Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy

References

• Stockdale A, Kreuels B, Henrion M., et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73:523–532. doi:10.1016/j.jhep.2020.04.008
   PubMed Web of Science ®Google Scholar
• Giersch K, Bhadra O, Volz T, et al. Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo. Gut. 2019;68:150–157. doi:10.1136/gutjnl-2017-314713
   PubMed Web of Science ®Google Scholar
• Zhang Z, Ni Y, Lempp F, et al. Hepatitis D virus-induced interferon response and administered interferons control cell division-mediated virus spread. J Hepatol. 2022;77:957–966. doi:10.1016/j.jhep.2022.05.023
   PubMed Web of Science ®Google Scholar
• Urban S, Neumann-Haefelin C, Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to treat disease. Gut. 2021;70:1782–1794. doi:10.1136/gutjnl-2020-323888
   PubMed Web of Science ®Google Scholar
• Farci P, Niro G. Clinical features of hepatitis delta. Semin Liver Dis. 2012;32:228–236. doi:10.1055/s-0032-1323628
   PubMed Web of Science ®Google Scholar
• Buti M, Homs M, Rodriguez-Frias F, et al. Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study. J Viral Hepat. 2011;18:434–442. doi:10.1111/j.1365-2893.2010.01324.x
   PubMed Web of Science ®Google Scholar
• Salpini R, D’Anna S, Piermatteo L, Svicher V. Novel concepts on mechanisms underlying hepatitis delta virus persistence and related pathogenesis. J Viral Hepat. 2022;29(12):1038–1047. doi:10.1111/jvh.13755
   PubMed Web of Science ®Google Scholar
• Alfaiate D, Clément S, Gomes D, Goossens N, Negro F. Chronic hepatitis D and hepatocellular carcinoma: a systematic review and meta-analysis of observational studies. J Hepatol. 2020;73:533–539. doi:10.1016/j.jhep.2020.02.030
   PubMed Web of Science ®Google Scholar
• Sandmann L, Wedemeyer H. Interferon-based treatment of chronic hepatitis D. Liv Int. 2022. doi:10.1111/liv.15410
   PubMedGoogle Scholar
• Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012;1:e00049. doi:10.7554/eLife.00049
   PubMed Web of Science ®Google Scholar
• Petersen J, Dandri M, Mier W, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol. 2008;26:335–341. doi:10.1038/nbt1389
   PubMed Web of Science ®Google Scholar
• Ni Y, Zhang Z, Engelskircher L, et al. Generation and characterization of a stable cell line persistently replicating and secreting the human hepatitis delta virus. Sci Rep. 2019;9:10021. doi:10.1038/s41598-019-46493-1
   PubMed Web of Science ®Google Scholar
• Lempp F, Schlund F, Rieble L, et al. Recapitulation of HDV infection in a fully permissive hepatoma cell line allows efficient drug evaluation. Nat Commun. 2019;10:2265. doi:10.1038/s41467-019-10211-2
   PubMed Web of Science ®Google Scholar
• Burwitz BJ, Zhou Z, Li W. Animal models for the study of human hepatitis B and D virus infection: new insights and progress. Antiviral Res. 2020;182:104898. doi:10.1016/j.antiviral.2020.104898
   PubMed Web of Science ®Google Scholar
• Giersch K, Dandri M. In vivo models of HDV infection: is humanizing NTCP enough? Viruses. 2021;13:588. doi:10.3390/v13040588
   PubMed Web of Science ®Google Scholar
• Blank A, Markert C, Hohmann N, et al. First-in-human application of the first-in-class hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65:483–489. doi:10.1016/j.jhep.2016.04.013
   PubMed Web of Science ®Google Scholar
• Sauter M, Blank A, Stoli F, Lutz N, Haefeli W, Burhenne J. Intact plasma quantification of the large therapeutic bulevirtide lipopeptide. Analyt Bioanalyt Chem. 2021;413:5645–5654. doi:10.1007/s00216-021-03384-7
   PubMed Web of Science ®Google Scholar
• Bogomolov P, Alexandrov A, Voronkova N, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65:490–498. doi:10.1016/j.jhep.2016.04.016
   PubMed Web of Science ®Google Scholar
• Wedemeyer H, Schöneweis K, Bogomolov P, et al. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR-202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 2022;23(1):117–129. doi:10.1016/S1473-3099(22)00318-8
   PubMed Web of Science ®Google Scholar
• Wedemeyer H, Schöneweis K, Bogomolov P, et al. 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection. J Hepatol. 2020;73(suppl 1):S52–3. doi:10.1016/S0168-8278(20)30651-6
   PubMedGoogle Scholar
• Asselah T, Arama S, Bogomolov P, et al. Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR-204 phase 2b study. International Liver Congress. 2021;1;54.
