PURPOSE: This study investigated whether Fibrosis-4 (FIB-4) score and its change can serve as predictors of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C (CHC) infection receiving direct-acting antivirals (DAAs). METHODS: This study identified 9679 patients who completed DAA treatment and achieved sustained virologic response (SVR) from the Taiwan Nationwide Real-World HCV Registry Program, and their risk of HCC was analyzed. RESULTS: Multivariable Cox regression analyses identified diabetes mellitus (DM), alpha-fetoprotein (AFP) level, and FIB-4 score as independent predictors of HCC in both Model 1 (baseline) and Model 2 (SVR). Change in FIB-4 score (△FIB-4) of <
  -0.9086 from baseline to SVR achievement was a significant predictor of HCC only in Model 2 (SVR). In Model 2 (SVR), DM (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 1.04-2.26, p = 0.033), FIB-4 score (≥3.25 vs. <
 3.25
  HR: 2.40, 95% CI: 1.63-3.53, p <
  0.002), △FIB-4 (greater reduction: <
 -0.9086 vs. smaller reduction: ≥-0.9086
  HR: 1.85, 95% CI: 1.25-2.74, p = 0.002), and AFP level (≥20 vs. <
 20 ng/mL
  HR: 16.40, 95% CI: 9.16-29.36, p <
  0.002) were significant predictors of HCC. At 3 years, the cumulative HCC incidence was 10.67% in patients with an FIB-4 score of ≥3.25 upon achieving SVR and △FIB-4 of <
  -0.9086 and 1.72% in those with an FIB-4 score of <
 3.25 upon achieving SVR and △FIB-4 of ≥ -0.9086. CONCLUSIONS: Posttreatment FIB-4 score and its change from baseline can be used to stratify HCC risk in patients with CHC receiving DAAs.
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