BACKGROUND AND AIMS: The impact of low-level viremia(LLV) on the efficacy of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma(uHCC) patients remains unclear. This study aims to investigate the effect of LLV on the outcomes of ICIs-based therapy in patients with uHCC. METHODS: In this multicenter retrospective study, we included patients with uHCC who received ICIs-based therapy at four centres between January 2019 and December 2022. All patients were positive for HBsAg and were on nucleos(t)ide analogues (NAs) antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance baseline characteristics between the LLV and maintained virological response (MVR) groups. Proteomic analysis was performed on a subset of patients to identify differential protein expression. RESULTS: A total of 329 patients (mean age 56 years
92.4% male
70.8% BCLC stage C) were included, with 170 patients in the LLV group and 159 in the MVR group. The objective response rate (ORR) was significantly lower in the LLV group compared to the MVR group (21.2% vs. 36.5%, p = 0.002), as was the disease control rate (DCR) (78.8% vs. 92.5%, p <
0.001). Median progression-free survival (mPFS) was shorter in the LLV group (7.6 vs. 12.6 months, p <
0.001), as was median overall survival (mOS) (22.8 vs. 40.0 months, p <
0.001). These differences remained consistent after PSM and IPTW adjustments. Multivariate analysis identified LLV as the only independent risk factor for overall survival (hazard ratio [HR] 0.522, 95% CI 0.348-0.781
p = 0.002). Proteomic analysis revealed significant differences in the expression of Flt3L, SLAMF1 and FGF-5 proteins between the LLV and MVR groups. CONCLUSION: LLV is associated with poorer responses to ICIs-based therapy and reduced survival in patients with HBV-related uHCC.