Last updated:
April 30, 2021
Years published: 2021
NORD gratefully acknowledges Robert J. Wong, MD, MS, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine and Veterans Affairs Palo Alto Healthcare System; Carol Brosgart, MD, Division of Global Health, University of California of San Francisco; Robert G. Gish, MD, Hepatitis B Foundation Medical Director, and the Hepatitis B Foundation for the preparation of this report.
Summary
Hepatitis D is a liver disease caused by the hepatitis delta virus (HDV). HDV is known as a “satellite virus” or an “incomplete virus” because it can only infect people who are also infected with the hepatitis B virus (HBV). Patients with an HDV infection may have an acute co-infection (an infection discovered at the same time as HBV) or a new or “superinfection” (when a patient already infected with HBV later acquires HDV). Both forms of infection can cause a chronic, long-term illness. Age of onset can occur at birth through mother to child transmission (rare), and more importantly, can occur through infection as an adult. Chronic HDV is one of the most severe forms of viral hepatitis (liver inflammation due to a viral infection) and causes more severe liver disease than having chronic HBV infection alone. Chronic HDV is also associated with a more accelerated progression of liver disease, a higher risk of liver cancer and early development of liver complications in patients who have already developed cirrhosis (end stage liver disease), liver failure, liver transplant, and death. An accurate prevalence of HDV is unknown given there is suboptimal awareness and testing for this disease both domestically and globally. However, recent studies estimate that the prevalence of HDV ranges from 12 to 74 million individuals affected worldwide, and it likely affects 5-10% of patients with chronic HBV infection. This emphasizes the need for further research and data in order to formulate an accurate estimate of HDV prevalence and to understand which individuals are at greatest risk of HDV infection. Despite the severity of this disease and how quickly it can lead to liver damage and deterioration, there are no current recommendations from the Centers for Disease Control (CDC) or World Health Organization (WHO) to make this a reportable disease, and there are no FDA-approved therapies available for HDV treatment. One medication called bulevirtide (Hepcludex, Myr/Gilead Sciences) is approved in Europe. In addition, there are many promising therapies for HDV on the horizon.
Introduction
One of the first physicians to describe HDV was Dr. Mario Rizzetto in the 1970s. Dr. Rizzetto detected a new antigen-antibody complex in the liver cell nuclei of patients with chronic HBV infection. Antigens are molecules capable of stimulating an immune response, and antibodies (immunoglobins) are Y-shaped proteins produced by B cells of the immune system in response to exposure to antigens. He used direct immunofluorescence (a technique for determining the location of an antigen/antibody in tissues by reaction with an antibody/antigen labeled with a fluorescent dye) to find this new antigen-antibody and he named this antigen delta. He observed that there was a higher prevalence of the delta antigen in chronic HBV patients with more severe liver damage. This delta antigen was ultimately confirmed by others and became what we know today as HDV. While the presence of HDV has been known for many years, the prevalence of HDV remains unclear, primarily due to suboptimal awareness and testing for this disease. There are many factors that contribute to suboptimal testing, including the need for wider availability of improved HDV diagnostic tests, the need for greater awareness of risks of this disease among patients and providers, more clear guidelines and recommendations about which populations to target for HDV testing, and lack of effective therapies to manage HDV. Given the aforementioned risks of HDV in contributing to more aggressive disease progression, including the higher risk of cirrhosis and liver cancer, early detection is critical. Emerging HDV therapeutics on the horizon should dramatically expand the treatment landscape in the future.
As previously noted, HDV can present as a co-infection or as a superinfection. Co-infection occurs when a person is simultaneously infected with both HBV and HDV, which is generally less common than superinfection. Superinfection occurs when a person who is already infected with HBV acquires HDV infection. Age of onset can vary from acquiring infection at birth via mother to child transmission to acquiring as an adult through different routes of infection detailed below.
