New Advances in Chronic Hepatitis B

StephenW

New Advances in Chronic Hepatitis B

Shannan R. Tujios; William M. Lee

Posted: 05/11/2012; Curr Opin Gastroenterol. 2012;28(3):193-197. © 2012 Lippincott Williams & Wilkins

Abstract and Introduction
Abstract
Purpose of review This article reviews recent developments in the evaluation and treatment of chronic hepatitis B (CHB) based on articles published between December 2010 and January 2012.
Recent findings The majority of patients infected with CHB have not been diagnosed and most at-risk individuals have not been immunized. Progression to cirrhosis depends on hepatitis B virus (HBV) genotype, hepatitis B e antigen (HBeAg) presence, persistently high levels of HBV DNA, and elevated alanine aminotransferase, although hepatitis B surface antigen (HBsAg) kinetics may help predict natural history and antiviral response. Antiviral resistance limits the success of nucleos(t)ide analogs and agents such as entecavir and tenofovir with high potency and high genetic barrier to resistance are considered first-line therapy. Specialized treatment of CHB in pregnancy, coinfection, decompensated cirrhosis, and posttransplant is safe and effective.
Summary The complications of CHB can now be avoided and reversed with potent antiviral suppression of HBV DNA. For now, treatment is long-term and further studies are needed to discern whether sequential or combination therapy may be superior to current monotherapy for certain patients. Increased awareness should improve screening resulting in more frequent treatment and immunization of at-risk individuals toward eventual CHB eradication.

Introduction
It is estimated that over 350 million persons are infected with chronic hepatitis B worldwide resulting in 600 000 deaths each year from cirrhosis and hepatocellular carcinoma.[1] As over 90% of infected newborns will develop chronic hepatitis, efforts for eradication have focused on universal vaccination and screening those born in endemic areas. Despite the availability of hepatitis B virus (HBV) vaccine since 1981, over 4000 cases of acute HBV are still diagnosed in the United States each year and more than 700 000 have chronic hepatitis B (CHB).[2••] Currently there are seven approved hepatitis B therapies that can manage 95% of CHB cases yet 67% of US patients and nearly 90% of European patients are unaware of their infection, highlighting the need for increased awareness and treatment to prevent deaths.[3,4]                        

Natural History
CHB is characterized by four phases: immune tolerance with the presence of hepatitis B e antigen (HBeAg), high HBV DNA with normal alanine aminotransferase (ALT) levels and little liver damage; immune clearance with declining viral loads with elevated ALT levels corresponding to increased hepatic inflammation and fibrosis; an inactive carrier state with loss of HBeAg, low levels of HBV DNA and normal ALT; and reactivation phase with absence of HBeAg but elevated ALT, fluctuating HBV DNA and commonly precore or core promoter mutants. When the virus finally clears, hepatitis B surface antigen (HBsAg) is absent from serum as is HBV DNA, and any residual liver inflammation resolves, whereas cirrhosis does not. Recently, the impact of viral and host factors on rates of HBV DNA clearance and HBsAg seroconversion has been further elucidated. In the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV study in Taiwan, a cohort of 3653 men and women positive for HBsAg was followed over 19 years. Annual seroclearance rate for HBeAg was 5.92, 1.97% for HBV DNA, and 2.26% for HBsAg with greater than 10 000 copies/ml. Female gender, ALT at least 45 IU, HBV DNA less than 100 000 copies/ml, HBV genotype B rather than C, and precore mutants all were associated with higher HBeAg seroclearance. After HBeAg clearance, the annual rate of HBV DNA clearance was 3.2% and subsequent annual rate of HBsAg clearance was 6%.[5•] A recent study of 46 Asian CHB primarily genotype B patients with spontaneous HBsAg seroclearance showed a rapid decline in HBsAg levels in the preceding 3 years. HBsAg titer less than 200 IU/ml with a drop of 1 log or more has a positive predictive value of 100% of HBsAg loss at 3 years.[6] In HBeAg-negative patients, HBsAg level less than 1000 IU/ml is an independent predictor of HBsAg loss over 5–10 years with highest rate of seroconversion occurring with titer less than 10 IU/l.[7]                        
The natural history of CHB in Mediterranean and African countries differs from much of Asia due to the predominance of genotypes A, D, and E as well as the more common mode of transmission being horizontal transmission during childhood. Less than a third of those infected during childhood will develop CHB and most will lose HBeAg rapidly, 14–16% per year. The vast majority of those with elevated ALT levels and histologically active disease are HBeAg negative but are still at risk for cirrhosis and hepatocellular carcinoma. Annual spontaneous clearance of HBsAg is 1% in childhood and up to 2% in adults.[8] A better understanding of the natural history of CHB as related to genotypes, environmental factors and serological predictors might shed light on underlying molecular mechanisms and potential treatment targets.

