[战胜乙肝网]长期核苷（酸）类似物治疗的现实问题

StephenW

长期核苷（酸）类似物治疗的现实问题更新时间：2014-9-5    作者：侯金林    文章来源：中国医学论坛报
侯金林教授：长期核苷（酸）类似物治疗的现实问题
作者  南方医科大学南方医院 侯金林 宁玲
　　今年5月，《消化道》（Gut）在线发表的我国香港地区的一项研究表明，在乙型肝炎e抗原（HBeAg）阴性的亚洲慢性乙肝患者中，停用恩替卡韦[依据亚太肝脏研究学会（APASL）指南停药标准]，可导致高病毒复发率，提示核苷（酸）类似物治疗应无限期应用，直至公认治疗终点――乙肝病毒表面抗原（HBsAg）血清清除。8月20日在线发表的针对该研究的述评则指出，临床医生应需要寻找HBsAg血清阴性前停用核苷（酸）类似物的适宜方法，采用适当的停药策略。
　　中华医学会感染病学分会主委侯金林教授、南方医科大学南方医院宁玲医生撰写评论文章，介绍我国当前抗病毒长期治疗的临床决策、主要问题以及应对和思考。
　　CHB患者规范化治疗和管理仍是当务之急
　　近二十年来，慢性乙型肝炎（CHB）的临床治疗和管理取得一系列突破性进展，特别是系统规范的抗病毒治疗可以减少肝硬化和肝癌发生风险。临床实践中，可供选择的抗病毒治疗策略包括以下两种：一是以干扰素α（IFN-α，包括普通IFN-α和聚乙二醇干扰素-α）为基础的治疗；另一种为以核苷（酸）类似物（NA）为基础的治疗，主要包括恩替卡韦、替诺福韦酯、替比夫定、阿德福韦酯和拉米夫定。然而，IFN-α治疗1年总体应答率不高（约30%），而且受干扰素须治疗注射用药及较多不良反应等因素的影响，我国仅约15%的CHB患者选择IFN-α抗病毒治疗，对于应答欠佳的患者多须再选择换用NA药物治疗。
　　我国超过80%患者选择口服NA抗病毒治疗，但NA只作用于乙型肝炎病毒（HBV）复制过程的逆转录环节，尽管能快速有效抑制HBV DNA的复制，但是无法将肝细胞内的共价闭合环状DNA（cccDNA）彻底清除。因此大部分患者仍须接受长期、乃至有可能终身抗病毒治疗，从而实现国内外CHB临床指南及共识所提出的治疗目标，即最大限度地长期抑制病毒复制，减少肝细胞炎症进展及纤维化，从而延缓肝脏疾病进展，大幅度降低肝硬化、肝细胞癌或肝衰竭发生率，提高患者生活质量。
　　临床上无论选择哪种治疗策略，抗病毒治疗都必须持之以恒，必须采用长治久安的策略，不能随意停药，因此CHB患者规范化治疗和管理成为当务之急！
　　长期NA药物治疗的现实问题
　　长期NA药物治疗可持续抑制病毒复制、实现HBeAg血清学转换，能减轻肝组织炎症坏死并逆转纤维化，从而降低肝硬化的发生率。
　　然而，长期NA治疗会面临各方面的挑战，包括耐药、安全性和经济负担等问题。由于长期服药尤其是一线抗病毒药物会产生巨大的经济负担，且长期服药的安全性尚不确定，因此患者对长期治疗的依从性在治疗中是极其关键的。
　　治疗中如何选择正确的停药时机，是目前CHB患者长期治疗中需要谨慎处理的一个关键问题，不规范和随意停药会使已经获得的治疗效果前功尽弃。综合考虑国外和中国制定的CHB管理共识或指南，针对HBeAg阳性和阴性患者NA的停药标准包括：①对HBeAg阳性患者，治疗中出现HBeAg血清学转换，经过巩固治疗1年可以考虑停药，我国指南认为疗程至少需要2年；②对于HBeAg阴性患者，停药标准存在较多争论，目前我国普遍采用的停药标准是，使用NA治疗总疗程大于2.5年，HBV DNA水平持续低于检测下限（至少复查3次，间隔6个月1次）者，可以考虑停药。国内外指南同时还指出，应尽可能延长治疗，并重视停药后监测。
　　有关国内外指南制定的停药标准在临床引发普遍争论，具有丰富临床经验的医生提出了众多质疑。实际上，这些标准的制定也受到不同国家医疗保险报销政策的影响。因此，临床实践中需要不断探索，进行高质量的临床研究。
高质量临床研究结果是治疗决策的重要依据
　　最近，我国香港学者塞托（Seto）等在《消化道》（Gut）上发表的一项临床研究表明，184名HBeAg阴性CHB患者接受恩替卡韦（ETV）单药抗病毒治疗，平均治疗时间为3年，按照亚太肝病研究学会（APASL）停药标准，停药后48周内病毒复发的比例为91%。
　　结合近几年的多项研究结果，我们发现，采用现行CHB管理指南或共识建议的标准停药，停药后的复发率仍达40%~90%，故制定更可靠的NA长期治疗CHB的停药标准迫在眉睫。
　　然而，针对现有的长期抗病毒治疗所面对的问题，制定可靠的个体化停药标准依赖于建立大规模、前瞻性的顶层设计，严格管理的长期随访临床队列，完善的患者精细化管理体制，并加强患者的依从性教育。
　　同时，我们还需通过研究进一步探索HBsAg定量、乙型肝炎病毒核心抗体定量和其他生物学标志物在指导临床停药时的价值。特别需要注意的是，已经有明确肝硬化的患者在接受抗病毒治疗后更不能随意停药。
　　此外，长期抗病毒治疗的安全性也需要进一步积累更多的研究数据。

