Hepatitis D

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Background

Hepatitis D virus (HDV) is an RNA virus that was discovered in 1977 and is structurally unrelated to the hepatitis A (HAV), hepatitis B (HBV), and hepatitis C (HCV) viruses. HDV causes a unique infection that requires the assistance of HBV viral particles to replicate and infect hepatocytes.[1, 2, 3, 4] Its clinical course is varied and ranges from acute, self-limited infection to acute, fulminant liver failure. Chronic liver infection can lead to end-stage liver disease and associated complications (including accelerated fibrosis, liver decompensation, and hepatocellular carcinoma).[5, 6, 7, 8, 9]

There are three known genotypes of HDV. Genotype 1 has a worldwide distribution; genotype 2 exists in Taiwan, Japan, and northern Asia; and genotype 3 is found in South America.

Simultaneous coinfection with HBV and HDV occurs in 5-15% of those with HBV[8, 10] and results in fulminant liver failure in 1% of patients. HBV-HDV coinfection is the most aggressive form of viral hepatitis.[8, 11, 12] Complete clinical recovery and clearance of HBV and HDV coinfection is the most common outcome. (See Prognosis and Workup.)

Infection with HDV in a patient who is already positive for the hepatitis B surface antigen (HBsAg) is known as superinfection and results in fulminant liver failure in 5% of patients. Approximately 80-90% develop chronic HDV infection. These patients progress more rapidly to develop cirrhosis and may develop hepatocellular carcinoma. (See Workup.)

A study from The Netherlands suggested that HDV may hinder the control of HBV. Xiridou et al used a mathematical model for the transmission of both viruses and calculated the reproduction numbers of single HBV infections and dual HBV/HDV infections.[3] The investigators looked at the endemic prevalence of both viruses and found that HDV modulates HBV epidemic severity and also hampers the impact on HBV interventions. Xiridou et al concluded that in endemic populations with HDV, control programs that ignore HDV presence may lead to an underestimation of the HBV epidemic and an overestimation of positive results, as control of HBV is dependent on the reproduction numbers of dual HBV/HDV infections.[3] (See Epidemiology.)

See the following topics for more information:

Etiology

Hepatitis D virus (HDV) infection is an acute and chronic inflammatory process involving the liver. HDV is transmitted parenterally; it can replicate independently within the hepatocyte, but it requires hepatitis B surface antigen (HBsAg) for propagation. Hepatic cell death may occur due to the direct cytotoxic effect of HDV or via a host-mediated immune response.

Risk factors include intravenous drug use and multiple blood transfusions.

Sexual transmission is less efficient than with hepatitis B virus (HBV).

Perinatal transmission is rare; no such cases have been reported in the United States.

Epidemiology

In the United States, hepatitis D virus (HDV) infection is observed more commonly among patients with a history of intravenous drug use and in persons from the Mediterranean basin.

Initial studies estimated approximately 15-20 million people are coinfected with HDV and HBV worldwide.[13, 10] More recent studies suggest that the global prevalence of HDV is probably two to three times higher than previously estimated.[10] Areas with the highest HDV prevalence include southern Italy; North Africa; the Middle East; the Amazon Basin[14] ; and the American South Pacific islands of Samoa, Hauru, and Hiue. China, Japan, Taiwan, and Myanmar (formerly Burma) have a high prevalence of HBV infection but a low rate of HDV infection.[15, 16]

A 2017 case-control study from Northern Spain (1983-2012) that evaluated the prevalence and epidemiology of HDV infection among those infected with HBV found an 8.2% prevalence of anti-HDV.[17] In the analysis of patients grouped into years 1983-1997 (group A) and 1998-2012 (group B), the investigators noted that the prevalence of anti-HDV fell from 9.4% in the first group to 6.1% in the second group. Moreover, independent risk factors related to the presence of anti-HDV differed between the two groups, with intravenous drug use (IVDA), blood transfusion, and high alanine aminotransferase (ALT) levels affecting the earlier group, whereas immigration, IVDA, promiscuous sexual activity, and elevated ALT levels predominantly affected the latter group.[17]

HDV infection is more common in adults than in children. However, children from underdeveloped, HDV-endemic countries are more likely to contract HDV infection through breaks in the skin, due to the presence of skin lesions.

