Hepatitis D virus is the most unusual of all hepatotropic viruses (Table 1).^10,11 It is essentially a defective virus that requires the simultaneous presence of HBV or other Hepadnaviridae to assist in viral replication and expression.^100,101,104 Slightly smaller than HBV, HDV has a hybrid structure that includes a 1,700-nucleotide, single-stranded RNA genome nonhomologous with the HBV genome, a nucleocapsid protein also bearing no sequence homology to any HBV proteins (the delta antigen), and an outer envelope of HBsAg indistinguishable from that of HBV. The replication strategy of HDV is similar to that of plant satellite viruses or viroids.^114,115 It is also the only virus in the satellite family known to infect animal species.^101,104 Viral replication is absolutely dependent on the helper function of HBV, and HDV infection does not outlast the duration of HBV infection.¹¹⁶

Transmission of HDV is thought to occur by person-to-person contact in areas where HDV is highly endemic, whereas it is thought to occur only through parenteral exposure to blood or body fluids in low-prevalence areas such as the US. Intravenous drug users and hemophiliacs have the greatest risk of HDV infection in the US. Transmission of HDV includes the following mechanisms: 1) direct percutaneous exposure to contaminated blood through the parenteral use of drugs or through a blood product transfusion, 2) horizontal, nonparenteral transmission of HBV among siblings (may play a major role in transmission between household members who are HBsAg carriers), 3) sexual contact, and 4) inapparent transmission through open skin lesions or environmental contamination.^{45,102,104,117} Perinatal transmission does not appear to be of great importance.^118,119

Clinical features. Hepatitis D infection usually carries some risk of increased severity of liver disease.^120–123 In a recently reported retrospective study in patients with compensated cirrhosis associated with HBV infection, the risk for HCC, decompensation, and mortality was increased by a factor of 3.2 (1.0 to 10), 2.2 (0.8 to 5.7), and 2.0 (0.7 to 5.7), respectively, for patients also positive for HDV.¹²⁴ Two patterns of HDV infection are recognized, depending on the initial HBV status of the host.^120,125,126 In patients simultaneously co-infected with HBV and HDV, the disease is self-limiting in the majority of cases (90%), with only 2% progressing to chronic infection. Fulminant hepatic failure (FHF) occurs in less than 10% of cases of co-infection.^120-123 The clinical course, however, may be quite different in HBV carriers subsequently infected with HDV. Termed "superinfection," 70% to 90% of cases result in chronic HDV carrier status, often with active liver disease. Fulminant hepatic failure can occur in 5% to 20% of cases of superinfection.^{121,127–129}