齐欢畅2

长期核苷（酸）类似物治疗的现实问题

齐欢畅2

我们还需通过研究进一步探索HBsAg定量、乙型肝炎病毒核心抗体定量和其他生物学标志物在指导临床停药时的价值。特别需要注意的是，已经有明确肝硬化的患者在接受抗病毒治疗后更不能随意停药。

sddp1

人们已经意识到核苷需要长期抗病毒，但是长期核苷，安全性如何？盼望治愈乙肝的鸡尾酒疗法！

StephenW

Lampertico博士是一个非常著名的意大利研究员, 他提供他的意见. 我想在接下来的几天里分享.他提出了自己对如何管理停药的方法。他解释关于停止治疗，为什么不同的临床结果.
他也对停止治疗
表达了强烈的意见.

口服抗病毒药物治疗HBeAg阴性慢性乙型肝炎：
停止还是继续更好？ Oral antiviral therapy for HBeAg negative chronic hepatitis B:
better stop or continue?

Pietro Lampertico

Treatment cessation is one of the few challenges left to clinicians to deal with after
the marketing and widespread use of third generation oral analogues (nucleos(t)ide analogue (NUC)), entecavir (ETV) and tenofovir (TDF) for the treatment of HBeAg negative chronic hepatitis B (CHB). Treatment efficacy is in fact unquestioned as more than 95% of patients, including NUC experienced and
resistant ones, achieve complete suppresion of viral replication and improvement
of hepatic inflammation and fibrosis within the first 5 years of treatment.[1–3] As a consequence, in a majority of patients, progression to cirrhosis is prevented, and
clinical decompensation and portal hypertension either improved or prevented,
with hepatocellular carcinoma (HCC) remaining the only complication in HBeAg
negative patients long-term treated for with ETV or TDF.4 Indeed, the yearly
attack rates of HCC range between 0.5% and 1% among non-cirrhotics and 2.5%
and 4% among compensated cirrhotics, incidence rates not very different from
what is expected in untreated patients.[4 5] In these patients, the recommended stopping rule of NUC therapy is HBsAg seroconversion, defined as HBsAg loss and anti-HBs titres >100–200 IU/L,[6–8] which has been proven to be safe in any clinical situation including patients with advanced liver disease, though a minority of patient clearing HBsAg following NUC therapy do not seroconvert to anti-HBs.[9 10]
口服抗病毒药物治疗HBeAg阴性慢性乙型肝炎：
停止还是继续更好？
彼得Lampertico

