Non-Invasive Risk Stratification for Hepatocellular Carcinoma after Hepatitis C Cure: Development of the CAL-HCC Index

Patients with chronic hepatitis C (CHC) retain a clinically significant risk for hepatocellular carcinoma (HCC) even after achieving sustained virologic response (SVR) with direct-acting antivirals (DAAs). This persistent threat, coupled with the inadequate predictive capabilities of standard non-invasive tools underscores the necessity for novel prognostic indices. This study aimed to develop and test the noninvasive CAL-HCC Index, a novel serum biomarker panel integrating fibrogenesis (Collagen III), hepatic function (albumin), and oncofetal activity (alpha-fetoprotein, AFP). The index was developed in a cohort (N=150; 75 HCC, 75 controls) of post-SVR patients. Cutoff values were determined by maximizing Youden’s index. The CAL-HCC Index achieved an AUC of 0.93 (95% CI: 0.88–0.98; P<0.0001), outperforming Collagen III (AUC 0.86; 95% CI: 0.79–0.94; P=0.02) At the Youden-optimized threshold, sensitivity was 86% (95% CI: 78–92%), specificity 97% (95% CI: 92–99%), for predicting de novo HCC. In conclusion, the CAL-HCC Index is simple and highly accurate tool for post-SVR HCC prediction. By integrating key biological drivers of hepatocarcinogenesis, it provides a powerful method to personalize surveillance, enabling clinicians to intensify monitoring for high-risk patients while potentially de-escalating for those at low risk.