Journal
GASTROENTEROLOGY
Volume 162, Issue 4, Pages 1160-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2021.12.286
Keywords
Chronic Hepatitis B; Viral Integration; Transcriptome Analysis; Antiviral Treatment; Hepatocellular Carcinogenesis
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Funding
- Gilead Sciences
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This study aimed to assess the effect of viral inhibition on hepatocellular carcinogenesis of hepatitis B virus (HBV) infection and explore the correlation between viral integrations and host gene dysregulation. The results showed that viral inhibition can reduce the number of transcriptionally active viral integrations and viral integrations are significantly correlated with host gene dysregulation.
BACKGROUND & AIMS: Hepatocellular carcinogenesis of hepatitis B virus (HBV) infection may arise from integration of viral DNA into the host genome. We aimed to gauge the effect of viral inhibition on transcriptionally active HBV-host integration events and explore the correlation of viral integrations with host gene dysregulation. METHODS: We leveraged data and biospecimens from an interventional trial, in which patients with HBV viremia above 2000 IU/mL and minimally raised serum liver enzyme were randomized to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years. Total RNA-sequencing was performed on paired liver biopsies taken before and after the 3-year intervention in 119 patients. Virus-host chimeric reads were captured to quantify the number of distinct viral integrations. Dysregulation of a host gene disrupted by viral integration was defined by aberrant expression >2 standard deviations away from samples without viral integration. RESULTS: The TDF (n = 64) and placebo groups (n = 55) were comparable at baseline. Expressed viral integrations were detected in all pre- and posttreatment samples. The number of distinct viral integrations significantly correlated with circulatory bio-markers indicative of viral activities including HBV DNA, RNA, and viral antigens (P <.0003 for all correlations). Moreover, TDF vs placebo achieved a significantly greater reduction in distinct viral integrations, with 3.28-fold and 1.81-fold decreases in the expressed integrations per million reads, respectively (analysis of covariance, P =.037). Besides, viral integrations significantly correlated with host gene dysregulation. CONCLUSION: Inhibition of viral replication reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with substantial viremia. Given the mutagenic potentials of viral integrations, such treatment effects should be considered in patient management.
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