Free textbook: Hepatology: A Clinical textbook 2012

StephenW

治疗方案

由于有限的耐受性不良反应事件，持续时间与聚乙二醇干扰素α被限制为6-12个月期间（最长24个月）。核苷和核苷酸类似物，具有良好的耐受性和长期治疗。然而，这些口服药物的疗效，可阻碍出现抗药性。两种干扰素和口服乙肝病毒聚合酶抑制剂是目前批准的标准干扰素α-2b干扰素和聚乙二醇干扰素α-2a的拉米夫定（LAM），阿德福韦酯（ADV），替比夫定（LDT），恩替卡韦治疗慢性乙肝病毒感染：（ETV）和替诺福韦酯富马酸（华盈）（见表2）。一年的治疗后，可以由个人与HBV DNA低于检测限的比例分摊药物，疗效，转氨酶正常化和HBeAg血清转换，如图6所示。



图5。根据德国指引（Cornberg 2011），慢性乙肝病毒感染的治疗方法。应始终被视为干扰素治疗的适应症。高基因屏障对电阻，如恩替卡韦或替诺福韦治疗核苷或核苷酸类似物，代理人应优先。





表2。概述目前批准用于治疗乙肝病毒感染的干扰素及口服抗病毒药物。

药物 名称 剂量 时间

干扰素α  
标准干扰素α-2a roferon®  2.5-5 MIO。表面3x/week u/m2身体 4-6个月

标准干扰素α-2b Intron® 5-10 MIO。国际单位3x/week 4-6个月

聚乙二醇干扰素α-2a的 PEGASYS® 180微克/周 于48周

核苷类似物

拉米夫定 zeffix® 100毫克/天 长期*

替比夫定 替比夫定® 600毫克/天 长期*

恩替卡韦 博路定® 0.5毫克/天 长期*
                          1毫克/天拉米夫定耐药患者 长期*

核苷酸类似物

阿德福韦 阿德福韦酯® 10毫克/天 长期*

富马酸替诺福韦酯 VIREAD® 300毫克/天 长期*

*参见图6


表3。核苷（酸）IDE类似物在临床实践中使用的建议。

药物
优点
缺点
建议

拉米夫定（Lam）
·治疗费用低
·口服液可用于儿童或个人剂量肾功能不全的情况下
·抵抗长期单一的高风险
·交叉耐药ETV和LDT
·只有在选择低病毒载量的患者作为第一线治疗使用
·防止加重在HBsAg +，HBV DNA的患者免疫抑制
·先发制人的情况下，HBsAg阴性，抗-HBc阳性患者免疫抑制治疗
·在怀孕期间使用的可能

阿德福韦（ADV），
·经验结合林
·无交叉耐药性，以林
·适度的抗病毒活性
·小学非在10-20％的情况下的反应
·缓慢，在治疗过程中病毒动力学
·病毒抗性在长期单一的风险
·肾毒性
·不被用来作为第一线治疗

替比夫定（LDT）
·高抗病毒疗效
·潜在的无交叉耐药性，以恩替卡韦
·中度风险病毒抗性在长期单一
·神经病和肌病
·第一线治疗
·可与TDF的结合

恩替卡韦（ETV）
·高抗病毒疗效
·病毒耐药拉米夫定初治患者长期单一的低风险
·与TDF的组合疗法作为抢救治疗
·口服液可用于个人剂量肾功能不全的情况下
·Lam经验的患者发展长期单一的病毒抗性和病毒学失败的高风险
·第一线治疗
·可与TDF的结合

富马酸替诺福韦酯（TDF的）
·高抗病毒疗效
·低风险，长期单一的病毒抗性
·肾毒性
·减少骨密度
·第一线治疗
·如果需要与ETV，LDT或LAM可结合

*在HBV-monoinfected的患者无肾毒性，在5年TDF的治疗观察

StephenW

Interferons INF α is a naturaloccurring cytokine with immunomodulatory, antiproliferative and antiviralactivity. During treatment, the therapeutic efficacy of INF α can often beclinically recognised by an increase of ALT levels to at least twice thebaseline levels. These ALT flares often precede virologic response.

The main aim of INF α treatment is to induce a long-term remission by finitetreatment duration. Overall a long-term response defined by either HBeAgseroconversion or durable suppression of HBV DNA to low or undetectable levelscan be achieved in approximately 30% of treated patients. In these respondersthe chance for HBsAg loss in the long-term is relatively high.

Figure 6. One-year efficacy of medications currentlyapproved for the treatment of chronic HBV infection (Lok 2009). Treatment efficacy is expressed as suppression ofHBV DNA below the limit of detection, ALT normalisation and rates of HBeAgseroconversion. As no head-to-head trials comparing the substances have beenundertaken, differences in antiviral efficacy have to be interpreted withcaution.

Standard INF α. StandardIFN α was approved for treatment of chronic hepatitisB in 1992. IFN α is applied in dosages ranging from 5million units (MU) to 10 MU every other day or thrice weekly. In ameta-analysis, a significant improvement in endpoints was shown in patientswith HBeAg-positive chronic hepatitis B being treated with standard IFNcompared to untreated patients (Craxí 2003). Complete remission of fibroticchanges was observed in some patients and the loss of HBsAg occurredcomparatively often. Furthermore, there was a trend towards reduction ofhepatic decompensation (treated 8.9% vs. untreated 13.3%), hepatocellularcarcinoma (1.9 vs. 3.2%), and liver associated deaths (4.9 vs. 8.7%) (Craxí2003).

A significant decrease in ALT and in HBV DNA serum levelswas also shown for standard IFN α in the treatment ofHBeAg-negative chronic hepatitis B (Brunetto 2003). However, a high percentage(25-89%) of these patients relapses after the end of treatment showingelevation of ALT levels and a return of HBV DNA levels. The relapse rate seemsto be higher when treatment duration is short (16 to 24 weeks) compared tolonger treatment (12 to 24 months). A retrospective comparison of IFN therapieslasting from 5 to 12 months showed that with longer treatment the chance of along-term response was 1.6 times higher (normalization of ALT, HBV DNA <1x106  copies/ml 1-7years after end of therapy). The overall response rates were 54% at the end oftherapy, 24% at 1 year after therapy, and 18% 7 years after therapy (Manesis2001).

Patients with long-term response to treatment have a morefavourable course than patients who were untreated, unresponsive, or who had arelapse interferon α therapy with respect to progressionto liver cirrhosis, liver associated deaths, and development of hepatocellularcarcinoma (Brunetto 2003, Lampertico 2003). However, due to higher antiviralefficacy PEG-IFN α should be preferred to standardIFN α.

PEG-INF α. Theaddition of a polyethylene glycol molecule to the IFN resulted in a significantincrease in half-life, thereby allowing administration once weekly. Two typesof subcutaneously administered PEG-IFN α weredeveloped: PEG-IFN α-2a and PEG-IFN α-2b,of which PEG-IFN α-2a was licensed for the treatmentof chronic HBV infections in a weekly dose of 180 µg for 48 weeks in bothHBeAg-positive and HBeAg-negative patients. However, PEG-IFN α-2bshows similar efficacy. After one year on treatment with PEG-IFN α-2aand α-2b, 22% to 27% of patients were reported toachieve HBeAg seroconversion (Janssen 2005, Lau 2005).

The safety profiles of standard IFN αand PEG-IFN α are similar. Following therapytermination a relatively high relapse rate is to be expected (>50%). Thedose of 180 µg per week applied for 48 weeks was recently shown to exert astronger antiviral efficacy compared to administration for 24 weeks or toadministration of 90 µg per week (Liaw 2011). In a small Italian study it wasshown that prolongation of 48 weeks of treatment with 180 µg PEG-IFN α per week by another 48 weeks of 135 µg PEG-IFN α-2a may enhance antiviral efficacy and increase the rateof patients achieving HBsAg loss, at least in HBeAg-negative patients with HBVgenotype D (Lampertico 2010). However, the optimal treatment duration forPEG-IFN α has not been defined yet and treatmentbeyond 48 weeks is not recommended by current guidelines.

