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Hepatitis D virus (HDV) is a unique pathogen that requires the presence of hepatitis B virus (HBV) for its replication and spread. HDV uses the HBV surface antigen as its envelope protein, making it dependent on the coinfection or superinfection with HBV to cause disease. Clinically, HDV infection can lead to more severe liver disease than HBV alone. In acute HBV-HDV superinfection, patients may experience a biphasic course with 2 distinct peaks in serum alanine aminotransferase, reflecting the sequential spread of HBV and HDV. Chronic infection with both viruses can result in faster progression to cirrhosis and liver failure. HDV also has the unique characteristic of suppressing HBV replication, although the mechanism remains unknown. Timely serological testing is crucial for identifying HDV infection in patients with HBV, as this coinfection requires specific management approaches. Participants in this course gain a comprehensive understanding of HDV, including its dependence on HBV for transmission, the clinical presentation of coinfection, and the associated complications. They learn how to evaluate patients with suspected HDV by conducting appropriate serological tests and recognize the importance of early diagnosis in improving outcomes. The course emphasizes the role of an interprofessional healthcare team, including hepatologists, infectious disease specialists, and nurses, in providing holistic care. Collaborating with this team enhances patient outcomes by ensuring that the complexities of managing HBV-HDV coinfection are addressed through coordinated efforts, tailored treatment plans, and comprehensive monitoring strategies. Objectives: Identify the key clinical features of hepatitis D virus infection in patients with chronic hepatitis B virus infection. Screen patients who have hepatitis B infection for hepatitis D virus coinfection using appropriate serological tests. Differentiate between acute and chronic hepatitis B and hepatitis D virus coinfection based on clinical presentation and laboratory findings. Coordinate care among the interprofessional healthcare team, including hepatologists, infectious disease specialists, and nurses to develop comprehensive treatment plans for patients with hepatitis B and hepatitis D virus coinfection. Access free multiple choice questions on this topic.

Hepatitis D virus (HDV) was discovered in 1977 in patients with chronic hepatitis B virus (HBV) infection.[1] Originally considered an unrecognized HBV antigen, the HDV nuclear antigen was later discovered to be a distinct pathogen, originally termed the delta agent. HDV is considered a hybrid virus because it uses hepatitis B surface antigen (HBsAg) as its envelope protein, allowing it to infect only patients who are concomitantly infected with HBV.[2] HDV also interferes with HBV replication, resulting in low levels of HBV DNA.[3] HDV is also unique because it is the smallest known virus to infect humans.

HDV infection causes acute and chronic inflammatory liver disease and is transmitted parenterally. While in developed nations this is usually due to intravenous drug use, in resource-limited settings, transmission occurs due to inadequate sterilization practices. Risk factors include blood transfusions and intravenous drug use.[4] Infection is categorized as either coinfection (acute simultaneous infection with HDV and HBV) or superinfection (HDV infection in a person with chronic hepatitis B).

Even though HDV depends on HBV, its geographical distribution differs from that of HBV, partly due to differences in transmission mode. HDV is transmitted via the parenteral route through blood or blood product exposure. Sexual transmission is infrequent, and vertical transmission is rare.[5][6] Information on HDV epidemiology has mostly been obtained from HBV carriers superinfected with HDV. Approximately 5% of HBV carriers are also estimated to have HDV.[7] Recently, there has been a significant decline in HDV transmission, primarily attributed to a decrease in the incidence of HBV infection. This decline is largely due to improved socioeconomic conditions, increased awareness of infectious disease transmission, and increased HBV vaccination rates.[7] Recent study results determined that the HDV prevalence among HBV-infected individuals in the United States was 1.2%, which is lower than previous estimates.[8] HDV is most prevalent in the Mediterranean, East Africa, the Amazon Basin, the Middle East, central and northern Asia, and certain areas of the Pacific.[9] In Western countries, HDV infection is infrequent, occurring only in high-risk populations such as intravenous drug users, individuals from areas with a high prevalence of HDV, and recipients of multiple transfusions. While the prevalence is less than 1% in North America, it exceeds 2% in other parts of the world, although few population-level studies exist.[10]

