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Mathematical modeling suggests that entry-inhibitor bulevirtide may interfere with hepatitis D virus clearance from circulation

  • Louis Shekhtman
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    Network Science Institute, Northeastern University, Boston, MA, USA
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  • Scott J. Cotler
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
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  • Alexander Ploss
    Affiliations
    Department of Molecular Biology, Princeton University, Princeton, NJ, USA
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  • Harel Dahari
    Correspondence
    Corresponding author. Address: 2160 S. First Ave., Maywood, IL 60153, USA; Tel. +1-708-216-4682.
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
    Search for articles by this author
Published:January 04, 2022DOI:https://doi.org/10.1016/j.jhep.2021.12.030

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      • Safety and effectiveness of up to 3 years’ bulevirtide monotherapy in patients with HDV-related cirrhosis
        Journal of HepatologyVol. 76Issue 2
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          The entry inhibitor bulevirtide (BLV) received conditional approval from the EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult-to-treat patients with HDV-related cirrhosis is presently unknown. Herein, we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to 3 years on a compassionate use program.
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      To the Editor:
      Loglio and colleagues,
      • 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.
      published a unique case study on hepatitis D virus (HDV) RNA kinetics under entry-inhibitor bulevirtide (BLV) monotherapy in 3 patients. Historically, mathematical modeling of viral hepatitis kinetics predicts a monophasic viral decline under antiviral treatment that blocks virus infection. Modeling suggests that the monophasic decline is driven by the rate of loss/death of virus productive-infected cells (parameter δ, Fig. 1A). Indeed, assuming that BLV’s only mode of action (MOA) is blocking HDV entry/infection (assuming η∼100%, Fig. 1A),
      • Urban S.
      • Bartenschlager R.
      • Kubitz R.
      • Zoulim F.
      Strategies to inhibit entry of HBV and HDV into hepatocytes.
      the model (Fig. 1A) fits well with the measured HDV data in patients 2 and 3 (Fig. S1) but not in patient 1, in whom a transient viral increase was seen during the first 4 weeks of treatment, consisting of a 0.4 log increase from pretreatment HDV-RNA level at week 2, followed by a monophasic HDV decline thereon (Fig. 1B). Such a transient viral increase can also be noticed in several hepatitis B virus (HBV) mono-infected patients treated with BLV 10 mg/day,

      Goyal A. Modeling HBV DNA and ALT responses observed under an entry inhibitor in HBV monoinfected individuals supports heterogeneity in the infected cell population. 5th workshop on virus dynamics. https://www.fredhutch.org/en/events/workshop-on-virus-dynamics/agenda.html2021.

