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.