WP1 is the first work package and will lay the foundation for WPs 2 to 5 in assessing the specific scientific questions on i) control of HDV replication, ii) individual determinants of fibrosis progression, and iii) treatment response. Three subprojects will be established with the first collecting in a cross-sectional approach 750 patients reflecting the entire spectrum HDV infection in Europe, the second consisting of a retrospective-prospective cohort of patients with liver biopsies taken 10-20 years ago to allow the investigation of intrahepatic immune correlates with disease progression and the third will be a prospective trial of patients being treated with the novel entry inhibitors bulevirtide.

This work package will be essential to perform a comprehensive virological characterization of these patients who are infected with two viruses HBV and HDV. As local diagnostics in particular for HDV but also for novel HBV markers have not been fully standardized, central testing with optimized methodology will be required. In addition, WP2 will perform an in-depth viral sequencing of both HBV and HDV which will be crucial to determine immune pressure on the virus and to dissect host-viral interactions.

WP3 starts with retrospective samples (cohort B) and will then continue with the other cohorts during the entire funding period. This work package will be the core project to identify novel biomarkers for the three key clinical challenges to be addressed in D-SOLVE. KI and HZI/CiiM will perform the respective screening in collaboration with MHH and INSERM.

This work package led by KI and MHH will explore mechanisms of biomarkers identified in WP3 but also focus on hypothesis-driven questions, in particular investigating intrahepatic immune innate and adaptive responses. Intrahepatic immune responses have rarely been studied in hepatitis D and thus completely novel data can be expected which can probably only generated within this D-SOLVE consortium combining translational clinical and basic expertise and providing the logistics to have access to the required patient material.

Given previous observations for HCV, it is likely that HDV control cure by either interferon-based therapies or in combination with novel antivirals like Bulevirtide will only partially eliminate HDV-induced modifications of the hepatocyte cell circuits or the innate and adaptive immune responses. These persistent perturbations of the liver cell circuits may contribute liver disease progression and HCC risk post cure. Supporting this concept, HDV induces DNA hypermethylation and histone modification in cell lines suggesting the existence of an epigenetic viral footprint relevant for viral pathogenesis and HCC risk. To address this question we will investigate HDV-induced transcriptomic and epigenetic modifications in liver tissues and PBMCs in a mouse model for HDV-HBV co-infection before and after antiviral therapies and then validate the identified modifications with samples from cohorts of WP1 and study their phenotype before and after antiviral treatment.

WPs 6 (Data management), 7 (Dissemination, exploitation, IP, communication & training) and 8 (Coordination & project management) will be carried out along the whole duration of the project.