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

doi:10.1016/j.jhep.2022.07.016

Journal of Hepatology

Volume 77, Issue 6, December 2022, Pages 1525-1531

https://doi.org/10.1016/j.jhep.2022.07.016 Get rights and content

Highlights

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

Introduction

Chronic hepatitis delta (CHD) is a severe form of chronic viral hepatitis that affects approximately 12-72 million patients worldwide.[1], [2], [3] Until now, the only therapeutic approach available was the off-label use of a 48-week course of pegylated-interferon-α (PegIFNα), an antiviral strategy characterized by limited off-therapy responses and an unfavorable safety profile.[4], [5], [6], [7]

In 2020, the European Medicines Agency provided conditional approval for bulevirtide (BLV) at the dose of 2 mg/day subcutaneously⁵ for the treatment of compensated CHD. BLV is a first in class entry inhibitor of HBV; it is a lipopeptide that mimics the Na+-taurocholate co-transporting polypeptide (NTCP) receptor binding domain, blocking HDV/HBV entry exclusively in liver cells and thereby preventing NTCP-mediated intrahepatic HDV spreading.

In phase II trials and in week 48 analysis of the phase III study, BLV treatment significantly reduced HDV RNA levels and improved alanine aminotransferase (ALT) levels, although these benefits were lost in most patients after drug withdrawal.[8], [9], [10], [11] When combined with PegIFNα, a synergistic effect on both HDV viremia and HBsAg decline was demonstrated.⁹^,¹⁰ Virological response was mirrored by a significant decline of intrahepatic HDV RNA levels and of the number of HDV antigen (HDAg)-positive cells in a subset of patients treated for 48 weeks.¹² Preliminary real-life studies not only confirmed the effectiveness and safety of this treatment strategy but also suggested that treatment extension may further improve both virological and biochemical responses.[13], [14], [15], [16], [17]

However, to date, the safety and effectiveness of BLV 2 mg/day in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH)[18], [19], [20], [21], [22] are poorly known, as these patients have been scarcely represented in clinical trials of BLV and there are only a few case reports in the literature.¹⁵ These difficult-to-manage patients face a substantial risk of developing decompensated liver disease and hepatocellular carcinoma (HCC) within a short period of time. Moreover, treatment with PegIFNα is contraindicated due to the severity of the underlying liver disease.

Our study aimed to explore the safety and effectiveness of BLV 2 mg/day monotherapy in patients with HDV-related compensated cirrhosis and CSPH with or without HCC.

Section snippets

Patient population

This is a single-center study that was performed at the outpatient Liver Clinic of the Hepatology Division of the Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico. All consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2 mg/day monotherapy from December 2020 were enrolled. CHD was defined as HDV RNA positivity >6 months. Cirrhosis was defined either histologically (METAVIR F4), non-invasively by liver stiffness measurement (LSM)²¹ or clinically

Baseline features

The baseline demographic, virological and clinical features of the 18 patients enrolled are shown in Table 1. Most patients were middle aged men with elevated HBsAg, ALT, HDV RNA, and LSM levels, with undetectable HBV DNA, negative HBeAg, low platelet counts and previous non-response to IFN. All patients were Caucasian with compensated cirrhosis (72% Child-Pugh A5, 28% A6) and HDV genotype 1 infections. All patients were receiving nucleos(t)ide analogue therapy for HBV (10 on tenofovir

Discussion

This study describes the effectiveness and safety of BLV 2 mg/day administered as monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and CSPH and/or active HCC. To our knowledge, this is the first report showing that BLV is effective and safe in these difficult-to-treat patients with advanced compensated cirrhosis who have been underrepresented in the phase II and III studies of new anti-HDV compounds.

The virological response to BLV 2 mg monotherapy observed in our

Financial support

This work was supported in part by a grant from “Ricerca Corrente RC2021/105-01”, Italian Ministry of Health, and by a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (reference: ANR-17-RHUS-0003).

Authors’ contributions

Concept and design: Elisabetta Degasperi, Alessandro Loglio, Pietro Lampertico. Data collection: Elisabetta Degasperi, Maria Paola Anolli, Alessandro Loglio, Marta Borghi, Riccardo Perbellini, Dana Sambarino, Floriana Facchetti, Sara Monico, Andrea Costantino, Mirella Fraquelli. Writing of the article: Elisabetta Degasperi, Alessandro Loglio, Pietro Lampertico. Statistical analysis: Elisabetta Degasperi, Pietro Lampertico. Virological analysis: Caroline Scholtes, Fabien Zoulim, Sara Uceda

Data availability statement

Data from the present study is kept confidential but can be provided upon direct request to the authors.

