Efficacy and safety of bulevirtide in patients with chronic hepatitis D and compensated cirrhosis

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Abstract

Aim. To study the efficacy and safety of bulevirtide, the HBV and HDV entry inhibitor.

Materials and methods. Analysis of the results of using bulevirtide in randomized controlled open-label comparative studies MYR202 and MYR203 in 56 patients with chronic hepatitis D and compensated cirrhosis, in monotherapy and combination with pegylated interferon alpha-2a (PEG-IFN).

Results. Monotherapy with bulevirtide for 24 weeks in the MYR202 study in 46 patients with compensated liver cirrhosis demonstrated: 1) a high rate of virological (100%) and biochemical response (alanine aminotransferase normalization rate – 45.7%), 2) superiority of bulevirtide in efficacy over the control group (tenofovir), 3) comparability of treatment efficacy in patients with and without cirrhosis, 4) no progression of liver fibrosis with elastometry in most patients.

Treatment with bulevirtide in monotherapy and combination with PEG-IFN for 48 weeks in 10 patients with compensated liver cirrhosis in the MYR203 study was accompanied by a high rate of virological response (80%) and normalization of alanine aminotransferase (70%).

Bulevirtide was well tolerated, there was no deterioration in tolerability compared with patients without cirrhosis, there were no serious adverse events and cases of treatment cancellation due to adverse events.

Conclusion. Bulevirtide is recommended as the first line of treatment for chronic hepatitis D in patients with compensated cirrhosis in monotherapy and combination with PEG-IFN.

About the authors

Pavel O. Bogomolov

Vladimirsky Moscow Regional Research Clinical Institute; Yevdokimov Moscow State University of Medicine and Dentistry

Author for correspondence.
Email: hepatology@monikiweb.ru
ORCID iD: 0000-0003-2346-1216

канд. мед. наук, рук. отд-ния гепатологии ГБУЗ МО «МОНИКИ им. М.Ф. Владимирского», доц. каф. фармакологии ФГБОУ ВО «МГМСУ им. А.И. Евдокимова»

Russian Federation, Moscow

Vladimir T. Ivashkin

Sechenov First Moscow State Medical University (Sechenov University)

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0002-6815-6015

акад. РАН, д-р мед. наук, проф., зав. каф. пропедевтики внутренних болезней ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова (Сеченовский Университет)»

Russian Federation, Moscow

Alexey O. Bueverov

Vladimirsky Moscow Regional Research Clinical Institute; Sechenov First Moscow State Medical University (Sechenov University)

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0002-5041-3466

д-р мед. наук, проф. каф. медико-социальной экспертизы, неотложной и поликлинической терапии ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова (Сеченовский Университет)», вед. науч. сотр. отд. гепатологии ГБУЗ МО «МОНИКИ им. М.Ф. Владимирского»

Russian Federation, Moscow

Igor V. Maev

Yevdokimov Moscow State University of Medicine and Dentistry

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0001-6114-564X

акад. РАН, д-р мед. наук, проф., зав. каф. пропедевтики внутренних болезней и гастроэнтерологии ФГБОУ ВО «МГМСУ им. А.И. Евдокимова»

Russian Federation, Moscow

Olga I. Sagalova

South Ural State Medical University

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0003-3814-7342

д-р мед. наук, зав. инфекционным отд-нием Клиники ФГБОУ ВО ЮУГМУ

Russian Federation, Chelyabinsk

Snezhana S. Sleptsova

Ammosov North-Eastern Federal University

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0002-0103-4750

д-р мед. наук, доц., зав. каф. инфекционных болезней, фтизиатрии и дерматовенерологии медицинского института ФГАОУ ВО «СВФУ им. М.К. Аммосова»

Russian Federation, Yakutsk

Nikolay D. Yushuk

Yevdokimov Moscow State University of Medicine and Dentistry

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0003-1928-4747

акад. РАН, д-р мед. наук, проф., зав. каф. инфекционных болезней и эпидемиологии, президент ФГБОУ ВО «МГМСУ им. А.И. Евдокимова»

