bedaquiline and Cardiovascular-Diseases

Bedaquiline and delamanid were recently approved for multidrug resistant tuberculosis (MDR-TB). Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the risks of QT prolongation and hepatotoxicity for bedaquiline and delamanid.. We retrospectively analyzed data of MDR-TB patients retrieved from the South Korea national health insurance system database (2014-2020) to assess the risks of all-cause death, long QT-related cardiac event, and acute liver injury associated with bedaquiline or delamanid, compared with conventional regimen. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Stabilized inverse probability of treatment weighting based on propensity score was used to balance characteristics between the treatment groups.. Of 1998 patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively. Compared with conventional regimen, bedaquiline and delamanid did not increase risk of all-cause death at 24-month (HR 0.73 [95% CI, 0.42-1.27] and 0.89 [0.50-1.60], respectively). Bedaquiline-containing regimen increased risk of acute liver injury (1.76 [1.31-2.36]), while delamanid-containing regimen increased risk of long QT-related cardiac events (2.38 [1.05-3.57]) within 6 months of treatment.. This study adds to the emerging evidence refuting the higher mortality rate observed in the bedaquiline trial population. Association between bedaquiline and acute liver injury needs careful interpretation considering for other background hepatotoxic anti-TB drugs. Our finding on delamanid and long QT-related cardiac events suggest careful risk-benefit assessment in patients with pre-existing cardiovascular disease.

Topics: Antitubercular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Bedaquiline was recently introduced into World Health Organization (WHO)-recommended regimens for treatment of drug resistant tuberculosis. There is limited data on the long-term safety of bedaquiline. Because bedaquiline prolongs the QT interval, there are concerns regarding cardiovascular safety. The Western Cape Province in South Africa has an established pharmacovigilance programme: a targeted spontaneous reporting system which solicits reports of suspected adverse drug reactions (ADRs) in patients with HIV-1 and/or tuberculosis infection. Since 2015, bedaquiline has been included in the treatment regimens recommended for resistant tuberculosis in South Africa. We describe ADRs in patients on bedaquiline-containing tuberculosis treatment that were reported to the Western Cape Pharmacovigilance programme.. We reviewed reports of suspected ADRs and deaths received between March 2015 and June 2016 involving patients receiving bedaquiline-containing tuberculosis treatment. A multidisciplinary panel assessed causality, and categorised suspected ADRs using World Health Organisation-Uppsala Monitoring Centre system categories. "Confirmed ADRs" included all ADRs categorised as definite, probable or possible. Preventability was assessed using Schumock and Thornton criteria. Where a confirmed ADR occurred in a patient who died, the panel categorised the extent to which the ADR contributed to the patient's death as follows: major contributor, contributor or non-contributor.. Thirty-five suspected ADRs were reported in 32 patients, including 13 deaths. There were 30 confirmed ADRs, of which 23 were classified as "possible" and seven as "probable". Bedaquiline was implicated in 22 confirmed ADRs in 22 patients. The most common confirmed ADR in patients receiving bedaquiline was QT prolongation (8 cases, 7 of which were severe). A fatal arrhythmia was suspected in 4 sudden deaths. These 4 patients were all taking bedaquiline together with other QT-prolonging drugs. There were 8 non-bedaquiline-associated ADRs, of which 7 contributed to deaths.. Confirmed ADRs in patients receiving bedaquiline reflect the known safety profile of bedaquiline. Quantifying the incidence and clinical consequences of severe QT-prolongation in patients receiving bedaquiline-containing regimens is a research priority to inform recommendations for patient monitoring in treatment programmes for drug resistant tuberculosis. Pharmacovigilance systems within tuberculosis treatment programmes should be supported and encouraged, to provide ongoing monitoring of treatment-limiting drug toxicity.

Topics: Adult; Antitubercular Agents; Cardiovascular Diseases; Diarylquinolines; Female; HIV Infections; Humans; Long QT Syndrome; Male; South Africa; Tuberculosis; Young Adult