血清乙型肝炎核心相关抗原（HBcrAg）与慢性乙型肝炎患者的

StephenW

J Hepatol. 2018 Dec 6. pii: S0168-8278(18)32582-0. doi: 10.1016/j.jhep.2018.11.030. [Epub ahead of print]
Serum Hepatitis B core-related antigen (HBcrAg) correlates with covalently-closed circular DNA transcriptional activity in chronic hepatitis B patients.
Barbara T1, Fanny L2, Caroline S3, Françoise B4, Clothilde M2, Miroslava S5, Alessandro L6, Floriana F6, Pietro L6, Massimo L7, Fabien Z8.
Author information

1
    INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
2
    INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France.
3
    INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Virology, Croix Rousse Hospital, Hospices Civils de Lyon, France.
4
    INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France.
5
    Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France.
6
    Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
7
    INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France; Department of Internal Medicine - DMISM and the IIT Center for Life Nanoscience (CLNS), Sapienza University, Rome, Italy.
8
    INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France. Electronic address: [email protected].

Abstract
BACKGROUND AND AIMS:

Serum Hepatitis B core-related antigen (HBcrAg) has been proposed to reflect the intrahepatic cccDNA levels, but a comprehensive investigation of its correlation with serum and intrahepatic viral markers and liver histology in a large number of patients is still lacking.
METHODS:

HBcrAg was measured by chemiluminescent enzyme immunoassay (Fujirebio Lumipulse® G HBcrAg) in 130 [36 HBeAg(+) and 94 HBeAg(-)] biopsy proven, untreated, CHB patients. HBcrAg levels were correlated with: a) serum HBV-DNA, quantitative (q)HBsAg and alanine aminotransferase (ALT) levels; b) intrahepatic total (t)HBV-DNA, cccDNA, pgRNA and cccDNA transcriptional activity (defined as pgRNA/cccDNA ratio); c) fibrosis and necroinflammatory activity scores.
RESULTS:

HBcrAg levels were significantly higher in HBeAg(+) vs HBeAg(-) patients and correlated with serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA and cccDNA levels and transcriptional activity. Patients who scored negative for HBcrAg (< 3 LogU/mL) had less liver cccDNA and lower cccDNA activity as compared to the HBcrAg(+) group. Principal component analysis coupled to unsupervised clustering identified a subgroup of HBeAg(-) patients with higher HBcrAg levels associated to higher serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA, cccDNA transcriptional activity and to higher scores of fibrosis and necro-inflammatory activity.
CONCLUSIONS:

Our results indicate that HBcrAg is a surrogate marker of both intrahepatic cccDNA and its transcriptional activity that can be useful in the evaluation of new antiviral therapies aiming at a functional cure of HBV infection either by targeting directly or indirectly the intrahepatic cccDNA pool.
LAY SUMMARY:

Hepatitis B virus causes a chronic infection which develops in severe liver disease and liver cancer. The viral covalently-closed-circular DNA (cccDNA) is responsible for the persistence of the infection in hepatocytes. To better manage patient treatment and follow up, and to develop new antiviral treatments directly targeting the intrahepatic pool of cccDNA, serum surrogate markers reflecting the viral activity in the liver are urgently needed. In this work, we demonstrate that quantification of HBcrAg in serum correlates with cccDNA amount and activity and could be used to monitor of disease progression.

Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KEYWORDS:

Biomarker; Chronic hepatitis B (CHB); Covalently-closed circular DNA (cccDNA); Hepatitis B virus (HBV); Patient management; Pregenomic RNA (pgRNA)

PMID:
    30529504
DOI:
    10.1016/j.jhep.2018.11.030

StephenW

J Hepatol。 2018年12月6日.pii：S0168-8278（18）32582-0。 doi：10.1016 / j.jhep.2018.11.030。 [提前打印]
血清乙型肝炎核心相关抗原（HBcrAg）与慢性乙型肝炎患者的共价闭合环状DNA转录活性相关。
Barbara T1，Fanny L2，Caroline S3，FrançoiseB4，Clothilde M2，Miroslava S5，Alessandro L6，Floriana F6，Pietro L6，Massimo L7，Fabien Z8。
作者信息

