A. Types

1. Interferon alpha
   1. IFNa 2a - normal human IFNa sequence (Roferon®); usually thrice weekly dosing
   2. IFNa 2b - differs by one amino acid from IFNa 2a (Intron A®)
   3. Polyethylene glycol (PEG)-ylated IFNa (PEG-Intron®) is now FDA approved for HCV [30]
   4. IFNa-2a covalented attached to 40K PEG molecule (Pegasys®)
   5. PEG-IFNa-2a is given once weekly and is more effective against HCV than IFNa [20]
2. Interferon beta
   1. IFNß 1a - normal sequence, normal glycosylation (Avonex®)
   2. IFNß 1b - bacterial source of recombinant protein (Betaseron®)
3. Interferon gamma
4. Consensus Interferon
5. All are ~15-18K proteins

B. IFNa Introduction

1. Produced mainly by fibroblasts
2. Multiple biological activities
   1. Induces increased antiviral activity in target cells
   2. Differentiating activities on some cell types
   3. Immunomodulating activities are not fully understood
3. Binds to IFN Receptor
4. Receptor binding activates JAK-STAT signalling pathway
5. Polyethylene Glycol (PEG) Derivatized-IFNa
   1. PEGylation reduces clearance and increases half-life
   2. Standard IFNa half-life is ~4-6 hours
   3. PEG-IFNa half-life is ~80-90 hours
   4. Permits once weekly dosing

C. Overview of IFNa Uses

1. Malignant Diseases
   1. Hairy Cell Leukemia (initial approval)
   2. Chronic Myelocytic Leukemia
   3. Multiple Myeloma
   4. Renal Cell Carcinoma
   5. Possible: melanoma
2. Infectious Disease
   1. Hepatitis B Virus
   2. Hepatitis C Virus
   3. Hepatitis D Virus (delta virus)
   4. Genital Warts / Human Papilloma Virus (HPV)
   5. Human Herpesvirus 8 / Kaposi Sarcoma
   6. Severe acute respiratory (coronavirus) syndrome (SARS) [38]
3. Churg-Strauss Syndrome
4. Behcet's Disease

