Phase 2 Randomised Study of Bulevirtide as Monotherapy or Combined With Peg-IFNα-2a as Treatment for Chronic Hepatitis Delta

Background and Aim: Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFN alpha-2a), with 24-week follow-up. Methods: Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFN alpha-2a 180 mu g once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFN alpha-2a 180 mu g QW; (C) BLV 5 mg QD + Peg-IFN alpha-2a 180 mu g QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFN alpha-2a 180 mu g QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72. Results: At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log(10) IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment. Conclusions: BLV combined with Peg-IFN alpha-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment. Trial Registration: NCT02888106