Highlights
- •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.
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.
Methods
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.
Results
Serum HBV-RNA was detected in 35 of 47 patients (74.47%, 2.33–4.80 log10 copies/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.
Conclusion
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.
Lay summary
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 01, 2017
Accepted:
August 18,
2017
Received in revised form:
August 17,
2017
Received:
February 23,
2017
Identification
Copyright
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
