INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
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.
J Hepatol. 2019 Apr;70(4):615-625. doi: 10.1016/j.jhep.2018.11.030. Epub 2018 Dec 7.
BACKGROUND & AIMS: It has been proposed that serum hepatitis B core-related antigen (HBcrAg) reflects intrahepatic covalently closed circular (ccc)DNA levels. However, the correlation of HBcrAg with serum and intrahepatic viral markers and liver histology has not been comprehensively investigated in a large sample. We aimed to determine if HBcrAg could be a useful therapeutic marker in patients with chronic hepatitis B.
HBcrAg was measured by chemiluminescent enzyme immunoassay in 130 (36 hepatitis B e antigen [HBeAg]+ and 94 HBeAg-) biopsy proven, untreated, patients with chronic hepatitis B. HBcrAg levels were correlated with: a) serum hepatitis B virus (HBV)-DNA, quantitative hepatitis B surface antigen and alanine aminotransferase levels; b) intrahepatic total (t)HBV-DNA, cccDNA, pregenomic (pg)RNA and cccDNA transcriptional activity (defined as pgRNA/cccDNA ratio); c) fibrosis and necroinflammatory activity scores.
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 were negative for HBcrAg (<3 LogU/ml) had less liver cccDNA and lower cccDNA activity than the HBcrAg+ group. Principal component analysis coupled with unsupervised clustering identified that in a subgroup of HBeAg- patients, higher HBcrAg levels were associated with higher serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA, cccDNA transcriptional activity and with higher fibrosis and necroinflammatory activity scores.
Our results indicate that HBcrAg is a surrogate marker of both intrahepatic cccDNA and its transcriptional activity. HBcrAg could be useful in the evaluation of new antiviral therapies aiming at a functional cure of HBV infection either by directly or indirectly targeting the intrahepatic cccDNA pool.
Hepatitis B virus causes a chronic infection which develops into 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 hepatitis B core-related antigen in serum correlates with cccDNA amount and activity and could be used to monitor disease progression.
已有研究提出，血清乙型肝炎核心相关抗原（HBcrAg）可反映肝内共价闭合环状（ccc）DNA 水平。然而，HBcrAg 与血清和肝内病毒标志物及肝组织学的相关性尚未在大样本中得到全面研究。我们旨在确定 HBcrAg 是否可作为慢性乙型肝炎患者的一种有用的治疗标志物。
我们采用化学发光酶免疫分析法检测了 130 例（36 例乙型肝炎 e 抗原[HBeAg]+和 94 例 HBeAg-）经活检证实、未经治疗的慢性乙型肝炎患者的 HBcrAg。HBcrAg 水平与：a）血清乙型肝炎病毒（HBV）-DNA、定量乙型肝炎表面抗原和丙氨酸氨基转移酶水平；b）肝内总（t）HBV-DNA、cccDNA、前基因组（pg）RNA 和 cccDNA 转录活性（定义为 pgRNA/cccDNA 比值）；c）纤维化和坏死性炎症评分相关。
HBeAg+患者的 HBcrAg 水平明显高于 HBeAg-患者，且与血清 HBV-DNA、肝内 tHBV-DNA、pgRNA 和 cccDNA 水平及转录活性相关。HBcrAg＜3 LogU/ml 的患者肝内 cccDNA 及 cccDNA 活性低于 HBcrAg+组。主成分分析结合无监督聚类分析显示，在 HBeAg-患者亚组中，较高的 HBcrAg 水平与较高的血清 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评分相关。
我们的研究结果表明，HBcrAg 是肝内 cccDNA 及其转录活性的替代标志物。HBcrAg 可能有助于评估旨在通过直接或间接靶向肝内 cccDNA 池实现乙型肝炎病毒感染功能性治愈的新型抗病毒疗法。
乙型肝炎病毒引起慢性感染，可发展为严重肝脏疾病和肝癌。病毒共价闭合环状（ccc）DNA 是导致肝细胞内病毒持续存在的原因。为了更好地管理患者的治疗和随访，并开发直接针对肝内 cccDNA 池的新型抗病毒治疗方法，迫切需要能反映肝脏病毒活性的血清替代标志物。在这项工作中，我们证明了血清乙型肝炎核心相关抗原的定量与 cccDNA 量和活性相关，可用于监测疾病进展。
