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•hcspFACTsheet• a series of fact sheets written by experts in the field of liver disease Hepatitis C Support Project • www.hcvadvocate.org Newer Version Available. Click Here. HCV Treatment: Types of Interferon & How They Work Liz Highleyman Interferon alpha (especially its pegylated form) is the mainstay of therapy for acute and chronic hepatitis C virus infection, and is also used to treat chronic hepatitis B. But several other types of interferon are also under study for the treatment of viral hepatitis. What are Interferons? are part of a complex cascade of signals that involves toll-like receptors and numerous interferon-signaling genes. Since they affect the immune system as a whole, interferons cause a variety of side effects – including the familiar “flu-like” symptoms of malaise, fever, fatigue, and muscle aches – that indicate an antiviral immune response. Paradoxically, interferons can both increase susceptibility to certain infections (for example, by causing depletion of white blood cells that fight bacteria) and lead to autoimmune conditions in which the immune system attacks the body’s own tissues. How Do Interferons Work? First discovered in the 1950s, interferons have been studied as treatments for a wide variety of viral diseases and malignancies. While their full range of activity is not completely understood, it is known that they work via several mechanisms: • Antiviral activity: When an infected cell dies and releases viruses, interferons “warn” surrounding cells and cause them to release protein kinase R and other messengers that interfere with the production of proteins needed to assemble new virus particles. Interferons also help prevent the entry of viruses into cells. Much of interferon alpha’s effect on HCV is attributed to direct antiviral activity. Interferons are natural chemical messengers, or cytokines, that play an important role in the body’s immune response to foreign pathogens – especially viruses – and cancerous cells. Part of the nonspecific immune system, interferons act at the earliest stages of viral infection before the production of antibodies. • Cytotoxicity: Interferons kill virus-infected cells by enhancing apoptosis, or programmed cell death. While the first phase of rapid HCV decline during interferon-based therapy is likely due to direct antiviral activity, the slower subsequent decrease is thought to be due to enhanced destruction of HCV-infected hepatocytes. Different types of interferons utilize different cell surface receptors, but act via common signaling pathways, of which the JAK-STAT pathway is the most fully understood. In the presence of viruses (in particular, viral double-stranded RNA), interferons • Immunomodulation: Interferons stimulate the production of cytokines that activate macrophages, natural killer cells (NK), and cytotoxic T-lymphocytes (CTLs or killer T-cells). The immunomodulatory effect of interferon alpha is thought to account for its effectiveness against HBV. HCSP • VERSION 1 • September 2007  • Enhanced MHC expression: Interferons enhance the expression of major histocompatibility complex (MHC) antigens on the surface of virus-infected cells, which enables CTLs and NK cells to recognize and destroy them. • Antiproliferative and antitumor activity: Interferons inhibit the excessive reproduction of malignant cells and also enhance CTL activity against tumor cells and inhibit angiogenesis, or production of new blood vessels needed for tumor growth. Types of Interferon Interferons were originally categorized into two broad classes, type I (alpha and beta) and type II (gamma). Recently, another group of substances (interleukins 28 and 29) with antiviral activity was recognized as a third class of interferons, type III (lambda). While each class acts through different cell receptors, their activity overlaps to a large degree. Interferon alpha (a family of more than a dozen related proteins) is most widely used in the treatment of hepatitis C, and is also approved for treating chronic hepatitis B and several types of cancer. Many controlled trials have documented the effectiveness of conventional interferon alpha-2a (Roferon-A) and -2b (Intron-A) in reducing HCV RNA levels, decreasing liver inflammation (indicated by elevated ALT and AST levels), and retarding – or even reversing – liver fibrosis. Unfortunately, nonresponse and relapse are common with conventional interferon alpha monotherapy, but some studies suggest treatment may improve fibrosis even in patients who do not achieve sustained virological response (SVR). Today’s standard of care for chronic hepatitis C is pegylated interferon alpha (Pegasys or PegIntron) plus ribavirin. Pegylation – the addition of polyethylene glycol to conventional interferon alpha – increases the length of time the drug stays in the body, so it can be injected less often. Consensus interferon alpha, also known as interferon alfacon-1 or