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. 2023 Mar 15;5(4):100686.
doi: 10.1016/j.jhepr.2023.100686. eCollection 2023 Apr.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients

Christopher Dietz-Fricke  1 , Frank Tacke  2 , Caroline Zöllner  2 , Münevver Demir  2 , Hartmut H Schmidt  3 , Christoph Schramm  3 , Katharina Willuweit  3 , Christian M Lange  4 , Sabine Weber  4 , Gerald Denk  4 , Christoph P Berg  5 , Julia M Grottenthaler  5 , Uta Merle  6 , Alexander Olkus  6 , Stefan Zeuzem  7 , Kathrin Sprinzl  7 , Thomas Berg  8 , Florian van Bömmel  8 , Johannes Wiegand  8 , Toni Herta  8 , Thomas Seufferlein  9 , Eugen Zizer  9 , Nektarios Dikopoulos  9 , Robert Thimme  10 , Christoph Neumann-Haefelin  10 , Peter R Galle  11 , Martin Sprinzl  11 , Ansgar W Lohse  12 , Julian Schulze Zur Wiesch  12   13 , Jan Kempski  12   14 , Andreas Geier  15 , Florian P Reiter  15 , Bernhard Schlevogt  16 , Juliana Gödiker  16 , Wolf Peter Hofmann  17 , Peter Buggisch  18 , Julia Kahlhöfer  1 , Kerstin Port  1 , Benjamin Maasoumy  1 , Markus Cornberg  1   19   20 , Heiner Wedemeyer  1   21   22   19 , Katja Deterding  1
Affiliations

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients

Christopher Dietz-Fricke et al. JHEP Rep. .

Abstract

Background & aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon.

Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D.

Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events.

Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment.

Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Keywords: Antiviral treatment; Bulevirtide; Hepatitis D; Real world experience; Viral hepatitis.

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Conflict of interest statement

