HBsAg Isoforms as Innovative Biomarkers in Predicting Virological Response to Bulevirtide in Patients With Chronic Hepatitis D.

Background and Aims: HDV exploits HBV surface‐protein (HBsAg) for entering into hepatocytes. HBsAg consists of 3 isoforms: Large‐ (L‐HBs, predominantly present in virions and mediating binding to NTCP‐receptor), Middle‐ (M‐HBs) and Small‐HBsAg (S‐HBs). Here, we investigated the kinetics of HBs isoforms under bulevirtide treatment (BLV). Methods: 67 consecutive patients with HDV‐related compensated cirrhosis starting BLV 2 mg/day were enrolled. L‐HBs, M‐HBs and S‐HBs were quantified by ad‐hoc ELISAs in baseline and week 48 (W48) samples. Results: At baseline, median (IQR) HDV‐RNA was 5.1 (4.3–5.7) log IU/mL while median (IQR) S‐HBs, M‐HBs and L‐HBs levels were 3801 (1401–7462), 743 (211–1710) and 5 (1–13) ng/mL. At W48, virological responses (VR) were observed in 72% (48/67) of patients, while 25.4% (17/67) achieved undetectable HDV‐RNA (11/17 with ALT‐normalisation). A decline of S‐HBs, M‐HBs and L‐HBs levels was observed in 51%, 63% and 31% of patients (median [IQR] decline: 961 [461–1985], 258 [68–626] and 4 [2‐12] ng/mL). Notably, patients with undetectable HDV‐RNA at W48 had baseline L‐HBs and S‐HBs levels lower than patients not achieving this end‐point (1 [0.3–7] vs. 6 [2‐13] ng/mL, p = 0.04 and 1570 [369–5185] vs. 4015 [1646–8687] ng/mL, p = 0.002). By AUROC, patients with baseline L‐HBs < 3 ng/mL or S‐HBs < 3400 ng/mL were more likely to achieve HDV‐RNA undetectability at W48 (39.3% vs. 15.8%, p = 0.04 and 38.7% vs. 13.9%, p = 0.03). Furthermore, the combination of pre‐treatment L‐HBs < 3 ng/mL + HDV‐RNA < 5logIU/mL and S‐HBs < 3400 ng/mL + HDV‐RNA < 5logIU/mL was the best predictor for achieving undetectable HDV‐RNA at W48 (56.3% vs. 15.7%, p = 0.002 and 60% vs. 11%, p < 0.001). Conclusions: Quantification of L‐HBs and of S‐HBs, along with HDV‐RNA, may reflect the burden of circulating infectious virions in HBV/HDV co‐infection, providing a promising tool to identify patients more likely to respond to BLV. [ABSTRACT FROM AUTHOR]