乙肝治疗：第7部（最后) 用哪种药疗法开始治疗？

StephenW

用哪种药疗法开始治疗？

做出开始用聚乙二醇干扰素或核苷酸类药治疗的决定应基于病人的特点和偏好。干扰素的主要好处是有限定用药期限。另一个好处是表面抗原下降率低，尤其是a基因型和其它基因类型的e抗原阳性病人相比较效果更明显。一个研究同时发现干扰素引致的e抗原

转换比核苷酸类药引起的更持久。[70] 干扰素的主要缺点是需要注射和其带来的不良反应。核苷酸类药口服给药且不良反应小但是停药后常见病毒复发，这样就必须长期服药，耐药风险，高成本，坚持服药的难度及潜在的不良反应一系列问题会随着长期服药

而出现。

临床研究表明使用聚乙二醇干扰素和拉夫米定联合用药可引起治疗期 HBV DNA水平更为明显的下降但是持续的病毒学应答率和单独使用聚乙二醇干扰素并无区别。[16,20] 就抗病毒效果而言任意两种核苷酸类药复合使用都没有聚乙二醇干扰素和拉夫米定复合使用这种效果。[71,72] 复合疗法和拉米夫定单一疗法相比的主要优势是减少拉米夫定耐药发生的机率。由于恩替卡韦或替诺福韦酯单一治疗的病毒抗药性很低，, 从头联合这两种中的任一种治疗优势有限。

目前, 建议初始治疗使用核苷酸类药或聚乙二醇单一治疗。不建议失代偿性肝炎患者，有医疗禁忌或抗精神药禁忌者使用干扰素。干扰素可用于肝合成功能正常且没有门静脉高压症症状的代偿性肝硬化患者。干扰素最适合的对象为不愿意长期治疗的

年轻病患以及治疗前谷丙转氨酶水平高或a基因型感染的e抗原阳性病患。[24]

核苷酸类药最适合的对象为失代偿性肝病患者，有干扰素使用禁忌的病人，以及愿意长期治疗的病患。五个经批准的核苷酸类药中，恩替卡韦和替诺福韦酯的安全性，药效和耐药性最好。可能考虑怀孕及以前曾使用过拉米夫定或替比夫定的病人偏向使用替诺福韦酯。有增加肾功能不全风险的其病症的偏向使用恩替卡韦。因拉米夫定和替比夫定的高耐药率，除非成本限制，否则治疗初期不应该使用二者。因为阿德福韦酯的抗病毒能力弱，治疗初期不应使用阿德福韦酯。

就孕期安全性分类，替诺福韦酯和替比夫定列为B级其它抗病毒药列为C级。还没有证据表明拉米夫定和替诺福韦酯与胎儿畸形有关，即使在孕期的前3个月服用。[73]

何时可以停止治疗？

理想情况下，抗病毒治疗应持续到表面抗原消失。然而，表面抗原消失的可能性很低：持续使用核苷酸类药4-5年后其概率为0–10%[36–40,42,47] ，聚乙二醇干扰素使用一年期完成后3-5年表原抗原消失率为接近10%。[19]

聚乙二醇干扰素

E抗原阳性和阴性者使用聚乙二醇干扰素48周。两个临床试验的原始数据表明e抗原阳性的病人使用聚乙二醇干扰素24周比使用48周的应答率低，另一个试验数据表明e抗原阴性的病人使用聚乙二醇96周对比使用48周的应答率要高。[74–76]

核苷酸类药

使用核苷酸类药要达到预期的终点才能停止。对于失代偿性肝硬化病人，考虑到中断后病情复发可致命建议终身服药。对于代偿性肝硬化病人，一般建议终身用药; 然而，表面抗原消失或e抗原转换后完成适当的巩固治疗期（治疗前e抗原阳性的病人）可以考虑中断治疗，但应密切监测以确保一旦病毒出现反弹或谷丙转氨酶数量升高要以及时重新治疗。

对于前期肝硬变的e抗原阳性病人，应该持续治疗直到e抗原发生转换(e抗原阴性，e抗体阳性且检测不到HBV DNA) 并完成12个月的巩固治疗。一项研究发现拉米夫定中断治疗的5年累计复发率为：62%（恐固治疗少于12个月）vs 9%（恐固治疗不少于12个月）。[35]

对于前期肝硬变的e抗原阴性病人，治疗终点不明确。大多数专家建议终身治疗直到表面抗原消失。一个小型研究的原始数据发现，在33名用阿德福韦酯治疗4-5年且至少持续 3 年检测不到血清中的HBV DNA 的病人中，18名出现长期临床缓解且9名在治疗后5年的跟踪中表面抗原消失。[77] 这些数据建议一些病人持续抗病毒治疗几年后可以停止治疗。