D. Specific Uses of IFNa

1. Hairy Cell Leukemia [1]
   1. 2MU/m2 three times per week for 12 months
   2. Partial responses occur in most patients (very few complete responses)
   3. Poorly tolerated side effects
   4. Has generally been replaced by chlorodeoxyadenosine
2. Chronic Myelocytic Leukemia [2,3,4]
   1. Prolongs time to progression after chemotherapy
   2. IFNa increased survival ~2 fold
   3. IFNa is more effective at high (versus low) doses and may be effective even after BMT
   4. IFNa is cost effective if quality of life issues due to side effects are acceptable
   5. IFNa is effective in elderly and younger patients and is preferred over BMT in older
3. Melanoma
   1. Conflicting reports of efficacy in adjuvant setting (Stages IIb and III disease) [27,28,42]
   2. IFNa 2a prolongs survival in advanced melanoma (Stage IV)
   3. IFN alpha 2a reduces recurrences and death by ~20% in 1.5-4mm melanomas [26]
   4. IFN alpha 2a is now FDA approved with surgery in patients at high risk for recurrence
   5. PEG-IFN-alpha 2b improves 4-year recurrence free (but not overall) survival from 38.9% with observation to 45.6% with average therapy duration of 12 months [27]
   6. Approved for adjuvant use in stages IIb and III melanoma [27]
   7. Very high doses of IFNa given intravenously are used (20 million U/m2)
   8. Lower doses 3 million U three times per week is not effective Stage III disease [28]
   9. Intermediate doses (10 million U five times per week) subcutaneously are not effective adjuvant therapy after surgery in stages IIb and III melanoma [42]
   10. Development of antithyroid, antinuclear, anticardiolipin or anti-DNA antibodies during treatment with intravenous IFNa2b associated with improved survival and response [39]
4. Renal Cell Carcinoma [6,13]
   1. IFNa has mild efficacy alone in renal cell adenocarcinoma
   2. IFNa is synergistic with IL2 in renal cell Ca
5. Multiple Myeloma [5]
   1. Main emphasis has been on improving duration of remission
   2. Maintenance therapy 2-3MU/m2 x 3 per week
   3. Some studies have shown benefit; others have not
   4. Rarely used at this time as other agents have shown improved activity
6. Hepatitis B and D Virus [7]
   1. IFNa doses typically 3-6 MU sc 3X per week
   2. Hepatitis B Virus (HBV) ~40% prolonged responses
   3. Hepatitis D Virus: ~50% complete response during therapy, with ~50% relapse
   4. Staggard combination PEG-IFNa2b with lamivudine in HBeAg+ patients lead to 36% virologic response rate versus 14% for LAM alone [12]
7. Hepatitis C Virus (HCV)
   1. IFNa doses typically 3-6 MU sc 3X per week
   2. For chronic HCV, pegylated-IFNa in combination with ribavirin is standard
   3. For acute HCV infection, IFNa-2b 5MU sc daily for 4 weeks, then 3X/week for 20 weeks is strongly recommended [31]
   4. With standard IFNa, 50-70% initial response; 30-60% relapse after stopping drug
   5. PEG-IFNa with ribavirin has 54% complete response in chronic HCV after stopping drugs [29]
   6. Reduces risk of hepatocellular carcinoma ~50% due to chronic HCV infection [14]
   7. Reduces risk of recurrent hepatocellular carcinoma in HCV+ patients after resection [22]
   8. In patients with HCV and virologic responses to IFNa, hepatitic fibrosis and inflammation improve considerably over >3 years [18]
   9. Interferon alpha (IFNa) therapy for cirrhotic HCV associated with reduced risk for developing HCC and improved survival [25]
8. Human Papilloma Virus
   1. HPV causes human genital warts
   2. IFNa is efficacious for warts when given as intralesional injection [8]
9. Kaposi Sarcoma [16]
   1. Treatment IFNa leads to regression of Kasposi Sarcoma lesions
   2. Likely that IFNa activity is against HHV-8, the viral cause of Kaposi Sarcoma
10. Churg-Strauss Syndrome [10]
    1. May be effective in patients with resistant or recurrent disease
    2. Initial dose is 3 million units 3 times weekly (tiw) subcutaneously
    3. May increase dose to 10 million units tiw during relapse
    4. Reduces eosinophilia very well
    5. Permitted reduction in doses of all other agents including glucocorticoids
    6. Consider use in patients who relapse with cytotoxics, or prior to cyclophosphamide
11. Behcet's Syndrome [17]
    1. Dose 3 million units qod for 6 months
    2. Combination therapy with penicillin and colchicine
    3. Particularly reduced ocular disease by ~80%
    4. Arthritis, vascdular events, and mucocutaneous lesions also reduced

1. SARS [26,38]
   1. IFNa (consensus IFNa, Alfacon-1®) has good in vitro anti-SARS activity
   2. Combination IFNa with prednisone or methylpresnisolone showed promising superior activity to glucocorticoids alone in probable SARS
   3. Alfacon-1 given 9µg/d SC for at least 2 days, then increase to 15µg/d if no response
   4. Alfacon-1 treatment was continued for one day after steroid tapering

D. Pegylated IFN Alpha [24,34]

1. PEG is polyethylene glycol, a macromolecular polymer of ethylene glycol
2. Attaching proteins to PEG groups increases half-life of the protein (delays clearance)
3. This increases the plasma concentration-time curve (AUC)
4. Hepatitis C Virus (HCV) Treatment
   1. PEG-IFNa Alpha 2b (PEG-Intron®) and PEG-IFNa Alpha 2a (Pegasys®) both approved
   2. PEG-IFNa Alpha 2b once weekly; more effective than Intron-A in HCV [67]
   3. PEG-Intron® dosed by weight: 40-120 mcg/kg (see prescribing instructions)
   4. PEG-IFNa-2a (Pegasys®) is given once weekly and is more effective than IFNa [62,63]
   5. Pegasys® is given 180 mcg sq (abdomen or thigh) once weekly
5. Combination with Ribavirin [45]
   1. Standard of care for chronic HCV infection
   2. Ribavirin available as Copegus® or Rebetol®
   3. Dose of ribavirin is 1000mg/d for <75kg, 1200mg/d for >75kg weight
   4. PEG-IFNa2b is superior to standard IFNa2b when combined with ribavirin in HIV+ patients infected with HCV [40]
6. Heptitis B Virus (HBV) Treatment [9]
   1. Dose is 180µg PEG-IFNa2a once weekly or 100µg PEG-IFNa2b weekly sc
   2. PEG-IFNa2a induces sustained complete responses (viral levels <400/mL) in ~20% versus 7% with Lamivudine (Epivir-HBV®) in chronic HBV (HBeAg-)
   3. Reponse rate (viral load <20,000/mL) ~60% with PEG-IFNa2a versus 44% with lamivudine
   4. PEG-IFNa2b 100µg weekly for 52 weeks cleared HBeAg in 35% of patients [41]
   5. No benefit to combining IFNa or PEG-INFa or PEG-IFNb with lamivudine in chronic HBV

