Hepatocellular carcinoma (HCC) remains a significant complication of hepatitis C virus (HCV) infection. This study investigates the potential of relative telomere length as a predictive biomarker in HCC patients, comparing non-DAA treatment groups with post-direct-acting antiviral (DAA).

Telomere length was measured using quantitative real-time PCR (qPCR) in tumor and adjacent non-tumorous tissues from 41 HCC patients, divided into de novo (n = 16) and post-DAA (n = 25) groups.

The mean telomere length was significantly higher in tumor than non-tumorous tissues (3.39 ± 4.05 compared to 1.01 ± 0.04; p = 0.001). Mean telomere length varied significantly between groups, with non-DAA group showing higher tumor telomere length (5.15 ± 4.88) compared to post-DAA patients (2.26 ± 3.01). Receiver Operating Characteristic (ROC) curve analysis revealed fair discriminatory ability in the non-DAA group (AUC 0.706, 95% CI: 0.524–0.888, p = 0.047). A significant correlation between tumor telomere length and carcinoembryonic antigen was observed in the post-DAA group. Non-DAA group showed more aggressive tumor grades, while post-DAA patients had better liver function. No significant association was found between relative telomere length and HCC risk.

Significant telomere length alterations and clinicopathological differences highlight molecular heterogeneity in HCV-related HCC, particularly post-DAA. While Relative telomere length (RTL) did not predict HCC risk, its correlations with tumor markers suggest potential as a prognostic biomarker, warranting further research in larger cohorts.