Chronic infection with hepatitis delta virus (HDV) affects between 12-20 million people worldwide and represents the most severe form of viral hepatitis, leading to accelerated liver disease progression, cirrhosis and its complications, such as end-stage-liver disease and hepatocellular carcinoma. From the discovery of HDV in 1977 by Prof. Mario Rizzetto, knowledge on the HDV life cycle and mechanisms of viral spread has expanded. However, little is still known about the natural history of the disease, host-viral interactions, and the role of the immune system in HDV persistence. Diagnosis of HDV is still challenging due to a lack of standardised assays, while accurate viral load quantification is needed to assess response and endpoints of antiviral treatment. Until recently, interferon has represented the only treatment option in patients with chronic hepatitis delta; however, it is associated with low efficacy and a high burden of side effects. The discovery of the entry inhibitor bulevirtide has represented a breakthrough in HDV treatment, by demonstrating high rates of viral suppression in phase II and III trials, results which have been confirmed in real-world settings and in patients with compensated advanced liver disease. In the meantime, other compounds (i.e. lonafarnib, new anti-hepatitis B virus drugs) are under development to provide alternative or combined strategies for HDV cure. The first international Delta Cure meeting was organised in Milan in October 2022 with the aim of sharing and disseminating the latest data; this review summarises key takeaway messages from state-of-the-art lectures and research data on HDV.

Autoimmune hepatitis may be frequently associated with chronic hepatitis C (HCV) infection, but there are few case reports regarding hepatitis B and Delta infection (HBV+HDV) as possible triggers. In this report, we present a 44 years old man who was diagnosed as autoimmune hepatitis (AIH) following the treatment of HBV+HDV hepatitis with pegylated interferon (PegIFN). He presented with complaint of fatigue. Laboratory indicated elevated liver enzymes, AST 64IU/L and ALT 112IU/L. The results revealed HBsAg and anti-delta antibody positivity. HBV-DNA was <31.6 IU/mL and HDV-RNA 487.300 copy/mL. Peg-IFN was initiated for 96 weeks. Without a serious adverse effect, the enzymes regressed to normal within 24 weeks. After 96 weeks of treatment, there was a three-fold increase in aminotransferases, with no cholestasis. Immunoglobulin-G (IgG) was 3686 mg/dL (reference 540-1822 mg/dL), anti-smooth muscle antibody (ASMA) and anti-nuclear antibody (ANA) were positive. The liver biopsy had all diagnostic clues for AIH. Methylprednisolone and azathioprine treatment was initiated with tenofovir (TdF) prophylaxis. Due to unresponsiveness, even with doubling the dosage for immunosuppressives, treatment was stopped and shifted to mycophenolate mofetil. The patient responded in the 6th month and still under treatment with TdF and mycophenolate mofetil with normal enzymes and negative HDV RNA.

Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs.