Early Antiviral Therapy and Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Patients with Normal Alanine Aminotransferase Levels: A Prospective Phase II Study

Background/Aims: Whether antiviral therapy with nucleos(t)ide analogs is necessary for chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels remains controversial.The D 2 AS score is a validated model for identifying patients at high risk of hepatocellular carcinoma (HCC) despite normal or mildly elevated ALT levels.We explored whether the observed HCC incidence with immediate antiviral therapy differed from that predicted by the D 2 AS model. Methods:In this prospective, multicenter phase II trial, 115 non-cirrhotic CHB patients with ALT <80 U/L and a D 2 AS score ≥2.0 received generic entecavir (0.5 mg daily) for 5 years.The primary endpoint was the standardized incidence ratio (SIR), defined as the ratio of the observed to the expected number of HCC cases based on the D 2 AS score.Results: The virological response rates were 79.4%, 90.2%, and 92.4% at 1, 3, and 5 years, respectively.The median ALT concentration decreased from 37 U/L at baseline to 23, 20, and 19 U/L at 1, 3, and 5 years, respectively.Six patients developed HCC, with cumulative incidences of 2.0%, 5.1%, and 6.1% at 1, 3, and 5 years, respectively.Although the observed HCC incidence was not significantly lower than expected overall, a decreasing trend was noted at year 5 (SIR, 0.53; 95% confidence interval, 0.24 to 1.20).Conclusions: Immediate antiviral therapy achieved sustained viral suppression and ALT reduction and showed a trend toward a lower-than-expected HCC incidence.Although exploratory, these findings provide a rationale for conducting future controlled studies to evaluate potential clinical benefits of early antiviral therapy in this population.(Gut Liver, Published online October 7, 2026)