Wang Jing, Yu Yiqi, Li Guojun, Shen Chuan, Meng Zhefeng, Zheng Jianming, Jia Yanhong, Chen Shaolong, Zhang Xiao, Zhu Mengqi, Zheng Jiangjiang, Song Zhangzhang, Wu Jing, Shao Lingyun, Qian Peiyu, Mao Xiaona, Wang Xuanyi, Huang Yuxian, Zhao Caiyan, Zhang Jiming, Qiu Chao, Zhang Wenhong
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China.
J Hepatol. 2017 Sep 21. doi: 10.1016/j.jhep.2017.08.021.
BACKGROUND & AIMS: In diagnostics, serum hepatitis B virus (HBV)-RNA levels are valuable when the HBV-DNA load in circulation is effectively suppressed by nucleos(t)ide analogue (NUC) therapy. This study aimed to determine the intrahepatic viral replication activity reflected in serum HBV-RNA and whether HBV-RNA contributes to liver histological changes in patients treated with NUC.
A cross-sectional set of serum and liver biopsy samples was obtained from patients treated with entecavir, who had undetectable levels of serum HBV-DNA. The correlations between serum HBV-RNA concentration and levels of peripheral and intrahepatic viral replicative forms, as well as histological scores, were analyzed. Quasispecies of serum HBV-RNA and intrahepatic viral replicative forms were examined by deep sequencing. HBV-RNA-positive hepatocytes were visualized by in situ hybridization.
Serum HBV-RNA was detected in 35 of 47 patients (74.47%, 2.33-4.80logcopies/ml). These levels correlated not only with the intrahepatic HBV-RNA level and the ratio of intrahepatic HBV-RNA to covalently closed circular DNA (cccDNA), but also with the histological scores for grading and staging. Regarding quasispecies, serum HBV-RNA was dynamic and more genetically homogenous to simultaneously sampled intrahepatic HBV-RNA than to the cccDNA pool. In situ histology revealed that HBV-RNA-positive hepatocytes were clustered in foci, sporadically distributed across the lobules, and co-localized with hepatitis B surface antigen.
Serum HBV-RNA levels reflect intrahepatic viral transcriptional activity and are associated with liver histopathology in patients receiving NUC therapy. Our study sheds light on the nature of HBV-RNA in the pathogenesis of chronic HBV infection and has implications for the management of chronic hepatitis B during NUC therapy.
Serum HBV-RNA levels are indicative of the intrahepatic transcriptional activity of covalently closed circular DNA and are associated with liver histological changes in patients with chronic B hepatitis who are receiving nucleos(t)ide analogue therapy.
在诊断中，当循环中的乙肝病毒（HBV）DNA载量被核苷（酸）类似物（NUC）治疗有效抑制时，血清HBV - RNA水平具有重要价值。本研究旨在确定血清HBV - RNA所反映的肝内病毒复制活性，以及HBV - RNA是否对接受NUC治疗的患者肝脏组织学变化有影响。
从接受恩替卡韦治疗且血清HBV - DNA水平检测不到的患者中获取血清和肝活检样本的横断面数据集。分析血清HBV - RNA浓度与外周血和肝内病毒复制形式水平以及组织学评分之间的相关性。通过深度测序检测血清HBV - RNA和肝内病毒复制形式的准种。通过原位杂交观察HBV - RNA阳性肝细胞。
47例患者中有35例检测到血清HBV - RNA（74.47%，2.33 - 4.80log拷贝/ml）。这些水平不仅与肝内HBV - RNA水平以及肝内HBV - RNA与共价闭合环状DNA（cccDNA）的比值相关，还与分级和分期的组织学评分相关。关于准种，血清HBV - RNA具有动态性，与同时采集的肝内HBV - RNA相比，其基因同质性更高，而与cccDNA库相比则较低。原位组织学显示，HBV - RNA阳性肝细胞聚集成灶，散在分布于小叶中，并与乙肝表面抗原共定位。
血清HBV - RNA水平反映肝内病毒转录活性，并与接受NUC治疗的患者肝脏组织病理学相关。我们的研究揭示了慢性HBV感染发病机制中HBV - RNA的本质，并对NUC治疗期间慢性乙型肝炎的管理具有启示意义。
血清HBV - RNA水平指示共价闭合环状DNA的肝内转录活性，并与接受核苷（酸）类似物治疗的慢性乙型肝炎患者的肝脏组织学变化相关。
