目前丙型肝炎的治疗取得了重大突破，甚至有乐观的观点称，“我们不再需要开发新的丙型肝炎药物了。丙型肝炎领域取得的成功极大地激发了人们抗击乙型肝炎的热情。大家期待着看到“不再需要研究乙型肝炎新药”的那一天。在第27届亚太肝病学会年会现场，《国际肝病》采访了法国国家健康与医学研究院病毒和肝脏研究所所长、斯特拉斯堡大学医院消化和肝病中心主任Thomas Baumert教授，他向我们展示了他心中乙型肝炎新药的研发前景。
Baumert教授首先表示，当前临床应用的治疗能有效控制HBV感染，抑制病毒载量，减少肝纤维化、肝硬化等肝病并发症的发生，并且降低（但不能消除）肝癌的发生风险。而我们的关键目标在于“治愈”病毒感染，这意味着从人体内清除病毒。
Baumert教授是一名临床医生，同时也涉及了制药企业的一些事务，他见证了抗HCV直接抗病毒药物的研发、获批和成功。他表示，“这给我们树立了一个巨大的希望：只要有深入的研究和创新的概念，乙型肝炎同样可以被治愈”。然而，HBV与HCV是两种不同的病毒，二者的自然史有别，而且作为病毒储存库的HBV cccDNA无法被轻易清除。另外，HCV是RNA病毒，既不会整合到基因组中，也不会有病毒基因组进入细胞核，HBV则相反。因此，治愈乙型肝炎要面临更多的挑战，任务更为艰巨。
抗宿主药物是在研乙型肝炎新药的一个重要组成部分。据Baumert教授介绍，宿主靶点可以简单地分为两类。一类是为病毒繁殖并产生感染性颗粒所需的宿主细胞蛋白、因子、小RNA等。另一类是宿主免疫系统。
Baumert教授个人认为，在诸多新药中，HBV进入抑制剂非常有意思，其中一些已经成功完成了概念验证，未来会有更多更有效的这类药物。另外，抑制cccDNA或使其降解的cccDNA靶向药物也很有前景，其靶点包括cccDNA生物学所需的宿主细胞蛋白，也包括降解cccDNA的基于免疫学的方法，已有细胞培养模型研究。“上述只是这些新观点的一部分，我想最终我们需要联合应用靶向于病毒、宿主细胞蛋白和基于免疫的方法”。
不过，合适的治疗终点始终是一个有很大争议的话题。围绕当前和今后的治疗方案的最佳治疗终点，有多个工作组和研讨会展开了讨论。Baumert教授认为，如果有新的标志物进入临床，将会有新的治疗终点可供应用，例如检测前基因组RNA的标志物。
最后，Baumert教授乐观地表示：“现在已经有新的模型系统供我们研究病毒在动物模型中的感染，我们对病毒持续存在和清除的临床机制也有了更好的认识。因此有了这些新的理论和靶点，我们能够复制在丙型肝炎领域中取得的成功”。
Hepatology Digest: Current therapies of hepatitis B can only control the disease but not cure it. What's the current definition of cure of hepatitis B?
Dr Baumert: Current therapies that are in clinical use can effectively control viral infection, suppress the viral load, and decrease the complications of disease (fibrosis, cirrhosis, and reduce (but not eliminate) the cancer risk). Our key goal is to cure the viral infection, which means eliminating the virus from the host.
Hepatology Digest: There are many direct acting antiviral agents (DAA) under different phase investigation. Do you think the DAA in HBV replicates the brilliant results of DAA in HCV?
Dr Baumert: The success in HCV has triggered enormous enthusiasm in the fight against the hepatitis B virus. As both a clinical doctor and through my involvement from the pharma industry perspective, I have witnessed the development, licensing and success of the direct-acting antivirals against the hepatitis C virus, and it builds great hope that with intensive research and new concepts, the hepatitis B virus can also be cured. It is more challenging because it is a different virus with a different natural history and cccDNA as a reservoir of infection that cannot be easily eliminated. The hepatitis C virus is a RNA virus and has neither integration of the genome nor any genome in the nucleus. So the task for HBV is more difficult. On the other hand, we have a new model system allowing us to study the virus infection with animal models, and we now better understand the clinical mechanisms of persistence and clearance. So I am optimistic that with these new concepts and new targets, we can replicate the successes against HCV.
Hepatology Digest: Host-targeting agents (HTAs) is another important arm in the development of novel antivirals to treat and cure HBV infection. That means targeting our human body. What potential molecules or pathways can be candidate targets?
Dr Baumert: They can basically be divided into two pathways. One is the host cell proteins, factors and microRNAs. The virus need them to propagate and produce infectious particles. The other target is the host immune system using immunomodulatory agents. There are many promising targets. Personally, I believe hepatitis B virus entry inhibitors are very interesting. There is proof-of-concept for some of them, so I think we will see more of them and more efficient therapies. Another approach is cccDNA targeting agents with inhibition of synthesis or inducing degradation. These target the host cell proteins required for cccDNA biology, but also using immune-based approaches that allow the degradation of cccDNA. This has already been demonstrated in cell culture models. These are some of the concepts, which, in the end, I think will be utilized in combination, with molecules targeting the virus, host cell proteins plus immune-based therapy.
Hepatology Digest: Many host-targeting agents are immunomodulator. If immune responses overreact, will it lead to serious negative outcome? How to manage it or prevent it?
Dr Baumert: With all host-targeting agents, there are concerns about off-target effects in the host, especially for the immunomodulators. Careful monitoring in clinical trials is required to detect any adverse effects. Also by selecting pathways that are very specific targeted pathways for achieving a HBV cure that are not relevant for other physiological mechanisms in the body that could result in autoimmune disorders or immune deficiency if the system is overstimulated or suppressed.
Hepatology Digest: Are the endpoints used currently optimal to assess the efficacy of these new drugs?
Dr Baumert: Endpoints are a big topic of debate. Many workshops and symposia have discussed the best endpoints for current and future therapies. I am sure we will see new endpoints suggested as new markers are being introduced into clinical use to detect pre-genomic RNA, for example. I am sure we will see new and improved assays to help monitor therapy and to address going beyond the functional cure we hope to achieve.