Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta

Authors

  • Benjamin Heidrich,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
    3. German Center for Infection Research (DZIF), partner site, Hannover-Braunschweig, Germany
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  • Cihan Yurdaydın,

    1. Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
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  • Gökhan Kabaçam,

    1. Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
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  • Boris A. Ratsch,

    1. Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
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  • Kalliopi Zachou,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, School of Medicine, Larissa, Greece
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  • Birgit Bremer,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • George N. Dalekos,

    1. Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, School of Medicine, Larissa, Greece
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  • Andreas Erhardt,

    1. Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany
    Current affiliation:
    1. Petrus Hospital, Wuppertal, Germany
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  • Fehmi Tabak,

    1. Department of Infectious Diseases, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey
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  • Kendal Yalcin,

    1. Division of Hepatology, Dicle University, School of Medicine, Diyarbakir, Turkey
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  • Selim Gürel,

    1. Division of Gastroenterology, Faculty of Medicine, Uludað University, Bursa, Turkey
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  • Stefan Zeuzem,

    1. Medizinische Klinik I, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
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  • Markus Cornberg,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. German Center for Infection Research (DZIF), partner site, Hannover-Braunschweig, Germany
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  • C.-Thomas Bock,

    1. Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
    3. German Center for Infection Research (DZIF), partner site, Hannover-Braunschweig, Germany
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  • Heiner Wedemeyer,

    Corresponding author
    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
    3. German Center for Infection Research (DZIF), partner site, Hannover-Braunschweig, Germany
    • Address reprint requests to: Prof. Dr. med. Heiner Wedemeyer, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover D-30625, Germany. E-mail: Wedemeyer.Heiner@mh-hannover.de; fax: +49-511-532-8662.

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  • and for the HIDIT-1 Study Group


  • Potential conflict of interest: Dr. Cornberg consults for, advises, is on the speakers' bureau for, and received grants from Roche. He advises, is on the speakers' bureau for, and received grants from Gilead. Dr. Wedemeyer consults for, advises, and received grants from Abbott, Bristol-Myers Squibb, Gilead, Merck, Novartis, Roche, and Siemens. He consults for and advises AbbVie, Biolex, Boehringer Ingelheim, Eiger, Falk, IST, Janssen-Cilag, Medgenics, Novira, Transgene, and ViiV. Dr. Yurdaydin advises and is on the speakers' bureau for Merck and Gilead. He is on the speakers' bureau for Roche and Novartis. Dr. Zeuzem consults and advises AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Roche, Santaris, and Vertex.

  • Supported by the Hep-Net Study House, the German Liver Foundation, the HepNet e.V. as well as in part by the Integrated Research and Treatment Center Transplantation (IFB-Tx Project 37; Reference No.: 01EO0802), Hannover Medical School, and the German Centre for Infection Research (“DZIF”)

Abstract

Interferon alpha is the only treatment option for hepatitis delta virus (HDV). Trials investigating the efficacy of pegylated interferon alpha (PEG-IFNa) showed HDV RNA negativity rates of 25-30% 24 weeks after therapy. However, the clinical and virological long-term outcome of HDV-infected patients treated with PEG-IFNa is unknown. We performed a retrospective-prospective follow-up of 77 patients treated for 48 weeks with either PEG-alfa-2a and adefovir (ADV) or either drug alone in the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-1) trial. Long-term follow-up data were available for 58 out of 77 patients (75%) with a median time of follow-up of 4.5 (0.5-5.5) years and a median 3 visits per patient. Patients treated with ADV alone received retreatment with PEG-IFNa (48% versus 19%; P = 0.02) more often. Hepatitis B virus surface antigen (HBsAg) became negative in six PEG-IFNa-treated patients until the end of long-term follow-up (10%). Sixteen patients tested HDV RNA-negative 6 months after PEG-IFNa treatment who were entered in the long-term follow-up study. Out of these, nine individuals tested HDV RNA-positive at least once during further long-term follow-up, with seven patients being HDV RNA-positive at the most recent visit. Clinical endpoints (liver-related death, liver transplantation, hepatic decompensation, hepatocellular carcinoma) were observed in three PEG-IFNa-treated (8%) and three ADV-treated (14%) patients during posttreatment long-term follow-up with an overall annual event rate of 2.5% (4.9% in cirrhosis). Sequencing confirmed the reappearance of pretreatment virus strains in all cases. Conclusion: Late HDV RNA relapses may occur after PEG-IFNa therapy of hepatitis delta and thus the term sustained virological response should be avoided in HDV infection. The annual posttreatment rate of clinical events in hepatitis delta patients eligible for PEG-IFNa therapy is about 2.5% and 4.9% in patients with cirrhosis. (Hepatology 2014;60:87-97)

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