Interferon Beta

Last review completed on
December 13th, 2020
Therapy Description

Interferon Beta is an immunomodulatory protein naturally produced by immune cells in response to foreign cells, bacteria, and viruses. Interferon antiviral effects include inhibition of viral replication, protein synthesis, maturation, and release. Antiviral effects also extend to the activation of macrophages, cytotoxic T-cells and natural killer cells. Previous studies have shown Interferon Beta activity against RNA viruses such as Hepatitis and other Coronaviruses; specifically, in vitro activity against MERS-CoV virus replication.

Recommendation

Currently there is not a large enough data pool that incorporates heterogenous populations showing improved outcomes due to treatment with Interferon Beta in patients with COVID-19.

There are a few studies that support its usage. However, those studies are limited by their small population sizes, and lack of heterogeneous treatment protocols. These positive results have been unable to be replicated in larger studies such as the WHO SOLIDARITY trial.

Therefore, although there is potential for usage, we require demonstration of efficacy in large, randomized trials before we can incorporate Interferon Beta into treatment protocols. Till then, it can only be utilized as part of a clinical trial.

Clinical Circumstances

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Medication Specific Circumstances

Based on the current literature, what dosing is recommended?

  • 44-µg (1200 IU) 3 times weekly for two weeks or 44µg every other day for 10 days
  • 8 million IU every other day for total of three days
Level of Evidence
= Supporting use article = Neutral Article  = Contradicting use article

Step 1 - In vitro SARS CoV-1/2 and MERS-CoV
Supportive Use article
Step 2 - In vivo MERS-CoV
Supportive Use articleEquivocal articleEquivocal article
Step 3 - In vivo SARS CoV-2
Supportive Use articleSupportive Use articleSupportive Use articleSupportive Use article
Equivocal articleEquivocal article
List of Evidence/ Discussion

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List of major peer-reviewed studies, and type of study