PEG-IFN α inHBeAg-positive patients. Four randomized, controlled studies investigatingthe efficacy of PEG-IFN α in HBeAg-positive patientshave been conducted (Crespo 1994, Chan 2005, Janssen 2005, Lau 2005). Thesestudies compared 180 µg PEG-INF α per week tostandard IFN, LAM, and/or a combination treatment with PEG-INF α+ LAM for 48 weeks. Sustained HBeAg seroconversion at the end of follow-up(week 72) was significantly higher in patients treated with PEG-IFN α-2a alone or in combination with LAM than in patientstreated with LAM alone (32% and 27% versus 19%) (Marcellin 2004).

Importantly, it was recently shown that PEG-IFN α can induce immunomodulatory effects which persist beyondthe end of therapy leading to high HBsAg clearance rates in the follow-upperiod. In a recent study, 97 patients with chronic HBV infection who hadreceived treatment with standard IFN α wereretrospectively analyzed for a median period of 14 (range, 5-20) years. Duringthe observation period, 28 patients (29%) of this cohort lost HBsAg (Moucari2009).

PEG-IFN α inHBeAg-negative patients. The efficacy and safety of 48 weeks treatment with180 µg PEG-IFN α-2a once weekly + placebo, + 100 mgLAM daily, or LAM alone was compared in 177, 179, and 181 HBeAg-negativepatients, respectively. After 24 weeks of follow-up, the percentage of patientswith normalisation of ALT levels or HBV DNA levels below 20,000 copies/ml wassignificantly higher with PEG-IFN α-2a monotherapy(59% and 43%, respectively) and PEG-IFN α-2a plus LAM(60% and 44%) than with LAM monotherapy (44% and 29%); the rates of sustainedsuppression of HBV DNA below 400 copies/ml were 19% with PEG-IFN α-2amonotherapy, 20% with combination therapy, and 7% with LAM alone.

Also in HBeAg-negative patients HBsAg loss can be induced insome patients by PEG-IFN α treatment. In a study in315 patients who were treated with either PEG-IFN α-2a,LAM 100 mg or a combination of both drugs for 48 weeks, three years after theend of treatment, the rate of HBsAg loss was 8.7% in those who had been treatedwith PEG-IFN α-2a alone or in combination with LAMwhile no patient treated with LAM as monotherapy cleared HBsAg (Marcellin2009a). Of the pa-tients who had received a PEG-IFN α-2aand who still had undetectable HBV DNA three years after treatment, 44% hadlost HBsAg.

Prolongation of PEG-IFN αtreatment beyond 48 weeks may increase sustained response rates. This was foundin an Italian study in 128 mainly genotype D-infected HBeAg-negative patientswho were randomized to either treatment with 180 µg/week PEG-IFN α-2afor 48 weeks or a continuing treatment with PEG-IFN α-2aat 135µg/week. Additionally, in a third arm patients received combinationtreatment with PEG-IFN α-2a 180µg/week and LAM 100mg/day, followed by 48 weeks of PEG-IFN α-2a in thedosage of 135 µg/week. As a result, 48 weeks after the end of treatment 26% ofpatients who had received 96 weeks of PEG-IFN treatment showed HBV DNA levels<2,000 IU/mL compared to only 12% of the patients who had received PEG-IFNfor 48 weeks. Combination with LAM showed no additional effect (Lampertico2010a).

StephenW

干扰素
α的INF是一个自然发生​​与免疫调节，抗增殖和抗病毒活性的细胞因子。的INFα的疗效在治疗过程中，经常可以在临床上公认的ALT水平提高到至少两次的基准水平。这些ALT突增，往往先于病毒学应答。

INFα治疗的主要目的是通过有限的疗程诱导一个长期的缓解。总体而言，无论是HBeAg血清转换持久抑制HBV DNA的低或检测不到的水平定义一个长期的响应可以达到治疗的患者中约30％。在这些反应的乙肝表面抗原长期亏损的机会也比较高。



图6。为期一年的药物的疗效，目前已获得批准用于治疗慢性乙肝病毒感染（乐）。疗效表现为抑制乙型肝炎病毒DNA低于检测限，ALT复常和HBeAg血清转换率。如无头头试验比较物质已开展抗病毒疗效的差异有解释要谨慎。



标准的INFα。在1992年被批准用于治疗慢性乙型肝炎的标准干扰素α。应用范围从500万台（MU），到10万亩，隔日或每周三次的剂量干扰素α。在一项荟萃分析显示，在终点的显着改善患者比未经治疗的患者（克拉克西2003）与标准干扰素治疗HBeAg阳性慢性乙型肝炎乙。完全缓解肝纤维化的变化，观察在一些患者和乙肝表面抗原的损失较常发生。此外，还有是朝着降低肝功能失代偿的趋势（处理与未经处理的13.3％，8.9％），肝癌（1.9比3.2％），以及肝脏相关死亡（4.9比8.7％）（克拉克西2003年）。

中ALT和血清HBV DNA水平显着下降也显示出标准干扰素α治疗HBeAg阴性慢性乙型肝炎（Brunetto 2003）。然而，这些患者的高比例（25-89％），复发后治疗显示海拔ALT水平和HBV DNA水平的回报的结束。复发率似乎更高时，治疗时间短（16至24周）相比较长的治疗（12至24个月）。持续5至12个月的干扰素治疗的回顾性比较表明，较长的治疗一个长期应对的机会高出1.6倍（（ALT），HBV DNA <1×106拷贝/ ml 1-7年的治疗结束后的正常化） 。整体回应率分别为54％，在治疗结束时，在治疗后1年的24％，治疗后7年（Manesis 2001）和18％。

长期治疗反应的患者有治疗，反应迟钝，或谁复发干扰素α治疗方面的进展为肝硬化，肝癌相关的死亡，和肝癌的发展（2003年Brunetto，比病人更有利的当然lampertico 2003）。然而，由于较高的抗病毒疗效的PEG-IFNα应首选干扰素α标准。

PEG-INF的α。此外干扰素的聚乙二醇分子中的半衰期显着增加，从而使管理，每周一次。开发了两种类型的皮下注射PEG干扰素α：PEG干扰素α-2a和聚乙二醇干扰素α-2b干扰素，聚乙二醇干扰素α-2a的治疗慢性乙肝病毒感染的许可在每周剂量为180微克在HBeAg阳性和HBeAg阴性患者为48周。然而，聚乙二醇干扰素α-2b显示了类似的疗效。与聚乙二醇干扰素α-2a和α-2b的治疗一年后，报告22％至27％的患者实现HBeAg血清转换（詹森2005年，刘2005）。

标准干扰素α和聚乙二醇干扰素α的安全性是相似的。终止治疗后复发率相对高是可以预期的（> 50％）。最近，剂量为180微克每周48周应用发挥更强的抗病毒疗效相比，24周的管理，或每周90微克（廖2011）管理。在小意大利的研究结果表明，180微克聚乙二醇干扰素α48周，每周135微克聚乙二醇干扰素α-2a的治疗48周延长可提高抗病毒疗效，增加患者HBsAg消失率达到至少在HBeAg阴性患者HBV基因型D（Lampertico 2010）。然而，聚乙二醇干扰素α的最佳治疗时间并没有被定义，但不超过48周的治疗建议由目前的指导方针。

在HBeAg阳性患者的PEG-IFNα。已进行了四个随机调查中HBeAg阳性患者的聚乙二醇干扰素α的疗效对照研究（2005年，刘2005年，詹森克雷斯波1994年，陈2005）。这些研究相比，每周180微克的PEG-INFα干扰素标准，林和/或48周的PEG-INFα+林联合治疗。在后续的持续HBeAg血清转换（72周）与聚乙二醇干扰素α-2a的单独或组合比林单独治疗的患者（32％和27％对19％）与林治疗的患者显着高于（Marcellin 2004年）。

重要的是，最近表明，聚乙二醇干扰素α可诱导免疫调节作用，坚持超越，导致高的HBsAg清除率在随访期间的治疗结束。在最近的一项研究中，中位数为14岁（范围5-20）期间曾收到与标准干扰素α治疗的慢性乙肝病毒感染的97例患者进行回顾性分析。观察期间，28例（29％），这个世代失去了HBsAg的（Moucari 2009）。

