乙肝疗法的进展

StephenW

Advances in hepatitis B therapeutics
Vicente Soriano  1 , Pablo Barreiro  2 , Edward Cachay  3 , Shyamasundaran Kottilil  4 , José V Fernandez-Montero  5 , Carmen de Mendoza  6
Affiliations
Affiliations

    1
    UNIR Health Sciences School and Medical Center, 28040 Madrid, Porto Velho, Madrid 76801-059, Spain.
    2
    Infectious Diseases Department, La Paz University Hospital, Madrid, Spain.
    3
    Infectious Diseases Unit, Owen Clinic, University of California, San Diego, CA, USA.
    4
    Infectious Diseases Department, Institute of Human Virology, University of Maryland, Baltimore, MD, USA.
    5
    Infectious Diseases Unit, NHS Ayrshire and Arran, University of Glasgow, Glasgow, UK.
    6
    Puerta de Hierro University Hospital and Research Institute, Majadahonda, Spain.

    PMID: 33117536 PMCID: PMC7570774 DOI: 10.1177/2049936120965027

Abstract

Despite the availability of both effective preventive vaccines and oral antivirals, over 250 million people are chronically infected with the hepatitis B virus (HBV). Globally, chronic hepatitis B is the leading cause of hepatocellular carcinoma, which represents the third cause of cancer mortality, accounting for nearly 1 million annual deaths. Current oral nucleos(t)ide therapy with tenofovir or entecavir suppresses serum HBV-DNA in most treated patients, but rarely is accompanied by HBsAg loss. Thus, treatment has to be given lifelong to prevent viral rebound. A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors. Some of them exhibit higher potency than current oral nucleos(t)ides. Drugs in more advanced stages of clinical development are bulevirtide, JNJ-6379, ABI-H0731, ARO-HBV and REP-2139. To date, only treatment with ARO-HBV and with REP-2139 have resulted in HBsAg loss in a significant proportion of patients. Combination therapies using distinct antivirals and/or immune modulators are expected to maximize treatment benefits. The current goal is to achieve a 'functional cure', with sustained serum HBsAg after drug discontinuation. Ultimately, the goal of HBV therapy will be virus eradication, an achievement that would require the elimination of the cccDNA reservoir within infected hepatocytes.

Keywords: antiviral therapy; bulevirtide; cccDNA; chronic hepatitis B; combination therapy; gene editing; hepatitis delta; resistance.

© The Author(s), 2020.

StephenW

乙肝疗法的进展
维森特·索里亚诺（Vicente Soriano）1，巴勃罗·巴雷罗（Pablo Barreiro）2，爱德华·查奇（Edward Cachay）3，什马孙达兰·科蒂利尔（Shyamasundaran Kottilil）4，何塞·费南德斯·蒙特罗（JoséV Fernandez-Montero）5，卡门·门多萨（Carmen de Mendoza）6
隶属关系
隶属关系

    1个
    UNIR卫生科学学院和医学中心，马德里28040，韦尔霍港，马德里76801-059，西班牙。
    2
    西班牙马德里拉巴斯大学医院传染病科。
    3
    美国加利福尼亚大学圣地亚哥分校欧文诊所传染病科。
    4
    美国马里兰州巴尔的摩市马里兰大学人类病毒研究所传染病系。
    5
    英国格拉斯哥大学，NHS艾尔郡和阿兰市传染病科。
    6
    西班牙马亚达洪达的普埃塔·耶罗大学医院和研究所。

    PMID：33117536 PMCID：PMC7570774 DOI：10.1177 / 2049936120965027

抽象

尽管有有效的预防疫苗和口服抗病毒药，但仍有超过2.5亿人长期感染了乙型肝炎病毒（HBV）。在全球范围内，慢性乙型肝炎是肝细胞癌的主要原因，它代表癌症死亡率的第三大原因，每年导致近100万人死亡。目前使用替诺福韦或恩替卡韦口服核苷酸治疗可在大多数患者中抑制血清HBV-DNA，但很少伴有HBsAg丢失。因此，必须终身治疗，以防止病毒反弹。可以在不同步骤阻断HBV生命周期的各种抗病毒药正在临床开发中，包括进入抑制剂，cccDNA干扰物/沉默子，翻译抑制剂，衣壳装配调节剂，聚合酶抑制剂和分泌抑制剂。它们中的一些表现出比目前的口服核苷（核苷酸）更高的效力。在临床开发的更高级阶段的药物是bulevirtide，JNJ-6379，ABI-H0731，ARO-HBV和REP-2139。迄今为止，仅使用ARO-HBV和REP-2139的治疗已导致相当一部分患者的HBsAg丢失。使用不同的抗病毒药和/或免疫调节剂的联合疗法有望最大化治疗益处。当前的目标是在停药后持续产生血清HBsAg，以实现“功能性治愈”。最终，HBV治疗的目标将是根除病毒，这一成就将需要消除感染的肝细胞内的cccDNA储存库。

关键词：抗病毒治疗；布列维肽cccDNA;慢性乙型肝炎联合疗法基因编辑；肝炎三角洲抵抗性。

©作者，2020年。

StephenW

https://journals.sagepub.com/doi/pdf/10.1177/2049936120965027