Hepatitis C Virus - HCV

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

• 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 cholangitis
  • 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
  • Wilson disease
  • Hemochromatosis
  • Alpha-1-antitrypsin deficiency
• 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], 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