Hepatitis delta: recent advances and future therapies

Abstract

Chronic hepatitis delta (CHD) affects millions worldwide with many undiagnosed. It requires the presence of hepatitis B virus (HBV) for viral propagation, and those who are coinfected have a more rapid development of cirrhosis, hepatocellular carcinoma and fulminant liver failure. Treatments licensed for HBV have been ineffective in those with CHD. As an orphan disease, there is only one licensed treatment for CHD in Europe, which has relatively limited efficacy and viral control. This review focuses on current treatments, recent advances and unresolved issues in hepatitis delta management.

Plain language summary

Chronic hepatitis delta is a very serious liver disease caused by the hepatitis delta virus, which can only infect people who already have hepatitis B. Worldwide, about 15 to 20 million people are affected. The disease can lead to severe liver damage and liver cancer.

Medications that work for hepatitis B do not work for hepatitis delta, and until recently, there were no specific treatments approved for it. A new drug called bulevirtide was approved in Europe in 2020, and the UK in 2023, and is showing promise in ongoing studies around the world. It offers hope for better management of the disease. However, it is a daily injection needed indefinitely. Many people do not completely clear the virus.

This article discusses new treatment strategies, including combining bulevirtide with other drugs, to improve the lives of the people living with the condition. These approaches aim to either significantly reduce the virus in the liver or (ideally) get rid of it completely.

Article highlights

Background

• Chronic hepatitis delta (CHD) is the most severe form of viral hepatitis, affecting 15–20 million people globally.

• The disease progresses rapidly and can lead to severe liver-related morbidity and mortality, with cirrhosis, liver cancer and fulminant liver failure.

• Hepatitis delta virus (HDV) relies on hepatitis B virus (HBV) for propagation.

• Drugs effective against suppressing HBV do not work against HDV.

• The first ever clinical guidelines were published on hepatitis delta management by the European Association for the Study of the Liver (EASL) in 2023.

• The first approved drug (bulevirtide) for HDV was approved in 2020 in Europe, and 2023 in the UK. It is currently not licensed in the USA.

Current treatments

• Treatment aims to prevent liver damage and improve life quality, ideally aiming for a finite treatment duration with complete viral suppression.

• Pegylated interferon-alpha (peg-IFNα) has been the standard treatment for decades (although this is used off-label) but is limited by side effects and partial efficacy. After a finite therapy duration, viral levels often rebound either shortly after or years after.

• Bulevirtide offers a new treatment avenue by blocking the virus's entry into hepatocytes, but it may require combination with other drugs for better effectiveness. There are no stopping criteria for this medication and many experience viral rebound if treatment is stopped.

Novel HDV therapies & targets

• Ongoing research targets various aspects of the HDV life cycle and the immune response to develop more effective treatments.

• Pegylated interferon-lambda (peg-IFN-L) shows promise due to fewer side effects compared with traditional interferons. However, recent clinical trials were terminated due to liver-related complications, and therefore safety and use need to be carefully re-examined.

• Lonafarnib, a drug inhibiting a critical viral process, shows potential in combination therapies, though side effects and optimal dosing need further research.

• Nucleic acid polymers (NAPs) and emerging treatments like monoclonal antibodies and siRNA are in development, targeting the viral components and processes more directly and potentially offering new treatment modalities.

Unresolved issues in hepatitis delta

• There is no international consensus on screening for CHD, leading to underdiagnosis and delayed treatment. Some countries are now implementing reflex testing in those with hepatitis b which will increase detection rates of delta.

• Diagnostic tools have until recently lacked standardization and fail to capture the full diversity of HDV, which hampers effective management. Better pangenotypic assays are essential.

• The optimal end points for treatment are debated, with ongoing discussions about how best to measure treatment success and the relevance of viral load and liver enzyme levels.

Conclusion

• HDV remains a complex viral infection with a significant impact on global health and lack of effective, widely applicable treatments.

• Recent advances in therapy and diagnostics are promising, but a finite cure remains elusive.

Future perspective

• Future research needs to focus on understanding the virus-host interactions and the dynamics of co-infections, to develop targeted and effective treatments.

Keywords: :

• Bulevirtide
• chronic hepatitis
• HDV co-infection
• hepatitis D virus
• interferon-alpha
• interferon-lambda
• Lonafarnib
• nucleic acid polymers

Author contributions

Z Cargill drafted manuscript and prepared for submission. I Careya and K Agarwal provided concept, manuscript editing and review.

Financial disclosure

K Agarwal has the following involvements: Gilead Sciences, Inc.: Speaking and Teaching; Saigmet: Consultant; Roche: Consultant; Janssen: Consultant; GSK: Consultant; Boehringer Ingelheim: Consultant; Bristol Myers Squibb: Consultant; Assembly Biosciences: Consultant; Gilead Sciences, Inc.: Consultant; Aligos: Consultant; Gilead Sciences, Inc.: Grant/Research Support; GSK: Speaking and Teaching; Janssen: Speaking and Teaching; Sobi: Speaking and Teaching; Drug Farm: Consultant; Vir: Consultant; Grifols: Consultant; PrecisionBio: Consultant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

K Agarwal has the following involvements: Gilead Sciences, Inc.: Speaking and Teaching; Saigmet: Consultant; Roche: Consultant; Janssen: Consultant; GSK: Consultant; Boehringer Ingelheim: Consultant; Bristol Myers Squibb: Consultant; Assembly Biosciences: Consultant; Gilead Sciences, Inc.: Consultant; Aligos: Consultant; Gilead Sciences, Inc.: Grant/Research Support; GSK: Speaking and Teaching; Janssen: Speaking and Teaching; Sobi: Speaking and Teaching; Drug Farm: Consultant; Vir: Consultant; Grifols: Consultant; PrecisionBio: Consultant. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.