2021欧洲艾滋病毒与肝炎学术会议于5月26日至28日以线上形式顺利召开。本次会议中，围绕不同肝炎疾病的多项研究及热点话题得以展示报告及讨论，其中包括热点主题话题——慢性乙型肝炎（CHB）。

CHB仍然是一个主要的全球健康问题，影响着全球超过2.4亿肝病相关的高发病率和死亡率[1]。但自1992年乙肝疫苗纳入计划免疫规划，到今天多种乙肝的新型抗病毒药物的研发及应用，乙肝治疗在临床上已取得了很大的进展，部分患者可通过抗病毒治疗实现功能性治愈[2,3]。而在当前的临床研究环境下，实现乙肝治愈还有多远？还存在着哪些困难及挑战？目前的研究进展如何？我们还需作出哪些方面的努力？

基于此，在2021欧洲艾滋病毒与肝炎学术会议期间，法国里昂大学Fabien Zoulim教授进行了一项关于“Progress and Challenges in Achieving Hepatitis B Virus Cure”的主题报告，并就上述问题接受了《国际肝病》的采访，具体内容如下。

《国际肝病》：HBV治愈如何定义？HBV感染的治疗策略及根本目标是什么？如何才能实现HBV的临床治愈？

Fabien Zoulim教授：临床治愈（或功能性治愈）指的是停止治疗后仍然保持乙肝表面抗原（HBsAg）阴性（伴或不伴有抗-HBs出现）、HBV DNA检测不到、肝脏生物化学指标正常。该定义是基于可用于常规检测的临床标志物，但通过分析观察肝脏的情况，我们能看到更多的复杂性，且我们可以观察肝脏中cccDNA的进化。在功能性治愈情况下，肝脏中cccDNA减少，也可以沉默，这解释了在患者中观察到的HBsAg丢失。另一个重要的临床定义是，乙肝停止治疗后达到持续的病毒学应答，即HBsAg的消失在治疗停止后具有持久性。

此外，如何才能实现HBV的临床治愈？这可以通过两种不同方面的新抗病毒方法来实现。一种是尝试用直接作用抗病毒药物来抑制病毒复制。另一种是尝试刺激激活抗病毒免疫应答来对抗病毒。在某种程度上，我们可能需要将直接作用抗病毒药物与刺激激活抗病毒免疫应答相结合，以实现患者的临床治愈。这是定义肝炎患者实现临床治愈的一个要点。

Hepatology Digest: How is HBV cure defined? What are the treatment strategies and fundamental goals of HBV infection? How can the clinical cure of HBV be achieved?

Professor Fabien zoulim:Functional cure is defined by the loss of HBsAg in the serum, with or without anti-HBs antibody seroconversion. This definition is based on clinical markers that can be used in the routine setting, but we can also add more complexity if we look at what is happening in the liver with assays, and we can look at the evolution of cccDNA in the liver. In the setting of functional cure, cccDNA is decreased in the liver, and it can also be silenced, which explains the HBsAg loss observed in patients. Another important clinical definition is that HBs loss should be sustained after treatment cessation and it should be durable once treatment has been stopped. 

The other part of the question was how we can achieve a functional cure in patients. This can be achieved with new antiviral approaches involving two different aspects. One is to try to inhibit viral replication with direct-acting antivirals. The other part is to try to stimulate the antiviral immune responses to combat the virus. At some point, we may need to combine direct-acting antivirals with immune stimulation to achieve a functional cure in patients. So this is a main point in the definition of achieving a functional cure in patients with hepatitis.

《国际肝病》：直接作用抗病毒药物治疗HBV感染后患者的临床结局如何？

Fabien Zoulim教授：对于直接作用抗病毒药物，目前我们可以应用的有核苷（酸）类似物，这类药物在病毒抑制方面可以实现HBV DNA检测不到，但HBsAg仍然可以检测到，因此需要继续治疗。

病毒抑制与ALT正常化、炎症减轻、纤维化进展/肝硬化风险降低和肝细胞癌风险降低相关。核苷（酸）类似物等抗病毒治疗可通过抑制病毒复制，减轻肝组织炎症，从而降低肝硬化和肝癌的发生风险，最终能够带来更好的临床结局。然而，癌症的风险并没有完全消除，甚至在病毒抑制的患者中，仍然存在癌症的残留风险。这就是为什么我们需要做得更多，而不仅仅是通过抑制病毒来实现功能性治愈，从而能够更有效地预防肝癌的发生。

Hepatology Digest:What are the clinical outcomes of patients with HBV infection treated with direct action antiviral drugs?

