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Monday, August 11, 2025

Antiviral interferons


Introduction

  • Antiviral interferons are cytokines with potent antiviral, immunomodulatory, and antiproliferative properties.

  • They belong to the body’s innate immune defense system, produced naturally by host cells in response to viral infection.

  • Pharmacologically, recombinant interferons are used to treat a range of viral infections and certain malignancies.

  • Major antiviral forms used clinically: Interferon alfa (α), Interferon beta (β), and Interferon lambda (λ) in specific contexts.

  • They act by enhancing the antiviral state of cells, boosting immune responses, and directly inhibiting viral replication.

Classification

Type I Interferons

  • Includes interferon alfa (multiple subtypes) and interferon beta.

  • Broad antiviral activity against RNA and DNA viruses.

  • Produced by most nucleated cells in response to viral infection.

Type III Interferons

  • Interferon lambda (e.g., peginterferon lambda).

  • More targeted activity to epithelial cells due to receptor distribution.

  • Potentially fewer systemic side effects than type I interferons.

Mechanism of Action

  • Bind to specific cell-surface interferon receptors (IFNAR for type I; IFNLR for type III).

  • Activate Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway.

  • Induce expression of interferon-stimulated genes (ISGs).

  • ISGs encode proteins that inhibit viral replication, degrade viral RNA, block protein synthesis, and enhance antigen presentation.

  • Enhance activity of natural killer (NK) cells, cytotoxic T lymphocytes, and macrophages.

  • Increase major histocompatibility complex (MHC) expression, improving viral antigen presentation to T cells.

Pharmacokinetics

  • Administration: Primarily subcutaneous (SC) or intramuscular (IM).

  • Absorption: Complete but slow; peak plasma concentrations within 4–12 hours.

  • Distribution: Widely distributed in extracellular fluids.

  • Metabolism: Proteolytic degradation in the kidney and liver.

  • Half-life: Standard interferons – 4–8 hours; pegylated forms – up to 72–96 hours, allowing once-weekly dosing.

Formulations

  • Conventional (non-pegylated) interferons: Require frequent dosing (three times per week).

  • Pegylated interferons: Covalently linked to polyethylene glycol, extending half-life and reducing dosing frequency (once weekly).

  • Examples: Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon lambda-1a.

Clinical Indications

Viral Hepatitis

  • Chronic hepatitis B (HBV) and hepatitis C (HCV) – historically mainstay therapy before direct-acting antivirals (DAAs).

  • Still used in certain HBV cases and in resource-limited settings for HCV.

Human Papillomavirus (HPV) Lesions

  • Treatment of condylomata acuminata (genital warts) via intralesional injection.

Respiratory Viruses

  • Interferon beta nasal sprays have been studied experimentally for prevention/treatment of viral respiratory infections.

Emerging Viral Infections

  • Investigated in SARS, MERS, COVID-19, and other viral diseases.

  • Interferon lambda explored for targeted mucosal antiviral effects.

Examples of Antiviral Interferons in Clinical Use

Interferon Alfa-2a

  • Broad antiviral and antiproliferative activity.

  • Used in chronic HBV and HCV, some cancers (hairy cell leukemia, Kaposi sarcoma).

Interferon Alfa-2b

  • Similar to alfa-2a, with broad antiviral activity.

  • Also used for condylomata acuminata and certain viral-induced cancers.

Peginterferon Alfa-2a / Alfa-2b

  • Long-acting pegylated versions for HBV and HCV treatment.

  • Superior convenience, improved adherence.

Peginterferon Lambda-1a

  • Targets epithelial cells, reducing systemic exposure.

  • Investigated in HCV and COVID-19 therapy.

Advantages

  • Broad-spectrum antiviral effect independent of specific viral mutations.

  • Can be used where resistance to other antivirals exists.

  • Dual antiviral and immunomodulatory action beneficial in chronic infections.

Limitations

  • Significant systemic side effects limit tolerability.

  • Less commonly used for HCV in high-income countries due to availability of DAAs.

  • Parenteral administration required.

Adverse Effects

Common

  • Flu-like symptoms (fever, chills, myalgia, headache) after injection.

  • Fatigue and malaise.

  • Anorexia and weight loss.

Neuropsychiatric

  • Depression, irritability, anxiety, cognitive dysfunction.

Hematologic

  • Leukopenia, thrombocytopenia, anemia.

Endocrine/Metabolic

  • Thyroid dysfunction (hypo- or hyperthyroidism).

  • Changes in glucose metabolism.

Hepatic

  • Transient elevations in liver enzymes.

Dermatologic

  • Injection site reactions, alopecia.

Contraindications

  • Severe psychiatric illness (especially untreated depression).

  • Autoimmune hepatitis or severe hepatic impairment.

  • Decompensated liver disease in cirrhosis.

  • Severe uncontrolled cardiac disease.

  • Known hypersensitivity to interferon preparations or PEG (in pegylated forms).

Precautions

  • Baseline psychiatric evaluation for risk of depression.

  • Monitor complete blood count (CBC), liver function tests, and thyroid function regularly.

  • Dose adjustment in renal impairment.

  • Avoid use in pregnancy unless benefits outweigh risks (teratogenic in animals).

Drug Interactions

  • Additive myelosuppression with zidovudine or other myelosuppressive agents.

  • Caution with drugs metabolized by CYP450 – interferons may alter metabolism.

  • Increased neurotoxicity risk with certain antiviral and psychiatric drugs.

Resistance and Efficacy Considerations

  • Viruses can develop strategies to evade interferon signaling (e.g., blocking JAK-STAT pathway).

  • Pegylated forms improve pharmacokinetics but do not eliminate resistance mechanisms.

  • In HBV and HCV, genetic factors (e.g., IL28B polymorphism) influence response rates.

Monitoring Parameters

  • CBC with differential – at baseline and periodically.

  • Liver function tests.

  • Thyroid function tests.

  • Mood and psychiatric status.

  • Virologic markers (viral load, antigen levels).

Future Directions

  • Development of targeted interferon therapies with reduced systemic toxicity.

  • Combination with direct-acting antivirals for synergistic effects.

  • Exploration of interferon lambda for selective antiviral immunity with fewer adverse effects.

  • Potential inhaled or intranasal interferon formulations for respiratory virus prophylaxis.





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