Structurally, HDV comprises a ribonucleic acid (RNA) genome, hepatitis D antigen (HDAg), and a lipoprotein envelope from HBV. The genome encodes only the HDAg. There are 2 types of HDAg, named after their size: long and short. Viral replication occurs in hepatocytes, and the virus is unique because it uses host RNA polymerase II to transcribe its messenger RNA. Although short HDAg proteins activate viral replication via direct binding to HDV RNA, the long HDAg proteins direct viral assembly and inhibit viral replication. The virus is completely assembled after incorporating the HBV envelope, after which it is released.[2][11][12] HDV infection only occurs in the presence of HBV. In individuals susceptible to HBV, coinfection with both viruses results in acute HBV and HDV infection. Clinically, coinfection resembles classic acute HBV, except for a biphasic course of 2 peaks in serum alanine aminotransferase levels, several weeks apart. HBV infection must be established first during acute coinfection before HDV replication begins. Coinfection may be more severe than HBV monoinfection, with an increased risk for liver failure. Most patients recover during acute coinfection with HBV and HDV, and approximately 5% of patients develop chronic infection, defined as persistence of infection beyond 6 months.[5][13] In individuals who are chronic carriers of HBsAg, a superinfection can occur, which may present as severe acute hepatitis or exacerbation of preexisting chronic HBV. In patients with chronic HBV infection, acute HDV infection may be mistaken for an HBV flare. In those with undiagnosed HBV infection, the clinical presentation and initial investigations may be mistaken for acute HBV infection if HDV superinfection is not considered. The clinical course of superinfection is often more severe than that during an HBV/HDV coinfection. Because HBsAg allows for continuous viral replication, 90% of these individuals progress to chronic HDV. Chronic HDV infection causes more severe morbidity (progressive fibrosis, cirrhosis, hepatocellular carcinoma, and hepatic decompensation) than chronic HBV infection.[14] In cases of triple infection with HBV,  hepatitis C virus (HCV), and HDV, either HDV or HCV will predominate, depending on the geographic region, host immune factors, activity, and HDV genotype.

In individuals who are chronic carriers of HBsAg, a superinfection can occur, which may present as severe acute hepatitis or exacerbation of preexisting chronic HBV. In patients with chronic HBV infection, acute HDV infection may be mistaken for an HBV flare. In those with undiagnosed HBV infection, the clinical presentation and initial investigations may be mistaken for acute HBV infection if HDV superinfection is not considered. The clinical course of superinfection is often more severe than that during an HBV/HDV coinfection. Because HBsAg allows for continuous viral replication, 90% of these individuals progress to chronic HDV. Chronic HDV infection causes more severe morbidity (progressive fibrosis, cirrhosis, hepatocellular carcinoma, and hepatic decompensation) than chronic HBV infection.[14] In cases of triple infection with HBV,  hepatitis C virus (HCV), and HDV, either HDV or HCV will predominate, depending on the geographic region, host immune factors, activity, and HDV genotype. Although the mechanism by which HDV induces liver damage is not entirely known, it is thought to be due to the host's immune response.[15] The spectrum of damage can range from asymptomatic to fulminant liver failure. HDV superinfection tends to have a more rapid course and increases the risk of hepatocellular carcinoma.[16] The degree of injury depends on various factors, including the HDV genotype, host immune response, and HBV genotype. Classically, there are 3 main HDV genotypes: 1, 2, and 3. Additionally, other genotypes have been identified but are not yet well characterized. Genotype 1 is the predominant type in Western countries and, when associated with acute hepatitis D, has a fulminant course.[17] Once chronic, genotype 1 can exacerbate existing HBV disease and rapidly progress to liver cirrhosis, but it can also have an indolent course. Genotype 2 is most common in Asia and is less frequently associated with fulminant liver disease and the progression of chronic liver disease.[18] Genotype 3 is most prevalent in South America and may cause severe acute hepatitis, which can progress to liver failure.[19] Other important risk factors include HDV RNA persistence, obesity, diabetes mellitus, and alcohol use.[20]

HDV causes the same histological changes in the liver parenchyma as other viral infections, resulting in necrosis and inflammation of hepatocytes. In acute disease, intralobular infiltration of inflammatory cells (lymphocytes, macrophages) is present along with cytoplasmic eosinophilia. Chronic hepatitis is characterized by periportal necrosis and is often accompanied by nodular changes.

Hepatitis D is clinically similar to other viral hepatic infections. Most patients are asymptomatic, but depending on the severity, signs and symptoms may include fever, abdominal pain, nausea, vomiting, jaundice, confusion, bruising, or bleeding.

In response to HDAg, antibodies (anti-HDV) of the IgM and IgG subtypes are produced. The 3 infection patterns (acute HDV/HBV coinfection, acute HDV superinfection, and chronic HDV infection) vary in the serum levels of HDV RNA, HDAg, and anti-HDV antibodies as well as HBV serum biomarkers (See Image. Hepatitis D Stages, Serological Markers, and the 3 Infection Patterns). Because HDV depends on HBV, the presence of HBsAg is required for diagnosis. Additionally, detecting IgM antibodies against the hepatitis B core antigen (IgM anti-HBc) is necessary to diagnose acute HBV/HDV coinfection.[21][22] HDAg is detected early but is short-lived in acute HDV infection, often requiring repeated confirmation testing. Detection of anti-HDV is delayed in acute infection and may be the only means to diagnose acute HDV if other HDV infection markers are absent. The pattern of the IgM class of anti-HDV antibodies depends on the course of acute hepatitis D. If HDV infection is self-limited, the detection of anti-HDV IgM is transient and delayed.[21][23][24] If HDV infection progresses to chronicity, anti-HDV IgM is present in high titers and for a prolonged duration. Because anti-HDV IgM occurs in both acute and chronic HDV infections, it cannot be used to distinguish between them.[25][26] Historically, HDAg detection was considered the gold standard for diagnosing active HDV infection. As anti-HDV antibodies form immune complexes with HDAg, detecting HDAg via the required immunoblot assay is difficult and time-consuming. Therefore, HDV RNA detection via reverse transcriptase–polymerase chain reaction is the most sensitive and practical test for detecting active HDV infection.[27][28] High-risk individuals (intravenous drug users, individuals from HDV-endemic areas) or those with a severe course and who have acute hepatitis B may have HDV coinfection. Patients with coinfection have high titers of IgM anti-HBc. In these individuals, HDV biomarkers can rise before or after HBV biomarkers. Occasionally, patients who present during the second phase of biphasic hepatitis seroconvert to anti-HBs, but may still have a positive result for high-titer IgM anti-HBc.

High-risk individuals (intravenous drug users, individuals from HDV-endemic areas) or those with a severe course and who have acute hepatitis B may have HDV coinfection. Patients with coinfection have high titers of IgM anti-HBc. In these individuals, HDV biomarkers can rise before or after HBV biomarkers. Occasionally, patients who present during the second phase of biphasic hepatitis seroconvert to anti-HBs, but may still have a positive result for high-titer IgM anti-HBc. When the etiology of hepatitis is undetermined in chronic HBV carriers, HDV testing should be performed to exclude acute HDV superinfection. Distinguishing between HDV superinfection and HBV/HDV coinfection can be difficult when superinfection occurs in undiagnosed chronic HBV carriers. In cases of superinfection, HBsAg and HDV RNA remain detectable without IgM anti-HBc. Notably, patients with undetected chronic HBV are at risk of missed diagnosis of HDV if they present with acute symptoms or flares. HDV testing should be considered in high-risk individuals with chronic hepatitis B to rule out concurrent chronic HDV infection. Coinfection can be diagnosed by detecting total anti-HDV antibodies, followed by confirmatory staining for HDAg in liver tissues or measuring serum HDV RNA. Because HBV replication is suppressed in chronic HDV infection, hepatitis B e-antibodies are typically present. Additionally, testing for hepatitis C, hepatitis A, and other causes of acute and chronic liver injury should be considered.

While no treatments are available for acute HDV infection, per the European Association for the Study of the Liver guidelines, chronic hepatitis D infection requires treatment.[29] Serum HBsAg, HDV RNA, anti-HDV antibodies, elevated liver enzymes, or evidence of chronic liver damage define chronic disease. Although not approved by the US Food and Drug Administration for chronic HDV, interferon alpha (IFN-α) has shown benefit in most clinical trials.[30] Expert guidelines recommend the pegylated form of IFN-α. IFN-α is available for off-label use in most countries for a 48-week course.[31][32] Decompensated liver disease is a contraindication because of the risk of further deterioration of liver function and opportunistic infection. Bulevirtide is an entry inhibitor that blocks sodium taurocholate cotransporting polypeptide (NTCP) receptor–mediated viral entry. Based on the trials in phases 2 and 3, this medication has been granted conditional approval in Europe.[33][34][33] Lonafarnib inhibits HDV assembly and is also being tested in late-stage clinical trials.[35] Given the lack of promising evidence, nucleotide analogues are not currently recommended to treat chronic hepatitis D infection. Tobevibart (VIR-3434) targets the antigenic loop of HBsAg, neutralizes HBV/HDV entry while reducing HBsAg levels, and is currently in clinical trials.[36] RNA interference therapies, such as JNJ-3989 and elecsiran, degrade HBV transcripts, including HBsAg messenger RNA, thereby indirectly inhibiting HDV replication. Results from the MARCH study found that elebsiran combined with pegylated IFN-α demonstrated robust HBsAg and HDV RNA suppression, supporting continued clinical investigation.[37][38]

