DIAGNOSIS AND TRETAMENT OF CHRONIC HEPATITIS C INFECTION

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
CirrhosisP-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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