How does the hepatitis D Virus bypass the immune system?

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

Projekt: B14

Dr. Lisa Sandmann

Project: B14

Dr. Helenie Kefalakes

Projekt: B14

Publications of the Project B14

Publications 2023 

3P and 5P models of limited value for the detection of clinically significant portal hypertension in patients with hepatitis delta. Sandmann L, Tergast TL, Wedemeyer H, Deterding K, Maasoumy B.  J Hepatol. 2023 Jul;79(1):e47-e49. doi: 10.1016/j.jhep.2023.01.004. Epub 2023 Jan 18. PMID: 36669702.

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, LĂŒtgehetmann 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.

Publications 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

Publications 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

Publications 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 Publications

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