恩替卡韦治疗初治慢性乙肝患者的全国人群在美国安全性和

StephenW

Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US – the ENUMERATE study

    J. Ahn1,*, H. M. Lee2, J. K. Lim3, C. Q. Pan4, M. H. Nguyen5, W. Ray Kim5, A. Mannalithara5, H. Trinh6, D. Chu7, T. Tran8, A. Min9, S. Do10, H. Te11, K. R. Reddy12 andA. S. Lok13

Article first published online: 28 OCT 2015

DOI: 10.1111/apt.13440

© 2015 John Wiley & Sons Ltd

Issue
Alimentary Pharmacology & Therapeutics
Alimentary Pharmacology & Therapeutics

Volume 43, Issue 1, pages 134–144, January 2016
Article has an altmetric score of 1


    1    Division of Gastroenterology & Hepatology, Oregon Health & Science University, Portland, OR, USA
    2    Gastroenterology/Hepatology Division, Tufts Medical Center, Boston, MA, USA
    3    Digestive Diseases, Yale University, New Haven, CT, USA
    4    Department of Medicine, NYU Langone, New York, NY, USA
    5    Division of Gastroenterology & Hepatology, Stanford University, Stanford, CA, USA
    6    San Jose Gastroenterology, San Jose, CA, USA
    7    Albert Einstein College of Medicine, New York, NY, USA
    8    Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
    9    Division of Gastroenterology, Mount Sinai Beth Israel, New York, NY, USA
    10    Digestive Health Associates of Texas, Plano, TX, USA
    11    Digestive Disease Center, University of Chicago, Chicago, IL, USA
    12    Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
    13    Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA

* Correspondence to:
Dr Joseph Ahn, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L-461, Portland, OR 97239, USA.
E-mail: [email protected]

    This article was accepted for publication after full peer-review.


Summary
Background

Entecavir (ETV) has been shown to be safe and efficacious in randomised controlled trials in highly selected patients with hepatitis B virus (HBV) infection.
Aim

To determine the safety and effectiveness of ETV in ‘real-world’ HBV patients in the United States (US).
Methods

Treatment-naïve HBV patients ≥18 years old who received ETV for ≥12 months between 2005 and 2013 were included in a retrospective, cohort study. Rates of ALT normalisation, undetectable HBV DNA, HBeAg and HBsAg loss/seroconversion, adverse events (AE) and clinical outcomes were evaluated.
Results

Of 841 patients, 658 [65% male, 83% Asian; median age 47 years] met the inclusion criteria. 36% were HBeAg+ and 9.3% cirrhotic. 89% had abnormal ALT. Baseline median HBV DNA was 5.8 log 10 IU/mL. Median duration of ETV treatment was 4 years. Rates of ALT normalisation at 1, 3 and 5 years were 37.2%, 48.7% and 56.2% in HBeAg+ and 39.6%, 46.8% and 55.6% in HBeAg- patients. HBV DNA was undetectable at 1, 3 and 5 years in 34.6%, 64.7% and 84.6% in HBeAg+ patients, and 81.9%, 90.3% and 96.2% in HBeAg patients. Five-year cumulative probability of HBeAg loss and seroconversion was 46% and 33.7% and HBsAg loss was 4.6%. ETV was discontinued due to adverse events in 1.2% of patients. Hepatic decompensation occurred in 0.8%, liver cancer in 2.7% and death in 0.6%.
Conclusion

Entecavir treatment was safe in a large cohort of US patients, but ALT normalisation and hepatitis B virus DNA suppression rates were lower than previously reported in clinical trials.

