乙型肝炎的管理：我们的实践和如何它涉及到指引

StephenW

Management of Hepatitis B: Our Practice and How It Relates to the Guidelines


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"Guidelines provide an evidence-based framework for managing patients; however, management of individual patients must be flexible, taking into account the patient's preference and other medical or psychosocial conditions, evolution in knowledge over time, and the provider's experience.....This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations, and we discuss what we do in our practice to illustrate factors that may influence decisions regarding hepatitis B management."

Clinical Gastroenterology and Hepatology
January 2014

Suna Yapali, Nizar Talaat, and Anna S. Lok
Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan

Seven drugs have been approved for the treatment of chronic hepatitis B. Antiviral treatment has been shown to be effective in suppressing hepatitis B virus replication, decreasing inflammation and fibrosis in the liver, and preventing progression of liver disease. However, current medications do not eradicate hepatitis B virus; therefore, a key question is which patients need to start treatment and which patients can be monitored. Professional societies have developed guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with chronic hepatitis B. These guidelines suggest preferred approaches, and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations, and we discuss what we do in our practice to illustrate factors that may influence decisions regarding hepatitis B management.

The advent of sensitive assays for the detection of hepatitis B virus (HBV) and the availability of potent antiviral agents have improved the management of patients with chronic hepatitis B (CHB); however, current treatment cannot eradicate the virus. Because of the high cost and risk of adverse events, as well as drug resistance with long-term treatment, the most important question regarding the management of hepatitis B is which patients need to be treated now and which patients can be monitored and have treatment deferred. The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) have developed clinical practice guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with CHB.1, 2, 3 These guidelines suggest preferred approaches and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient.

Recommendations of the 3 guidelines vary slightly because of differences in timing when the guidelines were issued and also differences in available resources. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations and we discuss what we do in our practice to illustrate factors that may influence the management of CHB.
“指南提供以证据为基础的框架，用于管理病人，但是，个别病人管理必须是灵活的，考虑到病人的偏好和其他医疗或心理状况，知识随着时间的演变，以及供应商的经验.....本文综述了乙肝指引和依据这些建议的建议，和大家讨论我们做什么，在我们的实践来说明关于乙肝的管理，可能会影响决策的因素。 “

临床胃肠病学和肝病学杂志
2014年1月

苏娜Yapali ，尼扎尔塔拉大街，和安娜S.乐
胃肠病学和肝病学杂志，密歇根大学健康系统，密歇根州安阿伯的划分

七药物已被批准用于治疗慢性乙型肝炎的抗病毒治疗的治疗已被证明是有效地抑制乙型肝炎病毒复制，减少炎症和纤维化肝脏中，并防止肝脏疾病的进展。然而，目前的药物治疗不根除乙肝病毒，因此，一个关键的问题是哪些患者需要开始治疗，哪些病人可以被监控。专业协会已经制定准则，以协助医生识别，诊断和治疗慢性乙型肝炎这些指南建议首选方法，医生预计行使临床判断，以确定根据个人的情况，选择最合适的管理优化管理耐心。本文综述了乙肝指引和依据这些建议的建议，和大家讨论我们做什么，在我们的实践来说明关于乙肝的管理，可能会影响决策的因素。

灵敏的分析方法对乙肝病毒（HBV）的检测和强效的抗病毒药物的可用性的出现改善了患者的慢性乙型肝炎（CHB ）的管理，但是，目前的治疗不能消除病毒。由于成本高，不良事件的风险，以及与长期的治疗，对于乙肝的哪些患者需要立即进行治疗，哪些病人可以监控和管理的最重要的问题，耐药性已经治疗递延。肝病研究的美国协会（ AASLD ） ，欧洲肝脏研究协会（ EASL ）的研究，以及亚太肝脏研究协会（ APASL ）的研究开发临床实践指南，以协助医生识别，诊断和预期的患者CHB.1 ，2，3 ，这些指南建议优选的方法和医师最佳管理锻炼临床判断，以确定基于个体患者的具体情况最适当的管理。

因为在当发行，也是指引可利用的资源不同时差的3准则的建议略有不同。本文综述了乙肝指南建议，并依据这些建议和我们讨论我们做什么，在我们的实践来说明，可能会影响慢性乙型肝炎的管理因素。

StephenW

Natural History of Chronic Hepatitis B Virus Infection

The natural course of chronic HBV infection consists of 4 phases; however, patients may not experience all phases (Figure 1).4
Figure 1 The natural course of chronic HBV infection consists of 4 phases. The immune tolerance phase is characterized by the presence of HBeAg, high HBV DNA levels, and persistently normal ALT levels, but no evidence of active liver disease. The immune clearance phase is characterized by the presence of HBeAg and high/fluctuating HBV DNA and ALT levels. An outcome of the immune clearance phase is HBeAg seroconversion. Most patients then enter the inactive HBV carrier phase, which is characterized by the absence of HBeAg and the presence of anti-HBe, low or undetectable HBV DNA levels (<2000 IU/mL), normal ALT levels, and no/minimal inflammation on liver biopsy. The reactivation phase is characterized by the absence of HBeAg, intermittent/persistently increased ALT and HBV DNA levels, and inflammation on liver biopsy.

