Free textbook: Hepatology: A Clinical textbook 2012

StephenW

A new publication incorporates current recommendations for hepatitis B treatment strategies that include AASLD, APASL, EASL, Belgian, Dutch, German, and Italian guidelines in Hepatology: A Clinical Textbook.  2012
Third Edition
546 pages
By Mauss et al

Free for download http://flyingpublisher.com/books.php

一个新的出版物合并乙肝APASL，肝病学会，欧洲肝病学会，比利时，荷兰，德国，意大利指引在肝病治疗策略，包括目前的建议：临床教科书。2012年
第三版
546页
莫斯等人

免费下载http://flyingpublisher.com/books.php

StephenW

[url=]Indication for antiviraltherapyChronic hepatitis B[/url]

All patients with HBsAg positivechronic hepatitis should be considered as possible candidates for antiviraltherapy especially in situations when there is a significant level of HBVreplication (Chen 2006, Iloeje 2006). Differentiation between HBeAg-positiveand HBeAg-negative chronic hepatitis B is not necessary anymore for treatmentindication, although with respect to the choice of the appropriate antiviraldrug these criteria may be still useful.

Table 1. Key guideline recommendations for indication for antiviral treatment of HBV infection.

AASLD   (Lok 2007, Lok 2009)	Consider treatment:    · HBeAg(+):  HBV DNA >20,000 IU/ml + ALT ≤2x ULN + biopsy shows moderate/severe  inflammation or significant fibrosis    · HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN. Observe  for 3-6 months and treat if no spontaneous HBeAg loss    · HBeAg(-): HBV DNA >20,000 IU/ml + ALT >2x ULN    Consider biopsy:    · HBeAg(+):  HBV DNA >20,000 IU/ml + ALT >2x ULN + compensated    · HBeAg(+):  HBV DNA >20,000 IU/ml + ALT 1-2x ULN + age >40 years or family history  of HCC    · HBeAg(-): HBV DNA >2,000-20,000 IU/ml + ALT 1-2x ULN
APASL   (Liaw 2008)	Consider treatment:    · All  patients: HBV DNA detectable + advanced fibrosis/cirrhosis    · HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN + impending/  overt decompensation    · HBeAg(-): HBV DNA > 2,000 + ALT >2x ULN + impending/ overt  decompensation
EASL   (EASL 2009)	Consider treatment:    · HBV DNA >20,000 IU/ml + ALT >2x ULN + moderate to severe  necroinflammation
Belgian   (Colle 2007)	Consider treatment:    · HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN (or moderate/severe  hepatitis on biopsy)    · HBeAg(-): HBV DNA ≥2,000 IU/ml and elevated ALT    Consider biopsy:    · Fluctuating or minimally elevated ALT (especially in those  older than 35-40 years)
Dutch   (Buster 2008)	Consider treatment:    · HBeAg(+) and HBeAg(-): HBV DNA ≥20,000 IU/ml and ALT  ≥2x ULN or active necrotic inflammation    · HBeAg(-): HBV DNA ≥2,000-20,000 IU/ml and ALT ≥2x  ULN (and absence of any other cause of hepatitis)
German   (Cornberg 2011)	Consider treatment:    · HBV DNA >2,000 IU/ml + minimal inflammation/low fibrosis or  ALT elevation
Italian   (Carosi 2008)	Consider treatment:    · HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x  ULN    · HBeAg(-): HBV DNA >2,000 IU/ml + abnormal ALT and or  fibrosis (Ishak ≥S2)    Consider biopsy:    · HBeAg(-): HBV DNA >2,000 IU/ml + borderline ALT, or if DNA  2,000-20,000 IU/ml + high ALT
Turkish TASL   (Akarca 2008)	Consider treatment:    · HBV DNA >2,000 IU/ml + histological fibrosis >2    · HBV DNA >20,000 IU/ml + any histological finding + ALT  >2x ULN

Current recommendations of the different national andinternational societies are shown in Table 1 (Akarca 2008, Carosi 2008, Colle2007, Cornberg 2011, EASL 2009, Janssen 2008, Juszczyk 2008, Keeffe 2007, Liaw2008, Lok 2009, Waked 2008). In most of these guidelines, the most relevantfactor for a decision to initiate treatment has shifted from histologicalproven disease activity to the level of HBV DNA. Thus, most of the recentlypublished guidelines now recommend antiviral treatment for patients with HBVDNA levels >2,000 IU/mL (corresponding to >10,000 copies/mL) inassociation with a sign of ongoing hepatitis which can either be ALT levelsgreater than 2 times the upper limit of normal or significant fibrosisdemonstrated by liver histology greater than A1/F1. The recently updated Germantreatment guidelines emphasise the importance of suppression of HBV replicationby recommending treatment in patients with HBV DNA levels >2,000 IU/mL and anyelevation of ALT levels or signs of fibrosis (Cornberg 2011).

All patients with liver cirrhosis or high-grade liverfibrosis and any measurable HBV DNA should be considered for antiviral therapy(EASL 2009, Lok 2007, Cornberg 2011). The indication for antiviral treatmentaccording to the recent German guidelines is depicted in Figure 2 (Cornberg2011). In patients with decompensated cirrhosis Child-Pugh score B or C, INF α is contraindicated.

Figure 2. Indication for antiviral treatment according tothe German guidelines for the treatment of chronic HBV infection. Treatment should be considered if HBV DNA levelsexceed 104 copies/ml and if ALT are elevated or if liver histologyis abnormal. Of note, asymptomatic carriers with family history of HCC shouldreceive treatment even if signs of hepatitis are absent (Cornberg 2011).

Inactive chronic HBsAg carriers,characterised by negative HBeAg and positive anti-HBeAg, low HBV DNA levels(<2,000 IU/ml) and serum aminotransferases within normal levels do not havean indication for antiviral therapy (Cornberg 2011, Brunettto 2011). However,differentiation between inactive HBsAg carriers and patients with chronicHBeAg-negative hepatitis may be difficult in some cases. Elevated transaminasesare no reliable parameter for assessing the stage of liver fibrosis andlong-term prognosis of HBV-infected patients. Even in patients with normal orslightly elevated aminotransferases there can be a significant risk for thedevelopment of HBV-associated complications (Chen 2006, Iloeje 2006, Kumar2008). It is reasonable to perform a liver biopsy in these individuals and tocontrol the level of HBV DNA at three-month intervals. However, a liver biopsyis not mandatory to initiate treatment for the majority of patients (Table 1).

HBV immunotolerant patients are mostly under 30 years oldand can be recog-nised by their high HBV DNA levels, positive HBeAg, normal ALTlevels and minimal or absence of significant histological changes. According tomost practice guidelines immediate therapy is not required (Akarca 2007, Balik2008, Carosi 2008, Colle 2007, Cornberg 2011, EASL 2009, Buster 2008, Juszczyk2008, Keeffe 2007, Liaw 2008, Lok 2009, Waked 2008). However, patients withelevated risk for HCC development, such as those with a positive familyhistory, and patients from high endemic areas like Asia or Africa may perhapsbenefit from early antiviral therapy (Cornberg 2011). Studies are under way tofurther clarify this issue, especially to answer the question whether earlyintervention with antiviral therapy will positively influence the long-termrisk for HCC.

Summary of treatment indicationsin the German Guidelines of 2011

-
All patients with chronic hepatitis B should be evaluated fortreatment. Indication for treatment initiation depends on the level of viralreplication (HBV DNA ≥2,000
IU/mL, corresponding to ml ≥10,000 copies/mL), any elevationof serum aminotransferases and the histological grading and staging.

-
Patients with advanced fibrosis or cirrhosis and detectableviremia need consistent antiviral therapy.

-
Reactivation of HBV replication due to immunosuppression shouldbe avoided by preventive therapy.

-
Alcohol and drug consumption are not a contraindication fortreatment with nucleos(t)ide analogs.

-
Therapy with nucleos(t)ide analogs during pregnancy may beconsidered if the benefit outweighs the risk. A running treatment with LAM orTDF can be continued during pregnancy.

-
Occupational and social aspects and extrahepatic complicationsmay justify therapy in individual cases.

StephenW

慢性乙型肝炎

应考虑所有与乙肝表面抗原阳性的慢性肝炎患者，尤其是在当有可能的候选人，为抗病毒治疗的HBV复制显着水平（陈2006年，2006年Iloeje）。 HBeAg阳性和HBeAg阴性慢性乙型肝炎之间的分化是没有必要了，治疗的指征选择适当的抗病毒药物方面，虽然这些标准可能仍然是有用的。



