BACKGROUND & AIMS: HBsAg specific antibody responses are difficult to detect during chronic hepatitis B infection (CHB) and often overlooked. The aim of this study was to examine whether anti-HBs may be involved in functional cure (FC), by profiling anti-HBs responses from CHB patients using a panel of specific assays. METHODS: Longitudinal serum samples were obtained from 25 CHB patients who were infected with HBV genotype A, and undergoing treatment with nucleos(t)ide analogue (NA). All patients. 14 achieved FC while 11 remained infected (non-FC). Anti-HBs immune complexes (HBsAg-IC), FcgammaRIIIa dimer binding, epitope-specificity and neutralization efficacy were measured. RESULTS: HBsAg-IC peaks were detected prior to HBsAg loss in 10/14 FC patients. These HBsAg-IC peaks overlapped with either an ALT flare (8/10 patients), or a rise in ALT (2/10 patients). HBsAg-IC peaks were detected in 7/11 non-FC patients, but were not associated with an ALT flare. FCgammaRIIIa binding was detected in 9/14 FC patients, independent from detection of overlapping HBsAg-IC/ALT peaks. FC patients had stable HBsAg epitope occupancy across the study, whereas non-FC patients had a reduction in HBsAg epitope occupancy within the first 12-24 weeks of NA treatment. Convalescent sera from FC patients recognised more HBsAg epitopes and neutralized HBV infection more potently than anti-HBs derived from vaccines. Neutralisation potency appeared to increase post HBsAg loss in 4/5 FC patients examined. CONCLUSIONS: Using these assays, here we confirm that anti-HBs responses are present and fluctuate over time in this cohort of HBeAg+ CHB patients infected with HBV genotype A and treated with NA. Key anti-HBs profiles associated with either FC, or failure to achieve FC were also identified, suggesting a role for anti-HBs responses in FC. LAY DESCRIPTION: Using a panel of assays to characterize anti-HBs responses in a group of chronic hepatitis B patients, we identified anti-HBs profiles associated with either functional cure, or failure to achieve functional cure. Functional cure was associated with immune complex peaks which overlapped with ALT flares, stable and broad anti-HBs diversity, potential Fc-mediated effector functions (such as ADCC), and seroconversion to potently neutralising anti-HBs. Conversely, in those who did not achieve functional cure, immune complex peaks were present, but were not associated with ALT flares, and a decline in anti-HBs diversity was observed early in treatment.
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