Strategies for treating latent multiple-drug resistant tuberculosis: a decision analysis

Abstract

Background: The optimal treatment for latent multiple-drug resistant tuberculosis infection remains unclear. In anticipation of future clinical trials, we modeled the expected performance of six potential regimens for treatment of latent multiple-drug resistant tuberculosis.

Methods: A computerized Markov model to analyze the total cost of treatment for six different regimens: Pyrazinamide/ethambutol, moxifloxacin monotherapy, moxifloxacin/pyrazinamide, moxifloxacin/ethambutol, moxifloxacin/ethionamide, and moxifloxacin/PA-824. Efficacy estimates were extrapolated from mouse models and examined over a wide range of assumptions.

Results: In the base-case, moxifloxacin monotherapy was the lowest cost strategy, but moxifloxacin/ethambutol was cost-effective at an incremental cost-effectiveness ratio of $21,252 per quality-adjusted life-year. Both pyrazinamide-containing regimens were dominated due to their toxicity. A hypothetical regimen of low toxicity and even modest efficacy was cost-effective compared to "no treatment."

Conclusion: In our model, moxifloxacin/ethambutol was the preferred treatment strategy under a wide range of assumptions; pyrazinamide-containing regimens fared poorly because of high rates of toxicity. Although more data are needed on efficacy of treatments for latent MDR-TB infection, data on toxicity and treatment discontinuation, which are easier to obtain, could have a substantial impact on public health practice.

Figure 1. Schematic of decision tree.

A. Primary tree showing decision point between regimens and probability of a positive or negative test given presence or absence of infection. B. Positive test subtree. Individuals begin “on treatment” then move to “off treatment” due to toxicity, non-adherence, or treatment completion. Patients in “off treatment” can develop active disease and move to “TB treatment;” after treatment for active disease, they move to “prior TB.” Age-related mortality and death from TB or toxicity is also included. The negative test subtree is similar to the positive test subtree without the “on treatment” branch. Abbreviations: MZ = moxifloxacin+pyrazinamide, ZEmb = pyrazinamide+ethambutol, MEth = Moxifloxacin+ethionamide, MP = moxifloxacin+PA-824, M = moxifloxacin monotherapy.

Figure 2. Cost-effectiveness plot for six regimens plus the “no treatment” strategy.

Superior regimens are lower in cost (toward the left) and greater in efficacy (toward the top). Incremental cost-effectiveness ratios (ICERs) are shown for the two most effective regimens referenced to the strategy of “no treatment.” Abbreviations: MZ = moxifloxacin/pyrazinamide, ZEmb = pyrazinamide/ethambutol, MEth = moxifloxacin/ethionamide, MP = moxifloxacin/PA-824, M = moxifloxacin monotherapy. ICER = incremental cost-effectiveness ratio in dollars per quality-adjusted life-year.

Figure 3. Strategy graph of efficacy vs. toxicity.

Solid lines indicate thresholds (“isoclines”) for indifference given monthly drug costs of $129 (pyrazinamide/ethambutol), $181 (moxifloxacin/ethambutol), and $404 (moxifloxacin/ethionamide) per month. Shaded area indicates combinations of toxicity and efficacy for which drug treatment is cost-effective compared to the “no treatment” strategy beneath each of these isoclines. Dotted lines indicate the base-case estimates for efficacy and toxicity of moxifloxacin/ethambutol.