表1。显示乙肝病毒感染的抗病毒药物治疗的关键指引建议。

肝病学会
（乐2009年2007年，乐）


考虑待遇：

·HBeAg阳性（+），HBV DNA> 20,000 IU /毫升+ ALT≤2倍ULN的活检显示中/重度炎症或明显纤维化

·HBeAg阳性（+）：血清HBV DNA> 20,000 IU /毫升+ Alt> 2倍正常值上限。 3-6个月的观察和治疗，如果没有自发的HBeAg消失

·e抗原（ - ），HBV DNA> 20,000 IU /毫升+ Alt> 2倍正常值上限

考虑活检：

·HBeAg阳性（+），HBV DNA> 20,000 IU /毫升+ ALT> 2倍正常值上限+补偿

·HBeAg阳性（+），HBV DNA> 20,000 IU /毫升+ ALT 1-2X ULN的+年龄> 40岁或肝癌家族史

·e抗原（ - ），HBV DNA> 2,000-20,000 IU /毫升+ ALT 1  -  2倍正常值上限

APASL
2008年（廖）


考虑待遇：

·所有的患者，HBV DNA检测+先进的肝纤维化/肝硬化

·HBeAg阳性（+），HBV DNA> 20,000 IU /毫升+ ALT> 2倍ULN的+即将/公开代偿

·e抗原（ - ），HBV DNA> 2000 + ALT> 2倍ULN的+即将/公开代偿

欧洲肝病学会
（EASL 2009）


考虑待遇：

·乙型肝炎病毒DNA> 20000 IU /毫升+ ALT> 2倍ULN的中度至重度坏死性炎症

比利时的
（科尔2007）


考虑待遇：

·HBeAg阳性（+），HBV DNA> 20000 IU /毫升+ Alt> 2倍正常值上限（或活检中度/重度肝炎）

·e抗原（ - ），HBV DNA≥2000 IU / ml和ALT升高

考虑活检：

·波动或ALT轻度升高（尤其是那些年龄超过35-40年）

荷兰人
（巴斯特2008）


考虑待遇：

·HBeAg阳性（+）和HBeAg（ - ），HBV DNA≥20000 IU / ml和ALT≥2倍正常值上限或积极的坏死性炎症

·e抗原（ - ），HBV DNA≥2,000-20,000 IU / ml和ALT≥2倍正常值上限（和肝炎的任何其他原因的情况下）

德语
（2011 Cornberg）


考虑待遇：

·HBV DNA> 2000 IU /毫升+最小的炎症/纤维化或低ALT升高

意大利的
（卡罗西2008）


考虑待遇：

·HBeAg阳性（+），HBV DNA> 20,000 IU /毫升+ ALT> 2倍正常值上限

·e抗原（ - ），HBV DNA> 2000 IU /毫升+ ALT异常和（或）纤维化（伊沙克≥S2的）

考虑活检：

·e抗原（ - ），HBV DNA> 2000 IU /毫升+边缘的ALT，或者如果DNA的2,000-20,000 IU /毫升+高ALT

土耳其TASL
（Akarca 2008）


考虑待遇：

·乙型肝炎病毒DNA> 2000 IU /毫升+组织纤维化> 2

·乙型肝炎病毒DNA> 20,000 IU /毫升+任何组织发现+ Alt> 2倍正常值上限



目前在不同的国家和国际社会的建议（2009年，欧洲肝病学会卡罗西2008 Akarca 2008年，2007年，科尔2011年，Cornberg 2008年，詹森2008年，Juszczyk 2007年，Keeffe 2008年，廖2009年，乐，唤醒2008）表1所示。在大多数这些准则，决定开始治疗的最相关的因素已证实疾病活动转移到HBV DNA水平。因此，现在最最近公布的指引建议患者HBV DNA水平> 2,000 IU /毫升（相当于10,000拷贝/毫升）在协会与持续性肝炎的迹象，这可以是ALT水平大于2倍的抗病毒治疗表现比A1/F1更大的肝脏组织学正常或显着纤维化的上限。德国最近更新的治疗指南强调抑制乙肝病毒复制的重要性，建议在治疗患者的HBV DNA水平> 2,000 IU / mL和任何海拔ALT水平或纤维化的迹象（Cornberg 2011），。

肝硬化或高档肝纤维化和任何可衡量的HBV DNA的所有患者，应考虑抗病毒治疗（欧洲肝病学会2007年2009年，乐，Cornberg 2011）。被描绘在图2（Cornberg 2011年）的抗病毒药物治疗，根据最近德国准则的迹象。在失代偿期肝硬化Child-Pugh评分B或C的患者，IFNα禁忌。





图2。抗病毒药物治疗，根据治疗慢性乙肝病毒感染的德国指引指示。应考虑治疗，如果HBV DNA水平超过104拷贝/毫升，如果ALT升高或肝脏组织学异常。值得注意的是，肝癌家族史的无症状携带者应该接受治疗肝炎的迹象，即使是缺席（Cornberg 2011）。

