Comprehensive insight of epidemiological and virological features underlying patients with HBV/HDV co-infection drug-naïve or treated with the recently approved entry inhibitor

Hepatitis Delta Virus (HDV) is a defective human virus, strictly dependent on its co-helper, represented by Hepatitis B Virus (HBV), for its morphogenesis and de novo entry into the hepatocytes. Indeed, HDV infectivity relies on HBV surface antigen (HBsAg), while its replication seems to be independent from HBV reservoir. HDV infection causes the most severe form of viral hepatitis, leading to a faster liver disease progression and to a more frequent development of cirrhosis, hepatocellular carcinoma and hepatic decompensation than that observed in HBV mono-infection. However, so far, epidemiological and virological aspects of HDV infection are still unclarified, due to the use of sub-optimal diagnostic assays and to the lack of effective specific anti-HDV treatments. This PhD thesis aims at unravelling HDV epidemiology in Italy, especially in people living with HIV, and at evaluating the complex interplay between HDV and HBV directly in the liver. Finally, this thesis aims at identifying novel virological predictors of HDV response in patients treated with the recently approved entry inhibitor Bulevirtide. Overall, the results obtained by the different studies included in this thesis depict an evolutionary scenario of HDV infection in Italy, with a still relevant circulation in high-risk groups, as Eastern European immigrants and people living with HIV. Furthermore, our findings provide novel insights of mechanisms underlying the interplay between HBV and HDV, highlighting the role of integrated HBV-DNA as a source of HBsAg and in turn in sustaining HDV persistence. Overall, the peculiar features underlying HDV infection stresses the need to unravel novel biomarkers of viral activity as well as of response to novel treatments in order to optimize the clinical management of patients with HDV related liver diseases.