Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy.
Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
J Hepatol. 2022 Feb;76(2):464-469. doi: 10.1016/j.jhep.2021.10.012. Epub 2021 Oct 23.
The entry inhibitor bulevirtide (BLV) received conditional approval from the EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult-to-treat patients with HDV-related cirrhosis is presently unknown. Herein, we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to 3 years on a compassionate use program. Patients were also monitored for HBcrAg and HBV RNA levels, and HDV- and HBV-specific T-cell markers. In the patient who stopped BLV at week 48, after achieving a virological and biochemical response, the initial virological and biochemical rebound was followed by alanine aminotransferase normalization coupled with low HDV RNA and HBsAg levels. In the 2 patients treated continuously for 3 years, virological and biochemical responses were maintained throughout the treatment period even after dose reduction. In a patient with advanced compensated cirrhosis, liver function tests significantly improved, esophageal varices disappeared, and histological/laboratory features of autoimmune hepatitis resolved. Overall, no safety issues were recorded, as bile salt increase was asymptomatic. While serum HBV RNA levels remained undetectable in all patients, HBV core-related antigen levels showed a progressive, yet modest decline during long-term BLV treatment. No HDV-specific interferon-γ-producing T cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment. In conclusion, this report shows that continuous administration of BLV monotherapy for 3 years leads to excellent virological and clinical responses in patients with HDV-related cirrhosis who had contraindications to interferon-based therapies.
进入抑制剂布乐维肽（BLV）于 2020 年 7 月获得 EMA 的有条件批准，用于治疗代偿期慢性乙型肝炎 delta 成年患者。然而，目前尚不清楚在 HDV 相关肝硬化的难治性患者中，BLV 单药治疗超过 48 周的有效性和安全性。在此，我们描述了首例接受 BLV（起始剂量为 10mg/天）治疗长达 3 年的 HDV 相关代偿性肝硬化患者，这些患者接受了同情用药项目的治疗。还监测了患者的 HBcrAg 和 HBV RNA 水平，以及 HDV 和 HBV 特异性 T 细胞标志物。在第 48 周停止 BLV 治疗的患者中，在实现病毒学和生化学应答后，最初的病毒学和生化学反弹后，丙氨酸氨基转移酶恢复正常，同时伴有低水平的 HDV RNA 和 HBsAg。在连续治疗 3 年的 2 名患者中，即使在减少剂量后，整个治疗期间仍维持病毒学和生化学应答。在一名晚期代偿性肝硬化患者中，肝功能试验显著改善，食管静脉曲张消失，自身免疫性肝炎的组织学/实验室特征得到缓解。总的来说，没有记录到任何安全问题，因为胆汁盐增加是无症状的。虽然所有患者的血清 HBV RNA 水平均保持不可检测，但在长期 BLV 治疗期间，HBV 核心相关抗原水平呈进行性但适度下降。在 HDV 再激活（在患者 1 中停用 BLV 后）或 BLV 治疗 3 年期间，均未检测到 HDV 特异性干扰素-γ产生的 T 细胞。总之，本报告表明，在有干扰素治疗禁忌证的 HDV 相关肝硬化患者中，连续 3 年给予 BLV 单药治疗可导致极好的病毒学和临床应答。