无效的慢性HBsAg携带者，HBeAg阴性和抗-e抗原阳性，低HBV DNA水平（<2,000 IU /毫升）和血清转氨酶在正常水平，没有抗病毒药物治疗（Cornberg 2011）2011年，Brunettto的迹象。然而，非活动性HBsAg携带者和HBeAg阴性慢性肝炎患者之间的分化在某些情况下可能很难。转氨酶升高是不可靠的参数评估肝纤维化和HBV感染患者的长期预后阶段。 HBV相关并发症的发展（陈2006年，2008年2006年，库马尔Iloeje），即使在正常或略有升高的转氨酶的患者能有一个重大风险。它是合理的，这些人进行肝活检和HBV DNA水平控制在3个月的时间间隔。然而，肝活检是不是强制性的启动，为广大患者（表1）治疗。

乙肝病毒免疫耐受的患者大多是30岁以下，并可以通过识别nised高HBV DNA水平，HBeAg阳性，ALT水平正常，很少或没有明显的病理改变。据大多数执业准则，不需要立即治疗（2011年，Cornberg Balik 2008 Akarca 2007年，2008年，卡罗西2007年，科尔2009年，欧洲肝病学会2008年，巴斯特2008年，Juszczyk 2007年，Keeffe 2008年，廖2009年，乐，唤醒2008年）。然而，高风险的患者与肝癌的发展，如阳性家族史的人，和高流行地区，如亚洲或非洲的病人也许受益于抗病毒药物治疗早期（Cornberg 2011）。的研究正在进行，以进一步澄清这个问题，特别是要回答这个问题是否与抗病毒治疗的早期干预，将产生积极的影响，为肝癌的长期风险。
在2011年德国指引治疗适应症综述

- 慢性乙型肝炎患者应该被评估为一疗程。开始治疗适应症上取决于病毒复制水平（血清HBV DNA≥2000 IU /毫升，相应的毫升≥10,000拷贝/毫升），任何血清转氨酶和病理分级和分期抬高。

- 晚期肝纤维化或肝硬化和检测血症患者需要一致的抗病毒药物治疗。

- 重新由于免疫抑制乙肝病毒复制，应避免通过预防性治疗。

- 酒精和毒品的消费是不是用核苷（酸）IDE类似物治疗的禁忌症。

- 治疗核苷（酸）IDE类似物在怀孕期间可以考虑，如果效益大于风险。在怀孕期间可以继续运行与LAM或TDF的治疗。

- 职业和社会各方面和肝外并发症的可能证明在个别情况下的治疗。

咬牙硬挺

深奥晦涩…学好英语很重要

StephenW

Endpoints of antiviraltreatment

Due to persistence of episomalcovalently closed circular DNA (cccDNA), a template of the HBV genome locatedin the nucleus of infected hepatocytes, a complete eradication of HBV infectionis currently impossible (Rehermann 1996). Reactivation of an HBV infection canoccur in certain circumstances from these nuclear reservoirs even decades afterHBsAg loss, for instance during immunosuppressive therapy. The aim of treatmentof chronic hepatitis B is to reduce complications such as liver failure and HCCand to increase survival (EASL 2009, Lok 2009, Cornberg 2011). To determine thesuccess of antiviral therapy surrogate markers are used during and aftertreatment. These parameters include virologic (HBeAg and HBsAg status, HBsAglevels, HBV DNA level) and patient-related parameters (aminotransferases, liverhistology).

Suppression of HBV replication. In two recent studiesa close correlation be-tween baseline HBV DNA levels and progression of thedisease was demonstrated. In the REVEAL study, 3774 untreated HBV-infectedindividuals were followed over a mean time period of 11.4 years in Taiwan (Chen2006, Iloeje 2006). HBV DNA levels at baseline were the strongest predictors ofcirrhosis and HCC devel-opment (Figure 1). In multivariate models, the relativerisk of cirrhosis increased when HBV DNA reached levels greater than 300copies/mL, independent of whether patients were negative or positive for HBeAg.In addition, individuals with HBV DNA levels ≥104 copies/mL(or ≥2,000 IU/mL) were found to have a 3-15 fold greater incidence of HCCas compared to those with a viral load <104  copies/mL. Accordingto these results, a meta-analysis covering 26 prospective studies revealed astatistically significant and consistent correlation between viral load levelsand histologic, biochemical, or serologic surrogate markers (Mommeja-Marin2003). It can therefore be concluded that the complete and persistentsuppression of HBV replication is a reliable endpoint for the treatment ofchronic HBV infection.

