Hepatitis B Delta: assessment of the knowledge and practices of hepato-gastroenterologists practicing in non-academic settings in France.

BACKGROUND: Data on the management of Hepatitis B-Delta (HB-D) by hepatogastroenterologists (HGs) practicing in nonacademic hospitals or private practices are unknown in France. OBJECTIVE: We aimed to evaluate the knowledge and practices of HGs practicing in nonacademic settings regarding HB-D. METHODS: A Google form document was sent to those HGs from May to September 2021. RESULTS: A total of 130 HGs (mean age, 45 years) have participated in this survey. Among HBsAg-positive patients, Delta infection was sought in only 89% of cases. Liver fibrosis was assessed using FibroScan in 77% of the cases and by liver biopsy in 81% of the cases. A treatment was proposed for patients with >F2 liver fibrosis in 49% of the cases regardless of transaminase levels and for all the patients by 39% of HGs. Responding HGs proposed a treatment using pegylated interferon in 50% of cases, bulevirtide in 45% of cases and a combination of pegylated interferon and bulevirtide in 40.5% of cases. Among the criteria to evaluate the treatment efficacy, a decrease or a normalization of transaminases was retained by 89% of responding HGs, a reduction of liver fibrosis score for 70% of them, an undetectable delta RNA and HBsAg for 55% of them and a 2 log 10 decline in delta viremia for 62% of the cases. CONCLUSION: Hepatitis Delta screening was not systematically performed in HBsAg-positive patients despite the probable awareness and knowledge of the few responders who were able to prescribe treatments of hepatitis delta.

Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D.

BACKGROUND & AIMS: Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown. METHODS: In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 µg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 µg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). RESULTS: Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12]). CONCLUSIONS: Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment. CLINICAL TRIAL REGISTRATION: NCT00932971.

Ergosterol peroxide blocks HDV infection as a novel entry inhibitor by targeting human NTCP receptor.

Hepatitis D virus (HDV), which co-infects or superinfects patients with hepatitis B virus, is estimated to affect 74 million people worldwide. Chronic hepatitis D is the most severe form of viral hepatitis and can result in liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Currently, there are no efficient HDV-specific drugs. Therefore, there is an urgent need for novel HDV therapies that can achieve a functional cure or even eliminate the viral infection. In the HDV life cycle, agents targeting the entry step of HDV infection preemptively reduce the intrahepatic viral RNA. Human sodium taurocholate co-transporting polypeptide (hNTCP), a transporter of bile acids on the plasma membrane of hepatocytes, is an essential entry receptor of HDV and is a promising molecular target against HDV infection. Here, we investigated the effect of ergosterol peroxide (EP) on HDV infection in vitro and in vivo. EP inhibited HDV infection of hNTCP-expressing dHuS-E/2 hepatocytes by interrupting the early fusion/endocytosis step of HDV entry. Furthermore, molecular modeling suggested that EP hinders LHBsAg binding to hNTCP by blocking access to S267 and V263. In addition, we generated hNTCP-expressing transgenic (Tg) C57BL/6 mice using the Cre/loxP system for in vivo study. EP reduced the liver HDV RNA level of HDV-challenged hNTCP-Cre Tg mice. Intriguingly, EP downregulated the mRNA level of liver IFN-γ. We demonstrate that EP is a bona fide HDV entry inhibitor that acts on hNTCP and has the potential for use in HDV therapies.

Hepatitis D: A Review.