在HBeAg阴性患者的PEG-IFNα。 180微克聚乙二醇干扰素α-2a的每周一次+安慰剂治疗48周的疗效和安全性，100毫克林每天或林单独进行了比较，177，179和181例HBeAg阴性患者。随访24周后，患者的ALT水平或HBV DNA水平正常化比例低于20,000拷贝/ ml显着高于聚乙二醇干扰素α-2a的单药治疗（分别为59％和43％）和PEG-干扰素α-2a加林（60％和44％），比单一林（44％和29％）;低于400拷贝/ ml的HBV DNA持续抑制率分别与聚乙二醇干扰素α-2a的单一19％，20 ％，联合治疗，并与林仅7％。

在HBeAg阴性患者HBsAg消失也可以在一些患者诱导聚乙二醇干扰素α治疗。在315人要么聚乙二醇干扰素α-2a的，林100毫克或48周的两种药物组合治疗的患者的研究，在治疗结束后三年，HBsAg消失率在那些谁中为8.7％经治疗后已与聚乙二醇干扰素α-2a的单独或与林的结合而没有耐心与林视为单一清除乙肝表面抗原（Marcellin 2009a的）。谁收到了一个陀螺干扰素α-2a和治疗三年后仍检测不到乙肝病毒DNA的患者，已经失去了44％，乙肝表面抗原。

延长聚乙二醇干扰素α治疗超过48周，可能会增加持续应答率。这是在意大利128主要是D基因型感染者的HBeAg阴性患者，随机要么用180微克/周聚乙二醇干扰素α-2a的48周或与聚乙二醇干扰素α-2a的继续治疗，在治疗研究中发现135μg/week。此外，在第三组患者配合治疗的PEG-IFNα-2a的180μg/week和林100毫克/天，48周PEG-干扰素α-2a的剂量为135微克/周。因此，在治疗结束48周后，26％曾接受96周的聚乙二醇干扰素治疗的患者显示HBV DNA水平<2000国际单位/毫升相比，谁收到了48 PEG-干扰素的患者中只有12％周。与林的结合表明没有附加效果（Lampertico 2010A）。

StephenW

Nucleoside andnucleotide analogs

Nucleoside and nucleotide analogs inhibit HBV replication by competing with the natural substrate deoxyadenosinetriphosphate (dATP) and causing terminating of the HBV DNA chain prolongation.They represent two different subclasses of re-verse transcriptase inhibitors:while both are based on purines or pyrimidines, acyclic nucleotide analogs have an open (acyclic) ribose ring that confers greater binding capacity to resistant HBV polymerase strains.

Treatment duration for nucleos(t)ide analogs is not well-defined but a short-term application of these agents for 48 weeks is associated with prompt relapse in viremia and they should be administered for longer periods.Treatment efficacy of nucleoside and nucleotide analogs implies complete suppression of HBV DNA levels in serum. This should be achieved within six months if agents with high risk for resistance development as LAM, ADV, and LdT are used.

Effective long-term control of HBV replication with nucleoside or nucleotide analogs is associated with a reduction of long-term complications such as HCC and development of liver cirrhosis (Toy 2009). Studies with different nucleoside and nucleotide analogs have demonstrated that suppression of HBV replication is associated with a significant decrease in histologic inflammatory activity and fibrosis, including partial reversion of liver cirrhosis (Chen 2006, Iloeje 2006, Mom-meja-Marin 2003, Chen 2010,Marcellin 2011, Schiff 2011). With increasing treatment duration HBeAg seroconversion rates increase (Liaw 2000, Lok 2000). Most importantly, there is also evidence that effective inhibition of HBV replication can reduce HBV cccDNA, possibly running parallel to the decline in serum HBsAg levels(Werle-Lapostolle 2004, Wursthorn 2006). These findings may indicate that long-term antiviral therapy may lead to a complete response in a significant number of patients.

A central aspect of HBV polymerase inhibitor treatment is the prevention and management of HBV resistance to these drugs (see Chapter10). Resistance against nucleoside or nucleotide analogs can occur during suboptimal treatment and often leads to aggravation of liver disease. Because of cross resistance between several nucleoside and nucleotide analogs,nucleoside-naïve and nucleoside-experienced patients have to be distinguished and prior nucleoside experience should be taken into account when choosing a second line therapy. However, highly potent sub-stances such as ETV and TDF show minimal or even no resistance development in treatment-naïve patients over5-6 years (Snow-Lampert 2011).

Lamivudine (LAM). LAM, a (-) enantiomer of 2'-3' dideoxy-3'-thiacytidine, is a nucleoside analog that was approved for the treatment of chronic HBV infection in 1988 with a daily dose of 100 mg. This dose was chosen based on a preliminary trial that randomly assigned 32 patients to receive 25, 100, or 300 mg of LAM daily for a total of 12 weeks (Dienstag1995). In this study the dose of 100 mg was more effective than 25 mg and was similar to 300 mg in reducing HBV DNA levels. LAM exerts its therapeutic action in its phosphorylated form. By inhibiting both the RNA- and DNA-dependent DNA polymerase activities, the synthesis of both the first strand and the second strand of HBV DNA are interrupted.

Long-term LAM treatment is associated with an increasing rate of antiviral drug resistance reaching approximately 70% after 5 years inpatients with HBeAg-positive HBV infections. Therefore, in many guidelines LAM is not considered a first-line agent in the treatment of chronic HBV infection any more. However, LAM still may play a role in combination regimens or inpatients with mild chronic hepatitis B expressing low levels of HBV DNA (<105 copies/ml). An early and complete virologic response to LAM within 6 months of therapy(<400 copies/mL) constitutes a prerequisite for long-term control of HBV infection without the risk of developing resistance.

Adefovir dipivoxil (ADV). Adefovir dipivoxilwas approved for treatment of chronic hepatitis B in the US in 2002 and in Europe in 2003. It is an oral diester prodrug of adefovir, an acyclicnucleotide adenosine analog that is active in its diphosphate form. Because the acyclic nucleotide already contains a phosphate-mimetic group, it needs only two, instead of three, phosphorylation steps to reach the active metabolite stage. ADV was the first substance with simultaneous activity against wild type,pre-core, and LAM-resistant HBV variants. It is active in vitro against a number of DNA viruses other than HBV and retroviruses (i.e., HIV). The dose of 10 mg per day was derived from a study comparing 10 mg versus 30 mg/d. The higher dosage leads to stronger suppression of HBV DNA levels but also to renal toxicity with an increase of creatinine levels (Hadziyannis 2003).

ADV was the first acyclic nucleotide that was widely used in the treatment of LAM-resistant HBV infections. However, the antiviral effect of ADV in the licensed dosage of 10 mg/day is rather low as compared to other available antivirals (Figure 4); this disadvantage makes ADV vulnerable to HBV resistance (Hadziyannis 2006a). Now that TDF is approved, ADV should not be used as first-line monotherapy.

Telbivudine (LdT). Telbivudine is a thymidine analog which is active against HBV but at least in vitro not active against other viruses, including HIV and hepatitis C virus (HCV). LdT at 600mg/day expresses higher antiviral activity compared to either LAM at 100 mg/day or ADV at 10 mg/day (Figure 4). More patients achieved HBeAg loss within 48weeks as compared to other nucleos(t)ides.

LdT was reported to be non-mutagenic, non-carcinogenic,non-teratogenic, and to cause no mitochondrial toxicity. A favourable safety profile at a daily dose of 600 mg was demonstrated (Hou 2008, Lai 2007).However, CK elevations were observed more often as compared to the group treated with LAM and neurotoxicity may be an issue when LdT is administered in combination with PEG-INF α  (Fleischer 2009). Thus,in the GLOBE trial, during a period of 104 weeks grades 3/4 elevations in CK levels were observed in 88 of 680 (12.9%) patients who received LdT and in 28of 687 (4.1%) patients who received LAM (p<0.001) (Liaw 2009). However,rhabdomyolysis was not observed. Peripheral neuropathy was described in 9 of 48(18.75%) patients who received combination therapy of PEG-INF αnd LdT and only in 10 of 3500 (0.28%) patients who received LdT monotherapy(Goncalves 2009).

