Clinical Trial: Hepatitis B Virus Genotype and a Combination of End‐of‐Treatment Biomarkers Predict Severe Flares After Nucleos(t)ide Analogue Cessation

Background Nucleos(t)ide analogue (NUC) cessation can induce a functional cure in chronic hepatitis B virus (HBV) infections, but severe post‐cessation virologic relapses (SVRel) and severe biochemical flares (SBF) frequently occur. Aims To identify predictive biomarkers for patients at highest risk for SVRel and SBF. Methods In the multicentre prospective COIN‐B trial, start‐of‐treatment HBeAg‐negative, long‐term virologically suppressed patients without advanced fibrosis are followed up for 72 weeks after NUC cessation. We performed a predefined exploratory analysis of the associations between HBV genotype, or end‐of‐treatment (EOT) biomarkers (HBcrAg, HBV RNA, HBsAg, and anti‐HBc IgG) and SVRel (HBV DNA > 5 log IU/mL) or SBF (ALT > 10× ULN) within 48 weeks post‐cessation. Results Of 91 recruited patients, 85 completed 48 weeks of follow‐up. SVRel and SBF occurred in 36 (42.4%) and 21 (24.7%) patients, respectively. Genotypes C, D, and E were associated with higher relapse and flare rates, whereas none of the 18 genotype A patients developed SBF. In multivariate analysis, SVRel was independently associated with detectable HBcrAg (aOR 3.93, p = 0.01), and SBF with non‐A genotype (aOR 19.03, p = 0.018), detectable HBV RNA (aOR 7.84, p = 0.005), and lower anti‐HBc IgG levels (aOR 0.31, p = 0.016). A risk stratification tool, the COBRA score, was developed incorporating HBcrAg, HBV RNA, and anti‐HBc IgG. A score ≥ 2 identified patients at increased risk, with 80.0% sensitivity and 90.7% NPV for SBF. Conclusions HBV genotype and EOT biomarkers, including HBcrAg, HBV RNA, and anti‐HBc IgG predict SVRel and SBF following NUC cessation. The COBRA score enables pragmatic, individualised risk stratification. Trial Registration ClinicalTrials.gov identifier: NCT04779970, EudraCT: 2021‐001003‐32