StephenW

慢性乙型肝炎的新进展

山南河Tujios;威廉·M·李

发布时间：2012年5月11日; CURR OPIN胃肠。 2012年，28（3）:193-197。 ©2012利平科特·威廉斯＆威尔金斯
摘要及简介

摘要

检讨的目的，本文回顾了最近的事态发展的评估和治疗慢性乙型肝炎（HBV）根据2010年12月至2012年1月发表的文章。
大多数慢性乙型肝炎感染的病人最近的调查结果还没有被确诊，最危险的个人不能接种疫苗。进展为肝硬化，取决于B型肝炎病毒（HBV）基因型，B型肝炎e抗原（HBeAg）的存在，坚持高水平的HBV DNA，谷丙转氨酶升高，虽然B型肝炎表面抗原（HBsAg）动力学可能有助于预测自然历史和抗病毒药响应。病毒抗药性，限制了核苷（酸）IDE类似物和代理商，如恩替卡韦和替诺福韦与高强度和高基因屏障的抵抗被视为第一线治疗的成功。在妊娠，合并感染，肝硬化失代偿期，及术后专门治疗慢性乙型肝炎是安全和有效。
现在可以总结慢性乙型肝炎的并发症和避免与强大的抗病毒HBV DNA的抑制逆转。现在，治疗是长期的，并辨别是否顺序或组合治疗可能优于单药治疗对某些病人还需要进一步研究。提高认识，要提高导致更频繁的治疗，并朝着最终的慢性乙型肝炎消除危险的个人免疫筛选。
介绍

据估计，超过350万人感染与慢性乙型肝炎导致全世界每年在600万人死于肝硬化和肝癌。[1]由于受感染的新生儿超过90％会发展成慢性肝炎，根除的努力都集中在通用接种疫苗和筛选那些在流行地区出生的。尽管自1981年以来，B型肝炎病毒（HBV）疫苗的可用性，仍然确诊超过4000例急性HBV在美国每年超过700万慢性乙型肝炎（CHB）[2]目前，有七个获批B型肝炎的治疗，它可以管理例慢性乙型肝炎患者的95％，但美国患者的67％和近90％是欧洲的病人不知道自己的感染，强调需要提高认识和治疗，以防止死亡[3,4]
自然历史

