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丁型肝炎病毒治疗药物的研究进展
DOI: 10.12449/JCH260205
利益冲突声明：刘阳、祁永和、周忠敏、隋建华、李文辉是华辉安健（北京）生物科技有限公司职工和/或持有该公司期权股票。
作者贡献声明：李文辉、隋建华负责设计论文框架；刘阳、祁永和负责拟定写作思路并起草撰写论文；周忠敏负责检索和收集相关资料并对论文进行修改；李文辉负责指导撰写文章并定稿。
Research advances in antiviral drugs for the treatment of hepatitis D virus infection
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摘要: 在病毒性肝炎中，丁型肝炎病毒（HDV）合并乙型肝炎病毒（HBV）感染是最为严重的类型，患者肝脏疾病进展快速，发生肝硬化与肝细胞癌的风险显著增加。治疗HBV的核苷（酸）类似物对HDV感染无效，亟需开发特异有效的抗HDV病毒治疗手段。近年来，针对HDV的特异性抗病毒药物研发取得重要进展，其中以靶向病毒入侵阶段的病毒进入抑制剂（布来韦肽）和单克隆抗体药物（立贝韦塔单抗）为代表的新药，为HDV感染治疗带来突破性进展。本综述简述HDV治疗药物的最新研究进展，重点介绍新近获批的HDV治疗新药的作用机制和临床研究数据，并探讨HDV治疗领域内仍待解决的问题，以期为了解丁型肝炎的治疗现状提供参考。Abstract: Co-infection of hepatitis D virus （HDV） and hepatitis B virus （HBV） is the most severe form of viral hepatitis and is associated with accelerated progression of liver disease and a significant increase in the risk of liver cirrhosis and hepatocellular carcinoma. Nucleo（s）tide analogues for HBV treatment are ineffective against HDV infection， necessitating the urgent need for developing specific and effective antiviral therapies for HDV. In recent years， significant advances have been made in the research and development of specific antiviral drugs against HDV， including entry inhibitors targeting viral entry （Bulevirtide） and monoclonal antibody drugs （Libevitug）， which bring ground-breaking advances in the treatment of HDV infection. This article briefly reviews the latest research advances in therapeutic drugs for HDV， introduces the mechanism of action and clinical research data of new drugs recently approved for the treatment of HDV， and discusses the challenges that need to be solved in the field of HDV treatment， in order to provide a reference for understanding the current status of hepatitis D treatment.
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Key words:
- Hepatitis Delta Virus /
- Antiviral Agents /
- Bulevirtide /
- Libevitug
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注： HBV，乙型肝炎病毒；RNP，核糖核蛋白；NTCP，钠离子牛磺胆酸共转运蛋白；HDV，丁型肝炎病毒；HSPG，硫酸肝素蛋白聚糖；NAP，核酸聚合物；L-HDAg，大丁型肝炎病毒δ抗原；S-HDAg，小丁型肝炎病毒δ抗原；L/M/S-HBsAg，乙型肝炎表面抗原大/中/小蛋白；mRNA，信使RNA；siRNA，小干扰RNA；Bulevirtide，布来韦肽；Libevitug，立贝韦塔单抗；Tobevibart，托韦拜单抗；SVP，亚病毒颗粒。
图 1 HDV生活史及药物靶点
Figure 1. HDV life cycle and drug targets
表 1 HDV治疗药物研究进展汇总
Table 1. Summary of research advances in HDV therapeutics
药物名称 药物类型/靶点 作用机制 开发阶段 Bulevirtide 多肽/NTCP 竞争性阻断病毒和受体结合，抑制病毒入侵 欧洲等地区上市 Libevitug 单克隆抗体/PreS1 通过特异性结合HBV/HDV表面的PreS1区域，阻断病毒和其受
体NTCP的结合，从而阻止病毒感染或再感染肝细胞中国附条件上市/临床
Ⅲ期Lonafarnib 小分子药物/法尼基转移酶 抑制L-HDAg的异戊二烯化修饰，阻断病毒组装 临床Ⅲ期/停止开发 Tobevibart 单克隆抗体/HBsAg 中和病毒感染，阻断病毒进入肝细胞 临床Ⅲ期 Brelovitug 单克隆抗体/HBsAg 中和病毒感染，阻断病毒进入肝细胞 临床Ⅲ期 Elebsiran siRNA/HBV X基因 沉默HBV mRNA，降低HBsAg表达水平，抑制HDV病毒组装 临床Ⅲ期 JNJ-3989 siRNA/HBV X基因 沉默HBV mRNA，降低HBsAg表达水平，抑制HDV病毒组装 临床Ⅱ期 RBD1016 siRNA/HBV X基因 沉默HBV mRNA，降低HBsAg表达水平，抑制HDV病毒组装 临床Ⅱ期 贺普拉肽 多肽/NTCP 竞争性阻断病毒和受体结合，抑制病毒入侵 临床Ⅱ期 REP 2139 核酸聚合物/HBsAg HBsAg分泌抑制剂，抑制病毒颗粒组装和释放 临床Ⅱ期 ABI-6250 小分子药物/NTCP 抑制病毒入侵 临床Ⅰ期 HH-1270 小分子药物/NTCP 抑制病毒入侵 临床前 注：Bulevirtide，布来韦肽；Libevitug，立贝韦塔单抗；Tobevibart，托韦拜单抗；NTCP，钠离子牛磺胆酸共转运蛋白；PreS1，乙型肝炎病毒前S1抗原；HBsAg，乙型肝炎表面抗原；siRNA，小干扰RNA；HBV X，乙型肝炎病毒X基因；HBV，乙型肝炎病毒；HDV，丁型肝炎病毒；L-HDAg，大丁型肝炎病毒δ抗原；mRNA，信使RNA。
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