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

ABSTRACT

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.

KEYWORDS:

• Hepatitis D
• clinical trials
• investigational drugs
• immunomodulation
• Bulevirtide

Article highlights

• Available chronic Hepatitis D virus (HDV) therapies are minimally effective.

• Traditional interferon-based therapies result in less than 30% of patients with sustained response.

• Increased understanding of the HDV lifecycle has provided new potential therapeutic drug targets.

• The identification of new investigational therapies based on the HDV life cycle and host immunomodulation appear to be promising options.

• Ongoing trials with RNAi (RNA interference molecules), anti-PDL (programmed death ligand) agents, and modified interferons give hope for HDV cure by targeting new mechanistic and biochemical aspects of HDV.

Insights into the host immune response against hepatitis delta, as well as interaction with Hepatitis B virus (HBV), are important in working to eradicate HDV.

Abbreviations

HDV, hepatitis delta virus; HDAg, delta antigen; HBV, hepatitis B; HBcAg, hepatitis B core antigen; PEG-IFN-α, peginterferon alpha; RNA, ribonucleic acid; HbsAg, hepatitis B surface antigen; NTCP, sodium taurocholate cotransporting peptide; ORF, open reading frame; HCV, hepatitis C virus; ALT, alanine aminotransferase; HIDIT-1, Hep-Net-International Delta Hepatitis Intervention Trial; TDF, tenofovir disoproxil fumurate; CHD, chronic hepatitis D; FDA, Food and Drug Administration; PO, per oral; BID, twice daily; LOWR, Lonafarnib with Ritonavir; D-LIVR, Delta liver improvement and virologic response; BLOQ, below the lower limit of quantification; NAP, nucleic acid polymer; LLOQ, lower limit of quantification; PD-1, programmed death receptor 1.

Disclosure Statement

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Expert opinion

Multiple therapeutic options for HDV have demonstrated promise in clinical trials with HDV RNA reduction and/or Hepatitis B surface antigen loss. New therapies in the development pipeline target host functions or aspects of the viral life cycle; a combination of host and viral targets will likely yield success in the near term. Future trials should address patients with cirrhosis, heterogenous genotypes, and standardized surrogate markers, including HBV functional cure.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded. The authors are supported by the Intramural Research Programs of the National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health.