Immune Tolerant Hepatitis B: A Clinical Dilemma

StephenW

Gastroenterol Hepatol (N Y). 2011 August; 7(8): 511–516.

PMCID: PMC3264935

Copyright  © 2011, Gastro-Hep Communications, Inc.
Immune Tolerant Hepatitis B
A Clinical Dilemma
Tram T. Tran, MD
Dr. Tran is Medical Director of Liver Transplantation at the Liver Disease and Transplant Center at Cedars-Sinai Medical Center in Los Angeles, California. She is also an Associate Professor of Medicine at the University of California in Los Angeles.

Corresponding author.
Address correspondence to: Dr. Tram T. Tran Liver Disease and Transplant Center Cedars-Sinai Medical Center 8635 W. 3rd Street, Suite 590W Los Angeles, CA 90048; Tel: 310-423-1971; E-mail: [email protected]
Abstract

Chronic hepatitis B virus infection remains a global health concern, with perinatal transmission still a problem in many countries. Several new therapies for chronic hepatitis B virus infection have recently been introduced that can safely and effectively suppress viral replication with a low risk of resistance; thus, it has become increasingly tempting for many clinicians to treat patients in the immune tolerant stage of infection who have high levels of viremia yet persistently normal levels of transaminases. However, understanding the natural history of hepatitis B virus infection and how it pertains to disease progression, as well as how current therapies alter or do not alter this natural history, is important when deciding whether to treat these patients. This article will review the definition and natural history of immune tolerance, the current world guidelines and recommendations for treatment of immune tolerant patients, and data on the effectiveness of current therapies in this patient population.
Keywords: Hepatitis B virus, immune tolerant, management, HBeAg, alanine aminotransferase
胃肠肝胆病杂志（N Y）。 2011年8月7（8）：511-516。

PMCID：PMC3264935
版权所有©2011年，胃喉癌通信公司
免疫耐受乙肝
临床困境
Tram陈德良，MD

陈德良博士是在Cedars-Sinai医疗中心在洛杉矶，加利福尼亚州的肝脏疾病和移植中心肝移植的医务主任。她也是在加州大学洛杉矶分校医学院副教授。
通讯作者地址：陈德良博士
肝脏疾病和移植中心Cedars-Sinai医疗中心8635西三街，套房590W洛杉矶，加利福尼亚90048电话：310-423-1971电子邮件：trant@ CSHS。 ORG

抽象
慢性乙型肝炎病毒感染仍然是一个全球性的健康问题，母婴传播，在许多国家仍然是一个问题。最近介绍了几种慢性乙型肝炎病毒感染的新疗法，可以安全地和有效地抑制病毒复制，低风险的阻力，因此，它已成为许多医生对待病人在感染免疫宽容阶段，谁拥有越来越诱人高水平的病毒血症，但转氨酶持续正常水平。然而，了解乙肝病毒感染的自然史和如何，它涉及到疾病的进展，以及目前的治疗方法如何改变或不改变这种自然历史，重要的是决定是否治疗这些病人时。本文将检讨的免疫耐受，当前世界的指引和建议，为免疫耐受患者的治疗，并在这个病患族群目前的治疗方法的有效性上的数据的定义和自然历史。
关键词：乙肝病毒免疫耐受，管理，HBeAg阳性，谷丙转氨酶

StephenW

Chronic hepatitis B (CHB) remains a global health problem, affecting 300 million people worldwide.1 Despite the availability and efficacy of the hepatitis B virus (HBV) vaccine, HBV continues to be transmitted perinatally and via blood and bodily fluids in high-risk individuals. In many countries that are considered by the World Health Organization to have an intermediate or high prevalence of HBV, birth dose vaccination schedules still do not include the HBV vaccine in 40–50% of births (Table 1). This shortfall highlights the ongoing worldwide problem of continued infection and transmission despite vaccine availability.2
Table 1
Hepatitis B Virus (HBV) Infection in World Health Organization Member Countries and Inclusion of Birth Dose HBV Vaccinations

