在24个国家进行随机试验的恩替卡韦或其他药物长期治疗慢性

StephenW

Clin Gastroenterol Hepatol. 2019 Jul 12. pii: S1542-3565(19)30743-8. doi: 10.1016/j.cgh.2019.07.010. [Epub ahead of print]
Outcomes of Long-term Treatment of Chronic HBV Infection With Entecavir or Other Agents From a Randomized Trial in 24 Countries.
Hou JL1, Zhao W2, Lee C3, Hann HW4, Peng CY5, Tanwandee T6, Morozov V7, Klinker H8, Sollano JD9, Streinu-Cercel A10, Cheinquer H11, Xie Q12, Wang YM13, Wei L14, Jia JD15, Gong G16, Han KH17, Cao W18, Cheng M19, Tang X20, Tan D21, Ren H22, Duan Z23, Tang H24, Gao Z25, Chen S26, Lin S27, Sheng J28, Chen C29, Shang J30, Han T31, Ji Y32, Niu J33, Sun J34, Chen Y34, Cooney EL35, Lim SG36.
Author information

1
    Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
2
    2nd Hospital Nanjing, Nanjing, China.
3
    Daegu Catholic University Hospital, Daegu, Korea.
4
    Thomas Jefferson University Hospital, Philadelphia, PA, USA.
5
    China Medical University Hospital, Taichung, Taiwan.
6
    Faculty of Medicine Siriraj Hospital, Bangkok, Thailand.
7
    LLC Medical Company "Hepatolog", Samara, Russian Federation.
8
    University of Würzburg Medical Center, Würzberg, Germany.
9
    Cardinal Santos Medical Center, Manila, Philippines.
10
    Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases "Prof. Dr. Matei Bals", Bucharest, Romania.
11
    Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
12
    Shanghai Rui Jin Hospital, Shanghai, China.
13
    Southwest Hospital, Chongqing, China.
14
    Peking University People's Hospital, Beijing, China.
15
    Beijing Friendship Hospital, Capitol Medical University, Beijing, China.
16
    The Second Xiangya Hospital of Central South University, Changsha, China.
17
    Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
18
    Tianjin Second People's Hospital, Tianjin, China.
19
    Affiliated Hospital of Guiyang Medical College, Guiyang, China.
20
    Guangzhou No.8 People's Hospital, Guangzhou, China.
21
    Xiangya Hospital, Central South University, Changsha, China.
22
    The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
23
    Beijing YouAn Hospital, Capital Medical University, Beijing, China.
24
    West China Hospital, Sichuan University, Chengdu, China.
25
    The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
26
    Jinan Infectious Disease Hospital, Jinan, China.
27
    The First Affiliated Hospital of Xi'An Jiaotong University, Xi'An, China.
28
    The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
29
    85th Hospital of People's Liberation Army, Shanghai, China.
30
    Henan Provincial People's hospital, Zhengzhou, China.
31
    Tianjin Third Central Hospital, Tianjin, China.
32
    Shanghai Jing'an District Central Hospital, Shanghai, China.
33
    The First Hospital of Jilin University, Changchun, China.
34
    Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
35
    Bristol-Myers Squibb Inc., Wallingford, CT, USA.
36
    National University Health System, National University of Singapore, Singapore.

Abstract
BACKGROUND & AIMS:

Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed patients treated with entecavir or another standard of care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response.
METHODS:

Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were randomly assigned to groups that received entecavir (n=6216) or an investigator-selected non-entecavir HBV nucleos(t)ide analogue (n=6162). Study participants were followed for up to 10 years in hospital-based or community clinics. Key endpoints were time to adjudicated clinical outcome events and serious adverse events. In a sub-study, we examined relationships between these events and virologic response.
RESULTS:

There were no significant differences between groups in time to event assessments for primary endpoints including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary endpoints of non-hepatocellular carcinoma, malignant neoplasms, or hepatocellular carcinoma. In a sub-study of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given non-entecavir drugs (0.8%) reported treatment-related serious adverse events.
CONCLUSIONS:

In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow up. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.

Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
KEYWORDS:

CHB; HCC; complication; long-term follow-up study

PMID:
    31306800
DOI:
    10.1016/j.cgh.2019.07.010

StephenW

Clin Gastroenterol Hepatol。 2019年7月12日.pii：S1542-3565（19）30743-8。 doi：10.1016 / j.cgh.2019.07.010。 [印刷前的电子版]
在24个国家进行随机试验的恩替卡韦或其他药物长期治疗慢性HBV感染的结果。
Hou JL1，Zhao W2，Lee C3，Hann HW4，Peng CY5，Tanwandee T6，Morozov V7，Klinker H8，Sollano JD9，Streinu-Cercel A10，Cheinquer H11，Xie Q12，Wang YM13，Wei L14，Jia JD15，Gong G16，韩KH17，曹W18，程M19，唐X20，谭D21，任H22，段Z23，唐H24，高Z25，陈S26，林S27，盛J28，陈C29，尚J30，韩T31，纪Y32，牛J33 ，Sun J34，Chen Y34，Cooney EL35，Lim SG36。
作者信息

