Hepatitis D

Hepatitis D, also called hepatitis delta, affects 15 to 20 million patients worldwide and is the most deadly of all forms of hepatitis.

Chronic hepatitis D infection (HDV) affects between 15 to 20 million patients worldwide. (For comparison, 35 millions patients are affected with HIV.) The natural evolution of the disease is that 80% of untreated patients with HDV will develop cirrhosis within 10 years of becoming infected. The only treatment that has shown any degree of efficacy is interferon. Unfortunately, it has been shown that long term administration of interferon can only prevent or delay the progression to liver cirrhosis, and rarely cures the disease. In most cases where interferon has some initial impact, the HDV infection will return within 2 to 6 months after interferon therapy is stopped. This is important to know because most patients will not tolerate the side effects associated with long term administration of interferon over years when the chance for a cure is so low. In addition, the cost of interferon for an extended period of time is hard to justify in the absence of a significant probability of cure. There is therefore a clear and urgent need to develop new effective therapies for this condition.

HDV infection is always associated with chronic hepatitis B infection (HBV) since the HDV virus needs the surface membrane proteins of the HBV virus (HBsAg) to complete the formation of the HDV virus.

HDV

Source: ViralZone

The requirement for the presence of HBV surface antigen (HBsAg), explains why HDV cannot exist without HBV and why patients immunized against HBV are also protected against HDV. It also explains why polymerase inhibitors used against HBV are useless in HDV infections since they can only lower titers of HBV virions but have no impact on the levels of HBsAg produced in infected cells.

NAPs have the potential to be effective against HBV / HDV co-infection.

HBsAg is an abundant viral protein found in the blood of patients with chronic hepatitis B or chronic hepatitis B / hepatitis D co-infection which has been shown to have important immuno-inhibitory activities in multiple peer-reviewed papers and is a major factor responsible for the chronicity of these infections. HBsAg interferes with many aspects of the immune response targeting both innate and adaptive immunity. See: Hepatitis B

An important part of the life cycle of the HDV virus is that it uses HBsAg (obtained from HBV) on its surface for cell entry into hepatocytes the same way than the HBV virus enters cells. The HBsAg present on the surface of the HDV virus can be targeted by anti-HBs to help remove the virus from the circulation and specifically block the entry of the virus into hepatocytes. This would prevent the replenishment of the virus in the hepatocyte over time and should lower viral HDV titers in the blood. Patients with HBV infections treated with NAPs and interferon have been able to generate high antibodies titers (see Science / HBV) that could effectively block HDV entry into hepatocytes and directly reduce HDV blood titers.

It is expected that the persistence of HBsAg in patients with chronic HDV infection prevents an optimal response to interferon like is the case for patients with chronic HBV infection. The removal of HBsAg with NAPs could therefore result in a significant improvement in the response to interferon for these patients.

In addition to the positive impact of HBsAg removal, NAPs have been shown to block the entry of duck HBV virus into primary hepatocytes by virtue of their chemical similarity to sulfated polysaccharides like heparin sulfate (Noordeen et al., 2013 AAC 57: 5291-5298) and as such will also be expected to block the entry of HDV as well because HDV uses the same entry mechanism as HBV.

Based on Replicor’s understanding of the life cycle and pathogenesis of the hepatitis D virus and Replicor’s understanding of the mechanisms of action of Replicor’s drug, Replicor expects that NAPs could also be effective in treating hepatitis D. Replicor is currently evaluating the activity of REP 2139 against HBV/HDV co-infection in an ongoing Phase II clinical trial NCTO2233075.

Preliminary data on this clinical trial was presented at EASL ILC 2015. Click here for the presentation.