HDV infection can occur and resolve suddenly (acute disease) or develop into a long-term illness (chronic disease). Signs and symptoms of acute HDV infection typically appear 3-7 weeks after initial infection and are indistinguishable from symptoms seen in other types of acute viral hepatitis infection. Some of these symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark-colored urine, clay-colored bowel movements, joint pain and jaundice. These symptoms can progress to liver failure and death in some instances or can resolve and develop into a chronic infection. Chronic HDV infection, on the other hand, accelerates disease progression in patients with chronic HBV, which leads to earlier development of cirrhosis, liver cancer and liver decompensation. A person with chronic HBV who acquires HDV infection has a very low chance of clearing the virus spontaneously, and over 80% of patients infected with HDV will develop chronic HDV infection as superinfection.
Hepatitis D is caused by the HDV, which is a unique virus with defective replication processes. Because it cannot replicate like other viruses, it requires co-infection with chronic HBV in order to survive and replicate. HDV is a single-stranded RNA virus and only codes for 2 proteins (HDV large and small antigen). As previously noted, it can present as simultaneous HBV-HDV co-infection or more commonly as a HDV superinfection in patients with underlying chronic HBV. HDV has 8 distinct genetic profiles (genotypes), each with 2-4 subtypes. Genotype 1 is the most prevalent worldwide and is seen predominantly in Europe and North America. Genotype 2 is seen more commonly in Asia and the Middle East. Genotype 3 is mostly seen in the Amazon Basin. Genotype 4 is seen in Taiwan, China, and Japan. Genotypes 5-8 are mostly seen in Africa, although some studies have reported presence of genotypes 5-7 in European regions with newer immigration patterns.
Existing studies vary in their estimates of global prevalence of HDV, estimating from 12 to 74 million, but many believe that the true prevalence is between 15 and 20 million. The variation in prevalence estimates is due to lack of high-quality data, which is further compounded by suboptimal awareness of testing, contributing to significant under-diagnosis of this disease. Existing studies estimate that prevalence of HDV in the US ranges from 100,000 to 150,000 individuals affected. While HDV is found globally, certain regions and countries have observed higher prevalence. For example, some of the highest reported prevalence has been observed in Mongolia, Somalia, the Punjab region of India and the Amazon Basin. HDV is mainly transmitted through activities that involve percutaneous contact (for example, a puncture through the skin) and to a lesser extent through mucosal contact (through the digestive, genital, and urinary tracts) with infectious blood or bodily fluids. Examples of potential routes of infection include: sexual contact with an infected individual; injection drug use that involves sharing needles, syringes or drug preparation equipment; contact with blood or open sores with blood from an infected person; needle sticks or exposures to sharp, contaminated instruments; sharing items such as razors or toothbrushes with an infected person; and mother to child via birth from an infected mother.
The detection and diagnosis of HDV is based on laboratory testing of blood samples. Recommendations from the American Association for the Study of Liver Diseases (AASLD) suggest testing for HDV with a total antibody test in patients with chronic HBV who are at high risk. One element of high risk is location, including individuals born in regions with high prevalence of viral hepatitis such as West Africa, the horn of Africa, Central and Northern Asia, Mongolia, Pakistan, Japan, Taiwan, Kiribati, Nauru, the Middle East region, Eastern Mediterranean regions, Turkey, the Amazon Basin and Greenland. Other high-risk individuals are persons who inject drugs, men who have sex with men, persons with HIV or hepatitis C co-infection, individuals at risk for sexually transmitted diseases and patients with elevated liver enzymes despite low HBV DNA levels. The Hepatitis B Foundation recommends testing for HDV in all HBsAg+ patients since risk based testing has been a failure and there are no peer reviewed references that support risk based testing will aid in viral hepatitis elimination.
Clinical Testing and Work-Up
Initial assessment for HDV includes laboratory testing of blood samples for anti-HDV total immunoglobulin G (IgG) and IgM antibodies. If anti-HDV total (including IgG) antibodies are detected, quantitative testing with polymerase chain reaction (PCR) should follow. The PCR test looks for evidence of active HDV infection, specifically HDV RNA, which provides evidence of active HDV replication that is present.
