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Abstract Details
No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta
J Hepatol. 2023 Apr 27;S0168-8278(23)00313-6. doi: 10.1016/j.jhep.2023.04.027.Online ahead of print.
1Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany.
2Gilead Sciences Inc., Foster City, California, USA. Electronic address: Yang.liu@gilead.com.
3Gilead Sciences Inc., Foster City, California, USA.
4Department of Hepatologi, Hôpital Beaujon, AP-HP, Université de Paris-Cité, INSERM UMR 1149, Clichy, France.
5Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy; A.M. e A. Migliavacca" Center for the Study of Liver Disease, Università Degli Studi di Milano, Italy.
6Medizinische Hochschule Hannover, Germany.
7Karolinska Universitetssjukhuset, Karolinska Institutet, Stockholm, Sweden.
8Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany. Electronic address: Stephan.Urban@med.uni-heidelberg.de.
Abstract
Backgrounds & aims: Bulevirtide (BLV) is a hepatitis D virus (HDV)/hepatitis B virus (HBV) entry inhibitor that has shown virologic response (responder, HDV-RNA undetectable or ≥2 log10 IU/mL decrease from baseline) in >50% of patients after 24-week treatment. However, some patients achieve <1 log10 IU/mL decline in HDV-RNA through 24-week treatment (non-responder). Here we report viral resistance analyses for BLV monotreated participants who were non-responders or experienced virologic breakthrough (VB, 2 consecutive increases in HDV-RNA of ≥1 log10 IU/mL from nadir or 2 consecutive HDV-RNA detectable if previously undetectable) in phase II study MYR202 and phase III study MYR301.
Methods: Deep-sequencing of BLV-corresponding region in HBV PreS1 and HDV HDAg gene and 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 within the BLV-corresponding region and HDAg associated with reduced susceptibility to BLV were identified in isolates from any of the 21 participants at BL and WK24. Although variants (HBV n=1; HDV n=13) were detected at BL in some non-responders or the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was found in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 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 BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment.