编者按：随着对慢性乙型肝炎病毒（ HBV）感染的病毒学、细胞生物学和宿主免疫的不断了解，乙型肝炎领域正在迅速发展，但从目前形势看，只有不同研究领域密切合作才能实现慢性 HBV 感染的功能性治愈。

 

为此，国际消除HBV联盟（ICE-HBV）与欧洲肝脏研究学会（EASL）于2021年第56届EASL年会期间联合举办“Understanding immunological and virologic responses in the liver to cure HBV infections”专题讨论会，旨在分享最新进展，为致力于开发治愈HBV持续感染方法的研究人员提供更多机会。

 

《国际肝病》有幸邀请到专题主持、ICE-HBV发起人之一、临床病毒性肝炎和抗病毒治疗领域的权威专家、法国里昂大学Fabien Zoulim教授展望治愈HBV的未来十年之路。
 

 

 

《国际肝病》：病毒性肝炎中，丙型肝炎已经可以实现治愈，但是乙型肝炎仍在艰难探索中。能否请您谈谈目前国际上普遍认可的治愈HBV感染的最终治疗靶点，以及追求或者未来有望实现的临床治疗目标？

 

Fabien Zoulim教授：这是一个非常重要的问题。正如您所说，现在使用新的治疗方法可以轻松治愈丙型肝炎。对于乙型肝炎，我们有核苷（酸）类似物来抑制病毒，但由于病毒在肝脏中持续存在，因此需要终生治疗。

 

现在，正在兴起的新治疗聚焦在实现功能性治愈，治疗时间有限且较短。功能性治愈定义为患者治疗停止后持续HBsAg消失，有望带来持续的抗病毒作用、改善肝脏疾病和预防肝细胞癌。这些都是非常重要的终点和目标。

 

: Among viral hepatitis, hepatitis C can be cured, but hepatitis B is still being explored hard. Could you please talk about the current internationally recognized ultimate therapeutic target for curing hepatitis B virus (HBV) infection, and the clinical treatment goals that are pursued or expected to be achieved in the future?

 

Prof. Fabien Zoulim: Hello everyone, and thank you for this invitation. This is a very important question. As you said, hepatitis C can be cured easily now with the new treatments. For hepatitis B, we have the nucleotide analogs to achieve viral suppression, but it requires lifelong therapy because of persistence of the virus in the liver. 

 

Now, the focus of new treatments that are emerging is to achieve a functional cure with a finite duration shorter treatment with functional cure defined by HBsAg loss that is sustained after treatment cessation. This is expected to bring about a sustained antiviral effect, improvement of liver disease, and prevention of hepatocellular carcinoma. These are very important endpoints and targets.

 

《国际肝病》：慢性乙型肝炎病毒（HBV）较难实现治愈的主要原因是什么？对此，目前我们已经采用或者正在探索的治愈策略有哪些？

 

Fabien Zoulim教授：又是一个很重要的问题。丙型肝炎病毒仅通过复制的方式来维持肝细胞感染状态。当我们阻止复制时，病毒就会逐渐消失而被消灭。对于乙型肝炎，我们有两种持续存在的机制，这就解释了为何治愈HBV感染如此困难。

 

第一种机制是病毒基因组库cccDNA作为微染色体持续存在于受感染细胞核中。目前无法将其消除，所以如果我们停止治疗，来自cccDNA的病毒感染就会复发。第二种机制是慢性感染患者中，机体针对HBV感染细胞的抗病毒免疫反应耗竭。

 

从当前已进入临床试验阶段的在研新方案看，治愈HBV的主要策略或目标是：①更有效地阻止复制以对 cccDNA 产生间接影响；②直接靶向cccDNA实现根除cccDNA的最终目标，但这非常具有挑战性；③恢复抗病毒免疫反应，刺激疲惫的免疫系统。

 

: What is the main reason that chronic hepatitis B virus (HBV) is difficult to cure? In this regard, what are the cure strategies that we have adopted or are exploring?

 

Prof. Fabien Zoulim: Again, a very important question. Hepatitis C virus is maintained in the infected cell just by replication. When we block replication, then the virus will fade away and be eliminated. With hepatitis B, we have two mechanisms of persistence, which explain the difficulty of curing an infection. 

 

One is the persistence of cccDNA, the viral genome archive, as a minichromosome in the nucleus of the infected cells. This can currently not be eliminated, so if we stop treatment, there is a relapse of viral infection coming from this cccDNA. The second mechanism is the fact that the antiviral immune responses against the HBV-infected cells are exhausted in chronically infected patients. 

 

Now, regarding the new strategies that are being developed, they aim to block replication much more efficiently to have an indirect effect on cccDNA, or to target cccDNA directly towards the ultimate goal of eradicating cccDNA, but this is very challenging. A third aspect is that we need to restore antiviral immune responses and stimulate the exhausted immune response. These are the main strategies that are being developed in clinical trials today.

 

《国际肝病》：围绕以上主要策略，目前相关新药研发，以及新治疗方案探索的进展如何？您认为未来研究的重点或者趋势是什么？

 

Fabien Zoulim教授：目前，这确实是一个非常活跃的领域，有很多令人兴奋的发现，我们有许多直接作用抗病毒药物（例如衣壳组装调节剂），RNA 靶向策略（例如siRNA和反义寡核苷酸）。我们有试图阻止病毒释放的策略，例如核酸聚合物，以及新型核苷类似物和病毒进入抑制剂。这些是非常令人兴奋的对抗病毒的工具。他们正在进行临床试验，包括Ib期、IIa期甚至IIb期。还有一些使用TLR激动剂、检查点抑制剂和治疗性疫苗的免疫调节策略正在临床试验中进行评估。

 

现在真正的挑战也是真正有趣的是，我们拥有不同的工具或直接或借助免疫反应来对抗病毒，但是我们如何将所有这些不同的药物结合起来，以使治疗更有效并且实现功能性治愈呢？联合治疗策略是未来非常有前景的方向，目前临床试验正在积极探索，所以我们应该在未来几年内能看到这方面的进展。

 

: Based on the above main strategies, what is the current progress in the research and development of relevant new drugs and the exploration of new treatment options? What do you think will be the focus or trend of future research?