Professor Fabien zoulim:With direct-acting antiviral drugs, we currently have nucleotide analogs (tenofovir, entecavir) available. With these drugs, we can achieve viral suppression with undetectable HBV DNA but HBsAg still detectable, so we need to continue treatment. 

Viral suppression is associated with normalization of ALT, a decrease in inflammation, decreased progression of fibrosis/risk of cirrhosis, and a decreased risk of hepatocellular carcinoma. The current direct-acting antiviral drugs in the form of nucleotide analogs achieve viral suppression and a better clinical outcome by preventing cirrhosis and decreasing the risk for cancer. However, the cancer risk is not completely eliminated and there is still a residual risk of cancer, even in patients with viral suppression. This is the reason why we need to do more than just viral suppression to achieve a functional cure to bring about more significant prevention of liver cancer.

《国际肝病》：您觉得应该如何对HBV感染患者进行管理？

Fabien Zoulim教授：对HBV感染患者进行管理，这确实取决于疾病感染的不同阶段。但总的来说，我认为我们需要通过筛查人群中的HBsAg来做出早期诊断，那些病毒载量高的患者应该尽早接受治疗。此外，我们知道，如果不抑制病毒的复制，病毒就会整合到肝细胞中，从而会加大肝癌的发生风险。因此，我们应该加大人群筛查的力度，做出早期诊断，然后对于病毒载量高且伴有或不伴有ALT升高的患者，我们可能需要尽快对其展开治疗，而不是等待病毒复制后才开始治疗，那样就太晚了。

Hepatology Digest:How do you think the patients with HBV infection should be managed?

Professor Fabien zoulim:For patients with HBV infection, it really depends on the stage of disease we would be managing, but overall, I think we need to make an early diagnosis by screening the population for HBsAg, and those with a high viral load should be treated as soon as possible. We know that if leave viral replication unchecked there will be integration of the virus into the liver cells, which is a molecular advantage to the development of liver cancer. So we should make a lot of effort to screen the population, make an early diagnosis and then for a patient, who has a high viral load with or without ALT elevation, we may decide to start treatment as soon as possible and not wait for viral replication to commence treatment, otherwise it could be too late.

《国际肝病》：目前临床上现有及新型治疗HBV的药物有哪些？各有什么特点？

Fabien Zoulim教授：目前，临床上有许多核苷（酸）类似物，在批准的药物中，主要包括恩替卡韦（ETV）、替诺福韦（TDF）和丙酚替诺福韦（TAF）这三种药物。聚合酶抑制剂可以阻断病毒复制，因此在使用上述药物治疗时我们可以看到病毒的抑制，最终可以使HBV DNA在患者血清中检测不到。另一类药物是干扰素，但由于其副作用和通过注射的给药方式，因此它并不常用。而核苷（酸）类似物是以片剂的形式提供，因此它们更易于使用。

Hepatology Digest:What are the existing and new drugs for treating HBV in clinical practice? What are their characteristics? 

Professor Fabien zoulim:Currently, what are available in the clinic are many nucleotide analogs. We have tenofovir. We have a prodrug which is tenofovir alafenamide (TAF). And we have entecavir. These are the three main drugs approved. The inhibitors of polymerase block viral replication, so with these drugs we should see viral suppression so HBV DNA is undetectable in serum in patients. The other drug class is interferon, but it is not commonly used because of side effects, as well as the mode of administration, as it is administered by injection. The nucleotide analogs are given as tablets, making them much easier to use.

