HDV, the smallest viral pathogen infecting humans, has biologic features similar to those of the viroids of plants.⁴ It belongs to the genus deltavirus within the family of Kolmioviridae.⁵ Eight genotypes with 81 to 89% sequence homology and many subgenotypes have been identified.⁶ Genotype 1, the most widely distributed, predominates in Europe and North America. Genotype 3, present only in the Amazon basin, has been associated with outbreaks of fulminant hepatitis D,³ whereas genotype 5, present in Africa, is associated with a more benign disease and has a better response to interferon than does the ubiquitous genotype 1.⁷

The genome is a circular, single-stranded RNA of approximately 1700 nucleotides. It is too small to code for replicative enzymes or envelope proteins and codes only for a small, nonenzymatic protein, hepatitis delta antigen (HDAg).⁸ Three HDV RNA species are found in humans: a 1.7-kb genomic RNA in the virions, a complementary antigenomic RNA of positive polarity and the same size in the liver, and a 0.8-kb messenger RNA (mRNA) of antigenomic polarity in the liver; the mRNA contains an open reading frame for translation of HDAg. The genomic and antigenomic RNAs contain a domain of approximately 100 nucleotides that acts as a ribozyme, cleaving the viral RNA at specific sites without the participation of viral encoded enzymes.⁹ Although in natural infections, intrahepatic HDV RNA replicates without assistance from HBV, HDV relies on HBV for all other functions of its life cycle, including viral packaging, infectivity, transmission, and inhibition of host immunity.^2,8-12