InpharmD™

What is the most updated evidence on the use of interferon-beta for treatment of COVID-19?

Comment by InpharmD Researcher

A small open-label study (N= 127) showed positive outcomes in coronavirus disease 2019 (COVID-19) patients who were treated with interferon-beta and other antivirals. Included patients had mild-to-moderate disease, and the treatment was initiated within seven days of symptom onset. Its efficacy in severe disease and in those presenting ≥7 days after onset of symptoms is unknown. Overall, the quality of evidence is low, and there is insufficient data.

PubMed search was conducted using key terms: interferon beta, COVID-19, treatment. Results were filtered to humans and English. Literature that evaluated efficacy and safety of interferon-beta as monotherapy or combination therapy for treatment of COVID-19 or SARS-CoV was included. Any studies evaluating efficacy of interferon-beta in other types of coronavirus (SARS, MERS) were excluded. Studies without results (e.g. study protocol) were also excluded.

Background

The National Institute of Health (NIH) guidelines state that there is insufficient evidence to recommend for or against use of interferon-β (IFN- β) in early (<7 days from symptom onset), mild to moderate COVID-19; however, they recommend against using interferons in severe and critical COVID-19, except in clinical trial settings. An open-label study showed that IFN- β -1b (8 million units subcutaneously every other day up to 7 days) with or without ribavirin may be associated with positive outcomes in patients presenting within seven days of onset of symptoms. However, its efficacy in those presenting ≥7 days after onset of symptoms remains unknown. [1]

According to the Infectious Disease Society of America (IDSA) guidelines, IFN- β-1b has shown to reduce viral load of middle east respiratory syndrome coronavirus (MERS-CoV), and use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is being evaluated in clinical trials. [2]

The Society of Critical Care Medicine (SCCM) guidelines provide no recommendation on the use of any recombinant interferon (rIFN) preparations alone or in combination with other antivirals in critically ill adults with COVID-19 due to lack of evidence. Most available evidence evaluates use of rIFN in MERS-CoV. Additionally, a trial of critically ill patients with MERS showed that rIFN preparations (rIFN-α2a, rIFN-α2b, rIFN-β1a and rIFN-β1b) with ribavirin is not associated with lower mortality (odds ratio 1.03; 95% CI 0.73-1.44) or reduced viral clearance. Among the various rIFN preparations, rIFN-β has shown to have the strongest MERS-CoV inhibition. Regarding its use in SARS-CoV2, unpublished in-vitro data suggest rIFN may inhibit SARS-CoV2; however, its clinical efficacy is unknown. [3]

It is stated that route of administration of IFN-β in COVID-19 may impact outcomes because of the difference in bioavailability. Although studies show that there is no difference in pharmacological effect between subcutaneous (S.C) and intravenous (I.V) IFN-β-1a, intravenous administration results in significantly higher total exposure compared to S.C injection (p= 0.0001). Subcutaneous IFN- β has demonstrated efficacy in a clinical trial; however, it should be noted that the patients had mild to moderate COVID-19 and presented within seven days of symptom onset. The efficacy in severe disease or in those presenting ≥7 days of onset of symptoms remains unclear. Additionally, the consideration of difference in bioavailability may be of a greater importance, especially in critically ill patients with compromised circulation. [4]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the most updated evidence on the use of interferon-beta for treatment of COVID-19?

Please see Tables 1-3 for your response.

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

Design

Phase II, multicenter, open-label, randomized trial; N= 127

Objective

To evaluate whether combination of three drugs can improve viral load profile and clinical parameters in hospitalized adult patients with COVID-19

Study Groups

Combination: (n= 86)

- Lopinavir/ritonavir (400/100 every 12 hours), ribavirin 400 mg every 12 hours, 1-3 doses of interferon-beta 1b 1mL (8 million international units/dose) every other day (n= 52)

- Lopinavir/ritonavir, ribavirin (same doseas above) (n= 34)

Control: Lopinavir/ritonavir (same dose above) (n= 41)

Methods

Diagnosis of SARS-CoV-2 was made upon admission using RT-PCR nasopharyngeal swab.

