Background and Aims: Most patients with HCC are diagnosed at a late stage, highlighting the need for more accurate surveillance tests. Although biomarkers for HCC early detection have promising data in Phase 2 case–control studies, evaluation in cohort studies is critical prior to adoption in practice. We leveraged a prospective cohort of patients with Child-Pugh A or B cirrhosis who were followed until incident HCC, liver transplantation, death, or loss to follow-up. We used a prospective specimen collection, retrospective, blinded evaluation design for biomarker evaluation of GALAD (gender × age × log alpha-fetoprotein [AFP] × des-gamma-carboxy prothrombin), longitudinal GALAD, and the HCC Early Detection Screening (HES) algorithm—compared to AFP—using patient-level sensitivity and screening-level specificity. Approach and Results: Of 397 patients with cirrhosis, 42 developed HCC (57.1% early stage) over a median of 2.0 years. Longitudinal GALAD had the highest c-statistic for HCC detection (0.85; 95% CI, 0.77–0.92) compared to single–time point GALAD (0.79; 95% CI, 0.71–0.87), AFP (0.77; 95% CI, 0.69–0.85), and HES (0.76; 95% CI, 0.67–0.83). When specificity was fixed at 90%, the sensitivity for HCC of single–time point and longitudinal GALAD was 54.8% and 66.7%, respectively, compared to 40.5% for AFP. Sensitivity for HCC detection was higher when restricted to patients with biomarker assessment within 6 months prior to HCC diagnosis, with the highest sensitivities observed for single–time point GALAD (72.0%) and longitudinal GALAD (64.0%), respectively. Sensitivity of single–time point and longitudinal GALAD for early-stage HCC was 53.8% and 69.2%, respectively. Conclusion: GALAD demonstrated high sensitivity for HCC detection in a cohort of patients with cirrhosis. Validation of these results is warranted in large Phase 3 data sets.
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