Chen Qin, Hu Airong, Ma Aixia, Jiang Feng, Xiao Yue, Chen Yanfei, Huang Ruijian, Yang Tianchi, Zhou Jifang
Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.
School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2022 Apr 20;13:813682. doi: 10.3389/fphar.2022.813682. eCollection 2022.
Tuberculosis drug-induced liver injury (TB-DILI) is a common and potentially severe adverse drug reaction leading to treatment interruption and treatment failure. The real-world preventive effectiveness of hepatoprotective agents for DILI is not well described. The aim of the study was to evaluate the patterns of prophylactic therapies in real-world settings and risks of DILI among adult TB patients without known risk factors for DILI. This is a population-based retrospective cohort study of patients receiving first-line anti-tuberculosis drugs in the Chinese Center for Disease Control and Prevention (CDC) TB registry linked to the Ningbo Regional Health Care Database (NRHCD) between 2015 and 2020. The primary exposure was any use of chemopreventive agents including silymarin and/or glycyrrhetinic acid during the 30-day period prior to TB diagnosis (index date). The main outcome measure was the occurrence of newly onset DILI following TB treatment. Eligible patients were followed until the earliest of any DILI, treatment discontinuation, death, or end of the study period (30 June 2020). Marginal structural competing risk models and Cox models inverse probability treatment weights using high-dimensional propensity scores were used to estimate subdistribution hazard risks (SHR) and 95% confidence intervals (CIs) for DILI risks, with adjustment for age, sex, TB-related characteristics, and comorbidities. We identified a cohort of 6,743 adult patients with TB (mean age of 47.1 [SD 18.7] years; 65.80% male), of whom 2,886 (42.8%) patients received hepatoprotective agents. A total of 895 DILI events and 111 all-cause death events without DILI were observed over a median follow-up of 367 days post-TB diagnosis. The incidence rates of composite outcomes combining DILI and all-cause mortality were 248.9 and 222.3 per 1,000 person-years in the hepatoprotective agent exposed and unexposed groups (relative hazard ratio 1.35, 95% CI 1.11-1.64), respectively. The incidence rates of DILI were 223.7 and 196.1 per 1,000 person-years in the hepatoprotective agent exposed and unexposed groups (relative hazard ratio 1.38, 95% CI 1.12-1.71), respectively. Patients with any chemopreventive agent use had comparable liver function changes as evidenced by laboratory tests. A non-trivial number of adult patients received chemopreventive agents for TB-DILI. However, prophylactic utilization of hepatoprotective agents was not associated with a reduction in TB-DILI risks.
结核病药物性肝损伤（TB-DILI）是一种常见且可能严重的药物不良反应，可导致治疗中断和治疗失败。肝保护剂对药物性肝损伤的实际预防效果尚未得到充分描述。本研究的目的是评估在现实环境中成人结核病患者（无已知药物性肝损伤风险因素）的预防性治疗模式及药物性肝损伤风险。这是一项基于人群的回顾性队列研究，研究对象为2015年至2020年期间在中国疾病预防控制中心（CDC）结核病登记系统中登记并与宁波地区医疗保健数据库（NRHCD）相关联的接受一线抗结核药物治疗的患者。主要暴露因素为在结核病诊断前30天内（索引日期）使用任何化学预防剂，包括水飞蓟素和/或甘草次酸。主要结局指标为结核病治疗后新发药物性肝损伤的发生情况。符合条件的患者随访至最早出现任何药物性肝损伤、治疗中断、死亡或研究期结束（2020年6月30日）。使用边际结构竞争风险模型和基于高维倾向评分的Cox模型逆概率治疗权重来估计药物性肝损伤风险的亚分布风险比（SHR）和95%置信区间（CI），并对年龄、性别、结核病相关特征和合并症进行调整。我们确定了一个由6743名成年结核病患者组成的队列（平均年龄47.1岁[标准差18.7]；65.80%为男性），其中2886名（42.8%）患者接受了肝保护剂治疗。在结核病诊断后的中位随访367天期间，共观察到895例药物性肝损伤事件和111例无药物性肝损伤的全因死亡事件。在接受和未接受肝保护剂治疗的组中，药物性肝损伤和全因死亡率综合结局的发病率分别为每1000人年248.9例和222.3例（相对风险比1.35，95%CI 1.11 - 1.64）。在接受和未接受肝保护剂治疗的组中，药物性肝损伤的发病率分别为每1000人年223.7例和196.1例（相对风险比1.38，95%CI 1.12 - 1.71）。使用任何化学预防剂的患者肝功能变化在实验室检查中表现相当。相当数量的成年患者接受了用于预防结核病药物性肝损伤的化学预防剂。然而，预防性使用肝保护剂与降低结核病药物性肝损伤风险无关。
