乙型肝炎的管理：我们的实践和如何它涉及到指引

StephenW

Which Should Be the First-Line Treatment?

Selection of first-line treatment should be based on the safety and efficacy of the medication, risk of drug resistance, cost of treatment, and patient preference. The main advantages of IFN include a finite duration of treatment and a higher rate of HBeAg and HBsAg loss, particularly in HBeAg-positive patients with genotype A. NUCs are well tolerated but most patients require many years or lifelong treatment. Entecavir, telbivudine, and tenofovir have more potent antiviral activity, and entecavir and tenofovir have very low rates of drug resistance.

The AASLD, EASL, and APASL guidelines all recommend initial treatment with PEG-IFN, entecavir, or tenofovir as monotherapy.1, 2, 3 Because of cost concerns and the lack of access to tenofovir in some Asian countries, the APASL guideline recommends entecavir, adefovir, telbivudine, or lamivudine as first-line treatment in treatment-naive patients.3 To avoid hepatic decompensation secondary to ALT flare, APASL recommends NUCs and not IFN in patients with an ALT level greater than 5 times the ULN.3 IFN is not recommended in patients with acute liver failure, decompensated cirrhosis, or severe exacerbations of CHB in all 3 guidelines. The EASL and APASL guidelines indicate PEG-IFN can be used with careful monitoring in patients with compensated cirrhosis because IFN has been shown to be safe in carefully selected patients with compensated cirrhosis in clinical trials.1, 2 The AASLD guideline states that patients with compensated cirrhosis are best treated with NUCs because of the risk of hepatic decompensation associated with IFN-related hepatitis flares.1 All guidelines recommend entecavir or tenofovir as the preferred treatment in patients with decompensated cirrhosis. Two randomized trials in patients with decompensated cirrhosis showed similar efficacy and safety after 1 to 2 years of treatment with tenofovir, emtricitabine/tenofovir, or entecavir in one study, and entecavir vs tenofovir in another study.34, 35

这应该是一线治疗？

选择第一线治疗，应根据药物的安全性和有效性，耐药性的风险，治疗成本和病人的偏好。干扰素的主要优点包括治疗的有限时间和更高的速率HBeAg和HBsAg消失，特别是在HBeAg阳性患者的基因型A. NUCs的耐受性良好，但多数患者需要许多年或终身治疗。恩替卡韦，替比夫定和替诺福韦具有更有效的抗病毒活性，和恩替卡韦和替诺福韦具有耐药率非常低。

在AASLD ， EASL ， APASL和指引的所有建议由于成本问题和缺乏获得替诺福韦在一些亚洲国家与PEG-IFN ，恩替卡韦初始治疗，或替诺福韦作为monotherapy.1 ， 2 ， 3， APASL指南建议恩替卡韦，阿德福韦，替比夫定或拉米夫定作为一线治疗在治疗初治patients.3为了避免肝功能失代偿继发ALT耀斑， APASL建议NUCs和患者的ALT水平IFN不大于5倍的ULN.3是干扰素不建议在急性肝功能衰竭，肝硬化失代偿期，慢性乙型肝炎或在所有3指引严重恶化。该EASL和APASL指南指出PEG-IFN可通过仔细监测患者的代偿性肝硬化使用，因为干扰素已被证明是安全的精心挑选的患者在临床trials.1代偿性肝硬化， 2 AASLD指南指出，患者的补偿肝硬化最好用NUCs治疗，因为干扰素相关的肝炎flares.1所有的指南建议恩替卡韦或替诺福韦的患者失代偿期肝硬化的首选治疗相关的肝功能失代偿的风险。患者失代偿期肝硬化的两个随机临床试验显示出相似的疗效和安全性后1〜 2年，替诺福韦，恩曲他滨/替诺福韦，恩替卡韦或在一项研究中，恩替卡韦和替诺福韦与另一study.34 ， 35治疗

