乙型肝炎病毒表面抗原（HBsAg）血清学清除被认为是慢性乙型肝炎（CHB）患者治疗的理想目标。以往的研究一致证明HBsAg血清学清除对肝细胞癌（HCC）发生风险存在有益影响。然而，HBsAg血清学清除对HCC根治性肝切除术后复发的影响尚不清楚。在今年的美国肝病研究学会年会（AASLD2021）期间，韩国首尔蔚山大学医学院牙山医学中心Jonggi Choi教授进行了一项题为“IMPACT OF HBsAg SEROCLEARANCE ON THE RECURRENCE OF HEPATOCELLULAR CARCINOMA AFTER CURATIVE LIVER RESECTION”的口头报告（AASLD2021. Oral 64.），该报告研究比较了有无实现HBsAg血清学清除患者之间的HCC复发率。本期《国际肝病》特别邀请到Jonggi Choi教授围绕该主题内容作进一步分享。

 

 

《国际肝病》：HBsAg血清学清除的相关机制是什么？此外，促进HBsAg清除或血清学转换的潜在治疗靶点有哪些？

 

Choi博士：HBsAg血清学清除被认为是慢性乙型肝炎患者治疗的理想目标。HBsAg血清学清除被称为功能性治愈。我们追求HBsAg消失的原因是，一旦实现HBsAg消失，我们就可以期待更好的长期结果，包括HCC的发展。然而，实现这种功能性治愈的主要障碍是HBV的复制和HBsAg的产生有多条途径。它可能来自肝细胞中的cccDNA，也可能来自宿主细胞中整合的HBV DNA。此外，乙肝感染患者通常对乙肝病毒的免疫反应减弱。问题是HBsAg消失在乙肝感染的自然病程中很少发生。为了实现这一目标，我们一直在进行各种抗病毒治疗，但目前的抗病毒治疗，如干扰素或口服抗病毒治疗，HBsAg消失非常低。最近一些研究表明，如果停用核苷（酸）类似物（NUC），可能会增加宿主免疫HBsAg消失的机会。然而，这种NUC停药策略在亚洲患者中效果不佳，总是有肝失代偿的风险，有时对患者来说是非常危险的。考虑到乙肝感染的自然生命周期，许多靶标可能帮助清除HBsAg，实现功能性治愈。目前正在研制一些药物以阻断这些靶标。有些药物，例如抗Cp抑制剂，阻止HBV进入肝细胞。有些药物可以阻断病毒RNA的翻译。有些药物会阻止衣壳的组装。还有一种药物可以减少HBsAg分泌到血液中。这些是实现慢性乙型肝炎患者功能性治愈的潜在治疗靶标。

 

Hepatology Digest: What is the relevant mechanism of HBsAg serological clearance? In addition, what are the potential therapeutic targets helpful to HBsAg clearance? and /or? sero-conversion?

 

Dr Choi: Basically, HBsAg seroclearance is regarded as a realistic goal in the management of patients with chronic hepatitis B. HBsAg clearance is called a functional cure. The reason why we are pursuing HBsAg loss is that once HBsAg loss is achieved, we can expect better long-term outcomes, including for the development of HCC. However, the main barriers to achieving this functional cure is that there are many avenues for hepatitis B replication and HBsAg production. It could be from cccDNA in the hepatocyte, or it could be from integrated HBV DNA in the host cells. In addition, patients with hepatitis B infection usually have impaired immune responses against the hepatitis B virus. The problem is that HBsAg loss occurs very rarely in the natural history of hepatitis B infection. We have been treating with various antiviral treatments to achieve this goal, however the rate of HBsAg loss is very low with the current antiviral treatments, such as interferon or oral antiviral treatment. Recently, some studies have shown that if NUCs are stopped, it might increase the chance of HBsAg loss by the host’s immunity. However, this NUC-stopping strategy did not work well in Asian patients. This stopping strategy always carried the risk of hepatic decompensation, which is sometimes very dangerous for patients. Regarding achieving HBsAg seroclearance, we have many targets for a functional cure considering the natural life cycle of hepatitis B infection. Drugs in the pipeline today try to block these targets. Some drugs, for example, anti-Cp inhibitors, do not allow HBV to enter the hepatocyte. Some drugs block translational viral RNA. And some drugs will block capsid assembly. There is also a drug that reduces secretion of HBsAg into the blood stream. So, these are the potential therapeutic targets for achieving functional cure in patients with chronic hepatitis B.

