编者按：Fabien Zoulim教授，法国里昂第一大学医学教授，里昂的癌症研究中心病毒性肝炎实验室主任，国际病毒性肝炎和抗病毒治疗的领域著名专家，已发表了超过350篇，在HBV分子生物学和抗HBV治疗领域做出了杰出贡献，被国际抗病毒学会授予威廉普鲁萨福奖（William Prusoff award）。
慢性乙型肝炎难以治愈之原因？
Zoulim教授：有几种原因可以解释为什么慢性乙型肝炎（CHB）难以治愈：第一，HBV以病毒微型染色体的形式，停留在受感染的肝细胞内，称之为cccDNA。在某种意义上，它与患者“共存共亡”，这使得根除HBV的目标很难实现；第二，机体对HBV感染细胞的特异性免疫应答通常非常微弱，我们观察到的慢性HBV感染患者多存在T细胞的“耗竭”；第三，在更大程度上是“全球性的原因，与疾病照护的可及性有关，在世界上HBV高度流行的很多地方，HBV感染者得到诊断和治疗的可及性受到限制，我们需要努力解决这一“全球性问题”。
Prof. Zoulim: There are several reasons that explain why HBV is so difficult to cure. The first is that the virus stays in the infected hepatocyte in the form of a viral minichromosome, which we call cccDNA, which persists for the whole life of the patient. This makes eradication very difficult to achieve. The second point is that immune responses specific to HBV-infected cells are usually very weak because of the T-cell exhaustion that we observe in chronically infected patients. The third reason is more of a global reason and related to access of care. In many parts of the world where HBV is highly endemic, access to diagnosis and treatment is limited and restricted. We also need to work on this aspect of the global situation.
距离治愈的目标更近了吗？
Zoulim教授： HBV领域的研究在近几年的确取得了快速进展。在HBV的生物学方面，已经有很多重大发现，诸如发现了受体和涉及cccDNA生物学的许多重要因素，并且发现了HBx蛋白的作用方式和功能。这些已取得的进展也将有助于我们开发新的工具，用于研究HBV并寻找新的治疗靶点。
在HBV免疫学方面也有一些发现，有助于确定免疫治疗的新概念。目前，有许多大型制药企业参与抗HBV新药的研究，也有小型生物科技公司参与研究，他们共同的目标即研发直接抗病毒药物或免疫治疗方法。因此，可以说HBV领域正在蓬勃发展，我们正在靠近治愈的目标。在未来五年内，通过多种形式的通力合作，包括：科研团队之间的合作、科研团队与制药企业的合作，以及基础研究、转化研究和临床研究的合作，将有望研发出新的治疗乙型肝炎的方法。
Prof. Zoulim: This is an important question. We highlight the fact that research in the field of HBV is growing and progressing fast. There have been major discoveries regarding the biology of HBV – the discovery of the receptor, the discovery of many important factors involved in the biology of cccDNA, as well as the discovery of the mode of action and function of the HBx protein. These have happened recently and will help in developing new tools for studying HBV and to identify new targets. There have been other findings in terms of the immunology of HBV that will also help to define new concepts of immunotherapy. There is a lot of pharma industry that are now involved in HBV research, either developing direct-acting antivirals or immunotherapeutic approaches. It is a blooming field of research and we have small biotech companies as well as big pharma involved in research and we need to have collaboration between academic teams doing basic research, translational research and clinical research as well as with pharma industry to develop new treatment paradigms within the next five years. We are close to that.
