Lampertico Pietro, Anolli Maria Paola, Roulot Dominique, Wedemeyer Heiner
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Gut. 2025 Apr 7;74(5):853-862. doi: 10.1136/gutjnl-2024-332597.
Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha (PegIFN-α) has represented the only therapeutic option, with limited virological response rates and poor tolerability. In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis. Long-term BLV monotherapy may reduce decompensating events in patients with cirrhosis. The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy. However, combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline.While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region.
慢性丁型肝炎（CHD）是最严重的病毒性肝炎形式，发生肝硬化及其并发症的风险更高。几十年来，聚乙二醇化干扰素α（PegIFN-α）一直是唯一的治疗选择，病毒学应答率有限且耐受性差。2020年，欧洲药品管理局批准了每日2毫克的布列韦肽（BLV），这是一种乙型肝炎病毒（HBV）/丁型肝炎病毒（HDV）进入抑制剂，在临床试验和真实世界研究中，包括肝硬化患者，该药作为单药治疗长达144周被证明是安全有效的。长期BLV单药治疗可能会减少肝硬化患者的失代偿事件。与PegIFN单药治疗相比，2毫克BLV与PegIFN-α联合使用可提高治疗期间HDV RNA不可检测率，但停药后则不然。然而，联合治疗而非BLV单药治疗可能会使一些患者出现乙型肝炎表面抗原（HBsAg）消失。由于肝毒性问题，PegIFN lambda研究已停止，而洛那法尼联合利托那韦在一项3期研究中显示停药后的疗效有限。基于核酸聚合物的治疗前景广阔，但仍缺乏大型研究。新的对照试验数据来自靶向HBsAg或HBV RNA的分子，如单克隆抗体和/或小干扰RNA，这些分子不仅显示出对HDV的显著抑制作用，还使HBsAg下降。在等待新化合物被批准作为单药治疗或联合治疗之前，每日2毫克的BLV单药治疗仍然是CHD唯一被批准的治疗方法，至少在欧盟地区是这样。
