Bulevirtide boasts high barrier to resistance for chronic hepatitis delta

A recent study has found no amino acid substitutions associated with reduced sensitivity to bulevirtide (BLV) monotherapy, a hepatitis D/B virus (HDV/HBV) entry inhibitor, at baseline or week 24 in patients with virologic breakthrough after BLV treatment.

Researchers conducted deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, for the single patient with virologic breakthrough (ie, two consecutive increases in HDV-RNA of ≥1 log₁₀ IU/ml from nadir or two consecutive HDV-RNA detectable results if previously undetectable) and for nonresponders (n=20) at baseline and week 24.

The research team did not detect any amino acid exchanges associated with reduced susceptibility to BLV treatment within the BLV-corresponding region or within HDAg in isolates from any of the 21 participants. Variants (HBV, n=1; HDV, n=13) were seen at baseline, but none of which correlated with reduced sensitivity to BLV in vitro. Notably, the same variant was also found in virologic responders.

In a comprehensive phenotypic analysis, BLV EC₅₀ values from 116 baseline samples were similar across nonresponders, partial responders (ie, HDV RNA decline ≥1 but <2 log₁₀ IU/ml), and responders, irrespective of the presence of HBV or HDV polymorphisms.

“Excluding resistance to BLV as an explanation for an insufficient decrease in HDV-RNA levels during BLV therapy is an important finding for patients, clinicians, and researchers. It demonstrates that BLV has a high barrier to resistance, indicating it is safe and suitable for long-term treatment, although long-term surveillance for resistance should be performed,” the researchers said.

“Our results hint at other still unknown mechanisms as an explanation for the persistence of serum HDV-RNA during inhibition of viral entry,” they added.