, Volume 68, Issue 9, pp 1273-1317

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

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Summary

Abstract

Peginterferon-α-2a (40 kD) [PEGASYS®] is a conjugate of recombinant interferon-α-2a and a 40 kD branched polyethylene glycol (PEG) moiety that is highly active against hepatitis C virus (HCV). Ribavirin (COPEGUS®) is a synthetic nucleoside analogue that acts in synergy with the antiviral activity of peginterferon-α-2a (40 kD). The combination of subcutaneous peginterferon-α-2a (40 kD) once weekly plus oral ribavirin twice daily is widely approved for use in adult patients with chronic hepatitis C, including those with persistently ‘normal’ ALT activity or HIV-HCV co-infection, and is recommended as a first-line treatment option for patients with chronic hepatitis C and compensated liver disease. In randomized, phase III trials, the combination has consistently demonstrated good therapeutic efficacy (i.e. high sustained virological response [SVR] rates) and has been generally well tolerated in both treatment-naive and treatment-experienced patients with chronic hepatitis C, including those with compensated advanced liver disease. Several baseline and dynamic (on-treatment) predictors of SVR that can be used to guide and optimize therapy were also determined in these trials and in subsequent analyses. By utilizing these predictors, therapy with peginterferon-α-2a (40 kD) plus ribavirin can be individualized to achieve the optimal balance between efficacy and tolerability, further increasing the usefulness of this drug combination. Thus, peginterferon-α-2a (40 kD) plus ribavirin remains a valuable therapy in patients with chronic hepatitis C, as a first-line option in those with compensated liver disease and as a second-line therapy in those with advanced liver disease.

Pharmacological Properties

Peginterferon-α-2a (40 kD) is a covalent conjugate of recombinant interferon-α-2a and a 40 kD single branched PEG moiety. Peginterferon-α-2a (40 kD) shows antiviral activity in vitro against HCV and clinically significant activity in patients with chronic hepatitis C. The anti-HCV activity of interferon-α-2a is augmented by pegylation. Ribavirin is a synthetic nucleoside analogue that shows activity in vitro against some RNA and DNA viruses. Although the exact mechanism is not known, ribavirin acts synergistically with peginterferon-α-2a (40 kD) in patients with chronic hepatitis C to improve SVR rates and reduce virological relapse after treatment cessation. In addition, the therapeutic efficacy of peginterferon-α-2a (40 kD) plus ribavirin is aided by the ability of both drugs to modulate and restore the impaired HCV-specific immune responses seen in patients with chronic HCV infection.

The pharmacokinetic properties of peginterferon-α-2a (40 kD) are largely influenced by the presence of the PEG moiety. As a consequence of pegylation, the drug is absorbed slowly following subcutaneous injection, has distribution restricted to the blood and highly perfused organs, is protected from rapid enzymatic degradation in the liver and has a slow clearance rate. Following subcutaneous administration of peginterferon-α-2a (40 kD) 180 µg once weekly, serum drug concentrations are maintained throughout the dose administration interval, with a narrow peak-to-trough concentration ratio.

Ribavirin is rapidly and extensively absorbed following oral administration. The absolute bioavailability of the drug is limited because of first-pass metabolism outside the liver, but can be improved with coadministration of a high-fat meal. Ribavirin is distributed widely in, and eliminated slowly from, the non-plasma compartments. The drug is mainly eliminated in the urine as metabolites or unchanged drug (5–15% of an administered dose).

Combined administration of subcutaneous peginterferon-α-2a (40 kD) and oral ribavirin does not seem to alter the pharmacokinetic properties of either drug.

Therapeutic Efficacy

In Treatment-Naive Patients: Subcutaneous peginterferon-α-2a (40 kD) 180 µg once weekly plus oral ribavirin 800 mg/day or 1000–1200 mg/day was previously shown to produce SVR (i.e. undetectable [<50 IU/mL] serum HCV RNA at 24 weeks’ follow-up) in 46–52% of treatment-naive patients with HCV genotype 1 infection, and 76–84% of those with HCV genotype 2 or 3 infection in two pivotal, well designed, phase III trials. Several retrospective multiple logistic regression analyses of data from trials of peginterferon-α-2a (40 kD) plus ribavirin, including these two trials, have suggested that achieving an SVR was dependent on several key baseline and/or on-treatment factors. Baseline factors more likely to result in an improved SVR rate included HCV genotype 2 or 3 infection, low baseline viral load, less advanced liver histology, younger patient age and lower patient bodyweight. The most important on-treatment predictors of SVR were a rapid virological response (RVR; HCV RNA <50 IU/mL at week 4) and early virological response (EVR; non-RVR but either HCV RNA <50 IU/mL at week 12, or ≥2 log drop in HCV RNA with HCV RNA ≥50 IU/mL at week 12); an absence of EVR was predictive of non-response to therapy. The most recent analyses suggest that the time to undetectable HCV RNA is the most important predictor of SVR, regardless of baseline characteristics, and that RVR is the strongest predictor of SVR in all patient groups.

