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Interferons (Alfa, Beta)

Last Updated: July 17, 2020

Recommendation

The COVID-19 Treatment Guidelines Panel recommends against the use of interferons for the treatment of patients with severe and critical COVID-19, except in a clinical trial (AIII). There are insufficient data to recommend either for or against the use of interferon-beta for the treatment of early (i.e., <7 days from symptom onset) mild and moderate COVID-19.

Rationale

Studies have shown that there was no benefit when interferons were used in patients with other coronavirus infections (i.e., Middle East respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]) with severe or critical disease, and the significant toxicities of interferons outweigh the potential for benefit. Interferons may have antiviral activity early in the course of the infection.

Rationale for Use in Patients with COVID-19

Interferons, a family of cytokines with antiviral properties, have been suggested as a potential treatment for COVID-19 because of their in vitro and in vivo antiviral properties.

Clinical Data for COVID-19

Combination of Interferon Beta-1b, Lopinavir/Ritonavir, and Ribavirin in the Treatment of Hospitalized Patients With COVID-19

An open-label, Phase 2 clinical trial randomized 127 participants (median age 52 years) 2:1 to combination antiviral therapy or lopinavir/ritonavir. In the combination antiviral therapy group, the treatment regimen differed by time from symptom onset to hospital admission. Participants hospitalized within 7 days of symptom onset (n = 76) were randomized to triple drug therapy (interferon beta-1b 8 million units administered subcutaneously every other day for up to 7 days total, lopinavir/ritonavir, and ribavirin); those hospitalized ≥7 days after symptom onset (n = 51) were randomized to double therapy (lopinavir/ritonavir and ribavirin) because of concerns regarding potential inflammatory effects of interferon. Patients in the control group received lopinavir/ritonavir alone regardless of time from symptom onset to hospitalization. The study participants were patients in Hong Kong with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were hospitalized regardless of disease severity until they had two negative nasopharyngeal (NP) swabs.

The time to a negative result on a polymerase chain reaction SARS-CoV-2 test on an NP swab (the primary endpoint) was shorter in the combination therapy group than in the control group (median 7 days vs. 12 days, P = 0.001). The combination group had more rapid clinical improvement as assessed by the National Early Warning Score (NEWS) 2 and Sequential Organ Failure Assessment (SOFA) score and a shorter hospital stay (9 days vs. 14.5 days, P = 0.016). There was no difference in oxygen use between the groups. The antiviral and clinical effect was more pronounced in the patients hospitalized within 7 days of symptom onset suggesting that interferon beta-1b with or without ribavirin was the critical component of the combination antiviral therapy. The study provides no information about the effect of interferon beta-1b when administered ≥7 days after symptom onset.1

Interferon Alfa-2b Treatment for COVID-19

This study has not been peer reviewed.

In a retrospective cohort study of 77 adults with moderate COVID-19 in China, participants were treated with nebulized interferon alfa-2b, nebulized interferon alfa-2b with umifenovir (not available in the United States), or umifenovir only. The time to viral clearance in the upper respiratory tract and reduction in systemic inflammation was faster in the interferon alfa-2b groups than in the umifenovir only group. However, the results of this study are difficult to interpret because participants in the interferon alfa-2b with umifenovir group were substantially younger than those in the umifenovir only group (mean age 40 years vs. 65 years) and had fewer comorbidities (15% vs. 54%) at study entry. The nebulized interferon alfa-2b formulation is not approved by the Food and Drug Administration for use in the United States.2

Clinical Data for SARS and MERS

Interferon-beta used alone and in combination with ribavirin in patients with SARS and MERS has failed to show a significant positive effect on clinical outcomes.4-8

In a retrospective observational analysis of 350 critically ill patients with MERS5 from 14 hospitals in Saudi Arabia, mortality was higher among patients who received ribavirin and interferon (beta-1a, alfa-2a, or alfa-2b) than among those who did not receive either drug.

A randomized clinical trial that included 301 patients with acute respiratory distress syndrome9 found that intravenous interferon beta-1a had no benefit over placebo as measured by ventilator-free days over a 28-day period (median of 10.0 days vs. 8.5 days, respectively) or mortality (26.4% vs. 23.0%, respectively).

Clinical Trials

See ClinicalTrials.gov for a list of ongoing clinical trials for interferon and COVID-19.

Adverse Effects

The most frequent adverse effects of interferon-alfa include flu-like symptoms, nausea, fatigue, weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (depression and suicidal ideation). Interferon-beta is better tolerated than interferon-alfa.

Drug-Drug Interactions

The most serious drug-drug interactions with interferons are the potential for added toxicity with other immunomodulators and chemotherapeutic agents.

Considerations in Pregnancy

Data from several large pregnancy registries did not demonstrate an association between exposure to interferon beta-1b preconception or during pregnancy and an increased risk of adverse birth outcomes (e.g., spontaneous abortion, congenital anomaly), and exposure did not influence birth weight, height, or head circumference.

Considerations in Children

There are limited data on the use of interferons for the treatment of respiratory viral infections in children.

References

  1. 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;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.
  2. Zhou Q, Wei X, Xiang X, et al. Interferon-a2b treatment for COVID-19. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.04.06.20042580v1.
  3. Meng Z, Wang T, Li C, et al. An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area. medRxiv. 2020; Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.04.11.20061473v2.
  4. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis. 2014;20:42-46. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24406736.
  5. 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;70(9):1837-1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31925415.
  6. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14985565.
  7. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25278221.
  8. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alfa2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015;70(7):2129-2132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25900158.
  9. Ranieri VM, Pettila V, Karvonen MK, et al. Effect of intravenous interferon beta-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32065831.