Russian Federation, Moscow

Denis A. Gusev

Botkin Clinical Infectious Diseases Hospital

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0001-9202-3231

д-р мед. наук, проф., гл. врач ГБУЗ «Клиническая инфекционная больница им. С.П. Боткина»

Russian Federation, Saint Petersburg

Konstantin V. Zhdanov

Kirov Military Medical Academy

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0002-3679-1874

чл.-кор. РАН, д-р мед. наук, проф., нач. каф. инфекционных болезней (с курсом медицинской паразитологии и тропических заболеваний) ФГБВОУ ВО «ВМА им. С.М. Кирова»

Russian Federation, Saint Petersburg

Vladimir P. Chulanov

Sechenov First Moscow State Medical University (Sechenov University); National Medical Research Center of Phthisiopulmonology and Infectious Diseases

Email: hepatology@monikiweb.ru
ORCID iD: 0000-0001-6303-9293

д-р мед. наук, зам. дир. по научной работе и инновационному развитию ФГБУ НМИЦ ФПИ, проф. каф. ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова (Сеченовский Университет)»

Russian Federation, Moscow

References

  1. Rizzetto M. The discovery of the hepatitis D Virus: three princes of serendip and the recognition of autoantibodies to liver-kidney microsomes. Clin Liver Dis (Hoboken). 2020;16(Suppl. 1):1-11. doi: 10.1002/cld.1033
  2. Stockdale AJ, Kreuels B, Henrion MYR, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73(3):523-32. doi: 10.1016/j.jhep.2020.04.008
  3. Chen HY, Shen DT, Ji DZ, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2019;68(3):512-21. doi: 10.1136/gutjnl-2018-316601
  4. Da B, Heller T, Koh C. Hepatitis D infection: from initial discovery to current investigational therapies. Gastroenterol Rep (Oxf). 2019;7(4):231-45. doi: 10.1093/gastro/goz023
  5. Mentha N, Clément S, Negro F, et al: From virology to new therapies. J Adv Res. 2019;17:3-15. doi: 10.1016/j.jare.2019.03.009
  6. Gilman C, Heller T, Koh C. Chronic hepatitis delta: A state-of-the-art review and new therapies. World J Gastroenterol. 2019;25(32):4580-97. doi: 10.3748/wjg.v25.i32.4580
  7. Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364(4):322-31. doi: 10.1056/NEJMoa0912696
  8. Scheller L, Hilgard G, Anastasiou O, et al. Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients. Medicine (Baltimore). 2021;100(28):e26571. doi: 10.1097/MD.0000000000026571
  9. Wedemeyer H, Yurdaydin C, Hardtke S, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis. 2019;19(3):275-86. doi: 10.1016/S1473-3099(18)30663-7
  10. Bremer B, Anastasiou O, Hardtke S, et al. Residual low HDV viremia is associated with HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis D (delta): results from the HIDIT-II study. J Hepatol. 2020;73(Suppl. 1):S868.
  11. Abdrakhman A, Ashimkhanova A, Almawi WY. Effectiveness of pegylated interferon monotherapy in the treatment of chronic hepatitis D virus infection: A meta-analysis. Antiviral Res. 2021;185:104995. doi: 10.1016/j.antiviral.2020.104995
  12. 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;3:10.7554/eLife.00049. doi: 10.7554/eLife.00049
  13. Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol. 2005;79(3):1613-22. doi: 10.1128/JVI.79.3.1613-1622.2005
  14. Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology. 2014;147(1):48-64. doi: 10.1053/j.gastro.2014.04.030
  15. Blank A, Markert C, Hohmann N, et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65(3):483-9. doi: 10.1016/j.jhep.2016.04.013
  16. Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol. 2016;64(1 Suppl.):S32-S40. doi: 10.1016/j.jhep.2016.02.011
  17. Blank A, Eidam A, Haag M, et al. The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics. Clin Pharmacol Ther. 2018;103(2):341-8. doi: 10.1002/cpt.744
  18. Богомолов П.О., Ивашкин В.Т., Буеверов А.О., и др. Эффективность и безопасность булевиртида в лечении хронического гепатита D – результаты рандомизированных контролируемых исследований. Инфекционные болезни. 2020;18:153-62 [Bogomolov PO, Ivashkin VT, Bueverov AO, et al. Efficacy and safety of bulevirtide in the treatment of chronic hepatitis D: results of randomized controlled trials Infekc. bolezni (Infectious diseases). 2020;18:153–62. (in Russian)]. doi: 10.20953/1729-9225-2020-4-153-162
  19. Kang C, Syed YY. Bulevirtide: First Approval. Drugs. 2020;80(15):1601-5. doi: 10.1007/s40265-020-01400-1.
  20. 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(3):490-8. doi: 10.1016/j.jhep.2016.04.016
  21. Wedemeyer H, Bogomolov P, Blank A, et. al. Final results of a multicenter open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with tenofovir in patients with chronic HBV/HDV infection. J Hepatol. 2018;68(1):S3. doi: 10.1016/S0168-8278(18)30224-1
  22. Wedemeyer H, Schöneweis K, Bogomolov P, et al. Interim results of a multicentre, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of Myrcludex B in combination with Peg-Interferon alpha 2a in patients with chronic HBV/HDV co-infection. Hepatology. 2018;68:S11A.
  23. Asselah T, Loureiro D, Tout I, Castelnau C, Boyer N, Marcellin P, et al. Future treatments for hepatitis delta virus infection. Liver Int. 2020;40(Suppl. 1):54-60. doi: 10.1111/liv.14356
  24. Sandmann L, Cornberg M. Experimental Drugs for the Treatment of Hepatitis D. J Exp Pharmacol. 2021;13:461-8. doi: 10.2147/JEP.S235550
  25. Yurdaydin C, Abbas Z, Buti M, et al. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy. J Hepatol. 2019;70(5):1008-15. doi: 10.1016/j.jhep.2018.12.022
  26. Zhang Z, Urban S. New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies. J Hepatol. 2021;74(3):686-99. doi: 10.1016/j.jhep.2020.11.032
  27. Rizzetto M, Hamid S, Negro F. The changing context of hepatitis D. J Hepatol. 2021;74(5):1200-11. doi: 10.1016/j.jhep.2021.01.014
  28. 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(9):1782-94. doi: 10.1136/gutjnl-2020-323888
  29. Loglio A, Ferenci P, Renteria S, et al. Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: A case report of 3 patients. J Hepatol. 2019;71(4):834-9. doi: 10.1016/j.jhep.2019.07.003
  30. 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(7):1509-17. doi: 10.1111/liv.14950
  31. Masetti C, Aghemo A. Bulevirtide for treatment of patients with HDV infection and compensated cirrhosis: A (huge?) step in the right direction. Liver Int. 2021;41(7):1441-2. doi: 10.1111/liv.14967

