恩替卡韦的恩替卡韦与阿德福韦加乙肝病毒rtA181V / T单独突变

StephenW

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Antiviral efficacy of entecavir versus entecavir plus adefovir for hepatitis B virus rtA181V/T mutants alone

Myung Jin Oh1, Heon Ju Lee2
1 Department of Internal Medicine, CHA University School of Medicine, CHA Gumi Medical Center, Gumi, South Korea
2 Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, South Korea

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Date of Submission    19-Mar-2015
Date of Acceptance    12-Jun-2015
Date of Web Publication    12-Jan-2016


   Abstract         

Background/Aims: Hepatitis B virus (HBV) rtA181V/T mutants developed by long-term nucleos(t) ide analogue therapy are known to present cross-resistance for other nucleos (t) ide analogues, except entecavir (ETV). Some studies reported that HBV rtA181V/T mutants could induce cross-resistance to ETV and showed incomplete response as well as persistence of HBV DNA, despite rescue therapy by ETV. This study aimed to investigate the antiviral efficacy of ETV monotherapy and ETV plus adefovir (ADV) as rescue therapy for HBV rtA181V/T single mutation. Patients and Methods: A total of 30 patients who received ETV alone (1.0 mg/day, n = 16) or ETV plus ADV (10.0 mg/day, n = 14) over 48 weeks between April 2008 and October 2011 were enrolled. Virological, biochemical, and serological response at 48 weeks of rescue therapy were investigated retrospectively. Results: No significant difference in baseline characteristics was observed between the ETV group and the ETV plus ADV group. Virological response showed complete response (62.5 vs. 42.9%), partial response (6.3 vs. 28.6%), non-response (25.0 vs. 28.6%), and virological breakthrough (6.3 vs. 0%) in the two groups, respectively. Virological response did not statistically differ between both groups (P = 0.278). No significant difference in the mean reduction of serum HBV DNA and biochemical response was observed between both groups (4.3 ± 2.9 vs. 4.1 ± 1.8 log 10 IU/ml; P = 0.294 and 88.9 vs. 100%; P = 1.000, respectively). In addition, no significant difference in HBeAg loss or seroconversion was observed between the two groups (26.7 vs. 28.6%; P = 1.000). Conclusions: ETV monotherapy and ETV plus ADV therapy were clinically effective and comparable as rescue therapy for HBV rtA181V/T mutants alone.

Keywords: Adefovir, entecavir, hepatitis B virus, rescue therapy, rtA181V/T mutants
How to cite this article:
Oh MJ, Lee HJ. Antiviral efficacy of entecavir versus entecavir plus adefovir for hepatitis B virus rtA181V/T mutants alone. Saudi J Gastroenterol 2016;22:37-42

How to cite this URL:
Oh MJ, Lee HJ. Antiviral efficacy of entecavir versus entecavir plus adefovir for hepatitis B virus rtA181V/T mutants alone. Saudi J Gastroenterol [serial online] 2016 [cited 2016 Jan 12];22:37-42. Available from: http://www.saudijgastro.com/text.asp?2016/22/1/37/173757


Treatment of hepatitis B virus (HBV) infection has improved significantly due to development of nucleos (t) ide analogues (NA), including lamivudine (LMV), adefovir (ADV), telbivudine (LdT), clevudine (CLV), entecavir (ETV), and tenofovir (TDF). [1],[2],[3] Durable suppression of serum HBV DNA through NA therapy can prevent progression of serious HBV-related liver diseases such as cirrhosis and hepatocellular carcinoma. [4],[5] However, treatment of HBV infection with NA has a fatal weakness in that NA cannot remove covalently closed circular DNA in the nucleus of infected hepatocytes and the rate of virological relapse is high when NA therapy is discontinued. [6] Consequently, an indefinite therapeutic duration is essential in NA therapy for chronic hepatitis B. Prolonged treatment with NA inevitably results in development of drug resistance mutation, although it is rare in ETV or TDF therapy. [7],[8]

Of NA-related HBV mutants, HBV rtA181V/T mutants develop as a result of mutation of the HBV reverse transcriptase gene at position 181, where an alanine (A) is substituted with a valine (V) or threonine (T). HBV rtA181V/T mutants have been reported in chronic hepatitis B patients who received antiviral treatment with LMV, ADV, LdT, or CLV, and have been known to present cross-resistance against other NA, except ETV. [9],[10],[11] Thus, ETV with high susceptibility in vitro has been used primarily as rescue therapy for HBV rtA181V/T mutants. [12] However, some studies reported that HBV rtA181V/T mutants could even induce cross-resistance to ETV. [13],[14] In practice, a clinical investigation reported that HBV rtA181V/T mutants might present persistence of HBV DNA and showed an association with incomplete response, despite rescue therapy by ETV. [15]

