Hepatitis Delta Infection: A Clinical Review

Abstract

First discovered over 40 years ago, the hepatitis delta virus (HDV) is a unique RNA virus, requiring hepatitis B virus (HBV) antigens for its assembly, replication, and transmission. HBV and HDV can be acquired at the same time (coinfection) or HDV infection can occur in persons with chronic HBV (superinfection). Screening guidelines for HDV are inconsistent. While some guidelines recommend universal screening for all people with HBV, others recommend risk-based screening. Estimates of the global HDV prevalence range from 4.5 to 14.6% among persons with HBV; thus, there may be up to 72 million individuals with HDV worldwide. HDV is the most severe form of viral hepatitis. Compared to HBV monoinfection, HDV coinfection increases the risk of cirrhosis, hepatocellular carcinoma, hepatic decompensation, mortality, and necessity for liver transplant. Despite the severity of HDV, there are few treatment options. Pegylated interferon (off-label use) has long been the only available treatment, although bulevirtide is conditionally approved in some European countries. There are many potential treatments in development, but as yet, there are few effective and safe therapies for HDV infection. In conclusion, given the severity of HDV disease and the paucity of treatments, there is a great unmet need for HDV therapies.

Fig. 1

Global epidemiology of hepatitis delta virus and viral genotype.

Fig. 2

Structures of HBV and HDV. HDV is composed of an outer lipoprotein envelope, typically made of the three HBsAg subtypes (large, medium, and small). Inside is an inner ribonucleoprotein structure containing the single-stranded circular RNA HDV genome. The HDV genome encodes the DAg, which exists in two forms: small (S-DAg; 24 kDa, 195 amino acids) and large (L-DAg; 27 kDa, 214 amino acids). Ag, antigen; DAg, HDV antigen; ds, double stranded; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HDV, hepatitis delta virus.

Fig. 3.

Life cycle of HDV. ( 1 ) The HBsAg envelope of the HDV virion binds to the extracellular loop(s) of the sodium taurocholate cotransporting polypeptides (NTCP) receptor. This receptor, a transmembrane protein and the same receptor HBV uses for entry, mediates the transport of bile acids, removing them from circulation. ( 2 ) The binding with NTCP leads to endocytosis and thus the ribonucleoprotein (RNP) complex enters the hepatocyte cytoplasm. ( 3 ) This allows the HDV RNP complex to enter the nuclei of hepatocytes, where HDAg mRNA transcription and replication of HDV RNA occur. ( 4 ) L-HDAg is farnesylated by a cellular farnesyltransferase before being retranslocated to the nucleus. ( 5 ) S- and L-HDAg interact with the newly synthesized genomic RNA to form viral RNP that is exported to the cytoplasm. ( 6 ) Viral RNPs interact with the cytosolic part of HBsAg at the endoplasmic reticulum surface inducing their envelopment. ( 7 ) HDV virions are then secreted (modified from Sandmann and Cornberg, 2021 98 ). cccDNA, covalently closed circular DNA; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDV, hepatitis delta virus; hNTCP, human sodium taurocholate cotransporting polypeptide; L-HDAg, large hepatitis D antigen; S-HDAg, small HDAg.

Fig. 4

HDV therapies in development (modified from Sandmann and Cornberg, 2021 98 ). cccDNA, covalently closed circular DNA; EU, European Union; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDV, hepatitis delta virus; hNTCP, human sodium taurocholate cotransporting polypeptide; L-HDAg, large hepatitis D antigen.