“谁将玉笛弄中秋，黄鹤归来识旧游”，中国传统佳节中秋节刚刚过去，国内外众多传染病与肝病领域的专家学者齐聚江城武汉，出席传染病领域的盛会——人畜共患传染病重症诊治全国重点实验室2024年学术会议暨第六届中部肝病与感染学术会议（CCIFLDI 2024）。本次会议设置了多个话题，旨在从不同视角深入探讨临床热点与难点问题。会议期间，《国际肝病》编辑部邀请华中科技大学同济医学院附属同济医院宁琴教授和英国伦敦玛丽女王大学Patrick T.F. Kennedy教授，围绕病毒性肝炎与国际合作等问题展开深入讨论。

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《国际肝病》

两位在肝炎病毒感染研究领域都取得了很多成就。请问，关于乙型肝炎病毒感染的新治疗靶点，有哪些突破性发现？这些发现对临床治疗有何重要意义？

Kennedy教授

首先，感谢您的邀请和提问。我认为我们在慢性乙型肝炎领域已经取得了一些进展，但可能还没有达到可以说有重大突破的地步。在每年的国际肝病会议上，我们都会看到新的数据，研究数据的不断积累正逐步帮助我们实现功能性治愈的目标。但作为一名医生，我相信我和宁教授都一样——希望将来能有更多的进展，距离实现更高的功能性治愈率还有许多工作要做。

想要实现功能性治愈，需要考虑联合治疗策略。例如，抗病毒药物和免疫调节剂如何组合，以及组合的时间点？另外，如何选择合适的患者也是一个值得重点关注的问题。虽然目前慢性乙型肝炎相关研究已经取得了很多进展，但我们也认识到还有很多工作要做。为了实现慢性乙型肝炎功能性治愈这一目标，我认为我们需要采取更广泛的合作方式来开展临床试验，不仅仅局限于临床试验，还需要在包括病毒学、免疫学等方面的基础研究领域方面进行合作，这些研究工作将进一步推动相关领域进展，希望为我们指明实现功能性治愈的方向。

宁琴教授

我认为这是一个非常重要的问题，可能所有临床医生都想知道答案。但我同意Kennedy教授的观点。在治疗方面，至少从我的了解来看，暂时还没有一个重大的突破性的药物能够进入临床实践。然而，我们确实在基础研究和临床试验方面取得了许多进展。关于新的治疗靶点，我认为仍然分为两类：抗病毒药物，即直接作用抗病毒药物（DAAs），以及免疫调节治疗。

我们已经看到了许多新药的Ⅰ期、Ⅱ期临床试验，甚至部分已经进入了Ⅲ期临床研究。因此，我们期待随着新药的不断研发和临床试验的推进，将会带来更多有说服力的数据，不久的将来可能会有更多有效的治疗手段进入临床实践。我们在慢性乙型肝炎自然史以及功能性治愈优化治疗策略和管理路径方面已经有了深入的理解。最近，我组织了包括Kennedy教授、袁教授以及来自亚太地区、欧洲和美国的多位专家对功能性治愈路线图进行了更新。在更新版专家共识中，我们在慢性乙型肝炎自然史、功能性治愈治疗策略以及可能在不久的未来进入临床的新药方面进行了全面的更新。

Hepatology Digest：Both of you have made remarkable achievements in the research field of hepatitis virus infections. May I ask what are the breakthrough discoveries regarding new therapeutic targets for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections? What is the significance of these findings for clinical treatment?

Patrick T.F. Kennedy：First of all, thank you for the invitation and thank you for the question. I think we are seeing progress in the field of chronic hepatitis B, but I think we are maybe not quite at a point where I could say there’s been a major breakthrough. I think every year at the international liver meetings, we’re seeing new data which adds bit by bit towards the achievement of functional cure. But we, as physicians—both myself and Professor Ning, I’m sure—would like to have seen more progress than where we are now. And that underlines the work that still needs to be done to achieve functional cure.

So, will that be around certain combinations of strategies, be that antiviral or immunomodulatory agents, how they’re combined, and the timing of combination? Maybe patient selection is also an important area. So, while we recognize that there has been a lot of progress, we also recognize that there is a lot of work to be done. For us to do that, I think it will require a broad kind of collaborative approach in terms of how we approach clinical trials and not just the clinical trials but maybe some of the sub-studies around virology, immunology sub-studies, which will inform the progress and hopefully give us the direction to achieve functional cure.

Qin Ning：Thank you very much for the question. I think this is quite an important question that probably all the clinicians would like to ask. But I agree with Professor Kennedy. In terms of treatment, I think, at least from my knowledge, there has not been a major breakthrough that has come into clinical practice. However, it is true that we have seen many, many progresses in terms of basic research as well as clinical trials. So, regarding the new therapeutic targets, I think there are still twoifications: antiviral, directly acting antivirals (DAAs), as well as immune modulation.

