停药-长期的核苷（酸）类似物IDE治疗的e抗原阴性患者

StephenW

Systematic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B


    M.-L. Chang1, Y.-F. Liaw1,* andS. J. Hadziyannis2

Article first published online: 10 JUN 2015

DOI: 10.1111/apt.13272

© 2015 John Wiley & Sons Ltd

Issue
Alimentary Pharmacology & Therapeutics
Alimentary Pharmacology & Therapeutics

Volume 42, Issue 3, pages 243–257, August 2015
Article has an altmetric score of 2


    1    Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
    2    Second Department of Medicine at Hippokration Hospital, National and Kapodistrian University of Athens, Athens, Greece

* Correspondence to:
Prof. Y.-F. Liaw, Liver Research Unit, Chang Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
E-mail: [email protected]

    This uncommissioned review article was subject to full peer-review

Summary
Background

It has been debated whether finite nucleos(t)ide analogue therapy is feasible in HBeAg-negative chronic hepatitis B.
Aim

To review this issue systematically.
Methods

Using text terms HBsAg and various nucleos(t)ide analogues, PubMed was searched between 1995 and 2014 to find studies on therapy >6 months in adult HBeAg-negative chronic hepatitis B patients with off-therapy follow-up >6 months.
Results

Twenty-two studies with a total of 1732 patients were identified and included. The median duration of therapy, consolidation therapy and off-therapy follow-up ranged from 6 months to 8 years, 4 to 96 weeks and 6 to 80 months respectively. Patients were monitored with serum ALT and HBV DNA monthly in the first 1–3 months and every 3–6 months afterwards in most studies. The 1-year off-therapy ‘virological relapse’ (HBV DNA >2000 IU/mL) and ‘clinical relapse’ (HBV DNA > 2000 IU/mL + ALT elevation) occurred in <70% and <50% of the patients, respectively, and <40% of the patients received re-treatment. These rates were higher in patients with shorter treatment, shorter consolidation therapy and those treated with less potent nucleos(t)ide analogues. Off-therapy severe flares were rare and hepatic decompensation was reported in only one patient with cirrhosis. Biochemical relapse reflecting enhanced immune-mediated hepatocyte killing may lead to a higher chance for off-therapy HBsAg seroclearance and be possibly desirable.
Conclusion

With an appropriate stopping rule and a proper off-therapy monitoring plan, cessation of long-term nucleos(t)ide analogue therapy prior to HBsAg seroclearance in HBeAg-negative chronic hepatitis B is a feasible alternative to indefinite treatment.

StephenW

系统评价：长期的核苷（酸）类似物IDE治疗的患者与乙肝e抗原阴性的慢性乙肝停药

    M.-L.畅，Y.-F. Liaw1，*和S。 J. Hadziyann​​is2

文章首次在线发表：2015年6月10日

DOI：10.1111 / apt.13272

2015年©约翰·威利父子有限公司

问题
消化系统药理学和治疗
消化系统药理学和治疗

第42卷第3期，页243-257，2015年8月
文章有altmetric比分2


    1肝脏研究单位，长庚医院，医学长庚大学，台湾台北
    医学2二系Hippokration医院，国家和雅典Kapodistrian大学，雅典，希腊

*通讯作者：
Y.-F.教授廖，肝脏研究单位，长庚医院，199，华通北路，台北105，台湾。
电子信箱：[email protected]

    这uncommissioned评论文章是受到全同侪审查

总结
背景

它一直争论不休有限核苷（酸）类似物IDE治疗是否可行HBeAg阴性慢性乙型肝炎
目的

为了系统地审查这一问题。
方法

使用文本条款HBsAg和各种核苷（酸）类似物，考研被搜查1995年至2014年间，以找到治疗> 6个月的研究在成年HBeAg阴性慢性乙型肝炎患者的脱离治疗随访> 6个月。
结果