慢性乙肝的特点是四个阶段：与B型肝炎e抗原（HBeAg），高HBV DNA与正常的谷丙转氨酶（ALT）水平和肝功能损害小的存在免疫耐受，免疫清除病毒载量下降与ALT水平升高，相应的增加肝脏炎症和纤维化;非活动携带状态与亏损的HBeAg，HBV DNA和ALT正常水平低;和HBeAg阳性，但ALT升高，HBV DNA的波动和常见的前C区或核心启动子突变的情况下重新启动阶段。当最终清除病毒，乙肝表面抗原（HBsAg）血清缺席是乙型肝炎病毒DNA，并解决任何残余的肝脏炎症，而肝硬化不。最近，病毒和宿主对HBV DNA的清除乙肝表面抗原转阴率因素的影响，得到了进一步的阐明。在随后的病毒载量的提升和相关的肝脏疾病/癌症病毒研究在台湾的3653名男性和女性HBsAg阳性队列的风险评估超过19年。 HBeAg的年度廓清率为5.92，1.97％的HBV DNA，乙肝表面抗原大于10 000拷贝/ ml 2.26％。所有女性，谷丙转氨酶至少45 IU，血清HBV DNA小于100万拷贝/ ml，而不是C HBV B基因型，前C区突变与更高的HBeAg的血清廓清。后HBeAg阴转，HBV DNA的清除年增长率为3.2％，随后每年的HBsAg清除率为6％。[5] 46亚洲慢性乙型肝炎的近期研究主要是自发的HBsAg廓清B基因型患​​者表现出对HBsAg迅速下降前3年的水平。乙肝表面抗原滴度低于200 IU /毫升下降1日志或更多具有积极的预测值100％的HBsAg在3年亏损。[6]在HBeAg阴性患者，HBsAg水平低于1000 IU / ml的是独立预测的HBsAg滴度与血清转换发生率最高的超过5-10年的损失小于10 IU / L。[7]

由于亚洲大部分地区的优势基因型A，D和E，以及童年时的横向传输的传输模式较常见的慢性乙型肝炎在地中海和非洲国家的自然史不同。不到三分之一的儿童时期的感染者将发展CHB和大多数人会输HBeAg的迅速，每年14-16％。与ALT水平升高和组织学活动性疾病的人绝大多数是HBeAg阴性，但仍然在为肝硬化和肝癌的风险。每年自发清除乙肝表面抗原是在童年和1％至2％的成年人。[8]更好地了解相关的基因型，环境因素和血清学预测慢性乙型肝炎的自然史可能揭示潜在的分子机制和潜在的治疗目标。

