What does a positive anti-Hepatitis C Virus (HCV) test but a negative HCV Ribonucleic Acid (RNA) result indicate in an adult patient with a history of risk factors for hepatitis C, such as intravenous drug use or blood transfusions before 1992?

What Does Positive Anti-HCV but Negative HCV RNA Mean?

A positive anti-HCV antibody test with negative HCV RNA indicates either a false-positive antibody result or, more commonly, a past HCV infection that has spontaneously cleared—the next step is to perform repeat HCV antibody testing using a different assay platform to distinguish between these two possibilities. 1, 2

Immediate Diagnostic Algorithm

Step 1: Repeat Antibody Testing on Alternative Platform

• Perform a second HCV antibody test using a different antibody assay platform, as different assays use different antigens and test platforms, making biologic false positivity unlikely to occur across multiple tests 1, 2
• If the alternative assay is negative: The initial test was a false-positive, no HCV infection is present, and no further evaluation is needed 1, 2
• If the alternative assay is positive: The infection has cleared spontaneously, which occurs in approximately 20% of HCV infections overall 1, 2

Step 2: Consider Timing of Exposure

• If known HCV exposure occurred within 6 months before initial testing, repeat HCV RNA testing is warranted 1, 3, 2
• During acute infection, HCV RNA may be transiently negative as antibody titers rise, and HCV RNA can be detected 1-3 weeks after exposure while antibodies may take 2-6 months to develop 4, 2

Clinical Interpretation by Patient Age at Infection

The likelihood of spontaneous clearance varies significantly by age at acquisition:

• Older adults (>45 years): 15-25% spontaneously clear the infection 4, 1, 3
• Children and younger adults: 40-45% clear the infection 4, 1, 3

Special Circumstances Requiring Repeat RNA Testing

Beyond recent exposure, repeat HCV RNA testing should be considered in these specific situations 1, 3:

• Clinical evidence of active liver disease despite negative RNA
• Immunocompromised patients (HIV/AIDS, transplant recipients, hemodialysis patients)
• Concerns about specimen handling or storage
• Ongoing high-risk behaviors with potential reinfection

Important caveat: HCV RNA can be intermittently positive in persons with chronic infection, so a single negative HCV RNA result does not definitively exclude active infection without additional clinical context 4, 1

Management After Confirmed Cleared Infection

Once cleared infection is confirmed (positive antibody on alternative platform, negative RNA):

• No further HCV testing is required unless new risk exposures occur 3, 2
• No liver function tests, imaging, or hepatology referral is needed 2
• No hepatocellular carcinoma screening is indicated 2
• Patients are not infectious and antibodies may persist for life even after viral clearance 3

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 serial liver enzymes or liver imaging in RNA-negative patients, as this represents unnecessary testing 2
• Do not refer to hepatology unless RNA testing confirms active viremia 2
• Do not miss recent acute infection by failing to consider timing of exposure relative to testing 1, 2
• In low-prevalence populations, approximately 35% of reactive HCV antibody results are false-positives, emphasizing the importance of confirmatory testing 2