CD has received travel support from Gilead. FT has received grants or contracts from any entity from Allergan, BMS, Inventiva, Gilead; consulting fees from Allergan, Bayer, Gilead, BMS, Boehringer, Intercept, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk, Novartis; payment for expert testimony from Alnylam; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Pfizer. CZ has no COI. MD has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead and MYR, support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Gilead and MYR. HS has no COI. CS received support for attending meetings and/or travel from Abbvie and Gilead, participation on a Data Safety Monitoring Board or Advisory Board form Gilead. KW has no COI. CL has received consulting fees from CSL Behring, Boston Scientific, Astra Zeneca, Eisai, Shionogi, Sobi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Gilead, Falk, BSL Behring, Eisai; support for attending meetings and/or travel from Gilead and Abbvie. SW received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Falk and Abbvie; support for attending meetings and/or travel form Orphalan, Falk, Abbvie. GD received consulting fees from Alexion, Gilead, Intercept, Novartis, Orphalan, Univar; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Falk Foundation, Gilead, Intercept, Novartis, Orphalan; support for attending meetings and/or travel support form Gilead and Intercept. CB received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead; and support for attending meetings and/or travel from Gilead. JG has no COI. UM received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from CSL Behring, MSD, Falk, Univar, Microbiotica; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Takeda, Gilead, CSL Behring; AO has no COI; SZ reports speaker’s bureau and/or consultancy for Abbvie, BioMarin, Gilead, GSK, Intercept, Janssen, Madrigal, MSD/Merck, NovoNordisk, SoBi and Theratechnologies, GSK, Gilead, Intercept; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, BioMarin, Janssen, MSD/Merck; payment for expert testimony and support for attending meetings and/or travel from Gilead. KS received grants from Gilead; honoraria for lectures from Gilead, Abbvie and MSD; support for attending meetings and/or travel from Gilead and Abbvie; participated in advisory boards from Gilead. TB received grants or contracts from any entity from Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Novartis, Sequana Medical, received consulting fees from Abbvie, Alexion, Bayer, Gilead, Eisai, GSK, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, Roche, Sequana Medical, and Shionogi; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Alexion, Bayer, Gilead, Eisai, Intercept, Ipsen, Janssen, MedUpdate GmbH, MSD/Merck, Novartis, and Sequana Medica; has received support for attending meetings and/or travel Gilead, Abbvie, Intercept, Janssen. FB received grants or contracts from any entity from Gilead, Ipsen, Roche, Janssen; consulting fees from Gilead, Janssen, Astra Zeneca, MSD, Janssen, Advanz Pharma; support for attending meetings and/or travel from Advanz Pharma and Gilead, reports participation on a Data Safety Monitoring Board or Advisory Board from Janssen. JW has no COI. TH received author honoraria from Falk. TS has no COI. EZ has no COI. ND has no COI. RT has no COI. CNH received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Gilead, GSK, MSD, Falk Foundation. PG has no COI. MS participated in advisory boards from Gilead. AL received consulting fees from Roche, reports participation in advisory boards from Roche, MSD and Genfit. JSW received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and travel support from Gilead. JK has no COI. AG received payment for expert testimony from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana. FR received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Falk Foundation, Novartis, Ipsen and Gilead. BS received honoraria for lectures from Gilead and Alnylam, received consulting fees from Gilead and Univar, received travel support from Abbvie and Gilead. JG has no COI. WH received speakers honoraria from Gilead, Abbvie, Intercept, Norgine, Novo Nordisk, Falk; support for attending meetings and/or travel from Abbvie and Gilead. PB received consulting fees from Gilead; received payment for speakers bureau from AbbVie, Falk, Gilead, Roche, MSD, Myr; support for attending meetings and/or travel from Abbvie and Gilead. JK has no COI. KP has no COI. BM received grants or contracts from any entity from Roche Diagnostics and Fujirebio; consulting fees from Abbvie, Roche, Luvos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Roche, Gilead, Norgine, Fujirebio, Merck/MSD, Medical Tribune Forum; support for attending meetings and/or travel from Abbvie and Gilead; holds stocks or stock options from Biontech. MC received consulting fees from Abbvie, AiCuris, Gilead, GlaxoSmithKline, Janssen-Cilag, MSD Sharp & Dohme, Spring Bank Pharmaceuticals, Swedish Orphan Biovitrum AB (SOBI); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Gilead, GlaxoSmithKline, MSD Sharp & Dohme, Falk; reports participation on a Data Safety Monitoring Board or Advisory Board from Novartis; HW received grants or contracts from any entity from AbbVie, Biotest, BMS, Gilead, Merck/MSD, Novartis, Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott, AbbVie, Altimmune, Biotest, BMS, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens. KD has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead, Falk, Abbvie, MSD/Merck and Alnylam. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Viral kinetics and ALT decline in patients with virologic non-response at week 24 (n = 3). Displayed are individual HDV RNA and ALT levels of three patients with virologic non-response (<1-log-reduction) at week 24. Each patient is symbolized by a color. ALT, alanine aminotransferase.
Fig. 2
Fig. 2
Change in ALT levels grouped by virologic response at week 12 and week 24 (n = 33). (A) Patients who achieved a virologic response at week 12 and (B) those who achieved a virologic response at week 24. Bars represent mean ALT levels at week 0 (white), week 12 (grey) and week 24 (dark grey). Error bars show the SD. Individual data points are visualized by dots. Wilcoxon signed-rank tests were used for comparison of ALT at week 0 and 12 or 24; ∗p <0.05. ALT, alanine aminotransferase.
Fig. 3
Fig. 3
FIB-4 values at week 0, 12, 24 in patients without cirrhosis and with cirrhosis (n = 33). (A) Patients without cirrhosis and (B) patients with cirrhosis. Shown are boxplots of FIB-4 values of 33 patients at the three time points. Patients are grouped according to the presence of cirrhosis. Data were analyzed with a repeated-measurement ANOVA and post hoc Bonferroni-corrected paired t tests. ∗p <0.05.
Fig. 4
Fig. 4
IgG levels at week 0, 12 and 24 (n = 15). Boxplots show IgG levels in 15 patients. Data were analyzed using a repeated-measurement ANOVA and post hoc Bonferroni-corrected paired t test. ∗p <0.05.
Fig. 5
Fig. 5
Viral kinetics, ALT dynamics and platelet counts in patients with decompensated liver disease at treatment initiation (n = 5). Displayed are individual HDV RNA levels, ALT levels and the platelet count of five selected cases with evidence of decompensated liver disease at bulevirtide treatment initiation. ALT, alanine aminotransferase.
See this image and copyright information in PMC

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