Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety

Abstract

Background World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP). Methods AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort. Results By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1–2) and 33.1% as serious (Grade 3–5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75–169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually. Conclusions Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Assessment of Adverse Drug Events, Their Risk Factors, and Management Among Patients Treated for Multidrug-Resistant TB: A Prospective Cohort Study From Pakistan

“…This study investigated the safety of bedaquiline; patients who were without a bedaquiline regime have a higher chance of adverse events (OR 3.54; 95% CI 1.23-10.1) than the other group. The results of this study are consistent with previous studies ( Gao et al, 2021 ; Mbuagbaw et al, 2019 ; Lan et al, 2020 ). This indicates that bedaquiline added to a background regimen can improve the rate of successful outcomes and quality of life.…”

Bedaquiline-based treatment for extensively drug-resistant tuberculosis in South Africa: A cost-effectiveness analysis

“…If a serious adverse event (SAE) of the anti-TB regimen occurred, the patient would receive inpatient management. The SAE in both arms was defined as a life-threatening event resulting in hospitalization, prolongation of hospitalization, (persistent or significant) disability, or death [9,13]. By the end of the 2-year period, the patient might achieve favourable outcomes.…”

“…The BDQ-based regimens are also reported to be better tolerated than conventional therapy. A large cohort analysis in China (n = 1162 received BDQ-based regimens) reported that 66.9% of the adverse events were classified as minor events (grade 1-2) [13]. QTprolongation was reported infrequently (0.4%) [12], and gradually declined after BDQ treatment was discontinued [14].…”

Efficacy of integrating short-course chemotherapy with Chinese herbs to treat multi-drug resistant pulmonary tuberculosis in China: a study protocol

“…Patients who meet all the following inclusion criteria will be considered for recruitment: (1) M.tb strain positive diagnosed with culture from sputum or bronchoalveolar lavage fluid as identified using a BACTEC MGIT 960 automated mycobacterial detection system (Becton, Dickinson and 6) No history of allergies to drugs involved in the trial. (7) Patients must agree to the treatment voluntarily and provide signed informed consent.…”

“…Long therapeutic schedule includes the third-generation fluoroquinolone and a second-line injectable combined with at least five anti-tuberculosis medications considered to be effective, based on drug susceptibility testing (DST), or at least four considered effective plus pyrazinamide (PZA or Z) [ 6 ]. Adverse events (AEs) are thought to be the most important clinical consideration in the longer regimen, such as elevated liver enzymes, gastrointestinal disorders, and ototoxicity [ 7 ]. More than half of MDR-PTB patients experience one or more AEs during treatment procession [ 8 , 9 ].…”