Induction of HBeAg seroconversion. In HBeAg-positive patients, seroconversion from HBeAg to anti-HBe was found to be areliable surrogate marker for prognosis of chronic HBV infection leading inmany cases to an inactive HBsAg carrier state (Figure 3). In these patients,HBsAg remains detectable but HBV replication continues at low or evenundetectable levels and transaminases are generally within normal ranges.

Figure 3. Possible endpoints of treatment of chronic HBVinfection. After achieving HBeAg or HBsAg seroconversion, antiviral treatmentcan be stopped. However, it is recommended tomaintain treatment for a period of 6-12 months after HBeAg or HBsAgseroconversion.

Long-term observations reveal, however, that HBeAgseroconversion cannot always be taken as a guarantee of long-term remission. Areactivation of the disease with "seroreversion" (HBeAg becoming detectable again)as well as a transition to HBeAg-negative chronic hepatitis B with increased,often fluctuating, HBV DNA levels, can occur in up to 30% of patients(Hadziyannis 1995, Hadziyannis 2001, Hadziyannis 2006). Therefore, HBeAgseroconversion should be regarded as a stable treatment endpoint only inconjunction with durable  and complete suppression of HBV replication.

In the natural course of HBV infection, the time point ofHBeAg seroconversion is important regarding the probability of long-termcomplications. In a recent long-term observational study in 483 HBeAg-positivepatients achieving spontaneous HBeAg seroconversion, it was shown that for 15years after HBeAg seroconversion the incidence of cirrhosis and HCC was lowerfor patients who had achieved HBeAg seroconversion at an age <30 years oldcompared to patients achieving seroconversion at an age >40 years old (Chen2010). This observation raises the question of whether HBeAg seroconversionsduring antiviral treatment in patients older than 40 years are also associatedwith a higher risk of complications compared to patients who achieve HBeAgseroconversion at a younger age.

Sustained response and "immune control". The endpointof therapy for patients with HBeAg-negative disease is more difficult to assess.Long-term suppression of HBV replication and ALT normalization are the onlypractical parameters of response to therapy. Once antiviral therapy is stopped,durability of response is not guaranteed due to the fluctuating course ofHBeAg-negative chronic hepatitis B.

For treatment with PEG-IFN α in both, HBeAg-positive and-negative patients, the inducing of a so-called ‘immune control' status,characterized by persistent suppression of viral replication with HBV DNAlevels <2,000 IU/ml and normalisation of ALT levels was recently defined asanother, combined treatment endpoint (Marcellin 2009). If this condition ismaintained over time, it increases the probability of HBsAg loss and reducesthe development of liver fibrosis and HCC. Late relapse beyond 6 monthspost-treatment has been described, but a sustained response at 1 yearpost-treatment appears to be durable through long-term follow-up (EASL 2009,Marcellin 2009). However, the immune control status needs to be regularlymonitored, and treatment needs to be re-introduced in case of increase of HBVreplication. For patients presenting any signs of liver fibrosis or familyhistory of HCC, immune control should not be regarded as the treatment endpointbut rather the complete suppression of HBV replication.

Induction of HBsAg loss. The ultimate goal of antiviraltreatment is HBsAg loss or even seroconversion to anti-HBs. Because HBsAg lossor seroconversion is associated with a complete and definitive remission of theactivity of chronic hepatitis B and an improved long-term outcome, it isregarded as a cure from chronic hepatitis B. However, HBsAg loss orseroconversion can be induced in only a limited number of patients aftershort-term treatment (<5%). Interestingly, in recent follow-up studies inPEG-INF α as well as nucleoside/nucleotide analogtreated patients an increase of the rates of HBsAg loss during long-termstudies was shown (Marcellin 2009, Marcellin 2011). However, as the probabilityof HBsAg seroclearance during therapy with nucleoside or nucleotide analogs is linkedto the decrease of HBsAg levels during the early treatment period, it seemsquestionable if after a treatment duration of 4-5 years significantly higherrates of HBsAg loss can be expected (Marcellin 2011).