Chronic HBV prevalence	Number of countries	Countries with HBV birth dose in schedule
High (>8%)	87	38 (44%)
Intermediate (2–8%)	62	33 (53%)
Low (<2%)	44	10 (23%)

In the United States, the Institute of Medicine recently issued a report on the current status of HBV and hepatitis C virus infection, finding a continued lack of knowledge of the risks of transmission among both healthcare providers and at-risk populations. Many opportunities exist for improving surveillance, vaccination, and access to care.3
Over the past decade, significant advances have been made in the treatment paradigm for chronic HBV infection as new therapies have become available. However, 1 of the challenging clinical dilemmas remaining in HBV management is the question of whether treatment should be initiated in the immune tolerant stage of chronic infection.

慢性乙型肝炎（CHB）仍然是一个全球性的健康问题，影响300万人worldwide.1尽管B型肝炎病毒（HBV）疫苗的有效性和疗效，乙肝继续围产期，并通过血液和体液传播的高风险的个人。在许多国家是由世界卫生组织认为有乙肝病毒的中间或高患病率，出生剂量的疫苗接种时间表仍然不包括在40-50％的产（见表1）乙肝疫苗。这种短缺突出尽管疫苗availability.2，持续的全球性问题的持续感染和传播
表1

表1
B型肝炎病毒（HBV）感染，世界卫生组织成员国和出生接种乙肝疫苗接种纳入
在美国医学研究所最近发布了对乙型肝炎病毒和丙型肝炎病毒感染的现况报告，医疗服务提供者和高危人群中找到了知识传播的风险仍然缺乏。存在很多机会，提高监测，预防接种，并获得care.3
在过去的十年中，已取得重大进展为慢性乙肝病毒感染的新疗法已成为治疗模式。然而，在HBV管理剩余的具有挑战性的临床难题1，是否应在慢性感染免疫耐受阶段开始治疗的问题。

StephenW

Two of the major determinants of the outcome of acute HBV infection are age and immune competence at the time of infection. In neonates and young children, initial HBV infection is usually subclinical and results in high rates of chronic infection. In adult-acquired HBV, symptomatic disease often leads to clearance of the hepatitis B surface antigen (HBsAg).
The natural history of perinatally acquired, chronic HBV can be broadly classified into 4 stages: immune tolerance, immune active/clearance, inactive carrier state, and reactivation (HBeAg-negative CHB; Figure 1).4 Children who are infected perinatally remain in the immune tolerant phase into adolescence or early adulthood, with the longest duration of this stage reported in 1 study to be in genotype C patients.5 Immune tolerance is clinically described as HBeAg positivity with DNA levels at or above 20,000 IU/mL and no significant immune response to the virus; thus, these patients have persistently normal alanine aminotransferase (ALT) levels. Biopsies in immune tolerant patients are generally benign, without signs of significant inflammation or fibrosis.6 Spontaneous loss of HBeAg in this stage is very low, and these patients are highly contagious due to their high levels of viremia.

