Key Questions on Emerging Treatments for Hepatitis Delta

Hepatitis delta virus (HDV) exists only in the presence of hepatitis B surface antigen (HBsAg) and depends on HBsAg for its replication and life cycle. There are numerous treatment options for hepatitis B virus (HBV), but very few for HDV. Read my take on why studies of treatments for HDV are limited and what options we have on the horizon that will improve the treatment for HDV around the globe.

Study Obstacles
Patients infected with HDV have more advanced liver disease, and this makes it more difficult to study treatment approaches in these patients compared with patients infected with HBV or hepatitis C virus. Another complicating factor is that HDV is considered a rare disease and we do not have tens of thousands of patients in which we can explore different treatment regimens at different doses. Because of these issues, investigating treatments for HDV requires a clear and careful strategy.

Bulevirtide
Bulevirtide, an HDV entry inhibitor, has been available in Europe since September 2020, but it is not available in North America, where it has been granted Breakthrough Therapy and Orphan Drug designations by the FDA and where a biologics license application was submitted in November 2021.

To my mind, there are 3 questions that need to be answered for optimizing the use of bulevirtide:

1. If we use bulevirtide as monotherapy, is maintenance treatment required? For some patients treated with bulevirtide, we may be able to stop treatment. We have seen success with this in phase II clinical trials. But whether this applies to a larger patient population will be answered by the MYR301 study.
2. Is combination therapy with interferon an option? We have seen synergistic effects when using the 2 drugs together, but we lack final data. We do not know what happens when a patient discontinues both drugs. We should get answers from the ongoing MYR204 study.
3. Are there patients who may not respond to bulevirtide treatment? What factors may influence lesser response or nonresponse? Are there patients who may have a relapse after stopping treatment? If any of these cases are true, we may need alternative treatments to bulevirtide.

Other Emerging Treatments
A phase III trial investigating the prenylation inhibitor lonafarnib is ongoing. We have seen from phase II trials of lonafarnib that there is proof of antiviral efficacy based on declining viral loads. There is also evidence of synergistic effects of using lonafarnib in combination with interferon.

There are various other investigational treatment options to be explored, including nucleic acid polymers, interferon-λ, and anti-HBV small-interfering RNAs.

Goals of HDV Treatment
Because HDV only exists in the presence of HBV, a curative approach for HBV would also mean a cure for HDV. We use the term “functional cure” for HBV (defined as loss of HBsAg), but we do not know whether a functional cure for HBV also means the same for HDV. Most HDV clinical trials define therapeutic efficacy as decrease in or suppression of HDV RNA and normalization of alanine aminotransferase. The ultimate goal of HDV treatment is viral elimination, and we need improved treatment options and strategies for HDV that achieve sustained elimination of HDV RNA.

Your Thoughts?
What do you think is the most promising emerging treatment for HDV? Answer the polling question and join the conversation by posting a comment.