迈向乙型肝炎病毒的功能性治愈：2022 年新抗病毒策略更新

StephenW

迈向乙型肝炎病毒的功能性治愈：2022 年新抗病毒策略更新
伊丽莎白·德加斯佩里 1 、玛丽亚·保拉·阿诺利 1 、皮埃特罗·兰佩蒂科 1 2
隶属关系
隶属关系

    1个
    IRCCS Ca' Granda Ospedale Maggiore Policlinico 基金会消化内科和肝病科，20122 米兰，意大利。
    2个
    CRC“A.M. and A. Migliavacca”肝病中心，病理生理学和移植系，米兰大学，20122 米兰，意大利。

    PMID：36366502 DOI：10.3390/v14112404

抽象的

乙型肝炎病毒 (HBV) 的慢性感染是肝硬化及其并发症发展的主要原因之一。使用有效的第三代核苷（酸）类似物 (NUC) 进行治疗可使 HBV DNA 检出率超过 99%，并可防止纤维化进展和肝脏相关并发症。然而，NUC 无法诱导所谓的功能性治愈，即乙型肝炎表面抗原 (HBsAg) 丢失和抗 HBs 血清转化。因此，NUC 治疗目前旨在作为长期或终生治疗，导致需要进行临床监测并可能遇到依从性问题。因此，HBV 药物开发的目标是开发新药以实现 HBV 的功能性治愈。目前，三种主要策略包括：抑制病毒复制、抑制病毒抗原和免疫调节。本综述总结了这三个主要类别中有关 HBV 化合物的最新更新。

关键词：乙肝病毒；临床试验;功能性治愈；研究药物；核苷（酸）类似物。

StephenW

Towards a Functional Cure for Hepatitis B Virus: A 2022 Update on New Antiviral Strategies
Elisabetta Degasperi  1 , Maria Paola Anolli  1 , Pietro Lampertico  1   2
Affiliations
Affiliations

    1
    Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
    2
    CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.

    PMID: 36366502 DOI: 10.3390/v14112404

Abstract

Chronic infection with hepatitis B virus (HBV) represents one of the main causes of the development of cirrhosis and its complications. Treatment with potent third-generation nucleos(t)ide analogues (NUCs) results in >99% HBV DNA undetectability, and prevents fibrosis progression and liver-related complications. However, NUCs are not able to induce the so-called functional cure, which is hepatitis B surface antigen (HBsAg) loss and anti-HBs seroconversion. Consequently, NUC treatment is currently intended as being long-term or lifelong, resulting in the need for clinical monitoring and potentially suffering from compliance issues. Consequently, drug development in HBV has the goal of developing new agents in order to achieve a functional cure for HBV. Currently, the three main strategies include the following: inhibition of viral replication, inhibition of viral antigens, and immune modulation. This review summarizes the most recent updates concerning HBV compounds among these three main classes.

Keywords: HBV; clinical trials; functional cure; investigational drugs; nucleos(t)ide analogues.

StephenW

https://www.mdpi.com/1999-4915/14/11/2404/pdf?version=1667056224

StephenW

目前，正在进行的调查研究采用的最常见策略
基于不同 HBsAg 降低剂（siRNA 或 ASO）的组合
免疫调节剂的类型（TLR 激动剂、治疗性疫苗或免疫检查点
抑制剂）。假设的理由是降低 HBsAg 负荷将促进
或恢复免疫系统对免疫刺激作出反应的能力。为了
由于这些原因，许多正在进行的 1 期或 2 期试验的研究设计采用序贯
而不是从头组合，其中给予免疫刺激一些
siRNA/ASO 处理后数周/数月（始终使用骨干 NUC）。这是
正在进行的 OSPREY 1 期试验（siRNA JNJ-3989，随后添加 JNJ-
0535 治疗性疫苗）、ASO-001 2 期试验（贝匹罗韦森 12 或 24 周后
通过黑猩猩腺病毒载体 (ChAdOx1-HBV) 和异源修饰的 Ankara
boost (MVA-HBV)）和 OCTOPUS-1 2 期试验（siRNA JNJ-3989 持续 16 周，随后
通过添加 Nivolumab）。

【论文中的图2和图3很有意思】

Currently, the most common strategy adopted by ongoing investigational studies
is based on the combination of HBsAg lowering agents (siRNA or ASO) with different
types of immune modulators (TLR-agonists, therapeutic vaccines, or immune checkpoint
inhibitors). The supposed rationale is that lowering the HBsAg burden would facilitate
or restore the capability of the immune system to respond to immune stimulation. For
these reasons, the study designs of many Phase 1 or 2 ongoing trials adopt a sequential
instead of de novo combination, where the immune stimulation is administered some
weeks/months after the siRNA/ASO treatment (always with a backbone NUC). This is
the case of ongoing OSPREY Phase 1 trial (siRNA JNJ-3989 followed by addition of JNJ-
0535 therapeutic vaccine), ASO-001 Phase 2 trial (Bepirovirsen 12 or 24 weeks followed
by chimpanzee adenoviral vector (ChAdOx1-HBV), and a heterologous modified Ankara
boost (MVA-HBV)), and OCTOPUS-1 Phase 2 trial (siRNA JNJ-3989 for 16 weeks followed
by addition of Nivolumab).

[Figure 2 and 3 in the paper are very interesting]