编者按：Harry L.A. Janssen, PhD, MD  加拿大多伦多大学医学院教授，担任北美最大的肝脏诊所多伦多总医院及西部医院肝脏中心主任，他在慢性病毒性肝炎的免疫学治疗和疾病转归、肝病相关的高凝状态的研究取得了突出成就，Hepatology, Journal of Hepatology等著名杂志编委成员，已发表文章350余篇。在本届AASLD年会上，作为乙型肝炎Special Interest Group (SIG) 项目的客座教授，Janssen 教授做了题为“乙型肝炎新型治疗药物”的专题报告。会后，本刊非常荣幸地对Janssen 教授进行了专访。

治疗乙型肝炎几大治疗新策略

　　现今，丙型肝炎治愈使其已经成为了一个即将解决的问题。然而，现有治疗乙型肝炎的药物的疗效有限，需要寻找抗HBV的新策略，从而使乙型肝炎也成为一个可以治愈的疾病。目前，令人振奋的是，现在有很几种治疗慢性乙型肝炎的新药非常具有前景。许多公司在研发新型乙型肝炎药物上投入了大量的资金，希望实现疾病的功能性治愈，即临床上HBsAg的血清学转换。

　　Janssen教授认为，目前，我们可以通过不同的途径来实现这一目标：①靶向HBV病毒学通路的策略。我们可通过干扰HBV生命周期中的几个重要节点来阻断HBV复制；②免疫学策略，通过刺激人体免疫系统，使其控制病毒；③RNA干扰策略，通过引物的设计，可以精准地下调病毒蛋白如HBsAg和HBeAg的表达，最终实现对病毒的控制；④当然还有新一代的核苷（酸）类似物，它们可产生良好的病毒下降效果，但还可能实现对病毒的免疫控制。目前正在进行开发的病毒外壳蛋白抑制剂，可产生抗核颗粒物并抑制病毒复制，甚至最终清除病毒。但这些药物是否具有功能治愈的作用还是一个疑问。最有可行的方法是，我们将上述药物与干扰素、治疗性疫苗、PD-1和PD-L1阻滞剂的免疫类药物和Toll样受体激动剂组合用药，从多个途径来实现对病毒的控制，最终实现治愈。

　　Janssen教授强调“当然，我们也还有很长的路要走。大多数药物仍在早期研发阶段，还没有进入临床，最快的正在进行临床II期试验。我们课题组也在针对如何降解病毒复制模板ccc-DNA进行早期研究，期待其早期进入临床。”

　　There are several new compounds in development for hepatitis B which are very exciting. Hepatitis C is almost a solved problem now and is curable. Hepatitis B has only been a treatable disease thus far and we are hoping that hepatitis B will be curable as well in the future. There are many companies currently investing research dollars in the development of new hepatitis B drugs aimed at a functional cure of the disease usually seen in the clinic as surface antigen seroconversion.

　　There are different ways to do that. On the one hand, there is the virological pathway approach where we try to interfere with virus replication at several stages in the life cycle of the virus. Or, we could pursue an immunological approach whereby we stimulate the immune system in such a way that it takes control over the virus. One of the interesting compounds involves RNA interference where we can design drugs very precisely to reduce the amount of viral proteins like HBsAg and HBeAg. With that, it is hoped to mount an immune response to achieve control over the virus. There are other different compounds like the newer nucleoside analogs which produce a good viral decline but will probably not result in immune control over the virus. There are the capsid inhibitors in ongoing development which produce anti-core particles which inhibit viral replication and eventually shut the virus down. The question is whether these drugs on their own will give functional cure. It is most likely that we will have to combine them with immunological drugs and toll-like receptor agonists which stimulate interferon production, therapeutic vaccination, and PD-1 and PD-L1 blockade. These will all be ways to manipulate the immune system in such a way that combined with the virological approaches, will be capable of curing hepatitis B.

　　There is still a long way to go. Most of these drugs are still in very early development. We are also working on degradation of ccc-DNA which is the true template of viral replication, but that is in very early development and has yet to be tested in patients. The studies that are most advanced are in phase II and are given in combination with nucleoside analogs, but many of the compounds have not even got into the clinic yet.