E. Side Effects of IFNa

1. Flu-like syndrome including fevers
2. Gastrointestinal disturbances
3. Injection site inflammation
4. Thrombocytopenia
5. Neutropenia
6. Autoimmune Manifestations [36]
   1. Autoantibodies to thyroid, nuclear, dsDNA, parietal cells, platelets observed
   2. Autoimmune Thyroiditis
   3. Rarely: systemic lupus, arthropathies, thrombocytopenia, hemolytic anemia, diabetes
7. Depression exacerbation
   1. Increasing frequency and severity of depression with increasing doses
   2. Paroxetine (Paxil®) reduces risk of severe depression accompanying high dose IFNa [21]

F. Interferon Beta (IFNb)

1. Receptor is the same as that for IFNa
2. Antiviral activities present
3. Mechanism of Action [35]
   1. Remains unclear
   2. May involve interferance with IFNg activation of macrophages
   3. IFN-ß treatment may shift T helper cell profile towards Th2 lymphokine production
   4. Induces expression of tumor necrosis factor related apoptosis inducing ligand (TRAIL)
   5. May also block blood-brain barrier openings in MS
4. Multiple Sclerosis (MS) Treatment [11]
   1. IFNb (-1a, -ß1b) reduce relapse and disease progression in relapsing remitting MS
   2. IFNb reduces relapse and progression rates in secondary progressive MS
   3. IFN-ß1b reduces progression on EDSS in secondary progressive MS by ~35%
   4. IFN-ß1a (Avonex®) given intramuscular once weekly delays time to onset and progression in patients with initial demyelinating event [19]
   5. IFN-ß1a (Rebif®) given subcutaneously weekly after first clinical event reduces onset of definite MS by ~20% and delays progression [23]
   6. IFN-ß1b (Betaseron®) 250µg (8 MIU) sc qod reduced risk of relapse, new T2 lesions on MRI, and probably delayed disease progression compared with weekly IFN-ß1a [32]
   7. Betaseron® and Rebif® are more effective at preventing relapses within 2 years than Avonex®, likely due to doses used [33]
   8. Interferon alpha-2a is also active in relapsing-remitting MS
   9. Neutralizing anti-IFN antibodies develop in ~20-30% of patients on IFN-ß1b but did not correlate with efficacy in MS patients in an early study [32,33]
   10. Anti-IFN antibodies develop in 10% of patients on weekly IFN-ß1a [33]
   11. Presence of anti-IFNß antibodies appears to reduce effectiveness of INFß in MS [37]
   12. Early and sustained induction of TRAIL in MS patients receiving IFNß is a marker for response [35]
5. Flu-like symptoms are major problem with interferons, preventable with acetaminophen

G. Interferon Gamma (IFNg)

1. Produced by lymphocytes
   1. CD4+, Th1 helper cells and most cytotoxic (CD8+) T cells produce IFNg
   2. Stimulates macrophages, inducing phagocytic and killing activities
   3. Other, less well understood immune effects
   4. May help induce anti-tumor immunity
2. Initial approval in chronic granulomatous disease
   1. CGD is a disease of defective neutrophil function
   2. Chronic, recurrent supperative infections occur due to defective immune activity
3. Anti-Fibrotic Activities
   1. IFNg has anti-fibrotic activities, down regulating TGFß1 mRNA
   2. Inhibits the proliferation of fibroblasts, particularly in the lung
4. IFNg in CGD
   1. Improves symptoms, reduces infection rate
   2. Recombinant IFNg (Actimmune®) is approved for prophylaxis in CGD
   3. Dose is 50µg/m2 3X/week sc
   4. Well tolerated, reduces infections by ~70%
5. Idiopathic Pulmonary Fibrosis (IPF) [15]
   1. IPF is a chronic progressive fibrotic pulmonary disease
   2. Usually causes death within 4-5 years of diagnosis
   3. Lung capacity progressively declines
   4. In randomized Phase 3 clinical study, IFNg had no benefit in patients with IPF whose disease was resistant to glucocorticoids [15]
   5. Therefore, IFNg is not be recommended in IPF
6. IFNg also used in treatment of various cancers

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