The Human Hepatitis D virus (HDV) is one of the smallest human RNA viruses (22 nm), characterized by the peculiarity to require Hepatitis B virus (HBV) for its replication. Indeed, HDV utilizes HBV surface glycoprotein (HBsAg) for viral entry, assembly and release, implying the need for a intrahepatic transcriptionally active HBV to ensure HDV replication.

Chronic HBV/HDV coinfection is associated with a high risk of developing liver cirrhosis and hepatocellular carcinoma within 5–10 years, resulting in high fatality rate. Recent estimates suggest that 9-60 million individuals may be infected with HDV worldwide. However, these fluctuating estimates highlight a huge uncertainty about the real prevalence of HDV infection, mostly related to the lack of robust data on large populations of HBsAg positive patients undergoing HDV screening. This highlights the need of accurate screening programs that finely trace the circulation of HDV.

Currently, interferon-alfa treatment is the only therapeutic strategy against HDV. However, it is associated with only a 20% reduction in virological activity and a high risk of post-treatment virological relapse after therapy discontinuation. More recently, novel compounds for HDV treatment targeting host factors have been identified: the entry inhibitor Bulevirtide and the prenylation inhibitor lonafarnib. In particular, Bulevirtide is now approaching clinical practice. These novel strategies appear very promising, even though there was a high rate of virological rebound after therapeutic suspension in clinical trials. This could be related to suboptimal assays for residual HDV-RNA detection, but it could also be due to undefined mechanisms promoting HDV persistence.

Factors determining the outcome of HDV infection and response to antiviral treatment are largely unknown. In particular, eight distinct HDV genotypes (HDV-1 to -8) have been identified, though their correlation with disease progression and treatment response has been poorly clarified. In a similar direction, there is a lack of data available on the kinetics of HDV and HBV co-evolution and on the existence of viral genetic signatures associated with higher pathogenicity and poorer response to new drugs. Furthermore, it has been demonstrated that a transcriptionally active cccDNA is strictly required to sustain HDV replication. So far, different serum HBV/HDV biomarkers (such as HBsAg isoforms) have been proposed to improve the management of patients with HBV infection. The role of these viral biomarkers in predicting the outcome of HDV infection and particularly treatment response is an issue that deserves to be unraveled.

In this light, this Research Topic aims to:

- Provide findings that can help to accurately characterize the prevalence of HDV in different countries.

- Provide new insights on mechanisms underlying the pathogenetic potential of HDV.

- Define virological and immunological factors that can contribute to modulating a response to anti-HDV treatment.

- Characterize the role of novel HBV biomarkers in the setting of HDV coinfection.

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Frontiers in Medicine

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