Liver and Bile
J Hepatol. 2023;79(3):657–65
No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase 2 and 3 clinical trials for chronic hepatitis delta
Background and aims: Bulevirtide (BLV) is a hepatitis D virus (HDV)/hepatitis B virus (HBV) entry inhibitor that is associated with virologic response (responders, HDV RNA undetectable or ≥ 2 log10 IU/ml decrease from baseline) in > 50% of patients after a 24-week treatment. However, some patients only achieve a < 1 log10 IU/ml decline in HDV RNA after the 24-week treatment (non-responders). Here, the authors report a viral resistance analysis in participants receiving BLV monotherapy who were non-responders or experienced virologic breakthrough (VB, i.e., 2 consecutive increases in HDV RNA of ≥ 1 log10 IU/ml from nadir or 2 consecutive HDV RNA detectable results if previously undetectable) from the phase 2 MYR202 and phase 3 MYR301 study.
Methods: Deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, were performed for the participant with VB (n = 1) and non-responders (n = 20) at baseline (BL) and week 24 (WK24).
Results: No amino acid exchanges associated with reduced susceptibility to BLV within the BLV-corresponding region or within HDAg were identified in isolates from any of the 21 participants at BL or at WK24. Although variants (HBV, n = 1; HDV, n = 13) were detected at BL in some non-responders or in the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was detected in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 (half-maximal effective concentration) values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥ 1 but < 2 log10 IU/ml), and responders regardless of the presence of HBV and/or HDV polymorphisms.
Conclusions: No amino acid substitutions associated with reduced sensitivity to bulevirtide (BLV) monotherapy were detected at baseline or week 24 in non-responders or the participant with virologic breakthrough after 24-week BLV treatment.