HBV biomarkers outperform host genetic variants in distinguishing occult HBV infection from chronic carriers.

This study aimed to determine if host genetic variants could improve the differentiation of occult hepatitis B virus infection (OBI) from overt chronic infection in Chinese blood donors, beyond standard biomarkers. Through a multicenter screening of over 1.14 million donations and a two-year follow-up, we established a cohort of 147 confirmed carriers (74 OBI and 73 overt) who underwent whole-exome sequencing. A model based on 5 routinely available biomarkers-older age, higher HBV DNA Ct value (indicating lower viral load), elevated anti-HBs, decreased anti-HBc, and anti-HBe negativity-achieved high accuracy (AUCs: 0.898-0.910). In contrast, while 9 missense variants showed initial associations, none were validated, and their inclusion reduced model generalizability. We conclude that serological and virological biomarkers are highly effective for OBI risk stratification, whereas common host genetic variants offer minimal incremental value, highlighting the practical superiority of biomarker profiling and setting a benchmark for future research.