Re‐evaluating the diagnostic value of α‐fetoprotein for hepatocellular carcinoma in the direct‐acting antiviral era

BACKGROUND: Direct-acting antivirals (DAAs) achieve sustained virological response (SVR) in most hepatitis C virus (HCV) patients, reducing hepatic inflammation and baseline α-fetoprotein (AFP). Concurrent shifts toward nonviral hepatocellular carcinoma (HCC) may further improve AFP specificity. This study re-evaluated the diagnostic performance of AFP and des-γ-carboxy prothrombin (DCP). METHODS: The authors retrospectively analyzed 388 consecutive patients undergoing curative hepatectomy for HCC. Tumor marker levels measured 4 months postoperatively in recurrence-free patients at 1 year (n = 257) served as non-HCC reference values. Cohorts were stratified by era (pre-DAA vs. post-DAA). Diagnostic accuracy was assessed via area under the receiver operating characteristic curve (AUROC). Subgroup analyses used multivariable modeling to test fibrosis and viral status as predictors of baseline (postoperative) AFP. RESULTS: Baseline (postoperative) AFP was lower post-DAA (3 [2-4] ng/mL) than pre-DAA (4 [3-7] ng/mL; p < .001). AFP AUROC improved from 0.702 to 0.793 (p = .014), whereas DCP performance was unchanged. The proportion of HCV-related HCC declined (30% to 20%; p = .012) and nonviral HCC increased (58% to 66%; p = .093). HCV non-SVR and advanced fibrosis independently predicted higher baseline (postoperative) AFP. An updated AFP cutoff of 5 ng/mL is supported; the conventional DCP threshold of 40 mAU/mL remains appropriate. CONCLUSIONS: In the current era, lower baseline AFP levels are associated with improved diagnostic performance of AFP for HCC. Adoption of a 5 ng/mL AFP cutoff and 40 mAU/mL DCP cutoff appears appropriate for current clinical practice.