Periodic Reporting for period 1 - D-SOLVE (Understanding the individual host response against Hepatitis D Virus to develop a personalized approach for the management of hepatitis D)
Periodo di rendicontazione: 2022-10-01 al 2024-03-31
Hepatitis D is by far the most severe form of chronic viral hepatitis frequently leading to liver failure, hepatocellular carcinoma and death. Hepatitis D is caused by coinfection of hepatitis B patients with the hepatitis D virus (HDV). Up to 20 Million individuals are infected with HDV worldwide including about 250.000 patients in the European Union. There is very limited knowledge on disease pathophysiology and host-virus interactions explaining the large interindividual variability in the course of hepatitis D. It is in particular unknown why 20-50% are spontaneously able to control HDV replication, why the majority but not all patients progress to advanced stages of liver disease and why only some patients show off-treatment responses to antiviral treatment with either pegylated interferon alpha or the novel HBV/HDV entry inhibitor bulevirtide. As HDV is an orphan disease, no multicenter cohorts of HDV infected patients are available with appropriate biobanking. There is also no reliable animal model available allowing to study host responses. Thus, there is an urgent clinical, social and economic need to better understand individual factors determining the outcome of infection and to identify subjects benefitting from currently available treatments. Hepatitis D is a prototype infection which could hugely benefit from a novel individualized infectious medicine approach. We here aim to perform an unbiased screening of a large multicenter cohort of well-defined HDV-infected patients followed by mechanistic studies to determine the functional role of distinct molecules. Identified specific parameters could have an immediate impact on the personalized surveillance strategies and antiviral treatment approaches. D-SOLVE aims to reduce disease burden, improve patient?s quality of life and safe direct and indirect costs caused by HDV infection by combining exceptional clinical, immunological, bioinformatical and virological expertise from leading centers in Europe.
During the first 18 months of the project, the activities have focused on the setup of a cross-sectional, multicenter cohort of 750 HDV infected patients in Stockholm (Sweden), Bucharest (Romania), Milan (Italy) and Hannover (Germany). In addition to a detailed clinical characterization, we established a centralized biobanking in order to share plasma/ serum, immune cells, liver cells and liver tissue within the consortium. In the first period of the project, we achieved to establish the so far world's largest HDV cohort with almost 650 HDV infected patients and an extensive biosample collection. We harmonized sample processing and established protocols for the innovative, minimal-invasive fine needle aspiration procedure and the preparation of historical biopsies. Important progress has also been made with the development of a clinical study protocol for a structured bulevirtide discontinuation study. In total, in the first period the establishment of appropriate clinical cohorts, the setup of a harmonized biobanking and the establishment of the multi-omics approach formed the basis of the comprehensive and unbiased biomarker screening in well-defined HDV-infected patients and following mechanistic studies.
We successfully engrafted and infected chimeric mice with HBV and HDV/HBV and conducted ChIP-seq and RNA-seq from the livers of these animals. We identified a unique HDV-specific transcriptional signature of 748 genes, which associated with an epigenetic imprinting on gene enhancer-associated histone marks, and which is largely independent from a repressive histone mark. Among these epigenetically coded HDV signature genes are potentially secreted biomarker candidates, which are currently being validated in the blood of infected mice and patients. A second batch of 11 chimeric mice have been successfully transplanted and are currently infected with HDV/HBV for Bulevirtide treatment of 3 months compared to vehicle control.
We successfully engrafted and infected chimeric mice with HBV and HDV/HBV and conducted ChIP-seq and RNA-seq from the livers of these animals. We identified a unique HDV-specific transcriptional signature of 748 genes, which associated with an epigenetic imprinting on gene enhancer-associated histone marks, and which is largely independent from a repressive histone mark. Among these epigenetically coded HDV signature genes are potentially secreted biomarker candidates, which are currently being validated in the blood of infected mice and patients. A second batch of 11 chimeric mice have been successfully transplanted and are currently infected with HDV/HBV for Bulevirtide treatment of 3 months compared to vehicle control.
The D-SOLVE project will setup a personalized approach for the treatment of hepatitis D under consideration of individual biomarkers. The challenge with the recent treatment options is that it is not yet clear who needs to be treated with bulevirtide, for how long and why some patients respond to therapy and others do not. The understanding of individual factors and the link between patient characteristics, viral load, genetics and immune function within the HDV treatment is crucial for an individualized treatment of hepatitis D. The novel aspect would be to identify patients who need antiviral therapy and who would benefit from therapeutic intervention with bulevirtide and/or interferon alpha. The project affects the individual management of patients with this most severe viral hepatitis disease as well as health economic aspects by an individualized approach and thus a cost-efficient use of resources in the European health care systems.