Hepatitis C Virus Antibody

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States. It is estimated that 40% of chronic liver disease is HCV related and HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.

 Acute hepatitis C is generally a benign disease.  In transfusion transmitted infections, where the acute onset is best documented, 70% of cases are anicteric and asymptomatic; 30% have a bilirubin greater than 2.5 mg/dL and the mean peak ALT is 700 U/L.  However, patients with community acquired acute HCV, usually present with overt clinical illness; 70% are icteric and 75% have ALT levels that exceed 15 times the upper limit of normal. Approximately 50% of infected individuals evolve into chronic liver disease.  Chronic hepatitis C infection is the primary indication for liver transplantation.

 In 1998, CDC recommended HCV testing for individuals at high risk for HCV transmission, including those who had injected drugs, been hemodialysed, transfused or transplanted before July 1992, or received clotting factor concentrates produced before 1987. Screening also was recommended for persons with occupational sharps exposures, children born to HCV-infected mothers and individuals with persistently elevated ALT levels and individuals infected with HIV. (MMWR 1998; 47, No. RR-19):

1. Persons who ever injected illegal drugs

2. Persons with selected medical conditions, including those who received clotting factor concentrates produced before 1987, who were ever on chronic hemodialysis and those with persistently abnormal alanine aminotransferase (ALT) levels

3.  Prior recipients of transfusions or organ transplants, including persons who were notified that they received blood from a donor who later tested positive for HCV infection, persons who received a transfusion of blood or blood components before July 1992, persons who received an organ transplant before July 1992

Persons with other recognized exposures to HCV including occupational exposure through needles or other sharps and children born to HCV-positive mothers should also be tested.

 Unfortunately, this risk-based testing strategy had limited success, as evidenced by the substantial number of HCV-infected persons who remain unaware of their infection. Of the estimated 2.7–3.9 million persons infected with HCV in the United States, 45%–85% are unaware of their status.

A recent analysis of NHANES data determined that the prevalence of HCV antibody among persons in the 1945–1965 birth cohort was 3.25%, compared to 1.0 – 1.5% in the general population.  People within this age cohort account for approximately three fourths of all chronic HCV infections. 

In 2012, CDC published new birth-year based recommendations that target the baby boomer generation (MMWR August 17, 2012 / 61:1-18). These birth-year-based recommendations are intended to augment, not replace, the 1998 HCV testing guidelines. In addition to testing adults of all ages at risk, CDC now recommends that all adults born during 1945–1965 should be tested one-time with an HCV antibody test (anti-HCV). 

An immunocompetent person without risk factors who tests anti-HCV negative is not HCV-infected and does not require additional testing. Repeat testing should be considered for persons with ongoing risk behaviors. A person whose anti-HCV test is reactive should be tested for HCV RNA to distinguish active from cleared infection.

The recommended initial test is enzyme immunoassay (EIA) for HCV antibody.  The first enzyme immunoassay (EIA), which detected antibody to a single viral antigen, was introduced in 1989.   In 1992, this screening test was replaced by a more sensitive second generation EIA, which detects antibody to several viral antigens. Sensitivity of the current assay is ³97%. It does not distinguish between acute, chronic, or resolved infection.  The window period may be as long as 24 weeks. Only 40% of patients have detectable antibody within 10 weeks of infection and 80% have demonstrable antibodies at 15 weeks.  Transplant patients and immunosuppressed patients may not produce detectable antibody following infection. 

 Another shortcoming of HCV antibody testing is the significant number of false positive results among low-prevalence populations. For an immunocompetent population with HCV prevalence of <10%, the chance of a false positive antibody test ranges from 15-60%.

Another striking feature of HCV is its genetic heterogeneity, which has produced multiple mutant viruses.  Patients infected with less common variants mount different antibody responses that may not be detected by current EIA, since these tests are based on the predominant HCV genotype found in the U.S.  

The CDC published updated guidelines for reporting of HCV antibody in 2003(MMWR 2003;52 No. RR-3) based upon data review from thousands of tests from populations with HCV prevalence ranging from 2% to 25%. CDC recommended that HCV antibody reports should include the signal to cut-off (S/CO) ratio, which is calculated in the laboratory by dividing the value of the patient’s sample by the value of the negative-positive cut-off point for that run.

Samples with an S/CO ratio of 3.8 or above have a >95% probability of predicting true positive anti-HCV and are indicative of past or present infection. Supplemental testing by qualitative or quantitative PCR on these patients allows assessment of viral activity. HCV genotyping can be performed simultaneously on samples with detectable virus by PCR.

Samples that are reactive for HCV antibody, but have an S/CO ratio less than 3.8 may be false positive and require supplemental testing to determine the true HCV status. False positive tests are seen most often in the elderly, dialysis patients, and patients with autoimmune disease. These samples should have confirmatory testing by qualitative HCV PCR.

 Specimen requirement is one SST tube of blood. PCR & genotype testing can usually be performed on the residual serum sample used for the HCV antibody test. 

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