StephenW

Our Practice

We follow the 3 guidelines and recommend PEG-IFN, entecavir, or tenofovir monotherapy as first-line treatment to patients with no cirrhosis. Despite our experience with PEG-IFN and our belief that PEG-IFN has a higher chance of HBeAg and HBsAg loss in patients, less than 10% of our patients opt for PEG-IFN. We are more enthusiastic in recommending PEG-IFN to young patients, particularly those who are hesitant to commit to a long duration of treatment and young women who are planning to start a family within the next 2 to 3 years. For NUC-naive patients, we believe that entecavir and tenofovir are comparable. We prefer entecavir in patients who are at increased risk of renal impairment such as patients with decompensated cirrhosis, older patients, and patients with hypertension or diabetes. We prefer tenofovir in young women who might become pregnant during the course of treatment. During the past 5 to 6 years, we have not initiated treatment with lamivudine, telbivudine, or adefovir in any patient. In addition, we systematically have switched patients from adefovir to tenofovir because tenofovir is more potent. For patients taking lamivudine plus adefovir because of prior lamivudine resistance, we have switched them to tenofovir monotherapy if they have undetectable HBV DNA levels or to the combination pill Truvada (emtricitabine plus tenofovir; Gilead, Foster City, CA). We have switched most patients taking lamivudine monotherapy to tenofovir, except for a few who had been on lamivudine for many years with undetectable serum HBV DNA levels because the risk of antiviral drug resistance in these patients is very low.

我们的实践

我们按照3个指导方针和建议PEG-IFN ，恩替卡韦或替诺福韦单药作为一线治疗患者无肝硬化。尽管我们用PEG -IFN和我们的信念， PEG-IFN有HBeAg和HBsAg转阴的患者的机会较高的经验，我们的病人不到10 ％选择PEG-IFN 。我们在建议PEG-IFN对年轻患者，特别是那些谁是犹豫承诺治疗和年轻妇女谁正计划在未来2至3年内开始一个家庭的时间长更热烈。对于NUC初治患者，我们认为，恩替卡韦和替诺福韦具有可比性。我们喜欢恩替卡韦的病人谁在肾功能损害的风险增加，如失代偿性肝硬化，老年患者和高血压患者或糖尿病。我们更愿意在年轻女性治疗过程中谁可能怀孕的替诺福韦。在过去的5 〜6年，我们还没有开始治疗与拉米夫定，替比夫定，阿德福韦或任何病人。此外，我们系统皆已患者阿德福韦替诺福韦，因为替诺福韦是更有效的。对于服用拉米夫定，因为之前拉米夫定耐药加上阿德福韦的患者，我们皆已他们替诺福韦单药治疗，如果他们有检测不到HBV DNA水平或组合药片Truvada的（恩曲他滨加替诺福韦，基列，福斯特城，加利福尼亚州） 。我们已经切换服用拉米夫定单药治疗，以替诺福韦大多数患者，除了少数谁已对拉米夫定多年，检测不到血清HBV DNA水平，因为在这些患者抗病毒耐药的风险是很低的。

StephenW

Monitoring During Treatment and Deciding When to Stop Treatment  

Guidelines recommend all patients should be monitored closely during treatment to evaluate response, tolerability, and adherence. Patients receiving IFN require frequent clinical and laboratory monitoring. Guidelines recommend monitoring patients receiving IFN/PEG-IFN therapy with blood counts and a liver panel every 4 weeks initially and then every 4 to 12 weeks.1, 2, 3 The AASLD and EASL also recommend thyroid-stimulating hormone testing every 12 weeks.1, 2 The AASLD and APASL recommend monitoring HBV DNA levels every 12 weeks, and the EASL recommends HBV DNA testing at weeks 24 and 48.1, 2, 3 The EASL guideline also recommends monitoring HBsAg levels at week 12.2 For patients who initially were HBeAg positive, the AASLD and EASL recommend HBeAg and hepatitis B e antibody (anti-HBe) testing every 24 weeks during treatment, and the APASL recommends testing every 12 weeks.1, 2, 3 After completion of IFN/PEG-IFN therapy, blood counts, liver panel, HBeAg, and anti-HBe if initially HBeAg-positive should be tested every 12 weeks during the first 24 weeks. In the post-treatment period, the APASL recommends monitoring ALT and HBV DNA levels monthly for the first 3 months and then every 3 months in the first year.3 The AASLD and EASL recommend HBsAg testing every 6 to 12 months in patients with HBeAg seroconversion and undetectable HBV DNA levels.1, 2 Patients receiving NUC should have their renal function checked initially to ensure appropriate dosing. Patients who are at risk of impaired renal function should have their renal function monitored regularly, particularly if they are receiving adefovir or tenofovir because of the risk of nephrotoxicity. A phase 3 trial of tenofovir showed that only 1% of patients had an increase in serum creatinine level after 5 years treatment.9All guidelines recommend administration of PEG-IFN for 48 to 52 weeks in both HBeAg-positive and HBeAg-negative patients.1, 2, 3 There is some variation in recommendations regarding when NUC can be stopped. All guidelines recommend that in HBeAg-positive patients, NUC can be stopped when the patient has achieved HBeAg seroconversion and undetectable HBV DNA levels and completed 6 to 12 months of consolidation treatment.1, 2, 3Because of the high rate of relapse after withdrawal of NUC and the persistence of HBV replication in some patients despite HBeAg seroconversion, the EASL recommends continuing NUC until HBsAg loss in patients with severe fibrosis and cirrhosis.2 Given the low rate of NUC-induced HBsAg loss, most of these patients will remain on treatment indefinitely.