StephenW

Treatment Indications and Endpoints
The goal of antiviral therapy is to suppress HBV DNA replication and reduce necroinflammatory activity to prevent progression to cirrhosis and hepatocellular carcinoma. Surrogate markers for clinical success include normalization of ALT, improvement of histology, HBeAg loss, and ultimately HBsAg loss. HBsAg levels appear to correspond to transcriptional activity of covalently closed circular DNA but pangenotypic multicenter trials are needed to identify clinical thresholds of who should be treated and for how long.[13•,14,15,16•] Currently there are seven approved therapies including a-2a interferon, pegylated interferon, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. Pegylated interferon, entecavir, and tenofovir monotherapies have the highest efficacy and lowest risk for resistance and are recommended first-line treatment in naive patients. The benefits, disadvantages, and long-term success rates with each have been documented in detail previously.[17]                        
Treatments
Although the development of novel antiviral therapies has slowed, more information becomes available on the three preferred first-line therapies.
Pegylated Interferon
Approximately 30% of HBeAg-positive patients treated with pegylated interferon will achieve HBeAg seroconversion though current ability to predict an individual's response is limited. Recent genome-wide association studies identified polymorphisms of the interleukin (IL) 28B gene as a potent predictor of sustained viral response in interferon treatment of hepatitis C. Two hundred and five HBeAg positive CHB patients treated with pegylated interferon were analyzed for IL28B polymorphisms. The favorable AA or CC IL28B genotypes strongly predicted HBeAg seroconversion with 50% compared with 29% responding to interferon. However, end of treatment response was also reliant on viral characteristics with HBV genotype A achieving HBsAg seroconversion irrespective of IL28B genotype.[18•] HBV viral load and HBsAg decline at week 12 predicts sustained response to interferon in HBeAg-negative patients. Monitoring HBV DNA and HBsAg kinetics provides the ability for response-guided therapy with a stopping rule for those not responding to interferon.[19••] However, stopping rules with HBV DNA and HBsAg decline need to be validated in HBeAg-positive patients and across genotypes.
Entecavir
Long-term follow-up studies continue to show that entecavir effectively suppresses HBV DNA incurring very little resistance. In over 100 patients followed for 3 years, 92.1% had undetectable HBV DNA, 43.9% had HBeAg seroconversion, and 92% had normal ALT levels. The cumulative rate of entecavir-resistant mutations was 1.2% at year 3.[20•] In contrast to previous studies of interferon treatment and despite undetectable HBV DNA with entecavir monotherapy, monitoring decline in HBsAg titer at 12 and 24 weeks was not predictive of virologic response, or HBeAg seroconversion at 2 years.[21•] HBsAg levels appear to have little clinical utility in determining response with nucleos(t)ide therapy at this time.
Tenofovir  
After 3 years of treatment with tenofovir monotherapy, viral suppression with HBV DNA less than 400 copies/ml was achieved in 72% of HBeAg-positive patients and 87% of HBeAg-negative patients with normalization of ALT in 74 and 81%, respectively. No resistance was reported and 8% of HBeAg-positive patients lost HBsAg.[22•] A prospective study of 60 patients with lamivudine resistance treated initially with either change to or addition of adefovir demonstrated the benefit of tenofovir rescue therapy. At 96 weeks, 64% of patients were HBV virus negative on tenofovir and while potent, it is less than seen in naive patients. The decreased efficacy may be due to underlying adefovir resistance mutations.[23•] Tenofovir added to entecavir therapy was studied as a rescue strategy in 57 CHB patients with multidrug resistance or prior partial response. Fifty-one patients had undetectable HBV DNA after a mean of 6 months proving this to be an effective and safe strategy in a difficult-to-treat population.[24•]
Virological Breakthrough
In a large retrospective review of 11 000 CHB patients on nucleos(t)ide therapy, mean adherence rate to therapy was 87.8% with 1-year persistence of 81%. Although adherence to CHB therapy is high, new, and younger age patients tend to be less compliant.[25••] In a study of 148 CHB patients on nucleos(t)ide therapy with mean follow-up of 3 years, 39 patients had at least one virologic breakthrough with 38% having no genotypic resistance and 10 patients with further HBV DNA decline while continued on current treatment.[26•] Medication nonadherence is a common cause of intermittent virologic breakthrough and should be addressed before changing therapy.
In a study of 84 patients treated with lamivudine, adefovir, or entecavir who stopped therapy after reaching defined endpoints, 42% of HBeAg-positive and 47% HBeAg-negative patients had virologic relapse with HBV DNA more than 1000 copies/ml at a mean of 4.3 months. Preexisting lamivudine resistance, increased time to undetectable HBV DNA, and higher HBsAg level at end of treatment corresponded to relapse suggesting those with lamivudine resistance will need indefinite antiviral therapy.[27]                        

StephenW

治疗适应症和端点

抗病毒治疗的目标是抑制HBV DNA复制，减少坏死性炎症活动，以防止发展为肝硬化和肝癌。临床成功的替代指标包括ALT的正常化，组织学改善，HBeAg消失，并最终HBsAg消失。 HBsAg水平出现对应的共价闭合环状DNA的转录活性，需要但pangenotypic多中心临床试验，以确定谁应被视为与临床阈值有多长。[13，14,15,16]目前有7个批准的治疗包括A-2a干扰素，聚乙二醇干扰素，拉米夫定，阿德福韦，恩替卡韦，替比夫定，替诺福韦。聚乙二醇干扰素，恩替卡韦和替诺福韦单一疗法具有最高效率和最低的抵抗风险，建议初治患者的一线治疗。彼此的优点，缺点，和长期的成功率已经详细记录在前面。[17]
治疗

