Interferon therapy is associated with significant side effects, including flulike syndrome, fever, depression, insomnia, irritability, and bone marrow suppression (see Chapter 16). The interferon-induced flare of hepatitis may be severe and is particularly dangerous in patients with advanced liver disease and cirrhosis, who may not be able to tolerate a flare of hepatitis. For this reason, interferon therapy is relatively contraindicated in patients with cirrhosis caused by chronic hepatitis B infection. Another disadvantage is that patients with persistently normal liver enzyme levels, those who acquired the disease at birth, and those infected with HBV genotype C or D are unlikely to respond to interferon therapy. Finally, patients infected with the hepatitis B e-antigen mutant are less likely to achieve a lasting response to interferon. Interferons are a family of nonspecific regulatory proteins associated with a variety of antiviral, antiproliferative, and immunomodulating activities.289,290 There are two major types of interferons. Type 1 (α and β) interferons are secreted by all nucleated cells after viral infection; interferon-α is predominantly produced by virus-infected leukocytes, and interferon-β by fibroblasts. There are about 20 subtypes of interferon-α that share a high degree of amino acid sequence homology but have different antiviral and biologic effects on human cells in vitro. Type II (γ, or immune) interferon is the product of antigen- or mitogen-stimulated lymphocytes. In addition to being produced by different cells, the major types of interferon are immunologically distinct and have unique biologic effects and physicochemical properties.290 Interferons are active against a broad range of viruses; in general, RNA viruses are more susceptible than DNA viruses.