Managing and treating hepatitis C

October 2002

HCV infects approximately 4 million people in the United States and is the leading cause of cirrhosis and the primary reason for liver transplantation. There are 35,000 acute HCV infections annually. From 1990 to 2015, the prevalence of infection is projected to increase fourfold. HCV is a bloodborne ribonucleic acid (RNA) virus transmitted through injecting drug use, high-risk sexual behavior, blood transfusions and from mother to child during childbirth. Six genotypes and approximately 50 subtypes of HCV have been identified. The most prevalent genotypes in the United States and Western Europe are 1a, 1b, 2 and 3.

Acute HCV infection is characterized by jaundice, malaise, anorexia and an increase in serum alanine aminotransferase (ALT). After acute HCV infection, most patients will develop chronic HCV, which may lead to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment of chronic HCV may maintain hepatic health and slow progression to end-stage liver disease.

Sustaining viral response, defined as “the absence of detectable HCV RNA in the serum as shown by a qualitative HCV RNA assay with lower limit of detection of 50 IU/ml or less at 24 weeks after the end of treatment” is the goal of therapy for HCV infection. Undetectable serum HCV RNA is associated with a decreased incidence of liver fibrosis and HCV infection. HCV genotype, gender, age, degree of hepatic fibrosis, duration of chronic HCV, and presence of cirrhosis all influence treatment response. In the United States, genotype 1 is responsible for up to 75% of HCV infections and response to treatment is usually poor. Young, female patients with HCV genotype 2 or 3 for less than 5 years and no presence of cirrhosis usually respond well to therapy. HCV genotyping usually determines the aggressiveness of treatment.

Treatment options for chronic HCV include interferon-alpha, interferon-alpha and ribavirin, pegylated interferon-alpha (PEG interferon) and pegylated interferon-alpha and ribavirin. Treatment should be considered in every patient with chronic HCV, especially those at high risk for developing cirrhosis. Current recommendations suggest that patients with consistent ALT elevations but without biopsy-proven fibrosis be monitored frequently for changes in disease status, since data evaluating treatment in this population are limited.

Alpha interferons are cytokines that possess antiviral, antiproliferative and immune-modulating effects. By binding to specific cell receptors, they can alter gene transcription and cellular growth as well as cell antigen expression and macrophage activity. There are 16 subtypes of interferon-alpha. Types 2a, 2b, alfacon-1 and the two forms of PEG-interferon-alpha, 2a and 2b, are most commonly used to treat HCV. PEG interferons are synthesized by attaching polyethylene glycol to an interferon-alpha molecule, resulting in a longer half-life and duration of activity that helps maintain more consistent and longer-acting interferon serum concentrations compared with conventional interferon-alpha.

Absolute contraindications to interferon-alpha therapy include immunosuppression, autoimmune disorders, cirrhosis, uncontrolled seizures, heart symptoms, use in neonates, infants and nursing mothers. A black-box warning was issued in March 2002 stating use of alpha interferons may promote or exacerbate autoimmune, infectious, ischemic and neuropsychiatric disorders.

Approximately 92% of patients experience a flu-like syndrome consisting of fever, chills, headache and myalgia within one to two hours after administration. These may persist for 24 hours. Other frequently occurring adverse events include anorexia, nausea, diarrhea, taste disturbances, depression, suicidal ideation, thrombocytopenia, anemia, hyperglycemia, alopecia and injection site reactions.

Monotherapy with interferon alpha is associated with an initial response rate of 40%. However, sustained viral response is typically 20% particularly in patients with genotype 1. Specific dosing information is listed in Table 1.

Ribavirin

Ribavirin is a nucleoside analogue that interferes with RNA and DNA viral replication. It is available in 200-mg capsules under the brand name Rebetol and with interferon-alpha 2b as Rebetron. Ribavirin is classified as pregnancy category X. A barrier method and a second form of contraception are essential during ribavirin therapy and for six months after treatment is completed regardless of whether the man or the woman is receiving ribavirin. Hemoglobinopathies, renal insufficiency (CrCl <50 ml/min), and history of cardiac disease are other contraindications, because ribavirin can diminish cardiac function and exacerbate underlying cardiac conditions. This medication can cause a flu-like syndrome, pruritus, hemolytic anemia, depression and irritability. Ribavirin monotherapy has been associated with poor response and an increased incidence of infection relapse. Therefore, combination therapy with interferon-alpha is recommended.

Ribavirin dosing is adjusted according to weight, hemoglobin level and cardiovascular status. According to the manufacturer of Rebetron, dose adjustment and discontinuation may be required depending upon hemoglobin levels and complete blood cell count (see Table 2).

Combination therapy (interferon alpha with ribavirin) has been shown to be more effective (~40% increase in sustained viral response) in achieving high response rates compared with monotherapy with interferon-alpha or PEG-interferon. Three clinical trials have demonstrated superior efficacy with the combination of PEG interferon (both alpha 2a and alpha 2b) and ribavirin compared with combinations using standard interferon alpha and ribavirin (54% achieved sustained viral response; subgroup analysis of genotype 1: 42% sustained viral response; genotypes 2 and 3: 82% sustained viral response). Therefore, current NIH treatment recommendation for chronic HCV, is combination therapy with PEG interferon-alpha (2a or 2b) and ribavirin. Patients with genotype 1 are typically treated for 48 weeks while those with genotype 2 or 3 are treated for approximately 24 weeks (Table 1).

Retreatment

Retreatment may be advantageous in patients who never attained sustained viral response after initial therapy. Patients can be categorized according to response to therapy as responders, relapsers, partial responders and non-responders. Relapsers are patients who initially respond to treatment, attain an end of treatment response, but do not attain sustained viral response. Non-responders neither attain an end of treatment response nor sustained viral response. Partial responders are a subset of patients among the non-responders. They experience a significant reduction in HCV RNA during therapy but do not attain sustained viral response. Partial responders have a 1-2 log unit decrease in serum HCV RNA during treatment. Sustained viral response is the best measurement to determine if therapy is effective. However, hepatic histology can still improve despite unattained sustained viral response.

The decision to retreat depends upon the previous therapy used, initial response and tolerability, HCV genotype, and the degree of hepatic disease. Approximately 15-20% of patients who did not respond to conventional interferon-alpha and ribavirin are estimated to attain sustained viral response with PEG interferon and ribavirin therapy. Studies are being conducted to determine the efficacy of PEG interferon and ribavirin in relapsers that have previously received conventional therapy. In addition, HALT-C (a multicenter trial) is being conducted in the United States to evaluate response to continuous PEG interferon monotherapy in non-responders to PEG interferon and ribavirin combination therapy.

Conclusions

Therapy to decrease progression of HCV is vital. Treatment options include interferon alpha, interferon alpha and ribavirin, PEG interferon, and PEG interferon and ribavirin. Recent studies have demonstrated that combination therapy with interferon alpha, specifically PEG interferon, and ribavirin is more effective than monotherapy. PEG interferon-alpha and ribavirin combination therapy is now considered the treatment of choice for chronic HCV.

For more information:

• National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C: 2002. Final Report. Bethesda (MD): National Institutes of Health (US), Office of Medical Application of Research; 2002 June. Report No.19(1).
• Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345(1):41-52.
• Herrine SK. Approach to the patient with chronic hepatitis C virus infection. Ann Intern Med. 2002;136(#10):747-757.