Interferon

Interferons

  • Secretory glycoproteins in response to viral & non-viral stimuli; antiviral activity by rendering cells resistant to viruses
  • Activation requires binding to specific receptors on target cells & signaling via Janus kinase/signal transducers & activators of transcription (JAK/STAT) pathways
  • Biologic activity: 
    • Antiviral
    • Antiproliferative
    • Stimulation of cytotoxic activity 
    • Anti-angiogenic
    • Induction of pro-apoptotic genes
    • Modulation of differentiation 

Types

  • Type I: IFNα (2a & 2b) & β + many others 
  • Type II: IFNγ
  • Type III:  IFNλ (more selective, offering more targeted therapy)

IFNα

  • Peak effect 3-12 hours, ½ life 2-3 hours, 80% bioavailable
  • Pegylation by adding polyethylene glycol (PEG) prolongs therapeutic effect: administered less frequently + improved tolerability 
  • Can form neutralizing antibodies leading to decreased response to therapy

IFNγ

  • Peak effect 4-24 hours, ½ life 3 hours (intramuscular) 6 hours (subcutaneous), 30-70% bioavailable
  • All interferons degraded via renal catabolism
  • All Interferons: Pregnancy category C

Routes

  • Subcutaneous, intramuscular, intravenous, intralesional

Dose 

  • Condyloma acuminata:
    • 1ntramuscular IU/wart 3x/week x 4 weeks (5M IU/D max)
  • Melanoma:
    • High dose therapy: 20MIU/m2 intravenous 5/7 days x4 weeks then 10M IU subcutaneous 3/7 days for up to 1 year vs. Low dose therapy: 3MIU subcutaneous 3x/week

Antiviral 

  • Induction of 2’-5’A synthetase (degrade viral & cellular ribonucleic acid (RNA)), ribonuclease (degrade single-stranded viral ribonucleic acid (RNA)) & protein kinase P1 (inhibition of translation viral messenger ribonucleic acid (RNA))

Antiproliferative 

  • Induction of 2’-5’A synthetase
  • Inhibition of growth factors
  • Increase p53 tumor suppressor gene
  • Decrease MYC, FOX & RAS oncogenes

Immunoregulatory

  • Induction of MHC I & II antigens
  • Increase natural killer cells
  • Decrease Th2 cytokines

Anti angiogenic 

  • IFNa inhibit angiogenesis
  • IFNg destruct tumor blood vessels 🡪 necrosis 

Induction of proapoptotic genes 

  • Note: 2-5A synthases (2′-5′-oligoadenylate synthases) are IFN-induced antiviral enzymes that recognize virally produced double stranded ribonucleic acid (dsRNA) & initiate ribonucleic acid (RNA) destabilization

Food and drug administration (FDA) 

  • Condyloma acuminata (IFNα-2b) 
  • Melanoma as adjuvant (IFNα-2b)
  • Acquired immunodeficiency syndrome (AIDS) -associated Kaposi sarcoma (IFNα-2a & 2b)
  • Chronic granulomatous disease (IFNγ)

Off-label

  • Neoplastic (malignant):  basal cell carcinoma, Squamous cell carcinoma, keratoacanthoma, actinic keratosis, cutaneous T cell lymphoma (CTCL), adult T-cell leukemia lymphoma, etc.
  • Neoplastic (benign): Keloids, hemangioma
  • Viral: Verruca, Epidermodysplasia verruciformis, Herpes zoster, herpes simplex virus (HSV), Necrolytic acral erythema (with hepatitis C virus (HCV))
  • Infectious: Leishmaniasis, lepromatous leprosy, Mycobacterium avium complex
  • Autoimmune connective tissue disease: Lupus, alopecia areata, Behcet’s, scleroderma, scleromyxedema
  • Other: Atopic dermatitis

Absolute

  • – Allergy to interferon or mouse Immunoglobulin

Relative

  • Pregnancy
  • Organ transplant
  • Cardiac (unstable angina, arrhythmias, uncontrolled congestive heart failure)
  • Chronic obstructive pulmonary disease (COPD)
  • Diabetes (risk of ketoacidosis)
  • Psychiatric disorders (depression)
  • Hematological (leukopenia/anemia/ coagulopathies)
  • Children (Spastic diplegia)
  • Cosmetic permanent fillers

Dose-dependent, improve with continued therapy & rapidly reversible when treatment discontinued

Influenza-like symptoms (#1)

  • Fever, fatigue, chills, headache, myalgias, arthralgias (Subcutaneous IFN-α ≤3M IU every other day ➔ tolerable flu-like symptoms/no adverse effects, & prophylactic acetaminophen, aspirin, or non-steroidal anti-inflammatory drugs (NSAIDs), 1-2 hours prior to interferon to decrease side effects

Rhabdomyolysis

  • Rare but can be fatal; monitor creatinine kinase

Cardiovascular

  • Hypotension, dysrhythmia or tachycardia (arrhythmia risk higher with pre-existing hyperthyroidism)

Neurologic

  • Spastic diplegia (benzyl & phenol preservatives are the culprit), paresthesia, motor weakness, dizziness, confusion, dysarthria, short-term memory loss 

Psychiatric

  • Depression & suicidal behavior

Gastrointestinal

  • Nausea, vomiting, diarrhea, hepatitis

Hematologic

  • Bone marrow suppression

Thyroid stimulating hormone   (TSH) changes

  • In up to 40% of hepatitis C virus patients treated with IFNα

Dermatologic

  • Necrosis at injection site, post inflammatory hyperpigmentation, sarcoidosis, psoriasis (plaque at site of injection or flares), alopecia, vitiligo, Raynaud

  • Aminophylline: IFN decreases CYP450 (cytochrome P450) leading to decreased aminophylline clearance
  • Myelosuppresive (e.g. Zidovudine) or neurotoxic (e.g. Vinca alkaloids): Risk of myelosuppression 
  • Interleukin-2 with interferon: risk of renal failure

Baseline

  • Complete blood count, chemistry profile, liver functions, creatinine kinase, thyroid stimulating hormone   (TSH) +/- ECG (electrocardiogram) if pre-existing abnormalities / advanced cancer

Monitoring

  • Complete blood count, chemistry profile, liver function tests, creatinine kinase every 2 weeks after beginning treatment then monthly

Therapeutic guidelines

  • Side effects may require dose modification/ termination of treatment
  • Caution in patients with relative contraindications
  • If platelet count < 50,000 only give SC interferon, no intramuscular interferon