虽然新的抗病毒治疗的发展已经放缓，更多的信息成为首选的三个第一线疗法。
聚乙二醇干扰素

约30％的聚乙二醇干扰素治疗HBeAg阳性患者实现HBeAg血清转换，但目前能够预测一个人的反应是有限的。最近的全基因组关联研究发现干扰素治疗丙型肝炎一百五聚乙二醇干扰素治疗慢性乙型肝炎HBeAg阳性患者的持续病毒反应的一个强有力的预测28B基因多态性白细胞介素（IL）的IL28B多态性分析。有利的AA或CC IL28B基因型强烈的预测相比，29％的响应干扰素e抗原转阴50％。然而，结束治疗的反应也依赖于与乙型肝炎病毒基因型的病毒特征的一个实现表面抗原转阴IL28B基因型无关。[18] B型肝炎病毒负荷和12周时HBsAg的下降，预计在HBeAg阴性患者对干扰素的持续反应。监测HBV DNA和HBsAg动力学提供停车规则与那些没有响应干扰素响应引导治疗的能力。[19]然而，需要在HBeAg阳性患者验证，并与HBV DNA和HBsAg下降停止规则跨基因型。
恩替卡韦

继续长期随访研究显示，恩替卡韦有效地抑制乙型肝炎病毒DNA产生的阻力很小。在100 3年的患者中，92.1％检测不到HBV DNA的43.9％，HBeAg血清转换，92％ALT水平正常。恩替卡韦耐药突变的累积发生率为1.2％，3年。[20]在以往的研究干扰素治疗的对比，尽管检测不到HBV DNA的恩替卡韦单药治疗，监测乙肝表面抗原滴度在12和24周的下跌是无法预测的病毒学应答，或e抗原转阴2年。[21] HBsAg水平出现在核苷（酸）IDE治疗反应确定在这个时候，有临床应用少。
泰诺福韦

替诺福韦单药治疗，抑制病毒与乙型肝炎病毒DNA小于400拷贝/ ml的3年后达到72％的HBeAg阳性患者和87％，分别在74和81％的ALT正常化的HBeAg阴性患者。报告和无阻力，失去了乙肝表面抗原HBeAg阳性患者的8％。[22] 60例拉米夫定耐药患者治疗，要么改变或阿德福韦除了最初的前瞻性研究表明泰诺福韦抢救治疗的好处。在96周，64％的患者乙肝病毒呈阴性反应，对泰诺福韦而有力的，它是小于天真患者。减少的疗效可能是由于阿德福韦耐药突变的基础。[23]替诺福韦，恩替卡韦治疗57例慢性乙型肝炎患者多药耐药或部分缓解之前在救援策略研究。 51例，证明这是一个困难的治疗人群中有效和安全的战略后6个月平均不到的HBV DNA。[24]
病毒学突破

在一个大回顾11 000慢性乙型肝炎患者对核苷（酸）IDE治疗，坚持治疗率是87.8％，与1年81％的持久。虽然慢性乙型肝炎治疗是坚持高，新，和年轻的患者年龄往往是不太符合。[25]在核苷（酸）IDE治疗148例慢性乙型肝炎患者平均3年随访，39例患者的研究有38％没有基因型耐药和进一步的HBV DNA下降10例，同时继续对目前的治疗至少一个病毒学突破。[26]服药不依从是一个间歇性的病毒学突破的共同事业，应​​改变治疗之前解决。

拉米夫定，阿德福韦或恩替卡韦人停止治疗后到达终点定义治疗的84例患者的研究中，42％的HBeAg阳性和47％的HBeAg阴性患者在平均超过1000拷贝/ ml与HBV DNA病毒学复发4.3个月。 [27]已经存在拉米夫定耐药，增加检测不到乙肝病毒DNA，并在治疗结束时HBsAg水平更高，相当于建议那些与拉米夫定耐药的复发，将需要无限期的抗病毒药物治疗。

