Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV-DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.

中文翻译：

---

获得 HBV 治愈：有希望的前进道路

慢性 HBV 感染是一种全球公共卫生负担，估计影响全球近 3 亿人。尽管出现了有效抑制病毒复制的强效抗病毒药物，但由于共价闭合环状 DNA (cccDNA) 的持续存在、HBV-DNA 整合到宿主基因组中以及免疫反应受损，HBV 治愈仍然难以实现。大多数患者需要无限期治疗以维持病毒抑制水平。用于丙型肝炎治疗的直接抗病毒药物 (DAA) 的成功使对慢性乙型肝炎 (CHB) 治愈方法的研究重新焕发生机，尽管 HBV 治愈可能需要额外的一层：用于恢复强大免疫反应的免疫调节剂。DAA，例如进入抑制剂、衣壳组装调节剂、亚病毒颗粒释放抑制剂、cccDNA 沉默剂、和RNA干扰分子已达到临床开发。免疫调节剂，即先天性免疫调节剂（Toll 样受体激动剂）、治疗性疫苗、检查点抑制剂和单克隆抗体，也在向临床开发方向发展。HBV 治愈的未来可能在于对复制抑制、抗原减少和免疫刺激具有协同作用的三联疗法。仍然存在许多障碍，例如克服转化失败、使用正确的生物标志物选择正确的终点以及在联合方案中利用当前的治疗方法来提高反应率。本综述概述了当前的 CHB 疗法、用于评估治疗反应的 HBV 生物标志物、