乙型肝炎表面抗原的血清清除与慢性HBV感染患者的长期临床

StephenW

Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic HBV Infection: Systematic Review and Meta-analysis
Ryan T. Anderson, MS, MPH
Senior Research Associate, The Forum for Collaborative Research, University of California, Berkeley, School of Public Health, Washington, District of Columbia
Hannah S.J. Choi, MS
Graduate Student, Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
Oliver Lenz, PhD
Scientific Director, Janssen Research and Development, Antwerp, Belgium
Marion G. Peters, MD
AIDS Clinical Trial Group, Chicago Illinois
Harry L.A. Janssen, MD, PhD
Program Director, Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
Poonam Mishra, MD, MPH
Deputy Division Director for Safety, US Food and Drug Administration, Silver Spring, Maryland
Eric Donaldson, PhD
Clinical Virology Reviewer, US Food and Drug Administration, Silver Spring, Maryland
Gabriel Westman, MD, PhD
Senior Clinical Assessor, Swedish Medical Products Agency, Uppsala, Sweden; Researcher, Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden
Stephanie Buchholz, Dr rer nat
Clinical Assessor, Federal Institute for Drugs and Medical Devices, Bonn, Germany
Veronica Miller, PhD
Executive Director, The Forum for Collaborative Research, University of California, Berkeley, School of Public Health, Washington, District of Columbia
Bettina E. Hansen, PhD, MSc∗,'Correspondence information about the author PhD, MSc Bettina E. HansenEmail the author PhD, MSc Bettina E. Hansen
Senior Biostatistician, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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    Abstract

Abstract
Background & Aims

Seroclearance of hepatitis B surface antigen (HBsAg) is the desired endpoint of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of association between HBsAg seroclearance and long-term clinical outcomes.
Methods

We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow up. We performed a meta-analysis of rate ratios (RR) using a random effects model independently for each endpoint and for a composite endpoint.
Results

We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (P-Y) of follow up; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 P-Y for the HBsAg seroclearance group and 2.45/1000 P-Y for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation for liver decompensation (95% CI, 0.13–0.59; P=.001), 0.30 for HCC (95% CI, 0.20–0.44; P<.001), 0.22 for liver transplantation and/or death (95% CI, 0.13–0.39; P<.001), and 0.31 for the composite endpoint (95% CI, 0.23–0.43; 95% CI, .023–0.43; P<.001). No differences in RR estimates were observed among subgroups of different study or patient characteristics.
Conclusions

In a systematic review and meta-analysis, we found seroclearance of HBsAg to be significantly associated with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary endpoint of trials of patients with chronic HBV infection.
Keywords:
viral hepatitis, long-term outcomes, primary endpoint, HBsAg

StephenW

乙型肝炎表面抗原的血清清除与慢性HBV感染患者的长期临床结果之间的关联：系统评价和荟萃分析
瑞安·安德森（Ryan T.
加州大学伯克利分校公共卫生学院合作研究论坛高级研究员
汉娜·S·J。崔女士
加拿大安大略省多伦多市大学健康网络多伦多肝病中心研究生
奥利弗·伦茨博士
比利时安特卫普Janssen研究与开发科学总监
玛丽恩·彼得斯（MD）
艾滋病临床试验小组，伊利诺伊州芝加哥
医学博士哈里·詹森（Harry L.A. Janssen）
大学健康网络多伦多肝病中心项目主任，加拿大安大略省多伦多市
医学博士Poonam Mishra，MPH
美国食品和药物管理局安全部门副主任，马里兰州银泉
埃里克·唐纳森（Eric Donaldson）博士
美国食品药品监督管理局临床病毒学审阅者，马里兰州银泉
加布里埃尔·韦斯特曼，医学博士
瑞典乌普萨拉瑞典医疗产品局高级临床评估师；瑞典乌普萨拉大学乌普萨拉大学传染病科医学科学系研究员
斯蒂芬妮·布赫霍尔茨（Stephanie Buchholz）
德国波恩联邦药品和医疗器械研究所临床评估师
维罗妮卡·米勒（Veronica Miller）博士
加州大学伯克利分校公共卫生学院合作研究论坛执行主任
Bettina E. Hansen，博士，理学硕士，'有关作者PhD，MSc Bettina E.Hansen的通讯信息给作者博士学位，MSc Bettina E.Hansen的电子邮件
多伦多大学卫生政策，管理与评估研究所高级生物统计学家
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    抽象

抽象
背景与目标

根据指南，乙肝表面抗原（HBsAg）的血清清除是治疗慢性乙肝病毒（HBV）感染的理想终点。我们进行了系统的综述和荟萃分析，以评估HBsAg血清清除与长期临床结果之间的关联强度。
方法

我们对PubMed，EMBASE和Cochrane库数据库进行了系统评价，以评估文章中的HBsAg状况，并报告随访期间肝细胞癌（HCC），肝代偿失调，肝移植和/或全因死亡率的发生率。我们使用随机效应模型对每个终点和复合终点进行了比率比率（RR）的荟萃分析。
结果

我们分析了来自28项研究的数据，包括总共188,316例慢性HBV感染患者（已治疗和未治疗），以及1,486,081人年（P-Y）的随访。 26个报告了HCC数据，7个关于肝失代偿的数据和13个关于肝移植和/或死亡的数据。 HBsAg血清清除组的复合事件发生率为0.19 / 1000 P-Y，HBsAg持久性组的复合事件发生率为2.45 / 1000 P-Y。 HBsAg血清清除组的合并RRs为肝失代偿的肝失代偿率为0.28（95％CI，0.13-0.59; P = .001），HCC为0.30（95％CI，0.20-0.44; P <.001），0.22肝移植和/或死亡（95％CI，0.13-0.39; P <.001），以及复合终点的0.31（95％CI，0.23-0.43; 95％CI，.023-0.43; P <.001） 。在不同研究或患者特征的亚组之间，未观察到RR估计的差异。
结论

在系统的回顾和荟萃分析中，我们发现HBsAg的血清清除与患者预后的改善显着相关。结果在不同类型的研究中，在所有检查的患者亚人群中都是一致的，并支持将HBsAg血清清除作为慢性HBV感染患者试验的主要终点。
关键字：
病毒性肝炎，长期预后，主要终点，HBsAg