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Reverse inflammaging: Long-term effects of HCV cure on biological age

  • Carlos Oltmanns
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
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  • Zhaoli Liu
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
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  • Jasmin Mischke
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
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  • Jan Tauwaldt
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
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  • Yonatan Ayalew Mekonnen
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany

    Institute for Bioinformatics, University Medicine Greifswald, Greifswald, Germany
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  • Melanie Urbanek-Quaing
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
    Search for articles by this author
  • Jennifer Debarry
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
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  • Benjamin Maasoumy
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany
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  • Heiner Wedemeyer
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany
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  • Anke R.M. Kraft
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany
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  • Cheng-Jian Xu
    Footnotes
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany

    Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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  • Markus Cornberg
    Correspondence
    Corresponding author. Address: Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany.
    Footnotes
    Affiliations
    Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany

    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany

    German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

    TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH). Hannover, Germany

    Search for articles by this author
  • Author Footnotes
    † Shared last authorship
Published:September 21, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.042

      Highlights

      • Individuals with chronic hepatitis C have accelerated epigenetic age compared to healthy controls.
      • DAA treatment and HCV elimination partially reverse the accelerated epigenetic age during long-term follow-up.
      • Accelerated epigenetic aging was not reversed during follow-up in those who developed HCC after HCV elimination.

      Background & Aims

      Chronic hepatitis C virus (HCV) infection can be cured with direct-acting antivirals (DAAs). However, not all sequelae of chronic hepatitis C appear to be completely reversible after sustained virologic response (SVR). Recently, chronic viral infections have been shown to be associated with biological age acceleration defined by the epigenetic clock. The aim of this study was to investigate whether chronic HCV infection is associated with epigenetic changes and biological age acceleration and whether this is reversible after SVR.

      Methods

      We included 54 well-characterized individuals with chronic hepatitis C who achieved SVR after DAA therapy at three time points: DAA treatment initiation, end of treatment, and long-term follow-up (median 96 weeks after end of treatment). Genome-wide DNA methylation status was determined in peripheral blood mononuclear cells (PBMCs) and used to calculate epigenetic age acceleration (EAA) using Horvath’s clock.

      Results

      Individuals with HCV had an overall significant EAA of 3.12 years at baseline compared with -2.61 years in the age- and sex-matched reference group (p <0.00003). HCV elimination resulted in a significant long-term increase in DNA methylation dominated by hypermethylated CpGs in all patient groups. Accordingly, EAA decreased to 1.37 years at long-term follow-up. The decrease in EAA was significant only between the end of treatment and follow-up (p = 0.01). Interestingly, eight individuals who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR.

      Conclusions

      Our data contribute to the understanding of the biological impact of HCV elimination after DAA therapy and demonstrate that HCV elimination can lead to “reverse inflammaging”. In addition, our data support the potential use of biological age as a biomarker for HCV sequelae after SVR.

      Impact and implications

      Chronic hepatitis C virus infection is now curable with direct-acting antivirals, but it remains unclear whether hepatitis C sequelae are fully reversible after viral elimination. Our results suggest that epigenetic changes or acceleration of biological age are reversible in principle, but this requires time, while a lack of reversibility appears to be associated with the development of hepatocellular carcinoma. While most clinical risk scores now take chronological age into account, it may be worthwhile to explore how biological age might improve these scores in the future. Biological age may be a cornerstone for the individualized clinical assessment of patients in the future, as it better reflects patients' lifestyle and environmental exposures over decades.