In general, the majority of HBV rtA181V/T mutants are known to be induced after ADV therapy, along with the rtN236T mutant. Many guidelines published in Korea, the United States, and Europe recommend ETV plus TDF (or ADV if TDF is unavailable) as rescue therapy for HBV rtA181V/T mutants. [1],[2],[3] However, there is no specific therapeutic recommendation or clinical study on HBV rtA181V/T single mutation. Thus, antiviral therapy should be determined to support the decision on which rescue therapy, add-on therapy with ETV or switch to ETV monotherapy, is to be applied in patients who received prior ADV therapy for HBV rtA181V/T mutants alone. In other words, the aim of this study is to investigate the antiviral efficacy of ETV alone and in combination with ADV for HBV rtA181V/T single mutation.


   Discussion         Top


Development of NA with a high genetic barrier, such as ETV and TDF, has revolutionized our ideas regarding treatment of HBV. The optimal therapeutic goal or complete suppression of HBV DNA can be achieved in many CHB patients through ETV or TDF therapy. However, NA used prior to the introduction of ETV or TDF can hardly be free from the problem of development of drug resistance related to long-term medication. Above all, the emergence of cross-resistance or multidrug resistance of HBV can be more problematic due to sequential monotherapy for treatment of chronic hepatitis B. [11],[16],[17] Cross-resistance of HBV, including HBV rtA181V/T mutants, can result in development of serious liver-related diseases such as hepatic failure or progression to liver disease. [11],[15],[18],[19] HBV rtA181V/T mutants are more important in practice because a single mutation can confer multidrug resistance against the L-nucleoside LMV, CLV, and LdT, as well as the alkyl phosphonates ADV and TDF. [10],[11],[12] As a result, the standard of care for HBV rtA181V/T mutants has not been established and clinical evidence of optimal treatment for HBV rtA181V/T mutants is also lacking. Although many authorized guidelines have recommended the combination therapy of a nucleoside and a nucleotide analogue for multidrug resistance of HBV, the efficacy has not been confirmed in practice. [1],[2],[3] Thus, to the best of our knowledge, this research appears to be valuable as it provides rare clinical evidence of treatment of HBV rtA181V/T mutants alone.

In this study, all therapeutic responses of HBV rtA181V/T mutants alone, including decline of serum HBV DNA, virological, biochemical, and serological responses did not differ significantly between the ETV monotherapy group and the ETV plus ADV group (P > 0.05). In addition, a study on multidrug resistance of HBV reported a similar result showing that antiviral efficacy of ETV plus ADV combination therapy was not clinically superior to that of ETV monotherapy. [20]

In our study, virological breakthrough occurred in one patient belonging to the ETV monotherapy group. The patient had received CLV therapy prior to detection of the HBV rtA181V mutant. ETV alone was administered as rescue therapy for the HBV rtA181V mutant. Reduction of serum HBV DNA by more than 2 log 10 IU/ml was observed at 24 weeks. However, virological breakthrough occurred at 48 weeks. At 48 weeks, sequencing analysis for the reverse transcriptase gene of HBV was performed in order to detect the cause of the virological breakthrough. Newly developed HBV rtM204I and rtP237H mutants were detected, and the pre-existing HBV rtA181V mutant disappeared completely through rescue therapy. The patient received ETV plus TDF combination therapy after the introduction of TDF in Korea, and partial virological response has been shown. Although liver failure or serious complications related to HBV did not happen, occurrence of virological breakthrough by ETV monotherapy might be problematic. The appearance of mutations other than HBV rtA181V/T mutants in this case may be associated with sequential antiviral monotherapy, as mentioned above, and is a problem to be solved before agreement on use of ETV monotherapy for HBV rtA181V/T mutants.

In our study, the mean duration of previous antiviral therapy prior to rescue therapy was longer in patients of the ETV plus ADV group. The reason may be associated with the fact that physicians are concerned about the increased risk of development of drug resistance to HBV according to therapeutic duration. [2] Therefore, there was a high probability of intentional selection of ADV combination therapy. However, no statistically significant difference in therapeutic results was observed between the methods of rescue therapy. In addition, although there was no statistical significance, more ADV-experienced patients were recruited in the ETV plus ADV group. It seemed that more add-on therapy with ETV was intentionally selected in the patients who received prior ADV therapy.