We’ve seen many, many clinical trials in phase one, phase two, and some of them are even going into phase three. So, we are actually expecting more convincing data that could, in the near future, come into clinical practice. However, we do have tremendous understanding in terms of the natural history of the patients, as well as how to manage these patients to reach the endpoint of functional cure. So, recently, I, Professor Kennedy, Professor Yuan, and many experts from the Asia-Pacific region, as well as from Europe and the United States, we have updated the previous version of the roadmap for the functional cure. In this new version of the functional cure consensus, I think we have updated tremendous knowledge in terms of the natural history, the treatment strategies, and particularly the new potential agents that may be put into clinics in the near future.

《国际肝病》

Kennedy教授，您在本次会议中带来了题为“Utility of Novel Viral and Immune Markers in Predicting HBV Treatment Endpoints”的主题报告，能否请您简要介绍一下？

Kennedy教授

我今天作的报告是关于新型病毒和免疫标志物在确定治疗终点方面的应用。这些标志物不仅代表了我们在这一领域取得的显著进展，更是我们向慢性乙型肝炎功能性治愈目标迈进的重要工具。

具体而言，我的报告强调了两种新型标志物的应用：一是新型病毒学标志物，这些标志物在过去五到七年内可能还未被广泛认识和应用，但它们为我们提供了全新的视角来观察病毒动态；二是免疫学生物标志物，它们帮助我们更好地定义疾病、定义宿主免疫反应及免疫学控制。

这些新型标志物的出现，对于预测HBV治疗的效果、制定更为个性化的治疗方案以及最终实现功能性治愈具有重要意义。再者，这些标志物可以帮助界定治疗终点，确定安全停药的时机，识别能实现安全停药的患者，避免疾病进展或发展到肝细胞癌（HCC）的风险。

因此，我今天的演讲重点介绍了我们在新型病毒学和免疫学标志物方面的研究进展，还探讨了这些标志物如何助力宁琴教授谈到的功能性治愈路线图的制定，另一方面也让患者和医生了解安全停药时机。因此，新型标志物的研究和新药研发在实现慢性乙型肝炎治愈的方面同等重要，这些标志物将能够帮助我们更好地理解疾病和了解疾病的治疗终点。

宁琴教授

我完全同意Kennedy教授的观点，新型标志物在评估患者状态和监测治疗应答发挥关键作用。但我想就这一重要话题再补充一点。事实上，在我国国家重点研发计划中一个重要的研究目标，是研究和开发临床实用且简单易行的免疫检测方法，用于准确评估患者的免疫状态。这正是我们全国重点实验室承担的国家重点研发计划以及我所在部门目前正在积极推进的重点工作之一。我认为Kennedy教授在本次会议上提出的问题尤为关键。

Hepatology Digest : Professor Kennedy, you presented a keynote speech titled "Utility of Novel Virus and Immune Markers in Predicting HBV Treatment Endpoint" at this conference. Could you please briefly introduce it？

Patrick T.F. Kennedy：Yes, thank you. So, my presentation today was about the utility of novel viral and immune markers in determining treatment endpoints. And to pick up on what Professor Ning was saying, that presentation really highlights a lot of the progress that we've made in the field. So, it highlights the use of novel virological markers, for example, that we didn’t have maybe five or seven years ago. It highlights the progress that we are making in terms of immunological markers, in terms of better definition of disease and better definition of host immune responses and control.

So, these are really key elements in terms of predicting where we will go with treatment and with treatment endpoints and hopefully achieving functional cure. But again, more broadly, treatment endpoints are about where we can stop treatment, ideally, and the patient is safe, meaning there’s no disease progression or development of hepatocellular carcinoma (HCC). We need to be very clear that our patients are in the safest possible place before we start to determine that treatment can be stopped or not.And that is also about the prevention of dose sequelae, progression of disease, and development of liver cancer.

So, I would say my presentation today was highlighting the progress we’ve made around new novel virological markers, the progress we’ve made around immunological biomarkers, and the utility of these to help us one: develop that roadmap that Professor Ning is talking about to achieve functional cure, but also to inform patients and physicians about where it’s potentially feasible to stop treatment—where they will be safe, and there will be no disease progression or consequences of chronic hepatitis B. So, this work is equally important as the work around the development of novel agents to achieve a cure because we need the parameters and the tools to understand the disease and understand where patients will be in terms of treatment outcomes.

