Current Therapies for Chronic Hepatitis C

McKenzie C. Ferguson, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(1):92-111. 

In This Article

Diagnosis

The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines on the Diagnosis, Management, and Treatment of Hepatitis C represent the gold standard for guidance on the management of hepatitis C (Table 1).[7] These guidelines were approved and are supported by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology.[7]

A laboratory diagnosis of HCV is determined after screening for possible risk factors and evaluation of signs and symptoms. Acute illness manifests symptomatically in 20–30% of patients. Many patients with chronic HCV infection are asymptomatic or may exhibit only mild symptoms.[8] Possible symptoms include abdominal pain, fever, fatigue, loss of appetite, nausea, and vomiting.[3,8,9]

Risk Factors

Hepatitis C virus is transmitted by exposure to infected blood or blood products (Table 2).[1–3,7,9,10] Injection drug use is the most common route of exposure to hepatitis C.[1,7] All persons who report illicit drug use, including intranasal cocaine use, should be screened for HCV.[2,7] The prevalence of HCV reported in injection drug users is extremely high, with a proportional relationship to the duration of drug use. Within 5 years of beginning injection drug use, one in three persons will become infected with HCV.[11]

Other populations at risk for HCV infection include individuals who received a blood or blood component transfusion before 1992, individuals who provide health care to infected patients, individuals who receive long-term hemodialysis, persons with human immunodeficiency virus (HIV), children of HCV-infected mothers, and persons with multiple sexual partners, although transmission between monogamous partners is uncommon (Table 2).[1–3,7,9,10] The risk of HCV transmission between monogamous sexual partners is less than 1%.[3] Persons who have been receiving long-term hemodialysis, those with unexplained abnormal aminotransferase levels, or those infected with HIV are considered at risk because of the higher prevalence of infection in these patient populations.[7] Less than 5% of infants born to HCV-infected mothers will acquire the infection.[3] In addition, breastfeeding has not been linked to transmission of HCV.[3,7] Although HCV exposure through tattooing, acupuncture, and body piercing is possible, each has rarely been reported as the sole possible mode of transmission.[2,3,7,9]

Several risk factors are associated with progression to chronic disease. Nonmodifiable risk factors include advanced age at the time of initial infection, male sex, Hispanic ethnicity, and genetic factors linked to polymorphisms of specific genes involved in the rate of fibrosis and hepatocellular carcinoma.[10] Whereas African-American patients display a higher rate of development of hepatocellular carcinoma, a lower response to therapy, and higher liver-related mortality compared with Caucasian patients, studies have shown that they are actually less likely to progress to cirrhosis.[10] Limited evidence shows that Hispanic patients, on the other hand, progress faster to cirrhosis compared with Caucasian patients.[10] Potentially modifiable risk factors include elevated alanine aminotransferase (ALT) levels, alcohol intake, smoking, and coinfection with HIV or hepatitis B virus.[10]

Clinical features of disease progression to cirrhosis may include jaundice, enlarged liver and/or spleen, muscle wasting, and ascites. Elevated levels of alkaline phosphatase, γ-glutamyl transferase, and aspartate aminotransferase (AST) may also be seen. Low platelet and white blood cell counts may be observed. Extra-hepatic manifestations, such as cryoglobulinemia, glomerulonephritis, and porphyria cutanea tarda, are uncommon.[3]

The diagnosis of chronic HCV infection is established when anti-HCV is present and serum aminotransferase levels remain elevated for 6 months or longer.[3,7] Polymerase chain reaction (PCR) testing for HCV RNA will establish the diagnosis, and a positive result is indicative of current and active infection.

Laboratory Testing

Both qualitative and quantitative tests are used in the diagnosis of HCV. Enzyme immunoassay–confirmed anti-HCV is the initial serologic test used to establish exposure to HCV but is not necessarily indicative of current infection. The available enzyme immunoassays have specificity greater than 99%. Current infection can be established with quantitative analysis of HCV RNA through PCR or transcription-mediated amplification. Currently available PCR assays have excellent specificity (98–99%) and will detect HCV RNA in the serum to a lower limit of 50–100 copies/ml. Most patients with chronic HCV will have levels of HCV RNA (viral load) between 100,000 (105) and 10,000,000 (107) copies/ml (or 50,000–5 million IU/ml). Interpretation of anti-HCV and HCV RNA results is given in Table 3.[3,7]

Confirmatory testing is essential in high-risk patients who test negative for anti-HCV. Immuno-compromised patients, including those with HIV, solid-organ transplant recipients, or those receiving hemodialysis, may have false-negative test results due to the inability to mount a sufficient immune response. Likewise, persons with acute HCV infection may require up to 1 month or more for adequate antibody detection. Follow-up and/or confirmatory testing of HCV RNA for these patients may be warranted (Table 3).[3,7] Retesting for both anti-HCV and HCV RNA in 4–6 months may help to resolve issues with false-positive and false-negative results.[3,7]

In June 2010, the U.S. Food and Drug Administration (FDA) approved the first rapid blood test for antibodies to HCV (OraQuick HCV Rapid Antibody Test; OraSure Technologies, Bethlehem, PA). It is approved for use in patients aged 15 years or older. The test is approved for screening persons who are considered at risk for HCV infection and works from a sample of venous blood, with readable results in about 20 minutes.[12,13]

In patients with chronic HCV infection, ALT and AST levels may appear either normal or elevated. Elevations in ALT level are more frequently seen, usually less than 5 times but may be as high as 20 times the upper limit of normal.[3]

Liver biopsy is not needed to diagnose HCV but is useful in determining the grade and stage of liver disease. The grade of disease is determined by evidence of necrosis and inflammation in liver tissue, whereas the stage is determined by the extent and presence of fibrosis and cirrhosis. At this time, the decision to perform liver biopsy for prognostic purposes or to guide a treatment decision should be individualized, taking into consideration the probability of disease progression, patient willingness to undergo the procedure, and patient genotype.[3,7]

Genetic Variations

Six different genotypes and more than 50 subtypes exist for HCV. Genotype denotes nucleotide variation and is typically represented geographically by location for HCV. Genotype 1 is the most common in the United States, followed by genotypes 2 and 3. Genotype 4 is most represented in the Middle East, including Egypt and Africa, whereas genotype 5 is seen in South Africa and genotype 6 in Southeast Asia.[14,15] Genotypic variations aid in identifying patients likely to respond to treatment and guide the duration of therapy, both of which are critical to therapeutic decision making.[3,7]

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