二十二个，共1732患者的研究进行鉴定和包括在内。的治疗，巩固治疗和非治疗随访的中位数持续时间6个月分别介于到8年，4至96周和6至80个月。患者血清ALT和HBV DNA在每月的第一个1-3个月，每3-6个月之后，在大多数的研究监测。 1年离疗法“病毒学复发'（HBV DNA> 2000 IU / mL）和”临床复发“（HBV DNA> 2000 IU /毫升+ ALT升高）发生在<70％和患者<50％，分别与<的40％的患者接受再治疗。这些比率的患者有较高的治疗更短，更短的巩固治疗和那些不太有效的核苷（酸）类似物治疗。场外治疗重症耀斑罕见，肝功能失代偿报道，在只有一个肝硬化病人。生化复发反映增强免疫介导的肝细胞杀伤可能导致对场外治疗乙肝表面抗原血清学清除的机会较高，并可能可取的。
结论

用适当的停止规则和适当的场外治疗监测计划，长期核苷（酸）类似物IDE之前疗法对HBsAg血清清除HBeAg阴性慢性乙型肝炎停药是一种可行的替代治疗不定。

StephenW

Discussion

The results of this systematic review on the cessation of Nuc therapy in HBeAg-negative patients with CHB have shown remarkable variations across the studies. These include the study design (retrospective or prospective), Nuc used, stopping rule, duration of Nuc therapy/consolidation therapy, interval/duration of off-therapy monitoring, definition of relapse and indication for re-treatment. Most studies monitored the patients with serum ALT and HBV DNA monthly in the first 1–3 months and every 3–6 months afterwards (Table 2). Using the definitions of ‘virological relapse’ (HBV DNA >2000 IU/mL) and ‘clinical relapse’ (HBV DNA >2000 IU/mL + ALT elevation) of major liver associations,[3-5] the collective data showed an 1-year ‘virological relapse’ rate of <70% and ‘clinical relapse’ rate of <50% in most of the studies, being higher in patients with Nuc therapy ≤1 year and with a trend to be lower in patients treated with more potent Nucs and those with longer duration of Nuc therapy and/or consolidation therapy.[12, 14-19, 25, 26, 31-34] An 1-year ‘clinical relapse’ rate <30% was reported in patients with baseline HBV DNA ≤2×105 IU/mL [25] or those with maintained undetectable HBV DNA (consolidation therapy) >18 months before cessation of Nuc therapy.[25, 26, 32] Most relapses happened within 1-year off-therapy, slightly increased afterwards but rarely after year 2 off-therapy.[11-34] ‘Clinical relapse’ most frequently (~79%) occurred within 6-month off-therapy in patients treated with LAM, ADV or LdT[12, 15, 17, 25], but the majority (~75%) occurred beyond 6-month off-therapy in ETV-treated patients.[25, 29] Marked ALT flare was rare and hepatic decompensation was reported in only one patient with liver cirrhosis.[25, 31] Overall, the results have shown that cessation of Nuc therapy after maintained HBV suppression for at least 1 year is safe under proper off-therapy monitoring, and only 26–48% of the patients required re-treatment. In other words, 50–75% of the patients may enjoy Nuc-free life for at least the duration of the off-therapy follow-up listed in this systematic review. However, it is also obvious that proper off-therapy monitoring is mandatory to start re-treatment in time to prevent or rescue more serious relapse and hepatic decompensation.[11, 20, 23, 25, 29, 30]

