Advances in treatment of hepatitis delta virus infection: Update on novel investigational drugs

doi:10.5501/wjv.v14.i2.102673

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World Journal of Virology

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2220-3249

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Virol. Jun 25, 2025; 14(2): 102673
Published online Jun 25, 2025. doi: 10.5501/wjv.v14.i2.102673

Advances in treatment of hepatitis delta virus infection: Update on novel investigational drugs

Jiyoon Park, Amr Sayed, Syed Alishan Nasir, Joseph K Lim

Jiyoon Park, Amr Sayed, Syed Alishan Nasir, Division of Gastroenterology, Norwalk Hospital, Norwalk, CT 06856, United States

Joseph K Lim, Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, CT 06520, United States

Author contributions: Lim JK and Park J conceptualized and designed the manuscript; Park J, Sayed A, and Nasir SA drafted the manuscript; Lim JK provided critical revisions of the manuscript for important intellectual content and supervised the manuscript. All authors acquired, analyzed, and interpreted the data. All authors have approved the publication of this manuscript.

Conflict-of-interest statement: Lim JK received research contracts (to institution) from Gilead, Intercept, Inventiva, Novo Nordisk, Pfizer, and Viking. Park J, Sayed A, and Nasir SA report no conflicts of interest.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Joseph K Lim, MD, Professor, Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, Yale Liver Center, 333 Cedar Street, LMP 1080, New Haven, CT 06520, United States. joseph.lim@yale.edu

Received: October 27, 2024
Revised: February 25, 2025
Accepted: March 12, 2025
Published online: June 25, 2025
Processing time: 241 Days and 7.5 Hours

Abstract

Chronic hepatitis delta virus (HDV) represents a rare but important co-infection in approximately 5% of patients with chronic hepatitis B virus (HBV) infection, and is associated with significant morbidity and mortality due to an increased risk for liver cirrhosis, liver failure, and hepatocellular carcinoma relative to HBV monoinfected individuals. The current treatment of chronic HDV infection includes the off-label use of pegylated interferon (IFN), which is limited by poor safety, tolerability, and efficacy. Guidelines of the major international liver organizations such as the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary diagnosis and management of chronic HDV infection, including the incorporation of bulevirtide, a newly licensed antiviral agent in Europe. Significant unmet medical needs remain in the treatment of HDV, and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel IFNs (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and addresses future directions in HDV pharmacotherapy.

Keywords: Hepatitis D virus; Antiviral therapy; Interferon; Bulevirtide; Tobevibart; Elebsiran; Guidelines; Clinical trials

Core Tip: Current treatment of hepatitis delta virus (HDV) infection with off-label use of pegylated interferon (Peg-IFN) is limited by poor efficacy and safety. Guidelines of major international liver societies including the American Association for the Study of Liver Diseases, European Association for the Study of Liver and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary management of HDV infection with Peg-IFN and/or bulevirtide. Significant unmet medical needs remain in the treatment of HDV and recent advances in drug development offer hope for significant improvement in virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel interferons (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and report important advances with monotherapy and combination regimens which are associated with high rates of virologic response.