Reprinted with permission from Lok.4

Host, viral, and environmental factors influence progression of HBV-related liver disease. Recent studies have focused on the importance of HBV replication as an independent predictor of cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths.5, 6 However, other factors including sex, age, HBV genotype, co-infection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus, increased alanine aminotransferase (ALT) level, and alcohol and tobacco use also contribute to cirrhosis and HCC.

慢性乙型肝炎病毒感染的自然史

慢性HBV感染的自然过程分为4个阶段，但患者可能没有经历过的所有阶段（图1 ） .4

HBV1.gif
图1慢性HBV感染的自然过程分为4个阶段。免疫耐受期的特点是大三阳，高HBV DNA水平和ALT持续正常水平的存在，但没有证据显示活动性肝脏疾病。免疫清除期的特点是HBeAg和高/波动HBV DNA的存在和ALT水平。免疫清除期的结果是HBeAg血清学转换。大多数患者然后进入非活动性HBV载波相位，其特征是不存在的HBeAg和抗-HBe ，低或检测不到的HBV DNA水平（ < 2000国际单位/毫升） ， ALT水平正常，无/轻微炎症上的存在肝活检。在激活阶段的特点是没有大三阳的，间歇性的/持续增加ALT和HBV DNA水平和炎症的肝活检。

转载自Lok.4许可

主机，病毒，和环境因素影响HBV相关的肝脏疾病的进展。最近的研究集中在HBV复制的肝硬化的独立预测因子，肝细胞肝癌（HCC ） ，以及肝脏相关deaths.5的重要性6然而，其他因素包括性别，年龄， HBV基因型，合并感染人类免疫缺陷病毒，丙型肝炎病毒，或丁型肝炎病毒，增加了谷丙转氨酶（ALT ）水平，以及酒精和烟草的使用也有助于肝硬化和肝癌。

StephenW

Indications for Treatment

Practice guidelines recommend that the treatment decision be made based on clinical status, serum HBV DNA and ALT levels, hepatitis B e antigen (HBeAg) status, and liver histology if available.1, 2, 3

Who Should Be Treated?  

All guidelines recommend starting treatment as soon as possible in patients with life-threatening liver disease: acute liver failure, decompensated cirrhosis, or severe exacerbation of CHB regardless of HBV DNA and ALT levels. Although data from randomized controlled trials in these settings are lacking, in case series antiviral treatment has been shown to be beneficial with little or no adverse effects. In addition, for patients requiring liver transplantation, viral suppression decreases the risk of HBV recurrence after transplant.7

The AASLD and APASL guidelines recommend antiviral therapy in patients with compensated cirrhosis and serum HBV DNA level greater than 2000 IU/mL regardless of ALT level.1, 2, 3 For patients with increased ALT levels, the AASLD guidelines recommend treatment regardless of HBV DNA level.1 The EASL guideline recommends treatment of patients with any detectable level of serum HBV DNA.2 There is growing evidence that long-term treatment with nucleos(t)ide analogues (NUCs) not only prevents disease progression but also reverses fibrosis and cirrhosis. In a double-blind, randomized, placebo-controlled study of 651 patients with advanced fibrosis or cirrhosis, who were HBeAg-positive or had high levels of HBV DNA (>150,000 IU/mL), lamivudine therapy was shown to decrease progression of liver disease.8 A follow-up report of the phase 3 tenofovir vs adefovir trial including 348 patients who had paired biopsies at baseline and year 5 showed that 51% of patients had a decrease in fibrosis stage by 1 or more and 71 of 96 (74%) patients with cirrhosis on initial biopsy had regression of cirrhosis.9