In the guidelines of the major liver associations, drug therapy is not recommended for HBeAg-negative CHB patients with HBV DNA >2000 IU/mL without concomitant ALT elevation unless the patients have evidence of advanced fibrosis/cirrhosis.[3, 4, 36] Therefore, ‘clinical relapse’ is of more clinical significance than ‘virological relapse’; however, ‘virological relapse’ is also significant in patients with advanced fibrosis/cirrhosis and those with family history for severe liver disease or HCC. A few studies chose to re-treat the patients with ‘virological relapse’.[24, 26, 29, 31] Of the two Asian studies with ETV therapy using APASL stopping rule, the Taiwan study of 2-year ETV therapy showed a virological relapse rate of 57.8%, a clinical relapse rate of 45.2% and re-treatment was instituted in 35.8% of the patients.[25] In contrast, a recent Hong Kong study of 3-year ETV therapy showed an extremely high ‘virological relapse’ rate (91.4%), and very high (88.5%) proportion of the patients was re-treated for ‘virological response’ in spite of a low ‘clinical relapse’ rate (10.3%).[29] The reason(s) for these discrepancies are not clear. Importantly, it was well documented by Hadziyannis, et al.[23] that all of the 33 HBeAg-negative CHB patients who discontinued ADV therapy showed initial virological rebound, but 18 (55%) patients achieved sustained remission spontaneously and 13 (72.2%) of the 18 patients lost serum HBsAg during free of treatment follow-up, in contrast to HBsAg loss in only 1 (6%) of the 15 patients who received re-treatment. These findings suggest that the early biochemical relapse reflecting immune-mediated hepatocyte killing could be beneficial in reduction and dilution of the cccDNA in the infected hepatocytes,[37] and thus lead to a higher chance of HBsAg seroclearance, as shown in the study of Hadziyannis et al.[23] A most recent study not included in this systematic review also showed that 7 of the 59 HBeAg-negative patients who discontinued therapy lost serum HBsAg, none of whom had been re-treated.[35] Therefore, treating patients with off-therapy ‘virological relapse’ could hamper the chances for effective immune-mediated response,[29, 38, 39] thus re-treatment may only be considered when the clinical relapse is of high risk for hepatic decompensation, such as ALT flare with a HBV DNA level >3 × 108 IU/mL,[40] or in patients with persistent ALT elevation or repeated relapse.[38, 39, 41] For virological relapse with HBV DNA >20 000 IU/mL, re-treatment may be needed if there are other risk factors such as positive family history for severe liver disease or HCC. More frequent monitoring is required once virological relapse is detected, and weekly to biweekly follow-up including serum bilirubin and even prothrombin time may be required once ALT becomes abnormal, especially if ALT is rising or flare up to >5× ULN.[36]

It is a widely accepted belief that Nuc therapy in patients with liver cirrhosis should be lifelong and should be excluded from this finite Nuc therapy strategy.[3, 4, 23, 39] Notably, up to 41% of the patients in 18 studies, totally 165 patients, included in this systematic review had evidence of liver cirrhosis (Table S1), and only one patient who defaulted on off-therapy follow-up developed hepatic decompensation.[25] Recently, it was further shown that cessation of LAM therapy after recovery from a hepatitis B flare with decompensation was safe for most patients, including patients with cirrhosis, though some patients developed hepatic decompensation which could be prevented by proper off-therapy monitoring and rescued by timely Nuc re-treatment.[42] One may argue whether cessation of Nuc therapy in patients with cirrhosis would blunt the effect in reducing long-term adverse outcomes such as HCC and mortality. Studies not included in this review showed that the incidence of HCC after cessation of Nuc was not higher than those who continued Nuc therapy during a mean duration up to 90 months.[42, 43] All these findings may challenge the dogma of lifelong Nuc therapy in patients with cirrhosis or hepatic decompensation.[3, 4] These findings may also form the basis for large prospective controlled studies for longer duration to test or confirm the feasibility of finite Nuc therapy. Given that several factors have been reported to be significant for the off-therapy virological response, studies are also warranted to find the best approach for when and on what variables to discontinue long-term Nuc therapy in HBeAg-negative CHB as well as when to restart Nuc therapy.[44]

The role of serum HBsAg level in relation to off-therapy relapse was assessed in a few studies.[21, 22, 25, 28] Of the patients with end-of-therapy HBsAg ≤100 IU/mL, off-therapy HBV DNA increased >200 IU/mL in only 9–22%[21, 22], while <7% of the patients with end-of-therapy HBsAg <200 IU/mL developed HBV DNA relapse to >2000 IU/mL.[28] Most recently, it was also shown that patients with end-of-treatment HBsAg ≤100 IU/mL were 15-fold more likely to develop confirmed HBsAg loss after treatment discontinuation.[35] These findings suggest that HBsAg <100 or <200 IU/mL at the end of therapy is a good indicator of sustained response. These levels were also reported to be highly predictive for spontaneous HBsAg seroclearance within 1–3 year during the natural course of CHB.[45, 46] Unfortunately, not many patients can achieve such low HBsAg level during Nuc therapy. Further studies are required to find an optimal or a more practical HBsAg threshold for predicting sustained response after cessation of Nuc therapy.
Summary and conclusions

