Evolution of the HDV Treatment Paradigm

Hepatitis delta is the most severe form of viral hepatitis; it has the highest rates of progression to cirrhosis and hepatocellular carcinoma. Until recently, we have not devoted much time or effort toward addressing screening or developing effective treatment strategies for hepatitis delta virus (HDV). Read my take on new data that are driving improved screening and treatment of patients infected with HDV.

HDV Prevalence and Screening Approaches
Pockets of HDV exist across the world, influenced by immigration patterns, and that has made it hard to determine the true prevalence of HDV worldwide. Recent data modeling presented by Wong and colleagues at the European Association for the Study of the Liver (EASL) 2022 International Liver Congress in London found that there may be as many as 200,000 non–US-born adults with chronic hepatitis B (CHB) living in the United States who are coinfected with HDV. Finding these individuals is challenging, and suboptimal awareness of and testing for HDV in patients with CHB confound our understanding of true prevalence rates. Although the EASL guidelines recommend a universal screening approach, the American Association for the Study of Liver Diseases currently recommends a risk-based screening approach.

In my own practice, I screen for HDV in all individuals who have hepatitis B virus (HBV) in the hopes that I will find those with HDV and offer them both staging of their disease and a discussion of treatment options—of which many exciting options are on the horizon.

Lack of Treatment Options
One reason we have not screened aggressively for HDV in many parts of the world is because we have lacked effective treatments with high response rates that are well tolerated by patients like we have for other forms of viral hepatitis (eg, HBV and hepatitis C virus).

What we have been using, despite limited data, is a finite course of pegylated interferon alfa. The response rates are not as robust in HDV as in other forms of viral hepatitis, and there is considerably more relapse after stopping treatment, so we need better treatment options for HDV.

The good news is that new agents are being studied in HDV with promising results. There also is considerable interest in trying to achieve improved functional cure rates in HBV infection because if one successfully treats HBV and clears surface antigen, HDV is eliminated.

Future Treatment Options

Lonafarnib
What are some of these new drugs for HDV that are in clinical trials? One is lonafarnib, which is a farnesyl transferase inhibitor. It is an oral drug that requires ritonavir boosting and is effective at suppressing HDV RNA. Boosting with ritonavir improves its pharmacokinetic profile and tolerability so that it may be administered in combination with a nucleos(t)ide polymerase inhibitor. Current data suggest that there is improved viral suppression when combined with pegylated interferon. We eagerly await the results of a phase III trial studying lonafarnib in combination with pegylated interferon and nucleos(t)ide polymerase inhibitors and hope it will show that lonafarnib can be part of the therapeutic armamentarium to improve long-term response rates in those with HDV.

Bulevirtide
Bulevirtide is an injectable therapy with conditional approval in the European Union and has been granted breakthrough therapy and orphan drug designations in the United States. It is a small peptide that blocks engagement of the hepatitis B surface antigen (HBsAg), blocking HBV and HDV entry into hepatocytes. Studies have demonstrated that bulevirtide use leads to significant reductions in HDV RNA, and some patients have been able to clear HDV RNA completely. Bulevirtide has been studied as monotherapy and in combination with pegylated interferon, and the combination shows synergistic effects. At the EASL 2022 International Liver Congress, Wedemeyer and colleagues presented the Week 48 data from the MYR301 bulevirtide monotherapy study, which highlighted the efficacy and safety of prolonged bulevirtide treatment.

Nucleic Acid Polymers (NAPs) and Small Interfering RNA
NAPs, a new class of molecules, inhibit the assembly and release of HBsAg. REP-2139 is one such NAP being studied. When administered in combination with pegylated interferon, there is substantial decline in HDV RNA and clearance of HBsAg. Other small molecules showing HDV treatment efficacy are siRNA molecules, which target viral transcription.

Pegylated Interferon λ
Pegylated interferon λ is being investigated for treatment of HDV. This is a type III interferon, and its receptors are mainly found in hepatocytes, so it is a more liver-targeted therapy with fewer hematologic and neurologic adverse events. Like pegylated interferon alfa, pegylated interferon λ could logically be combined with new agents such as lonafarnib and bulevirtide to create synergistic efficacy. Newer pharmacokinetic data from the LIMT-1 study presented at the EASL 2022 International Liver Congress by Cardoza-Ojeda and colleagues demonstrated efficacious blockade of viral production with pegylated interferon λ monotherapy in patients with HDV, and a large phase III trial is currently enrolling patients that will evaluate 48 weeks of pegylated interferon λ for HDV infection.

Your Thoughts?
What do you think are the opportunities and challenges with using current and emerging treatment options for patients with HDV? Answer the polling question and join the conversation by posting a comment.