Supplementary files

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2. Fig. 1. Virological response rate in cirrhotic patients, %, 24 weeks of treatment (MYR202 study), p<0.0001 (Bulevirtide groups vs Tenofovir group).

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3. Fig. 2. Dynamics of HDV RNA in cirrhotic patients, log10 IU/ml, median, 24 weeks of treatment (MYR202 study), p<0.05 (Bulevirtide groups vs Tenofovir group).

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4. Fig. 3. Virologic response and alanine aminotransferase (ALT) normalization rates in cirrhotic and non-cirrhotic patients, %, 24 weeks of treatment (MYR202 study).

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5. Fig. 4. ALT normalization rate in cirrhotic patients, %, 24 weeks of treatment (MYR202 study), p<0.05 (Bulevirtide groups vs Tenofovir group).

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6. Fig. 5. Dynamics of ALT levels in cirrhotic patients, U/l, median, at baseline and after 24 weeks of treatment (MYR202 study).

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7. Fig. 6. Dynamics of liver tissue stiffness with elastometry in cirrhotic patients, kPa, median, 24 weeks of treatment (MYR202 study).

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8. Fig. 7. No progression of liver fibrosis with elastometry in cirrhotic patients, %, 24 weeks of treatment (MYR202 study).

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9. Fig. 8. Virologic response and ALT normalization rates in cirrhotic patients, %, 48 weeks of treatment (MYR203 study), Bulevirtide ± Pegylated interferon (PEG-IFN).

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