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HDV: How to Screen
How to Screen for Hepatitis Delta Virus

Released: February 23, 2023

Expiration: February 22, 2024

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Key Takeaways
  • All patients positive for HBsAg should be tested for HDV according to the screening algorithm.
  • Patients coinfected with HBV and HDV should receive ongoing monitoring for liver damage and HCC because they experience more rapid progression vs those with HBV monoinfection.
  • Reflex anti-HDV testing and other strategies should be employed to increase HDV testing rates and reduce loss to follow-up in persons positive for HBsAg.

The hepatitis delta virus (HDV) is a simple virus from a structural point of view, but it is complicated because it relies on hepatitis B virus (HBV) infection. It is important to understand how these 2 viruses are related and how various serum markers present over time to accurately diagnose HDV infection. 

Algorithm for the Evaluation of HDV
Accumulating data suggest that all patients who are hepatitis B surface antigen (HBsAg) positive should be tested for anti-HDV antibodies. HDV antibodies usually appear 4-8 weeks after acute HDV infection. Therefore, serial testing may be required before a positive antibody test is detected. 

If anti-HDV antibodies are present, the patient should then be tested for HDV RNA, which confirms the infection. The assay is very sensitive, but it should be noted that the quantification may vary between assays. If HDV infection is confirmed, the patient should be assessed for any liver damage. 

If the patient tests negative for HDV at any of these stages, they should be managed with the standard of care for HBV monoinfection. 

Acute vs Chronic HDV Infection
HDV infection can be both acute and chronic, and it is important to understand how serum markers and disease course vary between the 2 types of infection. Acute HBV/HDV coinfection is typically self-limited. HBsAg and HDV RNA typically become negative, and alanine aminotransferase (ALT) levels improve. This is followed by the appearance of anti-HDV immunoglobulin M and subsequently anti-HDV immunoglobulin G. This is associated with viral clearance. This scenario is seen very infrequently in the clinic, presumably because most people are asymptomatic or have very mild symptoms and will not seek medical care.

In HDV superinfection of a chronic HBV carrier—the more typical clinical scenario—HDV RNA persists, transaminase elevation persists, and HDV antibodies are detectable. Less frequently, HDV RNA clearance may occur even though HBsAg persists. 

Assessment of Liver Injury
In addition to assessing for HDV, we also must assess the degree of liver injury. ALT is a marker of neuroinflammatory activity. Numerous noninvasive tests are available to determine the degree of fibrosis. These include serum fibrosis markers such as APRI and FIB-4, as well as liver stiffness measurements with FibroScan or magnetic resonance elastography. Of note, however, these tests do have a lower performance accuracy in chronic HDV vs HBV or hepatitis C virus (HCV) monoinfection. The gold standard is, of course, liver biopsy, which assesses both necroinflammatory activity and degree of liver damage, but this test is invasive and subject to sampling error.

Finally, because patients with HDV are at an increased risk of progression to more severe liver disease and hepatocellular carcinoma (HCC), the American Association for the Study of Liver Diseases guidelines recommend HCC screening every 6 months with ultrasound, with or without alpha-fetoprotein. Admittedly, obtaining an ultrasound every 6 months can be challenging because of logistical barriers, but we should strive for this frequency. 

How Can We Increase HDV Testing Rates?
The current workflow of a patient who is eligible for HDV testing is serial in nature and subject to multiple points where the patient can be lost to follow-up. It has been suggested, therefore, that reflex testing be performed on patients who present and test positive for HBsAg. This action effectively eliminates several steps where the patient could be lost to follow-up. We know that this strategy works from the HCV arena and that it makes a big difference in terms of increasing rates of diagnosis. Furthermore, patients appreciate fewer lab visits. 

Data also are available to support this strategy. Indeed, a cross-sectional analysis of HDV testing among HBsAg-positive patients at 2 London centers from 2005-2012 showed that 99% of patients vs only 40% of patients were tested for HDV when reflex testing vs healthcare professional discretion was employed. Of these patients, 4.5% vs <1.0% of patients tested anti-HDV positive, showing that fewer patients will be missed if reflex testing is employed.

Your Thoughts?
Do you support reflex anti-HDV testing in patients who are HBsAg positive? Join the discussion by posting a comment.