长期使用 Bulevirtide 治疗慢性丁型肝炎患者的疗效——“真实

StephenW

长期使用 Bulevirtide 治疗慢性丁型肝炎患者的疗效——“真实世界”研究的结果

AASLD 2021 十一月 12-15

Teresa Binter1, Mathias Jachs2, Lukas Hartl2, Stephan
Aberle3、Heinz Zoller4、5、Elmar Aigner6、Albert Friedrich Stättermayer7、Karin Kozbial7、Petra E. Steindl-Munda8、David Bauer7、Heidemarie Holzmann9、Michael H. Trauner7、Matthias Mandorfer10、Thomas Reiberger7 和 Peter Ferenci7、

(1)维也纳医科大学内科III消化内科和肝病学科，(2)科
消化内科和肝病学系，内科 III，维也纳医科大学，维也纳，奥地利，(3) 维也纳医科大学病毒学中心，奥地利，(4) 内科 I，因斯布鲁克医科大学，奥地利因斯布鲁克, (5)Mediac, (6) 萨尔茨堡帕拉塞尔苏斯医科大学第一医学系, (7) 维也纳医科大学内科III 消化内科和肝病学系, (8) 消化内科III 内科学系和肝病学，维也纳医科大学，（9）维也纳医科大学病毒学中心，（10）维也纳大学医院内科三

抽象的

背景：Bulevirtide (BLV) 通过钠/胆汁酸协同转运蛋白阻断丁型肝炎病毒 (HDV) 进入肝细胞。 BLV 获得了 EMA 的有条件批准，但 BLV 疗效的真实数据有限。

方法：MyrPharma（莱比锡/德国）在 2020 年 8 月之前通过同情使用计划提供 BLV，此后通过奥地利健康保险开具处方。 HDV-RNA 通过 PCR 测定（根据 le Gal 等人，J.Clin Microbiol 2005；LLQ：100 拷贝/mL）。 BLV 剂量和治疗持续时间由研究者决定。计划在 HDV-RNA 检测不到 6 个月后终止治疗。

结13 名患者是 PEGIFN 无反应者，2 名是最近确诊的患者。在 BLV 单药治疗期间，13/14 的 HDV-RNA 至少下降了 1-log，其中 3 例的 HDV-RNA 检测不到，1 例的 LLQ 下降（图）。 2 名 HDV-RNA 检测不到的患者按计划终止 BLV 治疗 >6 个月。一名非肝硬化患者接受 BLV 10mg/d 持续 108 周，在接下来的 36 周内分别减至 5mg/d 和 2mg/d。从第 96 周开始，HDV-RNA 在治疗后 20 周一直检测不到。另一名患者（代偿性肝硬化）接受 2mg/d BLV 治疗 63 周，6 个月内检测不到 HDV-RNA，但 4 周后检测到 HDV-RNA。两名患者分别在 8 周和 24 周后因不依从而退出。 11 名患者仍在接受治疗（治疗 24 至 140 周）。值得注意的是，在 BLV 上 HDV-RNA 下降 <1log 的患者（箭头）（从 2mg/d 开始并增加到 10mg/d 共 54 周），添加 PEG-干扰素-α2a（PEGIFN，90μg/周）导致 HDV-RNA 迅速下降（总治疗 93 周）。在另一名患者中，PEGIFN 的 HDV-RNA 下降了 3-log，并且在添加 BLV 后，患者变为 HDV-RNA 阴性（图中未显示）。两个变为阴性（分别在第 90 周和第 128 周），一个在第 30 周的 LLQ，一个下降 > 4-log（目前是第 40 周）。一个 >3-log 下降（第 30 周），4 个最大下降 1-log（第 40、30、32 和 24 周）。 11 名 (84.6%) 患者的 ALT 水平恢复正常。在 BLV 治疗期间，HBsAg 变化水平没有变化，胆汁酸水平增加而没有瘙痒。

结论：BLV 可有效降低 HDV-RNA 和 ALT。实现持续抑制 HDV 的最佳治疗持续时间尚未确定，但可能会超过一年。治疗耐受性良好。数据清楚地表明，在治疗患有 BLV 的慢性丁型肝炎患者时需要采取个体化的方法。

