What is the significance of a reactive hepatitis C virus (HCV) antibody test and what are the appropriate next steps in evaluation and management?

Reactive HCV Antibody: Interpretation and Management

A reactive HCV antibody test requires immediate reflex HCV RNA testing to distinguish between current active infection, past resolved infection, or false positivity—this is the critical next step that determines all subsequent management. 1

What a Reactive HCV Antibody Means

A reactive HCV antibody result indicates one of three possibilities 1, 2:

• Current active HCV infection (requires treatment)
• Past resolved infection (either spontaneous clearance or successful prior treatment)
• False-positive result (particularly common in low-prevalence populations, occurring in approximately 35% of reactive results) 3, 2

The antibody test alone cannot distinguish between these three scenarios—only HCV RNA testing provides this critical information. 2

Immediate Next Step: HCV RNA Testing

Order HCV RNA testing immediately using nucleic acid testing (NAT) on the same blood sample whenever possible (reflex testing). 1, 4

Operational Approach:

• Single-visit sample collection is mandatory—collect sufficient blood at the initial visit to allow automatic reflex HCV RNA testing if the antibody is reactive 4
• The same venipuncture sample used for antibody testing should be reflexed to HCV RNA without requiring another blood draw 1
• Strategies requiring multiple visits for sample collection should be discontinued, as they result in approximately one-third of patients having incomplete testing 4

Interpretation Based on HCV RNA Results

If HCV RNA is DETECTED (Positive):

This indicates current active HCV infection requiring medical evaluation and antiviral treatment consideration. 1, 2

• The patient has chronic HCV infection in most cases 2
• The patient is infectious to others and requires counseling about transmission prevention 2
• Refer to hepatology or infectious disease for treatment evaluation 1
• Treatment with direct-acting antivirals achieves virologic cure, which reduces risk for hepatocellular carcinoma and all-cause mortality 1
• Counsel on alcohol avoidance/reduction and vaccination against hepatitis A and B 1

If HCV RNA is NOT DETECTED (Negative):

This definitively indicates no current HCV infection—the patient does not require treatment and is not infectious. 3, 2

The reactive antibody with undetectable RNA represents one of two possibilities 1, 3:

• Past resolved infection (15-25% of acute infections resolve spontaneously, or successful prior treatment) 3
• False-positive antibody test 3

Management When HCV RNA is Negative:

• No further action is required in most cases 3, 2
• The patient is not infectious and does not require isolation precautions 3
• Do not treat for hepatitis C 3
• Counsel that HCV antibodies do not provide protective immunity—reinfection can occur with future exposure 3, 2

Exceptions Requiring Repeat HCV RNA Testing

Repeat HCV RNA testing is indicated only in these specific situations 1, 3, 2:

• Recent exposure within the past 6 months (window period before antibody seroconversion or RNA detectability) 1, 3, 2
• Immunocompromised patients (may have delayed antibody response or false-negative antibody tests) 1, 3, 2
• Clinical evidence of active liver disease (elevated transaminases, symptoms suggesting hepatitis) 3, 2
• Concerns about specimen handling or storage 3, 2

Optional Confirmatory Antibody Testing

If you need to definitively distinguish between true past infection versus false-positive antibody (though this rarely changes clinical management) 1, 3:

• Perform a second HCV antibody assay using a different FDA-approved platform than the initial test 1
• Recombinant immunoblot assay (RIBA) can be used, though this is rarely necessary in clinical practice 3, 5
• Biologic false positivity is unlikely to be exhibited by multiple different antibody assays 1

Common Pitfalls to Avoid

• Never stop at antibody testing alone—approximately one-third of patients historically have incomplete testing, which prevents identification of those needing treatment 4
• Do not require patients to return for a second visit to collect blood for HCV RNA testing—this dramatically increases incomplete testing rates 4
• Do not assume a reactive antibody means active infection—35% are false-positives in low-prevalence populations 3, 2
• Do not assume antibodies provide immunity—patients with resolved infection can be reinfected 3, 2

Reporting Requirements

Positive HCV antibody and HCV RNA results are nationally notifiable conditions and must be reported to local health departments as mandated by local, state, or territorial law 1