 

《国际肝病》：哪些指标可预测HBsAg血清学清除？自发性和抗病毒治疗所致的HBsAg血清学清除有何异同点？

 

Choi博士：不幸的是，到目前为止，还没有强有力的指标来保证或预测HBsAg血清学清除率。不过一些研究报道，血液中HBsAg的滴度也许能反映自然病程和抗病毒治疗患者达到HBsAg血清学清除的可能性。HBsAg滴度越低，HBsAg清除率越高。

 

关于你的第二个问题，去年我们比较了自发性HBsAg丢失和治疗诱导的HBsAg丢失之间的长期结果。这项研究发表在去年的Hepatology杂志上。我们的研究结论是，这两种HBsAg丢失在长期预后（包括HCC、死亡和肝移植）方面没有显著差异。换句话说，一旦实现HBsAg消失，我们就可以期待良好的预后结果。因此，基于我们的研究，方法并不重要。随后中国香港开展的一项研究也显示出与我们一致的结果。总之，目前最重要的还是如何实现HBsAg消失，以及该如何提高HBsAg丢失率。

 

Hepatology Digest: What indicators can predict HBsAg serological clearance? What are the similarities and differences between the spontaneous HBsAg serological clearance and those induced after antiviral therapy?

 

Dr Choi: Unfortunately, there has been no strong indicator to guarantee or predict HBsAg seroclearance so far. However, some studies reported that when we measure HBsAg titer in the blood, this may reflect the possibility of HBsAg seroclearance in the natural history and in patients on antiviral treatment. The lower the HBsAg titer, the higher the probability of HBsAg clearance. For your second question, last year we compared the long-term outcomes between spontaneous HBsAg loss and treatment-induced HBsAg loss. This study was published in Hepatology last year. The conclusion of our study was that there is no significant difference in the long-term prognosis, including HCC, death and liver transplantation, between these two HBsAg losses. In other words, once HBsAg loss is achieved regardless of the way, we can expect a good prognosis. Therefore, the way is not important based on our study. A following study from Hong Kong also showed consistent results to ours. In conclusion, the most important thing again is how we can achieve HBsAg loss and how we can increase the rates of HBsAg loss, regardless of the way.

 

《国际肝病》：您的研究显示，HBsAg清除可降低HCC根治性肝切除术后复发风险；但复发风险仍然存在且逐年累积增长。对此，您的看法是什么？应该如何应对？

 

Choi博士：一般来说，肝癌根治术后肿瘤复发的风险在肝切除术后不久最高，接着慢慢下降到两年，然后风险从那时开始逐渐增加。不幸的是，复发的风险永远不会消失。基于此，根据复发时间的不同，肝切除术后复发可分为早期复发和晚期复发。当两年内复发时，通常视为早期复发。这种早期复发大多起源于未切除肝脏中的残余肿瘤，这基本上与侵袭性肿瘤生物学有关，例如大尺寸肿瘤、多发性肿瘤、有血管浸润的肿瘤。如果两年后复发，则视为晚期复发。晚期复发的风险因素与传统HCC风险因素相同，例如男性、高龄和未控制的潜在肝病。

 

在AASLD2021上报告的这项研究中，我们关注晚期复发而非早期复发，因为正如我前面提到的，我们想知道HBsAg血清学清除是否对肝切除术后HCC复发风险存在有益影响。有趣的是，我们的研究结果表明HBsAg丢失与HCC复发风险降低相关。我想从我们的研究中强调的一点是，首先，即使在HCC肝切除术后，HBsAg丢失仍然具有有益的作用，可以减少HCC复发。其次，大家可能还记得几年前关于丙型肝炎患者经DAA治疗后取得SVR是否影响HCC复发风险的争论。许多研究得出结论，复发风险与SVR或治疗无关，我们的研究也在关注类似的背景，唯一的变化是我们关注的是乙型肝炎病毒而不是丙型肝炎病毒。所以我想说，即使诊断为HCC，在患者接受了根治性治疗后，他们仍然可以成为HBV治愈的候选者，因为正如我们在研究中所显示的，HBsAg丢失将降低HCC复发的风险。

 

Hepatology Digest: A study presented at this AASLD shows that HBsAg clearance is associated with the reduction of the relapse risk of liver cancer after radical hepatectomy. However, the risk of recurrence still exists and increases over time. What is your opinion on this? How should we deal with it?

