根据HBV病毒复制水平、机体免疫系统状态和肝损害情况，慢性乙型肝炎（CHB）发展过程一般可分为4期，即免疫耐受期、免疫清除期、非活动期或低（非）复制期和再活动期。2017年EASL对CHB免疫耐受期的定义为：HBsAg阳性≥6个月，HBeAg阳性，HBV DNA＞106 IU/mL，ALT或AST水平正常或轻微增高，肝活检或无创检查显示无肝纤维化或轻微炎症。对于CHB免疫耐受期患者的治疗意见，EASL、AASLD、APASL等指南有不同的推荐意见，大多推荐一般情况下无需立刻治疗，监测随访为主。但近年来积累越来越多证据显示，处于免疫耐受期的CHB患者同样需要启动抗病毒治疗。
第57届欧洲肝病研究学会年会（EASL2022）暨2022年国际肝脏大会TM（ILC 2022）上，希腊雅典国立Kapodistrian大学George Papatheodoridis教授主持了主题为“免疫耐受期乙肝患者是否需要治疗”的专家论坛，《国际肝病》有幸在现场采访了George Papatheodoridis教授，围绕免疫耐受期CHB患者的管理要点、目前治疗方案、治疗时机以及未来新药研发方向等角度，展开深入、丰富的探讨。
《国际肝病》
近年来越来越多的证据显示，免疫耐受期乙肝患者的疾病进展风险被低估。请您结合临床实践谈一谈既往不推荐免疫耐受期患者接受抗病毒治疗的原因和考虑？
George Papatheodoridis教授
的确，最近有研究表明，免疫耐受患者可能存在进展期组织学病变。我认为这是由于有新的数据证明这个阶段的患者虽然符合免疫耐受的标准，但随着年龄增长，出现进展期更高的肝脏病变的风险肯定更大。这可能是由于在免疫耐受期，慢性活动性乙肝出现暂未被识别的阶段，这些阶段并不完全，也不会自发进展为HBeAg血清清除。所以，我们既往不建议对免疫耐受患者进行治疗的原因是没有非常好的药物，因为如果没有有效的治疗方法，就会犹豫要不要治疗。
我们用目前的药物治疗免疫耐受患者，干扰素实际上无效，且安全性和耐受性较差。此外，无论是HBeAg血清转换还是HBV DNA检测，应答率都非常低（< 5%）。核苷（酸）类似物（NAs）可以使得HBV DNA检测不出，但与慢性活动性乙肝患者相比，这一概率仍然较低（在免疫耐受患者中约为70%～75%，而在慢乙肝患者中＞90%～95%）。此外，HBeAg仍为阳性，因此即使在连续3或4年的NAs治疗后，HBeAg血清转换率也非常低（< 5%）。所以，过去不推荐这部分患者进行治疗，主要原因就是药物无效、没有进展期组织学病变（至少在我们过去认识的免疫耐受患者中）。
现在，由于这些患者年龄越来越大，组织学病变越来越严重，我认为大多数指南都建议开始治疗。事实上，欧洲指南建议，30岁以上的免疫耐受患者，不论肝脏组织学情况如何都应开始治疗。亚洲指南将这一年龄限制在35岁，而美国指南是40岁。所有的指南都建议在40岁后开始治疗，但欧洲指南建议在30岁后开始治疗。当然，年轻的免疫耐受患者还有其他治疗指征。比如我们现在不怎么做肝活检了，但做了很多肝纤维化的无创检测，肝脏瞬时弹性成像检测是最常用的。如果患者肝脏硬度>9 kPa且免疫耐受，则应进行治疗。如果患者有HCC家族史或HBV相关的肝硬化且免疫耐受，无论年龄多大都应接受治疗。还有其他治疗指征，比如孕妇应接受治疗以防止病毒垂直传播给新生儿。
英文原文：
: In recent years, there has been increasing evidence that the risk of disease progression in immune-tolerant hepatitis B patients is underestimated. Could you please talk about the reasons and considerations for not recommending antiviral therapy to immunotolerant patients in the past based on clinical practice？
Dr Papatheodoridis: It is true that there have been recent studies suggesting that there may be advanced histological lesions in patients who are considered to be immunotolerant. I believe this is because there are new data in patients who are in the immunotolerant phase who fulfill the criteria to be considered as immunotolerant, but with older age, definitely there is higher risk of more advanced liver lesions in these patients. This is probably due to temporary unrecognized phases of active chronic hepatitis B during this immunotolerant phase, where phases are not complete and do not progress into HBeAg seroclearance spontaneously. So, the reason we don’t recommend treatment in immunotolerant patients is because we don’t have very good drugs for that. If you don’t have a valid treatment, you hesitate to treat.
We treat immunotolerant patients with the current drugs. Interferon is practically ineffective and associated with a poor safety and tolerability profile in patients. Also, the response rates, either by HBeAg seroconversion or HBV DNA detectability are really very low (<5%). The nucleoside/nucleotide analogs may achieve HBV DNA undetectability but at lower rates compared to patients with active chronic hepatitis B (around 70-75% in immunotolerant patients, whereas it exceeds 90-95% in chronic hepatitis B patients). In addition to that, HBeAg remains positive, so there is very low probability (again, <5%) of achieving HBeAg seroconversion, even after three or four years of continuous nucleoside/nucleotide therapy. These are the main reasons: inefficacy of the drugs; and the absence of advanced histological lesions, at least in immunotolerant patients we knew in the past.
