In 1977, an Italian doctor named Mario Rizzetto discovered a new nuclear
antigen in the liver cells of patients infected with Hepatitis B Virus
(HBV). The antigen was thought to be a new protein encoded by HBV, and it
was labeled as the delta antigen. Subsequent research on chimpanzees,
however, indicated that this antigen was derived from a new virus, named
the Hepatitis Delta Virus (HDV).
HDV is the only virus in the genus, Deltaviridae. HDV is not classified
into a viral family because it is a unique virus dependent on
HBV. HDV is a co-infection of HBV. The envelope of HDV particles contains
the Hepatitis B surface antigen (HBsAg). The production and transmission
of HDV is entirely dependent on HBV to provide HBsAg. Thus, HDV is
considered a satellite virus of HBV. Unlike a classical satellite virus,
however, HDV does not share sequence similarity with HBV, and it can
replicate independently of HBV.
There are at least three HDV genotypes: I, II, and III. HDV isolates of
Genotype I have been reported in every part of the world, and the
pathogenesis of Genotype I infections varies from fulminant hepatitis to
asymptomatic chronic liver disease. The milder HDV II genotype is found
primarily in Asia, including Japan, Taiwan, and Russia. Some sequences
from Taiwan and the Okinawa islands have been assigned to a subtype of
Genotype II, called Genotype IIB. HDV genotype III has been isolated only
in northern South America (Peru, Venezuela, and Columbia) and is
associated with severe acute hepatitis. Furthermore, HDV genotype I is the
only genotype found in some locations, including Europe and North America.
Multiple genotypes have been detected in Africa and in Asia. Mixed
infections of genotypes I and II or II and IIb have been reported in
Taiwan. Furthermore, 15 of 22 recently characterized African sequences
formed new lineages and the other 7 are scattered within genotype I.
Therefore, recent work has indicated that the current classification of
HDV into only three genotypes is incomplete.
HDV consists of a single stranded, negative sense, circular RNA virus,
with an envelope made up of HBAg. Virions are 35-43 nm and are roughly
spherical, with no distinct nucleocapsid structure. The nucleocapsid is
made up of 60 large and small delta antigens. These are the only proteins
encoded by HDV. HDV relies on host cell machinery for replication, and the
viral genome (and antigenome) serves as ribozymes for self-ligation and
cleavage. Viral replication occurs in the nucleus of primary hepatocytes
using a double-rolling circle mechanism. New virions can be assembled only
in the presence of hepatitis B virus. The stages of the viral life cycle,
including replication, assembly, and transport, depend on the ratio of
small to large delta antigen.
Although variable, the clinical course of HDV is typically more severe
than that of the other hepatitis viruses. After an incubation period of
3-7 weeks, nonspecific clinical symptoms, including fatigue, lethargy,
nausea, and anorexia, begin and last for about 3-7 days. Viral replication
is usually diminished during this phase. Jaundice occurs in the next phase
of symptoms. Fatigue and nausea usually continue, and the serum bilirubin
level becomes abnormal. At the same time, the infected person may have
clay-colored stool and dark urine. This is evidence of the liver’s
diminished ability to excrete bilirubin.
Type D hepatitis should be considered in individuals who are HBsAg
positive or who have evidence of recent HBV infection. The diagnosis for
Hepatitis D infection is made following serologic tests for the virus.
Total anti-HDV antibodies are detected by radioimmunoassay (RIA) or enzyme
immunoassay (EIA) kits. To monitor ongoing HDV infection, reverse
transcriptase-polymerase chain reaction (RT-PCR) should be used. RT-PCR
can detect 10 to 100 copies of the HDV genome in infected blood serum.
Each of the markers of HDV infection, including IgM and IgG antibodies,
disappears within months after recovery. In chronic Hepatitis D infection,
on the other hand, HDV RNA, HDAg, IgM anti-HD antibodies, and IgG anti-HD
The outcome of disease depends on whether HDV is contracted as a
co-infection or a superinfection.
Co-infection: Co-infection occurs when both HDV and HBV are
simultaneously. This results in acute HDV and HBV infection. Depending on
the relative amounts of HBV and HDV, one or two episodes of hepatitis
occurs. Co-infections of HDV and HBV are usually acute and self-limiting
infections. HBV/HDV co-infections cause chronic HDV infections in less
than 5% of co-infected patients. Although clinical symptoms disappear,
fatigue and lethargy may persist for weeks or months.