根据患者的人群特征进行个体化治疗

　　Janssen教授认为个体化治疗概念的提出非常好，针对不同的患者选择不同的治疗方案。在干扰素的应用上也是如此，它在不同的患者中，治疗效果是不相同的，仅在30%的患者中有效，且有一定的副反应，因此我们需要根据HBV的基因型、病毒载量、肝脏炎症程度和其他一些因素来制定治疗方案，因为这些方面情况的。

　　在前述新药方面，我们应首先证明这些化合物的有效性，适用于哪些人群。一个典型的例子就是RNA干扰药物在HBeAg阳性患者中的疗效比HBeAg阴性患者显著，这可能和HBeAg阴性患者体内病毒DNA与宿主基因的整合有关。为使HBeAg阴性患者获得更好的疗效，我们可能需要对药物重新设计。事实上，只有我们了解更多的关于HBV生命周期的奥秘，才能在个体化治疗上取得成功。

　　The concept of individualized treatment is a very good one. A certain treatment is given to one specific patient while another patient might need another type of treatment. We have been doing that already with interferon. That is a toxic drug which is only effective in 30% of patients, so we have designed ways based on the HBV genotype, the amount of virus, the amount of liver inflammation and other factors, whereby some patients will respond much better than others. So there is a precedent already in the setting of hepatitis B for individualized or response-guided treatment. In the era of these new compounds, we need to first show that these compounds are effective. It is very difficult to say for in which population they will work best. A good example is one of the RNA interfering drugs which appears to work much better in HBeAg-positive patients than for HBeAg-negative patients. This might have to do with the fact that in the HBeAg-negative patients, the viral DNA is more often and more deeply integrated into the host genome than in the HBeAg-positive patients. That drug may have to be redesigned for HBeAg-negative patients to achieve the better results we might expect to see in the HBeAg-positive patients. With these new compounds, we are actually learning a lot more about the viral life cycle of hepatitis B. So it is also good in that sense in that they are giving us more insight into what the virus actually does in different stages of the disease.

大会点评： 3项有关乙型肝炎的突破性研究

　　在今年AASLD年会上，Janssen教授认为共有3项乙型肝炎的突破性研究值得一提。

　　1. Janssen教授课题组有关干扰素治疗乙型肝炎的全基因组关联研究，发现NCOA2基因附近一个重要蛋白质的编码基因的突变可能与干扰素应答有关。该蛋白可能参与细胞生长、代谢及癌变。这项研究为我们了解干扰素及免疫控制、消灭病毒的作用机制提供了重要信息。

　　2.  RNA干扰化药物ARC-520可降低患者的血清HBV DNA和HBsAg水平，这是RNA干扰技术首次在乙型肝炎患者中的应用。虽然患者没有治愈，但其HBV DNA和病毒抗原水平有显著下降。相信随着更高剂量和优化治疗的开展，特别联合免疫调节药物治疗，我们将可以实现功能性治愈。

　　3.  病毒核心抑制剂NVR3-778，它是一种靶向完全不同的抗病毒药物。

　　这些在乙型肝炎领域研发出的新型药物，让我们为之振奋。希望不久的将来我们能够看到通过不同途径的联合治疗，实现乙型肝炎的治愈。

　　There are three late-breaking abstracts on hepatitis B at this conference which deserve mention. One is an abstract from my own group that is a genome-wide association study on interferon treatment in hepatitis B. Interferon treatment is the only treatment that gives us cure of the disease (in a small section of patients); the nucleoside analogs do not provide that. With this particular genetic assessment, we have found that a mutation close to the gene NCOA2 which codes for a protein which might be of importance. It is associated with the response of interferon. We don’t know what this protein actually does which is usually the case with a GWAS which is hypothesis-generating research rather than hypothesis-driven. However, we do think this protein is involved with cell growth and metabolism and has also been described in the setting of liver cancer. That opens up new information which may give us a mechanism of response to interferon and more generally, a mechanism of response for immune control over the virus. The second abstract I would like to mention concerns a drug called ARC-520, an RNA-interfering compound. When given to patients, it reduced the amount of HBV DNA and HBsAg in those patients. This is the first time this concept has been shown to work in patients. Patients are not cured but we do see a decline in HBV DNA and viral antigens and with higher doses and optimized treatment we might be able to achieve a functional cure particularly where used in combination probably with the immune modulatory agents. The third study is on HBV Core inhibitors. This is a completely different mechanism of action to tackle hepatitis B virus. These drugs are new and we haven’t seen a lot of new agents in the HBV arena for years so it is exciting to see these new compounds being developed to act on HBV in a different way with the aim of making a treatable disease curable.