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Immediate-type hypersensitivity reaction to bulevirtide and successful desensitization in a patient with HBV/HDV-associated compensated cirrhosis

  • Caroline Schwarz
    Affiliations
    Department for Internal Medicine IV, Klinik Ottakring, Vienna, Austria

    Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria

    Division of Gastroenterology and Hepatology, Department for Medicine III, Medical University of Vienna, Vienna, Austria
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  • David Chromy
    Affiliations
    Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria

    Department for Dermatology, Medical University of Vienna, Vienna, Austria
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  • Christine Bangert
    Affiliations
    Department for Dermatology, Medical University of Vienna, Vienna, Austria
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  • Michael Schwarz
    Affiliations
    Department for Internal Medicine IV, Klinik Ottakring, Vienna, Austria

    Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria

    Division of Gastroenterology and Hepatology, Department for Medicine III, Medical University of Vienna, Vienna, Austria
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  • Mathias Jachs
    Affiliations
    Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria

    Division of Gastroenterology and Hepatology, Department for Medicine III, Medical University of Vienna, Vienna, Austria
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  • Thomas Reiberger
    Affiliations
    Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria

    Division of Gastroenterology and Hepatology, Department for Medicine III, Medical University of Vienna, Vienna, Austria
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  • Michael Gschwantler
    Correspondence
    Corresponding author. Address: Department of Internal Medicine IV, Klinik Ottakring, Montleartstraße 37, 1160 Wien, Austria; Tel.: +431/49 150-2401, fax: +431/49 150-2409.
    Affiliations
    Department for Internal Medicine IV, Klinik Ottakring, Vienna, Austria

    Sigmund Freud University, Vienna, Austria
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Published:March 16, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.004

