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Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension

Published:August 13, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.016

      Highlights

      • 48 weeks of bulevirtide 2 mg/day monotherapy was safe in patients with compensated cirrhosis and clinically significant portal hypertension.
      • Virological, biochemical, and combined responses were achieved in 78%, 83% and 67% of patients, respectively.
      • BLV treatment led to a significant improvement in most biochemical variables and an increase in liver function parameters.
      • Treatment was safe and well tolerated, an asymptomatic increase of bile acids was observed.

      Background & Aims

      Bulevirtide (BLV) has recently been conditionally approved for the treatment of chronic hepatitis delta (CHD) in Europe, but its effectiveness and safety in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) are unknown.

      Methods

      Consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2 mg/day were enrolled in this single-center study. Clinical/virological characteristics were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. HDV RNA was quantified by Robogene 2.0 (lower limit of detection 6 IU/ml).

      Results

      Eighteen Caucasian patients with compensated cirrhosis and CSPH under nucleos(t)ide analogue treatment were enrolled: median (IQR) age was 48 (29-77) years, and 67% were male. Median (IQR) platelet count was 70 (37-227) x103/μl, liver stiffness measurement (LSM) 16.4 (7.8-57.8) kPa, alanine aminotransferase (ALT) 106 (32-222) U/L, HBsAg 3.7 (2.5-4.3) log IU/ml, HDV RNA 4.9 (3.3-6.6) log IU/ml. During 48 weeks of BLV monotherapy, HDV RNA declined by 3.1 (0.2-4.3) log IU/ml (p <0.001 vs. baseline), becoming undetectable in 5 patients (23%). A virological response was observed in 14 (78%) patients while a non-response was observed in 2 (11%). ALT decreased to 35 (15-86) U/L (p <0.001 vs. baseline), normalizing in 83% of patients. A combined response was observed in 67% of patients. Aspartate aminotransferase and gamma-glutamyltransferase levels significantly improved. Concerning liver function parameters, albumin values significantly increased and bilirubin remained stable. LSM significantly improved in patients with virological response, while platelet count was unchanged. None of the patients developed decompensating events or hepatocellular carcinoma. BLV was well tolerated, no patient discontinued treatment and the increase in bile acids was fully asymptomatic.

      Conclusions

      A 48-week course of BLV 2 mg/day monotherapy is safe and effective even for difficult-to treat patients with HDV-related compensated cirrhosis and CSPH.

      Lay summary

      Hepatitis delta virus (HDV) is associated with the most severe form of viral hepatitis. A new treatment for HDV called bulevirtide has recently received conditional approval for patients with chronic HDV infection. However, its safety and effectiveness in patients with more advanced liver disease is not known. Herein, we show that it is safe and effective in patients with HDV-related cirrhosis and clinically significant portal hypertension.

