Inhibition of protein synthesis is the major inhibitory effect for many viruses. IFN-induced proteins include 2′-5′-oligoadenylate [2-5(A)] synthetase and a protein kinase, either of which can inhibit protein synthesis in the presence of double-stranded RNA. The 2-5(A) synthetase produces adenylate oligomers that activate a latent cellular endoribonuclease (RNase L) to cleave both cellular and viral single-stranded RNAs. The protein kinase selectively phosphorylates and inactivates a protein involved in protein synthesis, eukaryotic initiation factor 2 (eIF-2). IFN-induced protein kinase also may be an important effector of apoptosis. In addition, IFN induces a phosphodiesterase that cleaves a portion of transfer RNA and thus prevents peptide elongation. A given virus may be inhibited at several steps, and the principal inhibitory effect differs among virus families. Certain viruses are able to counter IFN effects by blocking production or activity of selected IFN-inducible proteins. For example, IFN resistance in hepatitis C virus is attributable to inhibition of the IFN-induced protein kinase, among other mechanisms.
Complex interactions exist between IFNs and other parts of the immune system, so IFNs may ameliorate viral infections by exerting direct antiviral effects and/or by modifying the immune response to infection (Biron, 2001). For example, IFN-induced expression of MHC antigens may contribute to the antiviral actions of IFN by enhancing the lytic effects of cytotoxic T-lymphocytes. Conversely, IFNs may mediate some of the systemic symptoms associated with viral infections and contribute to immunologically mediated tissue damage in certain viral diseases.
Absorption, Distribution, and Elimination. Oral administration does not result in detectable IFN levels in serum or increases in 2-5(A) synthetase activity in peripheral blood mononuclear cells (used as a marker of IFN's biologic activity). After intramuscular or subcutaneous injection of IFN-α, absorption exceeds 80%. Plasma levels are dose related, peaking at 4-8 hours and returning to baseline by 18-36 hours. Levels of 2-5(A) synthetase in peripheral blood mononuclear cells show increases beginning at 6 hours and lasting through 4 days after a single injection. An antiviral state in peripheral blood mononuclear cells peaks at 24 hours and decreases slowly to baseline by 6 days after injection. Intramuscular or subcutaneous injections of IFN-β result in negligible plasma levels, although increases in 2-5(A) synthetase levels may occur. After systemic administration, low levels of IFN are detected in respiratory secretions, CSF, eye, and brain.
Because IFNs induce long-lasting cellular effects, their activities are not easily predictable from usual pharmacokinetic measures. After intravenous dosing, clearance of IFN from plasma occurs in a complex manner (Bocci, 1992). With subcutaneous or intramuscular dosing, the plasma t1/2 of IFN-α ranges is variable, 3-8 hours. Elimination from the blood relates to distribution to the tissues, cellular uptake, and catabolism primarily in the kidney and liver. Negligible amounts are excreted in the urine. Clearance of IFN-α2B is reduced by ~80% in hemodialysis patients (Uchiharaa et al., 1998).
Attachment of IFN proteins to large inert polyethylene glycol (PEG) molecules (pegylation) slows absorption, decreases clearance, and provides higher and more prolonged serum concentrations that enable once-weekly dosing (Bruno et al., 2004). Two pegylated IFNs are available commercially: peginterferon alfa-2a (pegasys) and peginterferon alfa-2B (pegintron). PegIFN alfa-2B has a straight-chain 12,000-Da type of PEG that increases the plasma t1/2 from ~2-3 hours to ~30-54 hours (Glue et al., 2000). PegIFN alfa-2a consists of an ester derivative of a branched-chain 40,000-Da PEG bonded to IFN-α2A and has a plasma t1/2 averaging ~80-90 hours. PegIFN alfa-2A is more stable and dispensed in solution, whereas pegIFN alfa-2B requires reconstitution prior to use. For pegIFN alfa-2A, peak serum concentrations occur up to 120 hours after dosing and remain detectable throughout the weekly dosing interval (Bruno et al., 2004); steady-state levels occur 5-8 weeks after initiation of weekly dosing (Keating and Curran, 2003). For pegIFN alfa-2A, dose-related maximum plasma concentrations occur at 15-44 hours after dosing and decline by 96-168 hours. These differences in pharmacokinetics may be associated with differences in antiviral effects (Bruno et al., 2004). Increasing PEG size is associated with longer t1/2 and less renal clearance. About 30% of pegIFN alfa-2B is cleared by the kidneys; pegIFN alfa-2A also is cleared primarily by the liver. Dose reductions in both pegylated IFNs are indicated in end-stage renal disease.
