Supplementary Material for: Cardiac Risk Factors in Drug-Resistant Tuberculosis Patients on Bedaquiline: A Retrospective Cohort Study

Background: Bedaquiline improves treatment outcomes in drug-resistant tuberculosis (DR-TB), but prolongs the QT interval; the cardiac safety must be thoroughly evaluated in clinical applications. Objective: To evaluate the cardiac safety and possible risk factors of Bedaquiline-containing regimen in patients with DR-TB. Methods: This retrospective cohort study assessed cardiac safety in 202 patients diagnosed with DR-TB and treated with a Bedaquiline-containing regimen between March 2019 and May 2024. Follow-up was conducted from 2nd to 24th weeks after treatment, including cardiovascular-related symptoms, electrocardiogram (ECG) testing, serum electrolyte testing, combined use of medicines, etc. Results: Among 202 participants, 40 (19.80%) patients experienced an absolute change from baseline (QTcF) ≥ 60ms (including 1 patient QTcF > 500ms), 4 patients discontinued Bedaquiline due to adverse events. QTcF prolongation peaked at the 20th week, and the average QTcF values at each monitoring time point showed significant differences compared to baseline. According to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1) (DAIDS AE Grading Table, v2.1), 139 (68.81%) had no adverse cardiac events, 18 (8.91%) experienced grade 1-2 events, 44 (21.78%) had grade 3 events, and 1 (0.5%) developed grade 4 events. No heart failure cases or deaths were reported. Over 1,022.7 person-months of follow-up, 45 patients experienced grade ≥ 3 cardiac events, corresponding to an incidence rate of 4.40 events per 100 person-months. Compared to regimens without clofazimine, the concomitant use of clofazimine was significantly associated with an increased risk of grade ≥ 3 cardiac adverse events (OR=3.66, 95% CI: 1.59-8.39, p=0.002). Patients who experienced hypokalemia (4 of 202; 1.98 %) during treatment showed 24-fold higher odds of grade ≥ 3adverse cardiac events compared to those without hypokalemia (OR=24.77, 95% CI:2.44-251.78, p=0.007). Conclusion: QT interval prolongation is common in patients with DR-TB treated with Bedaquiline-containing regimens, but the incidence of discontinuation is low. The concomitant use of Clofazimine and the occurrence of hypokalemia during treatment will increase the risk of adverse cardiac events. It is recommended routine electrolyte monitoring, aggressive potassium supplementation, and cautious co-prescription of clofazimine or other QT-prolonging drugs for DR-TB patients on bedaquiline.

背景：贝达喹啉（Bedaquiline）可改善耐多药结核病（drug-resistant tuberculosis, DR-TB）患者的治疗结局，但会延长QT间期，因此临床应用中需对其心脏安全性进行全面评估。
研究目的：评估含贝达喹啉治疗方案用于耐多药结核病患者的心脏安全性及其潜在危险因素。
研究方法：本回顾性队列研究纳入2019年3月至2024年5月期间确诊为耐多药结核病且接受含贝达喹啉治疗方案的202例患者，对其心脏安全性进行评估。于治疗后第2周至第24周开展随访，监测内容包括心血管相关症状、心电图（electrocardiogram, ECG）检查、血清电解质检测、合并用药情况等。
研究结果：202例受试者中，40例（19.80%）的QTcF较基线绝对值变化≥60ms（其中1例患者QTcF＞500ms），4例患者因不良事件停用贝达喹啉。QTcF延长在治疗第20周达到峰值，各监测时间点的平均QTcF值与基线相比均存在显著差异。依据美国艾滋病分部成人与儿科不良事件严重程度分级表（校正版2.1，DAIDS AE分级表v2.1），139例（68.81%）未发生心脏不良事件，18例（8.91%）出现1~2级不良事件，44例（21.78%）出现3级不良事件，1例（0.5%）出现4级不良事件。未报告心力衰竭病例或死亡病例。在累计1022.7人-月的随访期间，45例患者发生≥3级心脏不良事件，对应发生率为每100人-月4.40例事件。与不含氯法齐明（clofazimine）的治疗方案相比，合并使用氯法齐明与≥3级心脏不良事件风险升高显著相关（OR=3.66，95%CI：1.59~8.39，P=0.002）。治疗期间发生低钾血症（hypokalemia）的患者（4例，占比1.98%），其发生≥3级心脏不良事件的比值比为未发生低钾血症患者的24倍（OR=24.77，95%CI：2.44~251.78，P=0.007）。
研究结论：接受含贝达喹啉治疗方案的耐多药结核病患者中，QT间期延长较为常见，但治疗中断发生率较低。合并使用氯法齐明及治疗期间发生低钾血症均会升高心脏不良事件风险。建议对接受贝达喹啉治疗的耐多药结核病患者开展常规电解质监测、积极补钾，并谨慎联用氯法齐明或其他可延长QT间期的药物。