Qin Ning：Yes, actually, I want to add one point to this important topic. I think I fully agree that the parameters to evaluate the patient's status, as well as to monitor the treatment response, are one of the key issues. In fact, one of the important projects among all national projects in China is to study, to investigate, and possibly make significant progress in developing clinically practical and easy-to-use parameters for immune assays—immune status assays—for these patients. This is one of the projects that we are undertaking in our national key laboratory, as well as in our department. I think Professor Kennedy brings up very, very key issues in this conference.

《国际肝病》

在跨学科合作方面，请问二位认为哪些领域的合作对于推动肝炎病毒感染、肝纤维化和脂肪肝的研究与治疗最为重要？

Kennedy教授

我认为，我们都深刻认识到慢性乙型肝炎治疗的复杂性，以及实现功能性治愈所面临的挑战。因此，宁教授和我无疑都认同，合作、交流以及方法共享对于诊断、治疗手段的提高并最终实现功能性治愈至关重要。就我个人看法而言，紧密的合作、在不同种族患者开展研究，如中国患者、欧洲患者，甚至是移居欧洲的非洲患者的研究数据，都会给领域的发展带来很大益处。

我相信，只有通力合作去更好地了解疾病、制定精准的个体化治疗方案，才能取得我们期望的进展。

宁琴教授

我完全赞同Kennedy教授的观点。然而，中国的肝病研究团队与世界其他地区相比有一定的区别。在我国的医学体系中，大多数管理病毒性肝炎患者的临床医生属于传染病科，而这个科室相对于内科或外科等其他科室来说规模较小。因此，我们必须积极寻求与其他科室和医生的合作。同时，国际交流与合作也是不可或缺的。我们最近深刻体会到，与人工智能科学家的合作对于提高大数据管理的敏感性和特异性至关重要。我们通过APASL、EASL和AASLD等国际肝病学会开展的国际交流与合作对于我们来说非常重要，我们之间的合作交流已经超过15年。

Hepatology Digest : In terms of interdisciplinary collaboration, which areas of collaboration do you both consider most important for advancing research and treatment of hepatitis virus infections, liver fibrosis, and fatty liver?

Patrick T.F. Kennedy: Yes, I think we all recognize the complexity of managing chronic hepatitis B, and we’ve just talked about the complexity of trying to achieve a functional cure. So, I think both Professor Ning and I definitely understand the importance of collaboration, the exchange of ideas, and sharing approaches to improve diagnostics, therapeutics, and ultimately achieve functional cure. Personally, I see very strong benefits in working closely together, sharing research on different populations—whether Chinese patients, European patients, or African patients who have migrated to Europe.

I believe that we won’t achieve the progress we want to make without working in a collaborative way to better understand the disease, individual patients, and the different approaches we can offer them.

Qin Ning: Yes, I entirely agree. The liver disease study group in China is a bit different from other parts of the world. Most viral hepatitis clinicians are part of the Infectious Diseases Department, which is relatively small compared to other departments, like Internal Medicine or Surgery. So, we must be strong and collaborate with other departments and doctors. Also, international exchange and collaboration are essential. We’ve recently realized the importance of collaborating with AI scientists to increase sensitivity and specificity in large data management. This international exchange, as we’ve been doing through organizations like APASL, EASL, and AASLD, is crucial, and we’ve known each other for over 15 years.

《国际肝病》

请问两位教授，在肝炎及其他肝病的研究与治疗领域，合作扮演了怎样的角色？合作的重要性如何体现？

Kennedy教授

作为临床医生和医学科学家，我们深知合作在课题合作、前沿分享以及促进跨地区团队合作方面的重要性。例如，除了慢性乙型肝炎外，代谢相关脂肪性肝病正在成为全球慢性肝病的主要病因。有效合作是帮助我们深入了解中国与欧洲或英国在疾病表现和治疗需求上的差异的关键。

宁琴教授

没错。我们目前面临的一个重大挑战是，在慢性病毒性肝炎合并脂肪肝的患者的抗病毒治疗领域尚未形成统一的共识和指南，因此需要进一步深入研究，为这些患者抗病毒治疗策略的制定提供更多的证据。

Hepatology Digest : May I ask, professors, what role does collaboration play in the research and treatment of hepatitis and other liver diseases? How is the importance of collaboration manifested?

Patrick T.F. Kennedy: Yes, exactly. I think as physicians and physician-scientists, we understand the importance of collaboration in securing grant funding, sharing ideas, and having team members work across different regions. For instance, metabolic liver disease, in addition to hepatitis B, is becoming more common. Understanding how this differs in China versus Europe or the UK is crucial, and collaboration is key to addressing these challenges.

Qin Ning: Exactly. One of the areas where we don’t yet have a consensus or guidelines is in the treatment of patients with chronic viral hepatitis and coexisting fatty liver disease. We need more studies to provide evidence supporting antiviral treatment strategies for these patients.