StephenW

Treatment in Special Populations
Clinical trials typically exclude patients that are pregnant, coinfected, or posttransplant yet these CHB patients are commonly encountered in practice in need of treatment.
Pregnancy
Recent analysis of 2356 children born to HBsAg-positive mothers revealed 9.26% of those born to HBeAg-positive mothers were HBsAg positive despite receiving hepatitis B immunoglobulin (HBIG) and three doses of recombinant HBV vaccine. Conversely, rate of CHB infection was so low (<1%) in those children born to HBeAg-negative mothers, HBIG did not appear to offer any additional protection to vaccination but may prevent infantile fulminant hepatitis.[28] In order to decrease vertical transmission, HBeAg-positive mothers with high HBV viral loads can be treated with antiviral therapy in the third trimester. Both tenofovir and telbivudine are class B with no apparent teratogenicity. Telbivudine has been reported to decreaseHBsAg positivity at 7 months from 8% to zero.[29••]                        
Coinfection With HIV or Hepatitis Delta                                                                 With 8.4% of HIV patients testing positive for HBsAg, CHB is 20 times more prevalent in HIV-infected patients than the general US population. Only a third of eligible HIV patients have been vaccinated and homosexual men comprise over 70% of HIV/HBV coinfected patients.[30] When selecting highly active antiretroviral therapy, medications active against HBV such as tenofovir, lamivudine, or emtricitabine are usually selected. In a recent study of 451 consecutive CHB patients, 246 HIV-positive patients had similar clinical presentation and degree of liver fibrosis as the 205 HIV-negative patients. Tenofovir used alone or in combination was noted to be equally efficacious in suppressing HBV DNA. In contrast to previous studies, HBsAg loss was more often seen in HIV-positive patients. HIV status did not seem to impact success of antiviral therapy.[31]                        
Hepatitis D virus (HDV) co-infection can lead to more rapid disease progress and precipitate decompensation. A recent study showed sustained HDV response in up to 25% of patients treated with 48 weeks of peginterferon with or without adefovir.[32••]                        
Decompensated Cirrhosis
In a phase 2 trial, 112 patients with decompensated liver disease were randomized to receive tenofovir, emtricitabine/tenofovir, or entecavir to gauge tolerability and efficacy. All treatments were well tolerated and resulted in clinical improvement.[33•] Similarly a meta-analysis of 22 studies of antiviral therapy in decompensated CHB cirrhosis showed improved virological, biochemical, and clinical parameters at 1 year with all agents but cautions resistance limits utility of lamivudine and telbivudine and adefovir has slow onset and weak viral suppression.[34] A recent prospective randomized trial compared entecavir with adefovir in patients with decompensated cirrhosis. Both entecavir and adefovir demonstrated clinical improvement and tolerability but entecavir was superior in HBV DNA suppression and ALT normalization.[35•]                        
Posttransplant
HBIG and antiviral therapy have reduced the recurrence rates of CHB to less than 1% posttransplant. However, HBIG is expensive and requires regular injections. In a prospective study, 80 CHB patients undergoing liver transplant received entecavir monotherapy. Only 26% had undetectable HBV DNA at time of transplant but 91% were HBsAg negative at 2 years and 98.8% had undetectable HBV DNA suggesting that an HBIG free, entecavir monotherapy regimen is effective posttransplant.[36••]                        
Conclusion
In the past year, determinants of the natural history of CHB continue to be defined in order to better select patients in need of long-term antiviral therapy. Studies support the safety and efficacy of potent antivirals with low development of resistance among a variety of patient populations. Increased awareness is needed for screening, treating, and vaccinating at-risk individuals for effective control of CHB.

StephenW

特殊人群的治疗

临床试验通常排除患者是孕妇，合并感染，或术后这些CHB患者通常需要治疗的实践中遇到的。
怀孕

最近对2356名儿童HBsAg阳性母亲所生的分析表明，HBeAg阳性的母亲所生的9.26％为HBsAg尽管接受B型肝炎免疫球蛋白（HBIG）和三个剂量重组乙肝疫苗的积极。相反，慢性乙型肝炎病毒感染的速度是如此之低，在HBeAg阴性母亲所生的儿童（<1％），乙肝免疫球蛋白并没有出现接种提供任何额外的保护，但可以预防小儿暴发性肝炎。[28]为了减少垂直可以治疗的传输，高HBV病毒载量的HBeAg阳性母亲在孕晚期的抗病毒药物治疗。泰诺福韦和替比夫定是B类，没有明显的致畸作用。替比夫定已上报decreaseHBsAg在7个月的积极性，从8％到零。[29••]
合并感染艾滋病毒或丙型肝炎三角洲

