Nucleos(t)ide Analog-Therapeutic Vaccination Switch: A Novel Approach for Safe and Effective Treatment Discontinuation in HBeAg (-) Chronic Hepatitis B Patients.

BACKGROUND/OBJECTIVE: Long-term nucleos(t)ide analog (NUC) therapy effectively suppresses hepatitis B virus (HBV) replication, but it rarely achieves a functional cure and typically requires lifelong administration. A major unmet need in chronic hepatitis B (CHB) is the development of safe and effective strategies to discontinue NUCs without compromising viral control or hepatic safety. This exploratory, randomized pilot study evaluated therapeutic immunization in the context of discontinuation of antiviral therapy in HBeAg-negative CHB. METHODS: Twenty-six HBeAg-negative CHB patients receiving long-term therapy with NUCs were randomized to either discontinue NUCs and switch to HeberNasvac (NASVAC), a therapeutic vaccine (n = 13), or receive NASVAC in addition to NUCs (n = 13). Virological, serological, biochemical, and safety parameters were assessed during a 52-week primary follow-up. In particular, ALT and AST were evaluated every 2 weeks during the first 6 months after NUC discontinuation. An extended monitoring period from weeks 96 to 192 was designed to assess virological and biochemical variables. RESULTS: At week 48, HBV DNA remained below 2000 IU/mL in 92.3% of patients who discontinued NUCs and received NASVAC and in 100% of those who received both NUCs and NASVAC. During extended follow-up, HBV DNA < 2000 IU/mL persisted in 84.6% and 76.9% of patients in the NUC discontinuation group at weeks 96 and 192, respectively, and in 100% of patients in the continuation group (NASVAC added to NUCs) at both time points. In the first 48 weeks after NUC discontinuation, NASVAC induced a limited but significant decline in serum quantitative HBsAg. Liver function, renal, and hematological parameters remained stable, without significant ALT abnormalities, biochemical exacerbations, fibrosis progression, or severe adverse events during primary or extended follow-up. None of the patients required restarting treatment. CONCLUSIONS: NASVAC-based immunotherapy demonstrated durable virological control, a limited but progressive reduction in qHBsAg, and a strong long-term safety profile following the complete withdrawal of antiviral therapy. This exploratory study suggests that NASVAC can be administered in the context of NUC discontinuation with an acceptable short- and long-term safety profile, but controlled trials are required to determine whether therapeutic vaccination contributes independently to sustained off-treatment viral control.