Level 5: Random Controlled Trial SARS CoV-2 articles listed below Randomized Control Trials:
  1. Supporting Use article Davoudi-Monfared E, Rahmani H, Khalili H, et al. A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e01061-20. doi: 10.1128/AAC.01061-20. PMID: 32661006; PMCID: PMC7449227.
    • Randomized Control Trial
    • Study performed by the Tehran University of Medical Sciences consisted of a 39-patient control group receiving national protocol medications consisting of hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir. The 42-patient treatment group received the national protocol medications in addition to 44µg/ml (12 million IU/ml) dose of Interferon β-1a subcutaneously three times weekly for two weeks. Based on clinical status both groups also received medications such as ascorbic acid, antibiotics, IVIG and corticosteroids. Results showed no difference between groups in clinical response, length of hospitalization, ICU stay or mechanical ventilation duration. Results did show a statistically significant decrease in 28-day mortality (19% vs. 43%, P= 0.015) and an increase in discharge rates at day 14 (OR 2.5; 95% CI 1.05 – 6.03) in the treatment group. The 28-day mortality decrease became even stronger (OR 4.05; 95% CI 1.42 – 11.55) after accounting for administration of IVIG and corticosteroids. Median time from onset of symptoms to IFN administration was 10 days with a reduction in mortality with early administration (OR 2.1; 95% CI 0.48 - 9.6).
  2. Supporting Use article Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-1704. doi: 10.1016/S0140-6736(20)31042-4. Epub 2020 May 10. PMID: 32401715; PMCID: PMC7211500.
    • Randomized Control Trial
    • This multicenter study of patients with COVID-19 in Hong Kong compared an 86 patient treatment group to a 41 patient control group. The control group received a 14 day course of lopinavir and ritonavir while the treatment group received both those medications with the addition of Ribavirin 400mg every 12hrs and 3 doses of 8 million IU’s of Interferon-β1a every other day. Study end point was time to a negative nasopharyngeal RT-PCR test Median number of days from symptom onset to treatment was 5. Results showed that the treatment group had a decreased time to negative nasopharyngeal RT-PCR, decreased time to symptom resolution and decreased length of hospital stays. These results were only present in those patients that received the additional treatment with 7 days of symptom onset.
  3. Supporting Use article Rahmani H, Davoudi-Monfared E, Nourian A, et al. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int Immunopharmacol. 2020 Nov;88:106903. doi: 10.1016/j.intimp.2020.106903. Epub 2020 Aug 24. PMID: 32862111; PMCID: PMC7445008.
    • Randomized Control Trial
    • This study from the Imam Khomeini Hospital Complex in Tehran, Iran evaluated a cohort of 66 individuals for treatment response to the addition of IFN-Beta 1b to the national protocol treatment. Subjects were patients admitted to the hospital requiring treatment for COVID 19. The 66 subjects were split into a control group and treatment group both consisting of 33 patients. The control group received only the national protocol medications consisting of Lopinavir/ritonavir or atazanavir/ritonavir plus hydroxychloroquine. The treatment group received the national protocol medication plus IFN-beat 1b 250 mcg every other day for two weeks. Study duration was two weeks with 4 weeks of follow up. A six-category ordinal scale was used to evaluate patients at 0,7,14 and 28 days. Time to clinical improvement defined as improvement of at least 2 points in the ordinal scale. was the primary outcome. The median time from symptom onset and hospitalization was 7 days for both groups. Time difference to clinical improvement in the IFN group (9 days) was shorter than the control group (11 days) ad statistically significant p=.002. Secondary outcomes in discharge rates at day 14 were also shorter in the IFN group (OR = 3.09; 95% CI 1.05-9.11). The ICU admission rates of the control group were significantly higher than the IFN group (66.66% vs. 42.42, p = 0.04). Rates of mechanical ventilation, length of ICU stay and all cause 28-day mortality were not statistically significant between the groups.
  4. Equivocal article Dastan F, Nadji SA, Saffaei A, et al. Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial. Int Immunopharmacol. 2020 Aug;85:106688. doi: 10.1016/j.intimp.2020.106688. Epub 2020 Jun 7. PMID: 32544867; PMCID: PMC7275997.
    • Prospective Non-controlled Trial
    • This study from Shahid Beheshti University of Medical Sciences in Tehran, Iran treated a cohort of 20 patients with hydroxychloroquine, lopinavir/ritonavir and 44µg (12 million IU’s) of IFN-β1a every other day until day 10. The primary outcome was symptom remission consisting of fever, cough, dyspnea, myalgia, malaise, rhinorrhea, arthralgia, chest pain, headache, vomiting, diarrhea, and sore throat. Average time from symptom onset to hospitalization was 6.5 days. Results showed mean time of hospitalization of 16.8 days, with no significant safety or adverse reactions.
  5. Equivocal article WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N Engl J Med. 2020 Dec 2. doi: 10.1056/NEJMoa2023184. Online ahead of print. PMID: 33264556
    • Randomized controlled, open label, international, multi-center clinical trial
    • Based on recommendations of a World Health Organization (WHO) group, a total of 11,330 patients were entered in the trial from 405 hospitals in 30 countries in all six WHO regions. The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control. The trial drugs were remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a (given with lopinavir until July 4). A total of 2063 patients were assigned to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. The regimen for interferon was three doses over a period of 6 days (the day of randomization and days 3 and 6) of 44 μg of subcutaneous interferon beta-1a; where intravenous interferon was available, patients receiving high-flow oxygen, ventilation, or extracorporeal membrane oxygenation (ECMO) were instead to be given 10 μg intravenously daily for 6 days. Death occurred in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No trial drug reduced initiation of ventilation among patients not already on ventilation, or hospital duration. Additionally, the rate ratio for death with interferon compared to its control was not affected by glucocorticoid use

