恩替卡韦与安慰剂的随机对照试验的儿童乙肝包膜抗原阳性

StephenW

Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen–positive chronic hepatitis B

    Maureen M. Jonas1,*, Mei-Hwei Chang2, Etienne Sokal3, Kathleen B. Schwarz4, Deirdre Kelly5, Kyung Mo Kim6, Simon C. Ling7, Philip Rosenthal8, Dumitru Oraseanu9, Laurie Reynolds10, Alexandra Thiry10 andPeter Ackerman10

Article first published online: 16 OCT 2015

DOI: 10.1002/hep.28015

© 2015 by the American Association for the Study of Liver Diseases

Issue
Hepatology
Hepatology

Volume 63, Issue 2, pages 377–387, February 2016
Article has an altmetric score of 5

    1   Boston Children's Hospital, Boston, MA
    2    National Taiwan University Hospital, Taipei, Taiwan
    3    Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium
    4    Johns Hopkins Children's Center, Baltimore, MD
    5    Birmingham Children's Hospital, Birmingham, UK
    6    Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
    7    The Hospital For Sick Children, and Department of Pediatrics, University of Toronto, Toronto, Canada
    8    University of California, San Francisco, CA
    9    Grigore Alexandrescu Emergency Hospital for Children, Bucharest, Romania
    10    Bristol-Myers Squibb, Wallingford, CT

*Address reprint requests to: Maureen M. Jonas, M.D., Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected]; fax: +1-617-730-0716.

    Potential conflict of interest: Dr. Jonas consults for and received grants from Gilead. She received grants from Bristol-Myers Squibb and Roche. Dr. Chang received grants from Bristol-Myers Squibb and Gilead. Dr. Schwarz consults for and received grants from Roche. Dr. Kelly consults for and received grants from Bristol-Myers Squibb. Dr. Ling received grants from Bristol-Myers Squibb. Dr. Rosenthal consults for and received grants from Gilead. He consults for Hyperion and AbbVie and received grants from Roche, Vertex, and Bristol-Myers Squibb. Dr. Reynolds is employed by and owns stock in Bristol-Myers Squibb. Dr. Ackerman is employed by and owns stock in Bristol-Myers Squibb. Dr. Thiry is employed by and owns stock in Bristol-Myers Squibb.

    This work is registered under study registration number: ClinicalTrials.gov NCT01079806.

   
This ongoing, randomized phase III study assesses the safety and efficacy of entecavir versus placebo in nucleos(t)ide-naïve children (2 to <18 years) with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B (CHB). Blinded treatment was administered for a minimum of 48 weeks. After week 48, patients with HBeAg seroconversion continued blinded treatment; those without switched to open-label entecavir. The primary endpoint was HBeAg seroconversion and HBV DNA <50 IU/mL at week 48. A total of 180 patients were randomized (2:1) and treated. Baseline median age was 12 years, with approximately 50% of children ages >12 to <18, and 25% each ages ≥2 to ≤6 and >6 to ≤12. Rates for the primary endpoint at week 48 were significantly higher with entecavir than placebo (24.2% [29 of 120] vs. 3.3% [2 of 60]; P = 0.0008). Furthermore, higher response rates were observed with entecavir compared with placebo for the key week 48 secondary endpoints: HBV DNA <50 IU/mL (49.2% [59 of 120] vs. 3.3% [2 of 60]; P < 0.0001); alanine aminotransferase normalization (67.5% [81 of 120] vs. 23.3% [14 of 60]; P < 0.0001); and HBeAg seroconversion (24.2% [29 of 120] vs. 10.0% [6 of 60]; P = 0.0210). Among entecavir-randomized patients, there was an increase in all efficacy endpoints between weeks 48 and 96, including an increase from 49% to 64% in virological suppression. The cumulative probability of emergent entecavir resistance through years 1 and 2 of entecavir was 0.6% and 2.6%, respectively. Entecavir was well tolerated with no observed differences in adverse events or changes in growth compared with placebo.

