What is the next step for someone with a positive Hepatitis C (Hep C) antibody test?

Management of Positive Hepatitis C Antibody Test

Order HCV RNA testing immediately to determine if the patient has active infection—this is the single most critical next step that distinguishes current infection requiring treatment from past resolved infection or false positivity. 1, 2

Immediate Testing Algorithm

Step 1: Order HCV RNA (PCR) Testing

• Request HCV RNA testing reflexively from the same blood sample used for antibody testing whenever possible to avoid delays and additional venipuncture 1
• Use an FDA-approved quantitative or qualitative HCV RNA assay with detection sensitivity ≤25 IU/mL 2
• This single test definitively determines whether active HCV infection is present 2, 3

Step 2: Interpret HCV RNA Results

If HCV RNA is DETECTED (positive):

• This confirms current, active HCV infection requiring treatment 1
• Proceed immediately with the following baseline evaluation:
  • Complete blood count and comprehensive metabolic panel 2
  • Hepatitis B testing: HBsAg AND anti-HBc (hepatitis B core antibody) to screen for coinfection—this is mandatory before initiating any HCV treatment due to risk of fatal HBV reactivation 2, 4, 5
  • HIV testing, as coinfection accelerates liver fibrosis 2
  • Assessment of liver fibrosis stage using noninvasive markers or biopsy to determine treatment urgency 2, 6
  • HCV genotype testing to guide treatment selection 2, 6
  • Quantitative HCV RNA (viral load) if not already performed, as this may affect treatment duration 2
• Counsel the patient about their infectious status and link them to specialist care for treatment evaluation 1
• Consider hepatocellular carcinoma screening if cirrhosis is present 2

If HCV RNA is NOT DETECTED (negative):

• This indicates one of three possibilities: past resolved infection (most common), false-positive antibody test, or intermittent viremia 1, 3, 7
• To distinguish between these scenarios, order confirmatory antibody testing using a different HCV antibody assay platform (different from the initial screening test) 1, 7
  • If the second antibody test is negative: the initial test was a false positive; no HCV infection present; no further testing needed 7
  • If the second antibody test is positive: the infection has spontaneously cleared (occurs in 15-25% of adults); no treatment needed 7
• Consider repeat HCV RNA testing in specific high-risk scenarios 1, 2, 3, 7:
  • Recent exposure within the past 6 months (window period before viremia becomes detectable)
  • Immunocompromised patients (may have delayed seroconversion or intermittent viremia)
  • Clinical evidence of liver disease (elevated ALT/AST or other hepatitis signs)
  • Concerns about specimen handling or storage

Critical Pitfalls to Avoid

• Never assume a single negative HCV RNA result definitively excludes infection without confirmatory antibody testing, especially in immunocompromised patients or those with recent exposure 1, 3, 7
• Never initiate HCV treatment without first testing for hepatitis B (HBsAg and anti-HBc)—HBV reactivation during HCV treatment has caused fulminant hepatitis, liver failure, and death 4, 5
• Do not misinterpret intermittent viremia: some patients with chronic HCV have fluctuating HCV RNA levels, making a single negative result difficult to interpret without clinical context 1, 3
• Avoid inadequate specimen handling for HCV RNA testing: serum/plasma must be separated within 2-6 hours and stored properly at 2-5°C for up to 72 hours or frozen at -20°C 3
• Do not order unnecessary repeat testing in patients with confirmed cleared infections (positive antibody, negative RNA, positive confirmatory antibody) 7

Special Populations Requiring Modified Approach

Immunocompromised Patients

• Antibody tests may be falsely negative 3
• Consider direct HCV RNA testing even with negative antibody if clinical suspicion is high 1, 3
• May require repeat HCV RNA testing due to intermittent viremia 1, 3

Recent Exposure (Within 6 Months)

• May be in the window period before antibodies or detectable viremia develop 1, 2
• Repeat HCV RNA testing in 2-3 months if initial testing is negative but exposure is confirmed 1

Patients with Elevated Liver Enzymes

• HCV RNA testing is particularly important even if antibody is negative, as this may represent acute infection before seroconversion 1, 3

Counseling and Follow-Up

• Provide comprehensive information about HCV infection, transmission prevention, and treatment options 1
• For patients with active infection, emphasize measures to limit disease progression: alcohol avoidance/reduction and vaccination against hepatitis A and B 1
• Inform patients of their infectious status to enable informed decisions about preventing transmission to others 1
• Ensure confidentiality of results and provide referral resources for specialist care, mental health support, and substance use treatment as needed 1