Peginterferon-α-2a (40 kD)

Peginterferon-α-2a (40 kD) [Pegasys®] comprises an inert, branched, 40 kD polyethylene glycol (PEG) moiety attached to interferon-α-2a. Subcutaneous peginterferon-α-2a (40 kD) is indicated for the treatment of adults with hepatitis B e antigen (HBeAg)-positive or -negative chronic hepatitis B who have compensated liver disease with evidence of viral replication and hepatic inflammation.

Subcutaneous peginterferon-α-2a (40 kD) has antiviral and immunomodulatory properties and a convenient once-weekly administration schedule. Forty-eight weeks of therapy with peginterferon-α-2a (40 kD) with or without lamivudine was more effective than lamivudine alone in achieving a sustained response in patients with HBeAg-positive or -negative chronic hepatitis B. A long-term follow-up study in patients with HBeAg-positive disease who received peginterferon-α-2a (40 kD) monotherapy revealed an HBeAg seroconversion rate of 42%, 1 year after the end of treatment. A long-term follow-up study in patients with HBeAg-negative disease who received peginterferon-α-2a (40 kD) with or without lamivudine revealed hepatitis B surface antigen (HBsAg) clearance in 12% of patients and inactive chronic hepatitis B in 17% of patients, 5 years after the end of treatment. Various predictors of response may be useful in terms of identifying patients who may be candidates for shorter or longer peginterferon-α-2a (40 kD) treatment durations. For example, quantifying serum HBeAg (in HBeAg-positive disease) and HBsAg levels during therapy may be useful. Adverse events typical of the influenza-like symptoms seen with α-interferons occurred more frequently in patients with chronic hepatitis B receiving peginterferon-α-2a (40 kD) with or without lamivudine than in those receiving lamivudine alone. In conclusion, peginterferon-α-2a (40 kD) is a valuable option for the first-line treatment of HBeAg-negative or -positive chronic hepatitis B.

Peginterferon-α-2a (40 kD) has antiviral and immunomodulatory effects. In patients with HBeAg-negative chronic hepatitis B, hepatitis B virus (HBV) kinetics in peginterferon-α-2a (40 kD) recipients differed to those in lamivudine recipients, most likely reflecting different mechanisms of action. During the first month of therapy, viral load decay showed a biphasic pattern with peginterferon-α-2a (40 kD) alone and a multiphasic pattern with peginterferon-α-2a (40 kD) plus lamivudine or lamivudine alone. Although the first slope of viral load decay, reflecting a direct antiviral effect, was significantly slower with peginterferon-α-2a (40 kD) than with lamivudine, peginterferon-α-2a (40 kD) may clear infected cells to a greater extent than lamivudine, possibly reflecting its immunomodulatory activity.

Attaching the large branched 40 kD polyethylene glycol molecule to interferon-α-2a optimizes its pharmacokinetics, allowing for once-weekly administration. Serum concentrations of peginterferon-α-2a (40 kD) are sustained over a 1-week period, and steady-state serum concentrations were reached within 5-8 weeks with once-weekly administration of peginterferon-α-2a (40 kD).

Forty-eight weeks therapy with peginterferon-α-2a (40 kD) with or without lamivudine was more effective than lamivudine alone in achieving a sustained response in patients with HBeAg-positive or -negative chronic hepatitis B, according to the results of two pivotal randomized, partially-blind, multicentre trials.

In HBeAg-positive disease, the proportion of patients with HBeAg sero-conversion or HBV DNA suppression to <100 000 copies/mL 24 weeks post-treatment was significantly higher among recipients of peginterferon-α-2a (40 kD) with or without lamivudine than in recipients of lamivudine alone. In addition, significantly more patients receiving peginterferon-α-2a (40 kD) with or without lamivudine versus lamivudine alone achieved a combined response or HBsAg seroconversion; however, there were no significant between-group differences in the histological response rate. Among peginterferon-α-2a (40 kD) monotherapy recipients who participated in a long-term follow-up study, the HBeAg seroconversion rate was 42% 1 year after the end of treatment, with 37% of patients achieving suppression of HBV DNA to <100 000 copies/mL.

