.
Figure 2: Comparison of theoretical and empirical (WHO) data.
Figure 3: Evolutionary relationships and predictions.
Figure 4: Results of multivariate sensitivity analysis.

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Acknowledgements

The authors gratefully acknowledge L. Ma for coding and assistance with numerical analyses, R. Smith for technical discussions and E. Bodine for editorial assistance. S.M.B. acknowledges financial support from NIAID/NIH (R01 AI041935). T.C. acknowledges financial support from the National Science Foundation through grant DMS-0206733. S.M.B. is extremely grateful to P. Farmer and to J. Kim for many discussions, over many years, of the transmission dynamics of MDRTB.

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  1. Department of Biomathematics and UCLA AIDS Institute, David Geffen School of Medicine at the University of California, 1100 Glendon Avenue, Penthouse 2, Westwood, Los Angeles, 90024, California, USA

    Sally M Blower & Tom Chou

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Correspondence to Sally M Blower.

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Blower, S., Chou, T. Modeling the emergence of the 'hot zones': tuberculosis and the amplification dynamics of drug resistance. Nat Med 10, 1111–1116 (2004). https://doi.org/10.1038/nm1102

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