Hepatitis C Virus - HCV

Hepatitis C virus (HCV) is a virally mediated disease of the liver with a propensity to cause chronic infection, leading to cirrhosis and an increased risk of hepatocellular carcinoma. Adults born between 1945 and 1965 should be screened for HCV infection; individuals with certain risk behaviors (eg, injection drug use) or risk exposures (eg, healthcare workers) should also be screened. Laboratory testing involves screening for HCV antibodies followed by confirmatory RNA testing for positive results.

Quick Answers for Clinicians

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Diagnosis

Indications for Testing

  • New onset of jaundice, anorexia, or dark urine
  • Elevated liver enzymes
  • Known or suspected exposure to HCV
  • Liver fibrosis or cirrhosis without identified etiology

Laboratory Testing

  • See Screening for information concerning at-risk individuals/those who should be screened
  • Testing recommendations for HCV (CDC)
    • Initial testing
      • HCV serology screen by chemiluminescence immunoassay (CIA), enzyme immunoassay (EIA)
        • Use for initial testing in patient with suspected HCV
        • High rate of false positives and positive serology due to past (inactive) infection – confirmatory testing for active infection by HCV RNA is required
    • Follow-up testing
      • HCV RNA
        • Indications
          • Positive HCV serology test – confirm active infection
          • Immunocompromised individuals – serology is dependent on ability to mount immune response; HCV RNA should be first test in these patients
          • HCV exposure in previous 6 months – test for RNA, not serology
          • Concern for reinfection following successful HCV treatment
          • Prior to start of treatment – document baseline RNA elevation
        • Tests
          • Quantitative – provides information about RNA viral load
          • Qualitative – less expensive than quantitative; however, in most cases quantification is needed for purposes other than confirmation, so quantitative testing is preferred over qualitative
      • HCV genotyping
        • Indications guide selection of direct acting antiviral (DAA) therapy
        • Tests
          • Traditional genotyping sequencing – usually sufficient to direct therapy
          • Next generation sequencing – sometimes indicated if relevant variants are suspected outside of the regions used to determine the standard genotype
      • Resistance-associated variant (RAV) testing – NS5A
        • Not appropriate to perform prior to genotype testing
        • Consider before treatment with NS5A inhibitors

Prognosis

  • Genotype influences response to therapy
  • Viral load (as measured by quantitative assay) predicts likelihood of treatment response
  • Coinfection with hepatitis B (HBV) predicts poorer prognosis
  • Presence or absence of cirrhosis (stable or decompensated) will influence response
  • With advent of new, highly effective therapies, compliance may be most influential determinant

Differential Diagnosis

Screening

  • Screening indications
    • Date of birth between 1945-1965 – test at least once (American Association for the Study of Liver Diseases [AASLD]/Infectious Diseases Society of America [IDSA], 2018; Smith, CDC, 2012; Moyer, U.S. Preventive Services Task Force [USPSTF], 2013)
    • Injection drug use or HIV infection in men who have unprotected sex with men – test annually
    • Risk behaviors or exposures for HCV infection (see AASLD/IDSA recommendations, 2018)  – test once
      • Risk behaviors
        • Injection drug use (current or ever, including one-time use)
        • Intranasal illicit drug use
      • Risk exposures
        • Patients with long-term hemodialysis (ever)
        • People with percutaneous exposures in unregulated settings
        • Healthcare, emergency medical, and public safety workers after needlestick, sharps, or mucosal exposure to HCV-infected blood
        • Babies born to HCV-infected mothers
        • Prior recipients of transfusions, including individuals who
          • Were notified that they received blood from a donor who later tested positive for HCV infection
          • Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992
          • Received clotting factor concentrates produced before 1987
          • Have been incarcerated
          • Are HIV positive
      • Other circumstances and medical conditions
        • HIV infection
        • Screening sexually-active persons about to start preexposure prophylaxis for HIV
        • Unexplained chronic liver disease and chronic hepatitis, including elevated alanine aminotransferase levels
        • Solid organ donation
  • Laboratory testing (refer to Diagnosis)
    • Initial screening for HCV antibodies by CIA, EIA, enzyme-linked immunosorbent assay (ELISA)
    • Confirmatory RNA testing required for positive result

Monitoring

  • HCV RNA quantitative assay
    • Establish viral load at baseline
    • Evaluate response to therapy at 4 weeks
    • Reevaluate at end of prescribed duration of therapy

Background

Epidemiology

  • Prevalence – estimated 2.7-3.9 million infected in the U.S. (CDC)
    • >50% of new cases are caused by intravenous drug use; majority of previous U.S. cases were attributed to transfusion of infected blood products
  • Sex – M:F, equal

Organism

  • Single-stranded RNA virus; member of Flaviviridae family (genus Hepacivirus)
  • Multiple genotypes with multiple subtypes (1a, 1b, 1c, etc.)
    • Genotype is an important predictor of virological response to HCV treatment
      • Type 1 is predominant genotype in U.S. and more difficult to treat
      • Clinically, type 1 subtypes (1a and 1b) are most relevant

Risk Factors

Refer to Screening.

