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      Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg‐positive chronic hepatitis B

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          Abstract

          Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG‐IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg‐positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99‐01 study). Patients received 52 weeks PEG‐IFN monotherapy (n = 136) or PEG‐IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG‐IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG‐IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow‐up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG‐IFN treatment. Early on‐treatment HBV RNA level may be used to predict nonresponse.

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          IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome.

          HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and in vivo, and pegylated IFN-α is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-α suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-α inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and subgenomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of IFN-α resulted in cccDNA-bound histone hypoacetylation as well as active recruitment to the cccDNA of transcriptional corepressors. IFN-α treatment also reduced binding of the STAT1 and STAT2 transcription factors to active cccDNA. The inhibitory activity of IFN-α was linked to the IRSE, as IRSE-mutant HBV transcribed less pgRNA and could not be repressed by IFN-α treatment. Our results identify a molecular mechanism whereby IFN-α mediates epigenetic repression of HBV cccDNA transcriptional activity, which may assist in the development of novel effective therapeutics.
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            Interferons alpha and beta as immune regulators--a new look.

            C A Biron (2001)
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              Attacking hepatitis B virus cccDNA--The holy grail to hepatitis B cure.

              HBV deposits a covalently closed circular DNA form, called cccDNA, in the nucleus of infected cells. As the central transcription template, the cccDNA minichromosome is a key intermediate in the HBV life cycle. Its location in the nucleus makes cccDNA a difficult target for antivirals and immune response, and therefore it is responsible for chronicity of HBV infection. While little is known about the mechanisms involved in cccDNA formation, current research is accumulating data on the mechanisms regulating transcription from cccDNA, and the first potential targeting approaches have been reported. This review will summarize our knowledge about cccDNA biology and the latest advances in cccDNA targeting strategies in order to finally achieve an HBV cure.
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                Author and article information

                Contributors
                harry.janssen@uhn.ca
                Journal
                J Viral Hepat
                J. Viral Hepat
                10.1111/(ISSN)1365-2893
                JVH
                Journal of Viral Hepatitis
                John Wiley and Sons Inc. (Hoboken )
                1352-0504
                1365-2893
                17 March 2020
                June 2020
                : 27
                : 6 ( doiID: 10.1111/jvh.v27.6 )
                : 610-619
                Affiliations
                [ 1 ] Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam The Netherlands
                [ 2 ] Department of Gastroenterology and Rheumatology Section of Hepatology University Hospital Leipzig Leipzig Germany
                [ 3 ] Institute of Health Policy, Management and Evaluation University of Toronto Toronto Canada
                [ 4 ] Toronto Center for Liver Disease Toronto Western and General Hospital University Health Network Toronto Canada
                Author notes
                [*] [* ] Correspondence

                Harry L.A. Janssen, Division of Gastroenterology, University Health Network, University of Toronto & Erasmus University Rotterdam, 399 Bathurst Street, 6B FP, Room 164, Toronto, ON, M5T 2S8.

                Email: harry.janssen@ 123456uhn.ca

                Author information
                https://orcid.org/0000-0003-0460-4920
                https://orcid.org/0000-0001-8607-1616
                Article
                JVH13272
                10.1111/jvh.13272
                7383601
                32052503
                6f6f1e1d-c762-4d50-86ec-28faa165da9a
                © 2020 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 15 October 2019
                : 15 January 2020
                : 24 January 2020
                Page count
                Figures: 5, Tables: 1, Pages: 10, Words: 6151
                Funding
                Funded by: Foundation for Liver Research , open-funder-registry 10.13039/501100000404;
                Funded by: F. Hoffmann‐La Roche Ltd. , open-funder-registry 10.13039/100007013;
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                June 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:27.07.2020

                Infectious disease & Microbiology
                chronic hepatitis b infection,functional cure,peginterferon treatment,serum marker,treatment response

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