Pathogenesis of and New Therapies for Hepatitis D

Abstract

Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease.

Keywords: Cancer; Drug Development; Epidemiology; HCC Risk.

Figure 1.. Map of the Prevalence of HDV Infection.

World map shows estimated prevalence of HDV infection and genotype distribution.

Figure 2.. HBV and HDV Structure

(A) The small delta antigen (SHDAg) and the large delta antigen (LHDAg) are each derived from the single expressed reading frame in the HDV genome. The SHDAg and LHDAg differ based on a specific RNA editing event, occurring during genome replication—this results in the addition of 19 amino acids to the SHDAg carboxyl terminus. (B) HBV and HDV share envelope proteins. HDV uses the envelope proteins of HBV for assembly and infection of new hepatocytes. Therefore, the presence of HBV infection is required for HDV infection and propagation in humans.

Figure 3.. HDV Life Cycle and Therapeutic Targets.

Myrcludex-B attempts was designed to block entry of HDV into hepatocytes (A). REP2055 and REP2139-Ca were designed to inhibit HBsAg secretion (B). Lonafarnib inhibits HDV prenylation, required for virus packaging and secretion (C).