Conflict of interest

Elisabetta Degasperi: Advisory Board: AbbVie; Speaking and teaching: Gilead, MSD, AbbVie; Alessandro Loglio: Travel grant for MYR Pharma, Speaker bureau for Gilead Sciences; Fabien Zoulim: Advisor for Aligos, Antios, Arbutus, Assembly, Gilead, GSK, MYR Pharma, Roche Pietro Lampertico: Advisor and speaker bureau for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie, Janssen, Arrowhead, Alnylam, Eiger, MYR Pharma, Antios, Aligos. Other authors have nothing to disclose.

Please refer to the accompanying

Acknowledgments

We thank Roche Molecular Diagnostics, Pleasanton, USA (Dr Marintha Heil) for providing HBV RNA kits.

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Cited by (28)

Modelling HDV kinetics under the entry inhibitor bulevirtide suggests the existence of two HDV-infected cell populations
2024, JHEP Reports
Bulevirtide (BLV) was approved for the treatment of compensated chronic hepatitis D virus (HDV) infection in Europe in 2020. However, research into the effects of the entry inhibitor BLV on HDV-host dynamics is in its infancy.
Eighteen patients with HDV under nucleos(t)ide analogue treatment for hepatitis B, with compensated cirrhosis and clinically significant portal hypertension, received BLV 2 mg/day. HDV RNA, alanine aminotransferase (ALT), and hepatitis B surface antigen (HBsAg) were measured at baseline, weeks 4, 8 and every 8 weeks thereafter. A mathematical model was developed to account for HDV, HBsAg and ALT dynamics during BLV treatment.
Median baseline HDV RNA, HBsAg, and ALT were 4.9 log IU/ml [IQR: 4.4-5.8], 3.7 log IU/ml [IQR: 3.4-3.9] and 106 U/L [IQR: 81-142], respectively. During therapy, patients fit into four main HDV kinetic patterns: monophasic (n = 2), biphasic (n = 10), flat-partial response (n = 4), and non-responder (n = 2). ALT normalization was achieved in 14 (78%) patients at a median of 8 weeks (range: 4-16). HBsAg remained at pre-treatment levels. Assuming that BLV completely (∼100%) blocks HDV entry, modeling indicated that two HDV-infected cell populations exist: fast HDV clearing (median t_1/2 = 13 days) and slow HDV clearing (median t_1/2 = 44 days), where the slow HDV-clearing population consisted of ∼1% of total HDV-infected cells, which could explain why most patients exhibited a non-monophasic pattern of HDV decline. Moreover, modeling explained ALT normalization without a change in HBsAg based on a non-cytolytic loss of HDV from infected cells, resulting in HDV-free HBsAg-producing cells that release ALT upon death at a substantially lower rate compared to HDV-infected cells.
The entry inhibitor BLV provides a unique opportunity to understand HDV, HBsAg, ALT, and host dynamics.
Mathematical modeling of hepatitis D virus (HDV) treatment with the entry inhibitor bulevirtide (BLV) provides a novel window into the dynamics of HDV RNA and alanine aminotransferase. Kinetic data from patients treated with BLV monotherapy can be explained by hepatocyte populations with different basal HDV clearance rates and non-cytolytic clearance of infected cells. While further studies are needed to test and refine the kinetic characterization described here, this study provides a new perspective on viral dynamics, which could inform evolving treatment strategies for HDV.
Unmet need in screening for hepatitis D virus: Time to take action
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Dynamics of Virological and Clinical Response Parameters of Bulevirtide Treatment for Hepatitis D: Real-World Data
2024, Gastro Hep Advances
The entry inhibitor bulevirtide represents the first specific treatment for hepatitis-D virus (HDV)-infected patients. In clinical trials, around 80% of patients achieve normalization of alanine aminotransferase (ALT) with about 60% virological response after 1 year, but little is known about the dynamics of responses and clinical predictors of treatment outcomes. We report our single-center data from 15 patients and describe response dynamics, clinical outcomes, and predictive factors for treatment response.
Retrospective data from 15 patients have been analyzed at our department who started treatment with bulevirtide between 10/2020 and 08/2022. According to our standard procedures, laboratory parameters were controlled monthly; transient elastography was performed every 3 months, and the treatment duration was 12 months.
Treatment response rates after 1 year of treatment were similar to published data from clinical trials. ALT normalization usually occurs between months 2–6 of treatment, followed by a virological response after ≥6 months. Patients with more severe hepatitis at the start of treatment were less likely to respond in the first year of treatment. Loss of HDV-RNA was observed in one-third of patients after ≥1 year of treatment. Low body mass index and high alpha-fetoprotein at baseline were possible predictors of a delayed treatment response.
Bulevirtide is a safe treatment option for HDV, leading to a fast hepatological response. Of note, decrease in transaminases precedes virological response. Patients with high viral load and ALT levels respond slower, but nonresponders (as classified by Food and Drug Administration criteria) still show a reduction in viremia. Longer observation periods are required to determine the optimal duration of bulevirtide monotherapy.
No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta
2023, Journal of Hepatology
Bulevirtide (BLV) is a HDV/HBV entry inhibitor that is associated with virologic response (responders, HDV-RNA undetectable or ≥2 log₁₀ IU/ml decrease from baseline) in >50% of patients after a 24-week treatment. However, some patients only achieve a <1 log₁₀ IU/ml decline in HDV-RNA after the 24-week treatment (non-responders). Here, we report a viral resistance analysis in participants receiving BLV monotherapy who were non-responders or experienced virologic breakthrough (VB, i.e., two consecutive increases in HDV-RNA of ≥1 log₁₀ IU/ml from nadir or two consecutive HDV-RNA detectable results if previously undetectable) from the phase II MYR202 and phase III MYR301 study.
Deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, were performed for the participant with VB (n = 1) and non-responders (n = 20) at baseline (BL) and Week 24 (WK24).
No amino acid exchanges associated with reduced susceptibility to BLV within the BLV-corresponding region or within HDAg were identified in isolates from any of the 21 participants at BL or at WK24. Although variants (HBV n = 1; HDV n = 13) were detected at BL in some non-responders or in the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was detected in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC₅₀ values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log₁₀ IU/ml), and responders regardless of the presence of HBV and/or HDV polymorphisms.
No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment.
This is the first study investigating the development of resistance in patients treated with BLV. Excluding resistance to BLV as an explanation for an insufficient decrease in HDV-RNA levels during BLV therapy is an important finding for patients, clinicians, and researchers. It demonstrates that BLV has a high barrier to resistance, indicating it is safe and suitable for long-term treatment, although long-term surveillance for resistance should be performed. Our results hint at other still unknown mechanisms as an explanation for the persistence of serum HDV-RNA during inhibition of viral entry.
NCT03546621 and NCT03852719.
EASL Clinical Practice Guidelines on hepatitis delta virus
2023, Journal of Hepatology
Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B virus to complete its life cycle and cause liver damage in humans. HDV is responsible for rare acute and chronic liver diseases and is considered the most aggressive hepatitis virus. Acute infection can cause acute liver failure, while persistent infection typically causes a severe form of chronic hepatitis which is associated with rapid and frequent progression to cirrhosis and its end-stage complications, hepatic decompensation and hepatocellular carcinoma. Major diagnostic and therapeutic innovations prompted the EASL Governing Board to commission specific Clinical Practice Guidelines on the identification, virologic and clinical characterisation, prognostic assessment, and appropriate clinical and therapeutic management of HDV-infected individuals.
Hepatitis D: Looking Back, Looking Forward, Seeing the Reward and the Promise
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The hepatitis D virus (HDV) or delta hepatitis is the most difficult form of viral hepatitis to treat. It is also the most aggressive, with the most rapid evolution to cirrhosis, hepatocellular carcinoma, and death. HDV is found globally with areas of greater prevalence, known as hotspots. Due to the dependence of HDV on the hepatitis B virus (HBV), it is likely that as HBV vaccination rates increase the population vulnerable to HDV will decrease. There is currently no HDV vaccine, leaving those infected with HBV vulnerable to HDV. HDV utilizes the host for almost all its replicative cycle, leading to a paucity of true antiviral targets. Diagnosis depends on accurate testing for HDV, and as testing has improved and expanded, the full extent of HDV has increasingly been appreciated. Although not satisfactory, the mainstay of therapy thus far has been interferon alpha and liver transplant where indicated. However, as the molecular virology of HDV has been unlocked, there has been a corresponding development of multiple therapeutic options. It is these therapeutic options that hold the promise of cure. Unmet needs include identifying patients infected with HDV, accurate noninvasive staging of their liver disease, and easy to administer curative therapies. It is hoped that the next decade will bring us substantively closer to meeting all unmet needs and closer towards the eradication of HDV.

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

Highlights

Background & Aims

Methods

Results

Conclusions

Lay summary

Graphical abstract

Introduction

Section snippets

Patient population

Baseline features

Discussion

Financial support

Authors’ contributions

Data availability statement

Conflict of interest

Acknowledgments

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

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J Hepatol

Clin Liver Dis

J Hepatol

Estimating the global prevalence, disease progression, and clinical outcome of hepatitis Delta virus infection

J Infect Dis

EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection

J Hepatol

Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease

Gut

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