Introduction
Entecavir (ETV) is a cyclopentyl guanosine analogue, with potent activity against the hepatitis B virus (HBV) DNA polymerase. In 2005, the US Food and Drug Administration (FDA) approved ETV for the treatment of HBV based on randomised controlled trials demonstrating efficacy and safety in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients that met entry criteria for those trials. These trials showed HBV DNA undetectable rates of 67%, alanine aminotransferase (ALT) normalisation rates of 68%, and HBeAg seroconversion rates of 21% after 1 year of treatment in HBeAg-positive patients.[1] For HBeAg-negative patients, HBV DNA undetectable rates were 90% and ALT normalisation rates were 78% at the end of 1 year of ETV treatment.[2] Subsequent rollover studies provided further follow-up data with undetectable HBV DNA in 94%, ALT normalisation in 80%, an additional HBeAg seroconversion in 23%, and hepatitis B surface antigen (HBsAg) loss in 1.4% of HBeAg-positive patients by year 5.[3] Follow-up data beyond year 1 for HBeAg-negative patients are less clear, as many of these patients had gaps in ETV treatment after year 1.[4] Overall, these studies confirmed long-term safety and a low rate of genotypic anti-viral resistance among nucleoside naïve patients of 1.2% at 6 years.[3, 5, 6]

Due to trial design, the majority of subjects in these Phase III trials had discontinuation or interruption of ETV after the first year.[1-3] Thus, the trial design does not allow assessment of the outcomes of continuous treatment with ETV at the approved dose of 0.5 mg daily. The need for confirmation of the efficacy and safety of continuous ETV treatment at the standard dose, along with growing awareness regarding the distinction between clinical trial efficacy and ‘real-world’ effectiveness led to studies of ETV treatment outcomes in clinical practice.[7-9] There have been several reports, mainly from Asia, showing variable effectiveness among patients treated with ETV in clinical practice attributed to enrolment of a more heterogeneous population as well as the challenges of supporting patients’ compliance to long-term treatment in the ‘real-world’.[10-17] However, there are limited data regarding the effectiveness and safety of ETV in the
US.[18, 19] We aimed to determine the safety and effectiveness of ETV in ‘real-world’ practice settings in the US.

Discussion
ENUMERATE is the largest US ‘real-world’ study of ETV treatment with 658 patients from 26 centers showing that ETV is safe and effective at HBV DNA suppression, ALT normalisation and HBeAg seroconversion. These patients were predominantly foreign-born (61%), Asians (83%), HBeAg negative (64%), with a relatively low baseline ALT (60 U/L) and HBV DNA level (5.8 log 10 IU/mL). Although 61 (9.3%) patients had cirrhosis at baseline, only five patients developed new hepatic decompensation and only two died due to liver-related causes during a median follow-up of 4 years. Eighteen patients were diagnosed with HCC including 10 who did not have cirrhosis at baseline. As liver biopsies or noninvasive assessments of cirrhosis were not routinely performed at the start of treatment, it is possible that some of these 10 patients may have had compensated cirrhosis that was not recognised. Given the small number of HCC cases, no clear relationship between HBV DNA suppression and the diagnosis of HCC can be concluded although it is of interest that undetectable HBV DNA was not protective against the subsequent development of HCC.

ALT normalisation rates at 1 year were 65.9% for HBeAg-positive and 72.8% for HBeAg-negative patients, similar to that reported in Phase III studies of 68% and 78%, respectively [1, 2] when a traditional cut-off of 40 U/L was used to define ‘normal” ALT, but significantly lower, 37.2% for HBeAg-positive patients and 39.6% for HBeAg-negative patients, when cut-offs of 30 U/L for men and 19 U/L for women were used. The possibility that concomitant liver disease such as alcoholic or nonalcoholic fatty liver disease, hepatitis C or hepatitis D could have contributed to the lower ALT normalisation rates cannot be excluded as the study design did not systematically record alcohol use or require baseline viral hepatitis C, hepatitis D or HIV testing or protocol liver biopsies. Undetectable HBV DNA rates at 1 year were lower in our study, 34.6% for HBeAg-positive and 81.9% for HBeAg-negative patients compared to 67% and 90%, respectively in Phase III trials. HBeAg seroconversion rate at 1 year was also lower in our study, 8.9% compared to 21% in the Phase III trial. These lower rates of response may reflect the difference between clinical trials that enrolled selected patients who were provided free medications and monitored closely and effectiveness observations in “real-world” settings enroling a more heterogeneous, potentially less-adherent patient pool with a wider possible range of comorbidities and demographics.