1
    INSERM U1052-里昂癌症研究中心（CRCL），法国里昂69008;里昂大学，UMR_S1052，CRCL，69008 Lyon，France。
2
    INSERM U1052-里昂癌症研究中心（CRCL），法国里昂69008;里昂大学，UMR_S1052，CRCL，69008 Lyon，France;法国里昂市居民区Croix Rousse医院肝病科。
3
    INSERM U1052-里昂癌症研究中心（CRCL），法国里昂69008;里昂大学，UMR_S1052，CRCL，69008 Lyon，France;法国里昂市中心收容所Croix Rousse医院病毒学系。
4
    INSERM U1052-里昂癌症研究中心（CRCL），69008 Lyon，France。
五
    法国里昂市居民区Croix Rousse医院肝病科。
6
    Gondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico，意大利米兰UniversitàdegliStudi di Milano，消化内科和肝脏病学系。
7
    INSERM U1052-里昂癌症研究中心（CRCL），法国里昂69008;里昂大学，UMR_S1052，CRCL，69008 Lyon，France;法国里昂市收容所Croix Rousse医院肝病科;内科 -  DMISM和IIT生命纳米科学中心（CLNS），Sapienza大学，罗马，意大利。
8
    INSERM U1052-里昂癌症研究中心（CRCL），法国里昂69008;里昂大学，UMR_S1052，CRCL，69008 Lyon，France;法国里昂市居民区Croix Rousse医院肝病科。电子地址：[email protected]。

抽象
背景和目的：

已提出血清乙型肝炎核心相关抗原（HBcrAg）反映肝内cccDNA水平，但仍缺乏对大量患者血清和肝内病毒标志物及肝脏组织学相关性的综合研究。
方法：

HBcrAg通过化学发光酶免疫测定法（FujirebioLumipulse®GHBcrAg）在130 [36 HBeAg（+）和94 HBeAg（ - ）]活检证实，未经治疗的CHB患者中测量。 HBcrAg水平与：a）血清HBV-DNA，定量（q）HBsAg和丙氨酸氨基转移酶（ALT）水平相关; b）肝内总（t）HBV-DNA，cccDNA，pgRNA和cccDNA转录活性（定义为pgRNA / cccDNA比率）; c）纤维化和坏死性炎症活动评分。
结果：

HBeAg（+）与HBeAg（ - ）患者HBcrAg水平显着升高，并与血清HBV-DNA，肝内tHBV-DNA，pgRNA和cccDNA水平及转录活性相关。与HBcrAg（+）组相比，HBcrAg评分为（<3 LogU / mL）的患者肝脏cccDNA较少，cccDNA活性较低。与无监督聚类相结合的主成分分析确定HBeAg（ - ）患者的亚组具有较高的血清HBV-DNA，肝内tHBV-DNA，pgRNA，cccDNA转录活性以及较高的纤维化和坏死性炎症活性相关的较高HBcrAg水平。
结论：

我们的研究结果表明，HBcrAg是肝内cccDNA及其转录活性的替代指标，可用于评估新的抗病毒疗法，旨在通过直接或间接靶向肝内cccDNA库来治疗HBV感染。
LAY概要：

乙型肝炎病毒引起慢性感染，其在严重的肝病和肝癌中发展。病毒共价闭合环状DNA（cccDNA）负责肝细胞中感染的持续存在。为了更好地管理患者治疗和随访，并开发直接靶向肝内cccDNA库的新的抗病毒治疗，迫切需要反映肝脏中病毒活性的血清替代标志物。在这项工作中，我们证明血清中HBcrAg的定量与cccDNA数量和活性相关，可用于监测疾病进展。

版权所有©2018欧洲肝脏研究协会。由Elsevier B.V.发布。保留所有权利。
关键词：

生物标志物;慢性乙型肝炎（CHB）;共价闭合环状DNA（cccDNA）;乙型肝炎病毒（HBV）;病人管理;前基因组RNA（pgRNA）

结论：
    30529504
DOI：
    10.1016 / j.jhep.2018.11.030