Response to antiviral therapy differed according to genotype. [21] A recent study reported that drug susceptibility of HBV rtA181V/T mutants was different, and the difference might be explained by a difference in HBV genotypes. [12] In addition, an investigation conducted in China reported that the genotype-dependent polymorphism feature of HBV reverse transcriptase sequences in treatment-naïve chronic hepatitis B patients would be an important basis for understanding evolution of NA resistance. [22] As a result, the antiviral efficacy of ETV or ETV plus ADV as rescue therapy for HBV rtA181V/T mutants may be related to the genotypes of HBV. However, the genotypes of HBV in most Korean patients were known to be genotype C2; therefore, in this study, HBV genotypes of the enrolled patients were not investigated. [23] Consequently, there is a limitation to application of our results for other genotypes of HBV, except for the predominant genotype C in Korea. Clinical researches for rescue therapy for HBV rtA181V/T mutants should be performed considering the discrepancy in genotypes of HBV.

There were some limitations in this study. This research was conducted retrospectively, with an insufficient number of subjects. Thus, there might be a limitation of selection bias. In addition, the duration of rescue therapy was relatively short term. The outcomes can change through a longer follow-up period. After rescue therapy for rtA181V/T mutants alone, newly developed mutants or disappearance of HBV rtA181V/T mutants were not evaluated in total. Finally, TDF, which is known to be a potent HBV inhibitor with a higher barrier to resistance, has recently been used in Korea. [24],[25] As a substitute of ADV, antiviral efficacy of TDF for HBV rtA181V/T mutants is still unclear in practice. Further investigation of rescue therapy, including TDF, for HBV rtA181V/T mutants alone will be necessary.


   Conclusion         Top


In conclusion, findings of this study demonstrated that ETV monotherapy and ETV plus ADV therapy were clinically effective and comparable as rescue therapy for HBV rtA181V/T mutants alone. However, occurrence of virological breakthrough by ETV monotherapy may be problematic. Large-scale, long-term studies of rescue therapy for HBV rtA181V/T mutants alone should be conducted, and therapeutic plans for achievement of further antiviral efficacy for HBV rtA181V/T mutants alone should be established and recommended.

StephenW

恩替卡韦的恩替卡韦与阿德福韦加乙肝病毒rtA181V / T单独突变体的抗病毒疗效

明金OH1，宪菊Lee2
内科，CHA大学医学院，CHA龟尾医疗中心，龟尾，韩国1系
内科，医学岭南大学，大邱，韩国2部

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提交日期19-MAR-2015
验收之日起12军，2015年
网络出版的12月 - 2016年的日期


   抽象

背景/目的：乙型肝炎病毒（HBV）rtA181V /长期核苷开发Ť突变体（t）的IDE类似物治疗是已知呈现交叉抗性对于其它核苷（酸）类似物，除了恩替卡韦（ETV）。有研究报告说，乙肝病毒rtA181V / T突变可引起交叉耐药性ETV，显示不完整的响应以及HBV DNA的持续存在，尽管抢救治疗用ETV。本研究旨在探讨ETV单药及ETV加上阿德福韦（ADV）作为抢救治疗乙肝病毒rtA181V / T单突变的抗病毒疗效。患者与方法：一共有谁收到单纯ETV 30例（1.0毫克/天，n = 16）或ETV加ADV（10.0毫克/天，n = 14）48周以上2008年4月和2011年10月之间的患者。病毒学，生化，并在48周抢救治疗的血清学反应进行回顾性调查。结果：恩替卡韦组和ETV加ADV组比较，观察基线特征没有显著差异。病毒学应答显示，在两个组完全缓解（62.5对42.9％），部分应答（6.3对28.6％），不答复（25.0对28.6％），和病毒学突破（6.3对0％），分别。病毒学应答没有统计学上两组（P = 0.278）之间的差异。两组之间观察到在平均减少的血清HBV DNA和生化反应无显著差异（4.3±2.9与4.1±1.8日志10国际单位/毫升; P = 0.294和88.9与100％，P = 1.000，分别） 。此外，两组（; P = 1.000 26.7与28.​​6％）之间，观察HBeAg转阴或血清学转换没有显著差异。结论：ETV单药及ETV加ADV治疗是临床上有效的，可比的抢救治疗单独的HBV rtA181V / T突变。