如何应对治疗失败的情形？

对于有明显适用治疗症状的病人，一般建议使有没有交叉耐药性的核苷酸类药来抢求治疗。对于没有明显适用治疗症状的病人，考虑中断治疗，持续监测。

缺乏初次应答

干扰素治疗初次应答的标准还没有建立。要预测干扰素的长期应答，监测表面抗原滴度比监测HBV DNA水平更准确,这些数据可能对制定出现高阴性预测值时的停止规则有用。[25]这些观念需要在前瞻性临床研究中得到验证。

在核苷酸类药治疗的第一个12-24周期间血清中HBV DNA水平下降不足或缓慢，这一现象表明后续治疗期间耐药风险会增加。[24,78] 这些发现促成了‘路线图’方法，用该方法初次应答不足时给病人用另一种核苷酸类似物。[79] 然而，这个观念来自拉米夫定和替比夫定的研究，这两种药都是低基因障碍的。恩替卡韦和替诺福韦酯的研究（这两种药更有力且耐药性更低），发现大多数保持同一药物治疗的病人血清中HBV DNA

水平持续下降且总体上耐药性非常低或不存在耐药问题。[80,81] 这些数据表明使用低基因障碍的核苷酸类药产生耐药的病人若初期病毒数量下降不足时应附加治疗。

但是使用高基因障碍的核苷酸类药的病人，若HBV
DNA水平持续下降，可以继续使用同一种药。

初始应答后病毒学突破

干扰素治疗期间HBV DNA水平初始下降后可能偶然增加，尤其是使用剂量减少时，但没有检测到这一现象和干扰素不相识耐药的关联。核苷酸类药用药期间的病毒学突破可能是耐药或未遵医嘱坚持服药的结果。出现病毒学突破的病人应按医嘱服药并1-3个月后复检血清中HBV
DNA水平以确定该突破。失代偿性肝病或严重肝炎发作时应立即开始抢救治疗，但是其他病人可以推迟到确认病毒学突破后，以避免不必要的更换药物。

抢救治疗的决定要基于当前或先前的治疗（若有），耐药突变的模式（如果知道的话），这些突变与其它核苷酸类似物的关联。检测耐药突变对已经用过多种药物的病人尤其重要。表格3 总结了抢救治疗的建议。对于拉米夫定或替比夫定耐药的病人，替诺福韦酯是优先选择的治疗药物(在可以使用替比夫定的国家)，因为替诺福韦酯比阿德福韦酯的抗病毒能力更强.初步研究表明出于阻止产生阿德福韦酯耐药的考虑，添加阿德福韦酯比换用阿德福韦酯单一治疗更为优先。[51,82] 使用替诺福韦酯抢救治疗时再继续使用拉米夫定或替比夫定是否必要仍有待确认。[51,82,83]虽然对用于拉米夫定耐药的HBV时，批准了一个较高的使用剂量(1.0毫克/天),恩替卡韦不是抢救治疗的最佳药品，因为先前存在的拉米夫定突变增加了随后使用恩替卡韦时的耐药风险。[49,50]

对于产生阿德福韦酯耐药的病人，恩替卡韦是优先选择的药物。已表明对这些病人换用替诺福韦酯可导致血清中HBV DNA水平下降，因为替诺福韦酯的批准剂量(300毫克/天)比阿德福韦酯的批准剂量（10毫克/天）抗病毒能力更强。然而，阿德福韦酯的耐药

突变降低了替诺福韦酯的药效且临床研究表明换用替诺福韦酯后这些突变并没有停止。83,84 对于产生恩替卡韦耐药的病人，替诺福韦酯是优先选用的替代药物，虽然在体内的作用有限。

对替诺福韦酯耐药的病人，优先选用恩替卡韦。特鲁瓦达，是恩曲他滨和替诺福酯的复方剂，可以用于产生拉米夫定，替比夫定，阿德福韦酯或恩替卡韦耐药的抢救治疗。[48]

结论

过去十年中，乙肝治疗取得了持续进展。现在有许多安全有效的药物可用于乙肝治疗。这些药物的作用是压抑乙肝病毒数量但不能根除乙肝病毒。为使治疗应答最大化,初始治疗应选用适当的时间，使用最有效的药物，且应密切监测治疗反应，确保治疗失败时可以修改治疗方案。

StephenW

StephenW

Which medication to start with?

The decision to start treatment with PEG-IFN or a nucleos(t)ide analogue is based upon patient characteristics and preference. The main advantage of IFN is that it is administered for a finite duration. Another advantage of IFN is the high rate of HBsAg loss, particularly among HBeAg-positive patients who have a genotype A infection compared with patients who are infected with other HBV genotypes. A study has also found that IFN-induced HBeAg seroconversion is more durable than nucleos(t)ide-induced HBeAg seroconversion.[70] The main disadvantages of IFN are the need for parenteral administration and the adverse effects. Nucleos(t)ide analogues are administered orally and are well tolerated but viral relapse is common when treatment is stopped, which necessitates long durations of treatment with the associated risks of antiviral drug resistance, high costs, problems with adherence and the potential for
adverse effects.

