What is the next step in managing a patient with a positive hepatitis C (HCV) antibody test?

Next Step After Positive Hepatitis C Antibody Test

The most appropriate next step is to order HCV RNA testing (nucleic acid testing/NAT) to determine if the patient has current, active HCV infection. 1

Why HCV RNA Testing is Essential

A positive HCV antibody result has three possible interpretations that cannot be distinguished without further testing 1, 2:

• Current, active HCV infection (requires treatment to prevent progression to cirrhosis, hepatocellular carcinoma, and death)
• Past, resolved infection (spontaneous viral clearance—no treatment needed)
• False-positive antibody result (no infection present)

HCV RNA detection by NAT is the gold standard for confirming active infection and is the critical determinant for all subsequent management decisions. 1

Testing Algorithm

Step 1: Order HCV RNA (Qualitative PCR)

• Use an FDA-approved NAT assay for HCV RNA detection in serum or plasma 1
• The same blood sample from the initial antibody test can be reflexed to HCV RNA testing without requiring another blood draw 1
• This is the single most important test to guide management 2

Step 2: Interpret Results Based on HCV RNA Status

If HCV RNA is DETECTED (positive):

• This confirms current, active HCV infection 1, 2
• The patient requires linkage to medical care and treatment evaluation 1
• Before initiating antiviral therapy, retest HCV RNA in a subsequent blood sample to confirm viremia 1
• Order additional baseline tests including liver function tests (ALT/AST) to assess liver damage 2
• Test for hepatitis B (HBsAg and anti-HBc) before starting HCV treatment, as HBV reactivation can cause fulminant hepatitis, liver failure, and death in coinfected patients 3, 4

If HCV RNA is NOT DETECTED (negative):

• This indicates either past resolved infection or false-positive antibody 1, 5
• Consider repeat testing with a different HCV antibody assay (RIBA) to distinguish true positivity from biological false positivity 1, 5
• If alternative antibody assay is negative, the initial test was false-positive and no further evaluation is needed 5
• If alternative antibody assay is positive, the infection has spontaneously cleared (occurs in 15-45% of cases depending on age at infection) and no treatment is required 5

Special Circumstances Requiring Additional Consideration

Repeat HCV RNA testing should be considered if: 1, 5

• Recent exposure within the past 6 months (may be in window period before viremia is detectable)
• Clinical evidence of liver disease despite negative HCV RNA
• Patient is immunocompromised (antibody tests may be falsely negative; go directly to HCV RNA testing) 1, 2
• Concerns about specimen handling or storage
• HCV RNA can be intermittently positive in chronic infection 5

Common Pitfalls to Avoid

• Do not assume a positive antibody test means active infection—85% of anti-HCV positive hemodialysis patients had viremia in one study, but this varies by population 6
• Do not assume a single negative HCV RNA definitively rules out infection without considering timing of exposure and clinical context 2, 5
• Do not order HCV genotyping or quantitative viral load at this initial stage—these are only relevant after confirming active infection and when considering treatment 7, 8
• Do not forget to test for hepatitis B coinfection before any HCV treatment, as HBV reactivation is a potentially fatal complication 3, 4
• Do not misinterpret signal-to-cutoff (S/CO) ratios—while very low S/CO ratios suggest false positivity, HCV RNA testing remains the definitive test 9

Why This Approach Prioritizes Morbidity and Mortality

Untreated chronic HCV infection leads to cirrhosis, hepatocellular carcinoma, and death 1. Modern direct-acting antivirals achieve viral clearance in over 95% of patients, and sustained viral clearance reduces risk of hepatocellular carcinoma and all-cause mortality 1. However, treatment is only indicated for active infection, making HCV RNA testing the critical branch point that determines whether this life-saving therapy is appropriate. Conversely, patients with resolved or false-positive antibody results do not benefit from treatment and should be spared unnecessary therapy and its associated costs.