Hepatitis C Virus - HCV

Background
Dx
Screen
Monitor
Lab Tests
Algorithm

Diagnostic Algorithm

Hepatitis C Virus Testing Algorithm

Hepatitis Virus Screening Algorithm

Clinical Background

Hepatitis C 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.

Epidemiology

Prevalence – 2% of U.S. population is infected
- >50% of new cases are caused by IV drug use
- 19,000 estimated new cases in 2006.
Age – peaks in 30s-40s
Sex – M:F, equal
Transmission – parenteral (only 50% have one of these known routes)
- IV drug use
- Blood and tissue products
- Organ transplantation
- HCV-positive sexual partner

Organism

Single-stranded RNA (ssRNA) virus, member of Flaviviridae family (genus Hepacivirus)
Six major genotypes with multiple subtypes (1a, 1b, 1c, etc.)
- Genotype is an important predictor of virologic response to HCV treatment
  - Type 1 is predominant genotype in U.S.
  - Types 2 and 3 are less aggressive and easier to treat

Risk Factors

Transfusion with blood or blood products prior to 1990
- Current risk is 1/400,000 units transfused
Infected with another blood-borne pathogen (eg, HBV, HIV)
History of IV drug or intranasal cocaine use
HCV-positive sexual partner
Organ transplant recipient

Clinical Presentation

HCV typically asymptomatic in acute infection
- Infection may be identified when patient has a positive anti-HCV in a blood donor screen or has high alanine aminotransferase (ALT) in blood chemistry testing for flu-like symptoms (10-20 times the upper limit of normal)
Chronic asymptomatic hepatitis may manifest with other systemic symptoms
- Mixed cryoglobulinemia – systemic vasculitis involving skin, kidneys, nervous system
- Sjögren syndrome – anti SSA and SSB antibodies are usually absent or present in low levels
- Lichen planus – violaceous papules on any skin site; oral most common
- Porphyria cutanea tarda
- Non-Hodgkin lymphoma (NHL) – B-cell type most common
Chronic disease states occur in up to 85% of patients
- Cirrhosis (20%) and hepatocellular carcinoma (1-5%)
Pregnant females
- Routine HCV screening not recommended
- Not transmitted to infant via breast feeding
- Pregnancy not contraindicated

Treatment

Moderately effective
Genotypes 2 and 3 have more favorable prognosis and treatment response

Diagnosis

Indications for Testing

New onset of jaundice, anorexia or dark urine
Known exposure to hepatitis
Suspicion of chronic hepatitis (elevated liver enzyme)

Laboratory Testing

Initial testing – rule out hepatitis A (HAV) or B (HBV) in acute presentation;
- Perform HAV antibody IgM, HBV core antibody IgM, HBV surface antigen, and HCV antibody testing
  - Positive HCV from hepatitis panel – perform HCV by CIA or ELISA
HCV by CIA or ELISA
- Low-positive – perform recombinant immunoblot assay (RIBA)
  - RIBA negative or indeterminate – patient never infected
  - RIBA positive – perform HCV RNA PCR quantitative test
    - Quantitative negative – prior infection but recovered or never infected (false-positive result)
    - Quantitative positive – currently infected (chronic HCV)
      - Perform HCV genotyping – genotype affects rate of treatment success
      - Consider biopsy (liver) – if patient is genotype 1 or 4, response rate to treatment is low and degree of fibrosis may determine whether to treat the patient
- High-positive – perform HCV RNA quantitative test
  - Quantitative negative – perform RIBA
    - RIBA negative – never infected (false-positive screen)
    - RIBA indeterminate – possible prior infection but recovered, or false positive screen
    - RIBA positive – prior infection but recovered
  - Quantitative positive – currently infected (chronic HCV)
    - Perform HCV genotyping – genotype affects rate of treatment success
    - Consider biopsy (liver) – if patient is genotype 1 or 4, response rate to treatment is low and degree of fibrosis may determine whether to treat the patient

Differential Diagnosis

Viral
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
- Herpes simplex virus (HSV)
- Varicella-zoster virus (VZV)
- Hepatitis A, B, D or E
Toxin exposure
- Alcohol
- Tetrachloride
Nonalcoholic acute steatohepatitis (NASH)
Drug-induced hepatitis
- Acetaminophen
- Antiseizure medications
- Isoniazid (Nydrazid)
- Oral contraceptives
- Rifampin (Rifadin)
- Sulfonamides
Autoimmune disease
- Systemic lupus erythematosus (SLE)
- Primary biliary cirrhosis (PBC)
- Sclerosing cholangitis
- Autoimmune hepatitis (AIH)
Bacterial infection
- Leptospirosis
- Q-fever (Coxiella burnetii)
- Rocky Mountain spotted fever (Rickettsia rickettsii)
- Secondary syphilis (Treponema pallidum)
- Sepsis
- Typhoid fever (Rickettsia typhus)
Granulomatous
- Mycobacterium tuberculosis (TB)
- Sarcoidosis
Hereditary
- Wilson disease
- Hemochromatosis
- Alpha-1-antitrypsin deficiency (AAT)
Ischemic
Parasitic
- Liver trematodes
- Toxocariasis

