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DIAGNOSIS AND TREATMENT OF CHRONIC HEPATITIS C INFECTION
Overview
The hepatitis C virus (HCV) is a major public health problem and a
leading cause of death from liver disease in the United States. Although
generally benign in its acute presentation, in more than 70% of
patients, HCV infection tends to become chronic, at which stage it can
induce end-stage liver disease and hepatocellular carcinoma. Thorough
investigation of chronic hepatitis is of vital importance to discover
the cause of liver inflammation, assess its severity, and plan
treatment. The diagnosis, staging, and treatment of HCV infection
according to the most recent studies and recommendations are discussed
here.
Diagnosis of HCV infection
Tests for diagnosis of HCV are divided into serologic and molecular
assays.
Serologic assays include the screening tests for antibodies to
HCV and supplemental antibody testing. The enzyme immunoassay (EIA) and
the enzyme-linked immunosorbent assay (ELISA) are the 2 most commonly
used screening tests for HCV antibodies. The positive predictive value
of ELISA depends on the patient being tested; it is greater than 95% in
patients at high risk for HCV infection and only 50-61% in patients at
low risk. Three generations of EIA testing have been developed. In
addition to its ease of use, low variability, and relatively low cost,
the newer generations of EIA have added HCV antigens in the test,
increasing its sensitivity and specificity. In certain patient
populations, mostly in immunosuppressed patients and patients on
long-term hemodialysis, an expression of antibody to HCV may be lacking.
ELISA testing may also fail to detect HCV in 2-5% of patients.
Supplemental testing using the recombinant immunoblot assay helps to
confirm positive values and may also help to resolve the false-positive
EIA results. Molecular assays testing for HCV RNA are replacing the use
of supplemental tests.
Molecular assays are divided into qualitative, quantitative,
and genotype tests. Qualitative tests sensitively detect the HCV RNA in
the patient’s blood serum. It can be detected by polymerase chain
reaction (PCR) or by transcription-mediated amplification. Quantitative
tests are used for quantifying HCV RNA viral load before, during, and
after treatment. Target amplification methods, such as quantitative PCR,
and signal amplification technologies, such as branched DNA assay, are
used.
Genotype testing is of vital importance in patients with
chronic HCV infection. It can be performed by direct sequence analysis,
by reverse hybridization to genotype-specific oligonucleotide probes, or
by restriction fragment length polymorphisms. HCV has 6 major genotypes.
The exact genotype should be determined in all persons infected with HCV
prior to treatment in order to determine the duration of therapy and the
likelihood of response.
To diagnose HCV infection, the patient is initially screened for
antibodies to HCV. In patients with positive antibodies to HCV or
potentially false-negative test results, the diagnosis is confirmed with HCV
RNA tests. Genotype testing is an important next step to determine the
duration of therapy and to predict the response to treatment. A liver biopsy
provides the most accurate estimation of the severity of tissue damage and
is indicated when results would influence whether treatment is recommended.
A biopsy is not mandatory in order to initiate treatment. Tests to detect
fibrosis look promising and may also be an alternative to liver biopsy in
the future, but they are currently used only for drug trials.
Pathologic classification of chronic HCV infection
The old qualitative classification of chronic hepatitis has now been replaced
by newer, semiquantitative scoring systems. In general, the 2 histologic
features used for semiquantitative classification are the degree of inflammation
and hepatocyte necrosis (activity) and the hepatic response (fibrosis). Each
classification system has advantages and disadvantages and, at present, none
uses all the clinical, etiologic, and histologic information available. The
METAVIR scoring system and the Ishak grading system have received the greatest
attention. The choice of the scoring system depends on its intended use (ie,
clinical work or research purposes). For routine reporting and clinical
follow-up, simpler systems, such as the METAVIR scoring system, could be used.
More detailed systems, such as the Ishak system, are more suitable for research
purposes. The METAVIR and Ishak systems are detailed in the table below.
Comparison of the METAVIR and Ishak systems
| Stage |
METAVIR System |
Ishak System |
| 0 |
No fibrosis |
No fibrosis |
| 1 |
Periportal fibrosis expansion |
Fibrous expansion of some portal areas, with or without short fibrous
septae |
| 2 |
P-P septae >1 septum |
Fibrous expansion of most portal areas, with or without short fibrous
septae |
| 3 |
P-C septae |
Fibrous expansion of most portal areas
with occasional P-P bridging |
| 4 |
Cirrhosis |
Fibrous expansion of portal areas with marked bridging (P-P or P-C) |
| 5 |
|
Marked bridging (P-P or P-C) with occasional
nodules (incomplete cirrhosis) |
| 6 |
|
Cirrhosis |
P-P: portal-portal; P-C: portal-central
Treatment of chronic HCV infection
The approval of the pegylated forms of interferon (alfa-2a and
alfa-2b) led to an improvement in the treatment of chronic hepatitis C.