   Google Scholar
• Asif B, Koh C. Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials. Exp Op Invest Drugs. 2022;31:905–920. doi:10.1080/13543784.2021.1977795
   PubMed Web of Science ®Google Scholar
• Wedemeyer H, Aleman S, Brunetto M, et al. Efficacy and safety of bulevirtide monotherapy given at 2 mg or 10 mg dose level once daily for treatment of chronic hepatitis delta: week 48 primary end point results from a phase 3 randomized, multicenter, parallel design study. J Hepatol. 2022;77(suppl 1):4–5. doi:10.1016/S0168-8278(22)00433-0
   Google Scholar
• Yurdaydin C, Abbas Z, Buti M, et al. Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy. J Hepatol. 2019;70:1008–1015. doi:10.1016/j.jhep.2018.12.022
   PubMed Web of Science ®Google Scholar
• Khalfi P, Kennedy P, Majzoub K, Asselah T. Hepatitis D virus: improving virological knowledge to develop new treatments. Antivir Res. 2023;209:105461. doi:10.1016/j.antiviral.2022.105461
   PubMed Web of Science ®Google Scholar
• Asselah T, Loureiro D, Le Gal F, et al. Early virological response in six patients with hepatitis D virus infection and compensated cirrhosis treated with Bulevirtide in real-life. Liver Int. 2021;41:1509–1517. doi:10.1111/liv.14950
   PubMed Web of Science ®Google Scholar
• De Ledinghen V, Hermabessiere P, Metivier S, et al. Bulevirtide with or without peginterferon in HDV infected patients in a real-life setting: two-year results from the French multicenter early access program. Hepatology. 2022;76(Abstract):28.
   Google Scholar
• Zoulim F, Fougerou C, Roulot D, et al. Efficacy and safety of treatment with bulevirtide in chronic hepatitis delta: preliminary results of the real-life ANRS HD EP01 Buledelta cohort. Hepatology. 2022;76(Abstract):1017.
   Google Scholar
• Degasperi E, Anolli MP, Uceda-Renteria SC, et al. Improvement of clinical parameters in HDV patients with advanced compensated cirrhosis treated with bulevirtide monotherapy for 48 weeks. Hepatology. 2022;76(Abstract):1011.
   Google Scholar
• Degasperi E, Anolli M, Renteria S, et al. Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension. J Hepatol. 2022;77(6):1525–1531.