Infergen, is a recombinant form developed by determining the most common amino HCSP • VERSION 1 • September 2007 acids at each position of the interferon alpha molecule. Consensus interferon has been extensively studied for the retreatment of hepatitis C in prior interferon alpha nonresponders and relapsers. While SVR rates in most studies have been relatively low – though often higher than those for retreatment with pegylated interferon – consensus interferon does offer some previous nonresponders, and especially relapsers, the chance for an SVR. Interferon alpha-n1, also known as lymphoblastoid interferon or Wellferon, is a combination of nine subtypes of interferon alpha. Approved for treatment of hepatitis C in Europe but not in the U.S., studies suggest that it is about as effective as conventional interferon alpha, and less so than pegylated interferon. Albumin interferon, or Albuferon, is a long-acting form of interferon alpha fused with the blood protein albumin that needs to be administered only once every two weeks or less. Preliminary clinical trials show that treatment results are comparable to pegylated interferon. Albuferon is currently in phase III clinical trials. Interferon beta, both -1a (Avonex) and -1b (Betaseron) are approved for the treatment of multiple sclerosis. This form of interferon has been studied for chronic hepatitis C, but its efficacy appears no better than that of interferon alpha, though it may produce milder side effects. Interferon gamma-1b, or Actimmune, is a recombinant version of the sole known type II interferon. In studies to date, interferon gamma-1b has not reduced HCV RNA in prior interferon alpha nonresponders and relapsers. Given its antifibrotic activity, interferon gamma has also been studied in patients with advanced liver fibrosis or cirrhosis. In a recent study of 420 participants with pre- and post-treatment liver biopsies, thrice-weekly interferon gamma did not reduce Ishak fibrosis scores more than placebo, though a subgroup of patients with specific cytokine profiles did seem to benefit.  Interferon lambda (interleukin 28/29) is a newly identified class of type III interferons just entering human clinical trials for hepatitis C. In laboratory studies, it demonstrated antiviral activity against both HBV and HCV, though it was less effective than interferon alpha in mouse studies. Since interferon lambda uses receptors that are not as widely distributed throughout the body, researchers hypothesize that it might cause fewer side effects. In January, ZymoGnetics announced that it had initiated a Phase I safety and pharmacokinetic study of pegylated interferon lambda (IL-29) in healthy volunteers. Interferon omega is a novel type I interferon that is currently in the early phase of clinical trials. Preliminary results show that interferon omega plus ribavirin achieved antiviral activity comparable to interferon alpha plus ribavirin. The current formulation must be injected daily, but Intarcia Therapeutics is planning to study a continuous release formulation using an implantable device, on the theory that maintaining continuous drug levels may minimize side effects compared with weekly injections of pegylated interferon alpha. The Future of Interferons While interferons continue to comprise the backbone of anti-HCV therapy, targeted agents that attack the virus directly (such as HCV protease and polymerase inhibitors) hold the promise for effective therapy with fewer side effects. Nevertheless, given its multiple modes of action, most experts predict that pegylated interferon alpha – and possibly novel types as well – will play an important role in hepatitis C treatment for the foreseeable future. HCSP • VERSION 1 • September 2007 Be Sure to Check out These other Factsheets in the Series HCV Treatment • Pegasys plus Copegus FDA Package Insert • Schering plus Rebetol FDA Package Insert • Adherence to HCV Therapy • Interferon and Ribavirin • Patient Assistance Programs • Predictors of HCV Treatment Response • Ribasphere http://www.hcvadvocate.org/hepatitis/factsheets.asp For more information about hepatitis C, hepatitis B and HCV coinfections, please visit www.hcvadvocate.org. •hcspFACTsheet• A publication of the Hepatitis C Support Project Executive Director The information in this fact sheet is Editor-in-Chief, HCSP Publications designed to help you understand and Alan Franciscus manage HCV and is not intended as medical advice. All persons with HCV Design should consult a medical practitioner for Paula Fener diagnosis and treatment of HCV. Production C.D. Mazoff, PhD This information is provided by the Hepatitis C Support Project • a nonprofit Contact information: organization for HCV education, support Hepatitis C Support Project and advocacy• © 2007 Hepatitis C PO Box 427037 Support Project • Reprint permission is San Francisco, CA 94142-7037 granted and encouraged with credit to alanfranciscus@hcvadvocate.org the Hepatitis C Support Project.