Ethnicity, genomic ancestry, and HBV genotype in off-treatment outcomes following nucleos(t)ide analogue cessation: a prospective multicentre trial (COIN-B)

Nucleos(t)ide analogue (NUC) cessation can induce functional cure, but outcomes vary. Ethnicity has been suggested as a determinant, but definitions are subjective and inconsistent. In this prospective, multicentre trial (NCT04779970, EudraCT 2021-001003-32), 91 long-term NUC-treated, start-of-treatment HBeAg-negative patients without advanced fibrosis discontinued treatment; 84 completed the 72-week protocol. In the prespecified analysis, off-treatment viral control at week 72 (primary endpoint) did not differ between Caucasians (n = 41) and non-Caucasians (n = 43) (41.5% vs 30.2%, p = 0.28). In exploratory analyses, HBsAg loss (7.1%, secondary endpoint) occurred exclusively in European or North African/Middle Eastern genomic ancestries, and ≥1 log IU/mL HBsAg decline was less frequent in Asian or Sub-Saharan African ancestries (p = 0.01). Lower end-of-treatment HBsAg independently predicted viral control, HBsAg loss and decline. Adjusted for end-of-treatment HBsAg, genotypes C and D achieved less viral control and required more retreatment than genotype A. Here, we show that genomic ancestry and HBV genotype capture clinically relevant heterogeneity, calling for more granular characterization of eligible populations. Clinical trial information EudraCT: 2021-001003-32. Date of registration: 7 June 2021 CTIS: 2024-511016-25-00. Date of transition from EudraCT: 15 January 2025 Clinicaltrials.gov: NCT04779970. Date of registration: 28 July 2021. Authors show that after stopping hepatitis B therapy, off-treatment outcomes were linked to viral genotype and genomic ancestry rather than conventional ethnicity. Biologically grounded, granular patient characterization may help identify who can safely stop treatment.