1
    南方医科大学南方医院肝病研究所传染病科，广州电子地址：[email protected]。
2
    南京第二医院，南京，中国。
3
    大邱天主教大学医院，大邱，韩国。
4
    托马斯杰斐逊大学医院，费城，宾夕法尼亚州，美国。
五
    中国医科大学附属台中医院。
6
    泰国曼谷Siriraj医院。
7
    LLC医疗公司“Hepatolog”，俄罗斯联邦萨马拉。
8
    维尔茨堡大学医学中心，德国维尔茨堡。
9
    菲律宾马尼拉红衣主教桑托斯医疗中心。
10
    Carol Davila医学和药学大学，国家传染病研究所“Matei Bals教授”，罗马尼亚布加勒斯特。
11
    Hospital de Clinicas de Porto Alegre，阿雷格里港，巴西。
12
    上海瑞金医院，中国上海。
13
    中国重庆市西南医院。
14
    北京大学人民医院，中国北京。
15
    北京友谊医院，国会医科大学，北京，中国。
16
    中南大学湘雅二医院，长沙，中国。
17
    韩国首尔延世大学医学院Severance医院。
18
    天津市第二人民医院，天津，中国。
19
    贵阳医学院附属医院，贵阳
20
    广州市第八人民医院，广州。
21
    中南大学湘雅医院，长沙，中国。
22
    重庆医科大学附属第二医院，重庆，中国。
23
    首都医科大学附属北京右安医院，中国北京。
24
    四川大学华西医院，中国成都。
25
    中山大学附属第三医院，广州，中国。
26
    济南市济南市传染病医院。
27
    西安交通大学第一附属医院，中国西安。
28
    浙江大学附属第一医院，杭州，中国。
29
    中国人民解放军第85医院，中国上海。
三十
    河南省人民医院，中国郑州。
31
    天津市第三中心医院，中国天津
32
    上海静安区中心医院，中国上海。
33
    吉林大学第一医院，长春，中国。
34
    南方医科大学南方医院肝病研究所传染病科，广州
35
    Bristol-Myers Squibb Inc.，Wallingford，CT，USA。
36
    国立大学卫生系统，新加坡国立大学，新加坡。

抽象
背景与目的：

用恩替卡韦治疗慢性乙型肝炎病毒（HBV）感染可抑制病毒复制并减少疾病进展，但可能需要终身治疗。为了研究与恩替卡韦长期治疗相关的临床结果事件和安全性，我们对接受恩替卡韦治疗或其他标准治疗HBV核苷（t）类似物治疗的患者进行了长达10年的随访。我们评估了长期结果和与病毒学反应的关系。
方法：

在亚洲，欧洲，北美洲和南美洲的299个中心患有慢性HBV感染的患者被随机分配到接受恩替卡韦（n = 6216）或研究者选择的非恩替卡韦HBV核苷（t）ide类似物的组中（n = 6162） ）。研究参与者在医院或社区诊所接受了长达10年的随访。关键终点是判定临床结果事件和严重不良事件的时间。在一项子研究中，我们检查了这些事件与病毒学应答之间的关系。
结果：
在主要终点（包括恶性肿瘤，肝脏相关的HBV疾病进展和死亡）的事件评估中，各组之间没有显着差异。在非肝细胞癌，恶性肿瘤或肝细胞癌的次要终点组之间没有差异。在中国5305名患者的子研究中，无论治疗组如何，病毒学应答与肝脏相关HBV疾病进展风险降低（风险比，0.09; 95％CI，0.038-0.221）和肝细胞癌（风险比，0.03; 95％CI，0.009-0.113）。给予恩替卡韦（0.2％）的12名患者和给予非恩替卡韦药物的50名患者（0.8％）报告了与治疗相关的严重不良事件。
结论：

在一项针对慢性HBV感染患者的随机对照试验中，我们将恩替卡韦治疗与10年随访期间的低比率不良事件联系起来。接受恩替卡韦与另一种核苷（酸）类似物的患者具有相当的肝脏和非肝脏相关临床结果事件的发生率。无论治疗组如何，维持病毒学应答的中国队列参与者的HBV相关结局事件（包括肝细胞癌）风险降低。 ClinicalTrials.gov标识号：NCT00388674。

版权所有©2019 AGA Institute。由Elsevier Inc.出版。保留所有权利。
关键词：

CHB; HCC;并发症;长期随访研究

结论：
    31306800
DOI：
    10.1016 / j.cgh.2019.07.010

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