The best overall results in phase III trials were achieved with peginterferon-α-2a (40 kD) 180 µg once weekly plus ribavirin 1000 or 1200 mg/day (for patients weighing <75 kg or ≥75 kg) as a 48-week regimen in patients with HCV genotype 1 or 4 infection, and peginterferon-α-2a (40 kD) 180 µg once weekly plus ribavirin 800 mg/day as a 24-week regimen in patients with HCV genotype 2 or 3 infection. An ongoing follow-up study of nine trials of peginterferon-α-2a (40 kD) with or without oral ribavirin (including the two pivotal trials) showed that SVR achieved with peginterferon-α-2a (40 kD) plus ribavirin is retained in >99% of patients for a mean 4.1 years (range 0.4–7 years) after treatment completion.

Other randomized trials showed that further individualization of therapy duration and ribavirin dosage to achieve optimum SVR, relapse rates and tolerability is possible. Shortening of treatment duration from 48 to 24 weeks may be possible in patients with HCV genotype 1 infection who achieve an RVR. Patients who achieve a complete EVR (non-RVR but HCV RNA <50 IU/mL at week 12) benefit from 48 weeks of treatment, and those with a partial EVR (non-RVR and ≥2 log drop in HCV RNA with HCV RNA ≥50 IU/mL at week 12) may require intensified treatment. Prolonging therapy from 48 to 72 weeks may be of benefit (higher SVR rates and reduced relapse rates) in patients with HCV genotype 1 infection who do not achieve an EVR. A 48-week combination treatment regimen of ribavirin plus an induction (360 µg once weekly) dosage of peginterferon-α-2a (40 kD) for the first 12 weeks followed by ribavirin plus a standard (180 µg once weekly) dosage of peginterferon-α-2a (40 kD) for the remaining 36 weeks achieved higher RVR and EVR rates in patients with HCV genotype 1 infection than ribavirin plus a standard peginterferon-α-2a (40 kD) dosage for 48 weeks.

The ACCELERATE and NORDYNAMIC trials found that SVR rates in patients with HCV genotype 2 or 3 infection were higher with 24 weeks than with 12 or 16 weeks of peginterferon-α-2a (40 kD) plus low-dose ribavirin (800 mg/day) combination therapy. However, SVR rates in patients with a low viral load at baseline (<400 000 IU/mL) did not differ between the 24-week and the 16-week regimen in the ACCELERATE trial, and other randomized trials using weight-based ribavirin regimens (800–1200 mg/day) concluded that the 12- or 16-week regimens were as effective as the 24-week regimen (only in patients with a low viral load at baseline [<300 000 IU/mL] in one study). Results of another combination therapy trial in patients with chronic HCV genotype 2 or 3 infection suggested that a reduction in the ribavirin dosage from 800 to 400 mg/day in a 24-week regimen may be possible without compromising SVR or relapse rates.

Retrospective analyses of data from the two pivotal trials and results from a prospective clinical trial emphasized the importance of exposure to ribavirin in preventing relapse after achieving an SVR. A reduction of ribavirin cumulative exposure to ≤80% was associated with a decrease in SVR rates, largely due to higher relapse rates. This effect was most pronounced if cumulative ribavirin exposure was ≤60% of the target dose.

In Treatment-Experienced Patients: Therapy with peginterferon-α-2a (40 kD) 180 µg once weekly plus ribavirin 1000–1200 mg/day for 48 weeks achieved an SVR in a significant proportion of patients with chronic HCV genotype 1 infection who were non-responders to conventional interferon-α or to conventional interferon-α plus ribavirin.

In the REPEAT trial, which enrolled patients with chronic hepatitis C who were non-responders to peginterferon-α-2b (12 kD) plus ribavirin (predominantly HCV genotype 1 infection), prolonged (72-week) peginterferon-α-2a (40 kD) plus ribavirin combination therapy, with or without an induction dosage of peginterferon-α-2a (40 kD), achieved higher SVR rates than re-treatment with standard peginterferon-α-2a (40 kD) plus ribavirin therapy for 48 weeks.

In Special Patient Populations: In patients with HCV genotype 4 infection, peginterferon-α-2a (40 kD) 180 µg once weekly plus ribavirin 800–1200 mg/day for 48 weeks or ribavirin 1000–1200 mg/day for 24 weeks achieved SVR rates of 63–79% in the pivotal phase III trials. In a Spanish trial in patients with HCV genotype 4 infection, 48 weeks of treatment with peginterferon-α-2a (40 kD) plus ribavirin 1000 or 1200 mg/day resulted in an SVR rate of 56%. Another trial suggested that in patients with HCV genotype 4 infection who achieve an RVR, 24 weeks’ treatment could be as effective as a 48-week regimen. Absence of EVR at week 12 was highly predictive of non-response to treatment in patients with HCV genotype 4 infection.

