Reevaluating antiviral thresholds in HBV DNA-negative inactive HBsAg carriers: a multicenter histopathological analysis.

Background: The definition of inactive HBsAg carriers (IHC) varies globally, particularly regarding HBV DNA thresholds. Whether HBV DNA negativity reliably predicts histological quiescence remains uncertain.

Aims: This study evaluated liver pathology in IHC patients to reassess antiviral therapy thresholds.

Methods: This multi-center, retrospective study included 231IHCs(2018-2023) stratified by HBV DNA negativity (< 20IU/mL). Liver biopsies assessed inflammation (G ≥ 2) and fibrosis (F ≥ 2); evident hepatic injury (EHI) was defined as G ≥ 2 and/or F ≥ 2. Multivariable models evaluated predictors.

Results: Among 231 IHC patients(median age:43 years old; 95.2% ≥30 years old), 35.9%(83/231) were HBV DNA negative. The median HBsAg and HBV DNA level were 132 IU/ml and 94 IU/ml, respectively. Notably, EHI prevalence was significantly higher in HBV DNA negative patients than positive ones(44.9% vs. 31%, P = 0.04), driven by fibrosis (F ≥ 2: 42.2% vs. 21.6%, P < 0.001), challenging the assumption that HBV DNA negativity ensures low histological risk. Male sex, HBV DNA negativity, and elevated liver stiffness measurement(LSM) independently predicted EHI (OR = 3.37, AUC = 0.747).

Conclusion: HBV DNA negativity does not guarantee histological quiescence in inactive HBsAg carriers aged ≥ 30 years, with 44.9% exhibiting significant liver injury. In this population, LSM > 6.4 Kpa should prompt consideration of liver biopsy and/or initiation of antiviral therapy.