StephenW

端点的抗病毒治疗

由于持久性的附加体式共价闭合环状DNA（cccDNA），位于感染的肝细胞的细胞核，彻底根除乙肝病毒感染的HBV基因组模板是目前不可能（Rehermann 1996）。乙型肝炎病毒感染的激活可以发生在某些情况下甚至几十年后，HBsAg的免疫抑制剂治疗期间损失的实例，这些核水库。治疗慢性乙型肝炎的目的是减少并发症，如肝功能衰竭和肝癌和提高生存率（欧洲肝病学会2009年，乐2009年2011年，Cornberg）。用于治疗期间和之后，以确定成功的抗病毒治疗的替代指标。这些参数包括病毒学（HBeAg和HBsAg状态，HBsAg水平，HBV DNA水平）和病人的相关参数（转氨酶，肝组织学）。

抑制乙肝病毒复制。之间的基线HBV DNA水平密切相关疾病的进展，在最近的两项研究结果表明。 3774未经处理的HBV感染者的研究揭示，随访超过11.4岁的平均时间在台湾期间（陈2006年，Iloeje 2006年）。在基线HBV DNA的水平是最强的预测肝硬化和肝癌发展opment（图1）。在多变量模型，肝硬化的相对危险性增加时HBV DNA的达成水平大于300拷贝/ ml，呈阴性或HBeAg阳性患者是否独立。此外，个人与HBV DNA水平≥104拷贝/毫升（或≥2000 IU / mL）的被发现有肝癌的发病率提高3-15倍，相比那些与病毒载量<104拷贝/毫升。根据这些结果，占地26前瞻性研究的荟萃分析显示病毒载量水平和组织学，生化或血清替代标记（2003）Mommeja，马林之间的统计学意义和一致的相关性。因此，可以得出结论的全面和持久抑制乙肝病毒复制，是治疗慢性乙肝病毒感染的可靠终点。

诱导HBeAg血清转换。在HBeAg阳性患者，HBeAg的抗-HBe血清转换被认为是慢性乙肝病毒感染导致在许多情况下，非活动性HBsAg携带状态（图3）预后的一个可靠的替代标记。在这些患者中，乙肝表面抗原仍然检测，但乙肝病毒复制继续在低或者甚至不到的水平和转氨酶一般在正常范围内。





图3。治疗慢性乙肝病毒感染的可能终点。实现HBeAg阳性或HBsAg血清转换后，可以停止抗病毒治疗。不过，建议维持治疗HBeAg阳性或HBsAg血清转换后的6-12个月期间。



然而，长期的观察发现HBeAg血清转换并不总是能保证作为一个长期的缓解。重新的“seroreversion”（HBeAg的再次成为检测）以及过渡增加，经常波动，HBV DNA水平与HBeAg阴性慢性乙型肝炎，这种疾病与患者（Hadziyann​​is 1995年的30％，可发生在Hadziyann​​is hadziyann​​is 2001年，2006年）。因此应被视为稳定的治疗终点，只在与持久的和完整的抑制乙肝病毒复制，HBeAg血清转换。

在HBV感染的自然过程中，HBeAg血清转换的时间点是重要的，关于长期并发症的可能性。在最近的一个长期在483实现自发HBeAg血清转换的HBeAg阳性患者的观察研究，结果表明，15年后HBeAg血清转换的肝硬化和肝癌的发病率是一个时代曾达到HBeAg血清转换的患者<30岁旧的相比，在年龄> 40岁（陈2010）血清转换的患者达到。此观察引发的问题是否在40岁以上的患者抗病毒治疗过程中HBeAg的的seroconversions也与实现HBeAg的血清转换在低龄患者相比，并发症的风险较高有关。

持续的反应和“免疫控制”。治疗终点是HBeAg阴性疾病患者更难以估量。长期抑制乙肝病毒复制和ALT正常化是唯一可行的治疗反应参数。一旦停止抗病毒治疗，耐久性的反应是由于HBeAg阴性慢性乙型肝炎的波动当然不能保证

为治疗与聚乙二醇干扰素α在HBeAg阳性和阴性的患者，诱导所谓的？免疫控制的状态，特点是病毒复制的持续抑制乙肝病毒DNA水平<2,000 IU / ml和正常化另外，综合治疗终点（Marcellin 2009）最近被定义为ALT水平。如果这种情况维持时间的推移，它增加了HBsAg消失的概率，并降低肝纤维化和肝癌的发展。已逾期超过6个月治疗后复发，但在治疗后1年的持续反应似乎是通过长期随访（欧洲肝病学会2009年2009年，Marcellin）耐用。然而，免疫控制状态，需要进行定期监测，治疗需要在乙肝病毒复制增加的情况下重新引入。为患者介绍肝纤维化或肝癌家族史的任何迹象，免疫控制不应该被视为治疗终点，而是完全抑制乙肝病毒复制。

