Peginterferon alpha-2a

Compound Name:Peginterferon alpha-2aMolecular Target:Type I interferon receptorsMolecular Structure:Recombinant human physiological protein, Type I interferon, conjugated to polyethylene glycolLicensed Indication:Chronic hepatitis C; Chronic hepatitis BManufacturer and/or Distributor:Hoffmann-La Roche/GenentechInitial FDA Approval2002SummaryPeginterferon alpha-2a (Pegasys) is a recombinant human protein (MW 19 kDa) produced in E. coli and conjugated to monomethoxy polyethylene glycol (PEG) for a total MW of about 60 kDa. It binds to the Type I interferon receptor, which is widely present on many cell types. This binding initiates a signaling cascade that leads to the diverse physiological effects of Type I interferons, including inhibition of viral replication, cellular proliferation, and angiogenesis; as well as pro-apoptotic and immunomodulatory activities. The addition of the PEG moiety results in a thirty-fold increase in the in vivo half-life of the agent. Peginterferon alpha-2a is administered by weekly subcutaneous injections. Peginterferon alpha-2a was first FDA approved in 2002 for treatment of adults who have chronic hepatitis C and compensated liver disease, including those with HIV and a CD4 count of >100cells/mm3. It is usually used in combination with ribavirin for this indication. In 2011, children over the age of 5 were included in the indication for treatment of chronic hepatitis C. In 2013, approval was given for use of peginterferon alpha-2a in combination with ribavirin and a protease inhibitor for children and adults with hepatitis C, especially in patients with genotype 1 or 4 hepatitis C virus (HCV). The recommended treatment durations vary, depending on the genotype of the HCV and whether other anti-HCV medications are being administered, but are generally 24-48 weeks in length and typically cost between $18-37,000. The high cost, need for weekly injections and data indicating reduced efficacy in patients with advanced cirrhosis, HIV co-infection, or IL28B TT genotype, in combination with newer interferon-free combination therapies may reduce the use of Peginterferon alpha-2a over time for HCV disease. In 2005, chronic hepatitis B in adults was added as an indication. Most experts consider therapy for patients with hepatitis B and acute liver failure, those with complications from hepatic cirrhosis, or patients with advanced liver fibrosis and high serum levels of hepatitis B virus (HBV) DNA. These treatment indications are irrespective of the patient’s hepatitis B e antigen (HBeAg) status. In addition, patients with undergoing chemotherapy or heavy immunosuppression may require treatment to suppress reactivation of chronic HBV. Use of Peginterferon alpha-2a for treatment of chronic hepatitis B is advantageous in that it does not select for resistant mutant viruses and yet confers a more durable response despite finite treatment duration. The disadvantages of this therapy are its cost and the fact that it cannot be used in decompensated liver disease or during pregnancy. In 2014, the FDA included warnings on the use of Peginterferon alpha-2a in combination with ribavirin, causing birth defects and fetal death. Like other Type I interferons, peginterferon alpha-2a induces local injection site reactions and systemic flu-like symptoms. Common non-severe adverse effects are very common with the use of Peginterferon alpha-2a. Serious safety concerns include hypersensitivity and a wide variety of manifestations affecting multiple systems: neuropsychiatric, cardiopulmonary, GI, endocrine, renal, hematopoietic, ophthalmologic, cerebrovascular, and infectious, as well as the potential to induce autoimmune syndromes and growth retardation in children.References

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