Resistance to LdT has been found to occur in up to 21% after 2 years of treatment (Tenney 2009), predominantly in patients who did not achieve undetectable HBV DNA level after 24 weeks of treatment (Zeuzem 2009).LdT shows cross-resistance to LAM and ETV. As a consequence LdT should not be used in LAM or ETV refractory patients.

Entecavir (ETV). Entecavir, a cyclopentylguanosine nucleoside analog, is a selective inhibitor of HBV replication and was licensed in 2006. Entecavir blocks all three polymerase steps involved in the replication process of the hepatitis B virus: first, base priming; second,reverse transcription of the negative strand from the pregenomic messenger RNA;third, synthesis of the positive strand of HBV DNA. In comparison to all othernucleoside and nucleotide analogs, ETV is more efficiently phosphorylated to its active triphosphate compound by cellular kinases. It is a potent inhibitor of wild-type HBV but is less effective against LAM-resistant HBV mutants.Therefore, ETV was approved at a dose of 0.5 mg per day for treating naïve HBeAg-positive and -negative patients at the dose of 1 mg per day for patients with prior treatment with LAM (Lai 2005, Sherman 2008). ETV and LAM are the only nucleoside analogs available as a tablet and an oral solution.

Treatment-naïve HBeAg-positive patients achieved undetectable HBV DNA levels in 67% and 74% after one and two years of ETV treatment,reaching 94% after five years, respectively (Figure 4, Figure 7) (Chang 2010).Long-term studies in ETV responder patients demonstrated that response can be maintained in nearly all patients over an observation period of up to six years. So far, the rate of resistance at six years of treatment is estimated to be approximately 1.2% for treatment-naïve patients (Tenney 2009). Loss of HBsAg occurs in 5% of treatment-naïve individuals after two years of ETV therapy(Gish 2010). A non-randomised Italian study in a mixed population of predominantly HBeAg-negative patients could demonstrate undetectable HBV DNAlevels in 91% and 97% of patients at 1 and 2 years of ETV treatment,respectively (Lampertico 2010).

In LAM-resistant patients ETV is less potent. Only 19% and40% of these patients achieved undetectable HBV DNA after one and two years,respectively, despite an increased dose of 1 mg/day (Gish 2007, Sherman 2008).Due to cross-resistance up to 45% of patients with LAM resistance develop resistance against ETV after 5 years of treatment (Tenney 2009).

ETV has a favourable tolerability profile and can be easily adjusted to renal function. However, ETV may cause severe lactic acidosis inpatients with impaired liver function and a MELD score of >20 points (Lange2009).

Figure 7. Percentage of patients achieving HBV DNA levels<400 copies/ml during long-term treatment with 1 mg ETV per day (Chang2010). The long-term cohort ETV-901 consists of HBeAg-positive patients initially treated in the study ETV-022 (ETV 0.5mg/day), which was designed for a duration of one year.

Tenofovir (TDF). Tenofovir disoproxilfumarate, an ester prodrug form of tenofovir (PMPA;(R)-9-(2-phosphonylmethoxypropyl)), is an acyclic nucleoside phosphonate, ornucleotide analog closely related to ADV. TDF has selective activity against retroviruses and hepadna viruses and is currently approved for the treatment of HIV infection and of chronic hepatitis B. TDF showed marked antiviral efficacy over five years with complete virologic response rates (HBV DNA <400copies/ml) reaching nearly 100% in treatment-naïve HBeAg-negative and -positive patients (Figure 8). In HBeAg-positive patients, 11% of patients experienced HBsAg loss (Marcellin 2011). Other clinical studies showing a high efficacy of TDF in LAM-resistant HBV infections irrespective of the mutation mediating LAM resistance (van Bömmel 2010, Levrero 2010). Due to possibly existing cross-resistance to ADV, the efficacy of TDF might be hampered by the presence of ADV resistance in patients with high HBV viremia; however, a breakthrough of HBV DNA during TDF treatment in patients with previous ADV failure or intreatment-naïve patients has not been observed (van Bömmel 2010, Levrero 2010,Snow-Lampert 2011).

Figure 8. Percentage of patients achieving HBV DNA levels<400 copies/mL during long-term treatment with 300 mg TDF per day (Marcellin2010). Patients were originally randomised to treatment with 300 mg TDF or 10 mg ADV per day. After one year, patients receivingADV were switched to TDF. Please note that the on-treatment analysis excluding the missing patients showed undetectable HBV DNA in 96% of the TDF-TDF group and in 100% of the ADV-TDF group.

TDF is generally well-tolerated and not associated with severe side effects. For HBV-monoinfected, treatment-naïve patients, renal safety during TDF monotherapy was investigated in three studies. In a randomized study comprising HBeAg-negative patients, none of 212 patients treated with TDF for three years and none of 112 patients who were treated with ADV for one year and then switched to TDF for two years had a decrease in GFR to levels of <50 ml/min or an increase of serum creatinine levels to >0.5mg/dl (Marcellin 2009). In a similar study in HBeAg-positive patients, of 130patients treated with TDF for 3 years and of 76 patients treated with ADV for one year and consecutively with TDF for 2 years, only one patients showed an increase in serum creatinine levels >0.5 mg/dl starting at year two(Heathcote 2011). In a sub-analysis of both studies in 152 HBeAg-positive and-negative Asian patients, no increase of serum creatinine >0.5 mg/dl or of eGFR <50 ml/min was found in up to 3 years of TDF treatment (Liaw 2009a). In contrast, in a recent study a benefit in renal function could be found in treated patients when compared to untreated patients with HBV infection, which might reflect a lower incidence of glomerulonephritis caused by HBsAg-induced immune complexes in treated patients (Mauss 2011).

The use of tenofovir in HIV-coinfected patients is discussed in detail in Chapter 17.

Combinationtherapy as first-line treatment.
As of now, first-line combination treatments with nucleoside and nucleotide analogs or PEG-IFN α +nucleos(t)ide analogs are not indicated. There is only one study comparing a combination therapy with LAM and ADV to LAM monotherapy in untreated patients(Sung 2008). In this study, there was no difference in the virologic and biochemical response between both groups. The rate of LAM resistance was much lower in the combination group. However, the development of resistance couldnot be completely avoided even with the use of an additional dose of ADV.Another study analyzing the combination of LAM with LdT also showed no benefit for combination therapy (Lai 2005).

Especially in patients with liver cirrhosis, a fast and complete suppression of HBV replication is desirable. A monotherapy with ETV was found to be as safe and effective as monotherapy with TDF, and an addition of emtricitabine to TDF showed no improvement in response. Therefore, in these patients as well, combination treatment is currently not recommended (Liaw2011).  

Combination treatment with LdT and PEG-INF αshould not happen. In a recent study, peripheral neuropathy was described in 9of 48 (18.8%) patients who received combination therapy of PEG-INF α and LdT and only in 10 of 3,500 (0.28%) patients who received LdT monotherapy (Goncalves 2009). Although combination of LAM plusPEG-IFN α failed to demonstrate benefit when evaluated at the end of follow-up in most studies, a more pronounced on-treatment virologic response (week 48) was observed with combination therapy as compared to LAM or PEG-IFN α alone. This more profound HBV DNA suppression induced by the combination regimen was associated with a lower incidence of LAM resistance (presence of resistance mutations in1% vs. 18% at the end of therapy).

However, combination therapies between PEG-IFN α and more potent nucleos(t)ide analogs may be attractive.Recently, a combination treatment of ETV and PEG-IFN αafter 4 years of complete response to ETV was superior to continuation of ETVtreatment by HBeAg and HBsAg loss and seroconversion rates (Ning 2011). Similarstudies are currently being undertaken investigating combination treatment ofPEG-IFN α and TDF. However due to the preliminarycharacter of the results a combination treatment of nucleos(t)ide analogs plusPEG-INF α is still not recommended.