The randomization window from symptom onset was changed to 14 days (previously 10 days) after study commencement because incubation period could go beyond 14 days.

In combination groups, if patients were admitted within 7 days of onset of symptoms, they were randomized to triple therapy. If it has been ≥7 days since onset of symptoms, they were randomized to double therapy.

Intervention had to be initiate within 48 hours of admission. All patients received supportive care and antibiotic treatments, if clinically indicated. Stress dose of corticosteroid (50 mg hydrocortisone every 8 hours IV, tapering over 7 days) was administered if oxygen desaturation was observed, and oxygen support was necessary. Any non-invasive or invasive ventilatory support beyond day 7 from symptom onset was determined by the treating physician.

Patients were monitored for clinical improvements, QTc prolongation, radiological outcomes, and other laboratory changes.

Duration

February – March 2020

Duration of treatment: 14 days

Outcome Measures

Primary: time to achieve negative RT-PCR in a nasopharyngeal swab sample

Secondary: time to resolution of symptoms (NEWS2 of 0 for 24 hours), daily NEWS2 and SOFA, length of stay, 30-day mortality, virologic endpoints (time to negative RC-PCR in all clinical samples, daily viral load change in the first 7 days, emergence of acid mutation), serum cytokine response, and adverse events.

Baseline Characteristics

	Combination group (n=86)	Control group (n=41)
Age	51·0 (31·0–61·3)	52·0 (33·5–62·5)
Men	45 (52%)	23 (56%)
Time from symptoms onset to start of treatment, days	5 (4–7)	4 (3–8)
Symptoms and signs
Fever	70 (81%)	32 (78%)
Chills	13 (15%)	6 (15%)
Cough	45 (52%)	23 (56%)
Sputum	29 (34%)	13 (32%)
Shortness of breath	7 (8%)	7 (17%)
Sore throat	16 (19%)	10 (24%)
Myalgia	10 (12%)	8 (20%)
Malaise	19 (22%)	5 (12%)
Nausea or vomiting	1 (1%)	0
Diarrhoea	17 (20%)	7 (17%)
Rhinorrhoea	14 (16%)	10 (24%)
Anosmia	4 (5%)	1 (2%)
Headache	3 (3%)	3 (7%)
Chest tightness	2 (2%)	0
Anorexia	1 (1%)	0
Baseline laboratory findings (normal range)
White cell count (3·89–9·93 × 10⁹ per L)	4·9 (3·7–6·2)	5·4 (4·6–6·4)
Neutrophils (2·01–7·42 × 10⁹ per L)	3·4 (2·4–4·3)	3·5 (2·9–4·5)
Lymphocytes (1·06–3·61 × 10⁹ per L)	1·0 (0·8–1·5)	1·3 (0·9–1·6)
Platelets (154–371 × 10⁹ per L)	195·0 (171·8–260·0)	192·0 (160·5–244·5)
Creatinine (49–82 μmol/L)	75·5 (65·0–92·0)	76·0 (62·5–96·0)
C-reactive protein (<0·76 mg/dL)	3·0 (2·0–9·2)	3·0 (1·5–7·2)
Erythrocyte sedimentation rate (<12 mm/h)	19·0 (11·0–48·0)	19·0 (9·8–37·8)
Baseline radiological findings (%)
Abnormal chest x-ray	64 (74%)	32 (78%)
Right upper zone infiltrate	0	0 (0%)
Right middle zone infiltrate	4 (5%)	6 (15%)
Right lower zone infiltrate	38 (44%)	18 (44%)
Left upper zone infiltrate	1 (1%)	0
Left middle zone infiltrate	7 (8%)	7 (17%)
Left lower zone infiltrate	27 (31%)	10 (24%)

No difference in other comorbidities. Most common diseases included hypertension, diabetes, and hyperlipidemia.

