The role of classical and novel peripheral markers of hepatitis B virus in reflecting the intrahepatic viral reservoir and their impact in improving the clinical management of hepatitis B infection

Traditional virological biomarkers, historically used to evaluate the natural course of Hepatitis B virus (HBV) infection and to guide treatment choices for chronically infected patients, are suboptimal. Indeed, these biomarkers are not exhaustive in terms of prognosticating the risk of liver disease evolution and the outcome of anti-HBV treatment, as well as they do not reflect adequately the intrahepatic HBV reservoir. In this light, in the recent years, multiple novel non-invasive biomarkers blowed up in the landscape of HBV diagnostics, being proposed as affordable surrogate markers of the pool and activity of HBV intraheaptic reservoir, and as promising tools for disease staging, HCC-risk stratification and anti-HBV therapy optimization. However, to date, the clinical application of these novel biomarkers is limited by the lack of specific criteria guiding their utilizaton in clinical practice. In order to fill this gap, the studies presented in this PhD thesis, aim at defining how the novel emerging peripheral HBV biomarkers can improve the estimation of HBV intrahepatic reservoir and the occurrence of HBV integration into human genome, an event known to promote hepatocarcinogenesis. Furthermore, the studies included in this thesis have also identified, for the first time, specific cut-offs for the application of these virological biomarkers in different clinical settings as HBeAg negative chronic infection, HIV co-infection and in patients developing HCC despite virological suppression. Overall, the data presented in this PhD thesis strongly enlarge the current knowledge on HBV novel biomarkers and their correlation with intrahepatic viral reservoir and pave the way for their extended clinical usage, coupled to classical HBV markers, in ameliorating the clinical management of HBV-infected patients.