In HBeAg-negative patients, the EASL and AASLD agree that NUC should be continued until the patient has achieved HBsAg clearance1, 2; however, the APASL recommends considering withdrawal of treatment in HBeAg-negative patients who have been treated for 2 years with undetectable HBV DNA levels documented on 3 separate measurements 6 months apart.3 The basis for the APASL recommendation is related mainly to cost.

All guidelines recommend lifelong NUC in patients with cirrhosis before treatment; however, discontinuation of treatment may be considered in patients who had compensated cirrhosis if they achieved HBsAg loss.1, 2, 3 After withdrawal of treatment, patients need to be monitored closely for relapse so that treatment can be re-instituted promptly if needed.

监测治疗期间及决定何时停止治疗

指南建议所有的患者应密切在治疗过程中进行监测，以评估反应，耐受性和依从性。接受IFN患者需要频繁的临床和实验室监测。指南推荐接受IFN / PEG-IFN治疗与血液计数和肝面板，每4周开始，然后每4至12 weeks.1 ，2，3的AASLD和EASL也建议促甲状腺激素测试每12周监测病人。 1 ， 2 AASLD和APASL建议监测HBV DNA水平，每12周，欧洲肝病学会推荐的HBV DNA检测在24周和48.1 ， 2 ， 3 EASL指南还建议监测HBsAg水平在12.2周的患者谁最初HBeAg阳性，在AASLD ，EASL和建议HBeAg和治疗过程中乙肝e抗体（抗-HBe ）测试，每24周， APASL建议测试每12 weeks.1 ， 2 ， 3干扰素/ PEG- IFN治疗，血球计数完成后，肝面板和HBeAg和抗-HBe如果最初HBeAg阳性应在第一个24周内测试每12周。在后处理期间， APASL建议监测ALT和HBV DNA水平为每月前3个月，然后每3个月在第一year.3的AASLD ，EASL和建议乙肝表面抗原检测，每6 〜12个月的患者HBeAg血清转换而检测不到HBV DNA levels.1 ， 2例患者接受国统会应该有自己的肾功能检查最初以确保适当的剂量。谁是病人在肾功能受损的风险应该有自己的肾功能定期监测，尤其是当它们被接受，因为肾毒性的危险阿德福韦或替诺福韦。替诺福韦的3期临床试验显示，只有1 ％的患者有增加血清肌酐水平5年后treatment.9所有指导方针， HBeAg阳性和HBeAg阴性患者推荐PEG-IFN给药48〜 52周。 1 ，2，3有一部分时NUC可以停止有关的变化的建议。所有的指南建议，在HBeAg阳性患者，国统会可以当患者已经达到HBeAg血清转换和检测不到HBV DNA水平，并停止完成6 〜12个月盘整treatment.1 ，停药后的高复发率的2 ， 3Because的国统会与部分患者HBV复制的，尽管HBeAg血清转换的持久性，在EASL建议继续NUC直至HBsAg消失重症患者纤维化和cirrhosis.2鉴于国统会诱发HBsAg消失率较低，这些患者大多会留在治疗无限期。

在HBeAg阴性患者中，欧洲肝病学会和美国肝病学会同意，国统会应持续至病人已达到乙肝表面抗原clearance1 ， 2 ，然而， APASL建议在谁已治疗2年，检测不到HBV HBeAg阴性患者考虑放弃治疗DNA水平上记载3个独立的测量6个月apart.3的基础APASL建议与主要成本。

所有的指南建议终身NUC患者治疗前肝硬化，但停药可谁曾代偿期肝硬化，如果他们取得的HBsAg loss.1 ， 2 ， 3停药治疗后的患者可以考虑，患者需要进行密切监测复发因此治疗可以，如果需要重新提起及时。

StephenW

Our Practice  

We follow the guidelines regarding monitoring of patients on treatment. In patients receiving IFN, we continue treatment if there is an ALT flare unless the patient is symptomatic or bilirubin level is increased. In patients receiving NUC, we monitor serum HBV DNA levels less often now than in the past when we were using drugs with a lower barrier to resistance. We test serum HBV DNA levels every 3 months until it becomes undetectable and every 6 months thereafter. We check HBeAg and anti-HBe levels every 6 to 12 months in patients who are HBeAg positive, and we check HBsAg every year in patients who are HBeAg negative with undetectable serum HBV DNA levels.