Clinical studies have shown that the combination of PEG-IFN and lamivudine results in a more marked decline in serum HBV DNA levels during treatment but no difference in the rate of sustained virologic response compared with PEG-IFN alone.[16,20] Studies comparing a combination of two nucleos(t)ide analogues have shown no benefit of these combinations compared with either drug alone regarding antiviral efficacy.[71,72] The main advantage of combination therapies is a reduction in the rate of lamivudine resistance compared with lamivudine monotherapy. Owing to the low rate of antiviral resistance associated with entecavir or tenofovir disoproxil monotherapy, the benefit of de novo combination therapy involving either of these two drugs is limited.

Currently, monotherapy with a nucleos(t)ide analogue or PEG-IFN is recommended as the initial therapy. IFN is not recommended for patients who have hepatic decompensation, immunosuppression or medical or psychiatric contraindications. IFN may be used in patients with compensated cirrhosis who have normal synthetic function and no evidence of portal hypertension. IFN is most appropriate for young patients, those who are reluctant to commit to a long duration of treatment, and HBeAg-positive patients who have high pretreatment ALT levels or genotype A infection.[24]

Nucleos(t)ide analogues are most appropriate for patients who have decompensated liver disease, patients with contraindications to IFN, and those who are willing to commit to long durations of treatment. Of the five approved nucleos(t)ide analogues, entecavir and tenofovir disoproxil have the best profile regarding safety, efficacy and drug resistance. Tenofovir disoproxil is preferred in patients who might be contemplating pregnancy and in those who might have been exposed to lamivudine or telbivudine in the past. Entecavir is preferred in patients who have other medical conditions that are associated with increased risks of renal insufficiency. Lamivudine and telbivudine should not be used as initial therapy because of the high rates of drug resistance unless cost is a limiting factor. Adefovir dipivoxil should not be used as initial therapy because of its weak antiviral activity.

Tenofovir disoproxil and telbivudine are categorized as class B regarding safety in pregnancy and the other HBV drugs as class C. Lamivudine and tenofovir disoproxil have not been shown to be associated with fetal abnormalities even when used during the first trimester of pregnancy.[73]

When can treatment be stopped?

Ideally, antiviral therapy should be continued until HBsAg loss. However, the likelihood that this will occur is low: 0–10% after 4–5 years of continuous nucleos(t)ide analogue therapy[36–40,42,47] and approximately 10% 3–5 years after completing a 1‑year course of PEG-IFN.[19]

PEG-IFN
PEG-IFN is administered for 48 weeks to both HBeAg-positive and HBeAg-negative patients. Preliminary data from two clinical trials indicate that response rates were lower in HBeAg-positive patients who received 24 versus 48 weeks PEG-IFN, and data from another trial indicate that response rates were higher in HBeAg-negative patients who received 96 versus 48 weeks PEG-IFN.[74–76]

Nucleos(t)ide analogues
Nucleos(t)ide analogues are administered until the desired end point is achieved. For patients who had decompensated cirrhosis, life-long treatment is recommended because of concerns about fatal flares when treatment is discontinued. For patients who had compensated cirrhosis, life-long treatment is generally recommended; however, discontinuation of treatment may be considered in patients who have lost HBsAg or who have completed adequate duration of consolidation therapy after HBeAg seroconversion (for those who were HBeAg positive before treatment) provided that these patients are closely monitored so that treatment can be promptly reintroduced if there is viral rebound or an ALT flare.

For HBeAg-positive patients who have precirrhotic liver disease, treatment should be continued until the patient has achieved HBeAg seroconversion (HBeAg negative, anti-HBe positive and undetectable serum HBV DNA) and completed 12 months of consolidation therapy. One study found that the 5‑year cumulative rate of relapse after discontinuation of lamivudine was 62% in patients with <12 months of consolidation therapy versus 9% in patients with ≥12 months of
consolidation therapy.[35]

For HBeAg-negative patients who have precirrhotic liver disease, the therapeutic end point is unclear. Most experts recommend life-long treatment or until HBsAg loss. Preliminary data from one small study found that among 33 patients who discontinued treatment after 4–5 years of adefovir dipivoxil therapy and had undetectable serum HBV DNA for at least 3 years, 18 had long-term clinical remission and nine lost HBsAg during 5‑year post-treatment follow-up.[77] These data suggest that treatment may be stopped in some patients who maintain viral suppression for a few years.

How should treatment failure be managed?

