2013年7月9日 星期二

Hepatitis D virus簡介，D肝病毒

D Is for Delta: A Primer on Hepatitis D Virus

Rowen K. Zetterman, MD

Jul 02, 2013

The Identification of Hepatitis D Virus

Hepatitis D virus (HDV) was identified in the 1970s in the hepatocyte nuclei of patients with chronic hepatitis B virus (HBV) disease.[1] HDV was observed in patients with more severe liver disease and was found only in patients infected with HBV. Initially thought to be a part of HBV, it was given the name "delta antigen" and was associated with development of a distinct anti-delta antibody. Delta antigen was subsequently determined to be an RNA virus covered by HBV surface antigens,[2] a distinct hepatotrophic virus occurring in patients in conjunction with HBV infection.

Hepatitis D Virology

HDV is an RNA virus circulating as a spherical particle with an RNA core and a capsid of small, medium, and large HBV envelope proteins (surface antigen).[3] HDV is composed of 1700 nucleotides in a single-stranded circular form[4] and is the only member of the deltavirus genus identified to date.

HDV is the smallest known animal virus and is a defective virus more related to plant viruses than to animal viruses.[5] It replicates only within the liver, where it encodes for a single protein, hepatitis D antigen (HDAg), which exists in 2 isoforms as small and large HDAg.[3] HDV does not require HBV proteins to replicate within a host cell, but uses host RNA polymerases and RNA-editing enzyme to complete its life cycle.[6] HDAg is the only protein expressed by the virus.

Eight genotypes of HDV have been identified[7]:

• Genotype 1 is distributed worldwide, including the Western Hemisphere;

• Genotype 2 is found in Eastern Asia and Russia;

• Genotype 3 is found in South America in the Amazon basin;

• Genotype 4 is largely found in Japan and China; and

• The remaining genotypes are present in Africa.

Patients with repeated exposure to HDV can have more than 1 circulating genotype. As a defective RNA virus requiring concurrent HBV infection to provide its virion coat of HBV envelope proteins, HDV infection will occur either as simultaneous coinfection with both viruses or as superinfection of a hepatitis B carrier from a person carrying both HBV and HDV.

Epidemiology of Hepatitis D Infection

HDV is endemic worldwide, and all age groups are affected.[8] Humans are the natural reservoir for HDV, with approximately 15,000,000 persons infected worldwide.[9] HDV is highly endemic in Eastern Europe, parts of Africa and the Middle East, and the Amazon basin, whereas prevalence is low in northern Europe and the United States.

The prevalence of HDV has been declining in the developed world,[10] possibly because of hepatitis B vaccination and improved public health standards, blood product screening, and HIV care. In the 1980s, HDV was found in 7% of HBV carriers without, and 24% of HBV carriers with, liver disease. By 1997, only 8% of HBV carriers with liver disease were found to be concurrently infected with HDV. Although the prevalence of HDV has fallen in some developed regions, increased immigration of people from highly endemic regions has resulted in the continuing presence of HDV in many countries.[11]

Onset and Clinical Course of Hepatitis D Infection

HDV infection always occurs in conjunction with HBV infection. Transmission is parenteral, and many infected individuals are intravenous drug users or recipients of multiple blood products. Associations with poor hygiene and intrafamilial spread have been noted. Perinatal transmission is uncommon. Although sexual transmission of HDV can occur, it is less likely than the transmission of HBV alone.

HDV infection has an incubation period of 28-140 days, with typical onset of symptoms at 3-7 weeks. The virus is not cytopathic, and hepatic injury is thought to be related to immune-mediated cytotoxicity of infected hepatocytes.[12] Viral load does not correlate with the abnormal aminotransferase levels of infected patients.

The spectrum of disease with HDV infection can range from asymptomatic infection to fulminant hepatitis.[13] Fulminant hepatitis is more likely with simultaneous coinfection with HBV and HDV than with HBV infection alone. The severity of clinical outcome may also vary on the basis of the genotypes of the infecting HBV and of HDV.[14] Chronic hepatitis from coinfection of HBV and HDV is uncommon and is more likely to develop from superinfection with HDV in an HBV-infected patient. Superinfection often results in histologically progressive disease, and as many as 80% of superinfected patients will develop cirrhosis in 5-10 years.[15] Chronically HDV/HBV-infected patients may also be at increased risk for hepatocellular carcinoma.[16]

Coinfection and Superinfection

Simultaneous HBV and HDV Infection

In the patient who is coinfected with HBV and HDV, clinical illness is usually moderate, but it can be severe with acute liver failure.[17] Fulminant hepatitis with coinfection is more likely than with infection with HBV alone.[18] Clinical illness may be biphasic, with 2 aminotransferase peaks -- first from HBV and then from HDV -- although a monophasic illness with a single peak of enzyme levels may also be observed. Coinfection is usually self-limited, and clearance of HBV results in clearance of HDV. Chronic HBV/HDV infection occurs in less than 5% of patients with coinfection.[19]

Infection With HDV After HBV

The patient with previous chronic HBV infection provides a potential milieu for superinfection with HDV after exposure to someone infected with both HBV and HDV. This may be observed as an acute flare of hepatitis and sometimes leads to initial discovery of the underlying HBV infection, with misidentification of the illness as acute HBV infection. Measurement of the IgM anti-HBc titer can assist in differentiating chronic from acute HBV disease; circulating titers are typically low (or negative) in chronic HBV carriers but high in patients with acute HBV infection. Testing for HDV should be considered in any patient with HBV who has an acute flare of hepatitis and risk factors for HDV infection.