StephenW

核苷和核苷酸类似物

核苷和核苷酸类似物抑制乙型肝炎病毒复制的竞争与自然底物脱氧腺苷三磷酸（dATP的）引起的乙型肝炎病毒DNA链延长终止。他们代表了两种不同的子类反转录酶抑制剂，非环核苷酸类似物，而两者都基于对嘌呤或嘧啶，有一个开放的（非周期性）核糖环，赋予更大的结合能力，耐药HBV聚合酶菌株。

核苷（酸）IDE类似物的治疗时间是没有得到很好的定义，但血症提示复发的48周的短期应用这些药物，并应更长的时间管理。核苷和核苷酸类似物治疗功效意味着完全抑制血清HBV DNA水平。这应达到6个月内，如果议员，ADV，LDT阻力，发展高风险的代理。

长期有效控制乙肝病毒复制与核苷或核苷酸分析日志减少长期并发症，如肝癌和肝硬化（玩具）的发展。不同的核苷和核苷酸类似物的研究表明，抑制乙肝病毒复制与组织学炎症活动的一个显着减少和纤维SIS，包括肝硬化的部分回归（陈2006年，2006年，妈妈，茉莉，马林2003，陈Iloeje 2010年，2011年2011年，希夫Marcellin）。与增加治疗期间HBeAg血清转换率增加（廖2000年，乐2000）。最重要的，也有证据，有效抑制乙肝病毒复制可以减少HBV cccDNA的，可能是平行的血清HBsAg水平下降（2004年拉珀斯托Werle-2006），Wursthorn。这些研究结果可能表明，长期抗病毒治疗，可能会导致在相当数量的患者完全缓解。

HBV聚合酶抑制剂治疗的一个中心环节，是抗乙肝病毒的预防和管理这些药物（见第10章）。对核苷或核苷酸类似物抗最理想的治疗过程中可能出现，并往往导致肝病加重。因为几个核苷和核苷酸类似物之间的交叉耐药性，核苷初治和核苷经验的患者必须是杰出的和核苷经验之前，应考虑选择第​​二线治疗时​​。然而，如教育电视和TDF高度烈性子的立场，显示最小或在治疗过的患者超过5-6年（2011年）雪 - 兰伯特甚至没有耐药性的发展。

拉米夫定（LAM）。林A（ - ）2'-3'脱氧-3'-thiacytidine对映体，是一种核苷类似物，于1988年被批准为治疗慢性乙肝病毒感染与每日剂量为100毫克。这个剂量是选择的基础上的初步试验，32例患者随机分配接受共12周（Dienstag 1995）25，100，或林每天300毫克。在这项研究中，100毫克剂量超过25毫克的有效，并在降低HBV DNA水平为300毫克。林发挥其治疗作用及其磷酸化形式。抑制的RNA和DNA依赖的DNA聚合酶活动，双方的第一链和第二链中HBV DNA的合成中断。

长期林治疗的抗病毒药物，在HBeAg阳性的乙肝病毒感染患者的5年后达到约70％的电阻率增加。因此，在许多指引林不认为在治疗慢性乙肝病毒感染任何第一线的代理。然而，林仍然可以发挥作用，在联合化疗方案或表达的HBV DNA水平低（<105拷贝/ ml）乙轻度慢性肝炎患者。治疗6个月内的早期和完整的病毒学应答林（<400拷贝/ ml）构成长期控制乙肝病毒感染的一个先决条件，没有发展性的风险。

阿德福韦酯（ADV）。阿德福韦酯被批准在2002年和2003年在欧洲，在美国治疗慢性乙型肝炎。它是一种口服阿德福韦酯前体药物，腺苷的无环核苷酸类似物，是活跃在其磷酸形式。由于无环核苷酸已经包含了磷酸盐模仿组，它需要只有两个，而不是三，磷酸化步骤，达到活性代谢产物的阶段。 ADV是同时活动的第一物质对野生型，预核心，林抗乙型肝炎病毒的变种。这是活跃在体外对一个比乙肝病毒的DNA病毒和逆转录病毒（即艾滋病病毒）。每天10毫克的剂量从10毫克与30毫克/ d比较研究得出。高剂量导致更强的抑制HBV DNA水平，但也肾毒性，肌酐水平增加（Hadziyann​​is 2003年）。

ADV是第一个非环核苷酸林抗乙肝病毒感染的治疗中被广泛使​​用。然而，阿德福韦持牌剂量在10毫克/天的抗病毒药物的作用是相当低，相比其他可用抗病毒药物（图4）;这个缺点使得ADV易受乙型肝炎病毒耐药（Hadziyann​​is 2006A）。现在，TDF的批准，ADV不应该被用来作为第一线单一。

替比夫定（LDT）。替比夫定是胸苷模拟，这是积极的，对乙肝病毒，但至少在体外不会主动对其他病毒，包括艾滋病毒和丙型肝炎病毒（HCV）。在600毫克/天的LDT表示较高的抗病毒活性相比，无论是在100毫克/天或10毫克/天（图4）进阶林。取得更多的患者在48周的HBeAg的损失比其他核苷（酸）的IDE。

LDT据报道，非致突变，无致癌，无致畸，并不会引起线粒体毒性。展示了一个良好的安全性，在每天600毫克剂量（侯，2007年2008年，赖）。然而，CK升高更经常与林治疗组相比，神经毒性可能是一个问题时，LDT是组合管理的PEG-INFα（弗莱舍2009年）。因此，在全球试验，在一个104周成绩期间CK水平的3/4的海拔，观察在收到LDT 680 88例（12.9％）和687（4.1％）谁收到林的患者（P 28 <0.001）（廖2009）。然而，横纹肌溶解症没有观察到。 9 48（18.75％）患者接受联合治疗的PEG-INFαndLDT和LDT单一（贡萨尔维斯2009）3500 10（0.28％）患者周围神经病变的描述。

抗到LDT已发现多达21％发生治疗（坦尼2009年）2年后，主要在患者经过24周的治疗（Zeuzem 2009）检测不到HBV DNA水平没有达到。LAM和ETV LDT显示交叉耐药性。因此LDT LAM或ETV的难治性患者不应使用。

恩替卡韦（ETV）。恩替卡韦，环戊基鸟嘌呤核苷类似物，是HBV复制的选择性抑制剂，并于2006年的许可。恩替卡韦阻止聚合酶参与B型肝炎病毒的复制过程中的所有三个步骤：第一，基地启动;第二，逆转录负链的信使RNA前基因组;第三，HBV DNA阳性链的合成。在所有其他核苷和核苷酸类似物相比，ETV更有效的磷酸化细胞激酶活性的三磷酸化合物。这是一个野生型HBV的有效抑制剂，但对林抗乙肝病毒突变是少有效。因此，ETV，每天0.5毫克剂量在每天1毫克剂量治疗天真的HBeAg阳性和阴性患者，为患者治疗前与LAM（赖2008）2005年，谢尔曼批准。 ETV和LAM是唯一的核苷类似物可作为片剂和口服液。

治疗初治的HBeAg阳性患者治疗ETV一台和两台年后取得了不到67％的HBV DNA水平和74％，五年后达到94％，分别为（图4，图7）2010年（张）。在ETV响应患者的长期研究表明，反应可以维持在几乎所有的患者超过一个长达6年的观察期。到目前为止，电阻率估计在6年的治疗是治疗初治患者（坦尼2009）约1.2％。发生HBsAg消失后两年ETV治疗（吉什2010）在5％的治疗天真个人。意大利混合人口的主要HBeAg阴性患者的一项非随机研究表明治疗ETV1年和2年的不到91％的HBV DNA水平和97％的患者，分别（Lampertico 2010）。

ETV在LAM耐的病人是那么有力。只有19％和40％的患者达到检测不到HBV DNA的，一两年后，尽管增加剂量1毫克/天（GISH 2007年，谢尔曼2008）。由于交叉耐药性高达45％的患者LAM抗对ETV发展阻力治疗（坦尼2009年）5年后。

ETV具有良好的耐受性，可以很容易地调整到肾功能。然而，ETV视可能会导致严重的乳酸性酸中毒，肝功能受损的患者和MELD评分> 20分（朗格2009）。







图7。实现HBV DNA水平<400拷贝/毫升，每天1毫克教育电视（张2010）在长期治疗的患者的百分比。由最初在研究ETV-022（ETV 0.5 mg /天），这是为期一年的设计治疗的HBeAg阳性患者的长期队列ETV-901。