All guidelines agree that treatment should be initiated in noncirrhotic patients with serum HBV DNA levels greater than 20,000 IU/mL and persistently increased ALT levels and/or histologic evidence of moderate/severe inflammation or fibrosis. However, cut-off values of HBV DNA and ALT levels and the need for liver biopsy in determining treatment indications vary slightly among the guidelines (Table 1). The AASLD guideline suggests an arbitrary HBV DNA level of 20,000 IU/mL for initiating treatment.1 The APASL guideline recommends an HBV DNA threshold of 20,000 IU/mL for HBeAg-positive patients and 2000 IU/mL for HBeAg-negative patients, whereas the EASL guideline recommends a cut-off value of 2000 IU/mL irrespective of HBeAg status.2, 3 All guidelines agree that serial HBV DNA and ALT level is more important than a single value in making treatment decisions. For patients who fulfill the criteria for HBV DNA, the EASL recommends treating patients with ALT levels greater than the upper limit of normal (ULN) if the liver biopsy (or noninvasive markers validated in HBV-infected patients) shows moderate-severe inflammation and/or at least moderate fibrosis, whereas the APASL and AASLD recommend treatment for patients with an ALT level greater than 2 times the ULN. The AASLD guideline suggested lower values be used to define the ULN for an ALT level of 30 U/L for men and 19 U/L for women, and a liver biopsy should be performed in patients with mildly increased ALT levels, particularly in patients older than age 40.1 Besides HBV replication status, ALT levels, and liver histology, all guidelines recommend that patient age, HBeAg status, family history of HCC, occupational requirements, family planning, and patient preference should be considered in making treatment decisions.

All guidelines recommend 3 to 6 months of observation in HBeAg-positive patients and treatment if there is no spontaneous HBeAg seroconversion, but a period of pretreatment observation is not necessary in HBeAg-negative patients who meet criteria for treatment. Recommendations for treatment of noncirrhotic HBeAg-positive and HBeAg-negative patients are summarized in Figures 2 and 3.
Figure 2

Algorithm showing guideline recommendations for the treatment of patients with HBeAg-positive CHB. *APASL recommends monitoring every 1 to 3 months. �EASL: age, >30 years; AASLD and APASL: age >40 years.

Figure 3

Algorithm showing guideline recommendations for the treatment of patients with HBeAg-negative CHB. *EASL indicates treatment may be initiated in patients with normal ALT level if the biopsy shows moderate-severe inflammation or fibrosis.

StephenW

【适应症】用于治疗

实践指南推荐的治疗决定，根据临床状态，血清HBV DNA和ALT水平，乙型肝炎e抗原（HBeAg ）状态，以及肝组织学做，如果available.1 ， 2 ， 3



谁应该治疗？

所有的指南建议患者危及生命的肝脏疾病尽早开始治疗：急性肝衰竭，肝硬化失代偿期，或慢性乙型肝炎的严重恶化，无论HBV DNA和ALT水平。虽然从这些设置中的随机对照试验数据缺乏，在病例系列抗病毒治疗已被证明是有益的，很少或没有不良影响。此外，对于需要肝移植的患者， transplant.7后病毒抑制乙肝病毒减少复发的风险

在AASLD和APASL指南建议抗病毒治疗患者的代偿性肝硬化和血清HBV DNA水平高于2000 IU / mL的不管ALT level.1的， 2 ， 3的患者有增加的ALT水平，在AASLD指南推荐的乙肝病毒DNA的治疗不管level.1的EASL指南推荐治疗的患者血清HBV DNA.2任何可检测的水平有越来越多的证据表明，核苷（酸）类似物（ NUCs ）长期治疗不仅可以防止疾病进展，但也逆转肝纤维化和肝硬化。在一项双盲，随机，安慰剂对照的651例晚期肝纤维化或肝硬化，谁是HBeAg阳性或有高水平的HBV DNA （ > 150,000 IU /毫升）的研究中，拉米夫定治疗被证明是减少肝进展disease.8 3期替诺福韦与阿德福韦试验，包括谁在基线和5年已配对活检348例患者的随访报告显示， 51％的患者有纤维化阶段减少1或更多， 96 71 （ 74 ％ ），肝硬化患者在初次活检有cirrhosis.9的回归

所有准则都认为治疗应在开始非肝硬化患者血清HBV DNA水平大于20,000 IU / mL和持续增加的ALT水平和/或中度/重度炎症或纤维化组织学证据。然而， HBV DNA和ALT水平的临界值以及需要在确定治疗适应症肝活检略有不同，其中的准则（表1） 。在AASLD指南建议的20,000国际单位/毫升发起treatment.1的APASL指南建议的20,000国际单位/毫升的HBeAg阳性患者和2000国际单位/毫升的HBeAg阴性患者的HBV DNA阈值的任意HBV DNA水平，而EASL指南推荐为2000 IU / mL的截止值，不论大三阳status.2的， 3所有指导方针同意，串行HBV DNA和ALT水平高于在作出处理决定的单个值更重要。对于谁符合标准的HBV DNA ，该EASL建议治疗患者的ALT水平大于正常上限（ULN ）的上限，如果肝活检（或验证在HBV感染患者的非侵入性标记物）示出中度 - 重度炎症和/患者或者至少是中度纤维化，而​​APASL和AASLD推荐治疗患者的ALT水平在正常值上限大于2倍。在AASLD指南建议较低的值可以用来定义ULN为30 U / L ，男性和19 U / L，女性的ALT水平和肝活检应在患者轻度增加ALT水平来进行，尤其是在年长患者比40.1岁除HBV复制状态， ALT水平和肝组织学检查，所有的指南建议，患者年龄， HBeAg状态，肝癌家族史，职业的要求，计划生育，以及患者的意愿应在作出处理决定予以考虑。