      suggesting that this transient viral increase may occur in some patients treated with BLV for both HBV and HDV. The nature of this early transient viral increase under BLV treatment is not known.
      Figure thumbnail gr1
      Fig. 1Mathematical modeling of HDV RNA kinetics under BLV-based treatment.
      (A) Schematic and model equations (Eq. 1) of HDV infection and treatment. Target cells, T0, become HDV-infected cells, I, at rate β. Infected cells are then lost or die at rate δ. Infected cells also produce virions, V, at rate p. Virions in circulation are cleared at rate c. BLV known MOA in blocking entry/infection is shown using solid green line (parameter η) and theoretical MOA are shown using dashed green lines (parameters θ representing reduced viral clearance and κp representing increase of viral production). Blocking HDV production by IFN, LNF or NAP is shown using red symbols (parameter ε). (B) Model fitting, using Python version 3.7.4 and Scipy version 1.3.1, with measured HDV kinetics from patient 1 in
      • 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.
      (symbols) assuming BLV MOA is blocking only viral infection (η∼100%) does not fit the data well (dotted line). Assuming that in addition to BLV η∼100%, viral clearance decreases (θ=66%, dashed line) or viral production increases (κp=3.5, solid line) the HDV kinetics fit the data well. Fixed parameters were c = 0.42 day-1, p = 10 virions/infected cell/day, and β = 1e-7 ml ·virions−1·day−1. Initial conditions were set such that V0 equaled its value at the first data point, and I0 and T0 were set by steady state conditions as done in.
      • Koh C.
      • Canini L.
      • Dahari H.
      • Zhao X.
      • Uprichard S.L.
      • Haynes-Williams V.
      • et al.
      Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.
      (C) Model simulations of HDV decline under antivirals that block HDV production (ε = 95%, solid line) alone or in combination with BLV (ε = 95%, η∼100%) assuming a BLV-induced decrease in viral clearance of θ = 66% (dashed line). We fixed δ = 0.042 day-1 with other model parameters fixed as described in (B). (D) Same as (C) but with ε = 50%. BLV, bulevirtide; IFN, interferon-α; LNF, lonafarnib; MOA, mode of action; NAP, nucleic acid polymer.
      Conceivably, the transient viral increase can be explained if one assumes that in addition to blocking viral infection, BLV also enhances viral production (parameter κp, Fig. 1A) or reduces viral clearance from circulation (parameter θ, Fig. 1A). The latter two theoretical BLV MOAs can fit data from patient 1 well, with BLV enhancing viral production by κp∼3.5-fold (Fig. 1B) or reducing viral clearance by θ∼66% (Fig. 1B). It is unlikely that BLV enhances viral production since BLV blocks the binding site of the human sodium taurocholate co-transporting polypeptide on the HBV envelope, thereby inhibiting the entry of the virus into hepatocytes.
      • Urban S.
      • Bartenschlager R.
      • Kubitz R.
      • Zoulim F.
      Strategies to inhibit entry of HBV and HDV into hepatocytes.
      However, reducing viral clearance by BLV may be a more plausible MOA if viral clearance from the circulation is interrupted by BLV blocking viral entry into hepatocytes. In that case, it is possible that there was a modest effect on patients 2 and 3 that was not recognized due to infrequent sampling (Fig. S2). We recently showed for hepatitis C virus (HCV) that, in some patients, the liver not only produces virus but also clears virus from the circulation,
      • Shekhtman L.
      • Navasa M.
      • Sansone N.
      • Crespo G.
      • Subramanya G.
      • Chung T.L.
      • et al.
      Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance.
      supporting the notion that blocking viral entry could reduce viral clearance by the liver in patient 1. In patients 2 and 3, other mechanisms of viral clearance (e.g., adaptive-immune response) that were not affected by BLV may have played a major role.
      Reminiscent of the notion of predicting the duration of anti-HCV treatment needed to reach <1 virus copy in a patient’s total extracellular-body fluid (BF),
      • Etzion O.
      • Dahari H.
      • Yardeni D.
      • Issachar A.
      • Nevo-Shor A.
      • Cohen-Naftaly M.
      • et al.
      Response guided therapy for reducing duration of direct acting antivirals in chronic hepatitis C infected patients: a Pilot study.
      modeling predicts <1 HDV copy per BF after 75, 50 and 90 weeks of 10 mg/day BLV in patients 1, 2 and 3, respectively (Fig. S3). Thus, modeling may explain, retrospectively, why patient 1 had viral rebound after 52 weeks of BLV and suggests that patients 2 and 3 who were treated for 144 weeks already reached HDV clearance in BF.
      We further investigated in silico the predicted effect of BLV on slowing HDV viral clearance from the circulation in combination with other drugs that are predicted to block HDV viral production, i.e. parameter ε in Fig. 1A (e.g., interferon-α, lonafarnib, and nucleic-acid polymers, Fig. 1C) that we have previously shown to cause a biphasic HDV decline.
      • Koh C.
      • Canini L.
      • Dahari H.
      • Zhao X.
      • Uprichard S.L.
      • Haynes-Williams V.
      • et al.
      Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.
      • Shekhtman L.
      • Cotler S.J.
      • Hershkovich L.
      • Uprichard S.L.
      • Bazinet M.
      • Pantea V.
      • et al.
      Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg.
      • Guedj J.
      • Rotman Y.
      • Cotler S.J.
      • Koh C.
      • Schmid P.
      • Albrecht J.
      • et al.
      Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.
      Mathematical modeling suggests that the first phase is driven by the rate of HDV clearance from the circulation (parameter c, Fig. 1B), which based on prior work we set to t1/2 = 1.6 days.
      • Koh C.
      • Canini L.
      • Dahari H.
      • Zhao X.
      • Uprichard S.L.
      • Haynes-Williams V.
      • et al.
      Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.
      • Shekhtman L.
      • Cotler S.J.
      • Hershkovich L.
      • Uprichard S.L.
      • Bazinet M.
      • Pantea V.
      • et al.
      Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg.
      • Guedj J.
      • Rotman Y.
      • Cotler S.J.
      • Koh C.
      • Schmid P.
      • Albrecht J.
      • et al.
      Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.
      The second phase is driven by parameter δ.
      • Koh C.
      • Canini L.
      • Dahari H.
      • Zhao X.
      • Uprichard S.L.
      • Haynes-Williams V.
      • et al.
      Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.
      • Shekhtman L.
      • Cotler S.J.
      • Hershkovich L.
      • Uprichard S.L.
      • Bazinet M.
      • Pantea V.
      • et al.
      Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg.
      • Guedj J.
      • Rotman Y.
      • Cotler S.J.
      • Koh C.
      • Schmid P.
      • Albrecht J.
      • et al.
      Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.
      Modeling predicts that in patients in whom BLV will slow HDV clearance (θ∼66%), BLV combined with drugs that block viral production (ε ≥95%
      • Koh C.
      • Canini L.
      • Dahari H.
      • Zhao X.
      • Uprichard S.L.
      • Haynes-Williams V.
      • et al.
      Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.
      • Shekhtman L.
      • Cotler S.J.
      • Hershkovich L.
      • Uprichard S.L.
      • Bazinet M.
      • Pantea V.
      • et al.
      Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg.
      • Guedj J.
      • Rotman Y.
      • Cotler S.J.
      • Koh C.
      • Schmid P.
      • Albrecht J.
      • et al.
      Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.
      ) will lead to a slower viral decline (Fig. 1C) compared to BLV monotherapy (Fig. 1C). However, BLV plus drugs with low efficacy (ε = 50%) will first lead to a slower viral decline during the first phase compared to BLV monotherapy (Fig. 1D), but later (∼11 weeks, Fig. 1D) BLV-based therapy will cause a higher suppression of HDV compared to therapy that blocks viral production without BLV. In patients in whom BLV will not or will only moderately slow HDV clearance (θ∼20%), modeling predicts enhanced viral decline under combination therapy compared to BLV monotherapy (Fig. S4), indicating the importance of including BLV in future anti-HDV regimens.
      Studies in experimentally tractable in vivo systems might be able to dissect the mechanism underlying the apparent increases in HDV and HBV viremia under BLV and to ultimately gain an in-depth understanding of BLV’s MOA.
      • Douam F.
      • Ploss A.
      The use of humanized mice for studies of viral pathogenesis and immunity.
      Previously, BLV efficiently limited HDV spread in serially transplanted humanized mice.
      • Giersch K.
      • Bhadra O.D.
      • Volz T.
      • Allweiss L.
      • Riecken K.
      • Fehse B.
      • et al.
      Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo.
      Future BLV perturbation experiments and theoretical modeling during HBV/HDV chronic infection are needed.
      In conclusion, the monophasic HDV decline observed in 2 patients is consistent with the known MOA of BLV as an entry inhibitor. The transient increase in HDV in a third patient with initiation of BLV raises the possibility that blocking HDV entry into the liver has a secondary effect of reducing viral clearance by the liver.