Similar to the Phase III trials, serious adverse events were rare and only eight (1.2%) patients required dose reduction or treatment discontinuation due to adverse events. However, overall changes in dose and treatment discontinuations were common. Of note, 8.1% of patients had increase in dose of ETV from 0.5 to 1.0 mg/day, mostly due to persis'tent viraemia. Virological breakthroughs were observed in only four (0.6%) patients though none were tested for genotypic resistance. Treatment was switched to tenofovir in two patients and ETV dose was increased in the other two patients.

ETV-related lactic acidosis was reported in five patients with decompensated cirrhosis but lactic acidosis was not observed in two prospective studies of ETV in patients with decompensated cirrhosis.[22-25] Two patients in our study who did not have baseline cirrhosis and did not progress to hepatic decompensation, developed nonfatal lactic acidosis. Both had ETV dose increase to 1.0 mg/day and were ambulatory patients with normal creatinine and bilirubin at the time of presentation with lactic acidosis. Neither required hospital admission. Both patients had no recurrence of symptoms after discontinuation of ETV and substitution with another anti-viral agent.

Results from other ‘real-world’ cohorts with chronic HBV who received ETV treatment are summarised in Table 3. Most of these were retrospective, single center studies with small sample size and short duration of follow-up, and variable response rates. The largest study to date was a subgroup analysis of 1663 (29% HBeAg-negative) Chinese patients showing a 1-year rate of undetectable HBV DNA of 60%, ALT normalisation of 87% and HBeAg seroconversion rate of 15% in HBV treatment-naïve patients; there were no significant adverse events.[12] Several multi-center studies from Europe reported similar results.[26, 27] An Italian multicenter study of 418 patients (83% HBeAg-negative, 49% cirrhotic) found that by year 5, 100% of both HBeAg-positive and HBeAg-negative patients had undetectable HBV DNA, 52% had HBeAg seroconversion and 33% had HBsAg loss.[28] The high rate of HBsAg loss in this study has not been observed in other studies. We observed lower rates of ALT normalisation when using the more stringent normal ALT cut-off of 30 for men and 19 for women, and undetectable HBV DNA compared to other ‘real-world’ studies. Our patients were predominantly Asian but our response rates remained lower even when compared to other studies from Asia.
The limitations of this study are inherent in its retrospective study design. The lack of a standardised monitoring protocol may have led to underreporting of adverse events or clinical outcomes. Laboratory tests were performed locally, which could have influenced our assessment of virological response. Nevertheless, the lower limits of detection of HBV DNA assays were fairly similar throughout the sites as all sites used PCR assays with detection limits between 10 and 400 IU/mL. The types and frequency of other laboratory tests varied widely across sites, and contributed to the exclusion of 166 patients due to incomplete baseline laboratory data. Our study included both university and community sites, and therefore reflects inherent ‘real-world’ variation in practice patterns, which differ significantly from standardised clinical trial protocols.

The potential weaknesses of the study such as allowing inclusion of a more heterogeneous pool of patients who would not qualify for Phase III studies e.g. patients who had normal ALT or low HBV DNA at baseline or those who were initiated on a higher ETV dose of 1.0 mg daily can be its strength as it can better reflect the ‘real-world’ practice of HBV treatment. The strengths of this study are its robust sample size, diverse mix of patients from university and community settings from different geographical regions of the US, and long-term follow-up of the cohort. We observed a high rate of treatment discontinuation, which did not appear to be attributable to treatment failure or provider recommendation, and likely reflect ‘real-world’ challenges in maintaining patients on long-term HBV treatment.

In summary, our study of a large cohort of ‘real-world’ patients who received ETV for chronic hepatitis B in the US demonstrated safety and long-term effectiveness despite a heterogeneous patient population and challenges in ensuring adherence to ETV and follow-up in clinical practice.

