The complex interplay between hepatitis D virus and the interferon response.

Hepatitis D virus (HDV) infection represents a major global public health challenge and is responsible for the most severe form of chronic viral hepatitis. Affecting an estimated 12 million individuals worldwide, chronic hepatitis D is associated with rapid progression to advanced liver disease, including cirrhosis and hepatocellular carcinoma. Despite its clinical burden, therapeutic options for HDV remain limited. In this context, pegylated interferon alpha (PEG-IFN-α) continues to be the most widely used treatment globally, particularly outside Europe where access to newly approved therapies is restricted. However, PEG-IFN-α is characterized by modest and heterogeneous antiviral efficacy, frequent viral relapse, and a high rate of adverse effects, highlighting the need for improved therapeutic strategies. A better understanding of the mechanisms underlying interferon responsiveness and resistance in HDV infection is therefore essential. The complex interplay between HDV and the innate immune response plays a central role in determining viral persistence and treatment outcome. HDV is sensed by innate immune receptors and induces type I and type III interferon responses, yet these responses are insufficient to control viral replication. Viral nuclear replication, interferon-stimulated gene accessibility, and active interference with interferon signaling pathways contribute to the limited antiviral activity of interferons against HDV. This review synthesizes current knowledge on the interactions between HDV and the interferon response, discusses experimental models used to study these mechanisms, and highlights key limitations and open questions that must be addressed to optimize future interferon-based and combination therapies.