Conclusion: In childhood CHB, entecavir demonstrated superior antiviral efficacy to placebo with a favorable safety profile. These results support the use of entecavir as a therapeutic option in children and adolescents with CHB. (Hepatology 2016;63:377–387)

StephenW

恩替卡韦与安慰剂的随机对照试验的儿童乙肝包膜抗原阳性的慢性乙型肝炎

    莫林M. Jonas1，*，美Hwei长2，艾蒂安Sokal3，凯瑟琳B. Schwarz4，迪尔德丽Kelly5，庆莫Kim6，西蒙C. Ling7，菲利普Rosenthal8，杜米特鲁Oraseanu9，劳里Reynolds10，亚历山德拉Thiry10 andPeter Ackerman10

文章首次在网上公布：2015年10月16日

DOI：10.1002 / hep.28015

©2015年肝病研究的美国协会

问题
肝病
肝病

卷63，第2期，页377-387，2016年二月
文章的altmetric比分5

    1波士顿儿童医院，马萨诸塞州波士顿
    2台大医院，台北，台湾
    15-9诊所3圣Universitaires吕克，鲁汶天主教大学，布鲁塞尔，比利时
    4约翰斯·霍普金斯儿童中心，马里兰州巴尔的摩
    5伯明翰儿童医院，英国伯明翰
    6峨山医学中心儿童医院，蔚山医学院，首尔，韩国的大学
    7病童医院，儿科，多伦多大学，加拿大多伦多部
    加利福尼亚州，旧金山，加州的8大学
    9格里戈里Alexandrescu的应急儿童医院，布加勒斯特，罗马尼亚
    10施贵宝，沃灵福德，CT

*地址转载请：莫琳·乔纳斯先生，医学博士，波士顿儿童医院，300朗伍德大道，马萨诸塞州波士顿02115.电子邮件：[email protected];传真：+ 1-617-730-0716。

    的利益冲突：乔纳斯博士的咨询和Gilead公司收到的补助金。她收到的赠款来自Bristol-Myers Squibb公司和罗氏。张博士获得资助来自Bristol-Myers Squibb公司和Gilead公司。施瓦茨博士咨询并从罗氏获得资助。凯利医生咨询并从施贵宝公司收到的补助。灵博士获得赠款施贵宝。罗森塔尔博士咨询并从Gilead公司收到的补助金。他咨询了海波龙和艾伯维和罗氏，顶点获得补助金，并施贵宝。雷诺兹博士被采用，拥有股票的施贵宝。阿克曼博士被采用，拥有股票的施贵宝。 THIRY博士被采用，拥有股票的施贵宝。

    ClinicalTrials.gov NCT01079806：这项工作正在研究注册号注册。

   
这种持续的，随机的III期临床研究评价乙肝包膜抗原（HBeAg）阳性的慢性乙型肝炎（CHB）的核苷（酸）IDE-天真的孩子的安全和恩替卡韦与安慰剂疗效（2至<18岁）。盲治疗给药最少48周。 48周后，患者出现HBeAg血清学转换继续蒙蔽处理;那些没有切换到开放标签恩替卡韦。主要终点是HBeAg血清转换和HBV DNA <50 IU / mL的，在总共180例患者随机48周（2：1），并进行处理。基线平均年龄为12岁，年龄的儿童大约50％> 12 <18，和25％各年龄≥2为≤6和> 6≤12。率在48周主要终点均显著高于恩替卡韦比安慰剂（24.2％[120 29]对3.3％[60 2]，P = 0.0008）。此外，更高的响应率，观察恩替卡韦与安慰剂的关键周48的次要终点相比：HBV DNA <50IU /毫升（49.2％[120 59]对3.3％[2 60]，P <0.0001）;丙氨酸转氨酶正常化（67.5％[120 81]与[60 14] 23.3％，P <0.0001）;和HBeAg血清转换（24.2％[120 29]与10.0％[60 6]; P = 0.0210）。在恩替卡韦随机患者中，有一个增加周48和96，包括增加，从49％至64％病毒学抑制之间的所有疗效终点。急诊恩替卡韦耐药经过1年和第2恩替卡韦的累积概率分别为0.6％和2.6％。恩替卡韦耐受性好，不良事件或与安慰剂相比变化生长没有差异。

结论：在慢性乙型肝炎的童年，恩替卡韦表现出了超强的抗病毒疗效与安慰剂一个良好的安全性。这些结果支持使用恩替卡韦在儿童和青少年慢性乙型肝炎患者的治疗选择。 （肝病2016年; 63：377-387）