替诺福韦（TDF的）。富马酸替诺福韦酯，酯药物泰诺福韦的形式（PMPA;（R）的-9  - （-phosphonylmethoxypropyl）），是一个无环核苷膦酸酯，或核苷酸类似物以ADV密切相关。 TDF的选择性活性，对逆转录病毒和嗜肝，目前批准用于治疗艾滋病毒感染和慢性乙型肝炎TDF的显示超过五年完整的病毒学应答率达到近100％（血清HBV DNA <400拷贝/ ml）标记的抗病毒疗效在治疗初治的HBeAg阴性和阳性的患者（图8）。在HBeAg阳性患者中，11％的患​​者出现HBsAg消失（Marcellin 2011）。其他临床研究显示在林抗乙肝病毒感染的TDF的疗效高，不论调解林耐（2010年2010年，Levrero范博梅尔）的突变。由于可能存在交叉耐药性ADV，TDF的疗效可能会阻碍高病毒血症患者阿德福韦电阻的存在，但是，HBV DNA的突破与先前ADV失败患者的华盈在治疗期间或在治疗初治患者并没有被观察到（范博梅尔2010年，2010年，斯诺 - 兰伯特2011 Levrero）。





图8。实现TDF的每天300毫克（Marcellin 2010）的长期治疗过程中HBV DNA水平<400拷贝/ ml的患者的百分比。患者最初随机TDF的300毫克或10毫克，每天ADV治疗。一年后，患者接受ADV切换到TDF的。请注意，不含缺失患者的治疗分析显示，在华盈，华盈集团的96％和100％，ADV-TDF的组中检测不到HBV DNA的。



TDF的一般耐受性良好，并没有严重的副作用。对于HBV-monoinfected的，治疗过的病人，在TDF的单一的肾脏安全三项研究调查。包括两年的HBeAg阴性患者，没有与TDF的治疗的212例患者，三年和112用ADV治疗一年然后切换到TDF的患者在随机研究水平在GFR下降< 50 ml / min或血清肌酐水平增加> 0.5毫克/升（Marcellin 2009年）。在一个类似的研究与TDF的治疗130例，为3年和一年，并连续2年与华盈用ADV治疗的76例患者中，HBeAg阳性患者中，只有一个病人表现为增加血清肌酐水平> 0.5毫克/ DL在今年（希思科特2011）开始。在152亚洲HBeAg阳性和阴性的患者，血肌酐没有增加这两项研究的子分析> 0.5 mg / dl或的eGFR <50毫升/分被发现在长达3年（廖2009a的TDF的治疗）。相反，在肾功能的好处，在最近的一项研究，可以发现在治疗的患者比未经治疗的患者与乙肝病毒感染，这可能反映了乙肝表面抗原引起的免疫复合物治疗的患者（莫斯2011）引起的肾小球肾炎的发病率较低。

在艾滋病毒合并感染的患者使用替诺福韦在第17章中详细讨论。
作为第一线治疗的综合疗法。截至目前，第一线的组合治疗，核苷和核苷酸类似物或聚乙二醇干扰素α+核苷（酸）IDE类似物都没有表示。只有一个研究与LAM和ADV联合治疗，林在未经治疗的患者（宋2008）单一。在这项研究中，有没有在这两个群体之间的病毒学和生化反应的差异。联合组的林电阻率要低得多。然而，发展的阻力，不能完全避免的，即使使用额外剂量阿德福韦。与LDT的组合分析，林的另一项研究也表明没有造福联合疗法（赖2005）。

尤其是在肝硬化患者，快速和完整的抑制乙肝病毒复制是可取的。一个单一与教育电视被认为是为安全和有效地与TDF的单一，除了华盈恩曲他滨的反应未见改善。因此，在这些患者中，联合治疗目前不建议（廖2011）。

LDT的PEG-INFα结合治疗不应该发生。在最近的一项研究中，周围神经病变的描述9 48（18.8％）患者接受联合治疗的PEG-INFα和LDT和LDT单一（贡萨尔维斯2009）3500 10（0.28％）患者。虽然林，加上聚乙二醇干扰素α联合未能证明效益评估在后续年底时，在大多数研究中，更明显的治疗病毒学应答（48周）联合治疗比林或PEG干扰素α单。这更深刻的组合方案引起的HBV DNA抑制与发病率较低的林耐（存在耐药突变在1％和18％，在治疗结束）。

然而，聚乙二醇干扰素α和更有力的核苷之间的联合疗法（t）的IDE类似物可能是有吸引力的。最近，ETV和聚乙二醇干扰素α联合治疗后完全缓解4年，以ETV优于继续ETV治疗HBeAg和HBsAg消失和血清转换率（宁2011）。类似的研究，目前正在开展调查相结合的聚乙二醇干扰素α和TDF治疗。然而，由于结果的初步性质结合治疗的核苷（酸）类似物IDE加的PEG-INFα仍然不建议。

StephenW

Choosing the right treatment option

One can choose either to treat with PEG-IFN α in order to induce a long-term control by finite treatment or with nucleos(t)ide analogs to inhibit HBV replication in the long-term (Figure 5).

At first, interferon therapy should be evaluated. However, if a patient does not fulfil the criteria for PEG-IFN α, has contraindications, or is intolerant, long-term therapy with nucleos(t)ide analogs is recommended. If a nucleos(t)ide analog is chosen several parameters have to be considered prior to therapy: the antiviral efficacy of the drug, the durability of response, the resistance barrier, and the stage of liver disease.

If the initial viral load is low and liver cirrhosis has been excluded, any approved drug may be used. The use of LAM, however, should be restricted to patients with mild fibrosis and HBV DNA levels <2,000 IU/mL (or <105 copies/mL). For patients with high-level HBV replication (>2 x 108 IU/mL or >109 copies/mL) only drugs with a high genetic barrier should be used (i.e., ETV or TDF)  (Table 3).

选择正确的治疗方案

一个可以选择以通过有限的待遇或核苷（酸）IDE类似物诱导长期的控制，以抑制长期（图5）HBV复制与聚乙二醇干扰素α治疗。

起初，干扰素治疗应当进行评估。但是，如果病人不符合标准，聚乙二醇干扰素α，有禁忌症，或者是不能容忍的，长期与核苷（酸）IDE类似物治疗建议。如果1核苷（酸）IDE模拟选择了几个参数，必须考虑到之前的治疗：抗病毒疗效的药物，反应的耐久性，耐障碍，肝脏疾病的阶段。

如果最初的病毒载量低，已排除肝硬化，可用于任何批准的药品。但是，LAM
的使用，
应该被限制给患者与轻度纤维化和HBV DNA水平<2,000 IU/毫升（或<105拷贝/毫升）。对于高层次的乙肝病毒复制（> 2×108 IU / ml或> 109拷贝/毫升）患者应使用

具有高基因屏障的唯一药物，（即，ETV或TDF）（见表3）
。

StephenW

Prognostic factors for treatment response

Several factors are positivelyassociated with long-term remission and may help to guide treatment decisions.Pretreatment factors predictive of HBeAg seroconversion are low viral load,high ALT levels (above 2-5 x ULN) and high histological grading (Flink 2006,Hadziyannis 2006a, Lai 2007, Perrillo 1990, Perrillo 2002, Wong 1993, Yuen2007, Zoulim 2008). These general baseline predictors are relevant especiallyfor treatment regimens with PEG-IFN α but may in partbe relevant also for nucleos(t)ide analogs (Table 4).

A pooled analysis from the two largest trials using PEG-IFN α-2a or -2b in chronic hepatitis B tried to calculate ascore predicting successful interferon therapy based on an individual patient'scharacteristics (viral load, ALT level, HBV genotype, age, gender). However,this approach may only be feasible in HBeAg-positive patients (Buster 2009).

Table 4. Predictors of response to antiviral therapy.