关键词：阿德福韦，恩替卡韦，乙型肝炎病毒，抢救治疗，rtA181V / T突变
如何引用这​​篇文章：
哦，MJ，李HJ。恩替卡韦的恩替卡韦与阿德福韦加单独乙型肝炎病毒rtA181V / T突变体抗病毒的功效。沙特ĴGastroenterol 2016年; 22：37-42

如何引用本网址：
哦，MJ，李HJ。恩替卡韦的恩替卡韦与阿德福韦加单独乙型肝炎病毒rtA181V / T突变体抗病毒的功效。沙特ĴGastroenterol [串行在线] 2016年[引用2016年1月12日]; 22：37-42。可从：http://www.saudijgastro.com/text.asp?2016/22/1/37/173757


乙型肝炎病毒（HBV）感染的治疗已显著由于核苷（酸）类似物（NA），包括拉米夫定（LMV），阿德福韦（ADV），替比夫定（LDT），克立夫定（CLV），恩替卡韦发展改善（ETV ），和替诺福韦（TDF）。 [1]，[2]，血清HBV DNA的[3]通过NA疗法耐用抑制可预防严重HBV相关的肝疾病，如肝硬化和肝细胞癌发展。 [4]，[5]然而，治疗HBV感染的带NA有一个致命的弱点在于NA不能在感染的肝细胞的细胞核和病毒学复发率除去共价闭合​​环状DNA是高时NA治疗被中断。 [6]因此，不确定的治疗持续时间是在NA治疗慢性乙型肝炎长时间治疗用NA不可避免地导致抗药性突变的发展至关重要，尽管它是罕见的ETV或TDF疗法。 [7]，[8]

NA有关的HBV变异株的，乙型肝炎病毒rtA181V / T突变体开发为HBV逆转录酶基因的突变的，其中在一个丙氨酸（A）取代为缬氨酸（V）或苏氨酸（T），位置181，一个结果。乙肝病毒rtA181V / T突变体已报道谁接受抗病毒治疗与LMV，ADV，LDT，或CLV的慢性乙肝患者，并已经知道存在交叉耐药性对其他NA，除了ETV。 [9]，[10]，[11]因此，ETV具有高敏感性体外已被主要用作救援治疗的HBV rtA181V / T突变体。 [12]然而，一些研究报告说，乙肝病毒rtA181V / T突变体甚至可能诱导交叉耐药性ETV。 [13]，[14]在实践中，临床调查报告说，乙肝病毒rtA181V / T突变可能出现HBV DNA的持续存在并呈关联不完整的响应，尽管抢救治疗用ETV。 [15]

在一般情况下，大多数的HBV rtA181V / T突变体是已知ADV治疗之后被诱导，伴随着rtN236T突变体。发表在韩国，美国和欧洲的许多指南推荐ETV加TDF（或ADV如果TDF是不可用）作为抢救治疗乙肝病毒rtA181V / T突变。 [1]，[2]，[3]然而，存在对HBV rtA181V / T单突变没有具体的治疗建议或临床研究。因此，抗病毒治疗要下决心支持决定哪些抢救治疗，添加治疗恩替卡韦或改用恩替卡韦单药治疗，是谁收到事先ADV治疗HBV单独rtA181V / T突变的患者得到应用。换句话说，本研究的目的是单独和与ADV乙肝rtA181V / T单突变的组合，调查ETV的抗病毒效力。


   讨论顶部


NA开发具有高基因屏障，如ETV和TDF，彻底改变了我们对治疗乙肝的想法。最佳的治疗目标或HBV DNA的完全抑制可以在许多慢性乙肝患者通过ETV或TDF治疗来实现。然而，NA用于引入ETV或TDF之前很难不受药物抗性相关的长期服药的发展的问题。首先，交叉耐药性或HBV的多药耐药性的出现，可以是更多的问题，由于连续的单一疗法用于治疗慢性乙型肝炎的[11]，[16]，[17]的交叉耐药的HBV，包括HBV rtA181V / Ť突变体，可导致严重的肝脏相关疾病，如肝衰竭或进展到肝脏疾病的发展。 [11]，[15]，[18]，[19]的HBV rtA181V / T突变体是在实践中更重要，因为一个单突变可以赋予针对的L-核苷LMV，CLV和LDT多药耐药，以及烷基膦酸盐ADV和TDF。 [10]，[11]，[12]其结果，护理乙肝rtA181V / T突变体的标准尚未建立和乙肝rtA181V / T突变体最佳治疗的临床证据也缺乏。虽然许多授权的指引建议核苷和乙肝病毒耐药核苷酸类似物的联合治疗，疗效还没有得到证实的做法。 [1]，[2]，[3]因此，为了在我们所知，本研究似乎是有价值的，因为它提供了治疗单独的HBV rtA181V / T突变的罕见临床证据。

