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.
