What does it mean if a patient is Hepatitis C Virus (HCV) antibody positive but has a negative HCV quantitation result?

HCV Antibody Positive but HCV RNA Negative: Interpretation

A positive HCV antibody with negative HCV RNA quantitation indicates either a false-positive antibody test or, more commonly, a resolved (cleared) HCV infection—to distinguish between these two possibilities, you must perform confirmatory antibody testing using an alternative assay platform. 1

Immediate Next Step

Perform repeat HCV antibody testing using a different antibody assay platform (different antigens, test platforms, or performance characteristics) to distinguish false-positive from cleared infection 1:

• If the alternative assay is negative → The initial test was a false-positive; no HCV infection present, no further evaluation needed 1
• If the alternative assay is positive → The infection has cleared (resolved); approximately 20% of HCV infections spontaneously clear 1

Clinical Interpretation Algorithm

Most Likely Scenario: Cleared Infection

• When both antibody tests are positive but HCV RNA is negative, this typically represents spontaneous viral clearance 1
• Among adults who acquired HCV infection at older ages (>45 years), 15-25% clear the infection; this rate is higher (40-45%) in those infected as children or younger adults 1
• These patients do not have active HCV infection and do not require antiviral treatment 1

Less Common Scenario: False-Positive Antibody

• False-positive screening tests occur, particularly in low-risk populations 1
• Biologic false positivity is unlikely to be exhibited by more than one test when multiple assays are used on the same specimen 1
• If confirmed false-positive, reassure the patient they are not infected 1

Important Caveats and Exceptions

When to Repeat HCV RNA Testing

Consider repeating HCV RNA testing in specific circumstances 1, 2:

• Recent exposure within past 6 months → May represent early acute infection before viremia is detectable 1, 2
• Clinical evidence of liver disease → Intermittent viremia can occur in chronic HCV infection 1, 2
• Concerns about specimen handling or storage → Improper handling can cause false-negative RNA results 2
• Immunocompromised patients → May have intermittent or low-level viremia 1

Intermittent Viremia

• HCV RNA can be intermittently positive in persons with chronic infection 1
• A single negative HCV RNA result does not definitively exclude active infection without additional clinical context 1, 2
• Serial HCV RNA determinations may be needed if clinical suspicion remains high 1

Counseling Points for Patients

If Cleared Infection (Alternative Assay Positive)

• Inform the patient they do not have active HCV infection and do not need follow-up HCV testing 1
• No antiviral treatment is indicated 1
• Antibodies will persist for life but do not indicate current infection 1

If False-Positive (Alternative Assay Negative)

• Reassure the patient they are not infected with HCV 1
• No further HCV evaluation is needed unless new risk exposures occur 1

Common Pitfalls to Avoid

• Do not assume a single negative HCV RNA definitively rules out infection without confirmatory antibody testing on an alternative platform 1, 2
• Do not order unnecessary repeat testing in confirmed cleared infections (both antibody assays positive, RNA negative) 1
• Do not miss recent acute infection by failing to consider timing of exposure relative to testing 1, 2
• Do not overlook specimen handling issues that can cause false-negative RNA results 2
• Do not forget that immunocompromised patients may have false-negative antibody tests or intermittent viremia requiring different testing strategies 1, 2