Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients

• Published in: Journal of hepatology Vol. 68; no. 1; pp. 16 - 24
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2018; Elsevier Science Ltd
• Subjects: Biopsy; Chronic hepatitis B; Chronic infection; Circular DNA; Circular RNA; Deoxyribonucleic acid; DNA; Hepatitis; Hepatitis B surface antigen; Hepatocytes; Histopathology; Liver; Medical treatment; Nucleos(t)ide analogues; Pathogenesis; Ribonucleic acid; RNA; RNA viruses; Transcription; Viral replication; Viral RNA; Viral RNA; Nucleos(t)ide analogues; Histopathology; Chronic hepatitis B; Viral replication
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2017.08.021

[Display omitted] •Detectable HBV-RNA in serum of NUC successfully treated patients.•Serum HBV-RNA is indicative of the transcriptional activity of cccDNA.•Quasispecies of serum HBV-RNA and intrahepatic HBV-RNA are similar.•Levels of HBV-RNA correlate with histopathological scores. 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%, 2.33–4.80log10copies/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.