   PubMed Web of Science ®Google Scholar
• Jachs M, Schwarz C, Panzer M, et al. Response-guided long-term treatment of chronic hepatitis D patients with bulevirtide-results of a “real world” study. Aliment Pharmacol Ther. 2022;56:144–154. doi:10.1111/apt.16945
   PubMed Web of Science ®Google Scholar
• Zöllner C, Hofmann J, Lutz K, Tacke F, Demir M. Real-life experiences with bulevirtide for the treatment of hepatitis delta-48 weeks data from a German centre. Liver Int. 2022;42:2403–2407. doi:10.1111/liv.15408
   PubMed Web of Science ®Google Scholar
• Herta T, Hahn M, Maier M, et al. Efficacy and safety of bulevirtide plus tenofovir disoproxil fumarate in real-world patients with chronic hepatitis B and D co-Infection. Pathogens. 2022;11:517. doi:10.3390/pathogens11050517
   PubMed Web of Science ®Google Scholar
• Giordan M, Bengone-Abogourin J, Aherfi S, Allemand I, Colson P. Hepatitis delta treatment with bulevirtide in real life: a case report. Int J Antimicrob Agents. 2022;59:106562. doi:10.1016/j.ijantimicag.2022.106562
   PubMed Web of Science ®Google Scholar
• Degasperi E, Anolli MP, Lampertico P. Bulevirtide for patients with compensated chronic hepatitis delta: a review. Liver Int. 2022. doi:10.1111/liv.15389
   PubMedGoogle Scholar
• Lampertico P, Roulot D, Wedemeyer H. Bulevirtide with or without pegIFNα for patients with compensated chronic hepatitis delta: from clinical trials to real-world studies. J Hepatol. 2022;77(5):1422–1430. doi:10.1016/j.jhep.2022.06.010
   PubMed Web of Science ®Google Scholar
• Loglio A, Ferenci P, Uceda-Renteria S, et al. Safety and effectiveness of up to 3 years’ bulevirtide monotherapy in patients with HDV-related cirrhosis. J Hepatol. 2022;76:464–469. doi:10.1016/j.jhep.2021.10.012
   PubMed Web of Science ®Google Scholar
• Buti M, Wedemeyer H, Aleman S, et al. Bulevirtide improves health related quality of life measured by EQ-5D VAS in patients with chronic hepatitis delta: an exploratory analysis of a phase 3 trial at 48 weeks. Hepatology. 2022;76:1019.
   Web of Science ®Google Scholar
• Allweiss L, Volmari A, Ladiges Y, et al. Strong intrahepatic decline of hepatitis D virus RNA and antigen after 48 weeks of treatment with bulevirtide in chronic HBV/HDV confected patients: interim results from a multicenter, open-label, randomized phase 3 clinical trial (MYR-301). Hepatology. 2021;74:S148A.
   Web of Science ®Google Scholar
• Hollnberger J, Schlund F, Schöneweis K, Zehnder B, Urban S. Rare cases of non-response in bulevirtide (BLV) treated patients from the MYR-204/301 studies are not associated with the development of BLV resistance. Hepatology. 2021;74:S426A.
   Web of Science ®Google Scholar
• Asselah T, Lampertico P, Aleman S, et al. Bulevirtide monotherapy is safe and well tolerated in patients with chronic hepatitis D: an integrated safety analysis of 48-week data. Hepatology. 2022;76(Abstract):1016.
   Google Scholar
• Schwarz C, Chromy D, Bangert C, et al. Immediate-type hypersensitivity reaction to bulevirtide and successful desensitization in a patient with HBV/HDV-associated compensated cirrhosis. J Hepatol. 2022;77:254–255. doi:10.1016/j.jhep.2022.03.004
   PubMed Web of Science ®Google Scholar
• Behrendt P, Traidl S, Böker K, Wedemeyer H, Deterding K. T-cell driven allergic cutaneous reaction complicating treatment of hepatitis delta virus infection with bulevirtide. Liver Int. 2022;42:1770–1771. doi:10.1111/liv.15330
   PubMed Web of Science ®Google Scholar
• Jachs M, Reiberger T, Ferenci P. Reply to: pegylated interferon combined with bulevirtide for chronic hepatitis delta – new life for an old timer? Aliment Pharmacol Ther. 2022;56(5):914. doi:10.1111/apt.17138
   PubMed Web of Science ®Google Scholar
• Yuen M, Lim S, Plesniak R, et al.; B-Clear Study Group. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med. 387;2022:1957–1968. doi:10.1056/NEJMoa2210027
   PubMed Web of Science ®Google Scholar
• Asselah T. Beyond bulevirtide: alternative therapeutic options for the management of HDV. J Viral Hepat. 2022. doi:10.1111/jvh.13789
   Web of Science ®Google Scholar
• Brancaccio G, Gaeta G. Treatment of chronic hepatitis delta due to hepatitis B and hepatitis delta virus coinfection. Int J Antimicrob Agents. 2019;54:697–701. doi:10.1016/j.ijantimicag.2019.09.012
   PubMed Web of Science ®Google Scholar
• Heidrich B, Yurdaydin C, Kabacam G, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60:87–97. doi:10.1002/hep.27102
   PubMed Web of Science ®Google Scholar
• Wranke A, Hardtke S, Heidrich B, et al. Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta. J Viral Hepat. 2020;27:1359–1368. doi:10.1111/jvh.13366
   PubMed Web of Science ®Google Scholar
• Sandmann L, Yurdaydin C, Deterding K, et al.; HIDIT-II Study Group. HBcrAg levels are associated with virological response to treatment with interferon in patients with hepatitis delta. Hepatol Commun. 2022;6:480–495. doi:10.1002/hep4.1821
   PubMed Web of Science ®Google Scholar
• Kilic Z, Koksal A, Kalkan IH, Suna N, Yildiz H, Kacar S. Long term efficacy of pegylated interferon in the treatment of delta hepatitis: a single center experience. Acta Gastroenterol Belg. 2016;79:329–335.