所有的指南建议3 〜6个月的观察中HBeAg阳性患者和治疗，如果没有自发性HBeAg血清学转换，但经过一段时间的预处理观察是没有必要的HBeAg阴性患者谁符合治疗标准。治疗肝硬化的HBeAg阳性和HBeAg阴性患者的建议总结在图2和图3 。

HBV2.gif
图2

显示算法用于治疗HBeAg阳性慢性乙型肝炎治疗指南推荐。 * APASL建议监测每1〜 3个月。 EASL ：年龄> 30岁; AASLD和APASL ：年龄> 40岁。

图3

显示算法用于治疗HBeAg阴性CHB治疗指南推荐。 * EASL表示可以治疗的患者ALT正常启动，如果活检显示重度炎症或纤维化。

HBV3.gif

StephenW

Our Practice

In our practice, we initiate treatment as soon as we recognize that the patient has acute liver failure or severe acute hepatitis B (prolonged jaundice or coagulopathy), severe exacerbation of CHB, or decompensated cirrhosis, regardless of ALT or HBV DNA levels. For patients with compensated cirrhosis, we follow the AASLD guidelines, although increasingly we initiate treatment even in patients with HBV DNA levels less than 2000 IU/mL. We have become more liberal in treating patients with compensated cirrhosis because of the high barrier to resistance of the newer antiviral agents entecavir and tenofovir, the established safety of these drugs, and the difficulty in predicting which patient with cirrhosis will develop HCC. For patients without cirrhosis, we follow the AASLD guidelines and recommend treatment if HBV DNA level is greater than 20,000 IU/mL and ALT level is greater than 2 times the ULN. For both HBeAg-positive and HBeAg-negative patients in the gray zone, we recommend liver biopsy particularly if they are older than age 40. We inform the patients that a histologic finding of moderate/severe inflammation/fibrosis will urge us to treat, but the absence of these findings does not rule out the risk of HCC. For patients who decline a liver biopsy, we rely on a combination of ultrasound and laboratory tests including the aspartate-aminotransferase-platelet-ratio index to assess stage of liver disease because liver stiffness measurement is not readily available in the United States.

我们的实践

在我们的实践中，我们只要我们认识到，病人有急性肝功能衰竭或严重急性乙肝（长期黄疸或凝血功能障碍） ，慢性乙型肝炎的严重恶化，或失代偿性肝硬化，无论ALT或HBV DNA水平的开始治疗。对于患者的代偿性肝硬化，我们按照AASLD指南，虽然越来越多，我们开始治疗，即使患者的HBV DNA水平低于2000 IU / mL的。因为高门槛较新的抗病毒药物的耐药性，我们已成为在治疗患者的代偿性肝硬化更自由的恩替卡韦和替诺福韦，这些药物的安全性建立和难度预测哪些病人有肝硬化会发展肝癌。患者无肝硬化，我们按照AASLD指南和建议的治疗，如果HBV DNA水平大于20,000 IU / mL和ALT水平是正常值上限大于2倍。对于HBeAg阳性和HBeAg阴性患者中的灰色地带，我们建议肝活检尤其是当它们是年龄超过40岁。我们告知患者的中度/重度炎症/纤维化的组织学发现将促使我们去治疗，但由于没有这些发现并不排除肝癌的危险。对于谁拒绝肝活检的患者，我们依靠超声和实验室检查，包括天冬氨酸氨基转移酶 - 血小板比值指数来评估肝脏疾病的阶段，因为肝脏硬度测量是不容易获得在美国的组合。

StephenW

Who Can Be Monitored?  

All guidelines agree that treatment is not required in the immune tolerance phase because liver injury is mild and the likelihood of response (in particular HBeAg seroconversion) to available treatment is low.1, 2, 3 Liver biopsy should be considered in patients with persistent borderline normal or slightly increased ALT levels, particularly those older than age 40 (age 30 according to the EASL guidelines), and treatment should be recommended if the biopsy shows moderate/severe inflammation and/or fibrosis. All guidelines recommend that patients in the inactive carrier phase do not require treatment.1, 2, 3

谁可以被监控？

所有准则都认为不需要治疗在免疫耐受期，因为肝损伤是轻微的和响应（尤其是HBeAg血清转换） ，以提供治疗的可能性low.1 ，二，三肝活检应在患者持续性交界性考虑如果活检显示中度/重度炎症和/或纤维化正常或轻度增加ALT水平，尤其是那些年龄超过40岁（ 30岁根据EASL指南） ，和治疗应建议。所有指导方针建议患者在非活动载波相位不要求treatment.1 ，2，3