Given that all patients with HDV will have chronic HBV infection, a comprehensive assessment of HBV should already have been performed. This includes qualitative testing for hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe) and quantitative HBV DNA PCR, as well as quantitative testing for hepatitis B surface antigen, if available. All individuals should also be evaluated for immunity to hepatitis A virus, with a test that detects hepatitis A virus total antibody (includes IgG) antibodies. If negative, appropriate vaccination should be provided. All patients should also be tested for hepatitis C virus and HIV.
In order to track progression of disease, all individuals being evaluated for HDV infection should also have routine testing to establish a baseline and measure against that baseline over time. Evaluation of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, is needed. Liver function tests, including bilirubin (direct bilirubin), albumin, and prothrombin time (PT)/international normalized ratio (INR), should also be conducted. Platelet count should be included as an indirect assessment of portal hypertension, as that is an indication of cirrhosis. Assessment of liver scarring (hepatic fibrosis) should also be performed. This can be done in a number of ways: using non-invasive serology-based fibrosis prediction scores (such as fibrosis-4 {FIB-4} score), using an aspartate aminotransferase-to-platelet ratio index (APRI), using proprietary tests (such as Fibrosure) or enhanced liver fibrosis tests. Non-invasive imaging-based assessment of hepatic fibrosis can also be performed with options like Fibroscan transient elastography, ultrasound-based shear-wave elastography or magnetic resonance elastography. Given the availability of several non-invasive options of assessing hepatic fibrosis, liver biopsy is less commonly used for staging degree of hepatic fibrosis, but may still be useful when the diagnosis is not clear or to evaluate for other liver diseases that may also be present, such as nonalcoholic steatohepatitis (NASH) and alcohol associated liver disease (AALD).
Treatment
The goal of HDV treatment is to suppress HDV replication and normalize alanine aminotransferase levels, which helps reduce risks of disease progression, cirrhosis and liver cancer. While there are no currently FDA-approved therapies for the treatment of HDV, interferon-based therapies (which use signaling proteins to cause nearby cells to heighten their anti-viral defenses) have been used. Peginterferon-alfa-2a (PEGASYS) is the most commonly used interferon treatment for HDV. However, the effectiveness of this therapy is limited, with only approximately 40% of treated patients achieving undetectable HDV RNA at 24 weeks following completion of treatment. Follow-up data demonstrated that only 12% of treated patients have sustained suppression of HDV 4 years after treatment. Achieving suppression of HDV RNA is associated with greater likelihood of normalizing alanine aminotransferase. The European Medicines Agency (EMA) has approved bulevirtide (Hepcludex), an entry inhibitor, to treat HDV and is available in in multiple countries in the European Union and Russia. There is an urgent unmet need for newer and more effective therapies for HDV. Given that all HDV patients have underlying chronic HBV infection, treatment with HBV therapies should also be implemented to suppress HBV DNA
There are many investigational therapies under evaluation for the treatment of HDV. These different therapies focus on a variety of targets and include agents such as viral entry inhibitors, prenylation/farnesylation inhibitors, silencing or interfering RNA, nucleic acid polymers and interferons. One such agent, Hepcludex, is a viral entry inhibitor that was approved by the EMA in 2020 and is undergoing evaluation in the US and globally. Viral entry inhibitors work by blocking a virus from entering a cell, which is required for replication. Lonafarnib is a small molecule oral prenylation inhibitor that is also in advanced stages of testing. Prenylation inhibitors can disrupt the virus life cycle processes that are needed for survival and replication. In 2021, lonofarnib is undergoing phase 3 evaluation in the US.
Information on current clinical trials is posted on the Internet at https://www.clinicaltrials.gov. All studies receiving US government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: https://www.centerwatch.com/
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Journal Articles
Da BL, Rahman F, Lai WC, Kleiner DE, Heller T, Koh C. Risk factors for delta hepatitis in a North American cohort: Who should be screened? Am J Gastroenterol. 2021;116(1):206-209.
Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C, et al. The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis. J Hepatol. 2020;73(3):523-532.
Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis. 2020;221(10):1677-1687.
Chen H-Y, Shen D-T, Ji D-Z, Han P-C, Zhang W-M, Ma J-F, et al Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2019;68(3):512-521.
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