On‐Treatment Reassessment of Type IV Collagen 7S and M2BPGi‐Qt Improves Long‐Term Hepatocellular Carcinoma Risk Stratification in Chronic Hepatitis B

AIMS: Hepatocellular carcinoma (HCC) remains a major complication in patients with chronic hepatitis B receiving nucleos(t)ide analogue (NA) therapy despite effective viral suppression. Although on-treatment assessment of indirect fibrosis indices has been associated with HCC risk, the prognostic value of direct fibrosis markers, particularly type IV collagen 7S (4COL7S), during antiviral therapy remains poorly defined. We investigated whether on-treatment 4COL7S predicts HCC development, with M2BPGi-Qt evaluated as a supportive comparator. METHODS: This retrospective cohort study included 319 patients with chronic hepatitis B who initiated NA therapy. Serum 4COL7S and M2BPGi-Qt were measured at baseline and 1 year after treatment initiation. The primary endpoint was HCC development. Landmark, Kaplan-Meier, and multivariable Cox analyses were performed. RESULTS: During a median follow-up of 12.6 years, 45 patients (14.1%) developed HCC. Baseline 4COL7S and M2BPGi-Qt did not significantly stratify cumulative HCC incidence. In contrast, elevated 1-year levels of both markers were significantly associated with increased HCC risk. In multivariable analyses, 1-year 4COL7S remained independently associated with subsequent HCC development after adjustment for baseline mPAGE-B, 1-year HBsAg-HQ, and 1-year HBcrAg (adjusted hazard ratio [HR], 1.167; 95% confidence interval [CI], 1.001-1.344; p = 0.042). M2BPGi-Qt showed consistent supportive findings (adjusted HR, 1.272; 95% CI, 1.101-1.468; p = 0.001). CONCLUSIONS: On-treatment 4COL7S was independently associated with subsequent HCC development and may serve as a novel direct fibrosis marker for long-term risk stratification in NA-treated chronic hepatitis B. M2BPGi-Qt provided supportive prognostic information, underscoring the clinical relevance of reassessing residual fibrosis-related risk after antiviral treatment initiation.