Longitudinal Effects of Glecaprevir/Pibrentasvir on Liver Function, Fibrosis, and Hepatocellular Carcinoma Risk in Chronic Hepatitis C: A Prospective Multicenter Cohort Study

<i>Background and Aims</i>: Glecaprevir/pibrentasvir achieves sustained virologic response (SVR) rates above 95% in chronic hepatitis C (CHC). Nevertheless, the residual risk of hepatocellular carcinoma (HCC) after SVR, especially in patients with advanced liver disease, has not been fully defined. We prospectively evaluated longitudinal changes in liver function and fibrosis and sought predictors of post-SVR HCC in a real-world multicenter cohort. <i>Methods</i>: A total of 395 CHC patients who attained SVR with glecaprevir/pibrentasvir were followed prospectively. Liver function tests, noninvasive fibrosis indices, and clinical outcomes were recorded at predefined intervals. Cox proportional hazards regression identified factors associated with incident HCC. <i>Results</i>: Over a median follow-up of 31.1 months, HCC occurred in 16 patients (4.1%). From univariate analysis, baseline FIB-4 > 3.25, APRI > 1.5, MELD ≥ 10, Child-Pugh score ≥ 6, and clinically significant portal hypertension were associated with HCC. Multivariate analysis retained FIB-4 > 3.25 (<i>p</i> = 0.003) and MELD ≥ 10 (<i>p</i> = 0.032) as independent predictors. Cumulative incidence rose stepwise with the number of risk factors. <i>Conclusions</i>: Despite a virologic cure, patients with advanced fibrosis or impaired liver function remain susceptible to HCC. Risk stratification using FIB-4 and MELD and continued surveillance are therefore warranted.