诱导HBsAg消失。抗病毒治疗的最终目标是HBsAg消失，甚至转阴，抗-HBs。 HBsAg转阴或血清转换与慢性乙型肝炎的活动和改善长期的结果完整和明确的缓解，因为它被视为治愈慢性肝炎B.然而，只可在诱导HBsAg转阴或血清转换有限数量的患者经过短期治疗（<5％）。有趣的是，在最近的后续研究中的PEG-INFα以及核苷/核苷酸类似物治疗的患者，在长期研究中HBsAg损失率增加（Marcellin 2009年2011年，Marcellin）所示。然而，由于在核苷或核苷酸类似物治疗乙肝表面抗原血清廓清的概率是挂在早期治疗期间HBsAg水平下降，这似乎值得商榷，如果经过4-5年的治疗时间显着较高的HBsAg转阴率可以预期（Marcellin 2011年）。

StephenW

Reversion of liver fibrosis. With long-term treatment withdifferent nucleoside and nucleotide analogs it has been demonstrated that liverfibrosis and even cirrhosis can be reverted in the majority of patients. Thiswas recently impressively shown in a subgroup of 59 patients from a rolloverstudy including two Phase III trials of the efficacy of ETV in treatment-naïvepatients. Liver biopsies from baseline and after a median treatment duration of6 years (range, 3-7 years) found an histologic improvement, defined as adecrease of 2 points or greater in the Knodell necroinflammatory score inabsence of worsening of the Knodell fibrosis score, in 96% of patients. Inaddition, an improvement of more than 1 point in the Ishak fibrosis score wasseen in 88%, including all 10 patients who had advanced fibrosis or cirrhosiswhen they entered the Phase 3 studies (Chang 2010a). More recently, in asubanalysis of the tenofovir Trials 102 and 103 evaluating 348 patients whounderwent biopsies before and after five years of therapy, 88% experienced animprovement in overall liver histology as measured by an improvement of atleast two points in the Knodell score of HAI (histologic activity index)(Figure 4). Of the 94 patients who had cirrhosis at the start of therapy, 73%experienced regression of cirrhosis, and 72% had at least a two-point reductionin fibrosis scoring (Marcellin 2011).

Figure 4. Changes in liverhistology after five years of TDF treatment.In a study looking at 348 patients with paired liver biopsies, regression ofliver fibrosis and even liver cirrhosis (Ishak score 5 and 6) was found in themajority of patients.

Criteriafor treatment response

Virologic response

-
sustained decrease of HBV DNA, to at least <2,000 IU/mL (correspondingto <10,000 copies/mL), ideally to <60 IU/mL (<300 copies/mL).

-
sustained HBe seroconversion in HBeAg positive patients

-
ideally, loss of HBsAg

Biochemical response

-
sustained ALT normalization

Histologic response

-
reduction of fibrosis (histological staging)

-
reduction of inflammatory activity (histological grading)

Potential long-term effects

-
avoidance of cirrhosis, hepatocellular carcinoma (HCC),transplantation, and death

StephenW

逆转肝纤维化。不同的核苷和核苷酸类似物长期治疗，它已被证明可以在广大患者恢复肝纤维化，甚至肝硬化。这是最近赫然显示在59例患者从侧翻研究群，包括两个第三阶段的教育电视在治疗初治患者的疗效试验。从基线和一个6岁（范围3-7岁），平均疗程后肝活检组织学改善定义为Knodell纤维化评分恶化的情况下的Knodell坏死性炎症评分下降了2点或更大， 96％的患者。此外，超过1点在Ishak纤维化评分改善88％，其中有10例晚期肝纤维化或肝硬化，当他们进入第三阶段的研究（张2010A）。最近，88％在泰诺福韦试验评估前和治疗5年后进行活检的348例的102和103的亚组分析，经历了一个整体的肝脏组织学改善Knodell评分至少有两点改进测量海（组织学活动指数）（图4）。至少有两点减少纤维化评分（Marcellin 2011）的有94例患者在开始治疗，73％的肝硬化经验的回归，和72％的肝硬化。







