Interferon‐based treatment of chronic hepatitis D

Sandmann, Lisa; Wedemeyer, Heiner

doi:10.1111/liv.15410

Cited by 37 publications

(35 citation statements)

References 98 publications

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“…Until 2020, the only antiviral treatment with proven efficacy against HDV has been administration of type 1 interferons, in clinical practice pegylated interferonα (PEG-IFNα) with limited short-term and long-term efficacy and poor tolerability. 15 The entry receptor sodium taurocholate co-transporting polypeptide (NTCP) has been identified as a liver specific receptor of HBV. 16 Bulevirtide (BLV) is a lipopeptide mimicking the NTCP receptor binding domain of the large HBsAg.…”

Section: Introductionmentioning

confidence: 99%

“…The 5‐year mortality is approximately doubled in patients with chronic hepatitis B/D coinfection compared with patients infected with hepatitis B alone. Until 2020, the only antiviral treatment with proven efficacy against HDV has been administration of type 1 interferons, in clinical practice pegylated interferon‐α (PEG‐IFNα) with limited short‐term and long‐term efficacy and poor tolerability 15 …”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…It leads to increased expression of IFN-stimulated genes encoding several proteins with antiviral properties potentially affecting various steps of the HDV life cycle. 16,66 In addition, IFN alpha possesses a broad range of effects on the adaptive immune system including activation of natural killer cells. In contrast, bulevirtide appears to be devoid of immune-modulatory properties.…”

Section: Viral Response As a Measure Of Treatment Response For The Tr...mentioning

confidence: 99%

Treatment endpoints for chronic hepatitis D

Metin

Zeybel

Yurdaydın

2022

Liver International

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Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds.

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“…Interferon alfa has been used for decades, but poor drug tolerance and low efficacy have discouraged its broader use. 4 , 9 …”

Section: Introductionmentioning

confidence: 99%

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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Interferon‐based treatment of chronic hepatitis D

Cited by 37 publications

References 98 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

Treatment endpoints for chronic hepatitis D

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

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