Serum soluble PD-L1 predicts hepatocellular carcinoma development across distinct virological cohorts of chronic hepatitis C.

[BACKGROUND] Soluble programmed death ligand 1 (sPD-L1) reflects immune-inflammatory activity and may serve as a circulating biomarker of hepatocarcinogenesis. Whether baseline sPD-L1 predicts de novo hepatocellular carcinoma (HCC) in patients without existing HCC remains unclear.

[AIMS] To determine whether serum sPD-L1 predicts future HCC across distinct virological backgrounds of chronic hepatitis C.

[METHODS] Two temporally and clinically distinct cohorts from Nagasaki Medical Center were analyzed. The SVR cohort included 430 patients who achieved sustained virological response after direct-acting antiviral therapy (2013-2017). A historical pre-DAA cohort (n = 692), consisting of viremic patients who underwent liver biopsy between 1992 and 2003, served as an independent temporal validation cohort. Baseline sPD-L1 was measured in all patients. Cox proportional hazards models, stratified analyses, landmark analysis, and time-dependent models were applied to assess the association between sPD-L1 and HCC.

[RESULTS] High baseline sPD-L1 independently predicted increased HCC risk in both cohorts (SVR: HR 2.61, 95% CI 1.02-6.71; historical: HR 1.90, 95% CI 1.32-2.74). In the SVR cohort, sPD-L1 stratified HCC risk within high-risk groups defined by aMAP, M2BPGi, or FIB-4. In the historical cohort, sPD-L1 stratified HCC risk even within low-risk strata defined by aMAP and FIB-4. Notably, patients with low sPD-L1 rarely developed HCC despite advanced fibrosis.

[CONCLUSIONS] Baseline sPD-L1 predicts de novo HCC development independently of virological status and fibrosis-based indices. Concordant findings across two distinct temporal cohorts support sPD-L1 as a robust preclinical biomarker of hepatocarcinogenesis. Incorporating sPD-L1 into surveillance algorithms may enhance individualized HCC risk stratification.