The hepatitis delta virus (HDV) is distributed worldwide and related to the most severe form of viral hepatitis. HDV is a satellite RNA virus dependent on hepatitis B surface antigens to assemble its envelope and thus form new virions and propagate infection. HDV has a small 1.7？Kb genome making it the smallest known human virus. This deceivingly simple virus has unique biological features and many aspects of its life cycle remain elusive. The present review endeavors to gather the available information on HDV epidemiology and clinical features as well as HDV biology. 1. Introduction In 1977, a novel antigen was found in the nucleus of hepatocytes from patients with a more severe form of hepatitis B. It was first thought to be a previously unknown marker of hepatitis B virus (HBV). Only later, it was found that the then called delta antigen was not part of HBV but of a separate defective virus that requires the presence of HBV for infection. The newfound virus was designated hepatitis delta virus (HDV) and, by 1986, its RNA genome was cloned and sequenced (reviewed by [1]). This peculiar virus has been classified as the only member of the genus Deltavirus due to its uniqueness [2]. The HDV virion is a hybrid particle, composed of the delta antigen and HDV RNA enclosed by the surface antigens of HBV (HBsAgs). HDV has the smallest RNA genome of all known animal viruses. However, it is comparable, although larger, to viroid RNAs, pathogenic agents of higher plants. 2. Epidemiology HDV infection is distributed worldwide, although not uniformly, and it is estimated that 5% of HBsAgs carriers are also infected with HDV, which signifies that there might be between 15 and 20 million HDV-infected individuals [3]. This is a very rough number because it lacks data from areas where HBV is highly prevalent and HDV is poorly studied. HDV is highly endemic in Mediterranean countries, the Middle East, northern parts of South America, and Central Africa [4]. HDV also has high prevalence in Turkey [5], Central Asia [6], and the Amazonian region of Western Brazil [7]. In Southern Europe, HDV infection has been highly prevalent, with studies from the 1980s and 1990s showing that the incidence of HDV in HBsAgs positive individuals was higher than 20% [8]. With the implementation of HBV vaccination programs in the 1980s, HDV prevalence considerably decreased to 5–10% by the late 1990s [9]. However, in the beginning of the XXI century, the number of HDV-infected HBsAgs carriers in Europe increased to 8–12% [9, 10]. This increase has been attributed to immigration of
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