Our Practice  

We do not recommend treatment of patients in the immune tolerance phase except in the context of clinical trials or in patients older than the age of 40. The rationale for treating HBeAg-positive patients who remain in the immune tolerance phase after the age of 40 is because the population-based REVEAL study, in which 67% of patients enrolled were older than age 39, showed that persistently high serum HBV DNA levels are associated with increased risk of cirrhosis, HCC, and liver-related death.5 Other studies in Taiwan found that patients who remained HBeAg-positive after age 40 had an increased risk of HCC.6 We do not recommend treatment of patients who are confirmed to be in the inactive carrier phase after 3 or more evaluations showing persistently normal ALT level and low (<2000 IU/mL) or undetectable HBV DNA level.
我们的实践

我们不建议治疗的患者在免疫耐受期，除了在临床试验的背景下，或年龄大于40岁的患者。用于治疗谁留在40岁以后的免疫耐受期的HBeAg阳性患者的理由是因为人口为基础的REVEAL研究中，患者入选67 ％的患者年龄大于39岁，结果显示，持续的高血清HBV DNA水平肝硬化，肝癌和肝有关的death.5的风险增加在台湾的其他研究发现，谁仍然HBeAg阳性的40岁以后患者HCC.6的风险增加，我们不建议治疗的病人谁被确认有关联经过3个或更多的评价显示ALT持续正常水平低（ < 2000 IU / ml）或检测不到HBV DNA水平是在不活动载波相位。

StephenW

Other Indications for Treatment

The EASL guideline recommends that in women of childbearing age, the immediacy of their plans to become pregnant should be discussed before deciding to initiate treatment.2 Perinatal transmission of HBV has been reported to occur in 9% to 39% of newborns of highly viremic mothers (>7-8 log IU/mL).10, 11 The EASL and APASL recommends prophylactic antiviral treatment in pregnant women with high levels of viremia. Lamivudine, telbivudine, or tenofovir may be considered. Reactivation of HBV replication in patients receiving immunosuppressive therapy can lead to severe hepatitis, liver failure, and even death. The EASL and AASLD guidelines recommend testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) in patients who will be receiving chemotherapy or immunosuppressive therapy.1, 2 The APASL guideline recommends screening for HBsAg only, and additional testing for anti-HBc in patients who will be receiving biologic treatment such as rituximab or anti-tumor necrosis factor-α.3 Prophylactic antiviral therapy has been shown to decrease the risk of HBV reactivation.12 All 3 guidelines recommend initiating prophylactic antiviral therapy in HBsAg-positive patients who will be receiving cancer chemotherapy or immunosuppressive therapy and monitoring of HBsAg-negative, anti-HBc-positive patients and initiating antiviral therapy when serum HBV DNA level becomes detectable.1, 2, 3 The EASL guideline recommends prophylactic antiviral therapy in patients who will receive rituximab or stem cell transplantation.2

其他适应症】用于治疗

该EASL指南建议，在生育年龄的妇女，他们的计划怀孕的紧迫性，应讨论决定发起乙肝病毒的治疗。2母婴传播之前有报道发生在9 ％至高度病毒血症母亲的新生儿39 ％ （ > 7-8登录国际单位/毫升） .10， 11 EASL和APASL建议预防性抗病毒治疗的孕妇高水平的病毒血症。拉米夫定，替比夫定，替诺福韦或可考虑。 HBV复制在接受免疫抑制剂治疗的患者活化可导致重症肝炎，肝功能衰竭，甚至死亡。该EASL和AASLD指南推荐用于检测乙肝表面抗原（HBsAg）和乙肝核心抗体（抗-HBc ）中谁将会接受化疗或免疫抑制therapy.1患者， 2 APASL指南建议筛查乙肝表面抗原只，和额外的在谁将会接受生物治疗，如利妥昔单抗或抗肿瘤坏死因子- α.3预防性抗病毒治疗的患者测试抗-HBc已经显示出降低的HBV的风险reactivation.12全部3指南建议开始预防性抗病毒治疗的谁将会接受癌症化疗或免疫抑制剂治疗和监测HBsAg阴性，抗- HBc抗体阳性患者和引发抗病毒治疗时血清HBV DNA水平变得detectable.1 ，2，3的EASL指南建议的预防性抗病毒治疗的HBsAg阳性的患者在谁将会收到利妥昔单抗或干细胞transplantation.2患者

Our Practice

We defer treatment in women who have plans to be pregnant unless they have active or advanced liver disease. We discuss the benefits and risks of prophylactic antiviral treatment with women who have serum HBV DNA level greater than 7 log IU/mL during the second trimester of pregnancy. We recommend starting antiviral treatment around week 30 if the patient agrees and prefer tenofovir in this setting. When the goal of treatment is to prevent perinatal transmission, we stop treatment immediately after delivery and emphasize the importance of monitoring for postpartum flares. We discuss the potential risk of exposing the infant to the antiviral medication if treatment is continued, but we do not advise against breastfeeding.