Superinfection with HDV can be self-limited and result in clearance of both viruses, although this outcome is uncommon.[20] Most patients with superinfection develop a progressive form of chronic hepatitis.[20,21] Superinfection is often seen as a worsening clinical illness in a previously stable chronic carrier of HBV. Clinical illness with superinfection can be rapidly progressive,[22] leading to cirrhosis within 2 years in 10%-15% of patients.[13] The genotype of HBV may also play a role in the rapidity and severity of progressive disease.[23] HDV will suppress HBV replication in simultaneously infected patients.[24] Even HBV/HDV-infected patients with coexisting hepatitis C virus (HCV) infection will have reduced HCV replication.[25]

Diagnosis of Hepatitis D Infection

Because HDV infection requires the presence of HBV, documentation of HBsAg should be initiated if HBV/HDV coinfection is suspected. One or 2 peaks of aminotransferase levels may be observed with acute coinfection, and clearance of the viruses will result in a normalization of liver tests. Chronic HBV/HDV infection can be associated with continued elevation of aminotransferases. With superinfection, an acute illness from HDV may result in sudden elevation of aminotransferases or with progressive liver disease and abnormal liver tests.[26]

IgM anti-HDAg antibody develops with acute HDV infection, becoming positive 7-15 days after onset of clinical illness and waning with recovery and resolution of HDV infection. During acute infection, HDV RNA can also be detected by polymerase chain reaction. After clearance of HDV, IgG anti-HDAg becomes positive.

With chronic HBV/HDV infection, both serum IgM and IgG anti-HDAg can be present in conjunction with detectable circulating HDV RNA. HDV RNA testing can be variable, and false-negative results occur in actively infected patients. HDV RNA levels do not correlate with the severity of disease or with clinical outcomes.[27] HDV RNA may be most useful in following treatment outcomes rather than in supporting the clinical diagnosis of HDV infection.[28]

One third of European patients, and an even higher percentage of Asian patients, with chronic HBV/HDV infection are also simultaneously infected with HCV,[28] raising the question of whether US patients with chronic HBV/HDV infection should also be screened for HCV.

Treatment of Hepatitis D Infection

The current treatment of patients with HDV infection is limited[14] because HDV does not code for enzymes that are easily targeted by antiviral therapy. Treatment of HBV infection with nucleoside/nucleotide agents has not been helpful in clearance of HDV, but it can reduce the HBV load.

Current treatment regimens for HDV still use unapproved interferon-based, high-dose, long-term therapy for 48 weeks[29,30] with either interferon alpha, 5 million U/day, or pegylated interferon alpha, 9 million U 3 times weekly. These regimens can reduce aminotransferase levels and possibly improve survival,[31] although viral HDV RNA can persist. Prenylation inhibitors have been shown to be effective in initial animal studies for HDV.[32] A phase 2 trial of lonafarnib is being conducted by the National Institute of Diabetes and Digestive and Kidney Diseases in the United States.[33]

Successful immunization against HBV with subsequent immunity to HBV can prevent HDV infection. No specific HDV vaccine is yet available.

Transplantation for HDV Infection

After transplantation in a patient with chronic HBV/HDV infection and cirrhosis, passive immunoprophylaxis against HBV results in a rapid decline of circulating HDV RNA levels,[34] which parallels the reduction of circulating HBV. Circulating levels of both viruses are typically undetectable 5-6 days after transplantation, and clearance of both HBV and HDV is possible.[35] HDAg continues to be detectable in some transplant recipients by immunohistochemical staining of the liver in the absence of circulating HBV or HDV.[34]

The 5-year survival of patients who undergo transplantation for end-stage liver disease from HBV/HDV is similar to that of patients coinfected with HBV and HCV.[36] HBV recurrence after transplantation is less likely in patients who are simultaneously infected with HBV and HDV viruses than in those who undergo transplantation for HBV disease alone.[34]

Recommendation for Identification of HDV-Infected Patients

In summary, consider HDV testing in all chronic HBV carriers, especially those with a history of intravenous drug use or with stable HBV infection who develop an acute flare of hepatitis or a deteriorating clinical course, and in those who present with fulminant hepatitis from HBV. Patients in whom HDV infection is suspected should be screened with antibody tests for HDAg, and the diagnosis confirmed with measurement of HDV RNA when necessary.

References

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