How does the hepatitis D Virus bypass the immune system?

Prof. Wedemeyer / Dr. Sandmann / Dr. Kefalakes

What is this research project about?

Schematic figure of the hepatitis B and hepatitis D virus (Created with Biorender).

What is this research project about?

Infection with the hepatitis D virus (HDV) induces the least frequent but most severe form of chronic viral hepatitis, inducing liver cirrhosis and hepatocellular carcinoma in ~70% of patients. Development of chronic infection is thought to be immune-mediated, however there is not sufficient data available to support this. Chronic HDV infection results from either simultaneous infection with the hepatitis B virus (HBV) or superinfection of patients already infected with HBV. The aim of this project is to define how HDV circumvents the immune system leading to chronic infection.

What’s the current status?

With high rates of chronicity and the associated risk for the development of end stage liver disease and hepatocellular carcinoma, prevention of infection and/or effective antiviral treatment options are decisive. Currently, the only available antiviral treatment options are pegylated-interferon alpha with an efficacy of 25-33% and bulevirtide. The latter has only a conditional authorization in Europe, as long-term data on its efficacy are still missing. Understanding mechanisms of chronicity and disease pathogenesis are essential for the development of personalized treatment options, which are not available for chronic HDV infection so far.

Overview of the planned study (created with Biorender).

What are the project goals?

The aim of the project is to characterize and understand why the immune system leads to the establishment and maintenance of chronic HDV infection. These insights will provide the cornerstone for the development of personalized treatment options and prevention strategies in the future. Thereby, the project will alleviate the burden of disease associated with HDV infection in the long-term.

How do we get there?

Our preliminary work shows that immune cells, and especially CD4+ T cells, are implicated in viral control during chronic HDV infection. Thus, we would like to use a systems immunology approach to dissolve the host susceptibility to HDV infection, with a special focus on CD4+ T cells. Here, immune-cell subsets will be analyzed in different patient cohorts by flow cytometry, single-cell transcriptomics, epigenetics and proteomics. Interesting findings will be validated in vitro and in vivo with an ultimate goal to generate an immunological biomarker or treatment approach.

Projectleader

Project title: Dissolving immune control of hepatitis D virus infection

Prof. Dr. Heiner Wedemeyer

Project: B14

CV & VIDEO

Dr. Lisa Sandmann

Project: B14

CV & VIDEO

Dr. Helenie Kefalakes

Project: B14

CV & CONTACT

Publications of the Project B14

Publikationen 2025

Quality of life improves during antiviral therapy with bulevirtide J. C. Eichholz, C. Dietz-Fricke, S. K. Mrowietz, K. Dinkelborg, K. Port, H. Wedemeyer, et al. Z Gastroenterol 2025 Vol. 63 Issue 9 Pages 930-941 Accession Number: 40934944 DOI: 10.1055/a-2633-6361

Droplet Digital PCR: A Powerful Tool for Accurate Quantification of Hepatitis D Virus RNA Levels and Verification of Detection Limits L. Sandmann, L. Windzio, B. Bremer, S. Falak, J. Beheim-Schwarzbach, A. Kummrow, et al. J Viral Hepat 2025 Vol. 32 Issue 6 Pages e70036 Accession Number: 40372088 PMCID: PMC12080313 DOI: 10.1111/jvh.70036

Sequence analysis of the hepatitis D virus across genotypes reveals highly conserved regions amidst evidence of recombination S. Chowdhury, C. Jacobsen, D. P. Depledge, H. Wedemeyer, L. Sandmann and H. Kefalakes Virus Evol 2025 Vol. 11 Issue 1 Pages veaf012 Accession Number: 40123834 PMCID: PMC11927530 DOI: 10.1093/ve/veaf012

A novel in vitro system for simultaneous infections with hepatitis B, C, D and E viruses R. Fouillé, E. R. Verrier, A. De Meyer, L. Verhoye, M. Michelet, R. Barnault, et al JHEP Rep 2025 Vol. 7 Issue 5 Pages 101383 Accession Number: 40242313 PMCID: PMC11999259 DOI: 10.1016/j.jhepr.2025.101383