停止治疗是为数不多的挑战之一留给医生处理后，
营销和广泛使用的第三代口服类似物（核苷（酸）类似物的IDE（NUC）），恩替卡韦（ETV）和替诺福韦（TDF）治疗HBeAg阴性慢性乙型肝炎（CHB）的治疗。治疗功效实际上是不容置疑的95％以上的病人，包括NUC经历和
抗病品种，
实现病毒复制和改善完全抑制

的前5年的治疗中肝脏炎症和纤维化[1-3]其结果是，在大多数患者中，发展成肝硬化的情况消失，并
临床失代偿和门静脉高压症或者改善或预防，
与肝细胞癌（HCC）剩余的HBeAg唯一的并发症
阴性患者的长期治疗与恩替卡韦或TDF.4事实上，每年的
肝癌范围内发病率在0.5％至1％之间的非肝硬化和2.5％
和补偿肝硬化之间4％，发病率不是很不同
什么是预期在未经治疗的患者。〔4 5〕在这些患者中，NUC治疗的建议停止规则是乙肝表面抗原的血清转换，定义为HBsAg消失和抗HBs抗体滴度>100-200 IU / L，[6-8]具有已被证明是安全的任何临床情况，包括治疗晚期肝疾病，虽然患者资料交换的HBsAg以下NUC治疗少数不血清转化到抗HBs[9-10]

StephenW

One major caveat of this stopping rule is the small number of HBeAg negative patients who achieve HBsAg seroconversion, no more than 1% after 5 years and 5% after 10 years of continuous treatment, thereby questioning whether it is appropriate to stop NUC therapy before achieving HBsAg seronegativity. Asian Pacific Association for the Study of the Liver (APASL) guidelines indeed suggest this, but so far clinical evidence supporting these recommendations is more than scanty.
此停止规则的一个主要的条件是在少数的HBeAg谁实现HBsAg的血清转化，之后不超过1％的5年，阴性患者的
经过10年的连续治疗的5％，因此质疑是否是适当停止国统疗法实现乙肝表面抗原血清阴性之前。亚太肝脏研究协会（APASL）的研究指导方针确实建议这个支持这些建议，但到目前为止，临床证据不止寥寥无几。

In the study by Seto et al, cessation was attempted in 184 HBeAg negative patients from Hong Kong treated with ETV monotherapy for 3 years on average. All these patients fulfilled the Asian Pacific consensus statement on NUC cessation in HBeAg negative patients, with undetectable HBV DNA (<20 IU/mL) documented in three separate occasions of at least 6 months apart.[8]The study showed that durability of post-treatment virological response was poor, with 91% of the patients having a virological relapse within 48 weeks of treatment cessation.
Post-treatment sustained immune control could not be predicted as HBsAg levels at ETV withdrawal were not associated with the probability of virological relapse. The authors conclude that given the poor off-treatment sustainability of ETV therapy, treatment of indefinite duration should be recommended.
在这项研究由濑户等人，停止试图在香港184 HBeAg阴性患者恩替卡韦单药治疗3年的平均水平。所有这些患者符合有关国统会终止HBeAg阴性患者亚太共识声明，检测不到HBV DNA（<20 IU/ mL）的记录在三个独立的至少相隔6个月的场合.[8]研究结果显示，治疗后病毒学应答耐久性差，有91％患者有治疗48周停止内的病毒学复发。
治疗后持续无法预测的免疫控制的HBsAg水平在ETV撤回未与病毒学复发的可能性相关联。作者认为，鉴于ETV治疗的差离治疗的可持续性，处理无限期的，应建议。

This study is challenged by a recent retrospective-prospective study from Taiwan where the APASL guidelines treatment cessation rules were validated in 95 HBeAg negative patients treated long-term with ETV.12 A clinical relapse, defined as an episode of ALT elevation >2× upper limit of normal (ULN) plus HBV DNA>2000 IU/mL, occurred in 43 (45%) of these patients only. The 1 year relapse rate was lower for patients with baseline HBVDNA <5 logs IU/mL (29%) and for high viral load patients who received consolidation therapy >64 weeks (33%).
这项研究是由最近的回顾性，前瞻性研究，从台湾那里的APASL指南停止治疗规则是在95验证挑战 HBeAg阴性患者的治疗长期与ETV.12临床复发，定义为ALT升高的一个小插曲>2×高标准上限（ULN），加上乙肝病毒DNA的限制
>2000 IU/ mL时，发生在43只有这些患者（45％）。 1年复发率为降低患者的基线HBVDNA<5logd IU/ml（29％）和谁收到巩固治疗高病毒载量的患者>64周（33％）。

