Modeling epidemics of multidrug-resistant M. tuberculosis of heterogenous fitness

Harvard University, Cambridge, Massachusetts, United States
Nature Medicine (Impact Factor: 28.05). 11/2004; 10(10):1117-21. DOI: 10.1038/nm1110
Source: PubMed

ABSTRACT Mathematical models have recently been used to predict the future burden of multidrug-resistant tuberculosis (MDRTB). These models suggest the threat of multidrug resistance to TB control will depend on the relative 'fitness' of MDR strains and imply that if the average fitness of MDR strains is considerably less than that of drug-sensitive strains, the emergence of resistance will not jeopardize the success of tuberculosis control efforts. Multidrug resistance in M. tuberculosis is conferred by the sequential acquisition of a number of different single-locus mutations that have been shown to have heterogeneous phenotypic effects. Here we model the impact of initial fitness estimates on the emergence of MDRTB assuming that the relative fitness of MDR strains is heterogeneous. We find that even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease.

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    • "It is well-known that the condition R 0 < 1 is necessary for disease eradication [26]. Here, the relative reproductive fitness function will be approximated by the basic reproductive number of infection (R 0 ) in the absence of treatment or the effective reproductive number (R) in the presence of treatment [9], [13]. "
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    ABSTRACT: Despite the availability of effective treatment, tuberculosis (TB) remains a major global cause of mortality. Multidrug-resistant tuberculosis (MDR-TB) is a form of TB that is resistant to at least two drugs used for the treatment of TB, and originally is developed when a case of drug-susceptible TB is improperly or incompletely treated. This work is concerned with a mathematical model to evaluate the effect of MDR-TB on TB epidemic and its control. The model assessing the transmission dynamics of both drug-sensitive and drug-resistant TB includes slow TB (cases that result from endogenous reactivation of susceptible and resistant latent infections). We identify the steady states of the model to analyse their stability. We establish threshold conditions for possible scenarios: elimination of sensitive and resistant strains and coexistence of both. We find that the effective reproductive number is composed of two critical values, relative reproductive number for drug-sensitive and drugresistant strains. Our results imply that the potential for the spreading of the drug-resistant strain should be evaluated within the context of several others factors. We have also found that even the considerably less fit drug-resistant strains can lead to a high MDR-TB incidence, because the treatment is less effective against them.
    Mathematical Biosciences and Engineering 08/2014; 11(4):971-993. DOI:10.3934/mbe.2014.11.971
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    • "To take into consideration the externalities associated with the treatment of infectious diseases and assess how disease spreads and resistance emerges under various drug deployment policies, we extend the simplest general disease model (SIS) [3] [18] that allows for treatment with more than one different drug to include the emergence and evolution of resistance to a drug (for a similar models see [12] [24]). "
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    ABSTRACT: The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context.
    Socio-Economic Planning Sciences 09/2013; 47(3):158–171. DOI:10.1016/j.seps.2013.04.001
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    • "Initially, it was believed that resistance was always associated with a fitness reduction (fitness cost). More recent models have allowed for the variation in the relative fitness of Mycobacterium tuberculosis (Mtb) [4] [5], as supported by experimental studies both in vitro or epidemiological studies [6]. In [5], it was argued that the long term epidemiological landscape would be shaped not only by the impact of the relative fitness in transmission by assuming a distinct transmission rate for sensitive and resistant strains (β s and β r ) but also by reinfection through the distinct contribute of mixed infections to transmission depending on within-host competition. "
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    ABSTRACT: A multi-scale model is proposed to study co-circulation of drug-resistant and -sensitive strains of Mycobacterium tuberculosis. At the population level, strain compe-tition depends first on strains ability to be transmitted among susceptible individuals, represented by the strain specific reproduction numbers, R 0s and R 0r . When reinfec-tion occurs a new level of competition can be considered. Hence, for mixed infections transmission depends on the competition outcome at the individual level. A between-host model is presented for which mixed infections transmission profile and infectious period are governed by a within-host model. The within-host model describes strain competition for a mixed infection during a disease episode with a fixed treatment schedule, depending on the relative fitness of strains, f . The linkage to the epidemiological model provides a comprehensive relation between pathogen-specific growth rates and general between-host transmission ability. Long-term behaviour of the epidemiological model is driven by both between and within-host traits.
    International Conference on Computational and Mathematical Methods in Science and Engineering, CMMSE 2012; 01/2012
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