StephenW

EFFICACY OF LONG-TERM TREATMENT OF CHRONIC HEPATITIS D PATIENTS WITH BULEVIRTIDE – RESULTS OF A “REAL WORLD” STUDY

AASLD 2021 Nov 12-15

Teresa Binter1, Mathias Jachs2, Lukas Hartl2, Stephan
Aberle3, Heinz Zoller4,5, Elmar Aigner6, Albert Friedrich Stättermayer7, Karin Kozbial7, Petra E. Steindl-Munda8, David Bauer7, Heidemarie Holzmann9, Michael H. Trauner7, Matthias Mandorfer10, Thomas Reiberger7 and Peter Ferenci7,

(1)Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, (2)Division
of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, (3)        Center of Virology, Medical University of Vienna, Austria, (4) Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria, (5)Mediac, (6)First Department of Medicine, Paracelsus Medical University Salzburg, (7) Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, (8) Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, (9)Center for Virology, Medical University of Vienna, (10)Department of Internal Medicine III, University Hospital Vienna

abstract

Background: Bulevirtide (BLV) blocks the uptake of the hepatitis D Virus (HDV) into hepatocytes via sodium/bile acid cotransporter. BLV was conditionally approved by EMA but real-life data on BLV efficacy are limited.

Methods: MyrPharma (Leipzig/Germany) provided BLV in a compassionate use program until 8/2020, and thereafter prescribed through the Austrian health insurance. HDV-RNA was determined by PCR (according le Gal et.al,J.Clin Microbiol 2005; LLQ:100 copies/mL). BLV dose and treatment duration was at the discretion of the investigator. It is planned to terminate treatment after HDV-RNA being undetectable for 6 months.

Results: 15 patients (m/f:6/9; mean age: 50.2 years; 9 [60%] compensated cirrhosis) received BLV (2mg/d in 12; 10 mg/d in 2), 14 as initial monotherapy. 13 patients were PEGIFN nonresponders, 2 were recently diagnosed patients. During BLV monotherapy, 13/14 had at least a 1-log HDV-RNA decline, including 3 with undetectable HDV-RNA and 1 with a decrease to LLQ (figure). BLV treatment was terminated as planned in 2 patients with undetectable HDV-RNA for >6 months. One non-cirrhotic patient received BLV 10mg/d for 108 weeks, tapered to 5mg/d and 2mg/d, respectively, over the next 36 weeks. From week 96 on, HDV-RNA was and remained undetectable 20 weeks after therapy. One other patient (compensated cirrhosis) received 2mg/d BLV for 63 weeks, HDV-RNA was undetectable for 6 months, but HDV-RNA became detectable after 4 weeks. Two patients dropped out due to noncompliance after 8 and 24 weeks, respectively. Eleven patients are still on treatment (24 to 140 weeks of therapy). Of note, in a patient (arrow) with <1log decline of HDV-RNA on BLV (starting with 2mg/d and increased to 10mg/d for a total of 54 weeks), adding PEG-Interferon-alfa2a (PEGIFN, 90µg/week) lead to a rapid decline of HDV-RNA (total treatment 93 weeks). In a further patient, HDV-RNA had declined on PEGIFN by 3-log and after addition of BLV, the patient became HDV-RNA negative (not shown in figure). Two became negative (at weeks 90 and 128, respectively), one at LLQ at week 30, one had a >4-log decline (currently week 40). one a >3-log decline (week 30), 4 had a maximum decline of 1-log (week 40, 30, 32 and 24). ALT levels normalized in 11 (84.6%) patients. During BLV therapy HBsAg changes levels did not change and bile acid levels increased without pruritus.

Conclusion: BLV is effective in decreasing HDV-RNA and ALT. Optimal treatment duration to achieve sustained HDV suppression has not been established yet, but it should likely exceed one year. Treatment was well tolerated. The data clearly show the need for an individualized approach when treating patients with chronic hepatitis D with BLV.