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HDV: Emerging Therapies
Updates on Emerging HDV Treatments

Released: February 14, 2023

Expiration: February 13, 2024

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Key Takeaways
  • Limitations to screening recommendations, limited accessibility/affordability of diagnostic tests, and limited therapeutic options are all challenges for HDV management.
  • Many promising HDV treatment options are on the horizon, including an entry inhibitor, a prenylation inhibitor, an immunomodulator, and nucleic acid polymers.

HDV Challenges
Unlike European guidelines, which recommend universal hepatitis delta virus (HDV) screening for all patients infected with hepatitis B virus (HBV), US guidelines remain restrictive and are risk based. Even with universal screening recommendations in Europe, nonadherence to screening is common, and many challenges to HDV management remain. 

HDV testing is not widely available and only recently has been picked up by commercial laboratories. Until access to HDV testing expands and becomes more cost-effective, screening will remain a challenge for healthcare professionals. 

In addition, available HDV treatment options are limited. Pegylated interferon (pegIFN) is the only HDV treatment available in the United States, where its use is off label. However, it is an exciting time for HDV, with several promising therapeutics on the horizon.

Bulevirtide
Bulevirtide, a viral entry inhibitor, is administered as a daily injection and is effective in decreasing HDV replication. Data are available from several clinical trials, as well as real-world studies from Europe, where the drug is available through conditional approval.

Virologic response rates (HDV RNA undetectable or ≥2 log10 IU/mL decline) from real-world studies have been similar to those from clinical trials (eg, at Week 24: 55% in MYR301 study, 52% in French study). Now we have efficacy data of bulevirtide administered up to 72 weeks from HEP4Di, a retrospective, real-world analysis of 93 patients with HDV from Italy. Virologic response was achieved by 75% of patients at Week 72 of treatment.

So, why did the FDA reject approval for bulevirtide in the United States? In its complete response letter, the FDA did not argue safety or efficacy results or request additional studies. Instead, concerns were raised about drug manufacturing and delivery. I think the manufacturer will be able to address these issues and the FDA ultimately will approve bulevirtide for HDV.

Based on current data, it is very promising that some patients have maintained a durable response, but early data from the French Early Access Program suggest that if you stop bulevirtide, HDV might become active again. In a subset of patients who received 12 months of bulevirtide monotherapy, combined virologic and biochemical response rates dropped from 39% (Month 12) to 12% (Month 18) after 6 months of treatment discontinuation. To me, this shows that the ideal treatment duration remains unclear. I suspect patients will need to receive bulevirtide long term, although not necessarily as lifelong treatment.

Lonafarnib
Lonafarnib is a novel prenylation inhibitor. The press release on D-LIVR is now available. These data have not yet been presented at a medical meeting or peer reviewed, but I expect more discussion about the results at the European Association for the Study of the Liver Congress in June.

In this randomized, controlled phase III trial, 407 patients with HDV received (1) lonafarnib plus ritonavir, (2) lonafarnib plus ritonavir and pegIFN-α, (3) pegIFN-α plus placebo, or (3) placebo alone. The primary endpoint (virologic and biochemical response at Week 48) was achieved by 10.1%, 19.2%, 9.6%, and 1.9% of patients, respectively. Looking just at virologic endpoints, virologic response was achieved by 32% of patients receiving combination with lonafarnib, ritonavir, and pegIFN-α vs 14.6% of patients receiving all-oral therapy with lonafarnib and ritonavir.

A histologic composite endpoint—defined as no worsening in fibrosis and ≥2-point improvement in Ishak histology activity index—also was assessed. Compared with placebo, a significant improvement in histologic response was observed in patients receiving lonafarnib, ritonavir, and pegIFN-α (53% vs 27%; P = .0129). For those receiving lonafarnib and ritonavir, a histologic response was observed in approximately one third of patients.

Although the virologic and biochemical efficacy was lower than I hoped, the combination of lonafarnib, ritonavir, and pegIFN-α may be a viable option for patients with HDV with few treatment options. Because our goal with therapy ultimately is to decrease liver-related complications and liver cancer, I find the histology results very encouraging.

The Pipeline
These novel HDV treatments are just the start of what we hope will be many treatment options. The drug development pipeline remains rich and includes agents such as another immunomodulator (pegIFN-λ) and nucleic acid polymers. 

The ultimate goal would be to have curative options for HBV, because HDV cannot occur without HBV. Several agents are under investigation for HBV, seeking to eliminate the hepatitis B surface antigen, which would make them promising treatment options for our patients with HDV, as well.  

Your Thoughts?
Which HDV therapeutic option are you most excited about? Join the discussion by posting a comment.