StephenW

Both these studies come from the same geographical areas, Asia, in patients with similar clinical profile, HBeAg negative CHB, infected by the same viral genotypes, B or C, treated with the same strategy, ETV monotherapy, and managed with similar treatment cessation rules, the APASL guidelines. The question is, how did these two papers reach opposite conclusions? What lessons can be drawn? Although these two publications differ in terms of study design and patient profile, the most important issue is the definition of the endpoint of the study which triggered re-treatment: a ‘virological relapse’ for the Hong Kong study and a ‘clinical relapse’ for the Taiwan study. Rescue was clearly too anticipated in the Hong Kong study, as ETV was restarted as soon as HBV DNA peaked above 2000 IU/mL, that is, patients were not given any chance to achieve HBsAg loss after ALT flare.
这两项研究都来自同一个地理区域，亚洲患者相似的临床轮廓，HBeAg阴性慢性乙型肝炎，感染了相同的病毒基因型，B或C，用同样的策略，恩替卡韦单药治疗，并与类似的戒烟治疗管理规则，在APASL指南。现在的问题是，怎么这两篇论文达到相反的结论？有什么经验教训可以得出？虽然这两个刊物的研究设计和患者个人资料方面的不同，其中最重要的问题就是研究它引发的再治疗的端点的定义：“病毒学复发”为香港的研究和“临床复发”的台湾的研究。救援显然也预计在香港学习，为ETV是尽快重新启动的HBV-DNA见顶2000以上的国际单位/毫升，也就是患者没有机会ALT耀斑后达到HBsAg消失。


Indeed, the whole dispute started few years ago when S. Hadziyannis and colleagues provided the first evidence that NUC cessation could be attempted before HBsAg clearance. Although all patients had an initial virological rebound, and this is a critical observation, high rates of immune control (55%) and HBsAg loss (39%) could be achieved during long-term post-treatment follow-up among 33 HBeAg negative, genotype D infected, NUC-naive Greek patients who had stopped adefovir (ADV) monotherapy after 4–5 years of successful treatment.[13] None of the patients with >1000 IU/mL HBsAg at the end of ADV treatment cleared HBsAg loss during follow-up, suggesting that qHBsAg levels at the end of treatment could be used to stratify the risk of relapse.
事实上，整个争端开始几年前，当南Hadziyannis和同事提供了第一个证据表明，国统会终止HBsAg清除之前尝试。虽然所有患者最初的病毒学反弹，这是一个关键的观察，可以在长期治疗后随访中33 HBeAg阴性实现免疫控制（55％）和HBsAg消失（39％）的高利率， D基因型感染了，谁已经停止阿德福韦NUC-天真希腊例（ADV）单药治疗后4-5年的成功治疗。[13]无的患者> 1000 IU/ mL的乙肝表面抗原为ADV治疗结束时清除HBsAg消失后续，表明qHBsAg水平在治疗结束时，可以使用分层的复发的风险