Prognosis

The prognosis is excellent for patients with coinfection in whom treatment eradicates both viruses.

The prognosis is variable for patients who are superinfected. It depends on the duration and severity of hepatitis B virus (HBV) infection, alcohol consumption, comorbid illnesses, and age.

In patients who undergo liver transplantation for chronic liver disease secondary to HBV and hepatitis D virus (HDV) infections, HDV seems to suppress the replication of HBV in the transplanted liver and may help to prolong graft survival. However, fulminant hepatitis from recurrent HBV and HDV infection in the transplanted liver has resulted in patient death or the need to retransplant.

HBV-HDV superinfection significantly increases adult morbidity and mortality.[18] In a 2017 nationwide study that evaluated risk factors associated with chronic HBV infection in France (2008-2013), investigators noted that coinfection with HDV or HCV, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease all increased the risk of all-cause mortality, particularly following progression of liver disease.[11]

Complications

Complications of HDV infection may include the following:

Patient Education

Educate patients regarding modification of high-risk behaviors, including intravenous drug use and unsafe sexual practices.

Promote the use of universal precautions for health care workers.

Discuss with patients with chronic hepatitis D virus (HDV) and hepatitis B virus (HBV) infections that they should not donate blood, share toothbrushes or razors, or consume alcohol. Precautions should be observed regarding blood and body fluids.

History and Physical Examination

Hepatitis D virus (HDV) infection is clinically indistinguishable from other forms of viral hepatitis.

As many as 90% of patients are asymptomatic.

The incubation period is 21-45 days but may be shorter in cases of superinfection.

Signs/symptoms include the following:

Signs/symptoms upon presentation include the following:

Laboratory Studies

The following serum test results are present in patients with coinfection with hepatitis D virus (HDV) and hepatitis B virus (HBV):

Hepatitis B surface antigen (HBsAg) is required for HDV replication but may be suppressed to undetectable levels with active HDV replication.

A potentially useful, semi-automated screening assay for identifying HDV host cell requirements and antiviral targets is under investigation.[20] It consists of a Huh-7/hNTCP cell culture–based system in a 96-well plate format, an automated microscope, and image acquisition in conjunction with CellProfiler software analysis to quantify the impact of different drugs on HDV infection (marked toxicity). Investigators found that interferons alpha-2a and beta-1a were inhibitory. When 160 human kinase inhibitors comprising all parts of the human kinome were evaluated, those that targeted the tyrosine kinase-like group had significant average anti-HDV activity, of which kenpaullone had the highest selective index.[20]

Imaging Studies

Right upper quadrant ultrasonography helps in the evaluation of biliary obstruction and hepatocellular carcinoma.

Perform cholescintigraphy (hydroxy iminodiacetic acid) to exclude acute cholecystitis, if clinically indicated.

Perform computed tomography (CT) scanning or magnetic resonance imaging (MRI) if hepatocellular carcinoma is suspected. (An alpha-fetoprotein [AFP] level greater than 250 ng/mL is highly suggestive of hepatocellular carcinoma [HCC].)

Histologic Findings

Results from liver biopsy in patients with acute disease are consistent with acute hepatitis, and, generally, a biopsy is not indicated. Consider liver biopsy if the serologic diagnosis of hepatitis is inconclusive.

In patients with chronic liver disease, liver biopsy is indicated to evaluate for the presence of fibrosis and cirrhosis.

HDV antigen immunohistochemical analysis of liver tissue is the criterion standard for establishing a diagnosis of persistent HDV infection.

Histologic features are very similar to those observed in patients with HBV infection. Acidophilic bodies and degeneration of hepatocytes with acidophilic cytoplasm are present. The few inflammatory cells (lymphocytes) likely represent the direct cytotoxicity of HDV. Results of immunohistochemical staining for HDV antigen are positive. With superinfection, staining often reveals that HBsAg is suppressed.

