What does a Hepatitis C (HCV) Antibody (Ab) reactive result with HCV RNA quantitative real-time Polymerase Chain Reaction (PCR) not detected indicate?

HCV Antibody Reactive with HCV RNA Not Detected: Interpretation

A reactive HCV antibody with undetectable HCV RNA most likely indicates either a past, resolved HCV infection (spontaneous viral clearance) or a false-positive antibody test, and you should perform confirmatory testing with a different HCV antibody assay platform to distinguish between these two possibilities. 1

Immediate Diagnostic Approach

Perform repeat HCV antibody testing using a different antibody assay platform to definitively determine whether the initial reactive result represents true HCV exposure or false positivity. 1

• If the second antibody assay is negative, the initial test was a false-positive, and the patient has never been infected with HCV—no further evaluation is needed. 1
• If the second antibody assay is positive, this confirms true HCV exposure with spontaneous viral clearance—the patient had HCV infection that has resolved. 1

Clinical Significance of Each Scenario

Scenario 1: Cleared HCV Infection (Both Antibody Tests Positive)

Approximately 20% of HCV infections spontaneously clear, with higher clearance rates (40-45%) in those infected as children or younger adults compared to lower rates (15-25%) in those infected at older ages (>45 years). 2, 1

• These patients do not have active HCV infection and do not require antiviral treatment. 1
• The antibody persists indefinitely after infection, even after viral clearance, which is why it remains detectable. 2
• No further HCV testing is needed in confirmed cleared infections. 1

Scenario 2: False-Positive Antibody Test (Second Antibody Test Negative)

False-positive HCV antibody results occur in approximately 35% of reactive screening tests in low-prevalence populations (general population, healthcare workers, blood donors). 2

• The patient has never been infected with HCV and requires no further HCV evaluation. 1
• This is why confirmatory testing is critical—relying solely on screening antibody tests leads to unnecessary anxiety and medical evaluations. 2

Important Exceptions Requiring Repeat HCV RNA Testing

Consider repeating HCV RNA testing (rather than just accepting a single negative result) in these specific circumstances: 2, 1

• Recent exposure within the past 6 months: HCV RNA becomes detectable 1-2 weeks after infection, but antibody seroconversion takes an average of 8-9 weeks. 2 A patient tested during this window period may have negative RNA if tested during the brief period when RNA levels are declining during acute infection. 2

• Clinical evidence of liver disease: Elevated ALT or other signs of hepatitis warrant repeat RNA testing, as intermittent HCV RNA positivity can occur in chronic infection. 2

• Immunocompromised patients: Those on hemodialysis, with HIV coinfection, solid organ transplant recipients, or with hypogammaglobulinemia may have chronic HCV infection with persistently negative antibodies or intermittently detectable RNA. 2

• Concerns about specimen handling or storage: Technical issues with the sample may yield false-negative RNA results. 2

Critical Pitfalls to Avoid

Do not assume a single negative HCV RNA definitively excludes active infection without confirmatory antibody testing on an alternative platform. 1 The significance of a single negative HCV RNA result is unknown without additional clinical context. 2

Do not miss early acute infection by failing to consider the timing of exposure relative to testing—if exposure occurred within 6 months, repeat testing is warranted. 2, 1

Do not order unnecessary repeat testing in patients with confirmed cleared infections (two positive antibody assays, negative RNA, no risk factors for reinfection). 1

Do not forget that HCV RNA can be intermittently positive in persons with chronic infection, so a single negative result does not definitively rule out chronic infection in high-risk scenarios. 2

Patient Counseling

For cleared infections: Inform patients they do not have active HCV infection, do not need follow-up HCV testing, and are not infectious to others. 2, 1

For false-positive results: Reassure patients they have never been infected with HCV and need no further HCV evaluation unless new risk exposures occur. 1