Addressing bedaquiline treatment interruptions in the treatment of drug-resistant TB.

SETTING: The recommended dosing regimen for bedaquiline (BDQ), consisting of a 2-week loading phase (400 mg/day), followed by a maintenance phase (200 mg three times/week), might pose challenges when treatment is interrupted and needs to be reinitiated. Guidance on BDQ treatment re-initiation is, therefore, needed.OBJECTIVE: This pharmacokinetic-based simulation study aimed to provide recommendations for re-initiating BDQ following treatment interruptions.DESIGN: Simulations of treatment interruptions, defined as any time a patient misses ≥2 consecutive BDQ doses for up to 56 consecutive days (2 months), were assessed using the BDQ population-pharmacokinetic model.RESULTS: Any treatment interruption lasting ≤28 days prior to completing the 14-day loading phase can be managed by completing the remaining loading doses. Scenarios when it is sufficient to simply restart maintenance dosing are discussed. In some scenarios, treatment interruptions require reloading for 1 week prior to restarting maintenance dosing.CONCLUSIONS: This simulation study provided recommendations for managing BDQ treatment interruptions and underscores the importance of having a robust population-pharmacokinetic model for TB drugs to inform clinical guidance. Such recommendations are valuable to help ensure optimal treatment with BDQ for treating multidrug-resistant TB.

Bedaquiline for multidrug-resistant TB in paediatric patients.

BACKGROUND: TMC207-C211 (NCT02354014) is a Phase 2, open-label, multicentre, single-arm study to evaluate pharmacokinetics, safety/tolerability, antimycobacterial activity and dose selection of bedaquiline (BDQ) in children (birth to <18 years) with multidrug-resistant-TB (MDR-TB).METHODS: Patients received 24 weeks' BDQ with an anti-MDR-TB background regimen (BR), followed by 96 weeks of safety follow-up. Results of the primary analysis are presented based on data up to 24 weeks for Cohort 1 (≥12-<18 years; approved adult tablet at the adult dosage) and Cohort 2 (≥5-<12 years; age-appropriate 20 mg tablet at half the adult dosage).RESULTS: Both cohorts had 15 patients, of whom respectively 53% and 40% of Cohort 1 and Cohort 2 children had confirmed/probable pulmonary MDR-TB. Most patients completed 24 weeks´ BDQ/BR treatment (Cohort 1: 93%; Cohort 2: 67%). Geometric mean BDQ area under the curve 168h values of 119,000 ng.h/mL (Cohort 1) and 118,000 ng.h/mL (Cohort 2) at Week 12 were within 60-140% (86,200-201,000 ng.h/mL) of adult target values. Few adverse event (AE) related discontinuations or serious AEs, and no QTcF >460 ms during BDQ/BR treatment or deaths occurred. Of MGIT-evaluable patients, 6/8 (75%) Cohort 1 and 3/3 (100%) Cohort 2 culture converted.CONCLUSION: In children and adolescents aged ≥5-<18 years with MDR-TB, including pre-extensively drug-resistant-TB (pre-XDR-TB) or XDR-TB, 24 weeks of BDQ provided a comparable pharmacokinetic and safety profile to adults.

The Bedaquiline Donation Program: progress and lessons learned after 4 years of implementation.

The Bedaquiline Donation Program was a global public-private partnership between the US Agency for International Development (USAID) and Janssen Therapeutics. The 4-year program was intended to accelerate access to bedaquiline (BDQ) by committing 30 000 treatment courses to more than eligible 100 countries. The program was designed to remove barriers by making the drug available through the Global Drug Facility (GDF); prepare TB programs to a changing drug-resistant TB (DR-TB) treatment landscape; improve quality of the entire DR-TB care paradigm; gather additional effectiveness and safety data in programmatic settings; and identify programmatic challenges associated with new TB drug introduction. By the end of the program (in April 2019), 80 countries had ordered 104 344 BDQ courses, of which 33 119 had been delivered (the rest were pending delivery). The introduction of new TB drugs offers hope to patients and an opportunity to transform DR-TB treatment with shorter, simpler and more tolerable regimens. The Bedaquiline Donation Program demonstrated that access to new drugs can be accelerated. Technical support to improve the overall quality of care is critical as are investments beyond the cost of the drug.

Modeling the impact of bedaquiline treatment strategies on the multidrug-resistant tuberculosis burden in India.

SETTING: Bedaquiline (BDQ) has been approved in India for the treatment of multidrug-resistant tuberculosis (MDR-TB), but is currently recommended for MDR-TB patients who have failed initial treatment with standard regimens. While some have argued that such deferred BDQ use allows a second line of defense with a potent drug, this strategy may not be optimal. OBJECTIVE: To compare several distinct scenarios of BDQ access and use, and their potential impact on the MDR-TB disease burden and the associated net economic benefit in India. METHOD: We used a state-transition model to carry out this evaluation. The scenarios differed in the timing and breadth of BDQ access. RESULTS: The simulations showed that a strategy reliant on reserving the use of BDQ for those who have failed other MDR-TB regimens is likely to result in worse treatment outcomes for patients and in inferior public health outcomes for communities, leading to reduced net monetary benefit. CONCLUSION: Our study suggests that deferring patient access to new drugs such as BDQ until front-line regimens have failed, in order to 'save' these drugs for later use, could be detrimental to patients and to public health, and could reduce the economic benefit of treating MDR-TB.

Assessment of tuberculosis burden in China using a dynamic disease simulation model.

SETTING: Although a preventable and treatable disease, tuberculosis (TB) is among the top 10 causes of death worldwide. A consequence of inadequately treated drug-susceptible TB (DS-TB) is multidrug-resistant TB (MDR-TB). OBJECTIVES: To improve our understanding of the primary drivers of incidence and prevalence of DS- and MDR-TB in China. METHODS: The Tuberculosis Disease Transmission Model (TBDTM) uses historical and current disease epidemiology and transmission trends and treatment effectiveness, and accounts for annual changes to these to estimate future DS-TB and MDR-TB burden. RESULTS: The model shows that in China, by 2050, incidence, prevalence and mortality of DS-TB will decrease by 32%, 50% and 41%, respectively, whereas MDR-TB will increase by respectively 60%, 48% and 35%. Reduction in DS-TB is a result of high treatment and cure rates leading to a decrease in the prevalence of latent tuberculous infection (LTBI), while the increase in MDR-TB is attributed to inappropriate treatment, leading to high transmission of infection and increased LTBI prevalence. CONCLUSIONS: These results demonstrate a reduction in DS-TB in China over the next 40 years, while MDR-TB will increase. Improvements in the diagnosis and treatment of MDR-TB are needed to counter this threat. The TBDTM tool has potential value in public health practice by demonstrating the impact of interventions and estimating their cost-effectiveness.