What further testing is recommended for a patient with a history of Hepatitis C (HCV) and a positive Hepatitis C antibody test?

HCV Antibody Positive: Next Steps

Yes, you must order HCV RNA testing immediately to determine if the patient has active infection—a positive antibody test alone cannot distinguish between current infection, past resolved infection, or a false positive result. 1

Immediate Testing Required

Order HCV RNA (PCR) testing as the essential next step. 1

• The HCV RNA test should ideally be reflexed automatically from the same blood sample used for antibody testing, avoiding the need for a return visit which is a major barrier in the continuum of care 1
• Use an FDA-approved quantitative or qualitative HCV RNA assay with a detection level of ≤25 IU/mL 1
• This single test will definitively determine whether the patient has active, current HCV infection requiring treatment 1

Interpretation of HCV RNA Results

If HCV RNA is Detected (Positive):

• This confirms current, active HCV infection requiring further evaluation and treatment 1
• Proceed with quantitative HCV RNA testing (viral load) prior to initiating therapy, as this may affect treatment duration with certain regimens 1
• Evaluate for liver fibrosis using noninvasive markers or liver biopsy to determine treatment urgency and need for cirrhosis management (hepatocellular carcinoma screening) 1
• Test for hepatitis B (HBsAg and anti-HBc) and HIV coinfection, as these accelerate liver fibrosis 1
• HCV genotyping is no longer universally required if using pangenotypic direct-acting antiviral regimens, though it remains recommended for treatment-experienced patients 1

If HCV RNA is Not Detected (Negative):

This indicates either past resolved infection or a false-positive antibody test—additional testing is needed to distinguish between these two scenarios. 2

• Order repeat HCV antibody testing using a different antibody assay platform (not the same assay) to distinguish false-positive from cleared infection 2
• If the alternative assay is negative, the initial test was a false-positive and no HCV infection is present—no further evaluation needed 2
• If the alternative assay is positive, the infection has spontaneously cleared (occurs in approximately 20% of HCV infections)—no treatment needed 2

Special Circumstances Requiring Repeat HCV RNA Testing

Even with a negative HCV RNA result, consider repeating HCV RNA testing in these specific situations: 1, 2

• Recent exposure within the past 6 months (patient may be in the window period before viremia is detectable) 1
• Immunocompromised patients (may have delayed or failed seroconversion, or intermittent viremia) 1
• Clinical evidence of liver disease (elevated ALT/AST or other signs of hepatitis) 1, 2
• Concerns about specimen handling or storage that could have led to RNA degradation 1, 2

The CDC specifically notes that HCV RNA can be intermittently positive in persons with chronic infection, making a single negative result difficult to interpret without additional clinical context 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 2, 3
• Do not fail to consider timing of exposure—testing too early in acute infection (within 6 months) may yield false-negative RNA results 1
• Do not order unnecessary repeat testing in confirmed cleared infections once two different antibody assays are positive but RNA remains negative 2
• Do not misinterpret antibody positivity alone as active infection—approximately 20-45% of HCV infections clear spontaneously, and these patients do not require antiviral treatment 2

Additional Baseline Testing for Active Infection

If HCV RNA confirms active infection, obtain: 1

• Complete blood count, comprehensive metabolic panel (including ALT/AST, bilirubin, albumin, creatinine)
• Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) to screen for HBV coinfection, as HBV reactivation can occur during HCV treatment 1
• HIV testing 1
• Assessment of liver fibrosis stage (noninvasive markers or biopsy) 1