Picture from CDC Website
Superinfection: Superinfection occurs when chronic HBV carriers are
infected with HDV. This leads to severe acute hepatitis and chronic
Hepatitis D infection in 80% of the cases. Superinfection is associated
with the fulminant form of viral hepatitis. Fulminant viral hepatitis, the
most severe form of acute disease, is about ten times more common in HDV
infections than in the other types. It is characterized by hepatic
encephalopathy that is manifested by changes in personality, disturbances
in sleep, confusion, difficulty concentrating, and sometimes abnormal
behavior and coma. The mortality rate of fulminant hepatitis is about 80%.
Chronic hepatitis D infection progresses to liver cirrhosis in about
60-70% of patients. Cirrhosis takes about 5-10 years to develop, but can
appear two years after the onset of infection. Hepatocellular carcinoma
occurs in chronically infected HDV patients with the same frequency as in
patients with ordinary HBV. Overall, the mortality rate for HDV infections
lies between 2% and 20%, values ten times greater than the mortality rates
Prevention of Hepatitis Delta Virus infection is based on prevention of
HBV, as HDV requires the surface antigen of HBV to cause infection. There
is no vaccine for HDV, but there is an effective vaccine for HBV. In order
to prevent HDV-HBV co-infection, the HBV vaccine or post exposure
prophylaxis (Hepatitis B Immune Globulin) can be used to prevent
infection. The only way to prevent HBV-HDV superinfection is to educate
chronic HBV carriers about transmission and risky behaviors. HDV can be
transmitted via blood exchange, sexual contact, sharing needles, and from
There is no specific treatment for HDV infections.
Immunosuppressive therapy has no positive clinical effect. Antiviral drugs, including
Acyclovir, Ribavirin, Lamivudine, and synthetic analogs of thymosin have
all proved ineffective. For infected patients, massive doses of
a-interferon have caused disease remission, but most patients remained
positive for HDV RNA whether or not there was improvement in disease
conditions. The effect of interferon therapy seems to be indirect, perhaps
via an effect on HBV or the immune response to the infection. Orthotopic
liver transplantation has proven useful for treating fulminant acute and
advanced chronic hepatitis D infections.
Hepatitis Delta Virus infections are found worldwide, but the
prevalence varies in different geographical areas. Anti-HDV
antibodies are found in 20-40% of HBsAg carriers in Africa,
the Middle East, and Southern Italy. HDV infection in the
United States is relatively uncommon, except in drug addicts
and hemophiliacs, who exhibit prevalence rates of 1-10%.
Homosexual men and health care workers are at high risk for
contracting HBV, but are surprisingly at low risk for HDV infection for
unclear reasons. Additionally, HDV infection is uncommon in
the large population of HBsAG carriers in Southeast Asia and
China. Additional high-risk groups for contracting HDV include
hemodialysis patients, sex contacts of infected individuals, and infants born to
infected mothers (rare). Worldwide, over 10 million people are infected
Fields, B. et al. Fields Virology. (2001) 4th Edition. Lippincott Williams
Hsu, S. et al. Interaction and Replication Activation of Genotype I and II
Hepatitis Delta Antigens. Journal of Virology. (Mar. 2004)
Kumar, V et al. Robbins & Cotran Pathologic Basis of Disease.
(2005) 7th edition. W.B. Saunders Company. =)
M M C Lai. The Molecular Biology of Hepatitis Delta Virus. Annual Review
of Biochemistry (1995) 64:259-86.
Radjef, Nadjia et al. Molecular Phylogenetic Analyses Indicate a Wide and
Radiation of African Hepatitis Delta Virus, Suggesting a
Deltavirus Genus of at Least Seven Major Clades. Journal of Virology.
(Mar 2004) 78(5):2537-2544.
Wang, Tzu-Chi et al. RNA Recombination of Hepatitis Delta Virus in
Natural Mixed-Genotype Infection and Transfected Cultured Cells. Journal
of Virology. (Feb 2005) 79(4):2221-2229.
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