StephenW

在列举的研究 - 恩替卡韦治疗初治慢性乙肝患者的全国人群在美国安全性和有效性

    J. Ahn1，*，HM Lee2，JK Lim3，CQ Pan4，MH Nguyen5，W·雷Kim5，A Mannalithara5，H Trinh6，D Chu7，T Tran8，A Min9，S. DO10，H TE11 ，KR Reddy12和A。 S. Lok13

文章首次在网上公布：2015年10月28日

DOI：10.1111 / apt.13440

©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43卷第1期，页134-144，2016年一月
文章的altmetric比分1


    肠胃病学和肝脏，俄勒冈健康与科学大学，俄勒冈州波特兰，美国1部
    2胃肠/肝病科，塔夫茨医学中心，波士顿，MA，USA
    3消化系统疾病，耶鲁大学，纽黑文，CT，USA
    医药，NYU朗格尼，纽约，纽约州，美国的4部
    肠胃病学和肝脏，斯坦福大学，斯坦福大学，加州，美国的5部
    6圣何塞消化内科，圣何塞，CA，USA
    医药，纽约，美国7爱因斯坦医学院
    医药，雪松Sinai医疗中心，洛杉矶，加州，美国的8部
    消化内科，西奈山贝斯以色列，纽约州，纽约州，美国9处
    得克萨斯州，普莱诺，德克萨斯州，美国10消化系统健康协会
    11消化系统疾病中心，芝加哥大学，芝加哥，伊利诺伊州，美国
    12科胃肠病学和肝病，宾夕法尼亚大学，费城，宾夕法尼亚州，美国
    13科胃肠病学和肝病，密歇根大学安娜堡分校，密歇根，美国

*通讯作者：
博士约瑟夫·安，俄勒冈健康与科学大学，3181 SW山姆杰克逊公园路，L-461，波特兰，俄勒冈97239，USA。
电子信箱：[email protected]

    这篇文章被接受后满同行评审的出版物。


概要
背景

恩替卡韦（ETV）已被证明是安全和有效的在高度选择的患者的乙型肝炎病毒（HBV）感染的随机对照试验。
目的

要确定在“现实世界”乙肝患者在美国（US）ETV的安全性和有效性。
方法

初治乙肝患者≥18岁，谁获得ETV为2005年至2013年间≥12个月被列入一个回顾性队列研究。 ALT复常，检测不到HBV DNA，HBeAg和HBsAg消失/血清学转换，不良事件（AE）和临床结果的发生率进行了评价。
结果

841名患者中，658 [65％为男性，83％为亚裔;平均年龄47岁]符合纳入标准。 36％为HBeAg +和9.3％的肝硬化。 89％的患者ALT异常。基线平均HBV DNA为5.8日志10 IU / mL的。 ETV治疗的时间中位数为4年。在1,3和5年的ALT正常化率分别为37.2％，48.7％和HBeAg的+和39.6％56.2％，46.8％和在个HBeAg-患者55.6％。 HBV DNA检测不到在1,3和5年在34.6％，64.7％和e抗原阳性患者84.6％，和81.9％，90.3％和HBeAg的患者为96.2％。 HBeAg消失和血清学转换五年累计概率为46％，33.7％和HBsAg消失率为4.6％。 ETV被中断，由于在患者的1.2％的不良事件。肝功能失代偿发生在0.8％，肝癌2.7％，死亡0.6％。
结论

恩替卡韦治疗是安全的，美国患者的大型队列，但ALT复常和乙肝病毒DNA抑制率低于先前的临床试验报告。

介绍
恩替卡韦（ETV）是环戊鸟苷类似物，用抗乙型肝炎病毒（HBV）DNA聚合酶的有效活性。 2005年，美国食品和药物管理局（FDA）批准ETV乙肝病毒的基础上的随机对照试验证实疗效和安全性乙型肝炎e抗原（HBeAg）阳性和HBeAg阴性患者能够满足入门标准，这些试验的治疗。这些试验表明HBV DNA的67％，丙氨酸氨基转移酶（ALT）的68％归一化率和21％治疗1年的HBeAg阳性患者后HBeAg血清学转换率检测不到率。[1]对于HBeAg阴性患者，HBV DNA检测不到率分别为90％和ALT复常率分别为78％，1年ETV治疗的结束。[2]提供了进一步的数据跟踪与检测不到HBV DNA在94％，80％，ALT复常，在随后侧翻研究另外HBeAg血清转换在23％以上，乙肝表面抗原（HBsAg）损失HBeAg阳性患者的1.4％到今年5 [3]超过1年随访数据，HBeAg阴性患者都不太清楚，因为许多这些患者在治疗ETV间隙年后1 [4]总的来说，这些研究证实长期安全和之间的1.2％的核苷初治患者基因型的抗病毒抗性在6年率低。[3，5,6 ]

