, Volume 65, Issue 6, pp 809-825
Date: 19 Sep 2012

Peginterferon-α-2a (40kD)

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Summary

Abstract

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.

Pharmacological Properties

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.

Therapeutic Efficacy

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.

Tolerability

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.

Various sections of the manuscript reviewed by: D.E. Bernstein, Gastroenterology, Hepatology and Nutrition, North Shore Long Island Jewish Hospitals, Manhasset, New York, USA; W.G.E. Cooksley, Department of Medicine, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia; J. García-Samaniego, Liver Unit, Hospital Carlos III, Madrid, Spain; S.J. Hadziyannis, Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece; G.K.K. Lau, Department of Medicine, The University of Hong Kong, Hong Kong; Y.-F. Liaw, Liver Unit and Department of Pathology, Chang Gung Memorial Hospital & Chang Gung Medical College, Taipei, Taiwan; P. Marcellin, Service de Hepatologie, Hôpital Beaujon, Clichy, France.

Data Selection

Sources: Medical literature published in any language since 1980 on peginterferon-α-2a (40kD) and hepatitis B, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘peginterferon alfa-2a’ or ‘pegylated interferon alfa-2a’ or ‘PEG-IFN alfa-2a’ and ‘hepatitis B’. EMBASE search terms were ‘peginterferon alfa-2a’ or ‘pegylated interferon alfa-2a’ and ‘hepatitis B’. AdisBase search terms were ‘peginterferon alfa-2a’ or ‘pegylated interferon alfa-2a’ or ‘PEG-IFN alfa-2a’ and ‘hepatitis-B’. Searches were last updated 7 March 2005.
Selection: Studies in patients with hepatitis B who received peginterferon alfa-2a. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Peginterferon-α-2a, hepatitis B, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.