Interferon Treatment

Interferon Treatment

24.11.-1.12.: entire page is in work. Many parts need checking.

Early administrated interferons look very promising to prevent disease progression including severe Covid and death.

Conceptual Summary

Interferons (IFNs) are signalling proteins which induce an antiviral state in their target cells. Interferons also can induce tissue inflammation - either direct or through a cascade of ongoing signals. Many interferons can be produced artificially. IFNs can be administrated either topically (=locally, e.g. aerosolized or by spray to the respiratory tract or as cream) or systemically (subcutaneous, intramuscular, intravenously).

Interferon treatments inhibit the replication of SARS-CoV-2 viruses in the respiratory tract and thereby, if administrated before there are many viruses, prevents disease progression: Early initiated interferon treatments have been shown to reduce the Covid mortality by over 75%. When patients are already at an advanced disease stage, systemically administrated interferons often have adverse effects on the outcome due to the mentioned inflammatory effects. For topical application even some benefits in mid to advanced disease stages are observed.

Summarized Observations

Summary Topical IFN Treatment

Overall topically administrated IFNs show improved outcomes, especially if the treatment is started early. At late disease stage the benefits are less though unlike systemic IFNs, for topical application no adverse outcomes are observed.

Topical IFN Alpha: Topical IFN alphas (all of subtype alpha-2b) reduce the mortality by 80% if early administrated. Even at mid disease stage an unfavorable disease progression is prevented in 50% of the cases. Treatments later than 10 days after symptom onset the beneficial effects are reduced, however no adverse effects on the outcomes are observed. -> Overview Topical IFN alpha

mostly based on retrospective uncontrolled (many different treatment combinations) studies with patients treated in early or mid 2020.

Topical IFN Beta: Nebulized IFN beta-1a reduces the progression to severe Covid by roughly 50% in a RCT by Monk et al in the UK. Another RCT by Khamis et al with IFN beta-1b found no effect. -> Overview Topical IFN beta

Topical IFN K: Early topical IFN K increases the viral clearance and accordingly the clinical improvement is faster. -> Overview Topical IFN K

Summary Systemic IFN Treatment

Systemic IFNs show benefits if given very early in a mild disease stage. At later stage no effect or even adverse effects are observed.

Systemic IFN alpha: Early IFN-α2b treatment induces a faster viral load clearance and a favorable disease progression. -> Overview Systemic IFN alpha

Systemic IFN beta: If administrated at severe disease stage (oxygen needed or even ventilated), systemic IFN beta treatment often increases the occurrence of adverse events and the mortality. If administrated upon exposure or in the mild disease stage beneficial effects are observed such as better prognosis and faster viral clearance. -> Overview Systemic IFN beta

Systemic IFN lambda: For early administration in mild SARS-CoV-2 infections, a shortened time to viral clearance has been observed. -> Overview Systemic IFN lambda

Introduction

The induction of interferons is one of the first immune responses upon a viral infection. Interferons induce an antiviral state of the cells. For many epithelial cells the metabolisms is slowed down or even paused [to specify and cite] and interferons activate the immune system. The timing for the treatment start is thus relevant and always specified as a category early, mid or late (Consideration on the Treatment Start).

Overview Topical IFN

Topical Administration

Topical administration can be done:

  • nebulized/aerosolized to the entire respiratory tract,
  • sprayed to the upper and to some extent to the respiratory tract
  • and as cream IFNs can be applied to the upper respiratory tract.

Overview Topical IFN Alpha

Author Type Treatment Treatment_Start (days from symptoms/admission; disease stage) Effects Early Administration Effects Mid Administration Effects Late Administration Notes_and_Comments
Yu retrospective, 1401 patients of which 852 with IFN 5 mio U of IFN-α-2b twice daily from symptom onset: early <=2;mid 3 to 8; late>= 9 days -85 % ICU, -90% life threating events -60 % ICU, -50% life threating events -25 % ICU, -35% life threating events large cohort and analysed by days after symptom onset (Yu et al)
Nan Wang retrospective, 446 patients IFN-α-2b for 10 days from admission: early less than 5 days; late = after 5 days -80% mortality; not much change on discharge time and CT improvement - late IFN increased mortality and discharge time data fairly heterogenous with different treatment combinations, not all efficacies observed are consistent; umifenovir has a similar efficacy profile as IFN
Liu retrospective, 103 case matched to 103 as control 89 patients: IFN-α2b 5 mIU as spray, 15 patients: IFN-α1b subcutaneous not specified, at wave peak -> mostly pneumonia cases in hospitals - -50% critical cases; -80% mortality - Wave peak in Wuhan
Chkihis retrospective, 37 IFN, 36 control IFN α 2b 10 mio IU spray 2 times a day for 5 days early after admission, mostly moderate pneumonia - -60% ventilation - inclusion criteria: SpO2 <90%, bilateral lung lesions, cough, fever
Mordyk prospective, comparative, controlled study, each group 70 patients IFN α 2b: rectal 3 mio IU three 3/day and gel 36K IU/g 5/day for nasal mucosa and tonsils for 14 days. patients were quite sick (fatigue, cough, shortness of breath common). - -25% time to viral clearance; much better CT outcome; up to 50% faster symptom resolution - unique administration: cream for nose and mouse, systemic via rectal depository

Overview Topical IFN Beta

Author Type Treatment Status at Treatment Start Eff Early Adm Effects Mid Administration Eff Late Adm Notes_and_Comments
Monk randomised, double-blind, placebo-controlled, phase 2 pilot trial at 9 UK sites SNG001 (6 MIU interferon beta-1a) median duration of symptoms was 10 days - -50% progression to severe Covid (OSCI>=5) - Mortality: 0 of 48 in IFN group an 3 of 49 in control
Khamis randomized, open-label controlled trial interferon beta-1b at a dose of 8 million IU (0.25 mg) twice a day less than 10 days after symptom onset - no effect on ICU and mortality - only study where topical IFN are not beneficial - possible cause: convalescent plasma administrated to more than 50% of the patients and most patients already had bilateral pneumonia (86%).