 

Prof. Fabien Zoulim: Currently, there is a lot of excitement and it is really a very dynamic field today where we have many drugs that are directed against the virus, the direct-acting antivirals, such as the capsid assembly modulators, RNA targeting strategies such as siRNA and antisense oligonucleotides. We have strategies trying to block viral egress, such as the nucleic acid polymers, as well as novel nucleoside analogs and virus entry inhibitors. These are very exciting tools to combat the virus. They are in clinical trials – phase Ib, phase IIa and even phase IIb. There are also immune modulatory strategies using TLR agonists, checkpoint inhibitors and therapeutic vaccines that are being evaluated in clinical trials. 

 

Now the real challenge, and what is really interesting, is that we have all the different tools to combat the virus either directly or via the immune response, but how are we going to combine all these different drugs to be more efficient and to achieve a functional cure in patients? Clinical trials are currently addressing the issues of combination treatment strategies, so we should see in the next couple of years how this will progress. There is a lot of hope in that direction.

 

《国际肝病》：您是临床病毒性肝炎和抗病毒治疗领域公认的专家，也是消除HBV国际联盟的发起人之一。面对WHO提出的“2030年消除病毒性肝炎作为重大公共卫生威胁”的目标，您认为未来3～5年，临床医生、科研人员，以及相关人员应如何努力来实现慢性HBV感染的功能治愈？

 

Fabien Zoulim教授：这是一个非常重要的公共卫生问题。HBV确实是一个全球性问题，有超过2.5亿慢性携带者处于肝癌高风险状态。在未来十年内，对于消除病毒性肝炎作为重大公共卫生威胁的目标，我们将寻找不同方法联合行动的策略。

 

第一，是有更好的疫苗接种覆盖率，以预防新发感染。这是首先要解决的问题，因为我们知道疫苗接种会使HBV流行率下降，同时降低人群中的HCC发病率。

 

第二，对于已经发生慢性感染的人群，首先是确保患者了解他们的状态，因此提高对乙型肝炎的认识并进行筛查计划以确定人们是否被感染是必不可少的。这不仅要求医生，而且患者及所有相关人员都需要具备这方面的知识，并且将筛查工作放在该战略的最前沿。

 

其次，一旦人们知道自己是病毒携带者，他们就建立了治疗连接。许多HBV感染者住在远离医院和转诊中心的地方，建立治疗连接对他们而言非常重要。最后，需要对患者进行最佳临床管理，以获得正确诊断，并个体化给予有治疗适应证的患者有效抗病毒治疗。核苷（酸）类似物可以抑制病毒复制，减少肝脏炎症和纤维化，并且降低但不能消除HCC的风险。

 

但是，以上所有措施都需要大量资源来支持，我们需要与每个国家的卫生部门合作，以了解每个地区肝炎问题的严重程度，并将资源相应合理地用于乙型肝炎管理。

 

显然，候补策略来自我们前面已经讨论过的研究，希望可以找到更好的治疗方法。这些新疗法可以口服给药，治疗持续时间短，功能性治愈率达到30%或更多。如此我们将能够治疗所有携带者，同时带来高比率的功能性治愈率。这些新疗法是未来十年的希望。

 

: You are a recognized expert in the field of clinical viral hepatitis and antiviral therapy, and one of the initiators of the International Coalition to Eliminate HBV (ICE-HBV). Facing the WHO's goal of "eliminating viral hepatitis as a major public health threat by 2030", how do you think clinicians, researchers, and related personnel should work hard to achieve the functional cure of chronic HBV infection in the next 3 to 5 years?

 

Prof. Fabien Zoulim: This is a very important public health question. HBV is really a global problem with more than 250 million chronic carriers at a high risk of liver cancer. The issue of eliminating viral hepatitis as a major public health threat within the next ten years is looking to combine different approaches. 

 

One is to have better coverage for the vaccination to prevent new infections. That is the first thing to work out since we know it results in a decreased prevalence of HBV and a decreased incidence of HCC at the population level. 

 

For those who are already chronically infected, the first issue is to ensure patients know their status, so raising awareness of hepatitis B and doing screening programs to identify if people are infected or not is essential. This requires that not only doctors, but also patients and all the stakeholders are armed with knowledge and that screening efforts are at the forefront of this strategy. 

 

The second thing is that once people know they are carriers of the virus that they are linked to care. This is a major issue, because many people infected with HBV are living far away from hospitals and referral centers. The linkage to care is very important. And then, there is a need for an optimal clinical management of patients for a correct diagnosis, and antiviral treatment with drugs that we know are effective for those patients in need (NUC can suppress viral replication, decrease inflammation and fibrosis in the liver, and decrease (but not eliminate) the risk of HCC). 

 

But all of this needs a lot of resources and we need to work with Ministries of Health in each country in order to understand the significance of the problem in each location, and that resources are devoted accordingly for the management of hepatitis B. 

 

Obviously, the complementary approach is to support research as we have discussed, looking for better treatments that can be administered orally with a short duration of treatment providing a functional cure of 30% or more. Then we would be able to treat all carriers and provide a high rate of functional cure. That is the hope for the next ten years.

 

来源：《国际肝病》编辑部