EASL專訪丨免疫耐受期乙肝患者是否需要治療？何時開始治療？
根據HBV病毒複製水平、機體免疫系統狀態和肝損害情況，慢性乙型肝炎（CHB）發展過程一般可分為4期，即免疫耐受期、免疫清除期、非活動期或低（非）複製期和再活動期。2017年EASL對CHB免疫耐受期的定義為：HBsAg陽性≥6個月，HBeAg陽性，HBV DNA＞106 IU/mL，ALT或AST水平正常或輕微增高，肝活檢或無創檢查顯示無肝纖維化或輕微炎症。對於CHB免疫耐受期患者的治療意見，EASL、AASLD、APASL等指南有不同的推薦意見，大多推薦一般情況下無需立刻治療，監測隨訪為主。但近年來積累越來越多證據顯示，處於免疫耐受期的CHB患者同樣需要啟動抗病毒治療。
第57屆歐洲肝病研究學會年會（EASL2022）暨2022年國際肝臟大會™（ILC 2022）上，希臘雅典國立Kapodistrian大學George Papatheodoridis教授主持了主題為「免疫耐受期乙肝患者是否需要治療」的專家論壇，《國際肝病》有幸在現場採訪了George Papatheodoridis教授，圍繞免疫耐受期CHB患者的管理要點、目前治療方案、治療時機以及未來新葯研發方向等角度，展開深入、豐富的探討。
EASL專訪丨免疫耐受期乙肝患者是否需要治療？何時開始治療？
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《國際肝病》
近年來越來越多的證據顯示，免疫耐受期乙肝患者的疾病進展風險被低估。請您結合臨床實踐談一談既往不推薦免疫耐受期患者接受抗病毒治療的原因和考慮？
George Papatheodoridis教授
的確，最近有研究表明，免疫耐受患者可能存在進展期組織學病變。我認為這是由於有新的數據證明這個階段的患者雖然符合免疫耐受的標準，但隨著年齡增長，出現進展期更高的肝臟病變的風險肯定更大。這可能是由於在免疫耐受期，慢性活動性乙肝出現暫未被識別的階段，這些階段並不完全，也不會自發進展為HBeAg血清清除。所以，我們既往不建議對免疫耐受患者進行治療的原因是沒有非常好的藥物，因為如果沒有有效的治療方法，就會猶豫要不要治療。
我們用目前的藥物治療免疫耐受患者，干擾素實際上無效，且安全性和耐受性較差。此外，無論是HBeAg血清轉換還是HBV DNA檢測，應答率都非常低（u0026lt; 5%）。核苷（酸）類似物（NAs）可以使得HBV DNA檢測不出，但與慢性活動性乙肝患者相比，這一概率仍然較低（在免疫耐受患者中約為70%～75%，而在慢乙肝患者中＞90%～95%）。此外，HBeAg仍為陽性，因此即使在連續3或4年的NAs治療后，HBeAg血清轉換率也非常低（u0026lt; 5%）。所以，過去不推薦這部分患者進行治療，主要原因就是藥物無效、沒有進展期組織學病變（至少在我們過去認識的免疫耐受患者中）。
現在，由於這些患者年齡越來越大，組織學病變越來越嚴重，我認為大多數指南都建議開始治療。事實上，歐洲指南建議，30歲以上的免疫耐受患者，不論肝臟組織學情況如何都應開始治療。亞洲指南將這一年齡限制在35歲，而美國指南是40歲。所有的指南都建議在40歲后開始治療，但歐洲指南建議在30歲后開始治療。當然，年輕的免疫耐受患者還有其他治療指征。比如我們現在不怎麼做肝活檢了，但做了很多肝纖維化的無創檢測，肝臟瞬時彈性成像檢測是最常用的。如果患者肝臟XXu0026gt;9 kPa且免疫耐受，則應進行治療。如果患者有HCC家族史或HBV相關的肝硬化且免疫耐受，無論年齡多大都應接受治療。還有其他治療指征，比如孕婦應接受治療以防止病毒垂直傳播給新生兒。
英文原文：
u0026lt;Hepatology Digestu0026gt;: 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 (u0026lt;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, u0026lt;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 u0026gt;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.
《國際肝病》
免疫耐受期乙肝患者是否需要治療？請談一下您的觀點。
George Papatheodoridis教授
這些患者需要治療。一方面，他們具有非常高的病毒血症水平，具有高度傳染性。我們應努力防止病毒傳播，而這些患者很有可能傳播給他們的性伴侶、子女或其他家庭成員。同時，患者也有肝病惡化的風險，因為我們不能足夠密切地隨訪，以避免這種情況。另一方面，開始治療后也要繼續隨訪。所有慢性乙肝患者都需要持續隨訪，不管是否開始治療。從我的角度，「免疫耐受期乙肝患者是否需要治療」不是問題，而「什麼時候是治療的最佳時機」才是問題。有時，我們在隨訪幾個月到一年後發現患者ALT升高，這就是啟動治療的較好時機，因為存在免疫激活，治療會有效得多。
英文原文：
u0026lt;Hepatology Digestu0026gt;: 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.
《國際肝病》
如果免疫耐受期乙肝患者接受治療，目前有哪些治療選擇？臨床醫生需要重點考慮哪些因素？
George Papatheodoridis教授
所有目前可用的治療方案對免疫耐受患者都無效。我們不使用干擾素，因為它有副作用，嚴重降低患者的生活質量，而且它幾乎沒有任何作用。NAs能降低大部分患者的HBV DNA水平，並實現HBV DNA的不可檢測。但這就是這些藥物的最佳表現了。我們尚未實現 HBsAg水平下降和HBeAg血清轉換。但預計未來會有新的治療選擇，可能會給這些患者帶來一些額外的獲益。
英文原文：
u0026lt;Hepatology Digestu0026gt;: 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.
《國際肝病》
應該如何對免疫耐受期乙肝患者進行有效的臨床管理？目前有哪些研究進展？
George Papatheodoridis教授
就在幾年前，我們還抱有希望，到2022/2023年能為患者提供一些新的治療選擇。遺憾的是，這些計劃被推遲了。HBV已被證明比我們幾年前預期的更難治，我們面臨的挑戰也更大。儘管如此，仍有一些進展。已有非常有效的藥物XXII期試驗，現在有不同類型的新葯正開始進行III期試驗，這些新葯將進一步抑制病毒複製以及病毒抗原的表達；此外，還有新的在研免疫調節劑和治療性疫苗。希望至少2類甚至3類新葯的組合將給患者帶來額外獲益，並最終也為免疫耐受患者提供有效的治療。
英文原文：
u0026lt;Hepatology Digestu0026gt;: 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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