Chronic hepatitis delta: A state-of-the-art review and new therapies

Abstract

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.

Keywords: Epidemiology; Hepatitis delta; Treatment.

Figure 1

World map illustrating the estimated prevalence of hepatitis D virus infection with genotypic distribution.

Figure 2

Structural representation of hepatitis B and delta viruses.

Figure 3

Hepatitis D virus viral life cycle and sites of investigative therapies. (1) Hepatitis D virus (HDV) virion attaches to the hepatocyte through interaction between HBsAg and NTCP; (2) HDV RNP is translocated to nucleus facilitated by HDAg; (3) HDV genome replication occurs via a “rolling cycle” mechanism; (4) HDV antigenome is transported out of the nucleus to the endoplasmic reticulum (ER); (5) HDV antigenome is translated in the ER into SHDAg and LHDAg; (6) SHDAg is transported into the nucleus; (7) SHDAg promotes HDV replication in the nucleus; (8) LHDAg undergoes prenylation prior to assembly; (9) LHDAg inhibits HDV replication in the nucleus; (10) New HDAg molecules are associated with new transcripts of genomic RNA to form new RNPs that are exported to the cytoplasm; (11) New HDV RNPs associate with HBsAg and assemble into HDV virions; and (12) Completed HDV virions are released from the hepatocyte via the trans-Golgi network.