      Graphical abstract

      Keywords

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      References

        • Stockdale A.J.
        • Kreuels B.
        • Henrion M.Y.R.
        • Giorgi E.
        • Kyomuhangi I.
        • de Martel C.
        • et al.
        The global prevalence of Hepatitis D virus infection: systematic review and meta-analysis.
        J Hepatol. 2020; 73: 523-532
        • Miao Z.
        • Zhang S.
        • Ou X.
        • Li S.
        • Ma Z.
        • Wang W.
        • et al.
        Estimating the global prevalence, disease progression, and clinical outcome of hepatitis Delta virus infection.
        J Infect Dis. 2020; 221: 1677-1687
        • Rizzetto M.
        • Hamid S.
        • Negro F.
        The changing context of hepatits D.
        J Hepatol. 2021; 74: 1200-1211
        • European Association for the Study of the Liver
        EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
        J Hepatol. 2017; 67: 370-398
        • 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
        • Lok A.S.
        • Negro F.
        • Tarik Asselah
        • Farci P.
        • Rizzetto M.
        Endpoints and new options for treatment of chronic hepatitis D.
        Hepatology. 2021; 74: 3479-3485
        • Yurdaydin C.
        • Abbas Z.
        • Buti M.
        • Cornberg M.
        • Esteban R.
        • Etzion O.
        • et al.
        Treating chronic hepatitis Delta: the need for surrogate markers of treatment efficacy.
        J Hepatol. 2019; 70: 1008-1015
        • Wedemeyer H.
        • Bogomolov P.
        • Blank A.
        • Allweiss L.
        • Dandri-Petersen M.
        • Bremer B.
        • 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 co-infection.
        J Hepatol. 2018; 68: S3
        • Wedemeyer H.
        • Schöneweis K.
        • Bogomolov P.O.
        • Chulanov V.
        • Stepanova T.
        • Viacheslav M.
        • et al.
        48 weeks of high dose (10 mg) Bulevirtide as monotherapy or with Peginterferon alfa-2a in patients with chronic HBV/HDV coinfection.
        J Hepatol. 2020; 73: S52
        • Asselah A.
        • Stefan Arama S.
        • Bogomolov P.
        • Bourliere M.
        • Fontaine H.
        • Gherlan G.S.
        • et al.
        Safety and efficacy of Bulevirtide monotherapy and in combination with Peginterferon alfa-2a in patients with chronic Hepatitis Delta: 24-week interim data of MYR204 Phase 2b study.
        J Hepatol. 2021; 75: S291
        • Wedemeyer H.
        • Aleman S.
        • Brunetto M.
        • Blank A.
        • Andreone P.
        • Bogolomov P.
        • 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: S4
        • Allweiss L.
        • Volmari A.
        • Ladiges Y.
        • Eggers C.
        • Giersch K.
        • Schöneweis K.
        • et al.
        Strong intrahepatic decline of Hepatitis D virus RNA and antigen after 48 weeks of treatment with bulevirtide in chronic HBV/HDV co-infected patients: interim results from a multicenter, open-label, randomized phase 3 clinical trial (MYR301).
        Hepatology. 2021; 74: S148A
        • Loglio A.
        • Ferenci P.
        • Uceda Renteria S.C.
        • Tham C.Y.L.
        • van Bömmel F.
        • Borghi M.
        • 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: 834-839
        • Asselah T.
        • Loureiro D.
        • Le Gal F.
        • Narguet S.
        • Brichler S.
        • Bouton V.
        • 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
        • Loglio A.
        • Ferenci P.
        • Uceda Renteria S.C.
        • Tham C.Y.L.
        • Scholtes C.
        • Holzmann H.
        • et al.
        Safety and effectiveness of up to 3 years' bulevirtide monotherapy in patients with HDV-related cirrhosis.
        J Hepatol. 2022; 76: 464-469
        • De Lédinghen V.
        • Metivier S.
        • Bardou-Jacquet E.
        • Hilleret M.N.
        • Loustaud-Ratti V.
        • Ganne-Carrié N.
        • et al.
        Treatment with Bulevirtide in patients with chronic HBV/HDV coinfection. Safety and efficacy at month 18 in real-world settings.
        J Hepatol. 2022; 77: S840
        • Jachs M.
        • Schwarz C.
        • Panzer M.
        • Binter T.
        • Aberle S.W.
        • Hartl L.
        • 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
        • Berzigotti A.
        • Seijo S.
        • Arena U.
        • Abraldes J.G.
        • Vizzutti F.
        • García-Pagán J.C.
        • et al.
        Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.
        Gastroenterology. 2013; 144: 102-111
        • D’Amico G.
        • Pasta L.
        • Morabito A.
        • D'Amico M.
        • Caltagirone M.
        • Malizia G.
        • et al.
        Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.
        Aliment Pharmacol Ther. 2014; 39: 1180-1193
        • de Franchis R.
        • VI Faculty Baveno
        Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
        J Hepatol. 2015; 63: 743-752
        • European Association for Study of Liver
        Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH clinical practice guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
        J Hepatol. 2015; 63: 237-264
        • Vuille-Lessard E.
        • Rodrigues S.G.
        • Berzigotti A.
        Noninvasive detection of clinically significant portal hypertension in compensated advanced chronic liver disease.
        Clin Liver Dis. 2021; 25: 253-289
        • European Association for the Study of the Liver
        EASL clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Boursier J.
        • Zarski J.P.
        • de Ledinghen V.
        • Rousselet M.C.
        • Sturm N.
        • Lebail B.
        • et al.
        Determination of reliability criteria for liver stiffness evaluation by transient elastography.
        Hepatology. 2013; 57: 1182-1191
        • Scholtès C.
        • Hamilton A.
        • Scott B.
        • Wang L.
        • Plissonnier M.L.
        • Berby F.
        • et al.
        Performance of a novel automated assay for the detection and quantification of HBV pregenomic RNA/circulating RNAs in chronic HBV patients.
        Hepatology. 2020; 72: S447A
        • Kim W.R.
        • Flamm S.L.
        • Di Bisceglie A.
        • Bodenheimer H.C.
        Public Policy Committee of the American Association for the Study of Liver Disease. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease.
        Hepatology. 2008; 47: 1363-1370
        • Li F.C.
        • Li Y.K.
        • Fan Y.C.
        Biomarkers for Hepatitis B virus replication: an overview and a look to the future.
        Expert Rev Gastroenterol Hepatol. 2020; 14: 1131-1139
        • Testoni B.
        • Lebossé F.
        • Scholtes C.
        • Berby F.
        • Miaglia C.
        • Subic M.
        • et al.
        Serum Hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic Hepatitis B patients.
        J Hepatol. 2019; 70: 615-625
        • Ghany M.G.
        • King W.C.
        • Lisker-Melman M.
        • Lok A.S.F.
        • Terrault N.
        • Janssen H.L.A.
        • et al.
        Comparison of HBV RNA and Hepatitis B core related antigen with conventional HBV markers among untreated adults with chronic Hepatitis B in North America.
        Hepatology. 2021; 74: 2395-2409
        • Zoulim F.
        • Testoni B.
        • Newsom C.L.
        • Plissonnier M.L.
        • Loglio A.
        • Scholtès C.
        • et al.
        Cross-sectional study of serum HBV RNA and HBcrAg in a real-life prospective cohort of 1500 chronic Hepatitis B patients followed in France and Italy.
        Hepatology. 2021; 74: S1408-S1409A
        • Loglio A.
        • Scholtès C.
        • Uceda Renteria S.C.
        • Charre C.
        • Facchetti F.
        • Plissonnier M.L.
        • et al.
        Divergent patterns of HDV-RNA and HBcrAg levels in chronic hepatitis Delta untreated patients: a large European cross-sectional study.
        Hepatology. 2021; 74: S419A