Bulevirtide is an entry inhibitor that blocks sodium taurocholate cotransporting polypeptide (NTCP) receptor–mediated viral entry. Based on the trials in phases 2 and 3, this medication has been granted conditional approval in Europe.[33][34][33] Lonafarnib inhibits HDV assembly and is also being tested in late-stage clinical trials.[35] Given the lack of promising evidence, nucleotide analogues are not currently recommended to treat chronic hepatitis D infection. Tobevibart (VIR-3434) targets the antigenic loop of HBsAg, neutralizes HBV/HDV entry while reducing HBsAg levels, and is currently in clinical trials.[36] RNA interference therapies, such as JNJ-3989 and elecsiran, degrade HBV transcripts, including HBsAg messenger RNA, thereby indirectly inhibiting HDV replication. Results from the MARCH study found that elebsiran combined with pegylated IFN-α demonstrated robust HBsAg and HDV RNA suppression, supporting continued clinical investigation.[37][38] The goal of treatment is suppression of HDV replication, demonstrated by the undetectable HDV RNA in serum and HDAg in the liver. The ideal endpoint would be clearance of HBsAg. Acceptable endpoints include alanine aminotransferase level normalization and greater than 2 log HDV RNA decline at treatment completion. As measured by HDV RNA, Virological response should ideally be assessed every 6 months during treatment and yearly thereafter.[29] HDV RNA suppression below the lower limit of quantification serves as an alternative therapeutic target, necessitating sustained virologic monitoring and individualized management.[39] Continuous HDV RNA suppression over 48 weeks for maintenance therapy minimizes hepatic inflammation and slows disease progression. In cases of decompensated liver disease, liver transplant is the only viable option.[40] However, there is a high risk of recurrence of HDV infection, so hepatitis B immunoglobulin and nucleotide analogues are strongly recommended for allograft recipients posttransplant.[29] The level of hepatitis B immunoglobulin should be maintained above 100 mIU/mL after liver transplant.[29]

The differential diagnoses for HDV include the following: Alcohol-associated hepatitis Autoimmune hepatitis Budd-Chiari syndrome Cholangitis Cholecystitis Hepatitis A virus infection Hepatitis B virus infection Hepatitis C virus infection Liver abscess

In patients of HDV-HBV coinfection, the risk of deterioration is greater than in those with HBV infection alone.[41] When HDV superinfects patients with chronic HBV, it most commonly results in chronic HDV infection; however, in a minority of patients, spontaneous resolution occurs in 20% to 30%. Approximately two-thirds of chronically infected individuals develop cirrhosis, and hepatocellular carcinoma may develop within 5 to 10 years.[42]

Acute HDV infection is associated with a greater risk of progression to acute liver failure. Chronic HDV infection increases the risk of cirrhosis compared with chronic HBV infection. Complications of decompensated cirrhosis include hepatic encephalopathy, variceal bleeding, ascites, and spontaneous bacterial peritonitis. Furthermore, the risk of hepatocellular carcinoma may also be increased.

HDV represents a severe hepatic infection that occurs exclusively in individuals with concurrent hepatitis B virus (HBV) infection. Patients should be educated on primary prevention strategies, including HBV vaccination, avoidance of percutaneous exposure through contaminated needles, and adherence to safe sexual practices. Clinical guidelines recommend systematic HDV screening for all patients with HBV infection, with an emphasis on individuals presenting with high-risk epidemiological factors or unexplained hepatic dysfunction. Patients should be educated that early identification coupled with appropriate lifestyle interventions, including abstinence from alcohol and hepatotoxic agents, can mitigate hepatic injury progression and optimize clinical outcomes.

The following are key points that clinicians should keep in mind regarding HDV: Because HDV depends on HBV, prevention is achieved with HBV vaccination. If an individual is immune to HBV, they are subsequently protected against HDV. Patients at risk of contracting HDV infection should be encouraged to receive the hepatitis B vaccine. Patients with unexplained acute flares of hepatitis and those with rapid progression to cirrhosis should be screened for HDV. Based on the most recent European Association for the Study of the Liver guidelines, screening for HDV should be performed at least once in all patients with positive HBsAg testing.[29] Retesting may be considered yearly in patients who remain at risk for infection.

Effective management of hepatitis D virus infection requires a comprehensive approach integrating clinical skills, ethical responsibilities, and coordinated strategies across the interprofessional team. Clinicians apply diagnostic and therapeutic expertise, while nurses provide patient education and monitoring to ensure adherence and safety. Pharmacists contribute by optimizing antiviral regimens, counseling on adverse effects, and reviewing drug–drug interactions. Ethical responsibilities include maintaining transparency in prognosis, ensuring informed consent, and addressing health disparities in high-risk populations. Communication among clinicians, nurses, pharmacists, and other healthcare professionals supports the timely identification of disease progression, coordinated care transitions, and the integration of preventive strategies, such as hepatitis B vaccination. This interprofessional collaboration enhances patient-centered care, improves outcomes, minimizes treatment-related risks, and strengthens overall team performance in managing HDV.