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Subcutaneous peginterferon-α-2a (40kD) [Pegasys®] is an effective and reasonably well tolerated treatment for the management of patients with hepatitis B e antigen (HBeAg)-negative or -positive chronic hepatitis B. It was significantly more effective than lamivudine monotherapy at inducing sustained virological response and ALT normalisation in both HBeAg-negative and -positive patients. Notably, the addition of lamivudine to peginterferon-α-2a (40kD) conferred no additional benefit versus peginterferon-α-2a (40kD) monotherapy. Moreover, in HBeAg-positive patients significantly more peginterferon-α-2a (40kD) recipients experienced HBeAg seroconversion than lamivudine recipients. The position of peginterferon-α-2a (40kD) relative to other treatment options remains to be fully determined. In the meantime, this agent appears to be a valuable new option for the management of patients with HBeAg-negative or -positive chronic hepatitis B.
A biomathematical model has been developed to describe hepatitis B virus (HB V) kinetics. The viral kinetic profile of peginterferon-α-2a (40kD) monotherapy appears different to that of peginterferon-α-2a (40kD) plus lamivudine, with HBV viraemic decline biphasic in monotherapy recipients and generally triphasic in recipients of combination therapy. Compared with lamivudine, peginterferon-α-2a (40kD) appears to inhibit HBV replication to a lesser extent, but has a similar or greater impact on overall clearance of infected cells, which may contribute to increased virological response.
Serum levels of subcutaneous peginterferon-α-2a (40kD) are maintained throughout the once-weekly dose administration interval.
Subcutaneous peginterferon-α-2a (40kD) administered once weekly has been evaluated in the treatment of adult patients with HBeAg-negative and -positive chronic hepatitis B in randomised, well designed trials. Endpoints assessed 24 weeks after treatment cessation are reported.
In patients with HBeAg-negative chronic hepatitis B, peginterferon-α-2a (40kD) 180 μg/week for 48 weeks as monotherapy or in combination with lamivudine was significantly more effective than lamivudine monotherapy, in terms of virological response (defined as an HBV DNA level of <20 000 copies/ mL [43% and 44% vs 29%]) or ALT normalisation (59% and 60% vs 44%). Peginterferon-α-2a (40kD) for 48 weeks was similarly effective in patients with HBeAg-positive chronic hepatitis B; in the corresponding treatment groups, the virological response rates (defined as an HBV DNA level of <100 000 copies/mL) were 32% and 34% versus 22% and the ALT normalisation rates were 41% and 39% versus 28%. Furthermore, in HBeAg-positive patients, HBeAg seroconversion rates were 32% and 27% in recipients of peginterferon-α-2a (40kD) administered alone or in combination with lamivudine, and were significantly higher than those in lamivudine monotherapy recipients (19%). In addition, hepatitis B surface antigen (HBsAg) seroconversion (indicative of complete response) occurred in a small group of peginterferon-α-2a (40kD) recipients, but in no recipients of lamivudine monotherapy. Notably in both HBeAg-negative and — positive patients, response rates in peginterferon-α-2a (40kD) recipients were similar irrespective of whether this agent was given as monotherapy or in combination with lamivudine.
Significantly more HBeAg-positive peginterferon-α-2a (40kD) recipients achieved a combined response of HBV DNA suppression (defined as an HBV DNA level of <500 000 copies/mL, serum ALT normalisation and HBeAg loss), compared with recipients of conventional interferon-α-2a (24% vs 12%) in a 24-week phase II proof-of-concept trial. Peginterferon-α-2a (40kD) also proved effective in several difficult-to-treat patient subgroups, including patients with HBV genotype C and those with high HBV DNA and/or low ALT levels at baseline.
The detrimental impact of peginterferon-α-2a (40kD) monotherapy on healthrelated quality of life in patients with HBeAg-negative and -positive chronic hepatitis B appears to be less than that historically seen in patients with chronic hepatitis C.
Subcutaneous peginterferon-α-2a (40kD) is reasonably well tolerated in adult patients, with ≤7% of patients discontinuing therapy because of adverse events. Treatment-emergent adverse events and laboratory abnormalities are typical of those documented previously with interferons, and the addition of lamivudine does not alter the tolerability profile of peginterferon-α-2a (40kD).
In the two largest trials, the most commonly occurring treatment-emergent adverse events in peginterferon-α-2a (40kD) recipients were pyrexia, fatigue, myalgia, headache, decreased appetite, alopecia, arthralgia, diarrhoea and injection-site reactions. At least one adverse event was reported in 87–89% of peginterferon-α-2a (40kD) recipients, and the incidence was similar irrespective of whether peginterferon-α-2a (40kD) was given as monotherapy or in combination with lamivudine. Among lamivudine monotherapy recipients, 56% of HBeAg-positive patients experienced at least one adverse event. The corresponding value in the HBeAg-negative group was 48% and was statistically significant versus peginterferon-α-2a (40kD) groups for overall treatment effect. Serious adverse events occurred in a similar proportion of patients across treatment groups (2–7%).
Among patients with HBeAg-negative chronic hepatitis B, dose modification for adverse events was necessary in 7% of peginterferon-α-2a (40kD) monotherapy recipients and in 13% of combination therapy recipients. Dose modification for laboratory abnormalities occurred in a similar incidence in the corresponding treatment groups (37% and 36%) and were commonly due to ALT elevation (8% and 3%), neutropenia (17% and 25%) and thrombocytopenia (19% and 12%). Dose modification for adverse events or laboratory abnormalities was not necessary in any HBeAg-negative lamivudine monotherapy recipients.
Patients with chronic hepatitis B appeared to tolerate peginterferon-α-2a (40kD) better than patients with chronic hepatitis C, with a lower incidence of depression and a generally lower incidence of individual adverse events.
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