The mechanism behind immune tolerance has not been fully elucidated, but HBV-specific T-cell hyporesponsiveness may be partly due to ineffective antigen processing and transport to major histocompatibility complex class I molecules.7 This inefficient T-cell response—with anergy, deletion, altered maturation of virus-specific effector cells, and expansion of regulatory T cells—may be a factor in immune tolerance.8 It has also been noted that lymphocytes bearing the classic NK phenotype dominate the immune effector cell population in immune tolerant patients, and the distribution of NK cells, CD4+ cells, and CD8+ cells resembles that seen in normal liver.9 In a recent study, intrahepatic and peripheral NK cells in immune activated and immune tolerant patients were studied, and researchers found that NK cells were activated with higher levels of interleukin (IL)-12, IL-15, and IL-18. Hepatic NK cells were also found to be more cytolytic than peripheral NK cells, which correlated with more inflammation and higher ALT levels in individuals who were immune activated.
As most immune tolerance is associated with perinatal transmission, knowing the mechanism for immune tolerance in early infancy is key; however, this mechanism is still not fully known. It is postulated to be associated with transplacental, maternal HBeAg induction of T-cell intolerance to hepatitis B core antigen (HBcAg) and HBeAg in the neonate.10 It has also been noted that neonates infected in utero do not have immunoglobulin (Ig)M antibodies to HBcAg, manifesting a lack of primary immune response.11,12 HBsAg is not believed to cross the placental barrier, but it is usually acquired at birth or shortly afterward.13 Thus, the presence of HBsAg in cord blood may indicate intrauterine infection.
One study conducted in 402 HBsAg-positive pregnant women showed that 15 newborns had detectable levels of HBsAg within 24 hours of birth; these infants were presumed to be cases of intrauterine HBV infection. Maternal serum HBV DNA levels, HBeAg status, and HBsAg titers were reported, along with data from histologic examination of the placenta, including in situ hybridization of HBV DNA and immunohistochemistry. Transplacental transmission was significantly associated with maternal HBeAg positivity, HBsAg titers, HBV DNA level, and history of threatened preterm labor. In addition, placental examination revealed a significant association between intrauterine infection and HBV infection in villous capillary endothelial cells. Thus, evidence of HBV infection decreased gradually from placental cell layers on the maternal side to layers on the fetal side.14
Clinically, the natural history of immune tolerant disease was studied by Hui and colleagues, who examined 57 adults (mean age, 31 years) with a normal serum ALT level of 30 IU/L (range, 4–42 IU/L) on 3 consecutive readings and liver biopsies at baseline showing minimal disease.15 Follow-up ensued every 6 months for 5 years, and 16% of patients developed ALT elevations during the study period. All 48 patients who remained in the immune tolerant phase for 5 years were biopsied at the end of the study: 85% of patients remained unchanged on repeat biopsy, while 6.3% (3/48) showed disease progression. Using a lower ALT serum cutoff value (30 IU/L for men and 19 IU/L for women) would have improved the test's sensitivity (from 84% to 94%) for predicting which patients would stay in the immune tolerant phase.15 This study and others emphasize that the key to determining true immune tolerance is close, long-term follow-up. Patients who have persistently normal ALT levels are more likely to have little disease progression, while those with borderline or fluctuating ALT levels may have disease progression.
After a variable period of immune tolerance, immune activity may commence; at this point, patients may show clinical evidence of elevated or fluctuating ALT levels, fluctuating HBV DNA levels, and histologic activity on biopsies indicative of inflammation and injury. If this immune activity is successful, immune clearance occurs, with HBeAg loss and development of anti-HBe, which signifies a less active disease state and the transition to inactive carrier status. If the immune active phase persists, with the patient's immune system being unsuccessful at inducing serologic HBeAg clearance, then liver damage may occur, which can lead to fibrosis, cirrhosis, and a higher risk of hepatocellular carcinoma (HCC). Even after HBeAg seroconversion and entrance into a quiescent HBV inactive carrier state, the emergence of precore/ basal core promoter mutations allowing viral replication and reactivation can lead to HBeAg-negative CHB, the fourth stage of disease.1 It is important to understand that the natural history of HBV appears to be dynamic, with progression from 1 stage to another being variable in duration and severity, as well as being reversible.

StephenW

急性HBV感染的结果的两个主要因素是年龄和感染时的免疫能力。初次HBV感染是新生儿和儿童，通常无临床症状和慢性感染率高的结果。在成人收购乙肝病毒，往往导致症状的疾病的乙型肝炎表面抗原（HBsAg）的清除。
围产期收购，慢性乙肝的自然史，大致可以分为4个阶段：免疫耐受，免疫活性/间隙，无效带菌状态，激活（HBeAg阴性慢性乙型肝炎;图1）.4感染的儿童围产期留在免疫耐受进入青春期或成年早期阶段，这一阶段的持续时间最长，在1研究报告çpatients.5免疫耐受临床描述与DNA水平达到或超过20000 IU / mL的HBeAg的阳性基因型和无显着性免疫反应的病毒，因此，这些患者有持续正常，谷丙转氨酶（ALT）水平。一般都是良性的，在免疫耐受患者的活组织切片检查无明显炎症或fibrosis.6在这个阶段HBeAg的自燃损失是非常低的迹象，这些患者由于高病毒血症水平，具有高度传染性的。
图1