与8.4％的艾滋病患者检测HBsAg阳性，慢性乙型肝炎是在感染艾滋病毒的患者更普遍比一般的美国人口的20倍。只有三分之一的符合条件的艾滋病患者已接种疫苗和男同性恋者包括艾滋病毒/ HBV合并感染的患者超过70％。[30]当选择高效抗逆转录病毒治疗，积极抗HBV药物，如替诺福韦，拉米夫定，恩曲他滨通常选择。在最近的连续451例慢性乙型肝炎患者的研究中，246例艾滋病毒阳性患者有类似的临床表现为205个艾滋病毒阴性的患者肝纤维化程度。有人指出，单独或组合使用泰诺福韦是同样有效的抑制HBV DNA。在以往的研究相比，更经常出现在HIV阳性患者HBsAg消失。艾滋病病毒感染状况似乎并没有影响到抗病毒治疗的成功。[31]

丁型肝炎病毒（HDV）合并感染可导致更快速的病情进展和沉淀代偿。最近的一项研究表明持续HDV回应或阿德福韦。[32] 48周的聚乙二醇干扰素治疗的患者的25％
肝硬化失代偿期

在第二阶段的试验中，112例失代偿性肝病患者随机接受替诺福韦，恩曲他滨/替诺福韦或恩替卡韦来衡量的耐受性和有效性。所有的治疗耐受性良好，导致临床症状明显改善。[33]同样的22失代偿期乙型肝炎肝硬化抗病毒治疗研究的荟萃分析显示，改善病毒学，生化，临床参数在所有代理1年，但警告电阻限制效用拉米夫定和替比夫定和阿德福韦具有起病缓慢和微弱的病毒抑制。[34]最近的一项前瞻性随机试验相比，在失代偿期肝硬化患者的阿德福韦恩替卡韦。恩替卡韦和阿德福韦表现出临床症状明显改善，耐受性，但恩替卡韦在HBV DNA抑制和ALT正常化优越。[35]
移植后

乙肝免疫球蛋白和抗病毒药物治疗，减少慢性乙型肝炎复发率小于1％，移植后。然而，乙肝免疫球蛋白是昂贵的，需要定期注射。在一项前瞻性研究，接受肝脏移植的80例慢性乙型肝炎患者接受恩替卡韦单药治疗。只有26％在移植时不到HBV DNA，但91％HBsAg阴性和98.8％，2年已检测不到HBV DNA的建议的乙肝免疫球蛋白自由，恩替卡韦单药治疗方案是有效的术后[36••]
结论

在过去的一年中，慢性乙型肝炎的自然史因素继续加以界定，以便更好地选择需要长期抗病毒治疗的患者。研究与发展之间的各种病人群体的低电阻支持强效抗病毒药物的安全性和有效性。需要提高认识，筛查，治疗慢性乙型肝炎的有效控制和预防接种有危险的个人。

StephenW

Key Points                                

• Initial selection of peginterferon, entecavir, or tenofovir in treatment of chronic hepatitis B (CHB) is preferred.
• HBsAg kinetics may be helpful in determining the natural history of CHB infection and response to peginterferon but current use in nucleos(t)ide treatment is limited.
• Screening, vaccinating, and treatment of high-risk individuals are necessary to impact the CHB epidemic.
  

关键点

    最初选择聚乙二醇干扰素，恩替卡韦或替诺福韦治疗慢性乙型肝炎（CHB）是首选。
    HBsAg的动力学可能有助于确定慢性乙型肝炎病毒感染的自然史和聚乙二醇干扰素，但目前使用在核苷（T）是有限的IDE治疗。
    筛选，疫苗接种，高危人群的治疗是必要的影响慢性乙型肝炎的流行。

咬牙硬挺

楼主辛苦了，路漫漫啊