      Graphical abstract

      Keywords

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      References

      1. World Health Organization. Hepatitis C: Key facts 2021.

        • Westbrook R.H.
        • Dusheiko G.
        Natural history of hepatitis C.
        J Hepatol. 2014; 61: S58-S68
        • Cacoub P.
        • Saadoun D.
        Extrahepatic manifestations of chronic HCV infection.
        New Engl J Med. 2021; 384: 1038-1052
        • van der Meer A.J.
        • Berenguer M.
        Reversion of disease manifestations after HCV eradication.
        J Hepatol. 2016; 65: S95-S108
        • Negro F.
        Residual risk of liver disease after hepatitis C virus eradication.
        J Hepatol. 2021; 74: 952-963
        • Ohlendorf V.
        • Schäfer A.
        • Christensen S.
        • Heyne R.
        • Naumann U.
        • Link R.
        • et al.
        Only partial improvement in health-related quality of life after treatment of chronic hepatitis C virus infection with direct acting antivirals in a real-world setting– results from the German Hepatitis C-Registry (DHC-R).
        J Viral Hepat. 2021; 28: 1206-1218
        • Kondili L.A.
        • Monti M.
        • Quaranta M.G.
        • Gragnani L.
        • Panetta V.
        • Brancaccio G.
        • et al.
        A prospective study of DAA effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort.
        Baltimore Md Hepatol. 2022; 76: 220-232
        • Hensel N.
        • Gu Z.
        • Sagar
        • Wieland D.
        • Jechow K.
        • Kemming J.
        • et al.
        Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection.
        Nat Immunol. 2021; 22: 229-239
        • Aregay A.
        • Owusu Sekyere S.
        • Deterding K.
        • Port K.
        • Dietz J.
        • Berkowski C.
        • et al.
        Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses.
        J Hepatol. 2019; 71: 889-899
        • Strunz B.
        • Hengst J.
        • Deterding K.
        • Manns M.P.
        • Cornberg M.
        • Ljunggren H.
        • et al.
        Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity.
        Nat Commun. 2018; 9: 2275
        • Yates K.B.
        • Tonnerre P.
        • Martin G.E.
        • Gerdemann U.
        • Al Abosy R.
        • Comstock D.E.
        • et al.
        Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans.
        Nat Immunol. 2021; 22: 1020-1029
        • Hlady R.A.
        • Zhao X.
        • El Khoury L.Y.
        • Luna A.
        • Pham K.
        • Wu Q.
        • et al.
        Interferon drives HCV scarring of the epigenome and creates targetable vulnerabilities following viral clearance.
        Hepatology. 2022; 75: 983-996
        • Hamdane N.
        • Jühling F.
        • Crouchet E.
        • El Saghire H.
        • Thumann C.
        • Oudot M.A.
        • et al.
        HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response.
        Gastroenterol (New York, N.Y. 1943). 2019; 156: 2313-2329.e7
        • Morales-Nebreda L.
        • McLafferty F.S.
        • Singer B.D.
        DNA methylation as a transcriptional regulator of the immune system.
        Translational Res : J Lab Clin Med. 2019; 204: 1-18
        • Horvath S.
        • Raj K.
        DNA methylation-based biomarkers and the epigenetic clock theory of ageing.
        Nat Rev Genet. 2018; 19: 371-384
        • Xu C.
        • Bonder M.J.
        • Söderhäll C.
        • Bustamante M.
        • Baïz N.
        • Gehring U.
        • et al.
        The emerging landscape of dynamic DNA methylation in early childhood.
        BMC genomics. 2017; 18: 25
        • Horvath S.
        DNA methylation age of human tissues and cell types DNA methylation age of human tissues and cell types.
        Genome Biol. 2013; 14
        • Ho D.E.
        • Imai K.
        • King G.
        • Stuart E.A.
        MatchIt: nonparametric preprocessing for parametric causal inference.
        J Stat Softw. 2011; 42
        • Hannum G.
        • Guinney J.
        • Zhao L.
        • Zhang L.
        • Hughes G.
        • Sadda S.
        • et al.
        Genome-wide methylation profiles reveal quantitative views of human aging rates.
        Mol Cel. 2013; 49: 359-367
        • Randolph J.J.
        • Austin K.F.
        • Manuel K.
        • Balloun J.L.
        • Randolph J.J.
        • Falbe K.
        • et al.
        A step-by-step guide to propensity score matching in R.
        Pract Assess Res Eval. 2014; 19
        • Aryee M.J.
        • Jaffe A.E.
        • Corrada-Bravo H.
        • Ladd-Acosta C.
        • Feinberg A.P.
        • Hansen K.D.
        • et al.
        Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays.
        Bioinformatics. 2014; 30: 1363-1369
        • Pidsley R.
        • Zotenko E.
        • Peters T.J.
        • Lawrence M.G.