Importance: Hepatitis D virus (HDV) infection occurs in association with hepatitis B virus (HBV) infection and affects approximately 12 million to 72 million people worldwide. HDV causes more rapid progression to cirrhosis and higher rates of hepatocellular carcinoma than HBV alone or hepatitis C virus. Observations: HDV requires HBV to enter hepatocytes and to assemble and secrete new virions. Acute HDV-HBV coinfection is followed by clearance of both viruses in approximately 95% of people, whereas HDV superinfection in an HBV-infected person results in chronic HDV-HBV infection in more than 90% of infected patients. Chronic hepatitis D causes more rapidly progressive liver disease than HBV alone. Approximately 30% to 70% of patients with chronic hepatitis D have cirrhosis at diagnosis and more than 50% die of liver disease within 10 years of diagnosis. However, recent studies suggested that progression is variable and that more than 50% of people may have an indolent course. Only approximately 20% to 50% of people infected by hepatitis D have been diagnosed due to lack of awareness and limited access to reliable diagnostic tests for the HDV antibody and HDV RNA. The HBV vaccine prevents HDV infection by preventing HBV infection, but no vaccines are available to protect those with established HBV infection against HDV. Interferon alfa inhibits HDV replication and reduces the incidence of liver-related events such as liver decompensation, hepatocellular carcinoma, liver transplant, or mortality from 8.5% per year to 3.3% per year. Adverse effects from interferon alfa such as fatigue, depression, and bone marrow suppression are common. HBV nucleos(t)ide analogues, such as entecavir or tenofovir, are ineffective against HDV. Phase 3 randomized clinical trials of bulevirtide, which blocks entry of HDV into hepatocytes, and lonafarnib, which interferes with HDV assembly, showed that compared with placebo or observation, these therapies attained virological and biochemical response in up to 56% of patients after 96 weeks of bulevirtide monotherapy and 19% after 48 weeks of lonafarnib, ritonavir, and pegylated interferon alfa treatment. Conclusions and Relevance: HDV infection affects approximately 12 million to 72 million people worldwide and is associated with more rapid progression to cirrhosis and liver failure and higher rates of hepatocellular carcinoma than infection with HBV alone. Bulevirtide was recently approved for HDV in Europe, whereas pegylated interferon alfa is the only treatment available in most countries.

Management of hepatitis D in general practice.

BACKGROUND: Hepatitis D virus (HDV) requires the presence of hepatitis B virus for replication and infection, and is associated with accelerated progression to cirrhosis and an increased risk of hepatocellular carcinoma. Approximately 4% of Australians living with hepatitis B are infected with HDV, although it is likely that HDV remains underdiagnosed. OBJECTIVE: This paper highlights the importance of screening for HDV in patients living with chronic hepatitis B (CHB) and provides an overview of diagnosis and treatment approaches for general practitioners (GPs), with the hope of reducing preventable liver-related morbidity and mortality in people living with CHB and HDV coinfection. DISCUSSION: The diversity of risk factors and geographical origins of patients in the multicultural Australian populace highlights the need for routine testing for HDV in patients diagnosed with CHB. GPs have a pivotal role in the diagnosis of HDV and should, if possible, promptly refer patients to non-GP specialist physicians to consider HDV therapy.

Hepatitis Delta Infection: A Clinical Review.

First discovered over 40 years ago, the hepatitis delta virus (HDV) is a unique RNA virus, requiring hepatitis B virus (HBV) antigens for its assembly, replication, and transmission. HBV and HDV can be acquired at the same time (coinfection) or HDV infection can occur in persons with chronic HBV (superinfection). Screening guidelines for HDV are inconsistent. While some guidelines recommend universal screening for all people with HBV, others recommend risk-based screening. Estimates of the global HDV prevalence range from 4.5 to 14.6% among persons with HBV; thus, there may be up to 72 million individuals with HDV worldwide. HDV is the most severe form of viral hepatitis. Compared to HBV monoinfection, HDV coinfection increases the risk of cirrhosis, hepatocellular carcinoma, hepatic decompensation, mortality, and necessity for liver transplant. Despite the severity of HDV, there are few treatment options. Pegylated interferon (off-label use) has long been the only available treatment, although bulevirtide is conditionally approved in some European countries. There are many potential treatments in development, but as yet, there are few effective and safe therapies for HDV infection. In conclusion, given the severity of HDV disease and the paucity of treatments, there is a great unmet need for HDV therapies.

Hepatitis D virus infection, innate immune response and antiviral treatments in stem cell-derived hepatocytes.

