Can the flu or viral infections cause cross-reactivity leading to false-positive Hepatitis C (HCV) antibody tests?

Can Flu or Viral Infections Cause False-Positive HCV Antibody Tests?

Yes, influenza vaccination and acute viral illnesses can cause false-positive HCV antibody test results, though this is primarily a historical issue with older test platforms that has been largely resolved with modern assays.

Evidence for Viral Cross-Reactivity

Influenza Vaccine-Associated False Positivity

• A 1995 case-control study demonstrated that recent influenza vaccination was significantly associated with multiple false-positive viral antibody screening tests, including HCV antibody tests (p < 0.05) 1
• The false reactivity was linked to test kits that reacted nonspecifically to donor immunoglobulin M, and the duration of HCV false reactivity lasted 3-6 months 1
• Importantly, this problem was resolved when newer generation HCV antibody tests replaced the older platforms, indicating this is primarily a historical concern with first-generation assays 1

Acute Viral Hepatitis and Cross-Reactivity

• In patients with acute viral hepatitis, false-positive antibodies occurred in 29% (7 of 24 patients) during the acute illness phase 2
• False-positive antibodies during acute viral hepatitis are associated with higher IgM levels and elevated ESR, suggesting a mechanism related to polyclonal B-cell activation 2
• Recent acute illness was significantly associated with false-positive HCV antibody results (p < 0.05) 1

Modern Testing Approach to Minimize False Positivity

Current CDC Recommendations

• When HCV antibody is reactive but HCV RNA is not detected, this definitively indicates "no current HCV infection" 3, 4
• Modern HCV antibody assays vary in their antigens, test platforms, and performance characteristics, so biologic false positivity is unlikely to be exhibited by more than one test when multiple tests are used 3, 5

Confirmatory Testing Algorithm

• If distinguishing between false positivity and cleared infection is desired, repeat testing with a different HCV antibody assay platform is recommended 3, 5
• If the alternative assay is negative, the initial test was false-positive and no HCV infection is present 5
• If the alternative assay is positive, the infection has cleared (occurs in approximately 20% of HCV infections) 5

Clinical Context and Prevalence Considerations

False-Positive Rates by Population

• In low-prevalence populations (such as blood donors or healthcare workers), approximately 35% (range: 15-60%) of reactive HCV antibody results are false-positives 3
• In a nationally representative study with 1% HCV prevalence, 22% of anti-HCV screening reactive results were confirmed false-positives by RIBA testing 6
• Among immunocompromised populations, the false-positive rate averages approximately 15% 3

Special Populations with Higher False-Positive Risk

• Patients with autoimmune hepatitis show particularly high false-positive rates: 88% tested positive by first-generation ELISA, but only 19% had detectable HCV RNA 7
• History of allergies was also significantly associated with false-positive results (p < 0.05) 1

Practical Management Recommendations

When to Suspect False Positivity

• Recent influenza vaccination (within 3-6 months) 1
• Acute viral illness or recent infection 2, 1
• Autoimmune conditions 7
• Low-risk population with no HCV exposure history 3, 6

Essential Follow-Up Testing

• All reactive HCV antibody tests should reflex to HCV RNA testing to confirm active infection 3, 4
• HCV RNA testing with detection level ≤25 IU/mL should be used 3
• If HCV RNA is negative and false positivity needs to be confirmed, use a different HCV antibody assay platform 3, 5

Critical Pitfall to Avoid

• Never rely exclusively on a single positive HCV antibody screening test to diagnose HCV infection, especially in the context of recent vaccination or acute illness 3
• The CDC explicitly states that screening-test-positive results should be verified with an independent supplemental test with high specificity 3