, Volume 64, Issue 24, pp 2823-2843
Date: 19 Sep 2012

Peginterferon-α-2a (40kD) Plus Ribavirin

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Summary

Abstract

Pegylated interferon plus ribavirin is the standard first-line treatment in patients with chronic hepatitis C virus (HCV) mono-infection. Although the optimal anti-HCV regimen is not established in the more difficult-to-treat population with HIV-HCV co-infection, much of the data in this clinical setting have been derived from studies evaluating peginterferon-α-2a (40kD) [Pegasys®] plus ribavirin (Copegus®), most notably the APRICOT (AIDS Pegasys Ribavirin International Co-Infection Trial) and the ACTG (AIDS Clinical Trial Group) A5071 study. In particular, results of APRICOT — the largest study conducted to date with a pegylated interferon plus ribavirin in patients with HIV-HCV co-infection-indicate that a substantial proportion of patients will achieve sustained virological response (SVR) at week 72 when these drugs are administered for 48 weeks in an appropriate dosage regimen. In general, the tolerability profile of peginterferon-α-2a plus ribavirin in APRICOT was similar to that previously reported in patients with HCV mono-infection.

Pharmacological Properties|

Interferons inhibit viral replication and/or function in infected cells via complex intracellular signalling processes induced by binding to specific cell surface receptors. The mechanism by which ribavirin exerts its antiviral effects against HCV is not known. Both peginterferon-α-2a and ribavirin have immunomodulatory effects, which may contribute to their activity.

Following subcutaneous administration of peginterferon-α-2a 180μg once weekly in patients with HCV infection, serum drug concentrations are sustained throughout the dosage interval, with peak concentrations approximately 1.5- to 2-fold higher than trough concentrations. Mean terminal elimination half-life (t1/2β) of peginterferon-α-2a is 80 hours compared with 5.1 hours for interferon-α-2a.

Ribavirin is rapidly and extensively absorbed following oral administration, although absolute bioavailability is only about 45–65%, probably as a result of first-pass metabolism. The drug has a very high volume of distribution (4500L) and long t1/2β (120–170 hours). Pharmacokinetic properties of ribavirin are similar in patients with HIV-HCV co-infection or HCV mono-infection.

Concomitant administration of peginterferon-α-2a and ribavirin in patients with HCV infection did not result in any pharmacokinetic interaction between these drugs. There is also no clinically significant interaction between peginterferon-α-2a and methadone.

A pharmacokinetic analysis in almost 50 patients with HIV-HCV co-infection receiving anti-HCV and antiretroviral therapy showed that ribavirin 800 mg/day does not affect the intracellular metabolism or plasma concentration-time profile of lamivudine (3TC), stavudine (d4T) and zidovudine (AZT). However, didanosine (dd1) is not recommended (and is generally strictly avoided in clinical practice) in patients receiving ribavirin, as fatalities and other serious adverse effects associated with didanosine have occurred as a result of increased formation of its active triphosphate anabolite.

Therapeutic Efficacy|

Optimal regimens of subcutaneous pegylated interferon plus oral ribavirin achieve SVR rates, defined as an undetectable HCV RNA level at the end of a 24-week untreated follow-up period, in excess of 50–60% in previously untreated patients with HCV mono-infection. However, SVR rates are typically much lower in patients with HIV-HCV co-infection.

SVR was achieved in 40% of co-infected patients who received peginterferon-α-2a 180μg once weekly plus ribavirin 800 mg/day as first-line therapy for 48 weeks in the large (n = 860), multinational study known as APRICOT. This was significantly higher than the SVR rate of 20% with peginterferon-α-2a monotherapy, or the 12% SVR rate with interferon-α-2a plus ribavirin. The difference in SVR rates between the latter two regimens was also statistically significant, indicating that peginterferon-α-2a monotherapy is a viable treatment option in co-infected patients who are unable to take ribavirin. The pattern of SVR (peginterferon-α-2a plus ribavirin > peginterferon-α-2a > interferon-α-2a plus ribavirin) remained the same when patients were grouped according to HCV genotype (1 vs 2 or 3) or by HCV RNA levels (high vs low) at baseline.

First-line therapy with peginterferon-α-2a 180μg once weekly plus ribavirin also achieved a significantly higher SVR rate than interferon-α-2a plus ribavirin (27% vs 12%) in 133 co-infected patients randomised in the ACTG A5071 study. A dose-escalation schedule for ribavirin was used in the ACTG A5071 study, which may not have provided optimal therapy.

Tolerability|

In general, the tolerability profile of peginterferon-α-2a plus ribavirin appears to be similar in patients with HIV-HCV co-infection to that in patients with HCV mono-infection. In addition, combination therapy with peginterferon-α-2a plus ribavirin was not associated with loss of HIV disease control in co-infected patients.

In the APRICOT study in patients with HIV-HCV co-infection, the most frequently reported adverse events with peginterferon-α-2a plus ribavirin (incidence ≥20%) were fatigue, pyrexia, headache, myalgia, nausea, diarrhoea, insomnia, asthenia and depression. Premature withdrawal from the trial because of adverse events or laboratory abnormalities occurred in 15% of patients in this treatment group, and 8% experienced a serious treatment-related adverse event. In general, there were few differences between treatment groups for most of these tolerability parameters. Although statistical analysis was not reported, clinically significant neutropenia was more likely to occur in treatment arms that included peginterferon-α-2a, and anaemia was more likely in treatment arms that included ribavirin.

In the ACTG A5071 trial, 12% of patients in both treatment groups discontinued therapy because of adverse events or laboratory abnormalities. The incidence of depression, influenza-like symptoms and laboratory abnormalities was also similar between treatment groups, although neutropenia of any grade was reported during the first 24 weeks of the trial in 55% of patients treated with peginterferon-α-2a plus ribavirin compared with 30% of those who received interferon-α-2a plus ribavirin (statistical analysis not reported).

Various sections of the manuscript reviewed by: F. Bonino, Ospedele Maggiore di Milano Policlinico, Milan, Italy; P. Ferenci, Innere Med Klin IV, University of Vienna, Vienna, Austria; J.K. Rockstroh, Outpatient Clinic and Department of Medicine I, University of Bonn, Bonn, Germany; R.K. Sterling, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA; F. Torriani, Epidemiology Unit, Department of Medicine, Division of Infectious Diseases, University of California, San Diego, California, USA; S. Zeuzem, Department of Medicine, Division of Gastroenterology, Hepatology and Endocrinology, Saarland University Hospital, Homburg/Saar, Germany.

Data Selection

Sources: Medical literature published in any language since 1980 on peginterferon alfa-2a plus ribavirin, 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’ and ‘ribavirin’ or ‘pegylated interferon alfa-2a and ribavirin’ and ‘hepatitis C’ and ‘HIV infections’. EMBASE search terms were ‘peginterferon alfa-2a’ and ‘ribavirin’ and ‘hepatitis C’ and ‘HIV’ or ‘human immunodeficiency virus’. AdisBase search terms were ‘peg-interferon-alpha-2a’ and ‘ribavirin’ or ‘pegylated interferon alfa-2a’ and ‘ribavirin’ and ‘hepatitis-C’ and ‘HIV-infections’. Searches were last updated 9 November 2004.
Selection: Studies in patients with hepatitis C virus co-infected with HIV who received peginterferon alfa-2a and ribavirin. 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 alfa-2a, ribavirin, hepatitis C infection, HIV, co-infection, pharmacodynamics, pharmacokinetics, drug interactions, tolerability, therapeutic use.