Background
Hepatitis D virus (HDV) is an RNA virus that causes a unique infection that requires the assistance of hepatitis B virus (HBV) particles to replicate and infect hepatocytes. [1, 2, 3, 4, 5, 6] HDV is structurally unrelated to the hepatitis A (HAV), HBV, and hepatitis C (HCV) viruses.
The clinical course of HDV 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). [7, 8, 9, 10, 11, 12]
There are eight known genotypes of HDV. Genotype 1 has a worldwide distribution, with predominance in Europe, the Middle East, United States, and North Africa; genotype 2 exists in Southeast and East Asia and Eastern Europe; genotype 3 is found in South America; genotype 4 is found in the Far East (Japan, China); and genotypes 5-8 are found in Africa. [13, 14]
Simultaneous coinfection with HBV and HDV occurs in 5-15% of those with HBV [10, 15, 16, 17] and results in fulminant liver failure in 1% of patients. HBV-HDV coinfection is the most aggressive form of viral hepatitis. [1, 2, 10, 16, 18, 19] Complete clinical recovery and clearance of HBV and HDV coinfection is the most common outcome.
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.
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. [5] 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. [5]
Etiology
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 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 (IVDU) and multiple blood transfusions. A study of 652 North American patients infected with HBV found 91 with concurrent HDV infection; independent risk factors for HDV included the following [20] :
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IVDU
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HBV-DNA measured below 2000 IU/mL
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ALT level above 40 U/L
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HDV endemicity at the country of origin
Sexual transmission is less efficient than with HBV.
Perinatal HDV transmission is considered to be rare and has not been reported in the United States.
Epidemiology
United States data
Infection with HDV is not a nationally notifiable condition and therefore is not tracked in the United States. Consequently, data regarding specific numbers of HDV cases are limited. [2, 16, 21]
Widespread vaccination against hepatitis B in developed nations has helped to reduce the incidence of HDV infection. [12] In the United States, HDV infection is observed more commonly among patients with a history of IVDU and in persons from the Mediterranean basin. Although the actual US prevalence of HDV is not known, a 2025 study by Stark et al found a 1.2% prevalence of HBV-positive samples, [16] and the American Gastroenterological Association estimates about 30,000-60,000 Americans have active HDV infection. [2]
International data
Earlier studies estimated approximately 15-20 million people worldwide are coinfected with HDV and HBV. [15, 22] More recent studies suggest that the global prevalence of HDV is probably double or triple than previously estimated. [15] Indeed, 12-72 million people may have HDV infection globally. [17, 23]
An Italian study estimated a 0.019% prevalence of chronic HDV in the adult population (n = 9360) in 2024, relative to a 0.22% prevalence of chronic HBV infection (n = 111,960). [24] Another study found a 6.3% prevalence of HDV infection in France (n = 364). [25] In Nigeria, the prevalence ranges from 2.0 to 31.6%, with the southwest region having the highest prevalence, whereas the southeast had the lowest. [26]
Areas with the highest HDV prevalence include regions with high migration of populations from HDV-endemic countries and less wealthy nations, [12] as well as southern Italy; North Africa; the Middle East; the Amazon Basin [27] ; and the American South Pacific islands of Samoa, Hauru, and Hiue. Although China, Japan, Taiwan, and Myanmar (formerly Burma) have a high prevalence of HBV infection, they generally have a low rate of HDV infection. [28, 29]
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 typically in over 90% of cases. [23] The prognosis is variable for patients who are superinfected (HDV infection in the setting of existing chronic HBV infection), but up to 80% of cases result in chronic HDV infection and more clinically severe disease. [23] Some individuals may have mild HDV infection; it depends on the duration and severity of HBV infection, alcohol consumption, comorbid illnesses, and age.
In patients who undergo liver transplantation for chronic liver disease secondary to HBV and 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 infections in the transplanted liver has resulted in patient death or the need to retransplant.
HBV-HDV superinfection significantly increases adult morbidity and mortality. [1, 2, 23, 30] Coinfection with HDV or HCV, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease all appear to increase the risk of all-cause mortality, particularly following progression of liver disease. [18] Chronic HDV infection is linked to an elevated risk of progression to cirrhosis, hepatic failure, and hepatocellular carcinoma compared with people infected with HBV alone. [2, 17] [23]
Although limited data exist regarding HDV infection in pregnancy, it is generally considered to be well tolerated albeit linked to more severe hepatic disease (progression to cirrhosis within 5 years and hepatocellular carcinoma within a decade). [21]
Complications
Complications of HDV infection may include the following:
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Liver failure
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Hepatocellular carcinoma
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Autoimmune manifestations, often including antinuclear antibodies and smooth muscle antibodies
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.
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Algorithm for the evaluation of chronic hepatitis D. Courtesy of Gastroenterology Report (Shah PA, Choudhry S, Reyes KJC, Lau DTY. An update on the management of chronic hepatitis D. Gastroenterol Rep (Oxf). 2019 Oct 19;7(6):396-402. PMID: 32494363; PMCID: PMC7249531).
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Algorithm for the treatment of chronic hepatitis D. Courtesy of Gastroenterology Report (Shah PA, Choudhry S, Reyes KJC, Lau DTY. An update on the management of chronic hepatitis D. Gastroenterol Rep (Oxf). 2019 Oct 19;7(6):396-402. PMID: 32494363; PMCID: PMC7249531).
