Hepatitis C Virus

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

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 of the liver leading to cirrhosis and an increased risk of hepatocellular carcinoma.

Epidemiology

Prevalence - greater than 50% of new cases in U.S. are caused by intravenous drug use
- 2% of U.S. population is infected
- 19,000 estimated new cases in 2006 in U.S.
Age - peak 30-49 years
Sex - equal M:F
Transmission
- Parenteral

Organism

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

Risk Factors

Transfusion with blood or blood products prior to 1990
- Current transfusion risk is 1/400,000 units transfused
Positive result for another blood-borne pathogen (eg, HBV, HIV)
History of intravenous drug or intranasal cocaine use
Sexual transmission from HCV-positive partner
Organ transplant recipient

Clinical Presentation

Typically asymptomatic in acute HCV infection
- HCV infection is usually not suspected until the patient donates blood and has a positive anti-HCV or patient has chemistry testing performed for flu-like symptoms and has a high ALT (alanine aminotransferase) (10-20 times the upper limit of normal)
Chronic asymptomatic hepatitis may manifest with systemic symptoms
- Mixed cryoglobulinemia - systemic vasculitis involving the skin, kidney and nervous system
- Sjögren syndrome - anti SSA and SSB antibodies are usually absent or only present in low levels
- Lichen planus - violaceous papules on any skin site; oral most common in HCV
- Porphyria cutanea tarda
- Non-Hodgkin lymphoma - 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

See Also

Cirrhosis

Cryoglobulinemia - Cryoglobulin

Hemochromatosis

Hepatitis A Virus - HAV

Hepatitis B Virus - HBV

Hepatitis Delta Virus - HDV

Hepatitis, Acute

Hepatitis, Autoimmune - AIH

Hepatocellular Carcinoma

Liver Disease Evaluation

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Hepatitis C Virus Testing Algorithm

Hepatitis Virus Screening Algorithm

Diagnosis

Indications for testing
- New onset of jaundice, anorexia or dark urine
- Known exposure to hepatitis
- Suspicion of chronic hepatitis (elevated liver enzyme)
- Screening for acute hepatitis indicates hepatitis C infection
  - Hepatitis screening panel test includes hepatitis B core antibody IgM, hepatitis A IgM, hepatitis C antibody and hepatitis B surface antigen
Laboratory testing
- HCV by CIA or ELISA
  - Low positive - perform RIBA
    - RIBA negative - patient was never infected
    - RIBA positive - perform hepatitis C virus RNA quantitative test
      - Negative quantitative test - infected, but recovered
      - Positive quantitative test - currently infected (chronic HCV)
        Perform hepatitis C genotyping - typing 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 hepatitis C virus RNA quantitative test
    - Negative - perform RIBA
      - RIBA negative - never infected
      - RIBA indeterminate - possibly infected but recovered
      - RIBA positive - infected and recovered
    - Positive - currently infected (chronic HCV)
      - Perform hepatitis C genotyping - typing 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

Disease Monitoring

Hepatitis C virus RNA quantitative test to monitor treatment effect - monthly until week 12 of treatment
Hepatitis C virus RNA qualitative test at end of treatment
- Negative result confirms successful treatment

Disease Screening

U.S. Preventative (2004) Services Task Force recommends against routine screening
National Gastroenterology and Hepatology societies disagree with the task force recommendation

Differential Diagnosis

Chronic hepatitis B
Autoimmune hepatitis
Toxin-induced hepatitis
Alcoholic liver disease
Nonalcoholic acute steatohepatitis (NASH)
Epstein-Barr virus
Cytomegalovirus
Enterovirus
Hepatitis E in patients from endemic area
Tuberculosis
Sarcoidosis
Drug-induced hepatitis
Hematochromatosis
Wilson disease
Alpha-1-antitrypsin

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Hepatitis C Virus Testing Algorithm

Hepatitis Virus Screening Algorithm

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Hepatitis C Virus Antibody

ARUP #: 0020099

Methodology: Chemiluminescent Immunoassay

Use:

Screen individuals at risk for HCV infection

Follow-up:

For high positive results, collect a new specimen and order quantitative hepatitis C viral load.

