Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B

Erken, R.; Loukachov, V.; Dort, K.; Hurk, A. den; Takkenberg, R.B.; Niet, A.; ... ; Kootstra, N. (2022)

Article / Letter to editor

Background and Aims: HBV can integrate in the host genome of the hepat-
ocyte and recent findings suggest that integrated HBV contributes to the per-
sistent production of viral proteins. Here, we quantified the levels of integrated
HBV in patients with chronic hepatitis B (CHB) and analyzed the relation be-
tween HBV integration, virological activity (plasma HBV DNA and HBsAg lev-
els), and clinical outcomes.
Approach and Results: We developed and validated a multistep Arthrobacter
luteus (Alu)- PCR that specifically amplifies integrated HBV and RT-Alu- PCR
detecting mRNA transcripts derived from integrated HBV. Pretreatment liver
biopsy samples and baseline characteristics of 124 patients with CHB either
treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or re-
ceiving no treatment were available for analysis. Integrated HBV sequences
containing open reading frame S and X (but not C) and S and X mRNA tran-
scripts derived from integrated HBV could be detected and quantified in liver
biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine
aminotransferase plasma levels, and the liver histology activity index but not
to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma
pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic
regression analysis showed that lower baseline HBV integration levels were
independently associated with HBsAg loss (functional cure) within 5 years
follow-up.
Conclusions: Integrated HBV levels are strongly correlated with surrogate
markers for virological activity but not to cccDNA levels and are predictive
for HBsAg loss. Our data suggest that integrated HBV is closely related to
HBV replication and may therefore be an important tool in the evaluation and
development of treatment modalities aiming to cure CHB.

• All authors: Erken, R.; Loukachov, V.; Dort, K.; Hurk, A. den; Takkenberg, R.B.; Niet, A.; Jansen, L.; Willemse, S.; Reesink, H.; Kootstra, N.
• Date: 2022-02-14
• Journal: Hepatology
• Volume: 76
• Issue: 1
• Pages: 196 - 206
• DOI: doi:10.1002/hep.32352
• Link: https://journals.lww.com/hep/fulltext/2022/07000/quantified_integrated_h...