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Monday, 27 March 2017 07:25

Paper 2017_03

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Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline:A Model-Based Analysis

Amber Kunkel, Frank G. Cobelens, Ted Cohen




New drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients' resistance patterns.



We created a Markov decision model to follow a hypothetical cohort of multidrug-resistant (MDR) TB patients under different bedaquiline use strategies. The explored strategies included making bedaquiline available to all patients with MDR TB, restricting bedaquiline usage to patients with MDR plus additional resistance and withholding bedaquiline introduction completely. We compared these strategies according to life expectancy, risks of acquired resistance, and the expected number and health outcomes of secondary cases. For our simulated cohort, the mean (2.5th, 97.5th percentile) life expectancy from time of initiation of MDR TB treatment at age 30 was 36.0 y (33.5, 38.7) assuming all patients with MDR TB received bedaquiline, 35.1 y (34.4, 35.8) assuming patients with pre-extensively drug-resistant (PreXDR) and extensively drug-resistant (XDR) TB received bedaquiline, and 34.9 y (34.6, 35.2) assuming only patients with XDR TB received bedaquiline. Although providing bedaquiline to all MDR patients resulted in the highest life expectancy for our initial cohort averaged across all parameter sets, for parameter sets in which bedaquiline conferred high risks of added mortality and only small reductions in median time to culture conversion, the optimal strategy would be to withhold use even from patients with the most extensive resistance. Across all parameter sets, the most liberal bedaquiline use strategies consistently increased the risk of bedaquiline resistance but decreased the risk of resistance to other MDR drugs. In almost all cases, more liberal bedaquiline use strategies reduced the expected number of secondary cases and resulting life years lost. The generalizability of our results is limited by the lack of available data about drug effects among individuals with HIV co-infection, drug interactions, and other sources of heterogeneity, as well as changing recommendations for MDR TB treatment.



If mortality benefits can be empirically verified, our results provide support for expanding bedaquiline access to all patients with MDR TB. Such expansion could improve patients' health, protect background MDR TB drugs, and decrease transmission, but would likely result in greater resistance to bedaquiline.



Comment from Frank van Leth:

The paper describes the results of a mathematical model assessing the effect of different strategies for bedaquiline use on life expectancy, transmission, and acquired resistance.

The rational foer the study is the reported mortality increase with bedaquiline use in the phase IIb study. Despite this observation, the drug was approved for use based on these results in a rather restrictive patient group (those without other treatment options).

The authors model the effect for adding bedaquiline to all patients with MDR, those with pre-XDR or XDR, or only those with XDR.

The authors conclude that a more liberal use of the drug in all patients with MDR is warranted if the unexplained mortality finding in the phase IIb trail can be refuted.


The study lacks real-life data and is subjective to input parameters, as with every modeling study. Despite this major drawback, studies like this identify research priorities and areas of uncertainty. It is up to us to react to these challenges




Read 2799 times Last modified on Wednesday, 12 July 2017 17:46