Clinical Presentation

  • HCV is typically asymptomatic as an acute infection
    • Infection may be initially identified when patient has positive anti-HCV in a blood donor screen or has high alanine aminotransferase level (10-20 times the upper limit of normal) in blood chemistry testing for flu-like symptoms
  • Chronic disease occurs in ~10-20% of patients
    • Cirrhosis – 20%
    • Hepatocellular carcinoma – 1-5%
  • Chronic asymptomatic hepatitis may manifest with other systemic symptoms
    • Mixed cryoglobulinemia – systemic vasculitis involving skin, kidneys, nervous system
    • Sjögren syndrome – anti-Sjögren syndrome A (anti-SSA) and anti-Sjögren syndrome B (anti-SSB) antibodies are usually absent or are present at low levels
    • Lichen planus – violaceous papules on any skin site; oral most common
    • Porphyria cutanea tarda
    • Non-Hodgkin lymphoma – B-cell type most common
  • Pregnant women
    • Not transmitted to infant via breastfeeding 
    • Pregnancy not contraindicated

ARUP Laboratory Tests

Preferred reflex test for screening and confirming HCV in at-risk individuals

Reflex pattern: if positive, reflexes to quantitative HCV NAAT to confirm HCV infection

Preferred single screening test for one-time screening of population born between 1945-1965 and individuals at risk for HCV

Positive results require confirmation by molecular testing (eg, HCV by quantitative assay or HCV by quantitative assay with reflex to HCV genotype by sequencing)

Preferred reflex test to confirm active HCV infection following positive HCV screen

Use when a higher level of subtype resolution is required

Reflex test to confirm active HCV infection following positive HCV screen

Reflex to genotype aids in prognosis and treatment selection

Preferred single test to confirm HCV infection following positive HCV antibody screen

Do not order prior to molecular confirmation of positive HCV screen

Due to high conservation of the 5' untranslated region of the HCV genome, this test has limitations in differentiating subtype 1a from 1b; therefore, these subtypes will be reported as "1a or 1b"

In rare instances, type 6 virus may be misclassified as type 1

Test may be unsuccessful if HCV RNA viral load is <log 3.6 or 4,000 IU/mL

Reflex genotyping panel for prognosis and treatment selection when a higher level of subtype resolution is required

Do not order prior to molecular confirmation of positive HCV screen

Test may be unsuccessful if HCV RNA viral load is <log 5.0 or 100,000 IU/mL

Reflex pattern: if initial result is 1a or 1b, a mixed genotype containing type 1 or type 6, then genotyping will be added

Predict response to peginterferon (PEG-IFNα)/ribavirin (RBV) therapy for chronic HCV genotype 1 (HCV-1) infection

Single nucleotide polymorphisms (SNPs) other than those targeted will not be detected

Usefulness of IL28B-associated SNPs for predicting therapy response for HCV genotypes other than HCV-1 is unknown

Other gene variants and nongenetic factors that may affect response to HCV therapy are not detected

Diagnostic errors can occur due to rare sequence variations

Related Tests

Evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes hepatitis A virus (HAV) IgM, HBV core antibody IgM, HBV surface antigen (HBsAg), and HCV antibody

Reflex pattern: if results for HBsAg are repeatedly reactive with an index value between 1.00-50.00, then HBsAg confirmation will be added

Can be ordered as part of the acute hepatitis panel, which includes HAV IgM, HBV core antibody IgM, HBsAg, and HCV antibody

Reflex pattern: if results for HBsAg screen are repeatedly reactive with an index value between 1.00-50.00, then HBsAg confirmation will be added

Diagnose acute HAV infection

Refer to panel test that includes HAV IgM, HBV core antibody IgM, HBsAg, and HCV antibody

Can be ordered as part of the acute hepatitis panel, which includes HAV IgM, HBV core antibody IgM, HBsAg, and HCV antibody to determine if patient has acute HBV infection

Refer to hepatitis panel, acute with reflex to HBsAg confirmation

Monitor postliver transplant therapy with hepatitis B immunoglobulin in HBV-positive patients and ascertain response to HBV vaccines

Noninvasive, serum surrogate marker test for assessment of liver fibrosis in patients with chronic viral hepatitis

Blood markers: alpha-2-macroglobulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), gamma glutamyl transferase (GGT), platelets, and prothrombin index

Noninvasive assessment of liver fibrosis in patients with chronic viral hepatitis B or C (with or without HIV coinfection) and in patients with hepatic steatosis

Test can performed only if the patient has a FibroScan score

Result based on both a panel of serum biomarkers (FibroMeter) and the FibroScan Vibration Controlled Transient Elastography (VCTE), a noninvasive, diagnostic ultrasound-based test that measures liver fibrosis

Order before initiating HCV therapy to aid in prognosis and therapy selection when a higher level of subtype resolution is required (ie, non 6a and 6b vs. type 1 and type 1a vs. 1b)

Do not order prior to molecular confirmation of positive HCV screen

Recommended testing for HCV genotype 1 patients prior to initiating simeprevir therapy

Order before initiating treatment with NS5A inhibitors

Determine HCV type 1-6 after molecular confirmation of positive HCV screen

Reflex pattern: if genotype “1a or 1b” is determined, then HCV NS5A for genotype differentiation and drug resistance by sequencing will be added

Order before initiating treatment with NS5A inhibitors

Do not order prior to molecular confirmation of positive HCV screen and confirmation of genotype 1a or 1b

Medical Experts

Contributor
Contributor
Contributor

McMillin

Gwendolyn A. McMillin, PhD
Professor of Clinical Pathology, University of Utah
Scientific Director, Mass Spectrometry Platform; Medical Director, Clinical Toxicology and Pharmacogenomics, ARUP Laboratories
Contributor

Slev

Patricia R. Slev, PhD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories
Medical Director, Serologic Hepatitis and Retrovirus and Immunology Core Laboratory
Co-Medical Director, Microbial Immunology, at ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®