	Nucleos(t)ide analogs	Peg-interferon α
Before treatment	Low viral load (HBV  DNA ≤107 IU/mL), high serum ALT levels (above 3 times ULN),  high activity scores on liver biopsy (at least A2)
During treatment	Undetectable HBV  DNA in a real-time PCR assay at 24 or 48 weeks is associated with HBeAg  seroconversion in HBeAg-positive patients and lower incidence of resistance	HBV DNA decrease  <20,000 IU/ml at 12 weeks is associated with 50% chance of HBeAg  seroconversion in HBeAg-positive patients and with a 50% chance of sustained  response in HBeAg-negative patients
HBeAg decrease		HBeAg decrease at  week 24 may predict HBeAg seroconversion
HBV genotype	HBV genotype shows  no influence on suppression of HBV DNA levels.    HBsAg  seroconversions only observed for genotypes A and D	Association with  HBV genotype A and B and response to IFN α is higher than with genotypes  C and D, however the association is weak and HBV genotype should not be the  only argument for treatment decision

HBV genotypes and treatment response. HBV genotypes have been shown to be associated with IFN αtreatment success. Patients with HBV genotype A, prevalent in northern Europeand the US, show a much higher rate of HBeAg and HBsAg seroconversion thanpatients with HBV genotype D, prevalent in the south of Europe, or the HBVgenotypes B or C originating from Asia (Keeffe 2007, Wiegand 2008). Duringtreatment with nucleos(t)ide analogs, suppression of HBV replication andinduction of HBeAg loss can be achieved regardless of the present genotype.However, HBsAg loss was almost exclusively observed in patients with genotypesA or D.

HBV DNA levels and treatment response. During antiviral therapy, the decrease of HBV DNA levels from baseline is the mostimportant tool in monitoring treatment efficacy. Complete response to antiviraltherapy is defined as suppression of HBV DNA to below the limit of detection asmeasured by a sensitive real time PCR assay (Figure 9). Incomplete suppressionis characterized by persistent HBV replication despite antiviral therapy.Ongoing HBV replication should be avoided to prevent the selection of resistantHBV strains by replication of the virus in the presence of drug in theso-called "plateau phases". An HBV DNA breakthrough despite continuousantiviral therapy is often caused by viral resistance. Measuring of HBV DNAkinetics early during therapy will help to guide antiviral treatment and toestablish early stopping rules or add-on strategies to avoid antiviral failure(Figure 9).

Figure 9. Possible courses of HBV DNA levels duringtreatment with nucleoside or nucleotide analogs.Incomplete suppression of HBV DNA results in either a "plateau phase" or in acontinuous slow decline. A plateau phase represents a high risk for selectionof resistant HBV variants, therefore treatment should be changed to a moreeffective agent or combination therapy. A continuous slow decline should inducea treatment change after 6 months if drugs with a low genetic barrier like LAMor LdT are used. If drugs with a high genetic barrier like ETV or TDF areapplied, a continuous slow decline can be monitored for at least 12 monthswithout increased risk of consecutive HBV resistance.

Incomplete or partial virologic response to oral nucleosideor nucleotide analogs is defined as a decrease of HBV DNA >1 log10but remaining measurable (Lavanchy 2004) (Figure 9).The definition ofpartial response depends on the type of treatment; thus, for agents with a highgenetic barrier against resistance like ETV or TDF partial response is definedafter 12 months and for substances with a low genetic barrier like LAM or LdT,after 6 months of monotherapy. In case of partial response to a drug with a lowgenetic barrier, an appropriate rescue therapy should be initiated. By currentguidelines, a combination treatment with a nucleotide analog is recommended forthese patients. However, it was recently shown that patients with partialresponse to LAM or to ADV have a high probability of responding to TDFmonotherapy, without risking the development of resistance (Heathcote 2011,Marcellin 2011b, van Bömmel 2010, Berg 2010). Patients with a partial responseto ADV were also shown to have a high probability of responding to a subsequentmonotherapy with ETV, irrespective of the presence of mutations associated withHBV resistance to ADV (Leung 2009, Leung 2009a).

For patients with partial response to a drug with a highgenetic barrier as ETV or TDF, current guidelines also recommend the initiationof a combination treatment. Recently published long-term studies have shownthat the continuation of a new monotherapy in these patients does increase thepercentage of patients with undetectable HBV DNA without increasing the risk ofdevelopment of resistance (Chang 2010, Marcellin 2011b, Snow-Lampert 2011)(Figure 7, Figure 8). Thus, during monotherapy with TDF in HBeAg-positive andHBeAg-negative patients, an increase of patients with complete suppression ofHBV DNA between the end of the first and the end of the fifth year of treatmentfrom 81% and 90% to 100% was shown.

For monotherapy with ETV at 1 mg/day, an increase from 55%to 91% and 94% after the fourth and fifth years was demonstrated (Chang 2010).In case of incomplete viral suppression at week 48, a continuation of monotherapywith TDF or ETV 1 mg is advisable as long as HBV DNA levels decreasecontinuously. However, the debate on whether switching or adding a second drugas optimal management is still unanswered.

Even though prolongation of monotherapy with ETV or TDF willprobably lead to undetectable HBV DNA in the long term in most patients, a fastsuppression of HBV replication is mandatory in some patients (e.g., those withliver cirrhosis) to stop the progression of liver disease. For these patients,no definite therapeutic strategies have been evaluated yet. Preliminary resultsof a study assessing the efficacy of a rescue combination therapy with ETV andTDF have recently been able to induce suppression to undetectable levels inmost patients with partial response; however, data on long-term efficacy andsafety are not available (Petersen 2011).

In any case of treatment failure, adherence to therapyshould be evaluated prior to treatment modification. Elimination of HBV DNAduring TDF-based therapeutic regimes can drop from 87% to 71% of cases ifadherence is not ensured, which is also important in preventing drug resistance(Berg 2010).

Since only 30-35% of all patients treated with PEG-IFN α reach HBeAg seroconversion after 48 weeks, studies havebeen conducted recently to predict the probability of seroconversion inrelation to viral kinetics. In one retrospective analysis early prediction ofstable seroconversion was possible by week 12 of therapy if HBV DNA had reachedlevels below 5 log10 UI/mL within this short treatment period (Fried2005). In 53% of these patients, HBeAg seroconversion was observed whilepatients with HBV DNA levels of 5 to 9 log10 copies/ml or levelsabove 9 log10 IU/mL achieved HBeAg seroconversion in only 17% and14%, respectively.

Timepoint of HBeAg loss. In one study with 172patients who were treated with PEG-IFN α-2b asmonotherapy or in combination with LAM, the loss of HBeAg within the first 32weeks of treatment was shown to be an on-treatment predictor for HBsAg lossduring a mean period of 3.5 years after the end of treatment. HBsAg loss wasfound in 36% of the patients with early HBeAg loss and only in 4% of thepatients with HBeAg loss after 32 weeks of treatment (Buster 2009).

HBsAg levels and treatment response. Response of HBeAg-positive and HBeAg-negative patients to PEG-IFN treatment can be predicted bymeasuring HBsAg levels before and changes of HBsAg levels during treatment(Figure 10).   

Figure 10. On-treatment prediction of treatment responseby HBsAg levels. In different trials, anassociation of the decline in HBsAg levels within the first 12 weeks of PEG-IFNα treatment and treatment response defined as HBV DNA levels <2,000copies/mL six months after treatment was found (Zonneveld 2010, Piratvis-uth2011, Lau 2009, Gane 2011, Rijckborst 2010, Moucari 2009). Patients showing nodecline in HBsAg levels at week 12 had only a very small chance of long-termresponse.

During PEG-IFN treatment for HBeAg-positive chronic HBVinfection, an absence of a decline in HBsAg levels at week 12 of treatmentreduces the probability of response to <5% in one study (Sonnefeld 2010). Inthe NEPTUNE trial investigating the predictive value of HBsAg levels in 114HBeAg-positive patients receiving PEG-IFN α2a over 48weeks, it was shown that in patients achieving suppression of HBsAg to levels<1,500 IU/mL after 12 weeks of treatment, the chance of reaching HBeAgseroconversion, suppression of HBV DNA to levels <2000 IU/mL and HBsAg loss6 months after treatment was 58%, 52% and 10%, compared to 42%, 31% and 0% inpatients with HBsAg levels between 1500-20,000. In this study, patients stillshowing HBsAg levels >20,000 IU/mL after 12 weeks of treatment achieved noneof the endpoints (Gane 2011). Beyond that, the probability of HBeAg loss roseto 68% in patients with elevation of ALT levels >2 x the upper limit ofnormal at treatment initiation (Figure 11).