Untoward Effects. Injection of recombinant IFN doses of ≥1 to 2 million units (MU) usually is associated with an acute influenza-like syndrome beginning several hours after injection. Symptoms include fever, chills, headache, myalgia, arthralgia, nausea, vomiting, and diarrhea. Fever usually resolves within 12 hours. Tolerance develops gradually in most patients. Febrile responses can be moderated by pretreatment with antipyretics. Up to one-half of patients receiving intralesional therapy for genital warts experience the influenzal illness initially, as well as discomfort at the injection site, and leukopenia.
The principal dose-limiting toxicities of systemic IFN are depression, myelosuppression with granulocytopenia and thrombocytopenia; neurotoxicity manifested by somnolence, confusion, behavioral disturbance, and rarely, seizures; debilitating neurasthenia and depression; autoimmune disorders including thyroiditis and hypothroidism; and uncommonly, cardiovascular effects with hypotension and tachycardia. The risk of depression appears to be higher in chronically infected HCV than in HBV patients (Marcellin et al., 2004). Elevations in hepatic enzymes and triglycerides, alopecia, proteinuria and azotemia, interstitial nephritis, autoantibody formation, pneumonia, and hepatotoxicity may occur. Alopecia and personality change are common in IFN-treated children (Sokal et al., 1998). The development of serum neutralizing antibodies to exogenous IFNs may be associated infrequently with loss of clinical responsiveness. IFN may impair fertility, and safety during pregnancy is not established. IFNs can increase the hematological toxicity of drugs such as zidovudine and ribavirin and may increase the neurotoxicity and cardiotoxic effects of other drugs. Thyroid function and hepatic enzymes should be monitored during IFN therapy.
Pegylated IFNs are generally better tolerated than standard IFNs, with discontinuation rates ranging from 2-11%, although the frequencies of fever, nausea, injection-site inflammation, and neutropenia may be somewhat higher. Laboratory abnormalities, including severe neutropenia and the need for dose modifications, are higher in HIV-co-infected persons.
Therapeutic Uses. Recombinant, natural, and pegylated IFNs currently are approved in the U.S., depending on the specific IFN type, for treatment of condyloma acuminatum, chronic HCV infection, chronic HBV infection, Kaposi's sarcoma in HIV-infected patients, other malignancies, and multiple sclerosis. In addition, interferons have been granted orphan drug status for a variety of rare disease states including idiopathic pulmonary fibrosis, laryngeal papillomatosis, juvenile rheumatoid arthritis, and infections associated with chronic granulomatous disease.
Hepatitis B Virus. In patients with chronic HBV infection, parenteral administration of various IFNs is associated with loss of HBV DNA, loss of HBeAg and development of anti-HBe antibody, and biochemical and histological improvement in ~25-50% of the patients.
Lasting responses require moderately high IFN doses and prolonged administration (typically 5 MU/day or 10 MU in adults and 6 MU/m2 in children three times per week of IFNα-2B for 4 to 6 weeks) (Sokal et al., 1998). Plasma HBV DNA and polymerase activity decline promptly in most patients, but complete disappearance is sustained in only about one-third of patients or less. Low pretherapy serum HBV DNA levels and high aminotransferase levels are predictors of response. Sustained responses are infrequent in those with vertically acquired infection, anti-HBe positivity, or concurrent immunosuppression owing to HIV. PegIFN alfa-2A appears superior to conventional IFN alfa-2A in HbeAg-positive patients (Cooksley et al., 2003), and treatment (180 μg once weekly for 24-48 weeks) is associated with normalization of aminotransferases in ~60% and sustained viral suppression in ~20% of HBeAg-negative patients (Marcellin et al., 2004). Responses with seroconversion to anti-HBe usually are associated with aminotransferase elevations and often a hepatitis-like illness during the second or third month of therapy, likely related to immune clearance of infected hepatocytes. High-dose IFN can cause myelosuppression and clinical deterioration in those with decompensated liver disease.
Remissions in chronic hepatitis B induced by IFN are sustained in >80% of patients treated and frequently are followed by loss of HBV surface antigen (HbsAg), histological improvement or stabilization, and reduced risk of liver-related complications and mortality (Lau et al., 1997). IFN may benefit some patients with nephrotic syndrome and glomerulonephritis owing to chronic HBV infection. Antiviral effects and improvements occur in about one-half of chronic hepatitis D virus (HDV) infections, but relapse is common unless HbsAg disappears. IFN does not appear to be beneficial in acute HBV or HDV infections.
