Real‐life experiences with bulevirtide for the treatment of hepatitis delta—48 weeks data from a German centre

Zöllner, Caroline; Hofmann, Jörg; Lutz, K.; Tacke, Frank; Demir, Münevver

doi:10.1111/liv.15408

Cited by 15 publications

(11 citation statements)

References 12 publications

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“…Virological response rates to BLV treatment in this cohort were well in line with phase 2 and 3 studies as well as with preliminary reports from other European real‐word cohorts 23–28,31 . Similarly, ALT declines were seen in a similar frequency as reported by others.…”

Section: Discussionsupporting

confidence: 90%

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA

Deterding

Port

et al. 2023

Journal of Viral Hepatitis

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Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+‐taurocholate co‐transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p = .0029) and evidence of portal hypertension (p = .0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = −0.577; p = .0078; rho = −0.635, p = .0026; rho = −0.577, p = .0077; rho = −0.519, p = .0191; rho = −0.564, p = .0119 and rho = −0.393, p = .087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV‐induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed.

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Section: Discussionsupporting

confidence: 90%

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA

Deterding

Port

et al. 2023

Journal of Viral Hepatitis

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“…Myrcludex B is an HBV entry inhibitor that blocks viral entry through interaction with the HBV receptor NTCP and has recently been licenced as a therapeutic for HBV and HDV. 26 Following infection of organoids with patient derived HBV genotype B and treatment with Myrcludex B either 1 day pre- or 1 day post-infection, antiviral activity was assessed by detection of HBV total RNA and confocal immunofluorescence microscopy to detect HBcAg at 21 days post infection (Fig 6A). Consistent with the mechanism of action of Myrcludex B as an entry inhibitor, pre-infection Myrcludex treatment resulted in significant reduction of HBV RNA and HBcAg whereas post-infection treatment with Myrcludex B did not as replication had been established (Fig 6A).…”

Section: Resultsmentioning

confidence: 99%

Human Liver Organoids as a Patient-derived Model for HBV Infection and Cellular Response

Lim

Romeo

Chilver

et al. 2022

Preprint

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Background & AimsCurrent HBVin vitromodel systems suffer from many physiological limitations that restrict understanding of complex viral-host interactions and thus prohibit prediction of diseasein vivo. We developed and assessed adult stem cell (AdSC) derived liver organoids as a novel model system for characterisation of the HBV lifecycle, the cellular response to infection and demonstrate their utility in assessing antiviral and immunomodulator response. This model system has the potential to be used in predicting individual HBV responses to antivirals and viral reactivation in the setting of immunosuppressive agents.MethodsDuctal stem cells were isolated from healthy tissue acquired from liver resections or biopsy (n=12). Wnt3a & RSPO-1 containing medium was used to stimulate ductal stem cell expansion into organoids which were subsequently differentiated into hepatocyte-like cells. Mature hepatocyte metabolic markers (albumin, CYP3A4) and HBV entry receptor (Na-taurocholate co-transporting polypeptide, NTCP) expression were evaluated throughout differentiation using qRT-PCR and confocal microscopy. We assessed the organoids culture conditions required for HBV infection and HBV life cycle using HepAD38 (genotype D) and plasma derived HBV (genotype B & C). HBV infection was confirmed using immunofluorescence staining (HBcAg), qRT-PCR (RNA, cccDNA, extracellular DNA) and ELISA (HBsAg and HBeAg). We also assessed drug responsiveness using antivirals and an immunosuppressive agent, and cellular responses (interferon-stimulated genes) using interferon-α and viral mimic (PolyI:C).ResultsFollowing differentiation, organoids underwent structural remodelling and changes in cellular polarity, accompanied with an increase in albumin, CYP3A4 and NTCP mRNA expression. Optimal HBV infection was achieved in well-differentiated organoids using spinoculation of at least 200 copies/cell of AD38 derived HBV. Infected organoids demonstrate time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBe and HBsAg consistent with viral replication and antigen secretion. Using these markers we assessed drug-responsiveness to the HBV entry inhibitor, Myrcludex B and the JAK inhibitor, Baricitinib. Despite having a very robust interferon stimulated gene response to interferon-α and PolyI:C stimulation, HBV infection in liver organoids did not reveal innate immune activation.ConclusionsAdSC derived liver organoids support the full life cycle of HBV with significant donor dependent variation in viral replication and cellular responses. These features can be utilised for development of personalised drug testing platform for antivirals.Lay SummaryHuman liver organoid culture provides a personalised assessment of HBV infection, replication and responsiveness to antiviral therapy. This model system has a robust innate immune response and could be used to assess novel immune-modulating curative therapy.

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“…Data were reported for 8 patients with chronic hepatitis delta, all being treated with nucleos(t)ide analogues, that were treated with BLV 2 mg/day for 16 weeks. 32 Mean HDV-RNA levels dropped by 0.5 log IU/mL. BLV was discontinued in 1 patient who did not show significant ALT or HDV-RNA responses.…”

Section: European Post-approval Studiesmentioning

confidence: 96%

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

Soriano¹,

Moreno-Torres²,

Treviño³

et al. 2023

DDDT

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It has been ten years since the identification of NTCP as the cell surface receptor for HBV and HDV entry into hepatocytes. The search for molecules interfering with the binding of NTCP and HBV/HDV led to design bulevirtide (BLV). This large polypeptide mimics a region of the pre-S1 HBsAg and blocks viral entry by inhibitory competition. BLV was initially tested in cell cultures, animal models and more recently in Phase I–III human trials (called ‘MYRS’). As monotherapy or in combination with peginterferon, BLV is well tolerated and exhibits potent antiviral activity. Plasma viremia significantly declines and/or becomes undetectable in more than 75% of patients treated for >24 weeks. However, serum HBsAg concentrations remain unchanged. No selection of BLV resistance in HBV/HDV has been reported in vivo to date. BLV is administered subcutaneously once daily at doses between 2 and 10 mg. BLV received conditional approval in Europe in 2020 to treat chronic hepatitis delta. The advent of peginterferon lambda or new specific anti-HDV antivirals (lonafarnib, etc.) will open the door for combination therapies with BLV. Since there is no stable reservoir for HDV-RNA within infected hepatocytes, viral clearance might be achieved using antivirals for a minimum timeframe. This is what happens in hepatitis C combining several antivirals, curing nearly all patients treated for 3 months. Clearance of HDV-RNA genomes may occur despite HBV persistence as cccDNA or chromosome integrated HBV-DNA within hepatocytes. This is supported by cases of HDV elimination using BLV despite persistence of serum HBsAg. Another path for HDV cure will derive from achieving HBsAg clearance, the goal of new promising anti-HBV gene therapies (bepirovirsen, etc.). In summary, the advent of BLV has triggered a renovated interest for antiviral therapy in hepatitis delta. We envision combination therapies that will lead to HDV cure in the near future.

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Real‐life experiences with bulevirtide for the treatment of hepatitis delta—48 weeks data from a German centre

Cited by 15 publications

References 12 publications

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA

Human Liver Organoids as a Patient-derived Model for HBV Infection and Cellular Response

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

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