At the 2024 American Association for the Study of Liver Diseases (AASLD) Annual Meeting, two landmark studies from Dr. Qin Ning’s team at Tongji Hospital, Huazhong University of Science and Technology, gained significant recognition. The first study explored a precision treatment strategy using sequential interferon (IFN) therapy for nucleos(t)ide analogs (NA)-treated chronic hepatitis B (CHB) patients based on viral antigen levels and host immune status. It highlighted the association between HBV antigen levels at the time of NA discontinuation and the efficacy of subsequent IFN therapy, revealing that patients with higher antigen levels were more prone to virological breakthrough (VBT).
The second study evaluated the efficacy of a triple therapy combining TLR-7 agonist TQ-A3334, PD-L1 antibody TQ-B2450, and NA in virologically suppressed CHB patients. The results demonstrated that the triple regimen significantly enhanced HBsAg reduction, with early ALT elevation and HBsAg decline emerging as predictive markers of sustained therapeutic efficacy. These findings offer innovative clinical strategies and renewed hope for CHB patients aiming for functional cure.
Study 1: Precision Treatment Using Sequential Interferon Therapy in NA-Treated CHB Patients
Functional cure in chronic hepatitis B (CHB) is marked by serum hepatitis B surface antigen (HBsAg) clearance, reducing long-term risks. However, cure rates with nucleoside analog (NA) or interferon (IFN) monotherapies are low. Sequential IFN therapy after NA treatment shows potential but virological breakthrough (VBT) after NA discontinuation is a concern. This study aimed to identify VBT factors and optimize treatment.
The study included 80 CHB patients with viral suppression after NA therapy. They received 48 weeks of NA and IFN combination therapy, followed by 48 weeks of IFN monotherapy. Virological and immune parameters were monitored.
Twelve patients (15%) experienced VBT after NA discontinuation, with significantly lower HBsAg clearance rates. Higher baseline HBcrAg levels were associated with VBT. HBcrAg and HBsAg levels at NA discontinuation were independent risk factors. Patients with high antigen loads had a higher VBT rate and no HBsAg clearance. Those with lower antigen loads showed partial immune recovery before NA discontinuation, while high-antigen-load patients had poor recovery, which worsened after discontinuation.
HBV antigen levels at NA discontinuation predict sequential IFN therapy efficacy. Transitioning to IFN monotherapy based on antigen levels prevents VBT and improves HBsAg clearance rates. Tailored strategies are crucial, as insufficient immune recovery in high-antigen-load patients leads to poor outcomes.
Study 2: Triple Therapy with TQ-A3334, TQ-B2450, and NA Enhances HBsAg Reduction (Oceancure05 Study)
A study evaluated the safety and efficacy of triple therapy combining NA, TLR-7 agonist TQ-A3334, and PD-L1 antibody TQ-B2450 in 24 CHB patients with suppressed HBV DNA but intermediate HBsAg levels. Patients were randomized into three groups: monotherapy, dual therapy, and triple therapy. After 24 weeks of treatment and 24 weeks of follow-up, triple therapy was found to be safe, with all adverse events being grade 1 or 2 and resolving by the end of follow-up. Triple therapy also achieved the greatest HBsAg reduction (0.45±0.55 log10 IU/mL) and HBV RNA decline (1.15±1.18 log10 copies/mL) compared to dual and monotherapy. Higher doses of TQ-A3334 in triple therapy resulted in more pronounced HBsAg reductions. Early ALT elevation and HBsAg reduction were positively correlated with sustained declines. The mechanism behind triple therapy’s efficacy involves the PD-L1 antibody blocking TLR-7 agonist-induced PD-L1 expression, enhancing the immune response. Peripheral plasmacytoid dendritic cells showed increased PD-L1 expression after TQ-A3334 exposure in vitro, which was significantly elevated in vivo in the dual therapy group.
