TABLE 2.
Currently employed and under development options for the treatment of HDV infection
| Name | Mechanism of action | Endpoint | Side effects | Duration of treatment | Status |
|---|---|---|---|---|---|
| PEG‐IFN‐α‐2a | Immune modulator; enhancement of innate immunity (induction of interferon‐stimulated genes) | Change from baseline in HDV viral load; normalisation of ALT | Flu‐like syndrome, myalgia, headache, fatigue, weight loss, depression, hair loss and local reactions at the site of injection. | Minimum 24–48 wk | Recommended by international guidelines; not approved by regulatory authorities |
| Nucleotide analogues a (entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide) | Inhibitors of HBV replication | HBV DNA undetectable | Gastrointestinal, nephropathy, Fanconi syndrome, osteomalacia, lactic acidosis | Long‐term | Approved by FDA and EMA for the treatment of HBV, no efficacy for HDV |
| PEG‐IFN‐λ | Immune modulator; enhancement of innate immunity (induction of interferon‐stimulated genes) | Change from baseline in HDV viral load; normalisation of ALT | Flu‐like symptoms, gastrointestinal, loss of appetite, back pain, dizziness, dry mouth, taste changes (milder than with PEG‐IFN‐α‐2a) | 48 wk | Phase 2 clinical trials; monotherapy or in combination with Lonafarnib or Ritonavir |
| Bulevirtide | Entry inhibitor | Change from baseline in HDV viral load | Raised levels of bile salts in the blood | 24 wk in studies, long‐term therapy (maintenance) | Conditional marketing authorisation by EMA; Phase 2 and 3 clinical trials with either Bulevertide alone or in combination with PEG‐IFN‐α‐2a |
| Lonafarnib | Prenylation inhibitor (assembly inhibitor) | Change from baseline in HDV viral load | Gastrointestinal | Not yet determined | Phase 2 and 3 clinical trials with Ritonavir/ PEG‐IFN‐α‐2a vs. with Ritonavir |
| Nucleic acid polymers | Multiple: attachment inhibitor, HBsAg release inhibitor, assembly inhibitor | Change from baseline in HDV viral load | None reported so far for REP 2139‐Ca and REP 21‐39‐Mg | 24 or 48 wk | Phase 2 clinical trials in combination with tenofovir disoproxil fumarate and PEG‐IFN‐α‐2a |
| siRNA a , b | Inhibitors of viral replication | HBsAg loss | Injection site reactions | Not yet determined | Phase 2 clinical trials for HBV monoinfection. Different siRNA’s are combined with nucleotide analogues +/− PEG‐IFN‐α‐2a or +/− capsid assembly modulators |
Abbreviations: ALT, alanine aminotransferase; EMA, European Medicine Agency; HBV, hepatitis B virus; HDV, hepatitis delta virus; HBsAg, hepatitis B virus surface antigen; wk, weeks.
a
Do not have a direct antiviral effect on HDV, but they reduce the formation rate of new HDV virions by inhibiting HBV replication and therefore limiting HBsAg availability.
b
siRNA have been studied so far only in clinical trials for HBV monoinfection, where they inhibit transcription from the cccDNA, therefore, reducing HBsAg production