Collative data in this systematic review have shown a 1-year ‘virological relapse’ rate of <70%, ‘clinical relapse’ rate of <50% and a lower than 40% rate of re-treatment. These rates are lower in patients with baseline HBV DNA ≤2 × 105 IU/mL or in those with a consolidation therapy >18 months and, actually, they are not higher than the rates in HBeAg-positive patients who had achieved seroconversion to anti-HBe and stopped therapy after adequate consolidation therapy.[35, 47] Given that cessation of Nuc therapy in HBeAg-positive CHB patients is accepted by all major liver associations,[3-5] conceivably cessation of Nuc therapy is also a feasible alternative to indefinite treatment prior to HBsAg seroclearance in HBeAg-negative patients with CHB who had Nuc therapy ≥2 years and if adequate stopping rules, including that of APASL or other more stringent rule with consolidation time >12 months and proper off-therapy monitoring plan, are followed. Notably, the off-therapy immune-mediated clinical relapses may resolve spontaneously with an increased chance of HBsAg seroclearance; thus, not all relapses require immediate re-treatment. The recommended strategy for cessation, follow-up monitoring and re-commencement of Nuc therapy in HBeAg-negative CHB are listed in Figure 2. This strategy of Nuc cessation with proper off-therapy monitoring would be much safer than stopping therapy by patients themselves for whatever reasons (financial, willingness, etc.) and hence lost to follow-up. Without adequate monitoring, such patients may encounter unpredictable untoward outcomes. Of note, actual adherence to frequent monitoring may be not easy in clinical practice but is of paramount importance and must be stressed when physician/patient consider stopping Nuc therapy. Finally, the collective data in this systematic review support that cessation of oral anti-viral therapy in patients with cirrhosis is also feasible and decompensation developed in only one of the 165 patients with cirrhosis included in 18 studies. However, a most recent study showed that two (HBeAg status not mentioned) of the 27 patients with cirrhosis developed hepatic decompensation off-therapy.[35] Therefore, more studies are needed to confirm the feasibility of stopping long-term nucleos(t)ide therapy in patients with cirrhosis.

StephenW

讨论

在国统会治疗HBeAg阴性慢性乙肝患者停止该系统评价的结果表明在整个研究显着的变化。这些措施包括研究设计（或追溯准），国统会使用，停止规则，国统疗法/巩固治疗，间隔/脱疗法监测时长，复发和适应症再治疗的定义的持续时间。大多数研究监测与血清ALT和HBV-DNA的每月的第一1-3个月的患者，每3-6个月后（表2）。使用“病毒学复发'（HBV DNA> 2000 IU / mL）和”临床复发“（HBV DNA> 2000 IU /毫升+ ALT升高）的主要肝脏协会的定义[3-5]集体数据显示一个1 <70％和<50％的临床复发“率在大多数研究中，作为更高的患者国统疗法≤1年，并与一个趋势是降低与更有效的治疗的患者 - 年”病毒学复发'速率Nucs和那些与国统疗法和/或巩固治疗的持续时间较长。[12，14-19，25，26，31-34]的1年的临床复发'率<30％被报道的患者基线HBV DNA的≤2×105 IU / mL的[25]或那些与维护检测不到HBV DNA（巩固治疗）>终止国统会治疗的前18个月[25，26，32]复发大多在1年期场外治疗发生，略有增加事后但很少年后2关疗法。[11-34]“临床复发”最常见（〜79％）6个月内与LAM，ADV或LDT [12，15，17治疗的患者发生过疗法， 25]，但大多数（〜75％）发生超出6个月休治疗ETV治疗的患者。[25，29]有标记的ALT耀斑是罕见和肝功能失代偿报告仅在一个肝硬化病人。[25 ，31]总之，结果显示国统会疗法的戒烟后保持抑制乙肝在至少1年在适当的场外治疗监测是安全的，只有26-48％的病人需要再治疗。换言之，患者的50-75％可以享受NUC-自由生活的关断疗法随访在本系统的审查中列出的至少持续时间。然而，同样明显的是适当的离治疗监测是强制性的，以开始重新处理时间，以防止或抢救更严重的复发和肝功能失代偿[11，20，23，25，29，30]