Pooled data from the two pivotal phase III trials indicated that in treatment-naive patients with chronic hepatitis C with compensated cirrhosis or bridging fibrosis, the best response (37% SVR rate) in patients with HCV genotype 1 infection was achieved with the 48-week regimen using ribavirin 1000–1200 mg/day, whereas in those with HCV genotype 2 or 3 infection, the highest SVR rate (75%) was achieved with the 24-week regimen using ribavirin 800 mg/day. Further analysis of these data suggested that HCV genotype was a significant and independent predictor of SVR in this patient population. Absence of EVR at week 12 was a strong predictor of non-response.

After 48 weeks of re-treatment with peginterferon-α-2a (40 kD) plus ribavirin therapy in a lead-in phase of the HALT-C trial, SVR rates in patients with bridging fibrosis or cirrhosis declined with increasing severity of liver disease. In addition, SVR rates varied according to the previous treatment regimen (conventional interferon with or without ribavirin or peginterferon with or without ribavirin). When analysed by HCV genotype, SVR rates in HALT-C were 14%, 65% and 54% in patients with HCV genotype 1, 2 and 3 infection, respectively. In patients with HCV genotype 1 infection, the SVR rate was dependent on a total dose of peginterferon-α-2a (40 kD) received within the first 20 weeks of treatment, as long as some ribavirin was received. Maintenance therapy with low-dose peginterferon-α-2a (40 kD) did not slow the rate of disease progression (including the development of hepatocellular cancer) in patients with advanced hepatic fibrosis, irrespective of the response to peginterferon-α-2a (40 kD) plus ribavirin therapy.

SVR rates with standard peginterferon-α-2a (40 kD) plus ribavirin combination therapy in African-American patients (HCV genotypes 1, 2 and 3) were lower than those seen in Caucasian-American patients (HCV genotypes 1, 2 and 3). In addition, Latino Caucasian patients (HCV genotype 1) achieved lower SVR rates than non-Latino Caucasian patients (HCV genotype 1). However, SVR rates in Japanese or Taiwanese patients with chronic hepatitis C who received standard combination therapy regimens were consistent with those seen in the general population in the pivotal phase III trials. For instance, in the subgroup of Taiwanese patients with HCV genotype 1 infection, a low viral load at baseline and an RVR at week 4, SVR rates with either 24 or 48 weeks of combination therapy were >96%.

In Routine Clinical Practice: In several open-label, multicentre, national studies reflecting a ‘real world’ setting, peginterferon-α-2a (40 kD) 180 µg once weekly plus ribavirin 800 or 1000 or 1200 mg/day achieved SVR rates consistent with those reported in pivotal phase III clinical trials in patients with chronic hepatitis C. The EVR at week 12 as a predictor of non-response was also confirmed in this setting.

Tolerability

The combination of peginterferon-α-2a (40 kD) plus ribavirin was generally well tolerated in randomized, phase III trials in patients with chronic hepatitis C. Most patients experienced at least one adverse event, which were generally mild to moderate in severity. The most common clinical adverse events included headache, fatigue, myalgia and pyrexia, and the most frequent laboratory abnormalities were neutropenia and thrombocytopenia associated with peginterferon-α-2a (40 kD) [which resolved within a few weeks of treatment cessation] and haemolytic anaemia associated with ribavirin. Approximately one-third of patients receiving peginterferon-α-2a (40 kD) plus ribavirin regimens required dosage reduction to manage adverse events or haematological abnormalities, and 11% of patients required complete drug discontinuation. The most frequent of these adverse events were therapy-related psychiatric, dermatological, gastrointestinal and ‘flu-like’ adverse events or haematological abnormalities. As might be expected, a lower incidence of ribavirin dose modifications because of adverse events or laboratory abnormalities was observed in patients who received shorter treatment regimens. However, extending treatment from 48 to 72 weeks did not significantly increase the incidence or severity of adverse events.

Various sections of the manuscript reviewed by: C.L. Berg, Department of Medicine, Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, Virginia, USA; G.R. Foster, Centre for Adult and Paediatric Gastroenterology, Barts, and The London School of Medicine and Dentistry, Queen Mary, University of London, London, England; S.J. Hadziyannis, Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece; D.M. Jensen, Center for Liver Diseases, University of Chicago, Chicago, Illinois, USA; E.M. Yoshida, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘peginterferon alfa-2a/ribavirin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). 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 and EMBASE search terms were ‘peginterferon alfa-2a/alpha-2a’ or ‘pegylated interferon alfa-2a/alpha-2a’, and ‘ribavirin’ and ‘hepatitis C’. AdisBase search terms were ‘peginterferon alfa-2a’ or ‘pegylated interferon alfa-2a’ or ‘peg-interferon alpha-2a’ or ‘peg IFN alpha-2a’, and ‘ribavirin’ and ‘hepatitis C’. Searches were last updated 20 May 2008.
Selection: Studies in patients with chronic hepatitis C who received peginterferon-α-2a (40 kD) plus 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-α-2a (40 kD), ribavirin, chronic hepatitis C, hepatitis C virus (HCV) infection, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.