• 3
    Jun
  • Pharmacotherapy for Hepatitis C Virus Infection: Virus Biology

First identified in 1988, HCV infection is caused by a small, single-stranded RNA virus that is a member of the genus Hepacivirus and the family Flaviviridae. HCV replicates in the cytoplasm of hepatocytes and B lymphocytes. Persistent infection or a lack of viral clearance is related to continuous virus production and to the loss of helper T-cells. Genetic analysis reveals the existence of numerous subtypes, or genotypes. HCV has at least six major genotypes (1-6), which are found in clusters around the world, and 50 subtypes (i.e., 1a, 1b)

The ability to identify the viral subtypes is extremely important in determining specific responses to treatment:

  • Genotype 1 is the most common subtype, accounting for 76% of HCV cases in the U.S. Genotypes 1a and 1b account for 45% and 30% of those cases, respectively.
  • Genotypes 2-6 are located throughout the world. Each has major epidemiological significance and varies greatly in sensitivity to antiviral therapy (Table 1).
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Patients with genotypes 1a and 1b, most commonly observed in African-Americans, do not respond effectively to interferon monotherapy, and only 10% to 15% of treated patients exhibit a long-term response. Genotypes 2 and 3 are more responsive to therapy, with patients sometimes receiving a shorter duration of treatment (24 weeks vs. 48 weeks).

Table 1   Geographic Sites of Hepatitis C Virus Genotypes

Genotype

Location

1a

U.S., Western Europe, Australia, Japan

1b

U.S., Western Europe, Australia, Japan

2a

U.S., Western Europe, Australia, Japan

2b

U.S., Western Europe, Australia, Japan

3

Southeast Asia and Indian subcontinent

4

Middle East, Central Africa

5

South Africa

6

Southeast Asia, Hong Kong

Viral Transmission

HCV is contracted primarily via blood or blood products, with intravenous (IV) drug use accounting for at least 68% of new HCV infections. Prior to the advent of blood donor screening and surrogate hepatitis testing (using diagnostic viral markers) in 1992, blood transfusions and plasma-derived products were associated with a significant risk of HCV transmission. Today, transfusions comprise only 3% of cases. Sexual transmission of HCV accounts for fewer than 10% of all cases, and infection is statistically associated with sexual exposure to high-risk individuals or people with a history of high-risk sexual activ-ity. Other routes of parenteral transmission are presented in Figure 2.
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Figure 2 Risk factors in the development of acute hepatitis C virus

Figure 2 Risk factors in the development of acute hepatitis C virus infection. IVDU = intravenous drug usage.

Disease Progression

Acute HCV infection is rarely studied, primarily because (1) the disease is asymptomatic, (2) the incidence is infrequent, (3) diagnostic tests are not commonly used, and (4) it is difficult to differentiate acute from chronic reactivation phases. Of those patients acutely infected with HCV, 81% progress to chronic HCV within six months.

A major concern for patients with chronic HCV is the time of progression to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). From analyses of retrospective and prospec­tive data, almost 15% to 20% of patients with HCV infection progress to cirrhosis, with 5% progressing to HCC. Numerous factors that result in advanced stages of liver disease (i.e., fibrosis) include older age, excessive alcohol consumption, or having an advanced state of fibrosis at the time of the initial liver biopsy. In general, the natural history of HCV differs according to geography, virus characteristics (e.g., genotype, viral load), co-infection with other viruses, and other unexplained factors.
Diagnosis

The HCV serological assays that are most commonly used to confirm antibody to HCV (anti-HCV) include the enzyme immunoassay (EIA) and the recombinant immunoblot assay (RIBA). Three generations of EIA antibody testing exist, all having a sensitivity and specificity exceeding 95%. EIA-2, the most commonly used assay, is recommended as the initial screening test; it is reproducible, inexpensive, and suitable for screening high-risk populations. Because of the high level of specificity and sensitivity of the EIA, confirmation with methods such as the RIBA are becoming unnecessary.

Quantitative HCV assays, such as polymerase chain reaction (qPCR) and branched-chain DNA (bDNA), are commonly used in clinical practice and also confirm the diagnosis of HCV by measuring HCV RNA particles in the blood.

The relevance of using serum amino-transferase (ALT) to determine disease activity has been extensively debated. ALT is the most inexpensive and non-invasive means of detecting disease activity, but it is limited in its ability to assess the degree of disease activity and disease progression. In the past, ALT had been a primary marker of liver disease; however, approximately 30% of patients with chronic hepatitis C have normal ALT levels, and another 40% have ALT levels that are less than two times the upper limit of normal (ULN). Patients with normal ALT levels have a decreased risk of disease progression and present with only minimal inflammation and mild or no fibrosis, although some may progress to advanced stages of disease even though they have normal ALT levels. Abnormal ALT levels lasting longer than six months, if confirmed on repeated testing, should prompt a search for risk factors for infection and a battery of serological tests, including those for hepatitis B virus and an EIA for the presence of HCV antibody.

The use of genotype assays is an excellent way of predicting patients’ responses to therapy, especially in patients with genotypes 1a and 1b.
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The liver biopsy, despite its cost and discomfort, is the most widely used diagnostic method of detecting liver disease. Although this high-risk, invasive procedure is not cost-effective, it provides important information (e.g., inflammatory grade and fibrotic stage) to help exclude other liver diseases as well as insight into early disease management and prog-nosis.

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