Hepatitis delta: virological and clinical aspects

Abstract

There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels.

Keywords: Clinical aspects; HDV; Virology.

Fig. 1

Schematic representation of HDV. The Hepatitis D virus wrapped in the HBV surface antigen. Outer HBsAg in black. With L (preS1 or large), M (preS2 or middle) and S (small) peripheral distribution of the three surface proteins. In the central portion, HDAg (HDAg-S and HDAg-L) is represented in blue and single-stranded RNA in red

Fig. 2

HDV RNA editing mechanism. Genomic RNA (gray rounded rectangle) serves as a template for mRNA synthesis which is translated into HDAg-S, which is necessary for synthesis of new RNAs. The genome serves as a template for the synthesis of the antigenome (rounded black rectangle), which also serves as a template for new genomic RNAs. A fraction of antigenomic RNAs are edited by the enzyme adenosine deaminase (ADAR-1) at the UAG site (stop codon), also called the Amber/W site (wavy and dotted arrow), wherein an adenine is replaced by inosine. The edited antigenomes serve as templates for the edited genomes (rounded rectangle edited for ACC). Edited genomes serve to synthesize edited messenger RNAs (with UGG – Tryptophan instead of UAG-stop codon) encoding HDAg-L, which is the key factor for enveloping the virus and inhibiting replication. The edited genome and antigenomes are simultaneously synthesized by a replication mechanism called rolling-circle. This way the editing levels accumulate replication products. Note that the numbering scheme is intended to indicate an increasing repertoire of activities that persist as replication occurs, rather than a gradual progression in which the above processes are terminated. (Source: [28]. Curr Top MicrobiolImmunol, our translation, modified)

Fig. 3

Structures of the two types of Delta antigen. (Source: [14], Journal of Virology, modified)

Fig. 4

Schematic representation of HDV RNAs. Antigenome and genome of approximately 1700 nucleotides in a circular conformation (black). HDAg-S with 195 amino acids (orange) and HDAg-L with 214 amino acids (orange + blue). Negative polarity, the genome has an inverse orientation from the messenger RNA

Fig. 5

Replication and assembly cycle diagram. (1) The virion adheres to the hepatocytes via an interaction between HbsAg-L and a membrane receptor that has not yet been characterized, in the host cell, (2) the virion enters the cell and loses its envelope. (3) The ribonucleoprotein (HDV RNA complexed to HDAg) is imported into the nucleus of the cell, (4) the genomic RNA is transcribed in the nucleus into mRNA and antigenomic RNA, which in turn serves as a template for new RNA genomic transcripts. (5) The mRNA is exported to the cytoplasm where it is translated into HDAg-S in the endoplasmic reticulum, (6) the new HDAg-S molecules return to the cell nucleus to support the replication of more RNA. The two forms of HDAg associate themselves with the new genomic RNA to form new ribonucleoproteins, (7) which are exported to the cytoplasm where they will interact with HBV envelope proteins through HDAg-L in the endoplasmic reticulum to form new viral particles. (8) These particles by budding in an intermediate compartment (9) are exported from the hepatocyte via the trans-Golgi network to re-infect new cells. (Source: [20], Lancet, modified)

Fig. 6

Schematic representation of the clinical course of hepatitis Delta

Fig. 7

Fluxogram for the diagnosis of hepatitis Delta