For patients who have clear indications for treatment, salvage therapy is generally recommended with a nucleos(t)ide analogue for which there is no cross-resistance. For patients who do not have clear cut indications for treatment, discontinuation of treatment and continued monitoring may be appropriate.

Lack of initial response
The criteria for initial response to IFN therapy have not been established. Data suggest that monitoring the HBsAg titer may be more accurate than monitoring serum HBV DNA levels for predicting long-term response to IFN therapy, and it may be possible to define early stop rules with high negative predictive values.[25] These concepts need to be validated in prospective clinical studies.

Inadequate or slow decline in serum HBV DNA levels during the first 12–24 weeks of nucleos(t)ide analogue therapy has been shown to be associated with an increased risk of antiviral drug resistance during continued therapy.[24,78] These findings prompted the development of the ‘road-map’ approach, in which a second nucleos(t)ide analogue is given to patients who have inadequate initial response.[79] However, this concept was derived from studies of lamivudine and telbivudine, which are both drugs that have a very low genetic barrier to resistance. Studies of entecavir and tenofovir disoproxil, which are more potent and have lower rates of drug resistance, found that serum HBV DNA levels continued to decline in most patients who remained on the same treatment and overall rates of antiviral resistance were very low or nonexistent.[80,81] These data indicate that patients receiving nucleos(t)ide analogues that have a low genetic barrier to resistance should receive additional therapy if initial viral decline is inadequate, but patients receiving nucleos(t)ide analogues that have a high genetic barrier to resistance may remain on the same drug provided that serum HBV DNA levelscontinue to decline.

Virologic breakthrough after initial response

Serum HBV DNA levels can occasionally increase during IFN treatment after an initial decline, particularly if the dose of IFN is reduced, but a correlation with IFN
resistance has not been examined.

Virologic breakthrough during nucleos(t)ide analogue treatment may be a result of antiviral drug resistance or medication nonadherence. Patients with virologic breakthrough should be counseled regarding medication adherence and breakthrough confirmed by retesting for serum HBV DNA levels after 1–3 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 virologic breakthrough is confirmed to avoid unnecessary changes in medications.

The choice of salvage therapy depends on current and prior treatment if any, the pattern of drug-resistance mutations if known, and the susceptibility of these mutations to other nucleos(t)ide analogues. Testing for drug-resistance mutations is particularly important for patients who have been exposed to multiple drugs. Table 3 summarizes the recommendations for salvage therapies. For patients who have lamivudine or telbivudine resistance, tenofovir disoproxil is the preferred treatment in countries where it is available because it has more potent antiviral activity than adefovir dipivoxil. Initial studies showed that add-on adefovir dipivoxil is preferred to switching to adefovir dipivoxil monotherapy in preventing adefovir dipivoxil resistance.51,82 Whether continuation of lamivudine or telbivudine is necessary when tenofovir disoproxil is used as salvage therapy remains to be determined.[51,82,83] Although a higher dose of entecavir (1.0 mg daily) is approved for lamivudine-resistant HBV, entecavir is not an optimal salvage therapy because the pre-existing presence of lamivudine resistance mutations increases the risk of subsequent entecavir resistance.[49,50]

For patients with adefovir dipivoxil resistance, entecavir is the preferred treatment. Switching to tenofovir disoproxil in these patients has been shown to lead to a decline in serum HBV DNA levels because the approved dose of tenofovir disoproxil (300 mg daily) has more potent antiviral activity than the approved dose of adefovir dipivoxil (10 mg daily). However, patients with adefovir dipivoxil resistance mutations have decreased susceptibility to tenofovir disoproxil and clinical studies have shown that these mutations persist after switching to tenofovir disoproxil.[83,84] For patients with entecavir resistance, the preferred treatment is tenofovir disoproxil although in vivo efficacy data are limited.

For patients with tenofovir disoproxil resistance, the preferred treatment is entecavir. Truvada, which is a co-formulation of emtricitabine and tenofovir disoproxil, may be used as rescue therapy for patients with lamivudine, telbivudine, adefovir dipivoxil or entecavir resistance.[48]

Conclusions

Substantial progress has been made in the treatment of hepatitis B in the past decade. Many safe and effective drugs are now available. These drugs suppress but do not eradicate HBV. To optimize treatment response, treatment should be initiated at an appropriate time using the best available drugs, and the response should be closely monitored so that treatment can be modified in patients with treatment failure.

春天的歌唱

感谢楼主一直以来勤奋地付出

梦人

感谢楼主一直以来勤奋地付出

lin12345

well done

汪从峰

开心D生活

看 了 学习 一下

aiduoduo

顶起，大家来学习

三国杀

楼主有木有 它引用的文献呀

整个观点没有很大的进展呀，可能是作者比较有名吧，所以，才发到NATURE，不过，好杂志的综述也只有大BOSS才能发表