Management of Positive HCV Antibody with Negative HCV RNA
A positive HCV antibody with negative quantitative HCV RNA indicates either past resolved infection (spontaneous clearance) or a false-positive antibody result—you should confirm with repeat antibody testing on a different assay platform to distinguish between these two possibilities. 1
Immediate Interpretation and Next Steps
The negative HCV RNA result definitively rules out current active HCV infection, meaning the patient does not have chronic hepatitis C and does not require antiviral treatment. 2, 1
Confirmatory Testing Algorithm
Perform repeat HCV antibody testing using a different manufacturer's assay platform (different antigens/methodology) to distinguish false-positive from resolved infection. 1, 3
If the second antibody test is negative: The initial result was a false-positive, no HCV infection ever occurred, and no further HCV-related evaluation is needed. 1, 3
If the second antibody test remains positive: The infection has been spontaneously cleared, which occurs in 15-45% of HCV infections depending on age at acquisition (older adults >45 years clear 15-25%; younger individuals clear 40-45%). 1, 3
Why This Approach Works
Modern HCV antibody assays use different antigens and platforms, so biologic false-positivity is unlikely to occur on two different tests simultaneously—this makes the second test highly specific for confirming true prior exposure. 3, 4
Special Circumstances Requiring Repeat HCV RNA Testing
Even with a negative RNA result, repeat HCV RNA testing is warranted in these specific situations:
Recent exposure within the past 6 months: HCV RNA becomes detectable 1-3 weeks after exposure, but antibodies may take 2-6 months to appear. A single negative RNA during this window does not exclude early acute infection. 2, 1, 3
Immunocompromised patients (HIV coinfection, solid organ transplant, hemodialysis, immunosuppressive therapy, hypogammaglobulinemia): These patients may have false-negative antibody tests despite active viremia, or delayed/intermittent viremia patterns. 2, 1
Clinical evidence of acute hepatitis: During acute HCV infection, approximately 50% of patients are antibody-negative at presentation, and HCV RNA can be transiently negative as antibody titers rise. 1, 3
Ongoing high-risk behaviors (active injection drug use, men with HIV having unprotected sex with men): These populations require at least annual HCV RNA testing because antibodies remain positive after prior infection, making RNA the only reliable marker for reinfection. 2, 1
Timing of Repeat Testing
If repeat RNA testing is indicated, perform it at least 1 month after the initial test to allow for seroconversion or viral rebound, and consider serial testing over several months to distinguish true clearance from intermittent viremia. 3
Patient Counseling
For Confirmed Cleared Infection (Positive on Both Antibody Tests)
Inform the patient they do not have active HCV infection and do not require antiviral treatment or hepatology referral. 2, 1
Counsel that they are NOT protected from reinfection: Anti-HCV antibodies are non-neutralizing and do not confer immunity—reinfection can occur with re-exposure. 2, 4
No routine follow-up HCV testing is needed unless new risk exposures occur. 1
For False-Positive Result (Negative on Second Antibody Test)
- Reassure the patient they were never infected with HCV and no further HCV evaluation is needed. 1, 3
What NOT to Do: Common Pitfalls
Do NOT order supplemental antibody testing (e.g., RIBA) as the immediate next step—HCV RNA testing provides definitive confirmation of active infection, and a second antibody assay on a different platform is the appropriate confirmatory test for antibody-positive/RNA-negative results. 1
Do NOT order serial liver enzymes, liver imaging, or hepatocellular carcinoma screening in RNA-negative patients—these represent unnecessary testing because there is no active liver disease from HCV. 1
Do NOT refer to hepatology unless RNA testing confirms active viremia. 1
Do NOT assume a single negative HCV RNA result is conclusive if recent exposure, clinical suspicion, or immunocompromise exists—repeat testing may be required. 1, 3
Do NOT interpret intermittent negative RNA results as definitive clearance without serial testing over several months, as HCV RNA can be intermittently positive in chronic infection. 1, 3
No Ongoing Monitoring Required
Patients who are HCV antibody-positive but HCV RNA-negative do not require:
- Liver function test monitoring 1
- Liver imaging or fibrosis assessment 1
- Hepatocellular carcinoma surveillance 1
- Specialist referral 1
The only exception is if the patient has ongoing risk factors for reinfection, in which case periodic HCV RNA testing (not antibody) should be performed at least annually. 2, 1