Repeated measurements of alpha fetoprotein and fibrosis-4 predict long term hepatocellular carcinoma and mortality risks after antiviral therapy

• Risks of liver cancer and death persist after antiviral cure • Rising AFP and FIB-4 levels strongly predict adverse outcomes • Continuous monitoring improves long-term risk assessment Hepatitis C virus (HCV) remains a major cause of morbidity and mortality among patients with chronic hepatitis or HCC. Although direct-acting antivirals (DAAs) achieve high cure rates, risks of hepatocellular carcinoma (HCC) and death persist. This study evaluated whether repeated alpha-fetoprotein (AFP) and fibrosis-4 (FIB-4) measurements improve prognostic assessment in DAA-treated patients. We analyzed a retrospective cohort of 1,018 patients with chronic hepatitis C after DAA therapy. Outcomes were incident HCC or mortality. AFP and FIB-4 were recorded at baseline and annually. Cox regression assessed baseline predictors, and joint models examined longitudinal associations. During follow-up, 70 patients (6.9%) experienced either HCC or mortality. Age (hazard ratio [HR] = 1.04, 95% CI: 1.01–1.08) and cirrhosis (compensated: HR = 4.31, 95% CI: 2.28–8.12; decompensated: HR = 9.88, 95% CI: 5.23–18.69) were independent baseline risk factors, while baseline AFP and FIB-4 were not significant. In patients with events, AFP and FIB-4 increased progressively, in contrast to stability in those without. Joint models showed repeated AFP (HR = 4.46, 95% CI: 2.73–7.49) and FIB-4 (HR = 2.48, 95% CI: 1.34–4.49) were significantly associated with outcomes. Compared to relying on baseline values of AFP and FIB-4, repeated measurements of AFP and FIB-4 provided stronger prognostic value, emphasizing the need for continuous monitoring.