Hepatitis C Virus. In chronic HCV infection, IFN alfa-2B monotherapy (3 MU three times a week) is associated with an approximate 50-70% rate of aminotransferase normalization and loss of plasma viral RNA, but relapse rates are high, and sustained virologic remission (absence of detectable HCV RNA) is observed in only 10-25% of patients.
Sustained viral responses are associated with long-term histological improvement and probably reduced risk of hepatocellular carcinoma and hepatic failure (Coverdale et al., 2004). Viral genotype and pretreatment RNA level influence response to treatment, but early viral clearance is the best predictor of sustained response. Failure to achieve an early viral response (nondetectable HCV RNA or reduction ≥2 log10 units compared with baseline at 12 weeks) predicts lack of sustained viral response with continued treatment (Seeff and Hoofnagle, 2002). Nonresponders generally do not benefit from IFN monotherapy retreatment, but they and patients relapsing after monotherapy often respond to combined pegylated IFN and ribavirin treatment. IFN treatment may benefit HCV-associated cryoglobulinemia and glomerulonephritis. IFN administration during acute HCV infection appears to reduce the risk of chronicity (Alberti et al., 2002).
Pegylated IFNs are superior to conventional thrice-weekly IFN monotherapy in inducing sustained remissions in treatment-naive patients. Monotherapy with pegIFN alfa-2A (180 μg subcutaneously weekly for 48 weeks) or pegIFN alfa-2B (weight-adjusted doses of 1.5 μg/kg/week for 1 year) is associated with sustained response in 30-39%, including stable cirrhotic patients (Heathcote et al., 2000), and it is a treatment option in patients unable to take ribavirin. Studies of prolonged (4 years) maintenance monotherapy with pegylated IFNs are in progress for those not responding to IFN-ribavirin combinations. A large randomized comparison of pegIFN alfa-2A versus alfa-2B combined with ribavirin found no difference in response rates (McHutchison et al., 2009).
The efficacy of conventional and pegylated IFNs is enhanced by the addition of ribavirin to the treatment regimens, particularly for genotype 1 infections. Combined therapy with pegIFN alfa-2A (180 μg once weekly for 48 weeks) and ribavirin (1000-1200 mg/day in divided doses) gives higher sustained viral response rates than IFN-ribavirin combinations in previously untreated patients (Fried et al., 2002). A shorter duration of therapy (24 weeks) and lower ribavirin dose (800 mg/day) are effective in genotype 2 and 3 infections, but prolonged therapy and higher ribavirin doses are needed for genotype 1 and 4 infections (Hadziyannis et al., 2004). Approximately 15-20% of those failing to respond to combined IFN-ribavirin will have sustained responses to combined pegIFN-ribavirin. Histological improvement may occur in patients who do not achieve sustained viral responses. In patients with compensated cirrhosis, treatment may reverse cirrhotic changes and possibly reduce the risk of hepatocellular carcinoma (Poynard et al., 2002).
Papillomavirus. In refractory condylomata acuminata (genital warts), intralesional injection of various natural and recombinant IFNs is associated with complete clearance of injected warts in 36-62% of patients, but other treatments are preferred (Wiley et al., 2002). Relapse occurs in 20-30% of patients. Verruca vulgaris may respond to intralesional IFN-α. Intramuscular or subcutaneous administration is associated with some regression in wart size but greater toxicity. Systemic IFN may provide adjunctive benefit in recurrent juvenile laryngeal papillomatosis and in treating laryngeal disease in older patients.
Other Viruses. IFNs have been shown to have virological and clinical effects in various herpesvirus infections including genital HSV infections, localized herpes-zoster infection of cancer patients or of older adults, and CMV infections of renal transplant patients. However, IFN generally is associated with more side effects and inferior clinical benefits compared with conventional antiviral therapies. Topically applied IFN and trifluridine combinations appear active in acyclovir-resistant mucocutaneous HSV infections.
In HIV-infected persons, IFNs have been associated with antiretroviral effects. In advanced infection, however, the combination of zidovudine and IFN is associated with only transient benefit and excessive hematological toxicity. IFN-α (3 MU three times weekly) is effective for treatment of HIV-related thrombocytopenia resistant to zidovudine therapy.
Except for adenovirus, IFN has broad-spectrum antiviral activity against respiratory viruses in vitro. However, prophylactic intranasal IFN-α is protective only against rhinovirus colds, and chronic use is limited by the occurrence of nasal side effects. Intranasal IFN is therapeutically ineffective in established rhinovirus colds. Systemically administered IFN-α may be beneficial in early treatment of SARS (Loutfy et al., 2003).