Results

Primary endpoint:

Time to achieve negative RT-PCR in a nasopharyngeal swab sample (Combination vs. control):

- 7 days (IQR 5-11) vs. 12 days (IQR 8-15 days); HR 4.37 (95% CI 1.86-10.24; p= 0.0010)

Secondary endpoints:

	Combination	Control	HR (95% CI)	p
Time to NEWS2 of 0, days (IQR)	4 (3-8)	8 (7-9)	3.92 (1.66 – 9.23)	<0.001
Time to SOFA score 0, days (IQR)	3 (1.0 – 8.0)	8 (6.5 – 9.0)	1.89 (1.3 – 3.49)	0.041
Duration of hospital stay, days (IQR)	9 (7-13)	14.5 (9.3 – 16.)	2.72 (1.2-6.13)	0.016
30-day mortality	0	0	-	1.00
Ventilator support	0	1	-	0.15
Antibiotic use, n (%)	44 (51%)	25 (61%)	-	0.33
Corticosteroid (stress dose), n (%)	6 (7%)	2 (5%)	-	0.65
Time to negative viral loads, days (IQR)
Nasopharyngeal	7 (5-11)	12 (8-15)	-	0.0010
All specimens	8 (6-12)	13 (8-15)	-	0.0010

All daily NEWS2 scores (p< 0.0001) and SOFA scores were (p< 0.05, except day 1 [p= 0.21]) significantly better in combination group vs. control group.

Subgroup analysis:

	< 7 days			≥7 days
	Combination	Control	p	Combination	Control	p
Time to NEWS 2 of 0, days	4.0 (3-5)	8 (6.5-9.0	<0.001	6 (5-10.8)	8.0 (5.5-8.0)	0.90
Time to SOFA 0, days	3 (1-5)	7 (1-9)	0.001	8 (1-8)	8 (1-0)	0.23
Duration of hospital stay	8 (6-12.5)	15 (9-16)	0.0030	13 (8-15)	13.5 (!2.3-21.8)	0.090
30-day mortality	0	0	1.00	0	0	1.00
Time to negative viral load, days
Nasopharyngeal swab	6.5 (4-8)	12.5 (8-14.8)	<0.001	10.5(8-12.3)	12 (8-17)	0.10
All specimens	7.0 (4-9)	13 (8-14)	<0.0001	12 (7.8 – 14)	12 (12-19)	0.080

Adverse Events

	Combination	Control	p
Nausea	30 (35%)	13 (32%)	0·87
Diarrhoea	34 (40%)	18 (44%)	0·54
Increased alanine aminotransferase	11 (13%)	7 (17%)	0·32
Hyperbilirubinaemia	4 (5%)	3 (7%)	0·54
Sinus bradycardia	3 (4%)	1 (2%)	0·77
Fever	32 (37%)	16 (39%)	0·73
Serious adverse events	0	1 (2%)	0·15
Duration of nausea, days	2 (1–2)	2 (1–2)	0·80
Duration of diarrhoea, days	3 (3–3)	3 (3–3)	0·88

Study Author Conclusions

Early triple therapy is safe and effective compared to lopinavir/ritonavir monotherapy in shortening duration of viral shedding and length of stay in mild to moderate COVID-19.

InpharmD Researcher Critique

The study lacked critically ill patients; therefore, results cannot be extrapolated to the group. Additionally, triple therapy was only assessed in early presenters; therefore, its efficacy in patients presenting ≥7 days of onset of symptoms remains undetermined.

References:

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(1-238): 1695-1704.

Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial

Design

Prospective, non-controlled trial; N= 20

Objective

To evaluate the therapeutic effects of interferon-beta-1a (IFN-β-1a) administration in COVID-19

Study Groups

IFN-β-1a 44 mg subcutaneously every other day up to 10 days (n= 20)

Methods

Inclusion:

- ≥18 years of age

- RT-PCR confirmed COVID-19 in the throat swab

- Onset of symptoms < 7 days

- Severe disease (RR ≥30 breaths/min, O2 ≤ 90% or PaO2/FiP2 ≤ 300 mmHg)

Exclusion:

- Pregnant/lactating

- Other illness that may have caused pneumonia (e.g. influenza, other infections)

In addition to interferon, patients received hydroxychloroquine 200 mg PO twice daily and lopinavir/ritonavir (200/50 mg; 2 tablets; four times daily) for 5 days. Other supportive care was provided as needed. Interferon treatment was initiated on day 1 of admission and continued till day 10. Injection was administered peri-umbilical area, and injection site was rotated each time.