For patients receiving NUC, we continue treatment indefinitely in those who had cirrhosis before treatment and in many older patients (>60 y) unless they lose HBsAg. For noncirrhotic HBeAg-positive patients, we discontinue treatment after 12 months of consolidation therapy because of reports of low durability of NUC-induced HBeAg seroconversion and the encouraging results of 12 months of consolidation therapy in one study.36 For noncirrhotic HBeAg-negative patients, we discontinue treatment after confirmed HBsAg loss, but this has happened to only 1 patient in the past 5 years. We have, however, discontinued treatment in several patients who can no longer afford or are no longer willing to commit to long-term treatment if they have completed at least 5 years of treatment with undetectable HBV DNA levels in the past 3 years. Although all patients experienced virologic relapse after treatment was stopped, most patients continue to have low HBV DNA levels and normal ALT levels and have not required resumption of treatment, confirming the observations of Hadziyannis et al.37

我们的实践

我们按照有关治疗监测患者的指导方针。在接受干扰素的患者，我们继续治疗，如果有一个ALT耀斑，除非病人有症状或胆红素水平升高。在接受NUC的患者，我们监测血清HBV DNA水平往往较低，现在比当我们在使用药物具有较低的耐药屏障过去。我们测试血清HBV DNA水平，每3个月，直到它变得无法察觉并每6个月以后。我们检查HBeAg和抗-HBe水平谁是HBeAg阳性，每6 〜12个月的患者，以及我们每年检查乙肝表面抗原的患者谁是HBeAg阴性检测不到血清HBV DNA水平。

对于接受国统会的患者，我们将继续无限期地治疗那些谁治疗前有肝硬化，而且在许多老年患者（ > 60岁），除非他们失去了乙肝表面抗原。对于肝硬化的HBeAg阳性患者，我们停止，因为的NUC引起的HBeAg血清学转换低耐久性和巩固治疗12个月在一个study.36对于肝硬化的HBeAg阴性患者的令人鼓舞的结果报告巩固治疗12个月后的治疗，我们停止治疗证实HBsAg消失后，但这个发生在只有1例患者在过去的5年。然而，我们有，在几个病人谁再也不能或不再愿意承诺长期治疗，如果他们已经完成了至少5年，在过去3年中检测不到HBV DNA水平治疗停止治疗。尽管所有患者经历病毒学复发治疗停止后，大部分患者继续具有低HBV DNA水平和ALT水平正常，并没有必要恢复治疗，证实Hadziyannis等al.37的观察

StephenW

Management of Treatment Failure

Recent studies have suggested that a lack of or insufficient decrease in HBsAg level by week 12 of PEG-IFN is associated with a low chance of sustained response.38, 39 The 2012 EASL guideline recommends discontinuation of PEG-IFN in HBeAg-positive patients who fail to achieve serum HBsAg levels of less than 20,000 IU/mL or who have no decrease in serum HBsAg levels by week 12 because these patients have a low probability of achieving HBeAg seroconversion.2 For HBeAg-negative patients, particularly those with genotype D, discontinuation of PEG-IFN is recommended if they fail to achieve any decline in serum HBsAg levels and a 2 log10 decrease or greater in HBV DNA levels by week 12.2 Patients who failed to respond to IFN therapy can be treated with NUC with the expectation of a similar response as treatment-naive patients.

Primary nonresponse is very rare with NUC therapy except for adefovir. An inadequate decrease in HBV DNA levels during the first 12 to 24 weeks of NUCs that have a low barrier to resistance is associated with a higher chance of subsequent antiviral resistance, prompting the roadmap approach that recommends the addition of a second NUC in patients with an inadequate initial response; however, these data do not apply to NUCs with a high barrier to resistance. Phase 3 trials and observations in clinical practice showed that patients with detectable HBV DNA levels after 48 weeks of entecavir or tenofovir have a very low rate of antiviral resistance even if they continue on the same treatment.26, 40 Guidelines recommend counseling patients with a virologic breakthrough regarding medication adherence and confirmation of breakthrough by retesting HBV DNA levels after 1 to 3 months. Salvage therapy should be initiated immediately in patients who have decompensated liver disease or severe hepatitis flares, but in other patients it can be deferred until after breakthrough is confirmed to avoid unnecessary changes in medications. The choice of salvage therapy depends on the current and prior treatments and the pattern of drug resistance mutations. The EASL and AASLD recommendations for salvage therapy are shown in Table 3.1, 2