BACKGROUND: Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) are a valuable model to investigate host-pathogen interactions of hepatitis viruses in a mature and authentic environment. Here, we investigate the susceptibility of HLCs to the hepatitis delta virus (HDV). METHODS: We differentiated hPSC into HLCs, and inoculated them with infectious HDV produced in Huh7NTCP . HDV infection and cellular response was monitored by RTqPCR and immunostaining. RESULTS: Cells undergoing hepatic differentiation become susceptible to HDV after acquiring expression of the viral receptor Na+ -taurocholate co-transporting polypeptide (NTCP) during hepatic specification. Inoculation of HLCs with HDV leads to detection of intracellular HDV RNA and accumulation of the HDV antigen in the cells. Upon infection, the HLCs mounted an innate immune response based on induction of the interferons IFNB and L, and upregulation of interferon-stimulated genes. The intensity of this immune response positively correlated with the level of viral replication and was dependant on both the JAK/STAT and NFκB pathway activation. Importantly, this innate immune response did not inhibit HDV replication. However, pre-treatment of the HLCs with IFNα2b reduced viral infection, suggesting that ISGs may limit early stages of infection. Myrcludex efficiently abrogated infection and blocked innate immune activation. Lonafarnib treatment of HDV mono infected HLCs on the other hand led to exacerbated viral replication and innate immune response. CONCLUSION: The HDV in vitro mono-infection model represents a new tool to study HDV replication, its host-pathogen interactions and evaluate new antiviral drugs in cells displaying mature hepatic functions.

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

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.

Treatment of hepatitis delta and HIV infection.

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15-25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct-acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow-up, we propose that HIV-HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta.

Hepatitis D virus: Improving virological knowledge to develop new treatments.

Hepatitis delta virus (HDV), a satellite of hepatitis B virus (HBV), possesses the smallest viral genome known to infect animals. HDV needs HBV surface protein for secretion and entry into target liver cells. However, HBV is dispensable for HDV genome amplification, as it relies almost exclusively on cellular host factors for replication. HBV/HDV co-infections affect over 12 million people worldwide and constitute the most severe form of viral hepatitis. Co-infected individuals are at higher risk of developing liver cirrhosis and hepatocellular carcinoma compared to HBV mono-infected patients. Bulevirtide, an entry inhibitor, was conditionally approved in July 2020 in the European Union for adult patients with chronic hepatitis delta (CHD) and compensated liver disease. There are several drugs in development, including lonafarnib and interferon lambda, with different modes of action. In this review, we detail our current fundamental knowledge of HDV lifecycle and review antiviral treatments under development against this virus, outlining their respective mechanisms-of-action. Finally, we describe the antiviral effect these compounds are showing in ongoing clinical trials, discussing their promise and potential pitfalls for managing HDV infected patients.

Pembrolizumab-induced acute exacerbation of hepatitis D.

A 55-year-old man was treated with combined immunochemotherapy (pembrolizumab, carboplatin and pemetrexed) because of non-small cell lung cancer (NSCLC). In addition, the patient had a medical history of chronic hepatitis B/D virus infection and cystic echinococosis. The viral hepatitis co-infection was treated with pegylated interferon (IFN)-alpha and tenofovir in the past (non-response after treatment), followed by maintenance therapy with tenofovir. Since the echinococosis was inactive, there was no need for specific treatment. The therapy for NSCLC had to be stopped after three weeks due to rising liver enzymes. HDV-RNA could be detected as high as 107 GE/mL in the serum, HBV-DNA was not detected. A liver biopsy was performed. Histological analysis showed a chronic and partly active hepatitis, but its aetiology remained unclear. Because of the stable viral load after the first administration of pembrolizumab, an autoimmune-induced liver injury was suspected. Thus, a prednisolone-treatment was initiated. Yet, the liver enzyme levels did not decline, so bulevirtide (2 mg/d s.c.) was added to the ongoing antiviral treatment with tenofovir. This new treatment combination led to a restitution of the elevated enzymes; HDV-RNA was below detection limit. Finally, the therapy for NSCLC could be continued. The antiviral therapy could improve the patient´s prognosis significantly. To our knowledge, this is the first reported case of a pembrolizumab-induced exacerbation of hepatitis D and a successful management by application of bulevirtide in the context of cancer.

