How do I screen a patient with a long-standing hepatitis B (HBV) carrier state for hepatitis D virus (HDV) superinfection?

Screening for Hepatitis D Virus in Hepatitis B Carriers

All patients with chronic hepatitis B (HBsAg-positive) should be screened at least once for hepatitis D virus using anti-HDV antibody testing, followed by HDV RNA testing if antibodies are positive. 1

Initial Screening Approach

Screen all HBsAg-positive patients with anti-HDV antibody testing using a validated assay. 1 The 2023 EASL guidelines provide the most current evidence-based approach, superseding older risk-based screening strategies that have been shown to miss a significant number of HDV cases. 1

Why Universal Screening Over Risk-Based?

• Risk-based screening misses a sizeable proportion of HDV infections—studies show that 60% of anti-HDV-positive individuals identified through universal screening did not have traditional risk factors. 1
• Implementation of reflex anti-HDV testing (automatic testing when HBsAg is positive) led to a 5-fold increase in HDV diagnoses. 1
• Early diagnosis is critical because HDV superinfection in HBV carriers results in chronic infection in over 90% of cases, compared to only 2-5% with acute coinfection. 1, 2

Diagnostic Algorithm

Step 1: Anti-HDV Antibody Testing

• Perform anti-HDV (IgG or total) antibody testing in all HBsAg-positive individuals at least once. 1
• This identifies exposure to HDV but does not distinguish between active and resolved infection. 1

Step 2: HDV RNA Testing for Confirmation

• All anti-HDV-positive patients must undergo HDV RNA testing using standardized, sensitive reverse-transcription PCR assays. 1
• HDV RNA positivity confirms active, ongoing infection. 1
• Results should be quantified in IU/mL using validated assays from reference laboratories. 1

When to Repeat Screening

Re-test for anti-HDV antibodies in the following situations:

• Whenever clinically indicated: aminotransferase flares, acute decompensation of chronic liver disease, or unexplained worsening of liver function. 1
• Yearly screening may be performed in HBsAg-positive patients who remain at ongoing risk (injection drug users, men who have sex with men, household/sexual contacts of HDV-positive individuals). 1

Critical Clinical Context for Your Patient

For a long-standing HBV carrier presenting with new symptoms or laboratory abnormalities, HDV superinfection should be high on the differential because:

• HDV superinfection manifests as severe "acute" hepatitis in previously asymptomatic HBV carriers or as exacerbations of underlying chronic hepatitis B. 1
• Unlike coinfection, HDV superinfection almost always results in chronic infection with both viruses (>90% of cases). 1, 2
• Chronic HBV/HDV coinfection leads to more rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma compared to HBV monoinfection. 1, 2
• Approximately 30-70% of patients with chronic hepatitis D have cirrhosis at diagnosis, and more than 50% may die of liver disease within 10 years without treatment. 2

Additional Evaluation in HBV Carriers

When evaluating your HBV carrier for HDV, the initial workup should also include:

• Assessment of liver disease severity: ALT, AST, bilirubin, albumin, INR, platelet count. 1
• HBV replication markers: HBeAg, anti-HBe, quantitative HBV DNA. 1
• Testing for other coinfections in at-risk patients: HCV antibody, HIV testing (particularly in injection drug users, men who have sex with men). 1
• Non-invasive fibrosis assessment or liver biopsy to determine extent of liver damage, especially if HDV RNA is positive. 1

Common Pitfalls to Avoid

• Do not rely on risk-factor assessment alone to decide whether to screen for HDV—universal screening in all HBsAg-positive patients is now the standard. 1
• Do not stop at anti-HDV antibody testing—always confirm with HDV RNA to distinguish active from past infection. 1
• Do not assume normal ALT excludes significant disease—HDV can cause progressive liver disease even with fluctuating or minimally elevated transaminases. 3
• Remember that HDV is absolutely dependent on HBV—all HDV-infected patients will be HBsAg-positive, and HDV cannot exist without concurrent HBV infection. 4, 2