Hepatitis D Virus

Picture From CDC Website

Aparna Chhibber and Melisa Shah
Fall 2005: Humans and Viruses
Professor Robert Siegel, Stanford University
Created November 24th, 2005

Introduction
Clinical Features
New Findings and Links
Pathogen Cards
- Aparna's
- Melisa's
References

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).

Classification

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.

Molecular Biology

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.

See the New Findings and Links for more details.

Clinical Features

Symptoms and Incubation

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.

Diagnosis

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 antibodies persist.

Outcomes

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 contracted 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 for HBV.

Picture from CDC Website

Prevention and Treatment

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 mother-to-child.

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.

Epidemiology

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 with HDV.
line

Picture from CDC Website

New Findings and Links

Pathogen Cards

Aparna's

1. Lymphocytic Choriomeningitis Virus
2. Human Adenovirus 2
3. Hepatitis D Virus (coming soon!)

Melisa's

1. Hepatitis B Virus
2. Human Adenovirus 7
3. O'nyong-nyong Virus

References

Fields, B. et al. Fields Virology. (2001) 4th Edition. Lippincott Williams & Wilkins.

Hsu, S. et al. Interaction and Replication Activation of Genotype I and II Hepatitis Delta Antigens. Journal of Virology. (Mar. 2004) 78(6):2693–2700.

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 Ancient 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.

Comments or Questions? Contact Aparna Chhibber (chhibber@stanford.edu) or Melisa Shah (melisa.shah@gmail.com)

Updated November 28, 2005