Screening

U.S. Preventative (2004) Services Task Force, American Gastroenterological Association, recommends against routine screening in low-risk populations
- National Gastroenterology and Hepatology societies disagree with the task force recommendation
Patients in high-risk populations (eg, IV-drug use, immigrant from endemic areas)

Monitoring

HCV RNA quantitative test – monitor effectiveness of treatment
- Monthly until week 12 of treatment
HCV RNA qualitative test – perform when treatment is completed
- Negative result confirms treatment success

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Hepatitis A Virus Antibody, IgM 0020093 Method: Chemiluminescent Immunoassay	Rule out acute HAV
Hepatitis B Virus Core Antibody, IgM 0020092 Method: Chemiluminescent Immunoassay	Rule out HBV
Hepatitis B Virus Surface Antibody 0020090 Method: Chemiluminescent Immunoassay	Determine immunity to HBV
Hepatitis C Virus Antibody by CIA 2002483 Method: Chemiluminescent Immunoassay	Screen individuals at risk for HCV infection		For high positive results, collect a new specimen and order quantitative hepatitis C viral load. Order genotyping once diagnosis is established
Hepatitis C Virus Antibody (RIBA), Supplemental 0020104 Method: Recombinant Immunoblot Assay	Use for patients with low-positive anti-HCV screening results	HCV RIBA is excessively ordered Do not use to confirm high positive anti-HCV screening results
Hepatitis C Virus RNA Quantitative, Real-Time PCR 0098268 Method: Real-Time Polymerase Chain Reaction	Diagnose HCV infection in anti-HCV positive patients Provide baseline for monitoring treatment efficacy Determine length of treatment Guide therapy by early identification of patients who are unlikely to have sustained therapeutic response (Failure to lower HCV quantitative levels during the first 12 weeks of therapy strongly predicts that a sustained therapeutic response will not be achieved) Assess transmission of HCV in newborns from HCV-positive mothers	Negative result does not rule out the presence of PCR inhibitors in the patient sample or the presence of HCV RNA concentrations below the level of detection by the assay False-positives may occur	For lower levels of HCV viremia, order HCV RNA qualitative testing
Hepatitis C Virus RNA Qualitative PCR 0098264 Method: Polymerase Chain Reaction	Quantitative test (0098268) generally preferred for monitoring early treatment Monitor ongoing viral response to therapy when quantitative test is negative Assess response at end of treatment Assess transmission of HCV in newborns from HCV-positive mothers	Negative result does not rule out the presence of PCR inhibitors in the patient sample or the presence of HCV RNA concentrations below the level of detection by the assay False-positives may occur
Hepatitis C Virus RNA Quantitative bDNA 0051811 Method: Branched Chain DNA	Diagnose HCV infection in anti-HCV positive patients Provide a baseline viral load for monitoring treatment efficacy Determine length of treatment Guide therapy by early identification of patients who are unlikely to have sustained therapeutic response (Failure to lower HCV quantitative levels during the first 12 weeks of therapy strongly predicts that sustained therapeutic response will not be achieved)	Low false-positives can occur Negative result does not rule out the presence of PCR inhibitors in the patient sample or the presence of HCV RNA concentrations below the level of detection by the assay Low-positive values may occasionally be seen in specimens from patients who are not infected Use HCV RNA Qualitative by PCR (0098264) to assess low levels of HCV viremia	For lower levels of HCV viremia, order HCV RNA qualitative PCR
Hepatitis C Virus Genotyping 0055593 Method: Polymerase Chain Reaction/Nucleic Acid Sequencing	Identify genotypes to determine therapeutic regimens Identify source of infection, particularly for geographically distinct subtypes	Very low viral loads may not amplify by PCR and, therefore, cannot be typed

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Hepatitis C Virus Antibody with Reflex to Supplemental RIBA 0020700 Method: Chemiluminescent Immunoassay/Recombinant Immunoblot Assay	Screen individuals at risk for HCV infection; includes automatic RIBA for low-positive screens
Hepatitis C Virus RNA Quantitative bDNA with Reflex to Hepatitis C Virus RNA Quantitative, Real-Time PCR 2002682 Method: Branched Chain DNA/Polymerase Chain Reaction	Used for diagnostic purposes
Hepatitis C Virus RNA Quantitative bDNA with Reflex to Genotype 2002681 Method: Branched Chain DNA/Sequencing	Diagnose HCV infection in anti-HCV positive patients and determine genotype Provide baseline viral load for monitoring treatment efficacy Determine length of treatment
Hepatitis C Virus RNA Quantitative Real-Time PCR with Reflex to Genotype 2002685 Method: Real-Time Polymerase Chain Reaction/Sequencing	Diagnose HCV infection in anti-HCV positive patients and determine genotype Provide baseline viral load for monitoring treatment efficacy Determine length of treatment
Hepatitis C Virus RNA Quantitative by Real-Time PCR with Reflex to Hepatitis C Virus Antibody (RIBA), Supplemental 2002686 Method: Real-Time Polymerase Chain Reaction/Recombinant Immunoblot
Hepatitis C Virus RNA Qualitative PCR with Reflex to Hepatitis C Virus Antibody (RIBA), Supplemental 2002684 Method: Real-Time Polymerase Chain Reaction/Recombinant Immunoblot