Duration

March 2020

Observation: 14 days

Treatment: 10 days

Outcome Measures

Primary: symptoms remission throughout 14 days.

Secondary: lung images during hospitalization (14 days), mortality rate, intensive care unit stay, hospital stay, adverse reaction, and virologic clearance

Baseline Characteristics

	Value
Mean age, years	58.55 ± 13.43
Male, n (%)	16 (80%)
Hypertension, n (%)	4 (20%)
Chronic pulmonary disease, n (%)	3 (15%)
Chronic cardiac disease, n (%)	2(10%)
Diabetes, n (%)	2(10%)
Benign prostatic hypertrophy, n (%)	1(5%)
Smoking, n (%)	1(5%)
Cerebrovascular disease, n (%)	0 (0%)
Time of symptom onset until hospitalization, mean (range)	6.5±2.8 days (2-12 days)
Fever, n (%)*	15 (75%)
Cough, n (%)	16 (80%)
Dyspnea, n (%)	17 (85%)
Mechanical venation (non-invasive), n**	3 (15%)
Duration of hospitalization, mean (range)	16.8± 3.4 days (14-25)

*fever resolved in all patients after 8 days

** weaned off after 5-10 days

Results

Most symptoms resolved by day 14 (0 patients), except for cough (n=9, 45%), dyspnea (n=2, 10%), myalgia (n=5, 25%), and malaise (n=10, 50%). No statistical analysis was performed for the primary outcomes.

Laboratory results at admission and at days 7 and 14 showed no significant improvements, except for creatinine (p= 0.035).

All patients had confirmed laboratory results on day 1. Fourteen patients had positive RT-PCR on day 5. On day 10, 2 patients tested positive.

Imaging showed ground glass opacity in 16 patients and bilateral infiltration in 14 patients. Recovery occurred after 14 days.

No deaths or serious drug reactions occured.

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: None

Study Author Conclusions

Interferon beta-1a in combination with hydroxychloroquine and lopinavir/ritonavir is a safe and effective treatment for COVID-19.

InpharmD Researcher Critique

Small sample size and lack of control group are limitation to the study. It also lacks statistical analysis for primary outcomes, which is a significant limitation. Additionally, hydroxychloroquine is no longer recommended in the US for COVID-19 treatment, except in clinical trials.

References:

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;106688 [published online 2020 June]

Are type 1 interferons treatment in Multiple Sclerosis as a potential therapy against COVID-19?
Design	Case report; N= 1
Objective	To report outcomes of a patient treated with type 1 interferon for multiple sclerosis (MS) who developed COVID-19
Results	A 31-year-old male patient with history of MS (on interferon-beta; 2 years) was diagnosed with COVID-19 one week after coming in contact with an infected individual. The patient presented with dry cough and shortness of breath. All physical and laboratory tests were normal, except for positive COVID-PCR from oropharyngeal and nasopharyngeal swab samples. CT showed subpleural located ground glass opacities in lower regions at right lung. Hydroxychloroquine, azithromycin, and enoxaparin sodium were started, and interferon was continued. Treatment continued for 5 days. He developed no other symptoms, except for cough. Laboratory values remained stable/normal, and no significant clinical events occurred. He was discharged on day 7.
Study Author Conclusions	Interferon may have positive effect on reducing severity of symptoms and length of stay in COVID-19 patients. However, further study is needed.
InpharmD Researcher Critique	This is low quality evidence. The patient is young with no other significant comorbidities, and therapy was started early (within 7 days), which may have contributed in having better outcomes.

References:

Gemcioglu E, Davutoglu M, Ozdemir EE, Erden A. Are type 1 interferons treatment in multiple sclerosis as a potential therapy against COVID-19? Mult Scler Relat Disord. 2020; 42: 102196.