由于试验设计中，大多数受试者在这些III期临床试验不得不中止ETV或中断后的第一年。[1-3]。因此，试验设计不允许连续治疗的效果的评估，ETV在批准剂量为0.5毫克，每天。需要确认的有效性和持续ETV治疗安全性的标准剂量，以及关于临床试验的疗效和区分“真实世界”的有效性导致ETV治疗结果的临床实践研究越来越认识的。[7- 9]已经有一些报道，主要来自亚洲，显示出其中恩替卡韦在归因于更多的异构人口入学率，以及支持患者符合长期治疗的“真正的挑战临床实践治疗的患者变量的有效性 - 世界'。[10月17日]然而，存在关于ETV在有效性和安全性的数据有限
美国[18，19]我们的目的是确定教育电视在美国的真实世界的实践设置的安全性和有效性。

讨论
列举为ETV治疗的658例患者来自26个中心显示，ETV是安全有效的HBV DNA抑制，ALT复常和HBeAg血清学转换的美国最大的“真实世界”的研究。这些患者主要是外国出生的（61％），亚洲（83％），HBeAg阴性（64％），与相对较低的基线ALT（60 U / L）和HBV DNA水平（5.8日志10国际单位/毫升）。尽管61（9.3％）的患者有肝硬化的基础，只有五名病人制定了新的肝功能失代偿和仅有的两个在平均随访4年因肝有关的原因死亡。 18例被确诊为肝癌，包括10谁没有在基线有肝硬化。作为肝活检或肝硬化的非侵入性的评估是未常规于治疗开始进行的，它是可能的一些这10例患者的可能有该未识别代偿性肝硬化。鉴于少数肝癌病例，HBV DNA抑制和肝癌的诊断之间没有明确的关系可以得出结论：尽管它是利益是检测不到的HBV DNA是不是能预防肝癌的后续发展。

ALT复常率1年是HBeAg阳性和72.8％，对HBeAg阴性患者，类似​​于相报的分别为68％和78％，III期研究65.9％[1，2]当传统的停产40 U / L来定义“正常”ALT，但显著降低，37.2％的HBeAg阳性患者和HBeAg阴性患者39.6％，当临界值30 U / L的男性和19 U / L为妇女使用。该伴随肝病如酒精性或非酒精性脂肪肝疾病，丙型肝炎或丁型肝炎可能在下部ALT正常化率起作用的可能性不能排除作为研究设计并没有系统地记录酒精使用，或需要的基线病毒性丙型肝炎，肝炎D或艾滋病病毒检测或协议肝活检。在1年时检测不到HBV DNA率较低在我们的研究中，HBeAg阳性和81.9％，对HBeAg阴性患者相比，67％和90％，分别为III期临床试验34.6％。 HBeAg血清转换率，1年也低于我们的研究中，8.9％相比，在III期临床试验的21％。回应这些较低的利率可能反映了临床试验的区别是参加谁是提供免费药物治疗和密切监测和效果的观察中的“真实世界”的设置enroling更异类，可能不太粘附患者提供更广泛的可能范围池中选择的患者的合并症和人口统计数据。

类似的III期临床试验，严重不良事件是罕见的，只有八（1.2％）的患者需要减量或停药由于不良事件。不过，在剂量和疗程停药总体变化是常见的。值得注意的是，患者的8.1％有增加ETV的剂量为0.5至1.0mg /天，主要是由于persis'tent病毒血症。病毒学突破，只有四个（0.6％）的患者进行观察，虽然没有进行测试的基因型耐药。处理被切换到替诺福韦在两个病人和ETV剂量在另外两个患者中增加。

