Hepatitis D: challenges in the estimation of true prevalence and laboratory diagnosis

Abstract

Hepatitis delta virus (HDV) is a defective single negative chain RNA virus, as its envelope protein synthesis is dependent on hepatitis B virus (HBV). Studies have consistently shown that coinfection of HBV and HDV is the most serious form of viral hepatitis, with accelerated progression to liver cirrhosis and hepatocellular carcinoma. About 74 million of HBV surface antigen (HBsAg) positive patients worldwide are also co-infected with HDV. Besides, patients with intravenous drug use and high-risk sexual behavior are at higher risk of HDV infection. Therapeutic schedules for HDV are limited, and relapse of HDV has been observed after treatment with pegylated interferon alpha. To reduce the transmission of HDV, all people infected with HBV should be screened for HDV. At present, several serological and molecular detection methods are widely used in the diagnosis of HDV. However, due to the lack of international standards diagnostic results from different laboratories are often not comparable. Therefore, the true prevalence of HDV is still unclear. In this manuscript, we have analyzed various factors influencing the estimation of HDV prevalence. We have also discussed about the advantages and disadvantages of currently available HDV laboratory diagnostic methods, in order to provide some ideas for improving the detection of HDV.

Keywords: Diagnostics; Hepatitis B; Hepatitis D; Hepatitis delta virus; Prevalence.

Fig. 1

HDV virion and nucleic acid structure diagram. A HDV virion has a ribonucleoprotein (RNP) complex inside and an HBV derived envelope outside. The RNP consists of the HDV genome and two isoforms of hepatitis D antigen (HDAg), L-HDAg and S-HDAg. B Structure of HDV RNA. Both genome and antigenome form an unbranched rod-like structure of 1700 bp containing a self-cleaving ribozyme (green boxs). The gray box represents HDAg ORF. Arrows on the RNA strands indicate the 5′–3′ direction. HDV hepatitis D virus; L-HDAg large hepatitis D antigen; S-HDAg small hepatitis D antigen

Fig. 2

Schematic representation of HDV life cycle. A HDV virion enters the hepatocyte via HSPGs and NTCP. B The virion loses its envelope and the RNP is imported into the nucleus of the cell. C Within the nucleolus, HDV RNA is replicated using a double rolling circle amplification to form the antigenomic RNA and more genomic RNA. D The mRNA is exported to the cytoplasm where it is translated at the endoplasmic reticulum (ER) to form HDAg. E HDAg return to the nucleus where the S-HDAg isoform promotes further genome replication. S-HDAg and L-HDAg bind to new transcripts of genomic RNA to form new RNPs. F RNPs are exported to the cytoplasm where L-HDAg facilitates association with HBsAg in the ER to assemble new virus particles. G They are then released out of the hepatocyte via the Golgi to infect neighboring cells. HDV hepatitis D virus; L-HDAg large hepatitis D antigen; S-HDAg small hepatitis D antigen; HBsAg hepatitis B surface antigen; RNP ribonucleoprotein; mRNA messenger RNA; NTCP sodium taurocholate cotransporting polypeptide; HSPGs heparan sulphate proteoglycans

Fig. 3

Serological patterns of HDV infection. A Coinfection is the simultaneous acute infection of HBV and HDV in a susceptible individual. Serum HDAg is detectable only transiently in blood specimens collected early at the onset of HDV, before the rising of antibodies. Anti-HDV IgM response is rapid and weak suggesting a resolution of infection. Anti-HDV IgG levels increased rapidly and persisted. B Superinfection is an HDV infection in an individual chronically infected with HBV. This pattern of infection has two components, the acute stage and the chronic stage. The acute phase is characterized by very high levels of HDV viremia and HDAg antigen in serum/liver. In the chronic period, HDV RNA, anti-HDV IgM and anti-HDV IgG persist. HDAg can be detected by liver biopsy. HDV hepatitis D virus; HBV hepatitis B virus; HDAg hepatitis D antigen; HBsAg hepatitis B surface antigen; Anti-HDV IgM immunoglobulin M antibody to the HDAg; Anti-HDV IgG immunoglobulin G antibody to the HDAg