TY - JOUR
T1 - Inhibition of Viral Replication Reduces Transcriptionally Active Distinct Hepatitis B Virus Integrations With Implications on Host Gene Dysregulation
AU - Hsu, Yao Chun
AU - Suri, Vithika
AU - Nguyen, Mindie H.
AU - Huang, Yen Tsung
AU - Chen, Chi Yi
AU - Tseng, Cheng Hao
AU - Chang, I. Wei
AU - Wu, Chun Ying
AU - Lin, Jaw Town
AU - Pan, David Z.
AU - Gaggar, Anuj
AU - Podlaha, Ondrej
N1 - Funding Information:
Conflict of interest These authors disclose the following: Yao-Chun Hsu: Research support from Gilead Sciences; advisory committee member for Gilead Sciences; paid lecture for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Novartis. Vithika Suri: Employment and stock ownership of Gilead Sciences. Mindie H. Nguyen: Research support from Glycotest, Gilead Sciences, Enanta, Pfizer, Vir, B.K. Kee Foundation, and National Cancer Institute; advisory board/consulting for Intercept, Novartis, Spring Bank, Gilead, Janssen, Eisai, Bayer, Laboratory of Advanced Medicine, Helio Health, and Eli Lilly. Cheng-Hao Tseng: Paid lecture for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Roche, and Bayer. Jaw-Town Lin: Research support from Gilead Sciences. David Z. Pan: Employment and stock ownership of Gilead Sciences. Anuj Gagger: Employment and stock ownership of Gilead Sciences. Ondrej Podlaha: Employment and stock ownership of Gilead Sciences. The remaining authors disclose no conflicts.
Funding Information:
The authors are grateful to all investigators who contributed in the TORCH-B trial (details listed below). Jaw-Town Lin acknowledges research support from the Taipei Institute of Pathology (TIP) and Taiwan Ministry of Science and Technology (MOST 109-2327-B-039-001). Yao-Chun Hsu acknowledges research support from the E-Da Hospital (EDPJ109060) and Taiwan Ministry of Science and Technology (107-2314-B-650-014-MY3). The authors thank Vlad Malkov and Emon Elboudwarej for statistical consultations, and Ying-Ju Lee for coordination among different institutes.
Funding Information:
The authors are grateful to all investigators who contributed in the TORCH-B trial (details listed below). Jaw-Town Lin acknowledges research support from the Taipei Institute of Pathology (TIP) and Taiwan Ministry of Science and Technology (MOST 109-2327-B-039-001). Yao-Chun Hsu acknowledges research support from the E-Da Hospital (EDPJ109060) and Taiwan Ministry of Science and Technology (107-2314-B-650-014-MY3). The authors thank Vlad Malkov and Emon Elboudwarej for statistical consultations, and Ying-Ju Lee for coordination among different institutes. The TORCH-B study group includes the following contributors in addition to the listed authors:, Ming-Jong Bair (Mackay Medical College, New Taipei City, Taiwan), Chi-Yang Chang (Fu-Jen Catholic University Hospital, Taipei, Taiwan), Chieh-Chang Chen (National Taiwan University Hospital, Taipei, Taiwan), Jyh-Jou Chen (Chi-Mei Medical Centre, Liouying Hospital, Tainan, Taiwan), Wen-Hui Ku (Taipei Institute of Pathology, Taipei, Taiwan), Teng-Yu Lee (Taichung Veterans General Hospital, Taichung, Taiwan), Lein-Ray Mo (Tainan Municipal Hospital, Tainan, Taiwan), Chi-Ming Tai (E-Da Hospital and I-Shou University, Kaohsiung, Taiwan), Ming-Shiang Wu (National Taiwan University Hospital, Taipei, Taiwan), Data collected for this study, including de-identified individual participant data and data dictionaries defining fields in the datasets will be made available on request to investigators for academic research after a proposal has been approved by the study committee identified for this purpose. The investigator will need to sign a data access agreement with consideration of potential overlaps between the proposal and ongoing efforts by the TORCH-B study group. Proposals should be directed to the corresponding author via email at [email protected]. Order of Authors (with Contributor Roles):, Yao-Chun Hsu, MD, PhD (Data curation: Equal; Formal analysis: Supporting; Funding acquisition: Lead; Methodology: Supporting; Project administration: Supporting; Supervision: Equal; Writing ? original draft: Equal; Writing ? review & editing: Lead) Vithika Suri, PhD (Data curation: Supporting; Funding acquisition: Supporting; Investigation: Equal; Project administration: Lead; Resources: Equal; Supervision: Supporting; Visualization: Supporting; Writing ? review & editing: Supporting) Mindie H. Nguyen, MD (Methodology: Supporting; Supervision: Supporting; Writing ? review & editing: Equal) Yen-Tsung Huang, MD (Formal analysis: Supporting; Methodology: Supporting; Software: Supporting; Supervision: Supporting; Writing ? review & editing: Supporting) Chi-Yi Chen, MD (Data curation: Supporting; Resources: Supporting; Writing ? review & editing: Supporting) I-Wei Chen, MD (Data curation: Supporting; Writing ? review & editing: Supporting) Cheng-Hao Tseng, MD (Data curation: Supporting; Writing ? review & editing: Supporting) Chun-Ying Wu, MD, PhD (Data curation: Supporting; Writing ? review & editing: Supporting) Jaw-Town Lin, MD, PhD (Funding acquisition: Supporting; Project administration: Supporting; Resources: Supporting; Supervision: Supporting; Writing ? review & editing: Supporting) David Pan, PhD (Formal analysis: Supporting; Methodology: Supporting; Software: Supporting; Visualization: Supporting; Writing ? review & editing: Supporting) Anuj Gaggar, PhD (Conceptualization: Supporting; Funding acquisition: Equal; Project administration: Supporting; Resources: Supporting; Supervision: Supporting; Writing ? review & editing: Supporting) Ondrej Podlaha, PhD (Conceptualization: Equal; Data curation: Supporting; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Visualization: Lead; Writing ? original draft: Equal; Writing ? review & editing: Equal) Funding This study was funded by Gilead Sciences.
Funding Information:
Funding This study was funded by Gilead Sciences.
Publisher Copyright:
© 2022 AGA Institute
PY - 2022/4
Y1 - 2022/4
N2 - 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 biomarkers 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.
AB - 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 biomarkers 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.
KW - Antiviral Treatment
KW - Chronic Hepatitis B
KW - Hepatocellular Carcinogenesis
KW - Transcriptome Analysis
KW - Viral Integration
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UR - http://www.scopus.com/inward/citedby.url?scp=85125910391&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.12.286
DO - 10.1053/j.gastro.2021.12.286
M3 - Article
C2 - 34995536
AN - SCOPUS:85125910391
SN - 0016-5085
VL - 162
SP - 1160-1170.e1
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -