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.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

New onset of jaundice, anorexia, or dark urine
Elevated liver enzymes
Known or suspected exposure to hepatitis C virus (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
      - Polymerase chain reaction (PCR) by Sanger – may be sufficient to determine genotype and direct therapy
      - Next generation sequencing, other deep-sequencing tests – sometimes indicated if further genotyping is required
  - Resistance-associated variant (RAV) testing – NS5A
    - Not appropriate to perform prior to genotype testing
    - Recommended at baseline for patients with HCV genotype 1a prior to initiation of treatment with NS5A inhibitors (eg, elbasvir plus grazoprevir)
    - Consider for patients with genotype 1a and cirrhosis prior to treatment with sofosbuvir plus daclatasvir

Prognosis

Genotype influences response to therapy
Viral load (as measured by quantitative PCR) 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

Viral
- Cytomegalovirus
- Epstein-Barr virus
- Herpes simplex virus
- Varicella-zoster virus
- Hepatitis A, B, D, or E
Toxin exposure
- Alcohol
- Tetrachloride
Nonalcoholic acute steatohepatitis
Drug-induced hepatitis
- Acetaminophen
- Antiseizure medications
- Isoniazid (Nydrazid)
- Oral contraceptives
- Rifampin (Rifadin)
- Sulfonamides
Autoimmune disease
- Systemic lupus erythematosus
- Primary biliary cirrhosis
- Sclerosing cholangitis
- Autoimmune hepatitis
Bacterial infection
- Leptospira spp
- Coxiella burnetii (Q-fever)
- Rickettsia rickettsii (Rocky Mountain spotted fever)
- Treponema pallidum (secondary syphilis)
- Sepsis
- Rickettsia typhi (typhus fever)
Granulomatous
- Mycobacterium tuberculosis
- Sarcoidosis
Hereditary
Ischemia
Parasitic
- Liver trematodes
- Toxocara spp

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], 2017; 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 hepatitis C (HCV) infection (see AASLD/IDSA recommendations, 2017) – test once
  - Risk behaviors
    - Injection drug use (current or ever, including 1-time use)
    - Intranasal illicit drug use
  - Risk exposures
    - Patients with long-term hemodialysis (ever)
    - 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 medical conditions
    - Unexplained chronic liver disease and chronic hepatitis, including elevated alanine aminotransferase levels
Laboratory testing (refer to Diagnosis)
- Initial screening for HCV antibodies by chemiluminescence immunoassay (CIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA)
- Confirmatory RNA testing required for positive result

Monitoring

Hepatitis C virus (HCV) RNA quantitative polymerase chain reaction (PCR) test
- 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 hepatitis C virus (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%) and 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 Lab Tests

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.

Hepatitis C Virus Antibody by CIA with Reflex to HCV by Quantitative PCR 2010784
Method: Qualitative Chemiluminescent Immunoassay/Quantitative Polymerase Chain Reaction

Recommended Use

Preferred reflex test for screening and confirming hepatitis C virus (HCV) in at-risk individuals

Reflex pattern – if positive, reflexes to quantitative HCV polymerase chain reaction (PCR) to confirm HCV infection

Hepatitis C Virus Antibody by CIA 2002483
Method: Qualitative Chemiluminescent Immunoassay

Recommended Use

Preferred single screening test for 1-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 PCR or HCV by quantitative PCR with reflex to HCV genotype by sequencing)

Hepatitis C Virus (HCV) by Quantitative PCR with Reflex to HCV Genotype by Sequencing 2002685
Method: Quantitative Polymerase Chain Reaction/Sequencing

Recommended Use

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

Reflex to genotype aids in prognosis and treatment selection

Reflex pattern – if PCR result is ≥3.6 log IU/mL, then HCV genotype by sequencing will be added

Limitations

If virus is not detected, result will be reported as <1.2 log IU/mL; if virus is detected but number of copies is not accurately quantified, result will be reported as not quantified

Hepatitis C Virus by Quantitative PCR 0098268
Method: Quantitative Polymerase Chain Reaction

Recommended Use

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

Limitations

If virus is not detected, result will be reported as <1.2 log IU/mL; if virus is detected but number of copies is not accurately quantified, result will be reported as not quantified

Hepatitis C Virus Genotype by Sequencing 0055593
Method: Polymerase Chain Reaction/Sequencing

Recommended Use

Preferred genotyping test for prognosis and treatment selection

Do not order prior to molecular confirmation of positive HCV screen

Assay does not differentiate between type 1a and type 1b

Limitations

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

Hepatitis C Virus (HCV) by Quantitative PCR with Reflex to HCV High-Resolution Genotype by Sequencing 2010793
Method: Quantitative Polymerase Chain Reaction/Sequencing

Recommended Use

Confirm active HCV infection following positive HCV screen when a higher level of subtype resolution is required

Reflex pattern – if PCR is ≥5.0 log IU/mL, then HCV high-resolution genotype by sequencing will be added

Limitations

If virus is not detected, result will be reported as <1.2 log IU/mL; if virus is detected but number of copies is not accurately quantified, result will be reported as not quantified

Hepatitis C Virus (HCV) Genotype with Reflex to HCV High-Resolution Genotype by Sequencing 2009255
Method: Polymerase Chain Reaction/Sequencing

Recommended Use

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

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

Limitations

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

Interleukin 28 B (IL28B)-Associated Variants, 2 SNPs 2004680
Method: Polymerase Chain Reaction/Single Nucleotide Extension

Recommended Use

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

Clinical sensitivity/specificity – unknown

Limitations

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

Medical Reviewers

Hillyard, David R., MD, Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Professor of Biology, University of Utah

Krautscheid, Patti, MS, LCGC, Genetic Counselor, Molecular Genetics and Special Genetics Laboratories at ARUP Laboratories

Lyon, Elaine, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, Medical Director, Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

McMillin, Gwendolyn A., PhD, Medical Director, Toxicology, and Medical Director, Pharmacogenetics, at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Slev, Patricia R., PhD, Laboratory Section Chief, Immunology, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Easterbrook PJ, WHO Guidelines Development Group. Who to test and how to test for chronic hepatitis C infection - 2016 WHO testing guidance for low- and middle-income countries. J Hepatol. 2016; 65(1 Suppl): S46-S66. PubMed

European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2014; 60(2): 392-420. PubMed

Full Report: HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. [Revised: Apr 2017; Accessed: Jun 2017]

Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB, American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011; 54(4): 1433-44. PubMed

Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection. World Health Organization. Geneva, Switzerland [Accessed: Jun 2017]

HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. AASLD/IDSA HCV Guidance Panel. [Updated/Changes: Apr 2017; Accessed: Jun 2017]

Moyer VA, U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013; 159(5): 349-57. PubMed

Ramos-Casals M, Zignego AL, Ferri C, Brito-Zerón P, Retamozo S, Casato M, Lamprecht P, Mangia A, Saadoun D, Tzioufas AG, Younossi ZM, Cacoub P, International Study Group of Extrahepatic Manifestations related to HCV (ISG-EHCV). Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection. J Hepatol. 2017; 66(6): 1282-1299. PubMed

Smith B, Morgan R, Beckett G, et al. Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965. Centers for Disease Control and Prevention. Atlanta, GA [Updated: Aug 2012; Accessed: Jun 2017]

General References

Ahlenstiel G, Booth DR, George J. IL28B in hepatitis C virus infection: translating pharmacogenomics into clinical practice. J Gastroenterol. 2010; 45(9): 903-10. PubMed

Albeldawi M, Ruiz-Rodriguez E, Carey WD. Hepatitis C virus: Prevention, screening, and interpretation of assays. Cleve Clin J Med. 2010; 77(9): 616-26. PubMed

Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010; 139(6): 1865-76. PubMed

Chakravarty R. Diagnosis and monitoring of chronic viral hepatitis: serologic and molecular markers. Front Biosci (Schol Ed). 2011; 3: 156-67. PubMed

Chan J. Hepatitis C. Dis Mon. 2014; 60(5): 201-12. PubMed

Chevaliez S, Hézode C. IL28B polymorphisms and chronic hepatitis C. Gastroenterol Clin Biol. 2010; 34(11): 587-9. PubMed

Cobb B, Heilek G, Vilchez RA. Molecular diagnostics in the management of chronic hepatitis C: key considerations in the era of new antiviral therapies. BMC Infect Dis. 2014; 14 Suppl 5: S8. PubMed