Natural history of untreated HDV patients: Always a progressive disease?

A severe course has been described in early studies on chronic hepatitis D (CHD), with faster pace towards liver cirrhosis with subsequent high liver-related morbidity and mortality in the majority of patients. Earlier studies have included risk groups as people using intravenous drugs (PWID) or those with multiple co-morbidities. During the last decade, the epidemiological landscape of CHD has changed with domestic cases decreasing while increasing cases of CHD consisting of younger persons immigrating from endemic regions to low-endemic regions. Recently, further insights into the spectrum of the disease with an indolent disease course in a substantial proportion of persons with CHD have been gained. At diagnosis, ≥30%-50% had already established liver cirrhosis. Older age, liver cirrhosis, co-infection with HIV and lack of interferon (IFN) therapy are the main predictors of worse clinical outcome. The newly introduced and upcoming antivirals against CHD are highly anticipated, considering the historically low virological response rates to antiviral therapy. Further knowledge is needed to fully comprehend the natural course and the spectrum of this severe form of viral hepatitis. This is also to be able to evaluate the long-term effects of the new antivirals on disease progression.

Bulevirtide for patients with compensated chronic hepatitis delta: A review.

Chronic hepatitis delta (CHD) affects approximately 10-20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end-stage liver disease, hepatocellular carcinoma). In the last 30 years, the only treatment option for CHD has been represented by the off-label administration of Interferon (or Pegylated Interferon)-alpha: antiviral treatment, however, resulted in suboptimal (20-30%) virological response and was burdened by several side effects, de facto contraindicating Interferon (IFN) administration in patients with more advanced liver disease. Recently, Bulevirtide (BLV), a first-in-class HBV-HDV entry inhibitor blocking Na+ -taurocholate co-transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real-life reports. In July 2020, BLV has granted conditional approval by EMA for treatment of compensated CHD, at the dose of 2 mg/day by self-administered subcutaneous injections. In Phase II and Phase III trials, BLV was evaluated at different doses (2 vs. 10 mg/day) for 24 or 48 weeks, either in monotherapy or in combination with PegIFN. Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%-83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%-78% ALT normalization. Combination therapy with PegIFN provided synergistic effects. These results were replicated in real-life studies and confirmed also in patients with advanced cirrhosis and clinically significant portal hypertension. BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids.

Medical Advances in Hepatitis D Therapy: Molecular Targets.

An approximate number of 250 million people worldwide are chronically infected with hepatitis B virus, making them susceptible to a coinfection with hepatitis D virus. The superinfection causes the most severe form of a viral hepatitis and thus drastically worsens the course of the disease. Until recently, the only available therapy consisted of interferon-α, only eligible for a minority of patients. In July 2020, the EMA granted Hepcludex conditional marketing authorization throughout the European Union. This first-in-class entry inhibitor offers the promise to prevent the spread in order to gain control and eventually participate in curing hepatitis B and D. Hepcludex is an example of how understanding the viral lifecycle can give rise to new therapy options. Sodium taurocholate co-transporting polypeptide, the virus receptor and the target of Hepcludex, and other targets of hepatitis D therapy currently researched are reviewed in this work. Farnesyltransferase inhibitors such as Lonafarnib, targeting another essential molecule in the HDV life cycle, represent a promising target for hepatitis D therapy. Farnesyltransferase attaches a farnesyl (isoprenyl) group to proteins carrying a C-terminal Ca1a2X (C: cysteine, a: aliphatic amino acid, X: C-terminal amino acid) motif like the large hepatitis D virus antigen. This modification enables the interaction of the HBV/HDV particle and the virus envelope proteins. Lonafarnib, which prevents this envelopment, has been tested in clinical trials. Targeting the lifecycle of the hepatitis B virus needs to be considered in hepatitis D therapy in order to cure a patient from both coexisting infections. Nucleic acid polymers target the hepatitis B lifecycle in a manner that is not yet understood. Understanding the possible targets of the hepatitis D virus therapy is inevitable for the improvement and development of a sufficient therapy that HDV patients are desperately in need of.