图1
慢性乙型肝炎病毒（HBV）感染的四个阶段。
转载从盐田黄建忠，等。肝病。 2006年，43：S173-S181。
背后的免疫耐受的机制尚未完全阐明，但HBV特异性T细胞低反应性，部分原因可能是无效的抗原加工和运输的主要组织相容性复合体类我molecules.7这种低效的T细胞反应与无能，删除，病毒特异性效应细胞，扩大调节性T改变成熟细胞可能是在免疫tolerance.8的因素，也有人指出，经典的NK细胞表型淋巴细胞轴承主导的免疫效应细胞在免疫耐受患者人口， NK细胞和CD4 +细胞，CD8 +细胞的分布类似于在正常liver.9看到在最近的一项研究，肝内及外周血NK细胞免疫激活和免疫耐受的患者进行了研究，研究人员发现，激活NK细胞具有较高水平白细胞介素（IL）-12，IL-15和IL-18。也发现了肝脏NK细胞较外周血NK细胞，与炎症和ALT水平较高，在个人谁是免疫激活相关的杀伤。
由于大多数免疫耐受相关的母婴传播，知道在婴儿早期免疫耐受机制是关键，但这个机制仍然不完全清楚。据推测将相关的胎盘，产妇e抗原诱导T细胞不容忍乙肝核心抗原（HBcAg）和e抗原在neonate.10它也已经注意到，在宫内感染的新生儿没有免疫球蛋白（Ig）男HBcAg的，缺乏表现的原发性免疫response.11抗体，乙肝表面抗原12不相信穿过胎盘屏障，但它通常是在出生时或不久afterward.13因此，收购，脐带血HBsAg的存在可能表明宫内感染。
在402例HBsAg阳性的孕妇进行的一项研究表明，有15新生儿出生后24小时内乙肝表面抗原的检测水平，这些婴儿被推定为HBV宫内感染的病例。孕妇血清HBV DNA水平，HBeAg状态，和HBsAg滴度的报道，随着从胎盘组织学检查的数据，包括HBV DNA和免疫组化原位杂交。胎盘传输显着相关，与母亲HBeAg阳性，乙肝表面抗原滴度，HBV DNA水平，并威胁早产史。此外，胎盘检查发现宫内感染和绒毛毛细血管内皮细胞HBV感染之间的显着关联。因此，乙肝病毒感染的证据逐渐下降，从产妇的胎盘细胞层层对胎儿side.14
临床免疫耐受疾病的自然史研究回族和他的同事，谁审查30 IU / L，与正常血清ALT水平（范围4-42 IU / L，）57月3成人（平均年龄31岁）连续的读数，并在基线肝活检显示最小disease.15后续随后每6个月，5年和16％的开发研究期间ALT升高的患者。 5年保持在免疫耐受阶段的所有48名患者在研究结束时进行切片：85％的患者仍然在重复活检不变，而6.3％（3/48），表明病情恶化。使用较低的血清ALT临界值（30 IU / L），男性和19 IU /妇女大号会有所改善测试的灵敏度（从84％至94％）预测哪些病人会留在免疫耐受phase.15这研究和其他强调，以确定真正的免疫耐受的关键是密切的，长期的后续行动。 ALT持续正常水平的患者更可能有小的疾病进展，而那些与边缘或ALT水平波动，可能有疾病的进展。
变量后的免疫耐受期，免疫活性可能展开，在这一点上，患者可能出现ALT水平升高或波动，波动的HBV DNA水平，对活检组织学活动性炎症和损伤的指标的临床证据。如果这种免疫活动是成功的，发生免疫清除，HBeAg转阴，抗-HBe，这标志着一个不太活跃的疾病状态和无效的承运人身份的过渡发展。如果免疫活性相仍然存在，与病人的免疫系统，诱导血清HBeAg阴转不成功，则肝功能损害，可能会发生，这可能导致纤维化，肝硬化和肝细胞癌（HCC）的风险较高。成一个静态的乙肝病毒非活动携带状态后HBeAg的血清转换和入口，甚至出现前C区/基本核心启动子突变使病毒的复制和激活可导致HBeAg阴性的慢性乙型肝炎，第四disease.1的阶段，重要的是要了解HBV的自然史，似乎是从1阶段到另一个变量，在持续时间和严重性以及作为可逆的进展与动态。