图4。 TDF的治疗五年后，在肝脏组织学变化。在研究在348例患者寻找配对的肝活检，肝纤维化的回归，甚至肝硬化（Ishak评分5和6）被发现在广大患者。


标准治疗反应

病毒学应答

- 持续下降的HBV DNA，至少<2,000 IU /毫升（<10,000拷贝/毫升），最好<60 IU /毫升（<300拷贝/毫升）。

- 持续HBeAg阳性患者HBe血清转换

- 理想，损失的HBsAg

生化反应

- 持续ALT正常化

组织学反应

- 减少纤维化（病理分期）

- 减少炎症活动（组织学分级）

潜在的长期影响

- 避免肝硬化，肝细胞肝癌（HCC），移植，死亡

疯一点好

StephenW

Treatment options

Because of a limited tolerabilitydue to adverse events, duration with PEG-IFN α islimited for a period of 6-12 months (maximum 24 months). Nucleoside andnucleotide analogs have a good tolerability and are used in long-termtreatment. However, the efficacy of these oral agents can be hampered byemergence of resistance. Two interferons and five oral HBV polymeraseinhibitors are currently approved for the treatment of chronic HBV infections:standard IFN α-2b and PEG-IFN α-2a,lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT), entecavir (ETV)and tenofovir disoproxil fumarate (TDF) (Table 2). The efficacy of theavailable drugs after one year of treatment, assessed by the proportion ofindividuals with HBV DNA below the limit of detection, normalised transaminasesand HBeAg seroconversion is shown in Figure 6.

Figure 5. Treatment algorithm for chronic HBV infectionaccording to the German Guidelines (Cornberg 2011). The indication for interferon therapy should always be considered. Fortreatment with nucleoside or nucleotide analogs, agents with high geneticbarrier against resistance such as entecavir or tenofovir should be preferred.

Table 2. Overview of interferons and oral antiviral drugscurrently approved for the treatment of HBV infection.

Drug	Name	Dose	Duration
Interferon α    Standard Interferon  α-2a	Roferon  ®	2.5-5 mio. U/m2  body surface 3x/week	4-6 months
Standard Interferon  α-2b	Intron A®	5-10 mio. IU 3x/week	4-6 months
Pegylated Interferon  α-2a	Pegasys  ®	180 µg/week	48 weeks
Nucleoside analogs    Lamivudine	Zeffix  ®	100 mg/day	long-term*
Telbivudine	Sebivo  ®	600 mg/day	long-term*
Entecavir	Baraclude  ®	0.5 mg/day	long-term*
		1 mg/day for patients with  lamivudine resistance	long-term*
Nucleotide analogs
Adefovir dipivoxil	Hepsera  ®	10 mg/day	long-term*
Tenofovir disoproxil fumarate	Viread  ®	300 mg/day	long-term*

* see Figure 6

Table 3. Recommendations for the use of nucleos(t)ide analogs in clinical practice.

Drug	Advantage	Disadvantage	Recommendation
Lamivudine (LAM)	· Low  treatment costs    · Oral  solution available for children or individual dosage in case of renal  impairment	· High  risk of resistance in long-term monotherapy    · Cross-resistance  to ETV and LdT	· Use  as first-line therapy only in selected patients with low viral load    · Prevention  of exacerbation in HBsAg+, HBV DNA- patients with immunosuppression    · Preemptive  therapy in case of HBsAg-negative, anti-HBc positive patients with  immunosuppression    · Use  in pregnancy possible
Adefovir dipivoxil    (ADV)	· Experience  in combination with LAM    · No  cross-resistance to LAM	· Moderate  antiviral activity    · Primary  non-response in 10-20% of cases    · Slow  viral kinetics during therapy    · Risk  of viral resistance in long-term monotherapy    · Nephrotoxicity	· Not  to be used as first-line therapy
Telbivudine (LdT)	· High  antiviral efficacy    · Potentially  no cross-resistance to entecavir	· Moderate  risk for viral resistance in long-term monotherapy    · Neuropathy  and myopathy	· First-line  therapy    · Can  be combined with TDF
Entecavir (ETV)	· High  antiviral efficacy    · Low  risk for viral resistance in long-term monotherapy in lamivudine-naïve  patients    · Combination  therapy with TDF as rescue therapy    · Oral  solution available for individual dosage in case of renal impairment	· In  LAM-experienced patients high risk for the development of viral resistance  and virologic failure in long-term monotherapy	· First-line  therapy    · Can  be combined with TDF
Tenofovir disoproxil fumarate (TDF)	· High  antiviral efficacy    · Low  risk for viral resistance in long-term monotherapy	· Nephrotoxicity    · Decrease  in bone mineral density	· First  line therapy    · Can  be combined with ETV, LdT or LAM if needed
* in HBV-monoinfected  patients no renal toxicity was observed in 5 years of TDF treatment