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Interferons for HDV Treatment
Interferons: Here to Stay for HDV Treatment?

Released: March 28, 2023

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Key Takeaways
  • Although achieving a functional cure would be desirable, many HDV therapies have not been found to affect HBsAg levels, except in a portion of patients who receive pegIFN-α.
  • PegIFN-α is associated with serious adverse effects that can limit its use.
  • PegIFN-λ, under investigation for HDV treatment, may provide a better safety profile; more data are needed in phase III studies.

The overarching goal for treatment of hepatitis delta virus (HDV) infection is to reduce the risk for liver complications such as fibrosis and hepatocellular carcinoma. However, when considering a surrogate markers for clinical success of HDV therapies, a functional cure through sustained hepatitis B surface antigen (HBsAg) loss is ideal. However, HDV RNA reductions are still very important markers of success and have been associated with improved clinical outcomes.

Although new treatment strategies for HDV—such as the entry inhibitor bulevirtide or the prenylation inhibitor lonafarnib—reduce HDV RNA levels, these drugs have not been shown to have an effect on HBsAg levels. My colleagues and I, along with many others, have found an association between interferon (IFN)-based treatments and improved clinical outcomes among patients with HDV, including HBsAg declines in a proportion of patients. I suspect, even after full approval of novel agents, IFNs such as peginterferon-α (pegIFN-α) will continue to have an important role in HDV treatment.

Interferons for HDV Treatment
There are several limitations to pegIFN-α use for HDV. First, in contrast to hepatitis C virus (HCV), for HDV, the host or viral biomarkers that predict response to pegIFN-α treatment before or during treatment are poorly defined. The IL-28B polymorphism may be associated with responses to pegIFN-α treatment for HDV infection, but more data are needed to confirm this. 

Second, not all patients can tolerate IFNs because of contraindications, such as advanced or decompensated liver disease, and adverse events (AEs), including neutropenia, thrombocytopenia, and psychiatric complications. 

About PegIFN-λ  
PegIFN-λ (type III IFN), another IFN under investigation for HDV treatment, could be an alternative to pegIFN-α (type I IFN). Type III IFNs are mainly expressed on epithelial cells, so even though signaling pathways are similar to type I IFNs, an improved systemic AE profile is expected, similar to what has been shown with pegIFN-λ vs pegIFN-α and pegIFN-β in previous hepatitis B virus (HBV) and HCV trials.

Results From LIMT-1
And what about the efficacy of pegIFN-λ in HDV? In February 2023, the long-awaited results from LIMT-1, the open-label phase II study of pegIFN-λ for HDV treatment, were published by Etzion and colleagues. Study participants from Israel, Pakistan, and New Zealand received pegIFN-λ 120 µg (n = 19) or 180 µg (n = 14) for 48 weeks. 

Virologic and biochemical responses were as expected based on previous experiences with HBV and HCV infection. Among patients receiving the higher 180 µg dose of pegIFN-λ, one half had at least a 2 log10 decline in HDV RNA and more than one third had undetectable HDV RNA at Week 48. After 24 weeks post treatment, 23% of patients achieved a durable virologic response (36% in the 180-µg arm; 16% in the 120-µg arm). 

In addition, alanine aminotransferase normalization was seen 24 weeks after the end of treatment in 36% of participants in the 180-µg arm and 26% of participants in the 120-µg arm. No significant changes in HBsAg levels were observed.

Of more importance, pegIFN-λ was well tolerated with low frequencies of hematologic lab abnormalities and psychiatric-related AEs observed. Only 1 case of neutropenia was reported, which resolved after a reduction in study drug dose, and no cases of thrombocytopenia resulted. There was 1 case of mild depression that did not require any medication.

Eight patients discontinued the study drug because of AEs; in all cases, discontinuations were because of hyperbilirubinemia with or without liver enzyme elevations. Bilirubin levels returned to baseline by the end of the study in all but 1 patient. The exact reason for bilirubin increases remain unclear, but investigators hypothesized a “transporter-based mechanism rather than hepatotoxicity.” More data are needed to clarify the clinical relevance of this AE to determine whether it is benign and a reversible effect or a true safety concern.

Future Implications of PegIFN-λ  
Results from LIMT-1 are interesting and promising. I look forward to the results from LIMT-2, an ongoing open-label, randomized phase III trial further assessing the safety and efficacy of pegIFN-λ monotherapy for HDV treatment. It will be interesting to see if pegIFN-λ will have the same effect on HBsAg levels as pegIFN-α. Future trials will need to examine its effect on HBsAg levels in a larger portion of patients, as well as explore its use in combination with other therapies for improved response rates. 

In addition, biomarkers are needed to identify individuals with lower or higher chances to respond to pegIFN-λ treatment. Based on results from LIMT-1, more than one half of the patients had no benefit from pegIFN-λ. PegIFN-λ is expected to carry similar contraindications to its use as other IFNs. For these reasons, alternative HDV therapies are urgently needed, in particular for patients with advanced or decompensated liver disease. 

In the meantime, until other therapies can reduce HBsAg levels, I suspect IFN-based therapies will remain an important component of HDV treatment. 

Your Thoughts? 
What biomarkers do you use to evaluate treatment response to IFN-based therapies for HDV treatment? Join the discussion by posting a comment.