StephenW

Defining Normal Alanine Aminotransferase Levels


Without the benefit of a liver biopsy in all patients, the definition of immune tolerant disease requires that clinicians take into account ALT as a major determinant. Over the past several years, the definition of a “normal” ALT level has been redefined. In a large, retrospective analysis of 6,835 first-time blood donors, Prati and colleagues reported that the normal limit for ALT should be 30 IU/mL for men and 19 IU/mL for women.16 Interpretation of these data concluded that these lower levels may be more appropriate than current reference laboratory values (when adjusting for factors such as body mass index [BMI] or dyslipidemia).16 A more recent study assessed ALT levels in 1,105 healthy Korean potential liver donors with biopsy-proven normal liver histology; this study found that healthy ALT values were 33 IU/L for men and 25 IU/L for women. This Asian study also noted the impact of age, BMI, and metabolic factors on ALT levels.17 These studies emphasize that utilization of appropriate ALT levels is key when trying to determine the stage of a patient's HBV infection and may make an important difference in treatment decisions.
If repeat monitoring shows ALT levels to be persistently normal, is it accurate to predict a benign liver biopsy? Lai and colleagues examined 192 patients with CHB: 59 had persistently normal ALT levels (defined as ALT ≤40 IU/L at the institutional laboratory), 26 had ALT levels 1.0–1.5 times the upper limit of normal (ULN), and 107 had ALT levels greater than 1.5 times ULN.18 Of those patients with persistently normal ALT levels, 34% had grade 2–4 inflammation, and 18% had stage 2–4 fibrosis.18 Older age was a significant factor in this study and in other studies, suggesting that even in patients with normal ALT levels, older patients with long-term infection may be candidates for liver biopsy to accurately assess the degree of ongoing liver injury.
定义正常谷丙转氨酶水平
免疫耐受疾病的定义没有一个肝活检，所有患者的利益，需要临床医生考虑的ALT采取作为一个主要因素。在过去的几年中，ALT水平“正常”的定义已被重新定义。在6835第一时间献血，普拉蒂和他的同事一个大的，回顾性分析报告，为ALT的正常上限应该是30国际单位/毫升，男性和19为women.16解读这些数据IU/ mL的结束，这些较低水平可能比目前的参考实验室值（身体质量指数（BMI）或血脂等因素进行调整时，）.16最近的一个研究评估在1105韩国健康与正常肝组织病理活检证实的潜在捐赠肝脏的ALT水平更合适;研究发现，健康的ALT值分别为33 IU/男性和25 IU/妇女大号大号。这个亚洲的研究还指出ALT键级岗位的年龄，BMI和代谢因素的影响，这些研究​​强调，利用适当的ALT水平的关键是试图确定病人的乙肝病毒感染的阶段时，可能使治疗中的重要区别决定。
如果重复监测显示ALT水平持续正常，这是准确的预测一种良性的肝活检？赖和同事研究了192例慢性乙型肝炎患者59例ALT持续正常水平（定义为ALT键≤40IU / L），在机构实验室，有26人ALT水平的1.0-1.5倍正常上限（ULN），有107 ALT水平大于1.5倍ULN.18与ALT水平持续正常的患者，34％有2-4级炎症，有18％的阶段2-4 fibrosis.18年龄大是一个重要的因素在这项研究中，在其他研究表明，即使在​​患者的ALT水平正常，长期感染的老年患者肝活检可能的候选人，以准确评估持续性肝损伤的程度。