Frequency, Severity and Impact of Pegylated Interferon Alpha-Associated Flares in Hepatitis D Infection S. Hardtke, C. Yurdaydin, F. A. Caruntu, M. G. Curescu, K. Yalcin, U. S. Akarca, et al. J Viral Hepat 2025 Vol. 32 Issue 4 Pages e70022 Accession Number: 40087915 PMCID: PMC11909584 DOI: 10.1111/jvh.70022

TIGIT-expression on natural killer cell subsets is an early indicator of alleviating liver inflammation following bulevirtide treatment in chronic hepatitis D P. C. Chen, K. Deterding, S. A. Engelskircher, K. Port, L. Sandmann, A. Chakkadath, et al. Hepatology 2025 Accession Number: 39847437 DOI: 10.1097/hep.0000000000001238

Phase 2 Randomised Study of Bulevirtide as Monotherapy or Combined With Peg-IFNα-2a as Treatment for Chronic Hepatitis Delta P. Lampertico, P. O. Bogomolov, V. Chulanov, T. Stepanova, V. Morozov, L. Allweiss, et al. Liver Int 2025 Vol. 45 Issue 2 Pages e70008 Accession Number: 39853842 PMCID: PMC11760647 DOI: 10.1111/liv.70008

Value and Kinetics of Virological Markers in the Natural Course of Chronic Hepatitis D Virus Infection L. Sandmann, V. Ohlendorf, A. Ehrenbauer, B. Bremer, A. R. M. Kraft, M. Cornberg, et al. Liver Int 2025 Vol. 45 Issue 2 Pages e70003 Accession Number: 39846714 PMCID: PMC11756344 DOI: 10.1111/liv.70003

Hepatitis D Virus Infection: Pathophysiology, Epidemiology and Treatment. Report From the Third Delta Cure Meeting 2024 E. Degasperi, L. Sandmann, H. Wedemeyer and P. Lampertico Liver Int 2025 Vol. 45 Issue 7 Pages e70189 Accession Number: 40540405 DOI: 10.1111/liv.70189

Publikationen 2024

The Challenge of Anticoagulation in Liver Cirrhosis. Eichholz JC, Wedemeyer H, Maasoumy B.  Visc Med. 2024 Jan;39(6):169-176. doi: 10.1159/000535438. Epub 2023 Dec 21. PMID: 38205270; PMCID: PMC10775854.

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication. Wißing, M. H., T. L. Meister, M. K. Nocke, A. Gömer, M. Masovic, L. Knegendorf, Y. Brüggemann, V. Bader, A. Siddharta, C. T. Bock, A. Ploss, S. P. Kenney, K. F. Winklhofer, P. Behrendt, H. Wedemeyer, E. Steinmann, and D. Todt. 2024. Nat Commun 15: 4855.

Management of chronic viral hepatitis B and D. Dietz-Fricke, C., and H. Wedemeyer. 2024. Clin Liver Dis (Hoboken) 23: e0221.

Hepatitis D virus – still the devil ! A. Wranke and H. Wedemeyer Hepatology 2024 Accession Number: 39471056 DOI: 10.1097/hep.0000000000001144

Antiviral therapy for chronic hepatitis delta: new insights from clinical trials and real-life studies P. Lampertico, M. P. Anolli, D. Roulot and H. Wedemeyer Gut 2024 Accession Number: 39663120 DOI: 10.1136/gutjnl-2024-332597

[Significant increase in newly diagnosed hepatitis B and C cases in Germany due to screening] D. Hüppe, Y. Serfert, M. Cornberg and H. Wedemeyer Z Gastroenterol 2024 Accession Number: 39586812 DOI: 10.1055/a-2435-5069

Publikationen 2023 

A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D. Wedemeyer H, Aleman S, Brunetto MR, Blank A, Andreone P, Bogomolov P, Chulanov V, Mamonova N, Geyvandova N, Morozov V, Sagalova O, Stepanova T, Berger A, Manuilov D, Suri V, An Q, Da B, Flaherty J, Osinusi A, Liu Y, Merle U, Schulze Zur Wiesch J, Zeuzem S, Ciesek S, Cornberg M, Lampertico P; MYR 301 Study Group.  N Engl J Med. 2023 Jul 6;389(1):22-32. doi: 10.1056/NEJMoa2213429. Epub 2023 Jun 22. PMID: 37345876.