In combination with ribavirin, both forms of pegylated interferon
produce a sustained virologic response 7-12% higher than regular
interferon combined with ribavirin. Pegylated forms of interferon
combined with ribavirin are the new standard of care for previously
untreatable patients with chronic hepatitis C. The duration of therapy
and dose of ribavirin are determined by the patient’s HCV genotype,
which is the single most important pretreatment predictor of response.
Patients with genotype 1 should receive treatment with peginterferon and
ribavirin (1000 or 1200 mg/d based on weight) for 48 weeks. Patients
with genotype 2 or 3 should receive 24 weeks of therapy of peginterferon
and a lower dose of ribavirin (800 mg/d). Until further guidelines are
established for the treatment of other HCV genotypes (4, 5, or 6),
therapy similar to that of genotype 1 is suggested. Peginterferon
monotherapy for 48 weeks may be considered for patients with
contraindications to ribavirin therapy, although the response rate to
monotherapy is likely to be lower than the response rate to combination
therapy.
Treatment of patients with HCV-HIV co-infection
The development of highly active antiretroviral therapy (HAART) and
the resulting increased survival rate of patients with HIV have led to
an increase in HCV-induced liver disease among patients co-infected with
HIV and HCV. HIV has been shown to accelerate progression of HCV-related
liver disease and mortality. HCV infection may worsen the prognosis of
HIV infection and decrease the rate of CD4 recovery on antiretroviral
therapy.
Initially, HAART is used before HCV treatment is initiated to
stabilize the CD4 count in patients who are co-infected. In certain
cases, including patients with an intact immune system (ie, high CD4
counts and no history of opportunistic infections) and patients with
advanced liver disease, treatment of HCV may be initiated first to
reduce hepatotoxicity for the treatment of HIV. Treatment with pegylated
interferon and ribavirin is usually offered to patients with a CD4 cell
count greater than 200/µL.
In patients with preexisting liver disease, transaminase levels
should be monitored every 2 weeks initially, then monthly (once
stabilized). Regular liver biopsies are also needed to monitor
inflammation and fibrosis. Side effects tend to be more severe in
patients with preexisting liver disease; therefore, these patients
should be monitored closely for therapy compliance.
Upon completion of therapy, patients demonstrated better tolerance to
HAART and slower progression of liver damage.
Important studies
A comparative analysis of the old qualitative classification of
chronic hepatitis and the newer semiquantitative scoring systems was
performed by Okafor et al. A good statistical correlation was found
among the semiquantitative scoring systems. This study has important
implications in comparison of results of therapeutic trials using any of
the 5 studied semiquantitative scoring systems. Also, the analysis makes
it possible to compare biopsied specimens from patients with chronic
hepatitis from different centers where any of those 5 semiquantitative
scoring systems are used.
Three important studies in 2004 supported the use of peginterferon in
combination with ribavirin in patients co-infected with HCV and HIV.
Torriani et al and Carrat et al showed the superiority of peginterferon
alfa-2a and peginterferon alfa-2b, respectively, when combined with
ribavirin as compared to the combination of standard interferon and
ribavirin in patients with chronic hepatitis C who were co-infected with
HIV. A study by Chung et al that supports these findings showed,
interestingly, a histologic improvement in 35% of subjects with no virologic
response who underwent liver biopsy procedures.
Future directions
Despite recent advances, improvement in the prevention, diagnosis,
and treatment of HCV infection remains necessary. Prevention is of vital
importance, given the chronicity of the disease and the asymptomatic
onset of acute infection. Stricter strategies to screen and identify
infected persons need to be in place. A prophylactic vaccine may result
in better control of this epidemic.
Future research efforts also need to focus on providing better
treatment options for patients with HCV. Newer treatments must be more
tolerable, more efficacious, cost effective, and available to all
patients.
More studies comparing efficacy, safety, and side effects of
peginterferon alfa-2a and peginterferon alfa-2b need to be conducted, taking
into consideration special patient populations such as patients co-infected
with HCV and HIV.
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