The hepatitis D virus (HDV) is composed of an envelope of hepatitis B surface antigen (HBsAg), a genome of 1.7 kb and the only encoded protein, hepatitis delta antigen (HDAg) [1-4]. HDV is of negative polarity and the HDAg is encoded by the antigenomic strand of the virus. There are two molecular weight forms of HDAg. The large HDAg (L-HDAg) that has an additional 19-amino acid (aa) extension at the C terminus after editing of the antigenomic HDV RNA plays a key role in the assembly of HDV virions [2-4]. However; it inhibits HDV replication in a transdominant negative manner. The small HDAg (S-HDAg) transactivates the replication of HDV RNA [2,3]. The HDV is a defective virus. It can replicate by itself, through a double-rolling circle mechanism, but it needs the supply of HBsAg from its helper hepatitis B virus (HBV) to complete the assembly of HDV particles and the subsequent secretion and transmission [5,6].

Although HDV infection is not a common cause of infection except in high risk groups and certain areas, it is one of the important etiologies of fulminant hepatitis and may aggravate the clinical course of chronic HBV infection to cirrhosis and liver failure [7-12]. However, a subclinical course or relatively slow progression have been reported in some HDV infections [13-15]. The causes of varied clinical manifestations and outcomes of HDV infection are not yet completely clear. Host and viral factors may b oth play roles in the wide spectrum of HDV infection. Of viral factors, persistent replication of HDV and/or HBV is related to elevated alanine transaminase levels and progression of liver disease [14, 16]. HDV genotypes may also influence viral behaviors and subsequent disease courses [17-19].

Based on sequence comparison and phylogenetic analysis, HDV is classified into three genotypes by Casey [17]. HDV genotype I is the most widely spread and is found in patients with chronic active hepatitis or fulminant hepatitis in Europe, North America, Asia and Africa [17, 18, 20-24]. Genotype II HDV is found in East Asia including Japan, Taiwan, and Yukutia [18, 25-26]; this genotype is less often associated with fulminant hepatitis or rapid progression to cirrhosis or hepatocellular carcinoma (HCC) as compared to genotype I [18]. Genotype III HDV is prevalent in South America (Peru, Colombia and Venezuela), and is often found in patients with severe acute hepatitis [17, 27]. A novel HDV isolate discovered by Wu et al. was originally named genotype IIB because of its relatively close association with genotype II sequences [28]. This novel subtype maybe the result of recombination between genotype I and II [28,29]. Genotype IIB was later found to be a dominant genotype in Okinawa [30-32]. Recently, a molecular phylogenetic analysis of HDV sequences that included novel divergent isolates from Africa suggested at least seven major clades [32], and the original genotype IIb was re-classified as a new clade, HDV-4 [33]. The novel divergent isolates were further classified into additional new clades, HDV-5, -6, and 7, and 8 [33] (see also the chapter by P. Deny, this volume).

Taiwan is an area of endemic HBV infection. The prevalence of HBV carriers is around 15% in adults. Both genotype I and II HDV have been discovered in this area. In addition, genotype IIb (HDV-4) was also discovered in Taiwan. In this setting, the clinical manifestations and virological characteristics of both HDV genotypes could be compared in patients with similar ethnic backgrounds. In the following sections we will report on the epidemiology and transmission of genotype II HDV, and the functional and clinical significance of genotype II HDV infection will be compared to that of genotype I. Although a recent report reclassified genotype IIb as belonging to a separate phylogenetic clade [33], it is also included in this review because of its initial association with genotype II and because of its prevalence in parts of east Asia.

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