Additional file 1: Table S1. of Health outcomes of bedaquiline in the treatment of multidrug-resistant tuberculosis in selected high burden countries

Summary of epidemiological data, economic profile, and MDR-TB interventions in high burden countries analyzed. (DOCX 64 kb

Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial

The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen.status: publishe

Cost-Effectiveness of Adding Bedaquiline to Drug Regimens for the Treatment of Multidrug-Resistant Tuberculosis in the UK

<div><p>Objective</p><p>To evaluate the cost-effectiveness of adding bedaquiline to a background regimen (BR) of drugs for multidrug-resistant tuberculosis (MDR-TB) in the United Kingdom (UK).</p><p>Methods</p><p>A cohort-based Markov model was developed to estimate the incremental cost-effectiveness ratio of bedaquiline plus BR (BBR) versus BR alone (BR) in the treatment of MDR-TB, over a 10-year time horizon. A National Health Service (NHS) and personal social services perspective was considered. Cost-effectiveness was evaluated in terms of Quality-Adjusted Life Years (QALYs) and Disability-Adjusted Life Years (DALYs). Data were sourced from a phase II, placebo-controlled trial, NHS reference costs, and the literature; the US list price of bedaquiline was used and converted to pounds (£18,800). Costs and effectiveness were discounted at a rate of 3.5% per annum. Probabilistic and deterministic sensitivity analysis was conducted.</p><p>Results</p><p>The total discounted cost per patient (pp) on BBR was £106,487, compared with £117,922 for BR. The total discounted QALYs pp were 5.16 for BBR and 4.01 for BR. The addition of bedaquiline to a BR resulted in a cost-saving of £11,434 and an additional 1.14 QALYs pp over a 10-year period, and is therefore considered to be the dominant (less costly and more effective) strategy over BR. BBR remained dominant in the majority of sensitivity analyses, with a 81% probability of being dominant versus BR in the probabilistic analysis.</p><p>Conclusions</p><p>In the UK, bedaquiline is likely to be cost-effective and cost-saving, compared with the current MDR-TB standard of care under a range of scenarios. Cost-savings over a 10-year period were realized from reductions in length of hospitalization, which offset the bedaquiline drug costs. The cost-benefit conclusions held after several sensitivity analyses, thus validating assumptions made, and suggesting that the results would hold even if the actual price of bedaquiline in the UK were higher than in the US.</p></div

Cost-effectiveness acceptability curve for bedaquiline + BR versus BR only from a UK payer perspective (assuming price of £18,800 per treatment course).

<p>BR: background regimen</p

Markov model state structure.

<p>MDR-TB: multi-drug resistant tuberculosis; TB: tuberculosis. *Transitions to the death state are possible from every state, but not shown on the diagram for clarity.</p

Total and per patient costs, split by category (UK base case).

<p>All costs reported in 2013 values</p><p>BR: background regimen; TB: tuberculosis</p><p>Total and per patient costs, split by category (UK base case).</p

Tornado diagram representing deterministic sensitivity analysis based on incremental cost per QALY.

<p>* Fixed ranges of +/- 20% were chosen due to the lack of available ranges in the literature. BR: background regimen; ICER: incremental cost-effectiveness ratio; QALY: quality adjusted life-year; TB: tuberculosis</p

Cost-effectiveness plane for bedaquiline + BR versus BR only from a UK NHS and PSS perspective.

<p>BR: background regimen; NHS: National Health Service; PSS: Personal Social Services; QALY: quality adjusted life-year</p