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA. Deterding K, Xu C, Port K, Dietz-Fricke C, Xun J, Maasoumy B, Cornberg M, Wedemeyer H.  J Viral Hepat. 2023 Jul;30(7):597-606. doi: 10.1111/jvh.13831. Epub 2023 Mar 28. PMID: 36924318.

Clinical long-term outcome of hepatitis D compared to hepatitis B monoinfection. Wranke A, Heidrich B, Deterding K, Hupa-Breier KL, Kirschner J, Bremer B, Cornberg M, Wedemeyer H.  Hepatol Int. 2023 Dec;17(6):1359-1367. doi: 10.1007/s12072-023-10575-0. Epub 2023 Oct 3. PMID: 37789170; PMCID: PMC10661878.

HDV RNA assays: Performance characteristics, clinical utility, and challenges. Wedemeyer H, Leus M, Battersby TR, Glenn J, Gordien E, Kamili S, Kapoor H, Kessler HH, Lenz O, Lütgehetmann M, Mixson-Hayden T, Simon CO, Thomson M, Westman G, Miller V, Terrault N, Lampertico P; HDV RNA Assays Writing Group at the HBV Forum.  Hepatology. 2023 Aug 28. doi: 10.1097/HEP.0000000000000584. Epub ahead of print. PMID: 37640384.

Interferon-based treatment of chronic hepatitis D. Sandmann L, Wedemeyer H. Liver Int. 2023 Aug;43 Suppl 1:69-79. doi: 10.1111/liv.15410. Epub 2022 Sep 2. PMID: 36002390.

Kinetics and predictive value of HBcrAg, HBV RNA and anti-HBc during bulevirtide treatment of chronic HDV-infected patients. Sandmann L, Deterding K, Bremer B, Port K, Cornberg M, Wedemeyer H, Maasoumy B.  J Viral Hepat. 2023 Apr;30(4):283-286. doi: 10.1111/jvh.13804. Epub 2023 Jan 23. PMID: 36648369.

Treating hepatitis D with bulevirtide – Real-world experience from 114 patients. Dietz-Fricke C, Tacke F, Zöllner C, Demir M, Schmidt HH, Schramm C, Willuweit K, Lange CM, Weber S, Denk G, Berg CP, Grottenthaler JM, Merle U, Olkus A, Zeuzem S, Sprinzl K, Berg T, van Bömmel F, Wiegand J, Herta T, Seufferlein T, Zizer E, Dikopoulos N, Thimme R, Neumann-Haefelin C, Galle PR, Sprinzl M, Lohse AW, Schulze Zur Wiesch J, Kempski J, Geier A, Reiter FP, Schlevogt B, Gödiker J, Hofmann WP, Buggisch P, Kahlhöfer J, Port K, Maasoumy B, Cornberg M, Wedemeyer H, Deterding K.  JHEP Rep. 2023 Mar 15;5(4):100686. doi: 10.1016/j.jhepr.2023.100686. PMID: 37025462; PMCID: PMC10071092.

Enhanced monitoring and detection of recent genotype 3 hepatitis E virus infection through urine antigen testing. Stahl Y, Kabar I, Heinzow H, Maasoumy B, Bremer B, Wedemeyer H, Schmidt HH, Pietschmann T, Schlevogt B, Behrendt P. Emerg Microbes Infect. 2023 Dec;12(2):2251598. Epub 2023 Aug 31. PMID: 37649441; PMCID: PMC10512750.