Additional studies have more recently looked at the same issue for HBeAg negative CHB patients. Among 64 Chinese, genotype B and C infected patients, treated with different NUC, the virological and clinical relapse rates were 30% and 10%, respectively.[14 ] Among 45 Korean patients fulfilling the APASL stopping rules after approximately 3 years of NUC treatment, 73% had a virological relapse while 53% had a clinical relapse.[15]  In another study from Taiwan, the cumulative rates of HBV relapse after lamivudine discontinuation among 105 HBeAg negative CHB patients were 43%, 60% and 68% at year 1, 3 and 6.[16] Old age, male gender and qHBsAg levels at the end of treatment independently predicted HBV relapse. The likelihood of a sustained immune control was 93% for patients with HBsAg levels <200 IU/mL at the end of treatment, while the probability of HBsAg clearance was 79% for those with qHBsAg <120 IU/mL at the end of therapy.[16]
进一步的研究，最近看了看同一个问题的负面大三阳略去慢性乙型肝炎患者。其中64中国，B，C基因型感染患者，用不同的NUC治疗，病毒学和临床复发率分别为30％和 10％，分别为[14]在45例患者朝鲜履行APASL停止规则大约3年后国统会的治疗，73％有一位病毒学复发，而53％的患者临床复发。[15]来自台湾的另一项研究中，累计乙肝复发的105间HBeAg阴性慢性乙型肝炎患者拉米夫定停药后分别为43％，60％和68％，在今年1,3和6。[16]老年，男性和qHBsAg水平在治疗结束独立预测乙肝复发。持续的免疫控制的可能性是为患者HBsAg水平<200国际单位/毫升，在治疗结束时的93％，而HBsAg清除的概率是对于那些具有qHBsAg<120国际单位/毫升，在治疗结束时为79％。 [16]

StephenW

Treatment cessation might be worth being explored in specific situations where for example drug cost is an issue, full reimbursement is not in place and compliance tends to fade over time. Physicians and patients willing to explore NUC cessation before HBsAg clearance must however be aware that to achieve a successful sustained immune control they must be ready to follow a specific ‘cessation’ strategy. This strategy is based on the following:
(1) monitor virological and clinical variables monthly for the first
6 months, every 2–3 months from months 7 to 12 and every 4–6 months afterward;
(2) do not rescue early virological relapse, and ‘early’ is defined as the first occurrence of HBV DNA or any increase of HBV DNA in the absence of ALT flare;
(3) do not rescue the first ALT flare or clinical relapse, as this event could be beneficial driving immune mediated elimination of the infected hepatocytes; and
(4) re-treat with NUC only after the second clinical relapse or at the time of the first clinical relapse if it is severe or expected to be severe.
This whole strategy is based on the fact that ‘immune control’ can be ‘primary’, that is, a smooth transition from a full viral suppression during therapy to a full viral suppression off
therapy without any virological rebound,or ‘secondary’, that is, an initial virological and clinical relapse followed by a immune control. The first modality is rare; the second much more frequent. Thereby physicians or patients unwilling to risk a virological rebound and an ALT flare should not try to stop NUC therapy before HBsAg loss. This is the reason why the study by Seto et al[11] failed to provide any major new information on this issue, as an almost universal virological rebound was expected as already demonstrated by previous studies in HBeAg negative patients.
停止治疗可能是值得探讨的特定情况下，例如药物的成本是一个问题，全额报销不到位和合规性趋于消失一段时间。医生和患者愿意探讨HBsAg清除之前，国统会终止然而，必须认识到，要实现成功的持续免疫控制，他们必须做好准备，以遵循特定的“停止”的策略。这种策略是基于
以下内容：
（1）监视病毒学和临床变量每月的第6个月，从7个月到12个，每2-3个月，每4-6个月之后;
（2）不救早期病毒学复发和“早”是指乙肝病毒DNA的第一次出现，或任何增加的HBV DNA在没有ALT耀斑的;
（3）不抢救第一ALT耀斑或临床复发，作为本次活动是有益的驾驶免疫介导的消除感染的肝细胞;和
（4）只有在第二临床复发或第一临床复发时再治疗与国统会，如果是重度或预计到很严重。
这整个的战略是基于一个事实，即“免疫控制”可以是“主要”，也就是从一个完整的病毒抑制治疗期间，一个完整的病毒抑制了平稳过渡治疗无任何病毒学反弹，或“次要”，也就是说，初始的病毒学和临床复发后跟一个免疫控制。第一个方式是罕见的;第二频繁得多。
因此医师或病人不愿意冒险病毒学反弹和ALT耀斑不应该试图阻止国统疗法前HBsAg消失。这就是为什么[11]的研究中Seto等人未能提供在这个问题上的任何重要的新信息的原因，
正如预期的几乎是普遍的病毒学反弹已经为HBeAg阴性证明了前人的研究患者。

