Optimal bedaquiline use strategy for different outcomes based on 5,000 simulation runs.

<p>The top half of the figure shows the results across all four potential bedaquiline use strategies. The bottom half shows results assuming bedaquiline is made available for at least some patients (i.e., no “none” strategy). The asterisk indicates that one simulation run resulted in this simulation being optimal. See tables for results on the magnitude of differences between strategies.</p

Life expectancy by DST method.

<p>Life expectancy by DST method.</p

Bedaquiline-associated parameter ranges.

<p>Bedaquiline-associated parameter ranges.</p

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

<div><p>Background</p><p>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.</p><p>Methods and Findings</p><p>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.</p><p>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.</p><p>Conclusions</p><p>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.</p></div

Optimal bedaquiline use strategy for different outcomes based on 5,000 simulation runs.

<p>The top half of the figure shows the results across all four potential bedaquiline use strategies. The bottom half shows results assuming bedaquiline is made available for at least some patients (i.e., no “none” strategy). The asterisk indicates that one simulation run resulted in this simulation being optimal. See tables for results on the magnitude of differences between strategies.</p

Percentage of the initial cohort acquiring different resistance patterns.

<p>Percentage of the initial cohort acquiring different resistance patterns.</p

Tornado plot displaying how the potential improvement in average life expectancy that would result from use of bedaquiline for all patients with MDR TB versus no patients depends on the values of particular parameters.

<p>The <i>y</i>-axis displays each bedaquiline-associated parameter as well as its high and low values.</p

Heat maps showing regions in which each bedaquiline use strategy would be preferred.

<p>The <i>x-</i> and <i>y</i>-axes show the explored rates of (relative) median time to culture conversion and added mortality associated with bedaquiline use. Remaining parameters are fixed at their values that least favor bedaquiline (left), their midpoints (middle), and their values that most favor bedaquiline (right). Colors indicate the optimal bedaquiline use strategy, and shading indicates the magnitude of difference in average life expectancy between the best and worst strategies, with the corner values listed on the figure (in years). The PreXDR+XDR strategy is never selected in the left subplot, and the XDR strategy is never selected in the left or center subplots.</p

Impact of different bedaquiline use strategies on the number and health outcomes of secondary TB cases.

<p>Impact of different bedaquiline use strategies on the number and health outcomes of secondary TB cases.</p

MDR-TB treatment as prevention: The projected population-level impact of expanded treatment for multidrug-resistant tuberculosis

<div><p>Background</p><p>In 2013, approximately 480,000 people developed active multidrug-resistant tuberculosis (MDR-TB), while only 97,000 started MDR-TB treatment. We sought to estimate the impact of improving access to MDR-TB diagnosis and treatment, under multiple diagnostic algorithm and treatment regimen scenarios, on ten-year projections of MDR-TB incidence and mortality.</p><p>Methods</p><p>We constructed a dynamic transmission model of an MDR-TB epidemic in an illustrative East/Southeast Asian setting. Using approximate Bayesian computation, we investigated a wide array of potential epidemic trajectories consistent with current notification data and known TB epidemiology.</p><p>Results</p><p>Despite an overall projected decline in TB incidence, data-consistent simulations suggested that MDR-TB incidence is likely to rise between 2015 and 2025 under continued 2013 treatment practices, although with considerable uncertainty (median 17% increase, 95% Uncertainty Range [UR] -38% to +137%). But if, by 2017, all identified active TB patients with previously-treated TB could be tested for drug susceptibility, and 85% of those with MDR-TB could initiate MDR-appropriate treatment, then MDR-TB incidence in 2025 could be reduced by 26% (95% UR 4–52%) relative to projections under continued current practice. Also expanding this drug-susceptibility testing and appropriate MDR-TB treatment to treatment-naïve as well as previously-treated TB cases, by 2020, could reduce MDR-TB incidence in 2025 by 29% (95% UR 6–55%) compared to continued current practice. If this diagnosis and treatment of all MDR-TB in known active TB cases by 2020 could be implemented via a novel second-line regimen with similar effectiveness and tolerability as current first-line therapy, a 54% (95% UR 20–74%) reduction in MDR-TB incidence compared to current-practice projections could be achieved by 2025.</p><p>Conclusions</p><p>Expansion of diagnosis and treatment of MDR-TB, even using current sub-optimal second-line regimens, is expected to significantly decrease MDR-TB incidence at the population level. Focusing MDR diagnostic efforts on previously-treated cases is an efficient first-step approach.</p></div