治疗失败的管理

最近的研究表明，缺乏或不足，减少乙肝表面抗原水平PEG-IFN的12周与持续response.38低可能性相关联， 39 2012年EASL指南推荐的PEG -干扰素停药HBeAg阳性患者谁不能达到低于20,000 IU / mL或谁拥有了12周的血清HBsAg水平没有降低血清HBsAg水平，因为这些患者具有实现大三阳seroconversion.2对于HBeAg阴性患者，特别是那些与D基因型的概率很低，如果他们不能达到血清HBsAg水平下降的任何一个和2个log10下降或更高的HBV DNA水平上一周12.2患者谁没有干扰素治疗的反应是可以治疗与国统会与一个预期的PEG -干扰素停药建议类似的反应作为治疗初治患者。

原发性无应答是非常罕见的与国统会的治疗，除了阿德福韦。在最初12 〜24周具有低耐药屏障NUCs的不足，降低HBV DNA水平与后续抗病毒耐药的机会较高相关，提示该路线图的方法，建议患者在增加第二个国统会的不足的初始响应，然而，这些数据并不适用于NUCs具有高阻挡性能。第3阶段临床试验和观察的临床实践表明，患者可检测到HBV DNA水平48周恩替卡韦或替诺福韦后具有抗病毒耐药率非常低，即使他们继续在同一treatment.26 ， 40指南推荐建议患者与病毒学突破就坚持服药，并重新检测HBV DNA水平后1 〜3个月确认的突破。抢救治疗应该在谁失代偿性肝病或重症肝炎患者耀斑立即启动，但在其他的病人可以延迟的突破确认，以避免不必要的药物治疗后的变化，直到。抢救治疗的选择取决于当前和以前的治疗和耐药突变的格局。为抢救治疗的EASL和AASLD建议如表3.1所示， 2

HBV4.gif

StephenW

Our Practice   Quantitative HBsAg assays are not available for clinical use in the United States. We recommend completion of the intended duration of PEG-IFN therapy unless the patient experiences serious adverse events or there is little or no decrease in serum HBV DNA level after 3 to 6 months treatment. For NUC-naive patients receiving entecavir or tenofovir, we have encountered only 1 patient (out of >200) with confirmed entecavir resistance and none with confirmed tenofovir resistance. We found that transient reappearance of serum HBV DNA at low levels, typically less than 100 IU/mL, occurs in some patients. Although many of these instances may be related to medication nonadherence, some, particularly those with levels below the limit of quantification, may represent false-positive results. In NUC-naive patients receiving entecavir or tenofovir monotherapy with detectable HBV DNA levels after 1 year of treatment, we have not adapted treatment as long as the HBV DNA level is low (<10,000 IU/mL) and continues to decrease. We have added a second drug in a few patients on dialysis receiving weekly dosing of entecavir and 2 patients with high baseline HBV DNA levels receiving immunosuppressive therapy. 我们的实践 HBsAg定量测定法不适用于在美国的临床使用。我们推荐的PEG- IFN治疗的预期持续时间的结束，除非患者经历严重的不良事件或存在于血清中的HBV DNA水平很少或不下降后3至6个月的治疗。 对于接受恩替卡韦或替诺福韦NUC初治患者，我们只遇到1例（满分> 200）证实恩替卡韦耐药，没有确诊替诺福韦阻力。我们发现，血清HBV DNA在较低水平，典型地小于100国际单位/毫升，瞬态再现发生在一些患者中。虽然许多这些实例可能与药物的不依从，一些，特别是那些低于定量限电平，可以表示假阳性结果。在治疗1年后接受恩替卡韦或替诺福韦单药治疗与检测HBV DNA水平NUC初治患者，我们没有，只要HBV DNA水平低（ < 10,000国际单位/毫升），并继续降低适应的待遇。我们已经在少数透析患者接受恩替卡韦和2例高基线HBV DNA水平接受免疫抑制剂治疗的剂量每周增加了第二种药物。 Conclusions Guidelines provide an evidence-based framework for managing patients; however, management of individual patients must be flexible, taking into account the patient's preference and other medical or psychosocial conditions, evolution in knowledge over time, and the provider's experience. 结论 指南提供以证据为基础的框架，用于管理病人，但是，个别病人管理必须是灵活的，考虑到病人的偏好和其他医疗或心理状况，演变知识随着时间的推移，与供应商的经验