Tag: hepatitis D

Scientists Reveal how Drug Locks Hepatitis D Virus out of Liver Cells

Colourised transmission electron micrograph of hepatitis B virus particles (colourised red and yellow). Credit: NIAID and CDC (Transmission electron micrograph image courtesy of CDC; colourisation by NIAID).

Over 12 million people worldwide suffer from a chronic infection with the hepatitis D virus. This most severe viral liver disease is associated with a high risk of dying from liver cirrhosis and liver cancer. It is caused by the hepatitis D virus (HDV), which uses the surface proteins of the hepatitis B virus (HBV) as a vehicle to specifically enter liver cells via a protein in the cell membrane – the bile salt transporter protein NTCP. This cell entry can be prevented by the active agent bulevirtide.

An international research team has now succeeded in deciphering the molecular structure of bulevirtide in complex with the HBV/HDV receptor NTCP at the molecular level. The research results published in the journal Nature Communications pave the way for more targeted and effective treatments for millions of people chronically infected with HBV/HDV.

The entry inhibitor bulevirtide is the first and currently only approved drug (under the drug name Hepcludex) for the treatment of chronic infections with the hepatitis D virus. The active agent effectively inhibits the replication of hepatitis D viruses and leads to a significant improvement in liver function. But the exact mechanism by which bulevirtide interacts with the virus entry receptor on the surface of the liver cells – the bile salt transporter protein NTCP (sodium taurocholate cotransporting polypeptide) – and thereby inhibits the entry of the viruses into the cells was previously unknown.

In order to understand the molecular interaction of bulevirtide and NTCP at the molecular level, the researchers first generated an antibody fragment that specifically recognises the NTCP-bulevirtide complex and makes it accessible for analysis when bound to nanoparticles. This complex was then analysed using cryo-electron microscopy, which allowed to visualise structural details with atomic resolution. The research results represent a milestone in understanding both the interaction of HBV and HDV with their cellular entry receptor NTCP and the mechanism of cell receptor blockade by bulevirtide.

How bulevirtide blocks the cell entry receptor NTCP

The analysis showed that bulevirtide forms three functional domains in the interaction with the HBV/HDV receptor NTCP: a myristoyl group that interacts with the cell membrane on the outside of the cell; an essential core sequence (‘plug’) that fits precisely into the bile salt transport tunnel of the NTCP like the bit of a key into a lock; and an amino acid chain that stretches across the extracellular surface of the receptor, enclosing it like a brace.

“The formation of a ‘plug’ in the transport tunnel and the associated inactivation of the bile salt transporter is so far unique among all known virus-receptor complexes. This structure explains why the physiological function of the NTCP is inhibited when patients are treated with bulevirtide,” says Prof Stephan Urban, DZIF Professor of Translational Virology and Deputy Coordinator of the DZIF research area Hepatitis, in whose laboratory at Heidelberg University the active agent bulevirtide was developed.

“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents – so-called peptidomimetics – with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.

Evolutionary adaptation of hepatitis B viruses to host species

The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.

“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.

“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents — so-called peptidomimetics — with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.

Evolutionary adaptation of hepatitis B viruses to host species

The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.

“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.

Source: German Center for Infection Research

Real-world Testing Confirms Bulevirtide Efficacy in Treating Hepatitis D

Colourised transmission electron micrograph of hepatitis B virus particles (colourised red and yellow). Credit: NIAID and CDC (Transmission electron micrograph image courtesy of CDC; colourisation by NIAID).

In 2020, bulevirtide (BLV) was conditionally approved for treating chronic hepatitis delta (CHD), an inflammation of the liver caused by hepatitis D virus (HDV). Now, as reported in the Journal of Hepatology, real-world studies confirm that long-term suppressive therapy with BLV monotherapy reduces viral replication and improves liver tests of these difficult-to-treat patients.

Two of the studies, led by Pietro Lampertico, MD, PhD, were designed to assess the effectiveness and safety of patients with advanced HDV-related compensated cirrhosis being treated with BLV 2mg monotherapy and the consequences of discontinuing this treatment.

“HDV is the most severe form of chronic viral hepatitis,” explained Dr Lampertico. “For many years, the only therapeutic option was the off-label administration of pegylated-interferon-alpha (PegIFNa), an approach characterised by suboptimal efficacy, an unfavourable safety profile and several contraindications.”

In a study of 18 patients with HDV-related advanced cirrhosis treated with BLV 2mg/day for 48 weeks, Dr. Lampertico and colleagues demonstrated significant virological, biochemical and combined response rates associated with improvement of liver function.

“The efficacy and safety of BLV monotherapy in patients with advanced compensated cirrhosis were unknown before this study. Virological and biochemical responses to BLV monotherapy that we observed in our difficult-to-treat patients with HDV-related compensated cirrhosis were similar to those shown in the phase III registration study,” Dr Lampertico noted.

In a case report, Dr Lampertico and colleagues demonstrated that HDV could be successfully eradicated from both serum and liver following a three-year course of BLV monotherapy. This was despite the persistence of HBsAg, in a patient with HDV-related compensated cirrhosis and oesophageal varices. During the 72-week off-BLV follow-up, liver biopsy, intrahepatic HDV RNA and hepatitis D antigen were undetectable, less than 1% of hepatocytes were HBsAg positive and all were negative for hepatitis B core antigen.

“We were surprised to demonstrate that HDV can be eradicated following a finite course of an entry inhibitor administered as monotherapy such as BLV 2mg/day, despite the persistence of HBsAg positivity,” commented Dr Lampertico.

In a study in JHEP Reports led by Katja Deterding, MD, investigators report the first data from the largest multicentre cohort of patients to date who were treated with BLV under real-world conditions. This included 50 patients with signs of significant portal hypertension, elevated pressure in the major vein that leads to the liver.

The retrospective analysis of 114 cases covered 4289 patient weeks of BLV treatment. Viral response was observed in 87 cases while hepatic inflammation improved, and treatment was well tolerated. More than 50% of patients showed a virologic response with less than 10% of patients not achieving an HDV RNA drop of at least 90% after 24 weeks. An improvement of biochemical hepatitis activity as measured by the liver enzyme alanine transaminase (ALT) values was observed regardless of virologic response. Investigators concluded that treatment was safe and well tolerated and associated with improvements in liver cirrhosis and portal hypertension with prolonged treatment.

“In line with other real-world cohorts and clinical trials our real-world study confirms the antiviral activity of BLV,” noted Dr Deterding. “We were surprised to see an improvement in biochemical hepatitis activity even in cases without viral response. Potential explanations for this phenomenon include anti-inflammatory properties of BLV.”

“This is the first time that patients with HDV-related chronic advanced liver disease can be treated with an antiviral therapy since 1977 when HDV was discovered. Long-term suppressive therapy with BLV 2mg/day has the potential to improve survival, of these difficult-to-treat patients for the first time in 45 years,” concluded Dr Lampertico. “We also found that BLV treatment can be successfully discontinued in some HDV patients who achieved long-term viral suppression while on therapy.”

HDV infection occurs when people become infected with both hepatitis B and D virus either simultaneously (co-infection) or acquire the hepatitis D virus after first being infected with hepatitis B (super-infection). According to the World Health Organization, HDV affects nearly 5% of individuals with a chronic infection resulting from hepatitis B virus (HBV). Populations that are more likely to have HBV and HDV co-infection include indigenous populations, haemodialysis recipients and individuals who inject drugs.

Source: Elsevier