Hepatology Digest: The topic of this meeting in Guangzhou is HBV. Prospective studies show that HBeAg positive patients with normal or near-normal ALT levels are defines as being in the immune tolerant phase of HBV infection. What is the significance of this phase of HBV infection with respect to treatment?

　　《国际肝病》：ALT水平正常或接近正常的HBeAg阳性患者处于HBV感染的免疫耐受期。就治疗而言，这一期的HBV感染有什么意义？

　　Prof. Dokmeci: This Guangzhou meeting is very important because a lot of international speakers have attended and the scientific standard is very high. I also recognize that there are over 1000 participants here making this single-topic congress one of the biggest of its kind in APASL history. For chronic hepatitis B, there are four stages. The first is the immune tolerant stage; the second is immune clearance; the third is the inactive stage; and the fourth is reactivation. The immune tolerant phase is very important because in this phase, ALT is normal and there is a high level of HBV DNA and HBeAg positivity. These patients are asymptomatic and there is minimal or no inflammation on liver biopsy. This phase is particularly important for HBV transmission in neonates and young children because infection is subclinical and leads to a high risk of chronic infection (up to 90%). In the adult, acute HBV infection is symptomatic and often leads to clearance of HBsAg and chronicity is less of a problem (only 5%). That is why in the immune tolerant phase, there is a balance between virus replication and host immune response which leads to immune tolerance. In this phase, virus replication is very high and there is no liver injury. An immune response initiates hepatocyte injury in which HBeAg acts as a viral protein and deletes the virus-specific T-cell so that transplacental transfer of maternal HBeAg has been suggested to elicit HBeAg specific T-cell clearance in utero. In the immune clearance phase, the HBV DNA level is decreasing and ALT increasing.

　　Dokmeci教授：慢性乙型肝炎有四期，即免疫耐受期、免疫清除期、非活动期和再活动期。免疫耐受期非常重要，处于该期的患者的ALT正常，HBV DNA水平高，HBeAg阳性，患者无症状，而且肝活检炎症极轻或无炎症。该期对于新生儿和幼儿的HBV传播尤为重要，因为感染无明显临床症状，导致慢性感染的风险很高（高达90%）。在成人中，急性HBV感染者有症状，常常引起HBsAg的清除， 慢性化比例很低（仅5%）。这就是为什么在免疫耐受期，病毒复制和宿主免疫应答之间存在平衡，导致免疫耐受。在该期，病毒复制水平非常高，但是没有肝损伤。在免疫应答启动的肝细胞损伤中，HBeAg担当病毒蛋白，消除病毒特异性T细胞，所以母亲的HBeAg经胎盘转移，可引起子宫内HBeAg特异性T细胞的清除。在免疫清除期，HBV DNA水平降低，ALT升高。

　　Hepatology Digest: Do you support treating immune tolerant hepatitis B?

　　《国际肝病》：您支持治疗免疫耐受期乙型肝炎吗？

　　Prof. Dokmeci:This is a very important question as there are a lot of opinions about immune tolerant patients and whether they should be treated or not. There are two different points of view. One is the optimistic view and suggests leaving the patient untreated with close follow-up. The pessimistic view is that the development of cirrhosis and the risk for cancer development calls for the treatment of these patients. There are no real evidence-based guidelines. If we decide to treat these patients it is because infection is not totally benign, there is a high level of virus replication and presence of detectable HBV DNA levels and to prevent disease progression. In contrast, if we decide not to treat these patients it is because of the elements of the benign long-term course of the immune tolerant phase and that there is a poor response to antiviral therapy, potential resistance development to long-term therapy as well as the heavy cost burden of treatment.

　　Dokmeci教授：这是一个非常重要的问题，因为关于免疫耐受期患者以及是否应该治疗存在不同的观点。一种是乐观的观点，建议不治疗患者，而是密切随访。另一种为悲观的观点，认为患者存在进展为肝硬化及肝癌的风险，应该给予治疗。但是，尚无真正的循证指南建议对这部分患者进行治疗。如果我们决定治疗这些患者，则是因为感染并非完全良性，存在高水平的病毒复制，治疗可抑制HBV DNA，进而预防疾病进展。相反，如果我们决定不治疗这些患者，则是因为免疫耐受期良性的长期病程特点，并且患者对抗病毒治疗应答较差，而且长期治疗可能会致耐药发生，同时治疗也会带来沉重的费用负担。

　　Hepatology Digest: How to decide to treat immune tolerant patients with chronic hepatitis B?

　　《国际肝病》：如何决策免疫耐受期患者是否应该治疗？

　　Prof. Dokmeci: In the immune tolerant phase, ALT is always normal or close to the upper limit of normal. That is why it is very difficult to decide when to treat immune tolerant patients. All three societies’ guidelines and recommendations are almost the same. We need to monitor these cases for 3-6 months to measure the ALT and once the ALT exceeds normal levels, then we have to perform liver biopsy. On the biopsy, if we see observe necrosis or injury to the liver, then we have to treat these cases. But liver biopsy is not always suitable because it is an invasive technique. More recently, we have been able to use FibroScan to decide whether we should treat immune tolerant cases or not.

　　Dokmeci教授：在免疫耐受期，ALT常常正常或者接近正常值上限，因此决定何时开始治疗非常难。三大肝病协会指南中的推荐意见基本一致。 我们需要监测患者的ALT水平3～6个月，一旦ALT超出正常水平，我们就应行肝活检。如果我们观察到肝活检标本中有肝脏坏死或损伤，则应给予患者及时治疗。但是，因为肝活检是一种有创技术，并非所有患者都能接受，最近几年， FibroScan的应用可以帮助我们决定是否应该治疗免疫耐受期患者。