在这项研究中，单纯乙肝病毒rtA181V / T突变，包括下降的血清HBV DNA，病毒学，生物化学和血清学应答所有治疗的反应并没有显著的ETV单药治疗组和ETV加ADV组（P> 0.05）之间的差异。此外，对HBV的多药耐药性的一项研究报道了类似的结果显示，ETV加ADV组合疗法抗病毒药疗效没有临床优于ETV单一治疗。 [20]

在我们的研究中，病毒学突破发生在一个病人属于ETV单药治疗组。该患者曾接受CLV治疗前检测乙肝病毒rtA181V突变。 ETV单独管理作为抢救治疗的乙肝病毒rtA181V突变。观察到在24周超过2日志10国际单位/毫升降低血清HBV DNA。然而，病毒学突破发生在48周。在第48周时，为了检测的病毒学突破的原因进行了测序分析乙肝病毒的逆转录酶基因。新开发的HBV rtM204I和检出rtP237H突变体，和预先存在的HBV rtA181V突变完全消失通过抢救治疗。患者接受ETV加TDF组合疗法在韩国采用的TDF后，和部分病毒学应答已被证明。虽然肝功能衰竭或与乙肝病毒严重并发症没有发生，发生病毒学突破，ETV单药治疗可能会出现问题。突变比HBV rtA181V / T突变体另外在此情况下的外观可能与序贯抗病毒药单一疗法相关联，如上所述，是一个问题之前就使用ETV单一疗法用于HBV rtA181V / T突变体的协议来解决。

在我们的研究中，指的是ETV加ADV组患者抢救治疗是延长现有在以往的抗病毒治疗的持续时间。其原因可能的事实，医生担心耐药性发展的风险增加对HBV根据治疗的持续时间相关联。 [2]因此，存在故意选择ADV联合治疗的高概率。然而，抢救治疗的方法之间，观察治疗效果无统计学差异显著。此外，虽然没有统计学意义，更多的ADV经验的患者被招募的ETV加ADV小组。它似乎更多的附加治疗ETV谁收到事先ADV治疗的患者是故意选择。

根据基因型响应于抗病毒疗法的不同。 [21]最近的一项研究报告指出，乙肝病毒rtA181V / T突变体药物的敏感性不同，且差异可能是由乙肝病毒基因型的差异来解释。 [12]另外，在中国进行的一项调查报告说，乙肝病毒逆转录酶序列的初治慢性乙肝患者的基因型依赖多态性的功能将是理解NA抗性演化的重要依据。 [22]这样一来，ETV教育电视或的抗病毒疗效加ADV的抢救治疗乙肝病毒rtA181V / T突变可能与乙肝病毒的基因型。然而，乙肝病毒在大多数韩国患者的基因型已知基因型C2;因此，在此研究中，已登记​​的患者的HBV的基因型没有调查。 [23]因此，存在一个限制申请的我们的结果对其他基因型的HBV的，除了在韩国主要基因型℃。临床研究抢救治疗HBV rtA181V / T突变体应进行考虑HBV基因型的差异。

有在这项研究中的一些限制。这项研究进行回顾，以学科数量不足。因此，有可能是选择偏倚的限制。此外，抢救治疗的持续时间是相对短期的。该成果可通过长期随访期间改变。抢救治疗单独rtA181V / T突变，新开发的突变体或HBV rtA181V消失后/ T突变株在总未评估。最后，TDF，这是已知的一种有效的HBV抑制剂具有较高屏障性，最近已应用在韩国。 [24]，[25]如ADV，TDF的乙肝病毒rtA181V / T突变体的抗病毒疗效的替代品目前还不清楚在实践中。抢救治疗的进一步调查，包括TDF，乙肝病毒rtA181V / T突变体本身将是必要的。


   结论顶部


总之，本研究的结果表明，ETV单药及ETV加ADV治疗是临床上有效的，可比的抢救治疗单独的HBV rtA181V / T突变。然而，发生的病毒学突破由ETV单一疗法可能会有问题。大型，抢救治疗单独的HBV rtA181V / T突变体的长期研究应进行，并为实现进一步的抗病毒疗效单独HBV rtA181V / T突变体的治疗方案应建立和建议。