      Keywords

      To the Editor:
      In July 2020, bulevirtide (BLV) – a new HDV hepatocyte entry-inhibitor – was licensed for the treatment of HBV/HDV coinfection in Europe. BLV showed excellent drug tolerability and safety in clinical trials and during the first months of clinical use.
      • Bogomolov P.
      • Alexandrov A.
      • Voronkova N.
      • Macievich M.
      • Kokina K.
      • Petrachenkova M.
      • et al.
      Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study.
      ,
      • 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.
      Notably, no allergic reactions associated with BLV have been recorded so far. We report a case of immediate-type hypersensitivity reaction to BLV and present a clinical approach for desensitization.
      A 35-year-old female patient of Romanian descent with HBV/HDV-associated compensated cirrhosis (Child-Pugh A, liver stiffness of 17.5 kPa on transient elastography in October 2020) had been treated with tenofovir (TDF) and pegylated interferon alpha (PEG-IFN) since July 2018 and June 2019, respectively.
      • Wedemeyer H.
      • Yurdaydin C.
      • Hardtke S.
      • Caruntu F.A.
      • Curescu M.G.
      • Yalcin K.
      • et al.
      Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial.
      Due to progressive thrombocytopenia and anemia as well as persisting HDV-viremia (HDV-RNA 10.040 copies/ml) under TDF and PEG-IFN, PEG-IFN was discontinued in exchange for BLV in December 2020. After unremarkable subcutaneous application of the first dose of BLV 2 mg at our outpatient clinic, the patient continued self-administered daily treatment according to current recommendations.
      After the sixth dose of BLV, the patient reported progressive pruritus and swelling of the upper extremities, of the face and lips as well as dyspnea starting after the third injection of BLV, indicative of type-1 allergic reaction. BLV was stopped immediately and the patient recovered quickly without any further intervention, therefore no corticosteroids were administered. Concurrent medication at this time included TDF, vitamin D substitution, and on-demand treatment with metamizole for recurrent headaches.
      Although the relation between treatment initiation and onset of symptoms (and symptom resolution after treatment cessation) was suggestive of a type-I allergic reaction, potential differential diagnoses were considered: Normal tryptase serum levels after all symptoms had resolved ruled out systemic mastocytosis. No intercurrent infections were reported and symptoms did not persist longer than 6 weeks, thus acute and chronic spontaneous urticaria were ruled out. No atopic predisposition was assumed as both serum IgE and eosinophil counts were within the normal range, and the patient reported an unremarkable family history regarding allergies. Of note, the patient reported a previous anaphylactic reaction to clarithromycin.
      Further diagnostic steps were performed at Department of Dermatology at the Vienna General Hospital: (a) prick testing with BLV (1 mg/ml) and (b) intradermal/intracutaneous skin testing with BLV (1:100, 0.01 mg/ml) did not provoke any reaction, however, higher intradermal/intracutaneous BLV concentrations (1:10 0.1 mg/ml; undiluted 1 mg/ml) induced an immediate reaction.
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      Positive intracutaneous skin testing is typically induced by IgE-mediated mast cell degranulation causing type-I hypersensitivity.
      • Vultaggio A.
      • Matucci A.
      • Nencini F.
      • Bormioli S.
      • Vivarelli E.
      • Maggi E.
      Mechanisms of drug desensitization: not only mast cells.
      Desensitization can be considered for IgE-mediated hypersensitivity under certain preconditions.
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      Due to the strong indication for HDV-active treatment and the previously insufficient response to PEG-IFN, BLV represented the only therapeutic option in this patient. Comedication with corticosteroids was not considered a rationale option due to the long-term treatment indication. Therefore, we decided to perform desensitization to BLV in an in-patient setting with emergency treatment being readily available. Since our patient demonstrated a strong skin reaction at 0.1 mg/ml (1:10 dilution) BLV, the starting dose was cautiously determined as 1/100 (0.03 mg) of the target dose (2 mg).
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      Over the course of 3 days, the patient received consecutive doses of BLV every 30 minutes. Doses were doubled each time until the per-day target dose was reached. Concomitantly, antihistaminergic treatment (levocetirizine 5 mg) was administered once daily (Table 1). Once regular dosing was established, the patient was discharged and self-administered subcutaneous treatment with BLV was continued at the recommended dosage of 2 mg once daily. Concomitant treatment with levocetirizine was discontinued 8 weeks after the re-initiation of BLV. No local or systemic adverse reactions were observed during re-exposure to BLV nor after withdrawal of the antihistaminergic comedication.
      Table 1Bulevirtide desensitization protocol used for our patient.
      Day 1 – 2 mg bulevirtide/2 ml aquaDay 2 – 2 mg bulevirtide/1 ml aquaDay 3 – 2 mg bulevirtide/1 ml aqua
      Start:0.03 ml (0.03 mg)0.50 ml (1 mg)1.0 ml (2 mg)
      30 min:0.05 ml (0.05 mg)0.50 ml (1 mg)
      60 min:0.15 ml (0.15 mg)
      90 min:0.30 ml (0.30 mg)
      120 min:0.50 ml (0.50 mg)
      150 min:0.97 ml (0.97 mg)
      Based on this case, the potentially life-threatening consequences of an immediate-type hypersensitivity reaction to BLV have to be considered in clinical application and in patients' counselling, especially since the distinction between common BLV-associated pruritus and incipient allergic reactions may be difficult. Importantly, HDV-related liver disease progression and complications will constitute the major prognostic factor in most HBV/HDV-coinfected individuals.
      • Kamal H.
      • Westman G.
      • Falconer K.
      • Duberg A.-S.
      • Weiland O.
      • Haverinen S.
      • et al.
      Long-term study of hepatitis delta virus infection at secondary care centers: the impact of viremia on liver-related outcomes.
      • Urban S.
      • Neumann-Haefelin C.
      • Lampertico P.
      Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease.
      • Jachs M.
      • Binter T.
      • Schmidbauer C.
      • Hartl L.
      • Strasser M.
      • Laferl H.
      • et al.
      Hepatitis D virus (HDV) prevalence in Austria is low but causes considerable morbidity due to fast progression to cirrhosis.
      • Schmidbauer C.
      • Chromy D.
      • Schmidbauer V.U.
      • Schwarz M.
      • Jachs M.
      • Bauer D.J.M.
      • et al.
      Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients.
      BLV, which is marketed as a soluble powder, does not contain any other potential allergens aside from BLV itself. While several mechanisms have been proposed to cause immediate-type hypersensitivity reactions, IgE-mediated hypersensitivity remains the “typical” pathway for type-I reaction. Positive skin testing confirmatory for IgE-mediated hypersensitivity supported our clinical approach to initiate desensitization, which was originally designed for IgE-mediated reactions.
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      ,
      • Vultaggio A.
      • Matucci A.
      • Nencini F.
      • Bormioli S.
      • Vivarelli E.
      • Maggi E.
      Mechanisms of drug desensitization: not only mast cells.
      Notably, the underlying mechanism of desensitization is currently not fully understood.
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      ,
      • Vultaggio A.
      • Matucci A.
      • Nencini F.
      • Bormioli S.
      • Vivarelli E.
      • Maggi E.
      Mechanisms of drug desensitization: not only mast cells.
      While patients have to be informed about the risk of a recurrent hypersensitivity reaction during re-exposure and its general experimental approach, successful desensitization may enable HDV-active antiviral therapy with BLV in patients with confirmed previous hypersensitivity reactions to BLV.
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      Importantly, adequate safety precautions have to be taken during re-exposure and uninterrupted treatment with BLV must be ensured after successful desensitization to avoid recurrent hypersensitivity reactions.
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      • Bircher A.
      • et al.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      Caroline Schwarz: received travel support from Gilead, Abbvie, and Gebro; speaking honoraria from Abbvie and Gilead; and payments for consulting from Gilead. David Chromy: received speaking honoraria and/or consultancy fees from MSD, Abbvie, and Gilead; and travel support from Abbvie and Gilead. Christine Bangert: received speaking honoraria and/or consultancy fees from Bayer, Mylan, LEO Pharma, Pfizer, Sanofi Genzyme, Eli Lilly, Novartis, Celgene, and AbbVie. Michael Schwarz: received travel support from MSD, Sandoz, BMS, Abbvie and Gilead; and speaking honoraria from BMS. Mathias Jachs: received speaking honoraria from Gilead. Thomas Reiberger: received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. Michael Gschwantler: received grant support from Abbvie, Gilead and MSD; speaking honoraria from Abbvie, Gilead, Janssen, Roche, Intercept, and MSD; consulting/advisory board fees from Abbvie, Gilead, Janssen, Roche, Intercept, Norgine, AstraZeneca, Falk, Shionogi and MSD; and travel support from Abbvie and Gilead.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      Authors’ contributions

      Caroline Schwarz: Conceptualization, methodology, investigation, data curation, writing - original draft. David Chromy: Conceptualization, methodology, investigation, data curation, writing - review & editing. Christine Bangert: Conceptualization, methodology, investigation, data curation, writing - review & editing. Michael Schwarz: Conceptualization, methodology, investigation, data curation, writing - review & editing. Mathias Jachs: Writing - review & editing. Thomas Reiberger: Supervision, writing - review & editing. Michael Gschwantler: Validation, writing - review & editing.

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