Likewise, there are quite a number of arguments against treatment cessation before HBsAg clearance. The risk and kinetics of a severe clinical flare cannot be easily anticipated even if a monthly monitoring of all possible virological and clinical variables is performed, considering that full interpretation of these data might require a solid expertise on this field. Cirrhotics must be excluded from this strategy but many centres rely nowadays on ultrasound findings or non-invasive tests to diagnose cirrhosis rather than on liver biopsy findings, which leads to systematic underestimating of the severity of liver disease among HBV patients. In case
of re-treatment, full suppression of viral replication might require some time to be achieved. Last but not least, necrosis, inflammation and hepatic regeneration which are all associated with a clinical flare are well known risk factors for HBV related HCC. In addition, while continuous therapy with third generation NUC would almost undoubtedly maintain viral replication fully suppressed, achievement of an immune control, defined as
HBVDNA <2000 IU/mL and normal ALT levels, does not coincide with undetectable viremia. The relevance of this post-treatment residual viremia as a risk factor for HCC is currently unknown.
同样，也有不少对HBsAg清除治疗前停止治疗的争论。严重的临床突发的风险和动力学不能轻易预料即使进行每月监测所有可能的病毒学和临床变量，考虑到这些数据充分解释可能需要在这一领域的专业知识扎实。肝硬化患者必须排除从该策略，但许多中心依靠现今对超声结果还是非侵入性测试，以诊断肝硬化，而不是在肝活检的结果，从而导致肝病中乙肝患者的严重程度进行系统的低估。如果的再处理，病毒复制的充分抑制可能需要一些时间来实现。最后但并非最不重要的，坏死，炎症和肝再生它们都具有临床耀斑关联是众所周知的风险因素为HBV相关HCC。此外，在持续治疗与第三代NUC
几乎毫无疑问，保持病毒的复制完全抑制，实现免疫控制，定义为乙肝病毒DNA<2000 IU/ mL和ALT水平正常，没有测不到病毒血症一致。在这个后处理残留的病毒血症为肝癌的危险因素的相关性目前尚不清楚。

StephenW

In conclusion, HBsAg seroclearance is the best and safest stopping rule for HBeAg negative patients, including cirrhotics, treated long-term with oral antivirals. While this stands as the current ‘default’ stopping rule, in selected clinical conditions, treatment cessation can be attempted before HBsAg clearance is achieved, provided that fully informed consent is
achieved, advantages and disadvantages of this strategy have been carefully weighted, and a proper ‘cessation strategy’, including strict monitoring and predefined rescue management, has been designed. Longer duration of HBV DNA undetectability during NUC and lower HBsAg levels before treatment cessation predicts post-treatment immune control. Physicians and patients who are anxious to stop long-term effective NUC therapy before HBsAg loss should keep in mind that not only current oral treatments are safe and very effective in improving patient survival, the goal of anti-HBV therapy, but that many new studies specifically testing new compounds and immunomodulatory strategies designed to foster HBsAg decline while on NUC therapy are ongoing and fully recruiting. Results are expected by 2015,only a few months to go.
总之，乙肝表面抗原转阴是HBeAg阴性患者的最佳和最安全的停止治疗
规则，包括肝硬化抽搐，治疗长期口服抗病毒药物。虽然这代表作为当前“默认”停止规则，在选定的临床条件系统蒸发散，治疗停止
可以尝试的HBsAg清除率达到之前，只要充分知情同意实现的，优势和该策略的优缺点都经过精心加权，和适当的“
停止治疗战略”，包括严格的监控和预定义的救助管理，已经设计。 HBV-DNA不可检测的时间更长NUC和较低的HBsAg水平在治疗前停止治疗
预测治疗后免疫控制。医生和病人谁是急于阻止长期有效NUC治疗HBsAg消失之前应记住，不仅目前的口服药物是安全的，非常有效的提高患者的生存率，抗乙肝病毒治疗的目的，但是，许多新的专门研究测试新化合物，并旨在促进HBsAg的下降，而在NUC疗法是持续和全面招募免疫
策略。结果是，到2015年预计，只有几个月去了。

肝肠欲断