Broad-spectrum activity of bulevirtide against clinical isolates of HDV and recombinant pan-genotypic combinations of HBV/HDV
Roberto Mateo, Simin Xu, Alex Shornikov, Tahmineh Yazdi, Yang Liu, Lindsey May, Bin Han, Dong Han, Ross Martin, Savrina Manhas, Christopher J. Richards, Caleb Marceau, Thomas Aeschbacher, Silvia Chang, Dmitry Manuilov, Julius Hollnberger, Stephan Urban, Tarik Asselah, Dzhamal Abdurakhmanov, Pietro Lampertico, Evguenia Maiorova, Hongmei Mo
Abstract
Background and AimsBulevirtide (BLV) is a small lipopeptide agent that specifically binds to the NTCP bile salt transporter and HBV/HDV receptor on the surface of human hepatocytes and inhibits HDV and HBV entry. As a satellite virus of HBV, HDV virions are formed after assembly of HDV RNA with the HBV envelope proteins (HBsAg). Because both viruses exist as eight different genotypes, this creates a potential for high diversity in the HBV/HDV combinations.To investigate the sensitivity of various combinations of HBV/HDV genotypes to BLV, clinical and laboratory strains were assessed.MethodsFor the lab strains, the different envelopes from HBV genotypes A through H were combined with HDV genotypes 1 through 8 in co-transfection assays. Clinical plasma isolates were obtained from clinical studies and academic collaborations to maximize the diversity of HBV/HDV genotypes tested.ResultsThe mean BLV 50% effective concentration against HDV laboratory strains ranged from 0.44 nM to 0.64 nM. Regardless of HBV and HDV genotypes, the clinical isolates showed similar sensitivities to BLV with mean values that ranged from 0.2 nM to 0.73 nM.ConclusionsThese data support the use of BLV in patients infected with any HBV/HDV genotypes.Impact and ImplicationsThis study describes the potent activity of BLV against multiple lab strains spanning all HBV/HDV A-H/1-8 genotype combinations and the most diverse collection of HDV clinical samples tested to date, including HBV/HDV genotype combinations less frequently observed in the clinic. Overall, all isolates and lab strains displayed similar in vitro nanomolar sensitivity to BLV. This broad-spectrum antiviral activity of BLV has direct implications on potential simplified treatment for any patient infected with HDV, regardless of genotype and supports the new 2023 EASL clinical practice guidelines on HDV that recommend antiviral treatment for all patients with CHD.