We recommend HBsAg and anti-HBc testing of all patients who will be receiving chemotherapy or immunosuppressive therapy and prophylactic antiviral therapy in patients at high risk of HBV reactivation: all HBsAg-positive patients and HBsAg-negative, anti-HBc-positive patients with hematologic malignancies or who will require rituximab or long-term high-dose steroid therapy.

我们的实践

我们暂且治疗谁有计划，除非他们有主动或晚期肝病是孕妇。我们讨论了预防性抗病毒治疗的好处和风险与谁拥有血清HBV DNA水平大于7登录国际单位/毫升妊娠孕中期妇女。我们建议在开始抗病毒治疗的大约30周，如果病人同意，宁愿替诺福韦在此设置。当治疗的目的是防止母婴传播，我们发货后立即停止治疗，并强调监测产后耀斑的重要性。我们讨论露出婴儿的抗病毒药物的潜在风险，如果继续治疗，但我们不建议您不要母乳喂养。

我们建议HBsAg和谁将会在HBV再激活的高危人群应在接受化疗的患者或免疫抑制治疗和预防性抗病毒治疗的所有患者的抗-HBc检测：所有的乙肝表面抗原阳性患者和HBsAg阴性，抗-HBc阳性患者的血液恶性肿瘤或谁需要利妥昔单抗或长期大剂量类固醇治疗。

StephenW

Monitoring of Patients With Chronic Hepatitis B Virus Infection

All guidelines recommend that patients who are not deemed to be treatment candidates at presentation and those who decide to defer treatment should undergo monitoring. Guidelines recommend monitoring immune tolerant patients at 3-6 month intervals and more frequent monitoring if ALT levels become increased.1, 2, 3 For HBeAg-negative patients with normal ALT and HBV DNA levels less than 2000 IU/mL, the AASLD guideline recommends testing for ALT level every 3 months during the first year to confirm that they are truly in the inactive carrier state.1 Thereafter, patients should be monitored by ALT and HBV DNA levels every 6 to 12 months.1, 2, 3 For patients with persistently normal ALT and HBV DNA levels between 2000 and 20,000 IU/mL, the EASL guideline recommends monitoring ALT level every 3 months and HBV DNA level every 6 to 12 months for the first 3 years.2

患者的监测慢性乙型肝炎病毒感染

所有的指引建议，谁不认为是治疗候选人介绍和那些谁决定推迟治疗的患者应进行监测。指南建议监测免疫耐受的患者在3-6个月的时间，更频繁的监测，如果ALT水平成为increased.1 ， 2 ， 3对于HBeAg阴性患者ALT正常和HBV DNA水平低于2000 IU / mL时， AASLD指南建议测试的ALT水平在第一年每3个月以确认他们是真正的非活动性携带state.1此后，患者应通过ALT和监测HBV DNA水平，每6〜 12 months.1 ， 2 ， 3对于患者2000年和20,000国际单位/毫升之间ALT持续正常和HBV DNA水平中， EASL指南建议监测ALT水平每3个月和HBV DNA水平，每6 〜12个月内第3年2。

Our Practice

We emphasize to all patients that HBV infection is a chronic condition and regular monitoring is critical. We follow up young (<30 y) patients in the immune tolerance phase every 6 to 12 months and older patients every 3 to 6 months. We monitor HBeAg-negative patients every 3 months over a 1-year period before determining they are truly in the inactive carrier phase, at which time we decrease monitoring to every 6 to 12 months. We ask patients to inform us if they have unexplained fatigue or if they are diagnosed with cancers or other medical conditions that require long-term steroid or other immunosuppressive therapy

我们的实践

我们强调所有患者的HBV感染是一种慢性疾病，并定期监测是至关重要的。我们跟进年轻（ < 30岁）患者在免疫耐受期，每6 〜12个月以上的患者，每3 〜6个月。我们监测HBeAg阴性患者每3个月超过1年的时间来决定他们是真正的非活动载波相位，届时我们减少监控，每6 〜12个月之前。我们要求患者通知我们，如果他们有不明原因的疲劳，或者如果他们被诊断患有需要长期的类固醇或其他免疫抑制剂治疗癌症或其他病症

StephenW

Hepatocellular Carcinoma Surveillance: Who and How?  

