Interferon: Potential COVID-19 Treatment

Interferons are a family of naturally-occurring proteins that are made and secreted by cells of the immune system (for example, white blood cells, natural killer cells, fibroblasts, and epithelial cells). Three classes of interferons have been identified:

1. alpha,
2. beta, and
3. gamma.

Each class has many effects, though their effects overlap. Commercially available interferons are human interferons manufactured using recombinant DNA technology. The mechanism of action of interferon is complex and is not well understood. Interferons modulate the response of the immune system to viruses, bacteria, cancer, and other foreign substances that invade the body. Interferons do not directly kill viral or cancerous cells; they boost the immune system response and reduce the growth of cancer cells by regulating the action of several genes that control the secretion of numerous cellular proteins that affect growth.

• interferon alfa-2a (Roferon-A)
• interferon alfa-2b (Intron-A )
• interferon alfa-n3 (Alferon-N)
• peginterferon alfa-2b (PegIntron , Sylatron)
• interferon beta-1a (Avonex )
• interferon beta-1a (Rebif)
• interferon beta-1b (Betaseron)
• interferon beta-1b (Extavia)
• interferon gamma-1b (Actimmune )
• peginterferon alfa-2a (Pegasys ProClick)
• peginterferon alfa-2a and ribavirin (Peginterferon)
• peginterferon alfa-2b and ribavirin (PegIntron/Rebetol Combo Pack)
• peginterferon beta-1a (Plegridy)
• interferon alfacon-1 (Infergen has been discontinued in the US)

Interferon beta-1a, currently in use to treat multiple sclerosis, and interferon alfa-2b are both under investigation as potential treatments for people with COVID-19 coronavirus disease, the deadly respiratory pandemic caused by the SARS-nCoV-2 virus.

• Essentially, when confronted with a virus, each cell shoots an emergency flare of interferon to tell the immune system to marshall its defenses.
• Interferon Beta 1a, specifically, activates macrophages that engulf antigens and natural killer cells (NK cells), a type of immune T-Cell. 
• Those cells are integral in the innate immune system.
• The theory is, interferon may be able to make the immune system stronger by turning on dormant parts and directing them toward the defense against SARS-nCoV-2's assault.

The problem is, when interferons ramp up the immune system, COVID-19's flu-like symptoms are likely to become worse before they get better; interferon naturally occurring in the body is responsible for all flu-like symptoms to begin with, whether you have the coronavirus or a common cold. 

So, if someone is already on a ventilator and symptoms are about to overwhelm them, giving them an interferon-based medicine could be catastrophic. This is why interferon therapies for viral infections are typically a last resort -- the potential for dire side effects.

Studies around the world, including a huge WHO study, are looking at different interferons to treat COVID-19 coronavirus, but no existing COVID-19 drug trials in the U.S. included interferons as of April 7, 2020. 

It is possible there is a hesitance to use interferon in America because it was used in the late 1990s and early 2000s to treat Hepatitis C, and its side effects caused a lot of injury to U.S. patients.

Clinicians were lucky if they saw a 30% cure rate treating Hep C with interferon, but the side effects were severe, including: 

• Drop in white blood cell levels,
• liver problems, and
• psychiatric issues.

People would become suicidal, fall into deep depressions.

Data for COVID-19 section provided by Dominic Chan, a Pharm. D. and infectious disease specialist at Legacy Health System in Oregon.

Common side effects of interferons (that may occur with all interferons) include flu-like symptoms following each injection such as:

• Fever
• Chills
• Headache
• Muscle aches
• Pains
• Malaise

These side effects vary from mild to severe and occur in up to half of all patients. The symptoms tend to diminish with repeated injections and may be managed with analgesics such as acetaminophen (Tylenol and others) and antihistamines such as diphenhydramine (Benadryl).

Tissue damage at the site of injection occurs with all of the interferons but more commonly with interferon beta-1b and pegylated interferon alfa-2b.

Other important side effects that may occur with all interferons, and that may be caused by higher doses are:

• Fatigue
• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Joint aches
• Back pain
• Dizziness
• Anorexia
• Congestion
• Increased heart rate
• Confusion
• Low white blood cell count
• Low platelet count (thrombocytopenia)
• Low red blood cell count
• An increase in liver enzymes
• An increase in triglycerides
• Skin rashes
• Mild hair loss or hair thinning
• Swelling (edema)
• Cough
• Difficulty breathing
• Allergic or anaphylactic reaction

Some interferons are associated with liver failure and periodic liver function tests are recommended during therapy.

Depression and suicide have been reported among patients receiving interferons; however, it is unclear whether depression and suicidal thoughts are caused by the diseases being treated or the interferons themselves. Therefore, all patients receiving treatment with an interferon should be observed for the development of depression and suicidal thoughts.

Since interferons enhance the immune system in many ways, they are used for many diseases that involve the immune system. For example:

• interferon alfa-2a (Roferon-A) is FDA-approved to treat hairy cell leukemia, AIDS-related Kaposi's sarcoma, and chronic myelogenous leukemia.
• interferon alfa-2b is approved for the treatment of hairy cell leukemia, malignant melanoma, condylomata acuminata, AIDS-related Kaposi's sarcoma, chronic hepatitis C, and chronic hepatitis B.
• Ribavirin combined with interferon alfa-2b, interferon alfacon-1 (Infergen), pegylated interferon alfa-2b, or pegylated interferon alpha-2a, all are approved for the treatment of chronic hepatitis C.
• interferon beta-1b (Betaseron) and interferon beta-1a (Avonex) are approved for the treatment of multiple sclerosis.
• interferon alfa-n3 (Alferon-N) is approved for the treatment of genital and perianal warts caused by human papillomavirus (HPV).
• interferon gamma-1B (Actimmune) is approved for the treatment of chronic granulomatous disease, and severe, malignant osteopetrosis.
• peginterferon beta-1a (Plegridy) is used for treating multiple sclerosis (MS)

Although interferons are very similar they affect the body differently. Therefore, different interferons are used for different conditions.

• Interferon alphas are used for treating cancers and viral infections;
• interferon betas are used for treating multiple sclerosis; and
• interferon gamma is used for treating chronic granulomatous disease.

Interferon alfa-2a, interferon alfa-2b, peginterferon beta-1a, and interferon beta-1b may increase blood levels of zidovudine (AZT, Retrovir). While this reaction may improve zidovudine's effectiveness, it also may increase the risk of blood and liver toxicity. Therefore, the dose of zidovudine may need to be reduced by as much as 75%.

Interferon alfa-2a and interferon alfa-2b may increase the time it takes for theophylline (for example, Theo-Dur) to be eliminated from the body, and the dose of theophylline may need to be reduced.