The trial in patients with HBeAg-negative chronic hepatitis B revealed that ALT normalization and HBV DNA suppression was seen in significantly more recipients of peginterferon-α-2a (40 kD) with or without lamivudine than in recipients of lamivudine alone, 24 weeks post-treatment. Moreover, significantly more peginterferon-α-2a (40 kD) monotherapy than lamivudine monotherapy recipients experienced a combined response, HBV DNA levels of <400 copies/mL, HBsAg loss or HBsAg seroconversion. In addition, significantly more patients receiving peginterferon-α-2a (40 kD) plus lamivudine than lamivudine monotherapy achieved a combined response or HBV DNA levels of <400 copies/mL. There were no significant between-group differences in histological response. Among patients who participated in a long-term follow-up study, an HBV DNA level of <10 000 copies/mL was achieved in 24% of patients who received peginterferon-α-2a (40 kD) with or without lamivudine after 4 years of follow-up; HBsAg loss occurred in 11% of patients receiving peginterferon-α-2a (40 kD) with or without lamivudine and in 2% of patients receiving lamivudine alone. In patients with HBeAg-negative disease who received peginterferon-α-2a (40 kD) with or without lamivudine, HBsAg clearance occurred in 12% of patients and inactive chronic hepatitis B occurred in 17% of patients, 5 years after the end of treatment.

Two studies compared peginterferon-α-2a (40 kD) with entecavir or adefovir dipivoxil in patients with HBeAg-positive chronic hepatitis B. After 48 weeks of therapy, rates of HBeAg and HBsAg seroconversion were significantly higher with peginterferon-a-2a (40 kD) than with entecavir; the on-treatment decline in HBeAg and HBsAg levels was also significantly greater with peginterferon-α-2a (40 kD) at weeks 24 and 48. There was no significant between-group difference in the proportion of patients with an HBV DNA level of <1000 copies/mL. In patients with HBeAg-positive chronic hepatitis B who were infected with lamivudine-resistant YMDD mutant strains of HBV, the HBeAg seroconversion rate at week 72 was significantly higher in patients receiving peginterferon-α-2a (40 kD) for 48 weeks than in those receiving adefovir dipivoxil for 72 weeks.

The addition of ribavirin or adefovir dipivoxil to peginterferon-α-2a (40 kD) therapy did not improve outcome in patients with HBeAg-negative chronic hepatitis B (assessed 24 weeks after the end of therapy).

Among patients with HBeAg-positive chronic hepatitis B, predictors of response to peginterferon-α therapy included female sex, high baseline ALT levels, low baseline HBV DNA levels and HBV genotype A infection. In this patient group, quantifying HBeAg levels after 24 weeks of peginterferon-α-2a (40 kD) therapy may be able to predict the absence of a response and provide sufficient information to decide if prematurely discontinuing therapy is justified (e.g. lower serum levels of HBeAg were associated with a greater likelihood of HBeAg sero-conversion). In addition, on-treatment HBsAg levels may also be useful as an early indicator of a sustained off-treatment response.

In patients with HBeAg-negative chronic hepatitis B, factors predictive of a sustained combined response 24 weeks after the end of peginterferon-α-2a (40 kD) therapy included high baseline ALT levels, low baseline HBV DNA levels, younger age, female sex, HBV genotype and type of treatment. HBV genotype and type of treatment remained predictive of a combined response to treatment 1 year after the end of therapy. In addition, suppression of HBV DNA levels to ≤400 copies/mL 6 months post-treatment was a good predictor of response 3 years post-treatment. Quantifying HBsAg levels may help identify which patients with HBeAg-negative chronic hepatitis B are likely to achieve a sustained response to peginterferon-α-2a (40 kD) therapy and which patients may benefit from a longer treatment duration.

In patients with HBeAg-negative or -positive chronic hepatitis B, the incidence of adverse events was higher in patients receiving peginterferon-α-2a (40 kD) alone or in combination with lamivudine than in those receiving lamivudine alone. The most commonly reported adverse events in recipients of subcutaneous peginterferon-α-2a (40 kD) 180 mg once weekly were typical of those seen with α-interferons and included pyrexia, fatigue, headache, myalgia, decreased appetite and alopecia. The proportion of patients with HBeAg-positive disease who discontinued therapy because of a safety reason was 3%, 4% and 1% among recipients of peginterferon-α-2a (40 kD) alone, peginterferon-α-2a (40 kD) plus lamivudine and lamivudine alone, respectively; rates in the corresponding treatment groups among patients with HBeAg-negative disease were 7%, 4% and 0%.

Peginterferon-α-2a (40 kD) dose modification was required in almost half of the patients who received peginterferon-α-2a (40 kD) with or without lamivudine (46–48% of patients). A laboratory abnormality (e.g. neutropenia, thrombocytopenia, elevated ALT levels) was the most common reason for dose modification (36–38% of patients) with adverse events accounting for dose modification in 7-13% of patients.

Mixed results were seen in pharmacoeconomic analyses involving patients with HBeAg-negative or -positive chronic hepatitis B, with incremental cost-effectiveness ratios for peginterferon-α-2a (40 kD) versus lamivudine falling below commonly accepted cost-effectiveness thresholds in most, but not all, analyses.