Lin Chih-Lin, Yang Hung-Chih, Kao Jia-Horng
Department of Gastroenterology, Ren-Ai branch, Taipei City Hospital, Taipei, Taiwan.
Department of Psychology, National Chengchi University, Taipei, Taiwan.
Liver Int. 2016 Jan;36 Suppl 1:85-92. doi: 10.1111/liv.13003.
Current antiviral therapies have dramatically improved the long-term outcomes of patients with chronic hepatitis B virus (HBV) infection. Both interferon (IFN) and nucleos(t)ide analogue (NA) treatments have been shown to reduce the progression of liver disease in chronic hepatitis B (CHB) patients. However, persistent covalently closed circular DNA (cccDNA) can result in a viral relapse after discontinuation of antiviral treatment. On the basis of extensive research on the HBV lifecycle and virus-host interactions, several new agents focusing on viral and host targets are under development to cure HBV. New polymerase inhibitors, tenofovir alafenamide and besifovir provide effective and safer treatment for CHB patients. Agents targeting cccDNA, such as engineered site-specific nucleases and RNA interference therapeutics could eliminate cccDNA or silence cccDNA transcription. Inhibitors of HBV nucleocapsid assembly suppress capsid formation and prevent synthesis of HBV DNA. The HBV entry inhibitor, Myrcludex-B, has been shown to effectively inhibit amplification of cccDNA as well as the spread of intrahepatic infection. Agents targeting host factors that enhance innate and adaptive immune responses, including the lymphotoxin-β receptor agonist, toll-like receptor agonist, immune checkpoint inhibitors and adenovirus-based therapeutic vaccine, could play a critical role in the elimination of HBV-infected cells. With all of these promising approaches, we hope to reach the ultimate goal of a cure to HBV in the near future.
目前的抗病毒疗法显著改善了慢性乙型肝炎病毒（HBV）感染患者的长期预后。干扰素（IFN）和核苷（酸）类似物（NA）治疗均已显示可降低慢性乙型肝炎（CHB）患者肝病的进展。然而，持续的共价闭合环状DNA（cccDNA）可导致抗病毒治疗停药后病毒复发。基于对HBV生命周期和病毒-宿主相互作用的广泛研究，几种针对病毒和宿主靶点的新型药物正在研发中，以治愈HBV。新型聚合酶抑制剂替诺福韦艾拉酚胺和贝西福韦为CHB患者提供了有效且更安全的治疗。靶向cccDNA的药物，如工程化位点特异性核酸酶和RNA干扰疗法，可消除cccDNA或使cccDNA转录沉默。HBV核衣壳组装抑制剂可抑制衣壳形成并阻止HBV DNA的合成。HBV进入抑制剂Myrcludex-B已显示可有效抑制cccDNA的扩增以及肝内感染的传播。靶向增强先天性和适应性免疫反应的宿主因子的药物，包括淋巴毒素-β受体激动剂、 Toll样受体激动剂、免疫检查点抑制剂和基于腺病毒的治疗性疫苗，可能在清除HBV感染细胞中发挥关键作用。通过所有这些有前景的方法，我们希望在不久的将来实现治愈HBV的最终目标。