在各大肝脏协会的指导方针，药物治疗，不建议HBeAg阴性慢性乙型肝炎患者HBV DNA> 2000 IU / ml，未伴随ALT升高，除非患者有晚期肝纤维化/肝硬化的证据。[3，4，36]因此，“临床复发”是比“病毒学复发”更具有临床意义;然而，“病毒学复发”也是在晚期肝纤维化/肝硬化和那些有家族史的严重肝脏疾病或肝癌显著。一些研究选择了再治疗患者的“病毒学复发”。[24，26，29，31]恩替卡韦治疗用APASL停止规则这两个亚洲研究，2年ETV治疗的台湾研究表明病毒学57.8％的复发率，45.2％临床复发率和再处理被设立的患者35.8％。[25]相反，3年ETV治疗最近香港研究显示出非常高的“病毒学复发'率（91.4％），和非常高的（88.5％）的患者的比例被重新处理''尽管低“临床复发”率（10.3％）的病毒学反应。[29]的原因（多个）这些差异是不明确​​的。重要的是，它是深受Hadziyann​​is等记录在案。[23]所有谁停止ADV治疗33例HBeAg阴性慢性乙肝患者表现出的初始病毒学反弹，但18（55％）患者自发地实现了持续缓解，13（72.2％ ）的18名患者的丢失血清HBsAg无治疗随访期间，在对比谁收到再治疗15例患者的HBsAg消失在只有1（6％）。这些结果表明，早期生化复发反射免疫介导的肝细胞杀伤可能是有益的减少和稀释的cccDNA在感染的肝细胞，[37]，并因此导致的HBsAg血清清除的机会较高，如图Hadziyann​​is的研究等[23]一个最近的研究不包括在此系统的审查还显示，7谁停止治疗失去了血清HBsAg，没有一个人实现了再治疗的59例HBeAg阴性患者。[35]因此，治疗病人与脱离疗法“病毒学复发'可能妨碍有效的免疫介导的反应的可能性，[29，38，39]因而再处理仅可当临床复发的高风险的肝功能失代偿，如ALT耀斑考虑与HBV DNA水平> 3×108 IU / mL时，[40]或在患者持续ALT升高或反复复发。[38，39，41]对于病毒学复发与HBV DNA> 20 000 IU / mL时，再治疗可能需要有其他危险因素，例如家族史为严重的肝脏疾病或肝癌。检测病毒学复发更频繁的监控是必需的一次，每周一次至每两周一次随访，包括血清胆红素，甚至凝血酶原时间可能需要一次ALT异常，特别是如果ALT上升或爆发至> 5×ULN。[36]

这是一个被广泛接受的信念，国统会在治疗肝硬化患者应终身，并应被排除在这个有限的国统会的治疗策略。[3，4，23，39]值得注意的是，高达41％的患者在18项研究，共165例患者，纳入本系统评价了肝硬化的证据（表S1），只有一个病人谁拖欠场外治疗后续开发的肝功能失代偿。[25]最近，它进一步表明LAM治疗的戒烟从乙肝耀斑与失代偿恢复后是安全的大多数患者，包括肝硬化患者，尽管有些患者出现肝功能失代偿这可以通过适当的场外治疗监测预防和及时通过重国统治疗获救。[42]一个可能认为戒烟治疗国统会肝硬化患者是否会在钝降低长期的不良后果，如肝癌和死亡率的影响。研究没有包括在本次审查表明，肝癌停止国统会后的发病率并不比那些谁继续在平均持续时间长达90个月国统疗法高。[42，43]所有这些研究结果可能挑战终身国统会治疗的教条肝硬化或肝功能失代偿。[3，4]这些发现也可形成更长的时间来测试或确认的有限国统会治疗的可行性的基础，大规模的前瞻性对照研究。鉴于多种因素已被报道为用于OFF疗法病毒学应答显著，研究也必要的，以找到有关何时以及在什么变量停止长期国统治疗HBeAg阴性的最佳方法，以及何时重新启动国统疗法。[44]