《国际肝病》：应用现有及新型治疗药物能否实现HBV的彻底治愈？若可以，请详述；若不行，那HBV治愈之路还有多远？

Fabien Zoulim教授：正如我前面概述的那样，通过直接作用抗病毒药物可以实现治愈。目前有新的抗病毒药物已经被开发出来，包括进入抑制剂、衣壳抑制剂和siRNA。此外，还有HBsAg释放抑制剂，一类直接作用抗病毒药物。在免疫治疗方面，有免疫刺激剂，包括先天免疫增强剂（例如TLR激动剂），免疫检查点抑制剂（如PD-1阻断剂），或通过治疗性疫苗刺激免疫应答。

因此，目前我们有很多治疗乙肝的抗病毒新药，并都具有临床意义。这些药物中，有的直接攻击病毒，有的则刺激免疫应答。我非常肯定，在未来几年内，我们会找到正确的药物组合，以提高功能治愈率。但目前我不确定这是否能治愈所有患者，不过肯定会增加获得功能性治愈的患者数量。

Hepatology Digest:Can the complete cure of HBV be achieved by using existing and new therapeutic drugs? If possible, please elaborate; If not, how far is a cure for HBV?

Professor Fabien zoulim:A cure can be achieved, as I outlined earlier, with the direct-acting antivirals. There are new antivirals that have been developed – entry inhibitors, capsid inhibitors. We also have siRNA. We have HBsAg release inhibitors which are direct-acting antivirals. There are also immune stimulants as part of an immunotherapeutic approach, which rely either on an innate immunity booster (TLR agonists, for instance), or adaptive immunity with checkpoint inhibitors (like PD-1 blockers), or stimulation of the immune response through therapeutic vaccines. 

So we have a lot of assets and all of them make sense. Some directly attack the virus, while others stimulate the immune response. I am pretty sure that in a few years from now we will find the right combination to increase the rate of functional cure. I am not sure if we can cure all patients, but we will certainly increase the number of patients with a functional cure.

《国际肝病》：要实现HBV的治愈，还存在哪些挑战或尚未解决的问题？

Fabien Zoulim教授：要实现HBV的功能性治愈，目前还伴随着一些挑战。首先是cccDNA，即病毒的微小染色体，由于乙肝病毒复制周期的特殊性，导致乙肝病毒无法从受到感染的肝细胞中根除。所以我提到的使用直接作用抗病毒药物的方法并不是直接针对cccDNA。如果我们想根除cccDNA并彻底治愈感染，那么我们就需要寻找针对消除cccDNA的药物，这些正在实验模型中进行研究，目前仍处于临床前评估阶段。

对于免疫应答来说，也存在着挑战。目前通过临床研究还很难克服T细胞或B细胞耗竭，因此我们需要更多地了解如何调节感染患者肝脏的免疫应答。

目前我们正在进行大量关于病毒和免疫应答方面的研究。我非常肯定，在不久的将来，我们可以在更多的患者身上实现功能性治愈。

Hepatology Digest:To achieve the cure for HBV, what are the challenges or unresolved problems?

Professor Fabien zoulim:To achieve functional cure, there are several challenges. The first is that cccDNA, the viral minichromosome, is very difficult to eliminate from infected cells, so the approaches I have mentioned using direct-acting antivirals are not directly targeting cccDNA. If we want to eradicate cccDNA and achieve a complete cure of infection, then we will need drugs that eliminate cccDNA. These are currently under investigation in experimental models. These are very interesting but still in preclinical evaluation. 

For the immune responses, there are challenges because in clinically infected patients, the adaptive immune responses are exhausted. It is very difficult to overcome this T-cell or B-cell exhaustion, so we need to learn more about modulating immune responses in the liver of infected patients. 

A lot of work is being done now both directly on the virus and the immune responses. I am pretty sure we can achieve a functional cure in many more patients in the near future.

参考文献

1)Mouzannar K, Liang TJ. Hepatitis B virus-recent therapeutic advances and challenges to cure. J Hepatol, 2020, 73(3): 694-695. 

2)闫永平, 张维璐, 苏海霞, 等. 我国乙型病毒性肝炎防治研究新进展和面临的挑战[J]. 中国热带医学, 2019, 19(10): 916-921.

3)刘小菊, 张政. 从HBV特异性免疫细胞角度谈慢性乙型肝炎功能性治愈[J]. 临床肝胆病杂志, 2020, 36(5): 977-979.