Objective: The impact of nucleos(t)ide analogues (NAs) therapy on the long-term outcomes in chronic HBV infection individuals outside 2025 European Association for the Study of the Liver (EASL) strongly recommended treatment indications remains uncertain. We aimed to assess the association between NAs therapy and the risks of cirrhosis and hepatocellular carcinoma (HCC) in Chinese chronic HBV infection individuals outside these criteria.
Design: We analysed data from 30 784 chronic HBV infection individuals across 12 centres in China. We categorised individuals outside 2025 EASL strongly recommended treatment criteria into four groups: (1) hepatitis B e antigen (HBeAg)-positive, high replicative (age <30, HBV DNA ≥8 log₁₀IU/mL, normal alanine aminotransferase (ALT), no/mild fibrosis, no family history of liver cancer); (2) HBeAg-positive, impending phase transition (typically age ≥30, HBV DNA ≥6 log₁₀IU/mL, normal ALT, no advanced fibrosis); (3) HBeAg-negative, low replicative (HBV DNA <3.3 log₁₀IU/mL, normal ALT, no/mild fibrosis); (4) HBeAg-negative, high replicative, low-risk (HBV DNA 3.3-4.3 log₁₀IU/mL, normal ALT, no/mild fibrosis). The primary endpoints were the incidence of cirrhosis and HCC.
Results: Up to 5 years of follow-up (117 814 person-years), we documented 635 incident cirrhosis and 164 HCC cases. In multivariable analyses, NA therapy significantly reduced risks of cirrhosis (HR 0.18, 95% CI 0.11 to 0.32) and HCC (HR 0.03, 95% CI 0.01 to 0.21) in Group 1, and cirrhosis (HR 0.50, 95% CI 0.41 to 0.61) and HCC (HR 0.25, 95% CI 0.16 to 0.41) in Group 2. No significant associations were observed in Groups 3 and 4. Findings were consistent in propensity score matching analyses.
Conclusion: NAs therapy was associated with reduced risks of cirrhosis and HCC in HBeAg-positive individuals with high replicative or impending phase transition phenotypes, supporting the expansion of chronic HBV infection treatment criteria.
Keywords: ANTIVIRAL THERAPY; CIRRHOSIS; HEPATITIS B; HEPATOCELLULAR CARCINOMA.
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