Durantel David
INSERM, U1052, Lyon, 69003, France; Cancer Research Center of Lyon (CRCL), Lyon, 69008, France; University of Lyon, UCBL1, UMR_S1052, UCBL, 69008, Lyon, France.
Best Pract Res Clin Gastroenterol. 2017 Jun;31(3):329-336. doi: 10.1016/j.bpg.2017.05.002. Epub 2017 May 22.
Current therapies of chronic hepatitis B (CHB) remain limited to pegylated-interferon-alpha (pegIFN-α) or any of the five approved nucleos(t)ide analogues (NA). If viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NA, i.e. entecavir and tenofovir, HBsAg loss is achieved by PEG-IFN-α and/or NA in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NA or a combination of NA and PEG-IFN-α have not provided a dramatic increase in the rate of "functional cure". Because of this and the need of long-term NA administration, there is a renewed interest regarding the understanding of various steps of the HBV replication cycle, as well as specific virus-host cell interactions, in order to define new targets and develop novel drugs. This includes the direct inhibition of several HBV life cycle steps by either entry inhibitors, drugs targeting cccDNA, siRNA targeting viral transcripts, capsid assembly modulators, and approaches targeting the secretion of viral envelope proteins. The addition of one or several new drugs to current therapies should offer the prospect of a markedly improved response to treatments and an increased rate of functional cure. This should lead to a reduced risk of antiviral drug resistance, and to a decreased incidence of cirrhosis and hepatocellular carcinoma (HCC). In this chapter, we review investigational and early clinical efforts regarding the identification and characterization of antiviral targets that are being evaluated for the development of innovative DAA concepts for chronic HBV infections.
慢性乙型肝炎（CHB）的现有治疗方法仍然局限于聚乙二醇化干扰素-α（pegIFN-α）或五种获批的核苷（酸）类似物（NA）中的任何一种。如果使用新一代具有高耐药屏障的NA（即恩替卡韦和替诺福韦）能够在大多数患者中实现病毒抑制，那么在经过5年随访后，只有10%的患者通过聚乙二醇化干扰素-α和/或核苷（酸）类似物实现了乙肝表面抗原（HBsAg）消失。尝试通过联合使用两种不同的核苷（酸）类似物或核苷（酸）类似物与聚乙二醇化干扰素-α的组合来提高应答率，并没有显著提高“功能性治愈”的比例。鉴于此以及长期使用核苷（酸）类似物的必要性，人们重新关注对乙肝病毒（HBV）复制周期各个步骤以及特定病毒-宿主细胞相互作用的理解，以便确定新的靶点并开发新型药物。这包括通过进入抑制剂、靶向共价闭合环状DNA（cccDNA）的药物、靶向病毒转录本的小干扰RNA（siRNA）、衣壳组装调节剂以及靶向病毒包膜蛋白分泌的方法直接抑制HBV生命周期的几个步骤。在现有治疗方案中添加一种或几种新药有望显著改善治疗应答并提高功能性治愈的比例。这将降低抗病毒药物耐药的风险，并降低肝硬化和肝细胞癌（HCC）的发病率。在本章中，我们综述了关于抗病毒靶点的鉴定和特性研究以及早期临床研究工作，这些靶点正在被评估用于开发针对慢性HBV感染的创新直接抗病毒药物（DAA）概念。
