Treatment

Alpha Interferon

The therapy for chronic hepatitis C has evolved steadily since alpha interferon was first approved for use in this disease more than 10 years ago. At the present time, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated alpha interferon and ribavirin.
Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. Recombinant forms of alpha interferon have been produced, and several formulations (alfa-2a, alfa-2b, consensus interferon) are available as therapy for hepatitis C. These standard forms of interferon, however, are now being replaced by pegylated interferon (peginterferon).
Peginterferon is alpha interferon that has been modified chemically by the addition of a large inert molecule of polyethylene glycol. Pegylation changes the uptake, distribution, and excretion of interferon, prolonging its half-life. Peginterferon can be given once weekly and provides a constant level of interferon in the blood, whereas standard interferon must be given several times weekly and provides intermittent and fluctuating levels. In addition, peginterferon is more active than standard interferon in inhibiting HCV and yields higher sustained response rates with similar side effects. Because of its ease of administration and better efficacy, peginterferon has replaced standard interferon both as monotherapy and as combination therapy for hepatitis C.

Ribavirin

Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV, but adding it to interferon increases the sustained response rate by two- to three-fold. For these reasons, combination therapy is now recommended for hepatitis C, and interferon monotherapy is applied only when there are specific reasons not to use ribavirin.

Combination Therapy

Combination therapy leads to rapid improvements in serum ALT levels and disappearance of detectable HCV RNA in up to 70 percent of patients. However, long-term improvement in hepatitis C occurs only if HCV RNA disappears during therapy and stays undetectable once therapy is stopped. Among patients who become HCV RNA negative during treatment, some will relapse when therapy is stopped. The relapse rate is lower in patients treated with combination therapy compared with monotherapy. Thus, a 48-week course of combination therapy using peginterferon and ribavirin yields a sustained response rate of about 55 percent. A similar course of peginterferon monotherapy yields a sustained response rate of only 35 percent. A response is considered “sustained” if HCV RNA remains undetectable for 6 months or more after stopping therapy.

Dosing

Two forms of peginterferon have been developed and studied in large clinical trials: peginterferon alfa-2a (Pegasys: Hoffman La Roche, Nutley, NJ) and peginterferon alfa-2b (Pegintron: Schering-Plough Corporation, Kenilworth, NJ). These two products are roughly equivalent in efficacy and safety, but have different dosing regimens.

• Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 micrograms (mcg) per week.
• Peginterferon alfa-2b is given subcutaneously weekly in a weight-based dose of 1.5 mcg per kilogram (kg) per week (thus in the range of 75 to 150 mcg per week).

Ribavirin is an oral medication, given twice a day in 200-mg capsules for a total daily dose based upon body weight. The standard dose of ribavirin is 1,000 mg for patients who weigh less than 75 kg (165 pounds) and 1,200 mg for those who weigh more than 75 kg. In certain situations, an 800-mg dose (400 mg twice daily) is recommended (see Duration).

Duration

The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. For patients treated with peginterferon monotherapy, a 48-week course is recommended, regardless of genotype. For patients treated with combination therapy, the optimal duration of treatment depends on viral genotype. Patients with genotypes 2 and 3 have a high rate of response to combination treatment (70 to 80 percent), and a 24-week course of combination therapy yields results equivalent to those of a 48-week course. In contrast, patients with genotype 1 have a lower rate of response to combination therapy (40 to 45 percent), and a 48-week course yields a significantly better sustained response rate. Again, because of the variable responses to treatment, testing for HCV genotype is clinically useful when considering starting combination therapy.
In addition, the optimal dose of ribavirin appears to vary depending on genotype. For patients with genotypes 2 or 3, a dose of 800 mg daily appears adequate. For patients with genotype 1, the full dose of ribavirin (1,000 or 1,200 mg daily depending on body weight) appears to be needed for an optimal response.
There is little information on the optimal regimen of peginterferon and ribavirin for patients with the rare genotypes 4, 5, and 6. These patients should probably receive the regimen of peginterferon and ribavirin that is recommended for genotype 1.
Many attempts have been made to identify patients who have a rapid response to treatment and who might be able to stop peginterferon and ribavirin early and be spared the further expense and side effects of prolonged therapy. Patients who test HCV RNA negative within 4 weeks of starting therapy are considered “rapid responders.” In several studies, rapid responders with genotypes 2 and 3 have been found to be able to stop therapy after 12 to 16 weeks (12 to 8 weeks early) and still achieve a high rate of response. Similarly, rapid responders with genotype 1 may be able to stop therapy at 24 weeks (24 weeks early) and achieve an excellent response rate. The consequence of early stopping, however, is a higher relapse rate and this approach of abbreviating therapy in rapid responders must be individualized based upon tolerance.