关于场外治疗复发血清HBsAg水平的作用是评估一些研究[21，22，25，28]患者结束治疗的HBsAg≤100IU / mL时，场外治疗乙肝病毒的DNA增加> 200 IU / mL的只有9-22％[21，22]，而<的患者结束治疗的乙肝表面抗原<200 IU / mL的7％发展HBV DNA复发到> 2000 IU / mL的。[28 ]最近，它也表明，患者最终的治疗乙肝表面抗原≤100IU / ml的15倍更有可能发展停药后证实HBsAg转阴。[35]这些结果表明，乙肝表面抗原<100 <200 IU / mL的在治疗结束是持续反应的良好指标。这些级别也被报道是在1-3年的乙肝表面抗原自发转阴高度预测慢性乙肝的自然过程。[45，46]不幸的是，许多患者可达到国统会在治疗过程中如此低的HBsAg水平。需要进一步的研究，以找到一个最佳或更实际的HBsAg阈预测停止国统疗法后持续反应。
摘要和结论

该系统评价校勘数据都显示出了1年的“病毒学复发'率<70％，”临床复发“的<50％的速度和再治疗一个低于40％的税率。这些利率降低患者的基线HBV DNA≤2×105 IU / mL或在那些与整合疗法> 18个月，实际上，他们并不比谁取得了血清转换到抗HBeAg阳性患者的速度高抗HBe并经过充分的巩固治疗停止治疗。[35，47]鉴于HBeAg阳性慢性乙型肝炎患者认为国统会治疗停止是由所有主要的肝协会接受，[3-5]可以想象停止国统会治疗也是一种可行的替代方案无限期治疗前的HBsAg血清清除HBeAg阴性慢性乙肝患者谁了国统疗法≥2年，如果没有足够的停车规则，包括APASL或固结时间> 12个月，过恰当的疗法监测计划等更严格的规则，是紧随其后。值得注意的是，关断治疗免疫介导的临床复发可能用HBsAg血清清除的机会增加自发消退;因此，并不是所有的复发需要立即再处理。推荐的策略停止，后续监测和HBeAg阴性CHB重新启动国统会疗法被列在图2。国统会终止与适当的场外治疗监测的这种策略会比病人停止治疗自己的更安全不管是什么原因（金融，意愿等），并因此失去了跟进。如果没有适当的监督，这样的患者可能会遇到不可预知的结果不幸。值得注意的是，实际坚持经常监测可能​​是在临床实践中并不容易，但是最重要的，必须强调，当医师/病人考虑停止治疗的国统会。最后，在这个系统评价支持的口服抗病毒治疗肝硬化患者的戒烟集体的数据也是可行的，代偿的发展只有一个165肝硬化患者纳入18项研究中。然而，最近的研究表明，在27个患者的肝硬化开发肝功能失代偿脱疗法即（未提及HBeAg状态）两种。[35]因此，需要更多的研究来确认停止长期核苷的可行性（t）的IDE治疗肝硬化患者。

StephenW

Figure 2. The recommended strategy for cessation, follow-up and re-commencement of Nuc therapy in HBeAg-negative CHB. ULN, upper limit of normal, Nucs: nucleoside/nucleotide analogue; ‘clinical relapse’: HBV-DNA level ≥2000 IU/mL and serum ALT levels >2× ULN.
http://onlinelibrary.wiley.com/s ... db43df7288e3f4e81a3

全文:
http://onlinelibrary.wiley.com/doi/10.1111/apt.13272/full

19721108

谢谢

682256

是否可以这样认为:表面抗原定量<100iu/ml，可以作为核苷药治疗的停药标准？当然治疗达到这个标准不是很容易的。

StephenW

回复 682256 的帖子

是否可以这样认为:表面抗原定量<100iu/ml，可以作为核苷药治疗的停药标准？
这是一个强烈的预测成功因素.

当然治疗达到这个标准不是很容易的。
不错.首先:
1.需要使用强效抗病毒药物恩替卡韦或替诺福韦
2.至少几年HBVDNA检测不到

研究人员发现, 以下几点可以降低血清HBsAg水平:
1. 停止恩替卡韦或替诺福韦, ALT会上升, 重复用药;
2. 与PegIFN同时使用;
3.REP9AC，ARC520..