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Chou R, Carson S, Chan BKS, et al. Drug Class Review: Pegylated Interferons for Chronic Hepatitis C Infection: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2007 May.

Cover of Drug Class Review: Pegylated Interferons for Chronic Hepatitis C Infection

Drug Class Review: Pegylated Interferons for Chronic Hepatitis C Infection: Final Report [Internet].

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Introduction

Hepatitis C virus (HCV) is the most common chronic blood borne pathogen in the United States. It is acquired primarily by large or repeated percutaneous exposures to blood, with a history of injection drug use the strongest risk factor. Approximately 1.6% of U.S. adults over the age of 20 (about 4.1 million persons) have antibodies to HCV, indicating prior acute HCV infection.1 Up to 84% of patients with acute HCV infection develop chronic HCV infection (about 3.2 million U.S. adults).

Chronic HCV infection has a variable course but can cause cirrhosis, liver failure, and hepatocellular cancer after a number of years. Up to 20% of persons with chronic HCV infection develop cirrhosis after 20 years.2 In the United States, HCV infection is associated with approximately 40% of cases of chronic liver disease.3 The number of liver-related deaths associated with chronic HCV infection was estimated at 13,000 deaths per year in 2000, but is thought to be on the rise.4 Around 40% of patients who undergo liver transplantation have chronic HCV infection.5

The specific HCV genotype is an important predictor of clinical outcomes and response to antiviral treatment.6 In the United States, genotype 1 infection is found in up to three-quarters of HCV-infected patients.7 It is associated with the poorest response to antiviral treatment. Genotypes 2 and 3 are present in about 20% of HVC-infected patients.

Recombinant type I interferons are administered to patients with HCV infection for their antiviral effects. Interferon-based therapy is also associated with flu-like symptoms, fatigue, and neuropsychiatric and hematologic adverse effects.8 Interferon monotherapy for chronic HCV infection began in the mid-1980s and was only modestly successful at suppressing HCV (Table 1).9–12 Subsequent trials found dual therapy with interferon and the synthetic nucleoside analogue ribavirin more effective than monotherapy, though the proportion of patients with sustained virologic response (SVR) rates remained under 50%.9, 10, 12

Table 1. Sustained virologic response rates with different antiviral regimens for hepatitis C virus infection.

Table 1

Sustained virologic response rates with different antiviral regimens for hepatitis C virus infection.

The first "pegylated" interferon was approved by the FDA in 2001. Pegylation refers to the cross-linking of polyethylene glycol (PEG) molecules to the interferon molecule, which delays renal clearance.16 An advantage of pegylation is that it permits less frequent dosing (once weekly versus three times a week with non-pegylated interferon). Dual therapy with pegylated interferon and ribavirin is associated with higher SVR rates than non-pegylated interferon plus ribavirin or pegylated interferon monotherapy (Table 1). Currently, two pegylated interferons are available. Both are Type I alfa interferons, but differ in size and structure of the interferon and polyethylene glycol molecules, as well as in pharmacokinetic properties (Table 2).16 One pegylated interferon consists of 31-kilodalton (kDa) interferon alfa-2b conjugated to 12-kilodalton (kDa) polyethylene glycol (trade name PEG-intron). The other consists of recombinant 20-kDa interferon alfa-2a linked to 40-kDa polyethylene glycol (trade name Pegasys). The dosing schedule is fixed for pegylated interferon alfa-2a and is based on weight for pegylated interferon alfa-2b. Each pegylated interferon is approved for dual therapy with ribavirin (Copegus for pegylated interferon alfa-2a and Rebetol for alfa-2b). Although each pegylated interferon is approved for combination therapy with a specific brand of ribavirin manufactured by the respective manufacturer, the ribavirin is pharmacologically identical.

Table 2. Pharmacokinetics, indications and dosing of included drugs.

Table 2

Pharmacokinetics, indications and dosing of included drugs.

Dual therapy with pegylated interferon and ribavirin is now recommended as the antiviral regimen of choice for chronic HCV infection in patients who meet criteria for treatment.6, 20 However, current guidelines make no recommendation for one pegylated interferon over the other, and it is unclear if there are clinically significant differences between dual therapy with pegylated interferon-alfa 2a versus pegylated interferon-alfa 2b. There is also uncertainty about comparative effectiveness and safety of dual therapy with pegylated interferons in subgroups of patients with HCV (such as those co-infected with HIV infection, those with higher fibrosis stage or higher viral load, those infected with genotype 1, or those who have already failed interferon-based therapy) and in how differences in duration of therapy or dose affect estimates of benefits and harms.

Scope and Key Questions

The purpose of this review is to compare the benefits and harms of different pharmacologic treatments for chronic hepatitis C infection. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project (DERP). The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

  1. What is the comparative effectiveness of regimens of peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C virus infection?
    1. How does duration of treatment or dosing protocols (including weight-based or maintenance dosing or dosing of ribavirin) affect estimates of comparative effectiveness?
  2. What is the comparative tolerability and safety of peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C virus infection?
  3. Does the comparative effectiveness or tolerability and safety of peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin vary in patient subgroups defined by demographics (age, racial groups, gender, genotype, markers of disease severity), use of other medications, or presence of co-morbidities (such as HIV infection)?
Copyright © 2007, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10664
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