Is it possible for a patient with a past medical history of Hepatitis B (HB) infection, who was previously Hepatitis B surface antigen (HBsAg) positive two years ago, to now test negative for HBsAg?

HBsAg Conversion from Positive to Negative: Yes, This Is Possible

Yes, it is absolutely possible for a patient who was HBsAg-positive two years ago to now test HBsAg-negative—this represents either spontaneous HBsAg clearance (functional cure) or, less commonly, occult hepatitis B infection. 1

Most Likely Scenario: Spontaneous HBsAg Clearance (Resolved Hepatitis B)

The most probable explanation is that your patient achieved spontaneous HBsAg loss, which occurs in 1-3% of chronic hepatitis B patients per year after several years of persistently undetectable or low HBV DNA levels. 1

Confirm True HBsAg Clearance with These Tests:

• Check anti-HBs (hepatitis B surface antibody): Patients who recover from HBV infection will test negative for HBsAg and positive for anti-HBs and anti-HBc. 1

• Check anti-HBc (total hepatitis B core antibody): This should remain positive for life after HBV infection and distinguishes true recovery from vaccination (where anti-HBc would be negative). 1, 2

• Measure HBV DNA by PCR: This is critical to distinguish true clearance (undetectable HBV DNA) from occult hepatitis B (detectable HBV DNA despite negative HBsAg). 1

• Check liver enzymes (ALT/AST): These should be persistently normal in resolved infection. 1

Alternative Explanation: Occult Hepatitis B Infection

In occult hepatitis B, HBsAg becomes undetectable while low-level HBV replication persists with detectable HBV DNA in the liver and sometimes in serum (<200 IU/mL). 1

Key Features of Occult HBV:

• HBsAg negative but HBV DNA may be detectable in serum (usually <200 IU/mL) or liver tissue. 1

• Anti-HBc remains positive with or without anti-HBs. 1

• Generally associated with improved outcomes but immunosuppression can cause reactivation. 1

• Measurement of serum HBV DNA by sensitive PCR is essential to detect this condition. 1

Critical Pitfall: HBsAg Assay Escape Mutants

Rarely, viral mutations in the S gene (particularly in the 'a' determinant region) can cause false-negative HBsAg results despite active viral replication. 3

• This is uncommon but has been documented in immunocompromised patients. 3

• If HBV DNA is detectable but HBsAg remains negative on multiple assays, consider escape mutants. 3

• Testing with different HBsAg assay platforms may be warranted if clinical suspicion is high. 3

Another Rare Possibility: False-Positive Initial Test

The original HBsAg-positive result two years ago could have been a false-positive due to heterophilic antibody interference, though this is uncommon. 4

• This would be supported by isolated HBsAg positivity without other HBV markers at the initial testing. 4

• Less likely if the patient had other confirmatory markers (anti-HBc, HBV DNA) at the time. 4

Durability of HBsAg Loss

Once confirmed, HBsAg loss is highly durable—95% of patients remain HBsAg-negative after a mean follow-up of 9.6 years, whether clearance was spontaneous or treatment-related. 5

• HBsAg seroreversion (reappearance) occurs in only 7% of treated patients. 5

• Development of anti-HBs increases over time, reaching 81% at long-term follow-up. 5

• HBsAg loss represents a robust endpoint for functional cure. 5

Critical Long-Term Monitoring Required

Even after confirmed HBsAg clearance with anti-HBs seroconversion, patients remain at risk for hepatocellular carcinoma (HCC), particularly if they had advanced fibrosis or cirrhosis before clearance. 6

• HBV DNA can remain detectable by PCR in serum even after HBsAg clearance and anti-HBs seroconversion. 6

• Patients may develop chronic active hepatitis, cirrhosis, or HCC even after HBsAg clearance. 6

• Continue HCC surveillance with ultrasound and AFP every 6 months if the patient had cirrhosis or advanced fibrosis. 1

Recommended Diagnostic Algorithm

1. Repeat HBsAg testing to confirm negativity (not a laboratory error). 1

2. Order complete hepatitis B panel: anti-HBs, anti-HBc (total), and HBV DNA by quantitative PCR. 1, 2

3. Check liver enzymes (ALT, AST) and assess liver synthetic function (albumin, PT/INR). 1, 2

4. Interpret results:

   • HBsAg negative + anti-HBs positive + anti-HBc positive + HBV DNA undetectable = Resolved HBV infection (functional cure). 1
   • HBsAg negative + anti-HBc positive + HBV DNA detectable = Occult HBV infection. 1
   • HBsAg negative + anti-HBs positive + anti-HBc negative = Prior vaccination (not applicable here given prior HBsAg positivity). 1

5. Assess for advanced fibrosis/cirrhosis using noninvasive testing (FIB-4, APRI, elastography) or review prior liver biopsy if available. 1

6. Continue HCC surveillance if cirrhosis or advanced fibrosis is present, even with HBsAg clearance. 1, 6