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

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.

Entry Inhibitors of Hepatitis B and D Viruses.

Human hepatitis B virus (HBV) and hepatitis D virus (HDV) cause acute and chronic infections. The latter poses a serious public health threat as it is the major cause of chronic hepatitis, liver failure, cirrhosis, and hepatocellular carcinoma (HCC). In nature, HBV and HDV have a narrow host range and highly hepatotropic, only infecting the hepatocytes of humans and a few primates. The elucidation of cell entry mechanism by HBV has made great progress in recent years, which strongly promotes the establishment of new HBV infection models and the development of viral entry inhibitors. The study of HBV entry inhibitors has culminated in the first direct antiviral treatment for HDV. This review provides a concise introduction on the progress of HBV/HDV entry inhibitors in the recent years.

Hepatitis D: advances and challenges.

ABSTRACT: Hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis with rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although discovered > 40 years ago, little attention has been paid to this pathogen from both scientific and public communities. However, effectively combating hepatitis D requires advanced scientific knowledge and joint efforts from multi-stakeholders. In this review, we emphasized the recent advances in HDV virology, epidemiology, clinical feature, treatment, and prevention. We not only highlighted the remaining challenges but also the opportunities that can move the field forward.

Chronic hepatitis D-What is changing?

Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.

[Bulevirtide as the first specific agent against hepatitis D virus infections-mechanism and clinical effect]. / Bulevirtide als erster spezifischer Wirkstoff gegen Hepatitis-D-Virusinfektionen ­ Mechanismus und klinische Wirkung.

Blocking the cell entry of pathogens is a suitable approach to prevent new infections. However, the therapeutic use of entry inhibitors in chronically infected patients has had limited success. For the treatment of chronic hepatitis D virus (HDV) infections, a promising agent based on this mode of action, Bulevirtide (BLV), was conditionally approved in July 2020. Previously, no drugs were available for HDV, and treatment relied on off-label use of interferon alpha/peginterferon alpha (IFNα/Peg-IFNα). In this review, we provide an overview of the basic mechanism of action of BLV and summarize the clinical data available to date.HDV infection manifests as a co-infection or superinfection of hepatitis B virus (HBV) infections and affects 4.5-15% of HBV patients worldwide. HDV utilizes the envelope proteins of HBV for dissemination. BLV acts by blocking the HBV/HDV receptor sodium taurocholate co-transporting polypeptide (NTCP), preventing HBV/HDV entry into hepatocytes. BLV lowers HDV serum RNA levels and normalizes alanine aminotransferase (ALT) levels in HBV/HDV-infected individuals. It has an excellent safety profile, even when administered at high doses (10 mg daily) for 48 weeks. In combination with Peg-IFNα, BLV shows synergistic effects on lowering serum HDV RNA, but also on hepatitis B surface antigen (HBsAg) levels. This resulted in a functional cure in a subset of patients when 2 mg BLV plus Peg-IFNα was administered. The mechanism of this likely immune-mediated elimination will be investigated in follow-up studies.

Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials.

INTRODUCTION: Chronic Hepatitis D virus (HDV) infection is a global disease leading to rapidly progressive liver disease with increased liver-related mortality and hepatocellular carcinoma. Therapies are minimally effective; however, an increased understanding of the HDV lifecycle has provided new potential drug targets. Thus, there is a growing number of investigational therapeutics under exploration for HDV with the potential for successful viral eradication. AREAS COVERED: This review discusses the clinical impact of HDV infection and offers an in-depth look at the HDV life cycle. The authors examine current and new drug targets and the investigational therapies in clinical trials. The search strategy was based on PubMed database and clinicaltrials.gov which highlight the most up-to-date aspects of investigational therapies for chronic HDV infection.