Approach Considerations

Treatment for infection with hepatitis D virus (HDV) consists primarily of supportive measures (in part owing to the fact that HDV is very host dependent and absent of potentially drugable enzyme in its genome[20] ). Observe synthetic liver function markers and mental status closely. Deterioration of either should prompt early consultation with hospital personnel capable of performing liver transplantation.

Liver transplantation is indicated in patients with fulminant liver failure. Patients with evidence of decompensated liver disease or fulminant liver failure should be immediately transferred to a center capable of performing a liver transplantation.

No pharmacologic treatment for HDV has been approved. Peginterferon alfa-2a (PEG-IFNa2a) and nucelos(t)ide analogues have been used to manage chronic HBV infection, but only PEG-IFN has shown anti-HDV activity.[8, 21, 22] However, a study of the efficacy of PEG-IFNa2a found that treatment with or without adefovir over 48 weeks resulted in sustained HDV RNA clearance in approximately one fourth of patients.[23] In another study, PEG-IFN achieved sustained viral response (SVR) and remission in only 29.4% of patients.[24] Thus, PEG-IFN2a has low rates of SVR and clinical improvement.[22] The efficacy rate of interferon-based therapy does not exceed 30%, with frequent termination of therapy owing to serious side effects, and the relapse rate is very high.[8]

Potential new therapies remain under investigation, including prenylation inhibitors (against HDV only), as well as viral entry inhibitors and HBsAg-release inhibitors (against HDV and hepatitis B virus [HBV] coinfection)[8, 25, 26]

Early notification of a hepatologist or gastroenterologist is warranted.

No vaccine is available for HDV, but the HBV vaccination is effective against HDV.

See the following articles for more information:

Diet

Diet need not be restricted. If enteral intake is poor, intravenous fluids can be administered. Total parental nutrition is seldom needed.

Prevention

Cost-effective, optimal strategies to reduce the prevalence of hepatitis B virus (HBV) in moderately endemic hepatitis D virus (HDV) regions include the implementation of all four of the following interventions[18] :

Long-Term Monitoring

Follow-up is recommended for at least 6 months to determine if chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) infection develop.

Perform a liver biopsy to stage liver disease prior to beginning interferon alfa therapy.

Treatment with interferon can be continued after the 1-year period if well tolerated and efficacy is demonstrated. Monitoring HDV RNA and hepatitis B surface antigen (HBsAg) levels may help in guiding therapy.[27]

Medication Summary

Antiviral therapy with interferon alfa can be considered in patients with chronic hepatitis D virus (HDV) infection. The treatment course is usually at least 1 year. Treating children with interferon alfa seems to be safe but is relatively ineffective. Treatment is not needed for patients with coinfection, given the high spontaneous clearance rates. Lamivudine, ribavirin, and corticosteroids have not been effective in treatment.

Interferon alfa-2a (Roferon)

Clinical Context:  Interferon alfa-2a has been used in several small studies to treat hepatitis D virus (HDV) infection. Dosages varying from 3-10 mU 3 times per week for as long as 12 months have been used. At the end of therapy, loss of HDV RNA and normalization of liver enzymes was seen in 50% of patients treated with 9 mU 3 times per week and in 21% in those treated with 3 mU. Half the responders remained in biochemical remission after the cessation of therapy, while no patients maintained a virologic response after cessation. Histologic improvement was observed in patients treated with interferon.

Class Summary

These are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions.

Author

Praveen K Roy, MD, AGAF, Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Rahaman Mujibur, MD, Academic Hospitalist/Hospitalist, Marshfield Clinic, St Joseph’s Hospital

Disclosure: Nothing to disclose.

Rajan Kanth, MD, Gastroenterologist, WellSpan Health

Disclosure: Nothing to disclose.

Sean R Lacey, MD, Associate Professor of Gastroenterology, Pennsylvania State University College of Medicine; Staff Physician, Division of Gastroenterology, Lehigh Valley Hospital and St Luke's Hospital

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

David Eric Bernstein, MD Director of Hepatology, North Shore University Hospital; Professor of Clinical Medicine, Albert Einstein College of Medicine

David Eric Bernstein, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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