StephenW

Significance of Viral Levels: The REVEAL Study
Many clinicians, citing a strong association between viral replication and the risk of HCC and cirrhosis, are advocating treatment of patients with high viral levels, irrespective of serum ALT levels. This recommendation stems in part from the seminal REVEAL study, which was a very large, 11-year, population-based study of 3,582 Taiwanese patients with CHB who were followed every 6–12 months with ultrasound examinations and clinic visits. These patients were studied before the Taiwanese national insurance instituted HBV treatment in 2003, so this study consisted of an untreated, natural history cohort.
Researchers measured HBV DNA viral levels and gathered data on sociodemographics and risk factors such as smoking, alcohol use, family history, and ALT levels. After adjusting for age, sex, smoking, and alcohol use, an HBV DNA level at or above 106 copies/mL at enrollment was associated with the highest incidence of cirrhosis (relative risk, 9.8; 95% confidence interval, 6.7–14.4; P<.001). Increasing HBV DNA levels were associated with increasing risk for cirrhosis incidence (P<.001). The cumulative incidence of cirrhosis was 4.5%, 5.9%, 9.8%, 23.5%, and 36.2% in patients with serum HBV DNA levels of less than 300 copies/mL, between 300 copies/mL and 9.9 × 103 copies/mL, 1.0–9.9 × 104 copies/mL, 1.0–9.9 × 105 copies/mL, and greater than 106 copies/mL, respectively. Further analysis from the same investigators showed a similar relationship between HBV DNA levels and development of HCC.19,20
While it is tempting to extrapolate from these data that all patients with high viral levels should be treated to bring their virus down to undetectable levels and thus reduce the risk of cirrhosis and HCC, closer examination of the REVEAL study cohort shows that although many of these patients did have normal ALT levels, 85% of these patients were HBeAg-negative, and the median age was 45 years. Thus, the natural history of these older patients with longer durations of infection and HBeAg-negative CHB would not be the same as the natural history of a 20-year-old, immune tolerant patient with HBeAg-positive CHB, a normal ALT level, and a high viral load. Therefore, in discussing the correlation between high viral levels and the risk of cirrhosis and HCC, the REVEAL data cannot accurately be applied to the truly immune tolerant patient, as this relationship is still largely unknown.
病毒水平的意义：研究揭示
许多医生，理由是病毒复制和肝癌和肝硬化的危险之间的强关联，所提倡的高病毒水平患者的治疗，不论血清ALT水平。此建议源于从开创性的研究揭示，这是一个非常大的，11年，人口为基础的研究台湾的3,582例慢性乙型肝炎患者随访超声检查和就诊每6-12个月的一部分。在2003年之前，台湾的国家保险实行乙肝治疗，这些患者进行了研究，因此本研究包括未经处理的，自然的历史队列。
研究人员测量了乙肝病毒DNA的水平和社会人口统计和风险因素，如吸烟，饮酒，家族史，ALT水平上的数据收集。在调整年龄，性别，吸烟，和酒精的使用，HBV DNA水平等于或高于106拷贝/毫升在入学，肝硬化的发病率最高（相对风险，9.8; 95％置信区间，6.7-14.4，P <.001）。增加乙肝病毒DNA水平与肝硬化的发病率增加的风险（P <0.001）。肝硬化累计发生率为4.5％，5.9％，9.8％，23.5％和36.2％的患者血清HBV DNA水平低于300拷贝/ mL之间，300拷贝/ ml和9.9×103拷贝/ ml，1.0 -9.9×104拷贝/毫升，1.0-9.9×105拷贝/毫升，超过106拷贝/ ml，分别更大。从调查的进一步分析表明，HBV DNA水平和发展的HCC.19之间的相似关系，20
虽然这是很有诱惑力的推断从这些数据，高病毒水平患者应及时治疗带来的病毒检测不到的水平，从而减少肝硬化和肝癌的风险，仔细的研究揭示队列的检查表明，虽然许多这些患者也有正常的ALT水平，85％的患者HBeAg阴性，平均年龄为45岁。因此，这些老年患者持续时间较长的感染和HBeAg阴性慢性乙型肝炎的自然史将不会作为一个20岁的HBeAg阳性慢性乙型肝炎，ALT正常水平，免疫耐受患者的自然史，和高病毒载量。因此，在讨论高病毒水平和肝硬化和肝癌风险之间的相关性，显示数据不能准确地被应用到真正的免疫耐受的病人，因为这种关系在很大程度上仍然是未知的。