Order genotyping once diagnosis is established

Test name: Hepatitis C Virus Antibody (RIBA), Supplemental

ARUP #: 0020104

Methodology: Recombinant Immunoblot Assay

Use:

Use for patients with low-positive anti-HCV screening results

Limitations:

HCV RIBA is excessively ordered

Do not use to confirm high positive anti-HCV screening results

Follow-up:

Test name: Hepatitis C Virus Antibody with Reflex to Supplemental RIBA

ARUP #: 0020700

Methodology: Chemiluminescent Assay/Recombinant Immunoblot Assay

Use:

Screen individuals at risk for HCV infection; includes automatic RIBA for low-positive screens

Limitations:

Follow-up:

Test name: Hepatitis C Virus RNA Quantitative, Real-Time PCR

ARUP #: 0098268

Methodology: Real-Time Polymerase Chain Reaction

Use:

Diagnose HCV infection in anti-HCV positive patients

Provide a baseline for monitoring treatment efficacy

Determine length of treatment

Guide therapy by early identification of patients who are unlikely to have a 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 mother-to-child transmission of HCV in newborns of HCV-positive mothers

Limitations:

A negative result does not rule out the presence of PCR inhibitors in the patient sample nor HCV RNA concentrations below the level of detection by the assay (75 IU/mL)

False-positive results may occur

Follow-up:

For lower levels of HCV viremia, order HCV RNA qualitative testing

Test name: Hepatitis C Virus RNA Qualitative PCR

ARUP #: 0098264

Methodology: Polymerase Chain Reaction

Use:

Most physicians prefer the quantitative test (0098268) for monitoring early treatment

Monitor ongoing viral response to therapy when quantitative test is negative

Assess end of treatment response

Assess mother-to-child transmission of HCV in newborns of HCV-positive mothers

Limitations:

A negative result does not rule out the presence of PCR inhibitors in the patient sample nor HCV RNA concentrations below the level of detection by the assay (50 IU/mL)

False-positive results may occur

Test name: Hepatitis C Virus RNA Quantitative bDNA

ARUP #: 0098757

Methodology: Branched Chain DNA

Use:

Diagnose HCV infection in anti-HCV positive patients

Provide a baseline viral load for monitoring treatment efficacy

Determine length of treatment

Limitations:

Low (<6000 IU/mL) false-positive results can occur

A negative result does not rule out HCV RNA concentrations below the level of detection by the assay (615 HCV IU/mL)

Caution should be taken in the interpretation of any single viral load determination

Follow-up:

For lower levels of HCV viremia, order HCV RNA qualitative PCR

Test name: Hepatitis C Virus Genotyping by PCR & Sequencing

ARUP #: 0055593

Methodology: Polymerase Chain Reaction/Nucleic Acid Sequencing

Use:

Identify genotypes to determine therapeutic regimens

Identify source of infection, particularly for geographically distinct subtypes

Limitations:

Very low viral loads (<1,000 IU/mL) may not amplify by PCR and, therefore, cannot be typed

Test name: Hepatitis C Virus RNA Quantitative by Real-Time PCR with Reflex to Genotype

ARUP #: 0055604

Methodology: Real-Time Polymerase Chain Reaction/Sequencing

Use:

Diagnose HCV infection in anti-HCV positive patients

Provide baseline viral load for monitoring treatment efficacy

Determine length of treatment

Determine genotype if infected

Limitations:

Follow-up:

Test name: Hepatitis C Virus RNA Quantitative bDNA with Reflex to Genotype

ARUP #: 0051306

Methodology: Branched Chain DNA/Sequencing

Use:

Diagnose HCV infection in anti-HCV positive patients

Provide a baseline viral load for monitoring treatment efficacy

Determine length of treatment

Determine genotype if infected

Limitations:

Follow-up:

Test name: Hepatitis C Virus RNA Quantitative with Reflex to Qualitative PCR

ARUP #: 0056114

Methodology: Polymerase Chain Reaction

Use:

Monitor ongoing treatment

Reflexes to more sensitive test, as needed

Test name: Hepatitis C Virus RNA Quantitative bDNA with Reflex to Qualitative PCR

ARUP #: 0051307

Methodology: Branched Chain DNA/Polymerase Chain Reaction

Use:

Monitor ongoing treatment

Reflexes to more sensitive test, as needed

Additional Tests Available

Test name: Hepatitis C Virus RNA Quantitative bDNA with Reflex to Genotype

ARUP #: 0051306

Methodology: Branched Chain DNA/Sequencing

Comments:

Test name: Hepatitis C Virus RNA Quantitative by Real-Time PCR with Reflex to Genotype

ARUP #: 0055604

Methodology: Real-Time Polymerase Chain Reaction/Sequencing

Comments:

Test name: Hepatitis C Virus RNA Quantitative with Reflex to Qualitative PCR

ARUP #: 0056114

Methodology: Polymerase Chain Reaction

Comments:

Test name: Hepatitis C Virus RNA Quantitative by Real-Time PCR with Reflex to Hepatitis C Virus Antibody (RIBA), Supplemental

ARUP #: 0051632

Methodology: Real-Time Polymerase Chain Reaction/Recombinant Immunoblot

Comments:

Test name: Hepatitis C Virus RNA Quantitative bDNA with Reflex to Hepatitis C Virus Antibody (RIBA), Supplemental

ARUP #: 0051630

Methodology: Branched Chain DNA/Recombinant Immunoblot Assay

Comments:

Test name: Hepatitis C Virus RNA Qualitative PCR with Reflex to Hepatitis C Virus Antibody (RIBA), Supplemental

ARUP #: 0051628

Methodology: Real-Time Polymerase Chain Reaction/Recombinant Immunoblot

Comments:

References

Guidelines

Diagnosis, management, and treatment of hepatitis C. American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2004 Apr. 25 pages. NGC:003591

Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. Centers for Disease Control and Prevention - Federal Government Agency [U.S.]. 2003 Feb 7. 14 pages. NGC:002846

Screening for hepatitis C in adults: recommendation statement. United States Preventive Services Task Force - Independent Expert Panel. 2004 Mar 16. 11 pages. NGC:003371

Sherman M, Bain V, Villeneuve JP, Myers RP, Cooper C, Martin S, Lowe C. The management of chronic viral hepatitis: a Canadian consensus conference 2004. Can J Gastroenterol. 2004;18(12):715-728.

NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19(3):1-46.

General References

Bialek SR, Terrault NA. The changing epidemiology and natural history of hepatitis C virus infection. Clin Liver Dis. 2006;10(4):697-715.

Blackard JT, Shata MT, Shire NJ, Sherman KE. Acute hepatitis C virus infection: a chronic problem. Hepatology. 2008;47(1):321-331.

Caruntu FA, Benea L. Acute hepatitis C virus infection: Diagnosis, pathogenesis, treatment. J Gastrointestin Liver Dis. 2006;15(3):249-256.

Chevaliez S, Pawlotsky JM. Hepatitis C virus: virology, diagnosis and management of antiviral therapy. World J Gastroenterol. 2007;13(17):2461-2466.

Craxi A, Laffi G, Zignego AL. Hepatitis C virus (HCV) infection: a systemic disease. Mol Aspects Med. 2008;29(1-2):85-95.

Degertekin B, Lok AS. Update on viral hepatitis: 2007. Curr Opin Gastroenterol. 2008;24(3):306-311.

Deutsch M, Hadziyannis SJ. Old and emerging therapies in chronic hepatitis C: an update. J Viral Hepat. 2008;15(1):2-11.

Ferreira-Gonzalez A, Shiffman ML. Use of diagnostic testing for managing hepatitis C virus infection. Semin Liver Dis. 2004;24 Suppl 2:9-18.

Galossi A, Guarisco R, Bellis L, Puoti C. Extrahepatic manifestations of chronic HCV infection. J Gastrointestin Liver Dis. 2007;16(1):65-73.

Hnatyszyn HJ. Chronic hepatitis C and genotyping: the clinical significance of determining HCV genotypes. Antivir Ther. 2005;10(1):1-11.

Kamal SM. Acute hepatitis C: a systematic review. Am J Gastroenterol. 2008;103(5):1283-1297.

Modi AA, Liang TJ. Hepatitis C: a clinical review. Oral Dis. 2008;14(1):10-14.

Mohsen A, Norris S. Hepatitis C (chronic). Clin Evid. 2006;(15):1061-1072.

Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA. 2007;297(7):724-732.

Sjogren MH. Management of hepatitis C. Gastroenterology. 2006;131(1):332-333.

Zoulim F. New nucleic acid diagnostic tests in viral hepatitis. Semin Liver Dis. 2006;26(4):309-317.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Konnick EQ, Erali M, Ashwood ER, Hillyard DR. Performance characteristics of the COBAS Amplicor Hepatitis C Virus (HCV) Monitor, Version 2.0, International Unit assay and the National Genetics Institute HCV Superquant assay. J Clin Microbiol. 2002;40(3):768-773.

Konnick EQ, Williams SM, Ashwood ER, Hillyard DR. Evaluation of the COBAS Hepatitis C Virus (HCV) TaqMan analyte-specific reagent assay and comparison to the COBAS Amplicor HCV Monitor V2.0 and Versant HCV bDNA 3.0 assays. J Clin Microbiol. 2005;43(5):2133-2140.

Liew M, Erali M, Page S, Hillyard D, Wittwer C. Hepatitis C genotyping by denaturing high-performance liquid chromatography. J Clin Microbiol. 2004;42(1):158-163.

Margraf RL, Erali M, Liew M, Wittwer CT. Genotyping hepatitis C virus by heteroduplex mobility analysis using temperature gradient capillary electrophoresis. J Clin Microbiol. 2004;42(10):4545-4551.

Margraf RL, Page S, Erali M, Wittwer CT. Single-tube method for nucleic acid extraction, amplification, purification, and sequencing. Clin Chem. 2004;50(10):1755-1761.

Medical Reviewers

Hillyard, David R., M.D. Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Slev, Patricia , Ph.D. Assistant Medical Director, Hepatitis and Retrovirus Serology and Special Chemistry at ARUP Laboratories

Comprehensive Review: September 2008
Last Update: September 2008