可指导治疗的新型生物学标志物？
Zoulim教授：目前，HBsAg定量检测是全世界比较普及的一个指标，它可以准确地确定患者疾病发生、进展的风险，并且它对于治疗监测也非常重要，可以观察患者是否发生HBsAg下降，明确治疗的有效性和患者的预后。除此之外，血清HBV RNA也是一种有效的生物学标志物，但是目前尚无标准化的检测方法，因此不能在临床实践中推广应用。有关血清HBV RNA与病毒生物学以及临床的关联还需要更多的研究进行证实。值得一提的还有一个指标——HBc相关抗原（HBcrAg），它由日本一家生物公司研发，可以检测患者血清中的衣壳蛋白以及HBeAg。对于cccDNA或整合DNA来说，HBc相关抗原是一个很有意义的无创性指标，可应用于衣壳抑制剂等新药研发中的检测。同样的，我们还需要对它做进一步研究，目前尚不能应用于临床实践。
Prof. Zoulim: Besides the different markers you have mentioned, there are others. One that is widely available in some parts of the world but not everywhere, is the quantification of HBsAg which is important to be more precise in the characterization of patients in terms of the risk of progression of liver disease. This marker will also be important for the monitoring of treatment to see whether or not a patient will undergo HBsAg decline with a new treatment. So quantitative HBsAg is a new marker. There is also viral RNA in serum but this needs to be confirmed with more data. We cannot use this marker in clinical practice because there is no standardized assay. We need to better understand the relevance to the biology of the virus and also the clinical relevance of this marker. Another marker is the HBc-related antigen (HBcAg). It is a test developed by a Japanese company that detects capsid proteins as well as HBeAg in the serum of patients. This may be an interesting non-invasive marker for cccDNA or integrated DNA that could be applied in conjunction with the new drugs in development like the capsid inhibitors. Again, these need to be further characterized and cannot be used in clinical practice yet. It is still a research tool that needs to be better characterized.
免疫耐受期患者是否进行治疗？
Zoulim教授：免疫耐受期的概念已经受到数项研究的挑战。几家研究团队通过分析这些所谓的免疫耐受期患者的免疫应答，认为将这些患者归为免疫耐受期是不正确的。原因是这些患者虽然存在T细胞应答，但是这种应答是耗竭的。他们认为应该将这一期称为疾病的非炎症期更为合适。
但是，目前对于这些所谓的免疫耐受期患者应用目前的核苷（酸）类似物进行治疗，以预防肝损伤，尤其是HBV在肝细胞内整合和克隆增殖时所发生的肝损伤，尚存争议。目前，我们已经有应用核苷（酸）类似物治疗的长期安全性数据，个人认为是时候考虑对这些患者更多进行治疗，以预防肝癌的远期发生。
Prof. Zoulim: The concept of immune-tolerant patients has been challenged by several studies in chronically infected patients. Several teams have done very detailed analyses of the immune responses in these patients and we should not call these patients immune-tolerant anymore because their T-cell response is there but they are exhausted. We should call this phase a non-inflammatory phase of the disease and there are several arguments to consider treatment even with the current nucleoside analogs in immune-tolerant patients to prevent liver damage occurring especially integration and clonal expansion of the hepatocytes. Now that we have safe nucleoside analogs with long-term data, it is time to be considering treating more of these patients to prevent the development of liver cancer in the long term.
可激活模式识别受体的乙型肝炎新药前景如何？
Zoulim教授：可以激活模式识别受体的乙型肝炎新药非常重要。有一些药物，特别是TLR7激动剂，正在进行临床研发，这是恢复固有免疫和获得性免疫的重要方法，在黑猩猩和土拨鼠的动物实验中观察到的数据非常理想。不过，在人类患者中TLR-7激动剂的疗效欠佳，并且有一些副作用。但是，随着我们对这些化合物有更多了解，TLR-9和TLR-8激动剂也处于研发中，相信最终将找到一种适合于临床的TLR激动剂。该药与核苷（酸）类似物或干扰素联合应用，或者与将来可用新药联合应用，可望获得满意的疗效。
Prof. Zoulim: The question of pattern recognition receptors with innate immunity is interesting. There are drugs, particularly agonists of TLR-7, that are in clinical development. These are an interesting way to restore not only innate immunity but also the subsequent adaptive immunity. Very nice data were observed in animal experiments in chimpanzees and woodchucks. In human patients, it seems these TLR-7 agonists are less effective and have some side effects; so clinical development is ongoing as we learn more about these compounds. There are also TLR-9 and TLR-8 agonists that are in development and we will see which of these is the best. These would have to be used in combination therapy, as having onlypattern recognition receptor agonists would make it extremely difficult to achieve a cure of infection. We would combine with at least the currently available NUCs or newer drugs in the future. They would have to be combined with either nucleoside analogs or interferon (which are already available), or maybe new drugs we will see in the future. But there is the potential for combination therapy.