   PubMed Web of Science ®Google Scholar
• Bremer B, Anastasiou O, Hardtke S, et al. Residual low HDV viremia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis delta: results from the HIDIT-II study. Liver Int. 2021;41:295–299. doi:10.1111/liv.14740
   PubMed Web of Science ®Google Scholar
• Kapuria D, Ben Yakov G, Koh C, Heller T. Spontaneous clearance of chronic delta hepatitis. Hepatology. 2020;71:873–875. doi:10.1002/hep.31073
   Web of Science ®Google Scholar
• Koh C, Canini L, Dahari H, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 2015;15:1167–1174. doi:10.1016/S1473-3099(15)00074-2
   PubMed Web of Science ®Google Scholar
• Yurdaydin C, Keskin O, Yurdcu E, et al. A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis. Hepatology. 2022;75:1551–1565. doi:10.1002/hep.32259
   PubMed Web of Science ®Google Scholar
• Etzion O, Hamid S, Lurie Y, et al. PS-052-End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with peginterferon lambda mono-therapy in patients with chronic hepatitis delta virus infection. J Hepatol. 2019;70:e32. doi:10.1016/S0618-8278(19)30058-1
   Web of Science ®Google Scholar
• Soriano V, Mendoza C, Barreiro P, Treviño A, Corral O. Envisioning a hepatitis delta cure with new antivirals. Future Microbiol. 2021;16:927–930. doi:10.2217/fmb-2021-0177
   PubMed Web of Science ®Google Scholar
• Shekhtman L, Cotler S, Hershkovich L, et al. Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg. Sci Rep. 2020;10:7837. doi:10.1038/s41598-020-64122-0
   PubMed Web of Science ®Google Scholar
• Anolli MP, Degasperi E, Allweiss L, et al. Cure of hepatitis delta infection following 3 years of bulevirtide monotherapy in a patient with compensated advanced cirrhosis. Hepatology. 2022;76:1012.
   Web of Science ®Google Scholar
• Yurdaydin C, Keskin O, Kalkan C, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: the LOWR HDV-1 study. Hepatology. 2018;67:1224–1236. doi:10.1002/hep.29658
   PubMed Web of Science ®Google Scholar
• Dassetto C, Borentain P, Gérolami R, Colson P. Bulevirtide 2mg-based real-life treatment of hepatitis Delta with genotypes 1 and 5 viruses at more than 20 months of follow-up. Res Hepatol Gastroenterol. 2022;46:102035. doi:10.1016/j.clinre.2022.102035
   PubMed Web of Science ®Google Scholar
• Wang W, Lempp F, Schlund F, et al. Assembly and infection efficacy of hepatitis B virus surface protein exchanges in 8 hepatitis D virus genotype isolates. J Hepatol. 2021;75:311–323. doi:10.1016/j.jhep.2021.03.025
   PubMed Web of Science ®Google Scholar
• Manhas S, Han B, Xu S, et al. Bulevirtide is broadly active against all HDV genotypes expressing envelopes from HBV genotypes A-H and a large panel of clinical isolates. J Hepatol. 2022;77(suppl 1):S244. doi:10.1016/S0168-8278(22)00858-3
   Google Scholar
• Kang C, Syed Y. Bulevirtide: first approval. Drugs. 2020;80:1601–1605. doi:10.1007/s40265-020-01400-1
   PubMed Web of Science ®Google Scholar