基于 PEG-IFN 治疗后实现功能性治愈的 HBsAg 阳性患者肝内，整合的 HBV DNA 和 cccDNA 维持转录活性。
Integrated HBV DNA and cccDNA maintain transcriptional activity in intrahepatic HBsAg-positive patients with functional cure following PEG-IFN-based therapy.
机构信息
Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
出版信息
Aliment Pharmacol Ther. 2023 Nov;58(10):1086-1098. doi: 10.1111/apt.17670. Epub 2023 Aug 29.
BACKGROUND
Hepatitis B surface antigen (HBsAg) seroclearance marks regression of hepatitis B virus (HBV) infection. However, more than one-fifth of patients with functional cure following pegylated interferon-based therapy may experience HBsAg seroreversion. The mechanisms causing the HBV relapse remain unclear.
AIM
To investigate the level and origin of HBV transcripts in patients with functional cure and their role in predicting relapse.
METHODS
Liver tissue obtained from patients with functional cure, as well as uncured and treatment-naïve HBeAg-negative patients with chronic hepatitis B (CHB) were analysed for intrahepatic HBV markers. HBV capture and RNA sequencing were used to detect HBV integration and chimeric transcripts.
RESULTS
Covalently closed circular DNA (cccDNA) levels and the proportion of HBsAg-positive hepatocytes in functionally cured patients were significantly lower than those in uncured and treatment-naïve HBeAg-negative patients. Integrated HBV DNA and chimeric transcripts declined in functionally cured patients compared to uncured patients. HBsAg-positive hepatocytes present in 25.5% of functionally cured patients, while intrahepatic HBV RNA remained in 72.2%. The levels of intrahepatic HBV RNA, integrated HBV DNA, and chimeric transcripts were higher in functionally cured patients with intrahepatic HBsAg than in those without. The residual intrahepatic HBsAg in functionally cured patients was mainly derived from transcriptionally active integrated HBV DNA; meanwhile, trace transcriptional activity of cccDNA could also remain. Two out of four functionally cured patients with intrahepatic HBsAg and trace active cccDNA experienced HBV relapse.
CONCLUSION
Integrated HBV DNA and cccDNA maintain transcriptional activity and maybe involved in HBsAg seroreversion in intrahepatic HBsAg-positive patients with functional cure and linked to virological relapse.
背景
乙肝表面抗原（HBsAg）血清学清除标志着乙型肝炎病毒（HBV）感染的消退。然而，在接受聚乙二醇干扰素治疗后实现功能性治愈的患者中，超过五分之一可能会出现 HBsAg 血清学反弹。导致 HBV 复发的机制仍不清楚。
目的
研究功能性治愈患者体内 HBV 转录本的水平和来源及其在预测复发中的作用。
方法
分析功能性治愈患者、未治愈和未经治疗的 HBeAg 阴性慢性乙型肝炎（CHB）患者的肝组织中肝内 HBV 标志物。采用 HBV 捕获和 RNA 测序检测 HBV 整合和嵌合转录本。
结果
与未治愈和未经治疗的 HBeAg 阴性 CHB 患者相比，功能性治愈患者的共价闭合环状 DNA（cccDNA）水平和 HBsAg 阳性肝细胞比例显著降低。与未治愈患者相比，功能性治愈患者的整合 HBV DNA 和嵌合转录本减少。在 25.5%的功能性治愈患者中存在 HBsAg 阳性肝细胞，而肝内 HBV RNA 仍存在于 72.2%的患者中。肝内 HBsAg 阳性的功能性治愈患者肝内 HBV RNA、整合 HBV DNA 和嵌合转录本水平更高。功能性治愈患者肝内残留的 HBsAg 主要来源于转录活跃的整合 HBV DNA；同时，cccDNA 也可能保持微量转录活性。4 例肝内 HBsAg 阳性且有微量活跃 cccDNA 的功能性治愈患者中有 2 例发生 HBV 复发。
结论
整合 HBV DNA 和 cccDNA 保持转录活性，可能与功能性治愈的肝内 HBsAg 阳性患者的 HBsAg 血清学反弹有关，并与病毒学复发相关。
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