      Financial support

      NIH grants R01AI144112 , R01AI138797 , R01AI107301 , R01AI146917 , and R01AI153236 .

      Authors’ contributions

      Louis Shekhtman: Data Curation, Formal Analysis, Writing - Original Draft, Writing - Review & Editing; Scott J Cotler: Writing - Original Draft, Writing - Review & Editing; Alexander Ploss: Methodology, Writing - Original Draft, Funding acquisition, Writing - Review & Editing. Harel Dahari: Conceptualization, Methodology, Supervision, Funding acquisition, Writing – original draft, Review & Editing.

      Data availability statement

      The authors declare that all data supporting the findings of this study are available in the article or supplementary information file.

      Conflicts of interest

      The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • 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
        • Urban S.
        • Bartenschlager R.
        • Kubitz R.
        • Zoulim F.
        Strategies to inhibit entry of HBV and HDV into hepatocytes.
        Gastroenterology. 2014; 147: 48-64
      1. Goyal A. Modeling HBV DNA and ALT responses observed under an entry inhibitor in HBV monoinfected individuals supports heterogeneity in the infected cell population. 5th workshop on virus dynamics. https://www.fredhutch.org/en/events/workshop-on-virus-dynamics/agenda.html2021.

        • Shekhtman L.
        • Navasa M.
        • Sansone N.
        • Crespo G.
        • Subramanya G.
        • Chung T.L.
        • et al.
        Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance.
        Elife. 2021; : 10
        • Etzion O.
        • Dahari H.
        • Yardeni D.
        • Issachar A.
        • Nevo-Shor A.
        • Cohen-Naftaly M.
        • et al.
        Response guided therapy for reducing duration of direct acting antivirals in chronic hepatitis C infected patients: a Pilot study.
        Sci Rep. 2020; 10: 17820
        • Koh C.
        • Canini L.
        • Dahari H.
        • Zhao X.
        • Uprichard S.L.
        • Haynes-Williams V.
        • 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
        • Shekhtman L.
        • Cotler S.J.
        • Hershkovich L.
        • Uprichard S.L.
        • Bazinet M.
        • Pantea V.
        • 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
        • Guedj J.
        • Rotman Y.
        • Cotler S.J.
        • Koh C.
        • Schmid P.
        • Albrecht J.
        • et al.
        Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.
        Hepatology. 2014; 60: 1902-1910
        • Douam F.
        • Ploss A.
        The use of humanized mice for studies of viral pathogenesis and immunity.
        Curr Opin Virol. 2018; 29: 62-71
        • Giersch K.
        • Bhadra O.D.
        • Volz T.
        • Allweiss L.
        • Riecken K.
        • Fehse B.
        • 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