List of major peer-reviewed studies providing context for therapy

Level 2: In vivo SARS CoV-1/MERS articles listed below In vivo SARS CoV-1/MERS
  1. Equivocal article Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin Infect Dis. 2020 Apr 15;70(9):1837-1844. doi: 10.1093/cid/ciz544. PMID: 31925415; PMCID: PMC7108209.
    • In Vivo, retrospective analysis
    • This retrospective analysis of multicenter data analyzed critically ill patients from 14 hospitals in Saudi Arabia from September 2012 to January 2018. The exposures used was Ribavirin/ rIFN therapy, Ribavirin alone, rIFN alone or neither Ribavirin or rIFN. The rIFn formulations used were rIFN -alpha2a, rIFN-alpha2b, rIFN-beta1a. The primary outcome of the analysis was 90 day mortality. The subject pool consisted of 349 critically ill patients. Ribavirin/rIFN initiation was at a median of 2 days from ICU admission, 5 days from hospital admission and 9 days from symptom onset. Patients that received Ribavirin/rIFN therapy were more likely to receive corticosteroids. Marginal Structural Model found that that Ribavirin/rIFN therapy was not associated with a decreased 90-day mortality (aOR 1.03; 95% CI 0.73-1.44; P = 0.87)
    • Equivocal article Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015 Jul;70(7):2129-32. doi: 10.1093/jac/dkv085. Epub 2015 Apr 21. PMID: 25900158; PMCID: PMC7202429.
      • In vivo, Retrospective Analysis
      • This study out of Jeddah, Saudi Arabia compared IFN-α2a to IFN-β1a, both in combination with Ribavirin. A retrospective analysis of 32 patients was done to assess for differences in mortality between those on IFN-α2a and IFN-β1a. Mortality rates in patients receiving IFN-α2a was 85% and 64% in those receiving IFN-β1a with a P value of 0.24. No statistical significance in mortality was found between these two types of Interferon medications.
    • Supporting Use article Sheahan, T.P., Sims, A.C., Leist, S.R. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 11, 222 (2020). https://doi.org/10.1038/s41467-019-13940-6
      • In Vitro/Vivo
      • This in vitro study used transgenic mice to simulate human lung and drug pharmacokinetic conditions to assess the efficacy of Remdesivir and lopinavir/ritonavir + IFN beta in MERS-CoV infected cells and animals. The study found that Remdesivir and IFN beta have superior in vitro antiviral activity against MERS-CoV compared to Lopinavir and Ritonavir. They also found that in combination lopinavir/ritonavir + IFN beta, antiviral activity is dominated by IFN beta. They also found that there was little benefit to prophylactic IFN beta nor was IFN-b effective in diminishing signs of acute lung injury but Remdesivir did. Overall, it was shown that Remdesivir had superior antiviral activity in vitro vs. lopinavir/ritonavir + IFN beta in MERS-CoV infections but IFN Beta still showed significant antiviral activity.
    Level 1: In vitro SARS CoV-1/2 and MERS-CoV articles listed below In vitro SARS CoV-2
    1. Supporting Use article Hensley LE, Fritz LE, Jahrling PB, et al. Interferon-beta 1a and SARS coronavirus replication. Emerg Infect Dis. 2004 Feb;10(2):317-9. doi: 10.3201/eid1002.030482. PMID: 15030704; PMCID: PMC3322919.
      • In vitro
      • In this study cells were treated with 5,000 to 500,000 IU/mL concentrations of IFN-β1a either 24 hours or I hour after inoculation with SARS-CoV. These cells were monitored for SARS virus production at 24, 48, 72 hours post infection. At 24 hours inhibition levels were at greater than or equal to 99.5% while at 72 hours inhibition levels were at greater than or equal to 70%.

    List of pre-peer reviewed/pre-publication studies.

