Antiviral Agents: Interferons

Interferons

The enhanced production of the cytokines called inter-ferons is one of the body’s earliest responses to a viral infection. These endogenous proteins exert potent an-tiviral, immunoregulatory, and antiproliferative effects and are classified according to the cell type from which they were initially derived. Interferon- (type I, leuko-cyte) and interferon β- β (type I, fibroblast) are synthe-sized by most types of cells in response to viral infec-tion, certain cytokines, and double-stranded RNA. Interferon-γ (type II, immune) is produced by natural killer (NK) cells and T lymphocytes in response to anti-gens, mitogens, and certain cytokines. Interferon- β and interferon- exert the most potent antiviral effects; interferon-γ is antiviral and strongly immunomodulatory.

Although interferons do not directly interact with vi-ral particles, they exert a complex range of effects on virus-infected cells that result in the inhibition of viral penetration, uncoating, mRNA synthesis, translation, and/or virion assembly and release. Interferons bind to cell surface receptors and initiate the JAK-STAT signal transduction pathway. This leads to the induction of nu-merous proteins, including 2’ -5’ -oligoadenylate syn-thetase (2’ -5’ OAS) and interferon-induced protein ki-nase. 2’ -5’ OAS initiates the activation of a cellular ribonuclease that cleaves single-stranded RNAs, and interferon-induced protein kinase phosphorylates and inactivates an elongation factor (eIF-2) involved in translation. Interferons also induce the production of inflammatory cytokines and biological oxidants that further enhance the host immune response. Viral fami-lies differ with respect to the step or steps at which in-terferons exert their effects. Certain viruses are resis-tant to interferons because they produce proteins that counteract interferon’s effects.

Absorption, Metabolism, and Excretion

Natural interferons produced by human leukocytes, re-combinant interferons produced in bacteria, and recom-binant interferons conjugated to monomethoxy polyeth-ylene glycol (PEG; pegylated interferons) are available in the United States. The various preparations may be administered subcutaneously, intramuscularly, intra-venously, or intralesionally (e.g., into genital warts). Natural or recombinant interferons typically achieve peak plasma levels within 4 to 8 hours of subcutaneous or intramuscular injection and are undetectable in the bloodstream within 16 to 36 hours. Maximal plasma con-centrations of pegylated interferons are reached 15 to 44 hours after subcutaneous or intramuscular injection and are sustained for much longer than nonpegylated prepa-rations (48 to 72 hours). Intralesional injection of in-terferons results in negligible systemic absorption. Interferons are eliminated from the bloodstream by a combination of cellular uptake and catabolism in the kidney and liver. Minimal amounts of intact protein are excreted in the urine or feces.

Clinical Uses

Interferon-α -2a (Roferon-A) is approved for the treat-ment of chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi’s sarcoma, and chronic phase Phila-delphia chromosome–positive chronic myelogenous leukemia. Interferon-α -2b (Intron A) is indicated for hairy cell leukemia, malignant melanoma, follicular lym-phoma, condylomata acuminata, AIDS-related Kaposi’s sarcoma, and chronic hepatitis B and C. A combination of interferon- α-2b and ribavirin (Rebetron) is used for the treatment of chronic hepatitis C. Interferon- α-n3 (Alferon N) is a solution of purified natural human in-terferon- proteins approved for the treatment of condy-lomata acuminata by intralesional injection. Interferon alfacon-1 (Infergen) is a recombinant interferon con-structed from the sequences of several naturally occur-ring interferon- subtypes. This recombinant protein contains the most frequently observed amino acid in each position of the sequence and exhibits in vitro specific activity at least 5 times higher than that of inter-feron α-2a or -2b. Interferon alfacon-1 and peg inter-feron- -2b (PEG-Intron) are approved for the treat-ment of chronic hepatitis C.

Interferon β-1a (Avonex) and interferon β-1b (Betaseron) are used in the treatment of multiple scle-rosis. Interferon γ-1b (Actimmune) is used to prevent and diminish the severity of infections associated with chronic granulomatous disease and for delaying the progression of severe, malignant osteopetrosis.

Adverse Effects, Contraindications, and Drug Interactions

Flulike symptoms, including fever, chills, weakness, fa-tigue, myalgia, and arthralgia, are the most common side effects of interferon therapy. These symptoms oc-cur in more than 50% of patients given injections of in-terferons either intravenously, intramuscularly, or sub-cutaneously. Intralesional injection may produce milder flulike symptoms with somewhat less frequency. Tolerance to these symptoms generally develops with repeated dosing.

Interferons are associated with a diverse range of common adverse effects. CNS complaints such as headache, dizziness, impaired memory and concentra-tion, agitation, insomnia, and anxiety occur with regu-larity. Depression is a common side effect of interferon-α and interferon-β . Suicidal behavior, although rare, can arise in depressed patients; therefore, these individuals should be closely monitored. Myelosuppression occurs frequently and may be dose limiting; potentially fatal aplastic anemia is rare. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and anorexia are com-mon; however, ulcerative colitis, pancreatitis, hyper-glycemia, and diabetes mellitus are rare. Elevation of hepatic enzymes can occur but rarely necessitate dis-continuation of treatment. Injection site reaction is common, as is alopecia, for certain interferon prepara-tions. Interferons can decrease fertility and may cause miscarriage at high doses.

Infrequent reactions to interferon therapy include proteinuria, renal toxicity, autoimmune disease, thyroid disease, ophthalmic toxicity, pulmonary dysfunction (pulmonary infiltrates, pneumonitis, and pneumonia), and cardiovascular effects (tachycardia, arrhythmia, hy-potension, cardiomyopathy, and myocardial infarction). Rarely, the body may develop antibodies against inter-ferons that inhibit their effectiveness.

Interferons are contraindicated in individuals with autoimmune hepatitis or other autoimmune disease, uncontrolled thyroid disease, severe cardiac disease, se-vere renal or hepatic impairment, seizure disorders, and CNS dysfunction. Immunosuppressed transplant recipi-ents should not receive interferons. Interferons should be used with caution in persons who have myelosup-pression or who are taking myelosuppressive drugs. Preparations containing benzyl alcohol are associated with neurotoxicity, organ failure, and death in neonates and infants and therefore are contraindicated in this population. Interferons should be used during preg-nancy only if the potential benefit justifies the potential risk to the fetus.

Interferons reduce the activity of hepatic cy-tochrome P450 enzymes and decrease the clearance of drugs such as theophylline. Their effects may be addi-tive with other drugs that have neurotoxic, hematotoxic or cardiotoxic activity.