Abstract
BackgroundWorld 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).MethodsAEs 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.ResultsBy 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.ConclusionsBedaquiline 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.
Highlights
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
Protocol training and data management According to the New Drug Introduction and Protection Program (NDIP) protocol, medical professionals of selected TB specialized hospitals capable of Multidrug-resistant tuberculosis (MDR-TB) diagnosis and treatment were well trained for patient enrolment, bedaquiline-containing regimen design, drug administration, treatment outcome and safety monitoring and evaluation
Background regimens consisted of the anti-TB drug formulations guided by drug susceptibility testing (DST), including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem and amoxicillin/clavulanate
Summary
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 multi‐ drug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP). The most frequently used background drugs included linezolid (n = 1030, 88.6%), cycloserine (n = 962, 82.8%), clofazimine (n = 694, 59.7%), protionamide (n = 592, 50.9%), amikacin (n = 482, 41.5%), moxifloxacin (n = 467, 40.2%), para-aminosalicylic acid (n = 399, 34.3%), and pyrazinamide (n = 293, 25.2%) (Table 2). Grades of the 1563 AEs are categorized in Additional files 1 as well
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