Figure 11. The level of HBsAg levels after 12 weeks oftreatment with PEG-IFN α-2a is predictive for HBeAg seroconversion sixmonths after treatment. A combination of ALTlevels and HBsAg decline improves positive predictive value in these patients(Gane 2011).

Also in HBeAg-negative patients the decrease of HBsAg after12 weeks of PEG-IFN α treatment can predict long-termresponse. This prediction can be made even more precise regarding the kineticsof both HBsAg and HBV DNA. In another study comprising 48 patients who weretreated with PEG-IFN α-2a, a decrease in serum HBsAglevels of 0.5 and 1 log10 IU/mL at weeks 12 and 24 of therapy wasassociated with a positive predictive value for HBsAg loss of 90% and 97% atweek 96 after treatment, respectively (Moucari 2009).

javeping

总结概下就可以了。

StephenW

Monitoring before andduring antiviral therapy

Before therapy, HBV DNA levelsshould be measured with a highly sensitive assay. These results should beconfirmed 1-2 months after initiation of therapy. In addition, ALT levelsreflecting the inflammatory activity as well as creatinine levels should bedetermined. HBV genotyping is only recommended in patients who are consideredcandidates for treatment with interferon. HBV resistance testing can be usefulin patients with prior failure to more than one nucleoside/nucleotide analog,but this is not yet a standard diagnostic approach. HBV resistance has to beexpected when an increase of HBV DNA of >1 log10 during antiviraltreatment is observed. In cases of primary treatment failure an appropriatesecond line treatment can be chosen without resistance testing.

During therapy, HBV DNA, ALT and creatinine levels should bemeasured initially, after 4 to 6 weeks and then every 3 months. The earlyidentification of viral resistance and an early adjustment of therapy arecrucial. Patients with suppression of HBV replication to <300 copies/ml (60IU/ml) for at least 2 years may perhaps be scheduled at 6 month intervals(Table 5). However, no studies have been performed that support this procedure.

In HBeAg-positive patients, HBeAg and anti-HBe as well asHBsAg and anti-HBs should be also measured if HBV DNA levels becomeundetectable to identify seroconversion as an endpoint of HBV therapy (Table5).

Because the risk for HCC development remains increased evenin patients with complete suppression during long-term treatment withnucleos(t)ide analogs, these patients should still regularly receive ultrasoundexaminations (Figure 12) (Papatheodoridis 2011).

Table 5. Recommendation for laboratory tests formonitoring antiviral therapy.

Tests before antiviral treatment	Interval
HBV DNA quantitative
HBeAg, anti-HBe
HBsAg quantitative	If IFN-based treatment is planned
HBV genotype	If IFN-based treatment is planned
ALT level
Creatinine level
Other chemistry tests
Tests during antiviral treatment	Interval
HBV DNA quantitative	After 4-6 weeks, after 12 weeks, then every 3-6 months
HBeAg, anti-HBe	3-6 months, if HBV DNA is undetectable
HBsAg, anti-HBs      HBV	3-6 months, in HBeAg-positive patients after HBeAg  seroconversion in and HBeAg-negative patients if DNA is undetectable
HBV resistance test	If HBV DNA increases >1 log during antiviral treatment  and pretreatment history is not tractable, but first check for treatment  adherence!
ALT level	Initially every month, than every 3-6 months
Creatinine level*	Every 3-6 months
Other chemistry tests	Every 3-6 months

* Patients treated with TDF should initially bemonitored every 4 weeks to watch for decrease of kidney function

Treatment duration andstopping rules

In HBeAg-positive patientscontinuous treatment with nucleos(t)ide analogs is necessary as long as HBeAgseroconversion is not achieved. Even after seroconversion antiviral therapyshould be continued for at least another 12 months to avoid the risk of"seroreversion" upon stopping the nucleos(t)ide analog therapy.

Criteria for optimal treatment duration with nucleos(t)ide analogsare still lacking in patients with HBeAg-negative chronic hepatitis B,therefore currently unlimited treatment with nucleos(t)ide analogs isrecommended.

PEG-IFN α should be administeredfor 48 weeks in HBeAg-positive and -negative patients.

Recently, the effect of stopping therapy after a long-termADV treatment of 4 to 5 years with complete viral suppression was recentlyevaluated (Hadziyannis 2008). Despite the fact that all patients suffered aslight virologic relapse within 3 months of stopping therapy, most patientswent below detection over the following 4 years without any therapy. Moreover,28% of the patients lost HBsAg. But final recommendations about the treatmentperiod with defined stopping rules do not exist for HBeAg negative patients.

In patients with liver cirrhosis oral antiviral treatmentshould not be discontinued at any time point because of the risk of liverdecompensation during a virologic rebound.

Figure 12. Cumulative incidence of hepatocellularcarcinoma (HCC) in 818 patients with HBeAg-negative chronic hepatitis B (CHB)treated with nucleos(t)ide analogs. Virologicalremission defined as durable suppression of HBV DNA to levels <200 IU/mL didnot significantly affect the HCC incidence in the long term (p=0.38)(Papatheodoridis 2011).

Treatment of HBV infectionin special populations

Pregnancy. For a neonate born to a mother with high levels of HBV DNA (>8 log10copies/mL) the risk of perinatal transmission is elevated. Therefore,antiviral treatment is principally recommended in these women. PEG-IFN α is not indicated in pregnant women, but mostnucleos(t)ide analogs can be used. The risk ofteratogenicity of nucleos(t)ide analogs is assessed by a classification basedon data gathered in clinical trials as well as through the FDA PregnancyRegistry. TDF and LdT are listed as pregnancy category B drugs and LAM, whereasADV and ETV as category C drugs.

In pregnant women with high levels of HBV DNA, LAM treatmentduring the last trimester of pregnancy was reported to reduce the risk ofintrauterine and perinatal transmission of HBV if given in addition to passiveand active vaccination by HBIg and HBV (van Zonneveld 2003). During treatmentwith TDF, the birth defect prevalence was recently shown to be as high asduring treatment with LAM (Brown 2009). Finally, LdTadministered for an average of 15 weeks at the end of pregnancy plusactive-passive immunization to neonates reduced vertical transmission ratesfrom 23% to 4% over immunization alone (Han 2011). However, treatmentwith nucleos(t)ide analogs during pregnancy should be carefully monitored andlimited to the second and third trimester. As exacerbations of chronichepatitis B may occur, women with HBV should be monitored closely afterdelivery (ter Borg 2008).

Immunosuppression. During immunosuppressive treatment, a reactivation of an asymptomatic or inactive HBV infection can occur in 20% to50% of patients (Lok 2009). Reactivations can occur in HBsAg carriers, but alsoin HBsAg-negative but anti-hepatitis B core antibody (HBc)-positive patients.These reactivations are characterised by increase in HBV replication followedby increase in liver inflammation during immune reconstitution resulting inliver damage or even liver failure in some patients (Feld 2010, Roche 2011).

HBV reactivation was especially frequently observed duringtreatment with corticosteroids and antitumor necrosis factor therapies (i.e.,infliximab, etanercept, adalimumab), anti-CD20 therapies (i.e,rituximab-containing chemotherapeutics), intra-arterial chemoembolisation forHCC (Vassilopoulos 2007, Moses 2006, Park 2005, Rutgeerts 2009). Reactivationsduring chemotherapy tend to appear predominantly in men as well as in thoseundergoing treatments for breast cancer or lymphoma.

Prior to initiating immunosuppressive therapies, screeningfor HBV infection is recommended (Lok 2009, EASL 2009). Patients with baselineHBV DNA levels <2,000 IU/mL should continue antiviral therapy for 6-12months after the discontinuation of chemotherapy/immunosuppression, whilepatients with baseline HBV DNA levels >2,000 IU/mL should continue HBVtherapy until they reach a treatment endpoint.

StephenW

回复 javeping 的帖子

这是一个医生的教科书，已经是一个关于乙肝的总结.

我学到了：
高病毒载量增加耐药的风险。因此
1。高病毒载量患者不应该用拉米夫定;
2。用耐药高风险的药，如果24周后病毒载量没有显着减少,考虑更换药物.

如果泰诺福韦是可以得到供应，不应该使用阿德福韦.