        • Risbridger G.P.
        • Molloy P.
        • et al.
        Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling.
        Genome Biol. 2016; 17
        • Illumina Inc
        BeadArray controls reporter software guide.
        2015
        • Pidsley R.,Y.
        • Wong C.C.
        • Volta M.
        • Lunnon K.
        • Mill J.
        • Schalkwyk L.C.
        A data-driven approach to preprocessing Illumina 450K methylation array data.
        BMC genomics. 2013; 14: 293
        • Oblak L.
        • van der Zaag J.
        • Higgins-Chen A.T.
        • Levine M.E.
        • Boks M.P.
        A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration.
        Ageing Res Rev. 2021; 69101348
        • Heyn H.
        • Li N.
        • Ferreira H.J.
        • Moran S.
        • Pisano D.G.
        • Gomez A.
        • et al.
        Distinct DNA methylomes of newborns and centenarians.
        Proc Natl Acad Sci - PNAS. 2012; 109: 10522-10527
        • Gross A.
        • Jaeger P.
        • Kreisberg J.
        • Licon K.
        • Jepsen K.
        • Khosroheidari M.
        • et al.
        Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA.
        Mol Cel. 2016; 62: 157-168
        • Horvath S.
        • Levine A.J.
        HIV-1 infection accelerates age according to the epigenetic clock.
        J Infect Dis. 2015; 212: 1563-1573
        • Tachiwana H.
        • Shimura M.
        • Nakai-Murakami C.
        • Tokunaga K.
        • Takizawa Y.
        • Sata T.
        • et al.
        HIV-1 vpr induces DNA double-strand breaks.
        Cancer Res. 2006; 66: 627
        • Gindin Y.
        • Gaggar A.
        • Lok A.S.
        • Janssen H.L.A.
        • Ferrari C.
        • Subramanian G.M.
        • et al.
        DNA methylation and immune cell markers demonstrate evidence of accelerated aging in individuals with chronic hepatitis B virus or hepatitis C virus, with or without human immunodeficienct virus Co-infection.
        Clin Infect Dis. 2021; 73: e184-e190
        • Horvath S.
        • Gurven M.
        • Levine M.E.
        • Trumble B.C.
        • Kaplan H.
        • Allayee H.
        • et al.
        An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease.
        Genome Biol. 2016; 17: 171
        • Ohnishi S.
        • Ma N.
        • Thanan R.
        • Pinlaor S.
        • Hammam O.
        • Murata M.
        • et al.
        DNA damage in inflammation-related carcinogenesis and cancer stem cells.
        Oxidative Med Cell longevity 2013. 2013; : 387014-387019
        • Esteban-Cantos A.
        • Rodríguez-Centeno J.
        • Barruz P.
        • Alejos B.
        • Saiz-Medrano G.
        • Nevado J.
        • et al.
        Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial.
        Lancet HIV. 2019; 8: e197-e205
        • Loo N.
        • Hanysak B.
        • Mann J.
        • Ramirez R.
        • Kim J.
        • Mitchell R.
        • et al.
        Real-world observational experience with direct-acting antivirals for hepatitis C: baseline resistance, efficacy, and need for long-term surveillance.
        Medicine (Baltimore). 2019; 98e16254
        • Kanwal F.
        • Kramer J.R.
        • Asch S.M.
        • Cao Y.
        • Li L.
        • El-serag H.B.
        Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
        Hepatology. 2020; 71: 44-55
        • Waziry R.
        • Hajarizadeh B.
        • Grebely J.
        • Amin J.
        • Law M.
        • Danta M.
        • et al.
        Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.
        J Hepatol. 2017; 67: 1204-1212
        • Perna L.
        • Zhang Y.
        • Mons U.
        • Holleczek B.
        • Saum K.
        • Brenner H.
        Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort.
        Clin epigenetics. 2016; 8: 64
        • Best J.
        • Bilgi H.
        • Heider D.
        • Schotten C.
        • Manka P.
        • Bedreli S.
        • et al.
        The GALAD scoring algorithm based on AFP, AFP-L3, and DCP significantly improves detection of BCLC early stage hepatocellular carcinoma.
        Z Gastroenterol. 2016; 54: 1296-1305
        • Marioni R.E.
        • Suderman M.
        • Chen B.H.
        • Horvath S.
        • Bandinelli S.
        • Morris T.
        • et al.
        Tracking the epigenetic clock across the human life course: a meta-analysis of longitudinal cohort data.
        Journals Gerontology Ser A, Biol Sci Med Sci. 2019; 74: 57-61
        • Kananen L.
        • Marttila S.
        • Nevalainen T.
        • Kummola L.
        • Junttila I.
        • Mononen N.
        • et al.
        The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies.
        AGE. 2016; 38: 1-15
        • Goossens N.
        • Negro F.
        Is genotype 3 of the hepatitis C virus the new villain?.
        Hepatology. 2014; 59: 2403-2412