Tang Liudi, Zhao Qiong, Wu Shuo, Cheng Junjun, Chang Jinhong, Guo Ju-Tao
a Microbiology and Immunology graduate program , Drexel University College of medicine , Philadelphia , PA , USA.
b Baruch S. Blumberg Institute , Hepatitis B foundation , Philadelphia , PA , USA.
Expert Opin Drug Discov. 2017 Jan;12(1):5-15. doi: 10.1080/17460441.2017.1255195. Epub 2016 Nov 11.
The current standard care of chronic hepatitis B fails to induce a durable off-drug control of hepatitis B virus (HBV) replication in the majority of treated patients. The primary reasons are its inability to eliminate the covalently closed circular (ccc) DNA, the nuclear form of HBV genome, and restoration of the dysfunctional host antiviral immune response against the virus. Accordingly, discovery and development of therapeutics to completely stop HBV replication, eliminate or functionally inactivate cccDNA as well as activate a functional antiviral immune response against HBV are the primary efforts for finding a cure for chronic hepatitis B. Area covered: Herein, the authors highlight the current efforts of HBV drug discovery and offer their opinions for the future directions of this research. Expert opinion: The authors believe that through a consecutive or overlapping three-stage antiviral and immunotherapy program to: (i) completely stop HBV replication and cccDNA amplification; (ii) reduce viral antigen load and induce HBV surface antigen (HBsAg) seroclearance through eradication or inactivation of cccDNA and RNA interference-mediated degradation of viral mRNA and (iii) activate a functional antiviral immune response against HBV through therapeutic immunization or immunotherapy, a functional cure of chronic HBV infection can be achieved in the majority of chronic HBV carriers.
目前慢性乙型肝炎的标准治疗方法无法在大多数接受治疗的患者中诱导持久的停药后乙肝病毒（HBV）复制控制。主要原因是它无法消除共价闭合环状（ccc）DNA（HBV基因组的核形式），也无法恢复针对该病毒的功能失调的宿主抗病毒免疫反应。因此，发现和开发能够完全停止HBV复制、消除或功能性灭活cccDNA以及激活针对HBV的功能性抗病毒免疫反应的治疗方法，是寻找慢性乙型肝炎治愈方法的主要努力方向。涵盖领域：在此，作者强调了目前HBV药物发现的努力，并对该研究的未来方向提出了自己的看法。专家意见：作者认为，通过连续或重叠的三阶段抗病毒和免疫治疗方案，即：（i）完全停止HBV复制和cccDNA扩增；（ii）通过消除或灭活cccDNA以及RNA干扰介导的病毒mRNA降解来降低病毒抗原负荷并诱导乙肝表面抗原（HBsAg）血清清除，以及（iii）通过治疗性免疫接种或免疫疗法激活针对HBV的功能性抗病毒免疫反应，大多数慢性HBV携带者可以实现慢性HBV感染的功能性治愈。