The AASLD guideline recommends HCC surveillance for HBV carriers who are Asian men older than age 40 and Asian women older than age 50, persons  with cirrhosis, persons with a family history of HCC, first-generation African Americans older than age 20, and any carrier older than age 40 with persistent or intermittent ALT increases and/or HBV DNA levels greater than 2000 IU/mL.1 Surveillance with ultrasonography at 6-month intervals is recommended by the EASL and AASLD guidelines.1, 13, 14 The APASL recommends a combination of ultrasound and α-fetoprotein (AFP) testing every 6 months.15


肝癌监控：谁和如何？

在AASLD指南建议肝癌监测乙肝病毒携带者谁是亚洲男性年龄超过40岁亚洲女性年龄超过50岁，有肝硬化者，肝癌家族史，第一代非裔美国人比20岁以上，而且任何载体的人年龄超过40岁有持续性或间歇性的ALT升高和/或HBV DNA水平大于2000 IU/mL.1监控与超声检查在6个月的间隔，建议由欧洲肝病学会和美国肝病学会指南。1 ， 13 ， 14 APASL推荐一个超声和α -甲胎蛋白的组合（ AFP）检测每6 months.15

Our Practice

We follow the AASLD guidelines regarding which patients should undergo HCC surveillance, but we rely on both AFP and ultrasound. Although AFP has limited sensitivity and specificity, the reliability of ultrasound in the surveillance of HCC is suboptimal and operator-dependent. Studies have shown that AFP and ultrasound are complementary. We evaluate absolute as well as delta AFP values.

我们的实践

我们遵循有关，患者应接受HCC监测的AASLD指南，但我们同时依赖AFP和超声检查。虽然法新社具有有限的灵敏度和特异性，超声在肝癌的监控的可靠性是一个次优和运营商而定。研究表明， AFP和超声是互补的。我们绝对评价，以及三角洲AFP值。

StephenW

First-Line Treatment  

Approved medications for chronic HBV infection include interferon (IFN), either standard or pegylated IFN (PEG-IFN), and NUCs, lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir disoproxil fumarate. Rates of response and resistance to these medications are summarized in Table 2.16

Interferon/Pegylated-Interferon

IFN has both antiviral and immunomodulatory activity, which may lead to a higher rate of HBeAg and HBsAg loss and more durable viral suppression. Phase 3 clinical trials showed that 1-year treatment with pegylated-interferon (PEG-IFN) with or without lamivudine in HBeAg-positive patients resulted in 29% to 32% HBeAg seroconversion and 3% to 7% HBsAg loss 24 weeks after completion of treatment.17, 18 In one study, follow-up evaluation of patients for 3.5 years after completion of treatment found that HBeAg loss was durable in 81% and HBsAg loss occurred in 30% (58% for genotype A and 11% for genotype non-A) of patients.19 Phase 3 clinical trials showed that 1-year treatment of PEG-IFN with or without lamivudine in HBeAg-negative patients resulted in a sustained response, defined as normalization of ALT level, suppression of HBV DNA levels to 10,000 IU/mL or less in approximately 25% of patients, and HBsAg loss in 9% at 3 years after completion of treatment.20

IFN is administered parenterally and has many side effects. High serum ALT levels, low viral load, HBV genotype A and B, and high histologic activity index are pretreatment predictors of IFN/PEG-IFN response in HBeAg-positive patients.21 Predictive factors for response in HBeAg-negative patients have not been defined clearly. On-treatment ALT flares and HBsAg decreases and interleukin-28B polymorphisms also have been reported to be associated with IFN/PEG-IFN response.18, 22, 23, 24


一线治疗

批准的药物用于治疗慢性HBV感染包括干扰素（IFN） ，无论是标准的或聚乙二醇化干扰素（ PEG-IFN ）和NUCs ，拉米夫定，阿德福韦酯，替比夫定，恩替卡韦，和富马酸替诺福韦酯。响应性和耐这些药物的速率汇总于表2.16

干扰素/聚乙二醇干扰素

干扰素具有抗病毒和免疫调节活性，这可能导致更高的速率HBeAg和HBsAg消失和更持久的病毒抑制。第3阶段临床试验表明，与聚乙二醇干扰素（ PEG-IFN ）有或没有拉米夫定治疗HBeAg阳性患者1年的治疗导致29 ％至32 ％的HBeAg血清转换和3 ％至7 ％的HBsAg完成税后亏损24周treatment.17 ， 18在一项研究中，患者接受治疗完成后3.5年后续评估发现， 81％的HBeAg消失是耐用， HBsAg消失发生在30 ％ （ 58 ％为基因型A和11 ％的非基因型- A的patients.19 3期临床试验）表明， 1年的治疗PEG-IFN的有或无拉米夫定治疗HBeAg阴性患者造成了持续的反应，定义为ALT正常化水平，抑制HBV DNA水平至10,000国际单位/毫升或更少的患者约25％，而HBsAg消失在9 ％ ，3年treatment.20完成后