     Level 5: Random Controlled Trial SARS CoV-2 articles listed below Randomized Control Trials:

    1. Supporting Use article Monk PD, Marsden RJ, Tear VJ, et al.; Inhaled Interferon Beta COVID-19 Study Group. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020 Nov 12:S2213-2600(20)30511-7. doi: 10.1016/S2213-2600(20)30511-7. Epub ahead of print. PMID: 33189161.
      • Double Blind, Randomized Controlled, Phase 2 Trial
      • This multicenter trial from the UK tested the use of inhaled IFN-Beta1a on patients admitted for SARS CoV-2 Infection. Patients were assigned in a 1:1 ratio with 48 in the treatment group receiving 6 million international units inhaled daily for 14 days and 50 in the placebo group. Primary outcome was improvement on the WHO Ordinal Scale for Clinical Improvement (OSCI). Median duration of symptoms before initiation of treatments was 10 days. Patients also received standard of care medications such as Remdesivir and dexamethasone. Results showed that patients in the treatment grouped had more than two-fold greater odds for clinical improvement at day 15 or 16 (OR = 2.32, 95% CI = 1.05 – 5.04, p = 0.033). At day 28, odds for patients in the treatment group for clinical improvement were greater than three-fold (OR = 3.15, 95% CI = 1.39-7.14, p = 0.006) when compared to placebo. There was no significant difference between odds of intubation, time to intubation or death between the two groups. At day 14 patients in the treatment group were twice as more likely to have recovered than in the placebo group (HR = 2.19, 95% CI 1.03-4.69, p = 0.043). Odds or recover on day 28 in the treatment group was over three-fold greater than placebo (OR = 3.58, 95% CI = 1.41-9.04, p = 0.007). There was no significant difference in odds of hospital discharge or time to hospital discharge. This study shows that there may be some benefits to inhaled IFN-B1a in improving clinical condition and recovery in patients admitted for COVID-19. This study postulates this benefit is due to the ability to reach higher concentrations of the medication in the lungs via inhalation versus injection.

    Current clinical trials

    1. Clinical Study for the Treatment With Interferon-ß-1a (IFNß-1a) of COVID-19 Patients (INTERCOP). [Recruiting]
    2. Adaptive COVID-19 Treatment Trial 3 (ACTT-3). [Active, Not Recruiting]
    3. IFN-beta 1b and Remdesivir for COVID19. [Recruiting]
    4. Dual Therapy with Interferon Beta-1b and Clofazimine for COVID-19. [Recruiting]
    5. Interferon Beta 1a in Hospitalized COVID-19 Patients (IB1aIC). [Enrolling]
    6. IFN Beta-1b and Ribavirin for Covid-19. [Recruiting]
    7. The Investigation into Beneficial Effects of High-dose Interferon Beta 1-a, Compared to Low-dose Interferon Beta 1-a in Moderate to Severe Covid-19. [Not Yet Recruiting]
    8. An Investigation into Beneficial Effects of Interferon Beta 1a, Compared to Interferon Beta 1b And The Base Therapeutic Regiment in Moderate to Severe COVID-19: A Randomized Clinical Trial (COVIFERON). [Completed]
    9. Treatments for COVID-19: Canadian Arm of the SOLIDARITY Trial (CATCO). [Recruiting]
    10. Double Therapy With IFN-beta 1b and Hydroxychloroquine. [Completed]
    11. Trial of Inhaled Anti-viral (SNG001) for SARS-CoV-2 (COVID-19) Infection. [Recruiting]
    12. Anti-Coronavirus Therapies to Prevent Progression of Coronavirus Disease 2019 (COVID-19) Trial (ACTCOVID19). [Recruiting]
    13. Treatment of COVID-19 by Nebulization of Inteferon Beta 1b Efficiency and Safety Study (COV-NI). [Suspended]
    14. Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment. [Completed]
    15. Trial of Treatments for COVID-19 in Hospitalized Adults (DisCoVeRy). [Recruiting]
    16. WHO COVID-19 Solidarity Trial for COVID-19 Treatments (SOLIDARITY). [Not Yet Recruiting]