Periodic Reporting for period 2 - D-SOLVE (Understanding the individual host response against Hepatitis D Virus to develop a personalized approach for the management of hepatitis D)
Reporting period: 2024-04-01 to 2025-09-30
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 which could explain the large interindividual variability in the course of hepatitis D. Particularly, it is unknown (i) why 20-50% are spontaneously able to control HDV replication, (ii) why the majority but not all patients progress to advanced stages of liver disease and (iii) why only some patients show off-treatment responses to antiviral treatment with either pegylated interferon alpha or the novel HBV/HDV entry inhibitor bulevirtide.
These examples clearly show that Hepatitis D is a prototype infection which could hugely benefit from a novel individualized infectious medicine approach. However, as HDV is an orphan disease, so far no multicenter cohorts of HDV infected patients with appropriate biobanking are available. 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 benefiting from currently available treatments.
With the D-SOLVE consortium we bring together exceptional clinical, immunological, bioinformatical and virological expertise from leading centers in Europe with the 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 resulting in reduced disease burden, improved patient’s quality of life and lowered direct and indirect costs caused by HDV infection.
These examples clearly show that Hepatitis D is a prototype infection which could hugely benefit from a novel individualized infectious medicine approach. However, as HDV is an orphan disease, so far no multicenter cohorts of HDV infected patients with appropriate biobanking are available. 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 benefiting from currently available treatments.
With the D-SOLVE consortium we bring together exceptional clinical, immunological, bioinformatical and virological expertise from leading centers in Europe with the 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 resulting in reduced disease burden, improved patient’s quality of life and lowered direct and indirect costs caused by HDV infection.
During the second reporting period, the D-SOLVE Consortium made substantial progress toward its scientific and translational objectives. Following the successful establishment of a multicenter, cross-sectional cohort of patients infected with hepatitis D virus (HDV) across Sweden, Romania, Italy, and Germany, the project now holds the world’s largest HDV cohort with a centralized biosample collection. This includes plasma, serum, immune cells, liver cells, and liver tissue, enabling a robust foundation for biomarker discovery and mechanistic studies.
A key achievement during this period was the initiation of a multicenter study on the structured discontinuation of bulevirtide (BLV), which is expected to be a landmark contribution to HDV therapy. This study aims to identify prognostic biomarkers for virological control following treatment cessation and has generated significant international interest. First results are expected in 2026. In parallel, preclinical investigations in HDV-infected mouse models revealed virus-specific transcriptomic and epigenetic perturbations in the liver, associated with inflammation and innate immune activation. These findings led to the identification of novel, previously unrecognized biomarker candidates, which are now being validated in patient samples through close collaboration between clinicians and scientists within the consortium. First insights into the cellular and molecular mechanisms underlying HDV control and liver disease progression were generated and further analysis are ongoing. The consortium identified immune signatures linked to fibrosis progression and viral replication, including specific gene programs and protein biomarkers. The project also generated high-dimensional data on the intrahepatic cellular composition of HDV-infected patients and initiated spatial transcriptomic profiling in both progressing and non-progressing cases. The successful implementation of these techniques represents a major milestone in HDV research and sets the stage for mechanistic insights into intrahepatic immunity. Notably, the immune checkpoint inhibitor TIGIT was identified on NK cell subtypes as a hallmark of liver inflammation in HDV infection. Its reappearance during BLV therapy may explain the rapid improvement in liver enzyme levels observed in treated patients. Immunological profiling revealed distinct immune signatures associated with cirrhosis and treatment response. In particular, anti-interferon alpha (IFNa) antibodies were identified as potential predictive markers for interferon treatment response, supporting the development of a personalized medicine approach in HDV therapy.
A key achievement during this period was the initiation of a multicenter study on the structured discontinuation of bulevirtide (BLV), which is expected to be a landmark contribution to HDV therapy. This study aims to identify prognostic biomarkers for virological control following treatment cessation and has generated significant international interest. First results are expected in 2026. In parallel, preclinical investigations in HDV-infected mouse models revealed virus-specific transcriptomic and epigenetic perturbations in the liver, associated with inflammation and innate immune activation. These findings led to the identification of novel, previously unrecognized biomarker candidates, which are now being validated in patient samples through close collaboration between clinicians and scientists within the consortium. First insights into the cellular and molecular mechanisms underlying HDV control and liver disease progression were generated and further analysis are ongoing. The consortium identified immune signatures linked to fibrosis progression and viral replication, including specific gene programs and protein biomarkers. The project also generated high-dimensional data on the intrahepatic cellular composition of HDV-infected patients and initiated spatial transcriptomic profiling in both progressing and non-progressing cases. The successful implementation of these techniques represents a major milestone in HDV research and sets the stage for mechanistic insights into intrahepatic immunity. Notably, the immune checkpoint inhibitor TIGIT was identified on NK cell subtypes as a hallmark of liver inflammation in HDV infection. Its reappearance during BLV therapy may explain the rapid improvement in liver enzyme levels observed in treated patients. Immunological profiling revealed distinct immune signatures associated with cirrhosis and treatment response. In particular, anti-interferon alpha (IFNa) antibodies were identified as potential predictive markers for interferon treatment response, supporting the development of a personalized medicine approach in HDV therapy.
The D-SOLVE project has significantly advanced the field of hepatitis D treatment by establishing a biomarker-driven, personalized therapeutic approach. Existing antiviral therapies, including bulevirtide and interferon alpha, lack clear criteria for patient selection and treatment duration. D-SOLVE addresses this limitation by identifying individual predictors of treatment response—such as viral load, immune function, and genetic markers—thus enabling tailored interventions that improve clinical outcomes and reduce unnecessary treatment exposure.
Beyond scientific innovation, the project has expanded its dissemination and outreach activities to enhance visibility and impact. A series of translational seminars were organized to bridge research and clinical practice. In collaboration with another EU-funded HBV initiative (project 848223), D-SOLVE launched an HDV awareness campaign, amplifying public and professional engagement. The consortium also played a leading role in shaping the DeltaCure Conference, now the world’s largest meeting dedicated to hepatitis D, fostering international collaboration and positioning HDV as a global health priority.
These efforts collectively elevate D-SOLVE beyond the current state of the art, contributing not only to clinical and scientific progress but also to policy awareness, stakeholder engagement, and the broader adoption of precision medicine in infectious disease management.
Beyond scientific innovation, the project has expanded its dissemination and outreach activities to enhance visibility and impact. A series of translational seminars were organized to bridge research and clinical practice. In collaboration with another EU-funded HBV initiative (project 848223), D-SOLVE launched an HDV awareness campaign, amplifying public and professional engagement. The consortium also played a leading role in shaping the DeltaCure Conference, now the world’s largest meeting dedicated to hepatitis D, fostering international collaboration and positioning HDV as a global health priority.
These efforts collectively elevate D-SOLVE beyond the current state of the art, contributing not only to clinical and scientific progress but also to policy awareness, stakeholder engagement, and the broader adoption of precision medicine in infectious disease management.