Health outcomes of bedaquiline in the treatment of multidrug-resistant tuberculosis in selected high burden countries

Management of MDR-TB is costly to national TB programs. In 122 mostly low- and middle-income countries, accounting for 95% of the global TB burden including MDR-TB, total spending for TB prevention, diagnosis, and treatment increased from US$3.3 billion in 2006 to US$6.3 billion in 2014 (US$3.8 billion for drug-susceptible TB and US$1.8 billion for MDR-TB); the estimated required funding for 2015 is US$8 billion [2]. Costs of managing patients who develop XDR-TB are even higher, as hospital stays and drug costs greatly increase [31]. Our study shows that the addition of bedaquiline to a BR decreased the DALY burden compared with BR alone. This study demonstrated that addition of bedaquiline to a BR reduced cases of acquired resistance. The current model did not account for potential increases in the number of people being treated due to improvements in diagnostic modalities such as molecular diagnostic platforms like the Xpert ® MTB/Rif and line probe assays (which can detect drug resistance within 2 days) that have been introduced in the field of MDR-TB [3]. Faster and more successful treatment of primary cases could reduce secondary transmission and decrease the number of new cases of MDR-TB.

The mortality imbalance observed in the C208 trial was unexplained. Subsequent analysis by an independent investigator determined that there was no causal relationship with bedaquiline and a missing = failure analysis used within the study accounted for these deaths, considering them as treatment ‘failures’[12]. In addition, recent data published based on early access (compassionate use) of bedaquiline, suggests a lower mortality rate than has been observed in clinical trials. In a retrospective cohort study of 35 patients treated with bedaquiline in France, only one patient died (3%), and the death was considered unrelated to TB or TB treatment by the investigator [42]. Similarly, an interim analysis of 91 patients treated with bedaquiline in South Africa reported 3 deaths (3.3%), none of which were considered related to bedaquiline by the investigator [43]. Therefore, although mortality was included in the model, no mortality difference was assumed between bedaquiline and BR treatment arms. Although the increased mortality observed in the bedaquiline arm of study C208 is not believed to be related to bedaquiline [12, 42, 43], we nonetheless conducted a scenario analysis to test how the inclusion of the death would influence the change in DALY. Results show that if the mortality rates from study C208 are separately accounted for in the analysis (instead of lumping the deaths with all those failing treatment, as was done in the original analysis), the number of DALY per patient is likely to increase as a result of the use of bedaquiline (Additional file 3: Table S3). The likely impact of sputum culture conversion in reducing infectiousness of patients with TB and the potential to reduce secondary MDR-TB cases is not accounted for. When transmission rates were included in sensitivity analyses, bedaquiline was associated with additional healthcare cost savings associated with the reduced number of cases (data not shown).

Increases in outpatient care costs observed with the addition of bedaquiline reflected increases in monitoring costs associated with the implementation of any new treatment. Addition of bedaquiline to a BR has been shown to result in faster and higher culture conversion rates compared with BR alone [13], an outcome that is likely to result in decreased need for hospitalization. MDR-TB guidelines in resource-rich settings typically require that patients be hospitalized during treatment [32, 40]; however, the rate of hospitalization in low-to-middle income countries tends to be low [8] and there is a push in such settings to drive community-based treatment [33]. In low-to-middle income countries where the majority of MDR-TB patients are managed in community-based settings, the price at which it is cost-effective to add bedaquiline to a BR may be very low, and may be lower than the price thresholds suggested in this analysis.

The current study expands on the results of a prior study conducted on behalf of the WHO, by using a comprehensive Markov state transition model over a longer time horizon (10 years, compared with 20 months in the WHO analysis), and incorporating more detailed transitions and events such as patient-level data to inform the state transitions, as well as covering additional countries [7]. The WHO analysis estimated that bedaquiline was likely to be cost-effective and cost-saving in Peru, Russia, Estonia, the Philippines, and China, where treatment and management costs are moderate to high. In low-income countries with low drug costs and hospitalization, such as Nepal, addition of bedaquiline to the treatment regimen was likely to not be cost-effective [7], whereas in lower middle-income settings in the current study (the Philippines and India), there was a 32%94% probability that bedaquiline would be cost-effective (in terms of cost per DALY). In high-income settings, such as the UK, previous studies have shown the addition of bedaquiline to BR to be cost-effective, when measuring cost-utilities such as QALYs gained, and DALYs avoided [9].

The price threshold analysis shown in this study suggests that prices higher than the price of bedaquiline in a high income setting, such as the United States, would meet WHO criteria for cost-effectiveness in several of the countries analyzed. While these prices may be cost-effective, many would raise the question as to whether or not such prices are affordable; in Table 4, the cost offsets (mostly attributable to savings from reduced hospitalization) show that in Estonia and Russia, approximately US$30,000 per patient will be saved with the use of bedaquiline; in South Africa, Peru, and China, between US$4,201-US$7,337 per patient; and the Philippines and India, between US$70-US$1,528. Prices that capture at least the cost-offsets are not only cost-effective, but arguably, affordable as long as they result in no net change in health care spending. While cost-effectiveness is an important measure to consider when evaluating new health interventions, budget impact and value for innovation for the first new treatment for tuberculosis in 40 years must also be taken into consideration.

The key strengths of the current study include its comprehensive health state structure, the use of patient-level data to inform state transitions, and the extent to which the model captures WHO guidance on treatment strategies for MDR-TB.

A limitation of the current analysis was that the clinical data were based on the multinational Phase II study for bedaquiline [13] and thus may not reflect local variations in treatment success rates. The study also used UK specific life tables to calculate DALYs as country specific life table data were difficult to source. If the UK life tables are not reflective of the country specific life tables, this could lead to over/underestimation of the DALY burden in each country setting. Other limitations of this study include the fact that possible increases in mortality due to treatment with bedaquiline have been excluded, as well as a lack of empirical data on the price of bedaquiline in the evaluated countries at the time of the analysis.

Treatment with bedaquiline plus BR is expected to improve health outcomes through reduced DALY burden compared with BR alone. Addition of bedaquiline to BR resulted in total healthcare cost offsets (excluding treatment acquisition costs). At prices required to satisfy the WHO CE threshold, the probability that bedaquiline would be cost-effective was 32%–94% in the high burden countries analyzed.