What are the next steps for diagnosis and treatment in a patient who is anti-Hepatitis C Virus (HCV) positive?

Anti-HCV Positive: Next Steps for Diagnosis and Treatment

All patients with a positive anti-HCV antibody test must undergo HCV RNA testing with a quantitative nucleic acid assay to determine if they have active infection requiring treatment. 1

Immediate Confirmatory Testing

• Order quantitative HCV RNA testing on the same serum sample if possible (reflex testing) to distinguish between current infection, resolved infection, or false-positive antibody result 1
• Use a sensitive molecular assay with a lower limit of detection <15 IU/ml for optimal accuracy 1

Interpretation of HCV RNA Results

If HCV RNA is Positive (Viremic):

• This confirms current, active HCV infection requiring medical evaluation and treatment 1, 2
• Obtain baseline laboratory assessment including:
  • Liver function tests (ALT, AST, bilirubin, albumin, prothrombin time) 1, 2
  • Complete blood count 1
  • Quantitative HCV RNA level (viral load) 3
  • HCV genotype testing (may influence treatment selection in some cases) 3
• Test for hepatitis B coinfection by measuring HBsAg and anti-HBc before initiating HCV treatment, as HBV reactivation can occur during HCV therapy and may result in fulminant hepatitis, liver failure, or death 4, 5
• Assess liver disease severity through noninvasive methods (FibroScan, APRI score, FIB-4) or liver biopsy if indicated 1
• Refer to hepatologist or specialist for treatment initiation 1

If HCV RNA is Negative:

• This indicates either resolved past infection or false-positive antibody test 1, 6, 2
• Perform confirmatory anti-HCV testing using a different antibody assay platform (different antigens/test platforms make biologic false positivity unlikely across multiple tests) 1, 6
  • If second antibody test is negative: initial test was false-positive, no further action needed 1, 6
  • If second antibody test is positive: indicates cleared/resolved infection 1, 6
• Exception: If recent exposure suspected (within past 6 months), repeat HCV RNA testing at 12 and 24 weeks, as antibodies develop 2-6 months after exposure while HCV RNA appears at 1-3 weeks 1, 3, 6
• If clinical evidence of liver disease exists despite negative RNA, repeat HCV RNA testing due to possibility of intermittent viremia (though uncommon) 1, 2

Special Populations Requiring Direct HCV RNA Testing

• Immunocompromised patients (HIV-positive, transplant recipients, chemotherapy patients): may have false-negative antibody tests, so include HCV RNA in initial evaluation 1, 2
• Suspected acute hepatitis C: only ~50% are antibody-positive at initial presentation, requiring HCV RNA testing 1, 3
• Patients at risk for reinfection after previous viral clearance: antibodies persist, so HCV RNA is the primary diagnostic test 3

Treatment Considerations

• Goal of therapy is viral eradication (sustained virological response, SVR) to prevent cirrhosis, hepatocellular carcinoma, and death 1, 3
• SVR is defined as undetectable HCV RNA 24 weeks after treatment completion using sensitive assay (<15 IU/ml), corresponding to cure in >99% of cases 3
• Modern direct-acting antiviral (DAA) regimens cure >90% of patients, including previously difficult-to-treat populations 1, 7
• Treatment regimens typically combine 2-3 DAAs targeting NS3/4A protease, NS5A protein, and/or NS5B polymerase 7
• Avoid P-gp inducers and moderate-to-strong CYP inducers (rifampin, St. John's wort, carbamazepine) during treatment, as they significantly reduce DAA concentrations and therapeutic efficacy 4, 5
• Amiodarone coadministration is not recommended due to risk of serious symptomatic bradycardia, including fatal cardiac arrest; if no alternative exists, requires 48-hour inpatient cardiac monitoring 4, 5

Common Pitfalls to Avoid

• Never assume a positive antibody test alone means active infection—approximately 15-45% of anti-HCV positive individuals have spontaneously cleared the virus 6
• Do not misinterpret negative HCV RNA as definitively ruling out infection without considering timing of exposure or performing confirmatory antibody testing 2
• Ensure proper specimen handling for HCV RNA testing: separate serum/plasma within 2-6 hours, store at 2-5°C for up to 72 hours or freeze at -20°C 2
• Do not delay HBV screening—test all patients for HBsAg and anti-HBc before starting HCV treatment to prevent potentially fatal HBV reactivation 4, 5