Li Rong, Li Wenli, Yang Qing, Guan Yujuan, Chen Yongru, Zhu Peilin, Su Kaiyan, Li Qi, Hu Xiaoyun, Zang Mengya, Zhao Miaoxian, Zhong Manhua, Yan Jingquan, Yang Keli, Zhu Wei, Lin Zhanzhou, Yuan Guosheng, Chen Jinzhang
State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
Department of Respiratory Medicine, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.
Liver Int. 2025 Apr;45(4):e70066. doi: 10.1111/liv.70066.
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.
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.
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.
LLV is associated with poorer responses to ICIs-based therapy and reduced survival in patients with HBV-related uHCC.
低水平病毒血症（LLV）对不可切除肝细胞癌（uHCC）患者免疫检查点抑制剂（ICI）疗效的影响尚不清楚。本研究旨在探讨LLV对uHCC患者基于ICI治疗结局的影响。
在这项多中心回顾性研究中，我们纳入了2019年1月至2022年12月期间在四个中心接受基于ICI治疗的uHCC患者。所有患者HBsAg均为阳性，且正在接受核苷（酸）类似物（NA）抗病毒治疗。采用倾向评分匹配（PSM）和逆概率加权法（IPTW）来平衡LLV组和维持病毒学应答（MVR）组之间的基线特征。对部分患者进行蛋白质组学分析以鉴定差异蛋白表达。
共纳入329例患者（平均年龄56岁；92.4%为男性；70.8%为BCLC C期），其中LLV组170例，MVR组159例。LLV组的客观缓解率（ORR）显著低于MVR组（21.2%对vs。36.5%，p = 0.002），疾病控制率（DCR）也是如此（78.8%对vs。92.5%，p < 0.001）。LLV组的中位无进展生存期（mPFS）较短（7.6个月对vs。12.6个月，p < 0.001），中位总生存期（mOS）也是如此（22.8个月对vs。40.0个月，p < 0.001）。在PSM和IPTW调整后，这些差异仍然一致。多因素分析确定LLV是总生存期的唯一独立危险因素（风险比[HR] 0.522，95%可信区间0.348 - 0.781；p = 0.002）。蛋白质组学分析显示LLV组和MVR组之间Flt3L、SLAMF1和FGF-5蛋白的表达存在显著差异。
LLV与HBV相关uHCC患者对基于ICI治疗的反应较差及生存期缩短有关。