Now, since these patients are getting older and their histological lesions are more severe, I think most of the guidelines recommend starting treatment. In fact, the European Guidelines recommend starting treatment regardless of the liver histology in immunotolerant patients above the age of thirty. The Asian guidelines have put the limit at 35 years of age, and the US guidelines are 40 years of age. So all of the guidelines recommend starting treatment after the age of 40, but the European Guidelines after the age of 30. Of course, there are additional treatment indications in young immunotolerant patients. For example, we don’t do many liver biopsies now, but we do a lot of non-invasive tests for liver fibrosis. Liver transient elastography is the most popular. If a patient has liver stiffness >9 kPa and immunotolerant, they should be treated. If a patient has a family history of HCC, or cirrhosis related to HBV, and immunotolerant, they should be treated regardless of age. There are additional criteria. If a woman gets pregnant, they should receive treatment to prevent vertical transmission of the virus to her newborn child. So, there are additional indications.
《国际肝病》
免疫耐受期乙肝患者是否需要治疗？请谈一下您的观点。
George Papatheodoridis教授
这些患者需要治疗。一方面，他们具有非常高的病毒血症水平，具有高度传染性。我们应努力防止病毒传播，而这些患者很有可能传播给他们的性伴侣、子女或其他家庭成员。同时，患者也有肝病恶化的风险，因为我们不能足够密切地随访，以避免这种情况。另一方面，开始治疗后也要继续随访。所有慢性乙肝患者都需要持续随访，不管是否开始治疗。从我的角度，“免疫耐受期乙肝患者是否需要治疗”不是问题，而“什么时候是治疗的最佳时机”才是问题。有时，我们在随访几个月到一年后发现患者ALT升高，这就是启动治疗的较好时机，因为存在免疫激活，治疗会有效得多。
英文原文：
: Whether does immune tolerance period second liver patient need to treat? Would you please share your opinion.
Dr Papatheodoridis: The reasons these patients need treatment are: firstly, they have very high viremia levels, so they are highly infectious. Also, we should try to prevent any transmission of the virus, which is a high probability for these patients, to sexual partners, their children, or other family members perhaps. But also there is the risk of progression of liver disease, because we cannot follow the patients closely enough to avoid this. On the other hand, we don’t get rid of follow-up even if we start treatment. All chronic liver disease patients need to be followed forever, regardless of whether they start or don’t start treatment. For me, for immunotolerant patients, it is not a question of if they need treatment or not. The question is when is the optimal timing for treatment? Sometimes, we will follow them, and after a few months to one year, they develop an elevated ALT, then it is a much better time for them to start treatment, because they have some immune activation and treatment will be much more effective.
《国际肝病》
如果免疫耐受期乙肝患者接受治疗，目前有哪些治疗选择？临床医生需要重点考虑哪些因素？
George Papatheodoridis教授
所有目前可用的治疗方案对免疫耐受患者都无效。我们不使用干扰素，因为它有副作用，严重降低患者的生活质量，而且它几乎没有任何作用。NAs能降低大部分患者的HBV DNA水平，并实现HBV DNA的不可检测。但这就是这些药物的最佳表现了。我们尚未实现 HBsAg水平下降和HBeAg血清转换。但预计未来会有新的治疗选择，可能会给这些患者带来一些额外的获益。
英文原文：
: What are the current treatment options for immunotolerant hepatitis B patients if they are treated? What factors should clinicians focus on?
Dr Papatheodoridis: As I said, all the currently available treatment options are not effective in immunotolerant patients. We don’t use interferon because it is associated with side effects that make the quality of life of patients very poor, and it offers practically no response. At least the nucleoside/nucleotide analogs decrease HBV DNA levels, and achieve HBV DNA undetectability, not in all, but a good proportion of patients. But this is the best these drugs can offer. We don’t have HBsAg levels declining. We don’t achieve HBeAg seroconversion. But, we anticipate new treatment options in the future, which may offer some additional benefits for these patients.
《国际肝病》
应该如何对免疫耐受期乙肝患者进行有效的临床管理？目前有哪些研究进展？
George Papatheodoridis教授
就在几年前，我们还抱有希望，到2022/2023年能为患者提供一些新的治疗选择。遗憾的是，这些计划被推迟了。HBV已被证明比我们几年前预期的更难治，我们面临的挑战也更大。尽管如此，仍有一些进展。已有非常有效的药物进入II期试验，现在有不同类型的新药正开始进行III期试验，这些新药将进一步抑制病毒复制以及病毒抗原的表达；此外，还有新的在研免疫调节剂和治疗性疫苗。希望至少2类甚至3类新药的组合将给患者带来额外获益，并最终也为免疫耐受患者提供有效的治疗。
英文原文：
: How to manage hepatitis B patients in immune-tolerant stage effectively? What is the current research progress?
Dr Papatheodoridis: I have already alluded to the research progress. Until a few years ago, we were hoping that by 2022/2023 we may have been able to offer some new treatment options to our patients. Unfortunately, these programs have been delayed. The hepatitis B virus has proven to be more difficult, and a greater challenge than we had expected a few years ago, but still there is some progress. We have very potent agents at least in phase II and now starting phase III trials in different classes which will further suppress viral replication, and further suppress the expression of viral antigens. There are also new immune modulators and therapeutic vaccines, and hopefully the combination of at least two or even three classes of these new agents will have additional benefits for our patients, and in the end, may offer some kind of effective treatment for immunotolerant patients as well.
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