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Diagnosing and Monitoring Tests in HCV For Patients: viral load, biopsy
Reported by Jules Levin
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Various tests are available for the diagnosis and monitoring of hepatitis C
infection. Tests
that detect antibody against the virus include the EIAs, which contain HCV
antigens from the
core and nonstructural genes, and the recombinant immunoblot assays (RIBAs).
The same HCV
antigens are used in both EIAs and the RIBAs. Targeted amplification
techniques using either
polymerase chain reaction (PCR) or transcription-mediated amplification (TMA)
have been
developed to detect HCV RNA. Liver biopsy can provide direct histologic
assessment of liver
injury due to HCV but cannot be used to diagnose HCV infection.
HCV Serologic Assays
EIA tests are reproducible, inexpensive, and FDA-approved for use in the
diagnosis of
HCV. They are suitable for screening at-risk populations and are recommended
as the initial test
for patients with clinical liver disease. The very high sensitivity and
specificity of the third-
generation EIAs (sensitivity greater than 99 percent, specificity 99 percent)
obviate the need for a confirmatory RIBA in the diagnosis of individual
patients, particularly those with risk factors
for HCV. A negative EIA test is sufficient to exclude a diagnosis of chronic
HCV infection in
immune competent patients. Rarely, patients on hemodialysis and patients with
immune
deficiencies may have falsely negative EIAs. Conversely, falsely positive
EIAs may occur in
patients with autoimmune disorders. In these patients, assays for HCV RNA are
necessary for
diagnosis. RIBA remains a useful supplemental assay in the setting of
large-scale HCV screening
of blood products.
Qualitative HCV Assays
Persistent HCV infection in a patient with a positive EIA test should be
confirmed by a
qualitative HCV RNA assay. The automated, FDA-approved, qualitative HCV PCR
assay has a
lower limit of detection of 50 IU/mL. More recently, a transcription-mediated
amplification
assay has been developed with a lower limit of detection comparable to the
qualitative PCR
assay. This latter assay has yet to be approved for use by the FDA. The
specificity of these
assays exceeds 98 percent. A single positive qualitative assay for HCV RNA
confirms active
HCV replication, but a single negative assay does not prove that the patient
is not viremic. A
followup qualitative HCV RNA should be performed to confirm the absence of
active HCV
replication. Once HCV infection is confirmed, repeat testing for qualitative
HCV RNA by
qualitative PCR is not helpful in the management of untreated patients.
Almost all patients
remain viremic, and a negative result may merely reflect a transient decline
in viral titer below
the level of detection of the assay.
Quantitative HCV Assays
Testing for HCV RNA level (or viral load) by a quantitative assay, either
quantitative
PCR (qPCR) or branched DNA signal amplification assay (bDNA), can provide
accurate
information on HCV viral titer. An HCV RNA standard has been introduced to
permit
normalization of reported viral titers in international units (IU). The
reported IU does not
represent the actual number of viral particles in a preparation. Significant
variability exists
between available assays. The dynamic range of each assay needs to be
observed, and
appropriate dilutions of sample material should be performed to obtain
accurate quantitative
results. The clinical utility of serial HCV viral titers in a patient is
predicated on continued use of the same specific quantitative assay used in
the initial determination of the viral titer. While there is little
correlation between disease severity or disease progression with the absolute
titer of HCV RNA, quantitative determination of the HCV titer provides
important information in assessing response to treatment.
Testing for serum ALT levels is the most inexpensive and noninvasive means of
assessing disease activity. However, a single determination of ALT levels
gives limited
information about the severity of the underlying liver disease. In most
studies, a weak association exists between the degree of ALT elevation and
severity of the histopathological findings on liver biopsy. Serial
determinations of ALT levels over time may provide a better means of
assessing liver injury, but the accuracy of this approach has not been shown.
Patients who
initially have a normal ALT level should undergo serial measurements over
several months to
confirm the persistence of normal ALT levels. Although loss or reduction in
HCV RNA is the
primary indicator of response to antiviral therapy, the resolution of
elevated ALT levels with
antiviral therapy appears to be an important indicator of disease response.
Serial determinations
of ALT levels can be recommended as the general means of monitoring patients
but is not
adequate to assess progression to cirrhosis.
Various noninvasive tests have been examined for monitoring patients with
chronic
hepatitis C infection. These include routinely available laboratory tests,
such as liver-associated
chemistries, platelet count, and prothrombin time, as well as specific serum
markers of fibrosis
and inflammation that are not currently widely available or well validated.
No single test or panel of serologic markers can provide an accurate
assessment of intermediate stages of hepaticfibrosis. Similarly, quantitative
tests of liver function and radiologic imaging of the liver are sensitive for
diagnosing advanced cirrhosis but are not useful in assessing hepatic
fibrosis and early cirrhosis.
Liver Biopsy
Liver biopsy yields information on fibrosis and histology assessment that is
not
obtainable by any other means. Various noninvasive methods based on
biochemical or serologic
tests have been evaluated in several studies. Liver enzymes have shown little
value in predicting
fibrosis. Extracellular matrix tests do predict severe stages of fibrosis but
cannot consistently
classify intermediate stages of fibrosis. Moreover, only liver biopsy
provides information on
possible contributions of iron, steatosis, and concurrent alcoholic liver
disease to the progression of chronic hepatitis C toward cirrhosis. It is
unusual for unexpected etiologies of liver disease to be discovered on liver
biopsies from patients undergoing evaluation of chronic hepatitis C. The
information obtained on liver biopsy does allow affected individuals to make
more informed choices with regard to initiation or postponement of antiviral
treatment. Adult or pediatric patients with persistently normal or slightly
elevated ALT and minimal or no fibrosis on liver biopsy may be reassured of
a favorable prognosis and decide to defer antiviral therapy. Since a
favorable response to current antiviral therapy in patients infected with
genotype 2 or 3 occurs in 80 percent, the necessity of routine pretreatment
liver biopsy in these patients requires further study. Baseline assessment of
liver histology offers the standard by which subsequent comparisons may be
made. There is little information, however, on the appropriate interval for
subsequent evaluations.
Hepatocellular Cancer Screening
HCC complicates cirrhosis secondary to HCV. It is estimated that HCC occurs
after the
development of cirrhosis at a rate varying from 0 to 3 percent per year. Few
studies examine
specific screening strategies for HCC in patients with advanced HCV. Alpha
fetoprotein (AFP)
and ultrasound every 6 months were used in a single study of patients with
cirrhosis secondary to HCV. Identification of HCC was not significantly
increased in the screened population.
Additional studies identifying new markers and testing specific screening
protocols are
warranted.
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