Hepatitis B virus reactivation in hepatocellular carcinoma patients undergoing immune checkpoint inhibitor and concurrent antiviral prophylaxis agents: A prospective observational study.

4127 Background: Immune checkpoint inhibitors (ICIs) have been recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, due to the potential hazard of hepatitis B virus (HBV) reactivation, all ICI-related phase 3 studies had strict restrictions on HBV-DNA load (e.g., < 500IU/ml). Meanwhile, delayed immunotherapy may lead to poor prognosis for patients with high HBV-DNA load. This study aims to compare the HBV reactivation between HCC patients with low or high HBV-DNA load undergoing ICIs and concurrent antiviral prophylaxis agents. Methods: This prospective, observational study (NCT04680598) recruited HCC participants who were consecutive hepatitis B surface antigen (HBsAg)-positive and received concurrent antiviral prophylaxis agents and initial ICIs. Participants were divided into low group (HBV-DNA≤500 IU/ml) and high group (HBV-DNA > 500 IU/ml) according to the baseline HBV-DNA level. HCC patients without ICIs from NCT02973685 were also included for analysis. The primary endpoint was the incidence of HBV reactivation. The secondary endpoints included HBV reactivation-associated hepatitis, ICIs disruption, overall survival (OS) and progression-free survival (PFS). Results: Between December 25, 2020 and February 23, 2024, a total of 1015 participants were enrolled: 356 in the low group and 659 in the high group. The median age was 51 years (range, 18-84) with majority being males (89.2%) and hepatitis Be antigen (HBeAg) positive (18.1%). Most participants did not receive previous anticancer treatment (84.5%). Participants in the high group were present with significantly higher HBeAg rate (7.0% vs 24.1%, p < 0.001), higher ALBI grade 2-3 rate (33.7% vs 49.9%, p < 0.001), larger tumor size (9.3 vs 10.9 cm, p < 0.001), more advanced BCLC stage C (72.5% vs 83.3%, p < 0.001). A significantly higher proportion of participants in the low group had previously received antiviral prophylaxis agents (16.3% vs 3.6%, p < 0.001). The HBV reactivation rate was 4.5% in the low group and 6.1% in the high group (relative risk, 1.24; 95% confidence internal [CI], 0.81-1.89, p = 0.30). The frequencies of HBV reactivation-associated hepatitis were 1.7% and 2.3%, respectively ( p = 0.53). There were 92 participants (25.8%) in the low group and 201 participants (30.5%) in the high group had interrupted the ICIs treatment ( p = 0.12). Compared with high group, the low group had shown significantly longer OS (29.8 vs 18.5 months, p = 0.0057) and PFS (9.1 vs 8.3 months, p = 0.043). However, participants in the high group had worse liver function and higher tumor burden compared with those in the low group, and the HBV-DNA group was not the independent risk factor for OS or PFS in the multivariable analysis. After included patients from NCT02973685 (n = 278), the HBV reactivation rate was 5.5% and 4.3% in patients treated with or without ICIs (p = 0.43). Conclusions: High HBV-DNA did not significantly increase the incidence of HBV reactivation in HCC patients treated with ICIs and concurrent antiviral prophylaxis. Clinical trial information: NCT04680598 .