StephenW

Current Treatment Recommendations
There are little data to support treatment in the immune tolerant pediatric patient, as progressive disease is unlikely in the short term. Although close monitoring for immune activity is warranted, a panel that recently convened on HBV infection in the pediatric population recommended deferring therapy in immune tolerant children due to concerns about long-term therapy—including the risks of resistance and low yield for clinical serologic endpoints— as well as a lack of data that therapy would alter the natural history of the disease in children.21
Carey and colleagues reported results of a study involving 23 children with HBV infection acquired in infancy and biopsy-proven immune tolerance who received lamivudine treatment for 8 weeks followed by combination therapy with interferon for an additional 44 weeks.8 Those patients who showed a serologic response had a more vigorous T-cell proliferation and CD8 response and fewer mutations. Interestingly, DNA levels decreased in both responders and nonresponders during the 8 weeks of therapy with lamivudine alone, but increased mutations were already being seen in nonresponders during this period; after interferon was initiated, responders showed a gradual broadening and strengthening of core-specific T-cell proliferation.8 Although treatment is not currently recommended, therapy involving better antiviral agents in combination with the immunomodulatory stimulation of interferon continues to hold appeal and is being further studied in both children and adults. For adults, all current national and international guidelines do not recommend therapy for immune tolerant patients with normal ALT levels (Table 2)
Table 2
Summary of Current International Guidelines and Clinical Recommendations Regarding Immune Tolerant Patients

Organization/Guidelines

Recommendations regarding immune tolerant patients

European Association for the Study of the Liver

Most patients under 30 years of age with persistently normal ALT levels, a high HBV DNA level (usually >107 IU/mL), no suspicion of liver disease, and no family history of HCC or cirrhosis do not require immediate liver biopsy or therapy. Follow-up is mandatory.

American Association for the Study of Liver Diseases

HBeAg-positive patients with persistently normal ALT levels should have their ALT levels tested at 3–6 month intervals. ALT and HBV DNA levels should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6–12 months.

Asian Pacific Association for the Study of the Liver

Patients with viral replication but persistently normal or minimally elevated ALT levels should not be treated, except patients with advanced fibrosis or cirrhosis. Immune tolerant patients need adequate follow-up and HCC surveillance every 3–6 months.

National Institutes of Health Consensus

Therapy is not recommended for patients who are in the immune tolerant phase, which includes the presence of HBsAg, high HBV DNA levels, normal ALT levels, and liver histology showing mild or minimal inflammation and fibrosis.

US Algorithm

Younger patients are often immune tolerant. A biopsy should be considered, particularly if a patient is older than 35–40 years of age. Patients should be treated if there is evidence of histologic disease on liver biopsy. In the absence of biopsy, patients should be observed for elevation in ALT levels.

In interferon treatment studies, HBeAg seroconversion rates were less than 10% when ALT levels were normal. In lamivudine studies, pretreatment serum ALT level was the strongest predictor of response among HBeAg-positive patients. Pooled data from 4 studies of patients who received lamivudine for 1 year found that HBeAg seroconversion occurred in 2%, 9%, 21%, and 47% of patients with ALT levels within the normal range, 1–2 times normal, 2–5 times normal, and greater than 5 times normal, respectively. In another study, lower seroconversion endpoints were noted in patients treated with newer antivirals, with entecavir (Baraclude, Bristol-Myers Squibb) having an HBeAg seroconversion rate of only 12% in patients with a pretreatment ALT level less than 2 times ULN.22
Although guidelines do not recommend therapy in immune tolerant patients, clinicians should note the importance of taking into account the age of the patient, duration of infection, whether ALT levels are truly normal for that patient, whether ALT levels are fluctuating, whether there is a family history of cirrhosis or HCC, the severity of histology, and other comorbidities.