 

Dr Choi: In general, when we look at the risk of recurrence after liver resection, the risk is highest shortly after the liver is sectioned, and then it goes down slowly up to two years, then the risk begins to increase gradually from that point. Unfortunately, the risk of recurrence is never going to disappear. Based on this, recurrence after liver resection can be divided into early and late recurrence, depending on the timing of recurrence. When the recurrence occurs within two years, this is usually regarded as early recurrence. This early recurrence mostly originates from residual tumor in the unresected liver, and this is basically associated with aggressive tumor biology, for example, a large size tumor, multiple tumors, tumors with vascular invasion. However, when recurrence happens after two years, then it is called late recurrence. This late recurrence is considered to be a newly developed tumor, even though it is still referred to as a recurrence. I would like to say that this would technically be a new tumor, therefore risk factors for late recurrence are shared with conventional HCC risk factors, for example, male, old age, and uncontrolled underlying liver disease. In the study presented at this AASLD 2021, we focused on late recurrence rather than early recurrence, because as I mentioned earlier, we would like to know whether there is a beneficial effect of HBsAg seroclearance in the risk of HCC recurrence after liver resection. Interestingly, the results of our study show that HBsAg loss was associated with a lower risk of HCC recurrence. The points I would like to stress coming out of our study are that first, even after liver resection for HCC, there is still a beneficial effect of HBsAg loss, which reduces recurrence. And second, you might remember a few years ago there was a debate regarding whether SVR in hepatitis C virus affects the risk of HCC recurrence. Many studies concluded that the risk of recurrence was not associated with SVR or treatment, and our study is looking at a similar context, with the only change being with hepatitis B instead of hepatitis C virus. So I would like to say that even after HCC diagnosis, once the patient has received curative treatment, they can still be a candidate for HBV cure, because, as we have shown in our study, HBsAg loss will reduce the risk of HCC recurrence.

 

《国际肝病》：请您谈一谈基于现有的以及更新的临床治疗方案，该如何提高患者HBsAg血清学清除率？

 

Choi博士：在过去的十年里，人们一直在努力提高HBsAg血清学清除率。对于现有的治疗方法（NUC或干扰素），我们并不满意。应用这两种疗法的HBsAg丢失率仍然很低，尤其是在亚洲患者中。然而，有许多抗HBV新药正处于研发中，它们作用于HBV生命周期的不同环节。一些新的治疗方法试图增强免疫以清除病毒。最近一些研究报告显示的数据可观，但是我们仍然需要进行更多的研究以解决临床的未满足需求。例如，哪一类药物对功能性治愈更有效——siRNA、CpAM或其他类型？此外，对于仅仅使用一类药物是否足够，或者联合用药是否更有效地实现功能性治愈，目前我们还没有答案。我认为，除了这些新的治疗方法外，还应该研究现有治疗方法的作用。NUC和干扰素——功能性治愈还需要它们吗？或者，哪种组合效果更好？这些问题应该在不久的将来进一步研究。

 

Hepatology Digest: Could you please talk about how to improve the HBsAg serological clearance rate with the existing and future therapy?

 

Dr Choi: There has been a lot of effort to try to improve the rate of HBsAg seroclearance over the past decade. With existing treatment （NUC or interferon）, we are not satisfied with these options to increase the rate of functional cure. The rate of HBsAg loss by applying these two treatments is still very low, especially in Asian patients. However, there are lots of new drugs in the pipeline for functional cure of HBV. New treatments in the pipeline work on various pathways of the HBV life cycle. Some new treatments try to enhance our immunity to clear the virus. Promising studies have been reported recently, however, we still need to wait for more studies, because many questions are still unanswered. For example, which class of drugs will be more effective for a functional cure - a siRNA, CpAM, or other classes? In addition, we have no answers at to whether just one class of drugs is enough, or whether a combination of drugs is more effective to achieve functional cure. I think, together with these new treatments, the role of existing treatments should also be studied. NUCs and interferon - are they still needed for functional cure? Or, what combination will work better? These questions should be further studied in the near future.