Peginterferon ??-2a (40KD) Plus Ribavirin

Abstract

Combination therapy with subcutaneous peginterferon α-2a (40KD) [Pegasys®] plus oral ribavirin (Copegus®) has been evaluated previously in patients with chronic hepatitis C and elevated ALT levels. A recent randomised, nonblind, multicentre trial examined the efficacy of this combination therapy in the treatment of patients with persistently ‘normal’ ALT levels. These trial results showed that combination therapy with peginterferon α-2a (40KD) plus ribavirin is effective in patients with chronic hepatitis C and persistently normal ALT levels. Overall, a sustained virological response occurred in over 50% of patients who received combination therapy for 48 weeks, albeit with a low daily dosage of ribavirin. The tolerability profile of combination therapy in patients with persistently normal ALT levels is similar to that seen in patients with elevated ALT levels. The decision as to whether or not treatment should be initiated in patients with chronic hepatitis C and persistently normal ALT levels should be made on an individual basis. If a decision is made to treat, combination therapy with peginterferon α-2a (40KD) plus ribavirin can be considered a first-line treatment option. Early viral kinetics following the initiation of peginterferon α-2a (40KD) plus ribavirin therapy in patients with chronic hepatitis C and persistently normal ALT levels were similar to those in patients with elevated ALT levels. The addition of ribavirin to peginterferon α-2a (40KD) therapy reduces virological relapse during follow-up, thereby increasing the sustained virological response rate, in patients with chronic hepatitis C; however, the mechanism by which ribavirin achieves this effect is not completely understood. Both peginterferon α-2a (40KD) and ribavirin have shown beneficial immunomodulatory effects in patients with chronic hepatitis C. Pegylation of interferon-α slows the absorption and reduces the renal clearance of the drug. Serum concentrations of peginterferon α-2a (40KD) were maintained throughout the dosing interval with once-weekly subcutaneous administration. Metabolism in the liver is the primary clearance mechanism for peginterferon α-2a (40KD). At steady state, a maximum ribavirin plasma concentration of 2748 ng/mL was reached at 2 hours when administered in combination with peginterferon α-2a (40KD) in patients with chronic hepatitis C; the drug accumulates with repeated administration. Ribavirin metabolism occurs via two pathways; both the parent drug and its metabolites are primarily excreted renally. The drug has an elimination half-life of ≈120–170 hours. Patients with chronic hepatitis C and persistently normal ALT levels were randomised to receive subcutaneous peginterferon α-2a (40KD) 180μg once weekly plus oral ribavirin 800 mg/day for 24 (n = 212) or 48 (n = 210) weeks or no treatment (n = 69) in a randomised, nonblind, multicentre trial; the sustained virological response rate was assessed 24 weeks after the end of treatment. The sustained virological response rate was significantly (p < 0.001) higher in patients who received peginterferon α-2a (40KD) plus ribavirin for 48 compared with 24 weeks in the combined patient group (52% vs 30%) and in patients infected with hepatitis C virus (HCV) genotype 1 (40% vs 13%). In patients infected with HCV genotypes 2 or 3, there was no significant difference in sustained virological response rates between patients treated for 24 weeks and those treated for 48 weeks (72% and 78%). None of the patients in the control arm had a sustained virological response. Patients who did not have an early virological response to peginterferon α-2a (40KD) plus ribavirin therapy were highly unlikely to attain a sustained virological response. For example, when patients receiving combination therapy for 48 weeks were considered, 97% of the patients without an early virological response did not achieve a sustained virological response. Similar results were seen in subgroups of patients infected with either HCV genotype 1 or non-1 genotypes. Health-related quality of life benefits occurred in patients who received peginterferon α-2a (40KD) plus ribavirin and achieved a sustained virological response compared with treated patients who did not achieve a sustained virological response. The adverse event profile reported in patients with chronic hepatitis C and persistently normal ALT levels who received peginterferon α-2a (40KD) plus ribavirin was typical of that expected with this combination therapy, with no new adverse events identified. The most commonly occurring clinical adverse events included headache, fatigue, myalgia, pyrexia, insomnia, nausea, arthralgia, depression, irritability, rigors, alopecia, asthenia, diarrhoea and pruritus. At least one adverse event was reported in 99% of peginterferon α-2a (40KD) plus ribavirin recipients and in 77% of untreated controls. Treatment-related adverse events were reported in 96% and 98% of patients who received peginterferon α-2a (40KD) plus ribavirin for 24 or 48 weeks. Most of the reported adverse events were of mild severity. Among patients treated for 24 or 48 weeks, clinical adverse events resulted in dose modification of peginterferon α-2a (40KD) in 11% and 19% of patients and in dose modification of ribavirin in 20% and 30% of patients. Laboratory abnormalities resulted in dose modification of peginterferon α-2a (40KD) in 16% and 22% of patients and in dose modification of ribavirin in 9% and 21% of patients.