StephenW

支持在免疫耐受的儿童患者的治疗，渐进性疾病，是不可能在短期内有很少的数据。虽然免疫活性密切监测是必要的，一个小组最近召开的乙肝病毒感染在儿科人口建议推迟治疗免疫耐受儿童由于长期治疗，包括抗风险和低产临床血清学终点关注以及缺乏数据，治疗会改变疾病的自然史中children.21
Carey和他的同事报道的一项研究结果，涉及23个孩子在婴儿和活检证实的免疫耐受，谁收到8个星期为一个额外的44 weeks.8谁发现这些患者的血清学反应结合干扰素治疗拉米夫定治疗乙肝病毒感染收购有一个更有力的T细胞增殖和CD8响应和更少的突变。有趣的是，DNA水平下降，反应和无效的，在治疗8周拉米夫定，但增加的基因突变已在无效在此期间干扰素开始后，反应表明一个渐进的扩大和加强核心特异性T -细胞proliferation.8虽然目前不建议治疗，参与结合干扰素的免疫刺激更好的抗病毒药物治疗继续举行上诉，并正在进一步研究，在儿童和成人。对于成年人来说，目前所有的国家和国际准则不建议ALT正常的水平（见表2）免疫耐受患者的治疗。
表2

表2
现行国际准则和有关免疫耐受患者的临床建议摘要
在干扰素治疗的研究中，HBeAg血清转换率分别为小于10％时ALT水平正常。在拉米夫定的研究，治疗前血清ALT水平是最强的预测HBeAg阳性患者的反应。从4患者谁收到拉米夫定1发现今年的研究汇集HBeAg血清转换发生在2％，9％，21％，47％患者的ALT水平在正常范围内的数据，正常的1-2倍，2-5正常，大于5倍正常，分别。在另一项研究中指出，降低血清转换端点分别在较新的抗病毒药物治疗的患者，恩替卡韦（BARACLUDE，施贵宝在HBeAg血清转换率只有12％的患者治疗前ALT水平低于2倍ULN.22）
虽然指引不建议在免疫耐受患者的治疗，临床医师应注意的重要性，考虑到病人的年龄，感染时间，ALT水平是否真正为病人正常，是否ALT水平波动，是否有家族病史的肝硬化或肝癌，组织学的严重性，和其他合并症。

StephenW

Conclusion
HBV infection is a perplexing and dynamic viral disease with a natural history that remains largely unpredictable to the clinician. Immune tolerant disease is best characterized by high viral replication in the setting of minimal liver inflammation and injury, and this stage can persist for decades. The risk of disease progression in the truly immune tolerant patient is believed to be low, but HCC risks are largely unknown and, again, unpredictable. We do not know whether current therapies will change the natural history of disease in these individuals, and whether we should commit these patients to long-term antiviral therapy—while enticing—is not yet a clinical question we can answer based on the currently available data. Many further studies are needed in this patient population.

结论
HBV感染是一个复杂和动态的一个自然的历史，临床医生在很大程度上仍然难以预测的病毒病。免疫耐受性疾病是最好的特点是高病毒复制，在设置最小的肝脏炎症和损伤，这个阶段可以持续数十年。被认为是真正的免疫耐受患者的疾病进展的风险低，但肝癌风险在很大程度上是未知的，再次，变幻莫测。我们不知道目前的治疗方法是否会改变疾病的自然史，在这些人，我们是否应该承担这些患者长期抗病毒治疗，而诱人的，还不是一个临床问题，我们可以回答的基础上的现有数据。在这个病患族群，很多还需要进一步研究。

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