干扰素是胃肠外给药，并有许多副作用。高血清ALT水平，病毒载量低， HBV基因型A和B ，以及高组织学活动指数是HBeAg阳性patients.21预测因素干扰素/ PEG-IFN应答的响应中HBeAg阴性患者治疗前预测尚未确定清楚了。对治疗ALT升高和降低乙肝表面抗原和白细胞介素-28B基因多态性也已被报道用IFN / PEG-IFN response.18 ， 22 ， 23 ， 24相关的
Nucleos(t)ide Analogues  

NUCs have become the mainstay of CHB treatment because they can be administered orally and have potent antiviral activity and very few side effects. A major drawback with earlier NUCs was the high rate of antiviral drug resistance; however, the new NUCs, entecavir and tenofovir, have high barriers to resistance, with rates of antiviral drug resistance reported to be 1.2% and 0% after 5 years of treatment, respectively, in phase 3 trials of NUC-naive patients.9, 20, 25, 26 The risk of entecavir resistance is much higher, 51% after 5 years of treatment, in patients with lamivudine-resistant HBV.27 Continued treatment with entecavir or tenofovir for up to 5 years resulted in undetectable serum HBV DNA levels in 94% to 98% of patients, HBeAg seroconversion in 40% to 41% of HBeAg-positive patients, and HBsAg loss in 3% to 10%.26, 28 Long-term viral suppression has been shown to reverse fibrosis and cirrhosis.9, 28

High pretreatment ALT level is the most important predictor of response to NUC treatment in HBeAg-positive patients.29 Predictors of response to NUC have not been identified for HBeAg-negative patients. Contrary to IFN, HBV genotype is not predictive of response to NUC, and NUC treatment results in a minimal decrease in HBsAg levels.

Resistance to lamivudine or telbivudine (M204V/I) increases the risk of resistance to entecavir, and resistance to adefovir (N236T) decreases susceptibility to tenofovir. To date, there has been no confirmed case of genotypic resistance to tenofovir in patients with HBV monoinfection. Combination of 2 NUCs with no cross-resistance have been proposed to prevent the development of drug resistance; however, the need for combination therapy is doubtful given the low rate of resistance to entecavir or tenofovir monotherapy. Furthermore, although combination of 2 NUCs can accelerate viral suppression in patients with high viremia,30 there is no evidence that combination therapy will result in incremental clinical benefit.

Approved NUCs for HBV are generally safe. Mitochondrial toxicity is a potential side effect of NUCs but is very rare. Myopathy and neuropathy have been reported in patients treated with telbivudine,31 lactic acidosis has been reported in patients with severely impaired liver function treated with entecavir,32 and nephrotoxicity and renal tubular dysfunction have been reported in patients receiving adefovir or tenofovir.33


核苷（酸）类似物

NUCs已成为慢性乙型肝炎治疗的中流砥柱，因为它们可以口服给药，并有强大的抗病毒活性，副作用很少。与早期NUCs一个主要缺点是抗病毒耐药率很高，但新的NUCs ，恩替卡韦和替诺福韦，具有高壁垒性，有报告了5年的治疗后为1.2 ％和0％的抗病毒药物耐药率，分别在相NUC-天真patients.9 ， 20 ， 25 ， 26 3试验恩替卡韦耐药的风险要高得多，后51 ％5年的治疗，患者恩替卡韦与拉米夫定耐药HBV.27继续治疗或替诺福韦为长达5年导致94 ％至98 ％的患者检测不到血清HBV DNA水平， HBeAg血清转换率在40 ％至HBeAg阳性患者的41 ％ ，而HBsAg消失在3 ％至10 ％ .26 28长期抑制病毒已显示逆转纤维化和cirrhosis.9 ， 28

治疗前高ALT水平是应对国统会处理响应NUC的HBeAg阳性patients.29预测的最重要的预测还没有被确定为HBeAg阴性患者。相反，干扰素，乙肝病毒基因型不能预测针对国统会，并NUC治疗结果在HBsAg水平的最小跌幅。

耐拉米夫定或替比夫定（ M204V / I）增加抗恩替卡韦的风险，和耐阿德福韦（ N236T ）降低易感性替诺福韦。到目前为止，已经替诺福韦基因型耐药患者HBV单一感染没有确诊病例。 2 NUCs无交叉耐药性组合已经提出防止产生耐药性的发展，但是，需要联合治疗是值得怀疑的给予耐恩替卡韦或替诺福韦单药治疗率低。此外，尽管2 NUCs组合能加速病毒抑制的患者具有高病毒血症， 30 ，没有证据表明，联合治疗将导致增加的临床益处。

批准NUCs乙肝一般是安全的。线粒体毒性是NUCs的一个潜在的副作用，但非常罕见。肌病和神经病变已报道在替比夫定治疗的患者中， 31乳酸性酸中毒已报道的患者恩替卡韦治疗肝功能严重受损， 32和肾毒性和肾小管功能障碍已报道在接受阿德福韦或tenofovir.33患者