Anti-HBs Immune Complex Levels: A Novel Marker of Hepatitis Flare Following Nucleos(t)ide Analog Withdrawal in HBeAg-negative Chronic Hepatitis B

BACKGROUND AND AIMS: Humoral immunity is thought to play a key role in the immunopathogenesis of chronic hepatitis B (CHB). Peaks in anti-HBs immune complexes (HBsAg-ICs) have been associated with subsequent HBsAg seroclearance. Discontinuation of nucleos(t)ide analog (NA) therapy can promote HBsAg seroclearance but also carries a risk of hepatitis flare. We evaluated the relationship between serum HBsAg-IC levels and hepatitis flare following NA cessation in HBeAg-negative CHB. METHODS: In a multicentre prospective cohort of noncirrhotic HBeAg-negative CHB patients undergoing NA discontinuation, we conducted a nested case-control analysis (n = 38). Stored serum samples were tested for HBsAg-IC at end-of-treatment (EOT) and at serial timepoints off-treatment. Cases (n = 24) experienced a hepatitis flare (ALT >5× upper limit of normal); controls (n = 14) did not. Associations between HBsAg-IC levels and clinical outcomes were analyzed. RESULTS: Serum HBsAg-ICs were detectable in 97% of participants at EOT. High HBsAg-IC levels (≥40 IU/mL) at EOT were less frequent among those who developed hepatitis flare (8%) versus controls (57%, P = .002). Individuals treated with tenofovir (vs other NAs) had lower EOT HBsAg-IC levels. Longitudinal analysis revealed dynamic increases in HBsAg-IC levels during hepatitis flare, peaking with maximal ALT. Participants who experienced beneficial flares (≥1 log₁₀ HBsAg reduction) had higher peak off-treatment HBsAg-IC levels compared to those with nonbeneficial flares. CONCLUSIONS: Serum HBsAg-ICs are detectable in patients with CHB, and low levels at EOT are associated with the risk of hepatitis flare after NA cessation. These findings support the role of humoral immunity in CHB immunopathogenesis. CLINICAL TRIALS REGISTRATION: The study clinical trial ID is NCT02581033.