ETV相关的乳酸性酸中毒报道5例失代偿期肝硬化，但乳酸性酸中毒未在ETV两个前瞻性研究观察患者的失代偿期肝硬化。[22-25]两个病人在我们的研究中谁没有基线肝硬化和没有进展肝功能失代偿，研发非致命性乳酸性酸中毒。两人都ETV剂量增加至1.0毫克/天，分别为卧床患者的正常肌酐和胆红素的表现与乳酸性酸中毒的时间。既不要求入院。这两名患者没有症状复发教育电视的停产和替代与另一种抗病毒制剂之后。

结果从慢性乙肝病毒等“真实世界”队列谁收到ETV治疗总结在表3中。这些大多是回顾性的，单中心研究，小样本大小和随访持续时间短，和可变的反应率。最大的研究，以日为1663（29％HBeAg阴性）的亚组分析中国患者呈现出1年期利率的检测不到HBV DNA的60％，87％，ALT复常和15％的乙肝病毒e抗原血清转换率处理 - 初治患者;没有显著的不良事件。来自欧洲的[12]有几个多中心研究报道了相似的结果。[26，27] 418例（83％HBeAg阴性，49％的肝硬化）的意大利多中心研究发现，5年， HBeAg阳性和HBeAg阴性患者的100％，未检出HBV DNA，52％的患者HBeAg血清学转换，33％的患者HBsAg转阴。[28] HBsAg消失在这项研究中高速率尚未在其他研究中观察到。我们使用相比其他'真实世界'的研究更严格的ALT正常截止30的男性和19女，和检测不到HBV DNA时发现ALT复常率较低。我们的病人是亚裔为主，但我们的反应率仍然较低，即使相比，来自亚洲其他研究。
本研究的局限性是固有其回顾性研究设计。标准化的监视协议的缺乏可能导致漏报不良事件或临床结果。实验室检查在当地进行的，这可能影响我们的病毒学应答的评估。然而，检测HBV DNA化验的下限为整个网站所使用PCR测定用10至400单位/ mL的检测限的所有网站相当类似。该类型和其他实验室检查的频率差别很大跨站点，并促成了166例排除由于不完整的基线实验室数据。我们的研究既包括学校和社区网站，因此反映在实践模式，从标准化的临床试验方案显著的不同内在'真实世界'的变化。

这项研究的潜在弱点，比如允许列入患者更多的异构池谁也不会晋级第三阶段的研究，例如谁曾ALT正常或低HBV DNA基线还是那些谁是病人在每天1.0毫克高剂量恩替卡韦启动可它的力量，因为它可以更好地反映乙肝治疗的“真实世界”的做法。这项研究的优势是其强大的样本量，患者的大学和社区中来自美国不同的地理区域不同的混合，以及长期随访队列。我们观察到一个高速率停药，这似乎没有归因于治疗失败或提供建议，并且很可能反映了“真实世界”的挑战中维护患者长期乙肝治疗。

总之，我们谁在美国获得ETV治疗慢性乙型肝炎'真实世界'患者进行大样本的研究表明安全性和长期有效性尽管异质的患者人群，并在确保遵守ETV挑战和随访临床实践。

StephenW

非常全面的报告:全文:
http://onlinelibrary.wiley.com/doi/10.1111/apt.13440/full

newchinabok

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newchinabok

请教sw，恩替的hcc发病率是多少？

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StephenW

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HCC was diagnosed in 18 (2.7%) patients, eight of whom had cirrhosis at baseline. Twelve of these patients achieved undetectable HBV DNA levels prior to the diagnosis of HCC but two of these 12 subsequently had detectable HBV DNA levels at the time of HCC diagnosis. Five patients were diagnosed to have HCC during the first 12 months of ETV therapy. Four (0.6%) patients died, two due to complications of cirrhosis or HCC and two from nonliver causes. Six patients, all of who had HCC, underwent liver transplantation.
肝癌诊断为18（2.7％）的患者，其中8人患有肝硬化在基准。这些患者十二至HCC的诊断达到不可检测HBV DNA水平之前，但其中的两个12的肝癌诊断时随后具有可检测的HBV DNA水平。五名患者被确诊时ETV治疗的头12个月有肝癌。四（0.6％）患者死亡，两人因肝硬化或肝癌，两个来自nonliver原因并发症。六名病人，所有谁了肝癌接受肝移植

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感谢sw解读

阳光醉人

SW辛苦了！