Hepatitis D Virus: Diagnostic Challenges and Emerging Therapeutic Strategies

Abstract

Hepatitis D virus (HDV) infection represents the most severe form of viral hepatitis and remains a major global health concern. First described in 1977 by Mario Rizzetto, HDV is a defective RNA virus that requires hepatitis B virus (HBV) for its replication and transmission. HDV infection is estimated to affect 12–72 million individuals globally, with a disproportionate burden in endemic regions and among high-risk populations, including people who inject drugs and individuals with HIV infection. HDV infection occurs in two distinct forms: as coinfection and superinfection. Coinfection is typically self-limiting, while superinfection is characterized by a high rate of chronicity. Superinfection is also associated with an aggressive disease course characterized by rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Liver injury in HDV superinfection is primarily immune-mediated. Diagnosis of HDV infection remains challenging due to limited clinical awareness and limited access to HDV RNA testing, the gold standard for confirming active infection. Although screening of hepatitis B surface antigen-positive individuals is recommended, its implementation remains suboptimal across many settings. Therapeutic options are limited, with pegylated interferon-alpha demonstrating modest efficacy. Emerging agents, including bulevirtide and lonafarnib, have shown promising antiviral activity and represent potential therapeutic advances. Prevention primarily relies on HBV vaccination, which effectively reduces HDV transmission. Strengthening screening strategies, improving access to diagnostic testing, and developing novel therapies are essential to reducing the global burden of HDV infection.