The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea.
Liver Int. 2024 Oct;44(10):2753-2762. doi: 10.1111/liv.16032. Epub 2024 Jul 29.
Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg.
This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed.
Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients.
HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.
驱动具有和不具有乙型肝炎 e 抗原（HBeAg）的免疫活性慢性乙型肝炎（CHB）的分子过程仍不完全清楚。本研究旨在研究具有和不具有 HBeAg 的免疫活性 CHB 患者的血清和肝内 HBV 标志物表达谱以及 HBV 的复制活性。
本研究招募了 111 例未经治疗的免疫活性 CHB（60 例 HBeAg 阳性和 51 例 HBeAg 阴性）患者，并定量检测了肝内共价闭合环状 DNA（cccDNA）、前基因组 RNA（pgRNA）、总 HBV DNA（tDNA）和复制中间体以及血清 HBV 标志物（HBV DNA、乙型肝炎表面抗原、乙型肝炎核心相关抗原）。分析了 HBV 标志物与影响 HBV 标志物表达水平的临床病毒学因素之间的相关性。
与 HBeAg 阳性患者相比，HBeAg 阴性患者的所有血清标志物和肝内 cccDNA/tDNA 以及 cccDNA 转录活性和病毒粒子产量均显著降低。此外，在 HBeAg 阴性个体中，肝内 cccDNA/pgRNA 与血清标志物之间的相关性受损。在 HBeAg 阳性患者中，天冬氨酸氨基转移酶水平与 cccDNA 转录活性呈正相关，但在 HBeAg 阴性患者中则不然。值得注意的是，在 HBeAg 阳性患者中，随着肝纤维化的进展，pgRNA 水平、转录活性和血清 HBV 标志物逐渐下降，而在 HBeAg 阴性患者中则没有观察到这种情况。
HBeAg 丢失与肝内 HBV 储库和 cccDNA 转录减少相关，导致血清 HBV 标志物水平降低。对于 HBeAg 阴性患者，循环 HBV 标志物不是肝内 HBV 复制活性的可靠指标。我们的发现揭示了具有和不具有 HBeAg 的免疫活性 CHB 之间的不同疾病表型，强调需要建立能够准确反映肝内病毒活性的最佳替代生物标志物，以帮助决策免疫活性 CHB 的抗病毒治疗。