Hepatitis D virus infection: Pathophysiology, epidemiology and treatment. Report from the first international delta cure meeting 2022
JHEP Rep. 2023 Jun 28;5(9):100818. doi: 10.1016/j.jhepr.2023.100818. eCollection 2023 Sep.
Pietro Lampertico , Elisabetta Degasperi , Lisa Sandmann , Heiner Wedemeyer ; Delta Cure 2022 Working Group

Quality-of-life scores improve after 96 weeks of PEG-IFNa-2a treatment of hepatitis D: An analysis of the HIDIT-II trial.  Dinkelborg K, Kahlhöfer J, Dörge P, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, Akarca US, Gürel S, Zeuzem S, Erhardt A, Lüth S, Papatheodoridis GV, Keskin O, Port K, Radu M, Celen MK, Idilman R, Weber K, Stift J, Wittkop U, Heidrich B, Mederacke I, von der Leyen H, Dienes HP, Cornberg M, Koch A, Manns MP, Wedemeyer H, Deterding K; HIDIT-2 Study Team. Liver Int. 2023 Aug;43(8):1663-1676. doi: 10.1111/liv.15602. Epub 2023 May 15. PMID: 37183524.

Publikationen 2021 

Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis delta: Results from the HIDIT-II study. Bremer B, Anastasiou OE, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, Akarca US, Gurel S, Zeuzem S, Erhardt A, Luth S, Papatheodoridis GV, Radu M, Idilman R, Manns MP, Cornberg M, Yurdaydin C, Wedemeyer H. Liver Int 2021;41(2):295-299

Liver-Resident Bystander CD8 T Cells Contribute to Liver Disease Pathogenesis in Chronic Hepatitis D Virus Infection. Kefalakes H, Horgan XJ, Jung MK, Amanakis G, Kapuria D, Bolte FJ, Kleiner DE, Koh C, Heller T, Rehermann B. Liver-Resident Bystander Gastroenterology 2021;161(5):1567-1583

Publikationen 2020 

Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta. Wranke A, Hardtke S, Heidrich B, Dalekos G, Yalcin K, Tabak F, Gurel S, Cakaloglu Y, Akarca US, Lammert F, Haussinger D, Muller T, Wobse M, Manns MP, Idilman R, Cornberg M, Wedemeyer H, Yurdaydin C.  J Viral Hepat 2020;27(12):1359-1368

Publikationen 2019

Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Wedemeyer H, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, Akarca US, Gurel S, Zeuzem S, Erhardt A, Luth S, Papatheodoridis GV, Keskin O, Port K, Radu M, Celen MK, Idilman R, Weber K, Stift J, Wittkop U, Heidrich B, Mederacke I, von der Leyen H, Dienes HP, Cornberg M, Koch A, Manns MP, HIDIT-II study team. Lancet Infect Dis 2019;19(3):275-286

Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells. Dias J, Hengst J, Parrot T, Leeansyah E, Lunemann S, Malone DFG, Hardtke S, Strauss O, Zimmer CL, Berglin L, Schirdewahn T, Ciesek S, Marquardt N, von Hahn T, Manns MP, Cornberg M, Ljunggren HG, Wedemeyer H, Sandberg JK, Bjorkstrom NK. J Hepatol 2019;71(2):301-312

Hepatitis D Virus-Specific CD8 T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection. Kefalakes H, Koh C, Sidney J, Amanakis G, Sette A, Heller T, Rehermann B. Gastroenterology 2019;156(6):1805-1819

previous Publikationen 

The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells. Schirdewahn T, Grabowski J, Sekyere SO, Bremer B, Wranke A, Lunemann S, Schlaphoff V, Kirschner J, Hardtke S, Manns MP, Cornberg M, Wedemeyer H, Suneetha PV.  J Infect Dis 2017;215(1):139-149

Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta. Wedemeyer H, Yurdaydin C, Dalekos GN, Erhardt A, Cakaloglu Y, Degertekin H, Gurel S, Zeuzem S, Zachou K, Bozkaya H, Koch A, Bock T, Dienes HP, Manns MP, HIDIT Study Grp. N Engl J Med 2011;364(4):322-331

Publications of the Project B14