Gullett JC, Nolte FS. Quantitative nucleic acid amplification methods for viral infections. Clin Chem. 2015; 61(1): 72-8. PubMed

Maheshwari A, Thuluvath PJ. Management of acute hepatitis C. Clin Liver Dis. 2010; 14(1): 169-76; x. PubMed

Morrison BJ, Labo N, Miley WJ, Whitby D. Serodiagnosis for tumor viruses. Semin Oncol. 2015; 42(2): 191-206. PubMed

Pearlman BL. The IL-28 genotype: how it will affect the care of patients with hepatitis C virus infection. Curr Gastroenterol Rep. 2011; 13(1): 78-86. PubMed

Sagnelli E, Santantonio T, Coppola N, Fasano M, Pisaturo M, Sagnelli C. Acute hepatitis C: clinical and laboratory diagnosis, course of the disease, treatment. Infection. 2014; 42(4): 601-10. PubMed

Viral Hepatitis - Hepatitis C Information - Testing Recommendations. Centers for Disease Control and Prevention. Atlanta, GA [Accessed: Dec 2016]

Webster DP, Klenerman P, Dusheiko GM. Hepatitis C. Lancet. 2015; 385(9973): 1124-35. PubMed

Wilkins T, Malcolm JK, Raina D, Schade RR. Hepatitis C: diagnosis and treatment. Am Fam Physician. 2010; 81(11): 1351-7. PubMed

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

Bossler A, Gunsolly C, Pyne MT, Rendo A, Rachel J, Mills R, Miller M, Sipley J, Hillyard D, Jenkins S, Essmyer C, Young S, Lewinski M, Rennert H. Performance of the COBAS® AmpliPrep/COBAS TaqMan® automated system for hepatitis C virus (HCV) quantification in a multi-center comparison. J Clin Virol. 2011; 50(2): 100-3. PubMed

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): 768-73. PubMed

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): 2133-40. PubMed

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): 158-63. PubMed

Mallory MA, Lucic DX, Sears MT, Cloherty GA, Hillyard DR. Evaluation of the Abbott realtime HCV genotype II RUO (GT II) assay with reference to 5'UTR, core and NS5B sequencing. J Clin Virol. 2014; 60(1): 22-6. PubMed

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): 4545-51. PubMed

Margraf RL, Page S, Erali M, Wittwer CT. Single-tube method for nucleic acid extraction, amplification, purification, and sequencing. Clin Chem. 2004; 50(10): 1755-61. PubMed

Melis R, Fauron C, McMillin G, Lyon E, Shirts B, Hubley LM, Slev PR. Simultaneous genotyping of rs12979860 and rs8099917 variants near the IL28B locus associated with HCV clearance and treatment response. J Mol Diagn. 2011; 13(4): 446-51. PubMed

Pyne MT, Hillyard DR. Evaluation of the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test. Diagn Microbiol Infect Dis. 2013; 77(1): 25-30. PubMed

Pyne MT, Konnick EQ, Phansalkar A, Hillyard DR. Evaluation of the Abbott investigational use only RealTime hepatitis C virus (HCV) assay and comparison to the Roche TaqMan HCV analyte-specific reagent assay. J Clin Microbiol. 2009; 47(9): 2872-8. PubMed

Pyne MT, Mallory M, Hillyard DR. HCV RNA measurement in samples with diverse genotypes using versions 1 and 2 of the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV test. J Clin Virol. 2015; 65: 54-7. PubMed

Slev P. Host genomics and HCV personalized medicine. Ann Clin Lab Sci. 2012; 42(4): 363-9. PubMed

Testing Algorithms

Hepatitis C Virus Testing Algorithm

Read more about Hepatitis C Virus Testing Algorithm

Hepatitis Virus Screening Algorithm

Read more about Hepatitis Virus Screening Algorithm

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Content Review:

May 2017

Last Update: March 2018


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Hepatitis C Virus - HCV

Tabs Content

Diagnosis

Indications for Testing

Laboratory Testing

Prognosis

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Organism

Risk Factors

Clinical Presentation

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

Hepatitis C Virus Testing Algorithm

Hepatitis Virus Screening Algorithm

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