血清乙型肝炎核心相关抗原（HBcrAg）与慢性乙型肝炎患者的

StephenW

Serum hepatitis B core-associated antigen (HBcrAg) is associated with covalently closed circular DNA transcriptional activity in patients with chronic hepatitis B
Barbara Testoni1, 2, †
, FannyLebossé1, 2, 3, †
, Caroline Scholtes 1, 2, 4
, FrançoiseBerby1
,Clothilde Miaglia1,2,3
, Miroslava Subic3
, Alessandro Loglio5
, Floriana Facchetti5
, Pietro Lampertico5
, Massimo Levrero 1, 2, 3, 6
, Fabien Zoulim1, 2, 3, low asterisk, 'Information about the author Fabien Zoulim Email author Fabien Zoulim
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DOI: https://doi.org/10.1016/j.jhep.2018.11.030 |
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Emphasize

• Liver HBV cccDNA is still the cause of the persistence of the virus despite antiviral therapy.
• cccDNA activity, not quantity, is associated with disease progression.
• Serum HBcrAg is highly correlated with intrahepatic cccDNA activity.
• Lower levels of HBcrAg are associated with a more favorable disease process.

Background and purpose

Serum hepatitis B core-associated antigen (HBcrAg) has been proposed to reflect intrahepatic covalently closed circular (ccc) DNA levels. However, the association of HBcrAg with serum and intrahepatic viral markers and liver histology has not been fully investigated in large samples. Our aim was to determine if HBcrAg might be a useful therapeutic marker for patients with chronic hepatitis B.
method

HBcrAg was determined by chemiluminescent enzyme immunoassay in 130 patients (36 hepatitis B e antigen [HBeAg] + and 94 HBeAg-) biopsy confirmed, untreated chronic hepatitis B patients. HBcrAg levels and: a) serum B Hepatitis B virus (HBV)-related DNA, quantification of hepatitis B surface antigen and alanine aminotransferase levels; b) total intrahepatic (t) HBV-DNA, cccDNA, pre-genome (pg) RNA and cccDNA transcriptional activity ( Defined as pgRNA / cccDNA ratio); c) fibrosis and necroinflammatory activity scores.
result

HBeAg+ and HBeAg-patients have significantly elevated levels of HBcrAg and are associated with serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA and cccDNA levels, and transcriptional activity. HBcrAg-negative (<3 LogU / ml) patients had less liver cccDNA and lower cccDNA activity than HBcrAg + group. Principal component analysis combined with unsupervised clustering identified higher HBcrAg levels in the HBeAg-patient subgroup with higher serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA, cccDNA transcriptional activity, and higher fibrosis and Necrotic inflammatory activity scores are related.
in conclusion

Our results indicate that HBcrAg is a surrogate marker for intrahepatic cccDNA and its transcriptional activity. HBcrAg can be used to evaluate new antiviral therapies aimed at achieving a functional cure for HBV infection by directly or indirectly targeting the intrahepatic cccDNA library.
Place summary

Hepatitis B virus causes chronic infection, which develops into severe liver disease and liver cancer. The covalently closed circular DNA (cccDNA) of the virus is responsible for the persistence of infection in hepatocytes. In order to better manage patient treatment and follow-up, and to develop new antiviral therapies that directly target the intrahepatic cccDNA library, serum surrogate markers reflecting viral activity in the liver are urgently needed. In this work, we demonstrate that quantification of hepatitis B core-associated antigens in serum correlates with the amount and activity of cccDNA and can be used to monitor disease progression.
Key words:
Hepatitis B virus (HBV), chronic hepatitis B (CHB), biomarkers, patient management, pregenomic RNA (pgRNA), covalently closed circular DNA (cccDNA)

StephenW

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 Testoni1,2，†
，FannyLebossé1,2,3，†
，Caroline Scholtes 1,2,4
，FrançoiseBerby1
，Clothilde Miaglia1,2,3
，Miroslava Subic3
，Alessandro Loglio5
，Floriana Facchetti5
，Pietro Lampertico5
，Massimo Levrero 1,2,3,6
，Fabien Zoulim1,2,3，low asterisk，'有关作者的信息Fabien Zoulim电子邮件作者Fabien Zoulim
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DOI：https：//doi.org/10.1016/j.jhep.2018.11.030 |
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注重

•尽管抗病毒治疗，肝脏HBV cccDNA仍然是病毒持续存在的原因。
•cccDNA活性而非数量与疾病进展相关。
•血清HBcrAg与肝内cccDNA活性高度相关。
•较低水平的HBcrAg与更有利的疾病过程相关。

背景和目的

已提出血清乙型肝炎核心相关抗原（HBcrAg）反映肝内共价闭合环状（ccc）DNA水平。然而，在大样本中尚未充分研究HBcrAg与血清和肝内病毒标志物和肝脏组织学的关联。我们的目的是确定HBcrAg是否可能是慢性乙型肝炎患者的有用治疗标记物。
方法

HBcrAg通过化学发光酶免疫测定法测定130名患者（36名乙型肝炎e抗原[HBeAg] +和94名HBeAg-）活检证实，未经治疗的慢性乙型肝炎患者。 HBcrAg水平和：a）血清B乙型肝炎病毒（HBV）相关DNA，乙肝表面抗原和丙氨酸氨基转移酶水平的定量; b）总肝内（t）HBV-DNA，cccDNA，前基因组（pg）RNA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 +和HBeAg-患者的HBcrAg水平显着升高，并与血清HBV-DNA，肝内tHBV-DNA，pgRNA和cccDNA水平以及转录活性相关。 HBcrAg阴性（<3 LogU / ml）患者肝脏cccDNA较少，cccDNA活性低于HBcrAg +组。主成分分析结合无监督聚类鉴定HBeAg患者亚组中HBcrAg水平较高，血清HBV-DNA较高，肝内tHBV-DNA，pgRNA，cccDNA转录活性较高，纤维化程度较高，坏死性炎症活动评分也相关。
结论

我们的结果表明HBcrAg是肝内cccDNA及其转录活性的替代标志物。 HBcrAg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文库来实现HBV感染的功能性治愈。
放置摘要

乙型肝炎病毒引起慢性感染，其发展为严重的肝病和肝癌。病毒的共价闭合环状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，并开发直接针对肝内cccDNA文库的新抗病毒疗法，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，我们证明血清中乙型肝炎核心相关抗原的定量与cccDNA的数量和活性相关，可用于监测疾病进展。
关键词：
乙型肝炎病毒（HBV），慢性乙型肝炎（CHB），生物标志物，患者管理，前基因组RNA（pgRNA），共价闭合环状DNA（cccDNA）