Overview Topical IFN Kappa

Author Type Treatment Status at Treatment Start Effects Early Administration Notes
Fu Trial Open-label, randomized, clinical trial 5 mg TFF2 plus 2 mg IFN-k via nasal mask SpO2 > 94% and moderate pneumonia -50% reduction time to viral clearance, -25% time to CT improvement and -25% hospital stay time  

Overview Systemic IFN

Overview Systemic IFN Alpha

Author Type Treatment Status_at_Treatment Start Effects Early Administration Effects Mid Administration Effects Late Administration Notes_______
Bhushan phase 3, multi-centric, randomized, comparator-controlled, open-label trial PEG IFN-α2b (1 μg/kg subcutaneous injection, single dose) moderate pneumonia, respiratory rate ≥24 breaths/min, SpO2 90–94% - faster viral load clearance (odds ratio 2.75), lower median oxygen support duration - 2 Covid deaths in IFN group, 0 in control
Pereda population cohort LPV/RTV + CQ + IFN-α2b for risk groups start upon exposure, else upon positive test Cuban Overall CFR was 3.70% and 0.92% for this group => -75% mortality     start upon exposure is great for IFN!!
Bo Wang   Subcutaneous injection of IFN alpha-2b (3 million IU/ dose), until viral clearance at admission patients moderately ill; early: 11 patients within 72 h of admission; 8 patients after 72 horus -50% hospital duration slight increase in hospital duration - IFN treatment yielded faster viral clearance (early and late combined) compared to control

Overview Systemic IFN Beta

Author Type Treatment Status_at_Treatment_Start Effects Early Administration Effects Mid Administration Effects Late Administration Notes
WHO Solidarity Trial Multicentre (across the world) randomized open label trial 44 μg of subcutaneous interferon beta-1a on day 0,3,6 (for severe cases sometimes intravenously) early: no oxygen; mid: oxygen; late: ventilation. //Classification into early/mid/late to fit table, the disease stages are more like: early to mid/late/very late early to mid:-20% mortality mid to late:+10% mortality very late:+30% mortality and increase of other adverse events very heterogenous since centres from across the world; better outcome for patients older than 65
Kalil double-blind, randomised, placebo-controlled trial at 63 hospitals (56 in the USA). 4 doses of 44 μg interferon beta-1a subcutaneously every other day; both groups intravenous remdesivir Grouping: mid: patients ordinal score of 4 or 5 (~450 patients per group); late: patients with score 6 (~35 patients; mostly with oxygen); //Patients included: symptom duration ~8.5 days; SaO2: 94% or less or oxygen but no ventilation; - overall not much effect; recovery rate ratio: ~1 +75% mortality (up to 7 from 4 in the control); recovery rate ratio: 0.4 slight overall benefit for patients older than 65;
Davoudi-Monfared randomized clinical trial in early 2020 44-microgram/ml (12 million IU/ml) dose of IFN beta-1a subcutaneously, 3 times per week for 2 weeks at admission mostly ill patients and 8 days post symptom onset. Administration was done early and late during hospitalization (early classified here as mid since patients quite sick) - -75% mortality increased mortality  
Hung multicentre, prospective, open-label, randomised, phase 2 trial subcutaneous_injection of beta-1b, 8 mio IU per dose; 2 doses for start on day 4, 1 dose for start on day 5/6 (=>no dose post day 7 mostly mild illness (fever and cough common); no IFN post day 7 of symptom onset -50% duration to SOFA==0 (3 days instead of 7) and -50% days in hospital (8 instead of 15) - - -

Overview Systemic IFN Lambda

Author Type Treatment Status_at_Treatment Start Effects_Mid_Administration Effects Late_Administration Notes
Jagannathan single-blind, placebo- controlled trial single, 180 mcg subcutaneous dose of Peginterferon Lambda 120 (60 per group) outpatients with mild to moderate COVID-19, outpatients with mean of 4 symptom days; seropositivity in treatment-group 35% and in control 47% - viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 (Lambda) and 9 (placebo) (HR 0.94; 95% CI 0.64 to 1.39) classified as late administration due to high seroprevalence
Feld double-blind, placebo-controlled trial subcutaneous injection of peginterferon lambda 180 μg outpatients with mean of 4.3 symptom days; seropositivity in treatment-group 0% and in control 21% viral load declines faster (difference of 2·42 log copies per mL at day 7); undetectable virus by day 7 more likely (odds ratio [OR] 4·12 [95% CI 1·15–16·73    

Changes in Treatment Outcomes

IFN treatment effects are possibly SARS-CoV-2 variant specific and change with the acquired immunity status:

To evaluate IFN treatments effects up-to-date and detect changing effects, analyzing whether individuals receiving IFN treatments for other indications (for example multiple sclerosis), have different probabilities to test positive and to be hospitalized due to Covid.

Similarly, the effects of interferon treatments on other viral infections (e.g. for influenza).

IFN Medications used

[in work]

IFN-alpha 2b

Considerations on the Treatment Start

Why the Treatment Start is relevant

The timing and the disease stage at the treatment start is relevant, since IFNs are most beneficial when administrated early. Interferons stimulate the immune response and thereby prevent reaching high viral loads or induce an earlier viral load clearance. If a strong immune response is already in place, interferons are usually not beneficial and can increase inflammation, especially observed for systemic administration.

Criteria to categorize Treatment Starts

Different studies use different measurements: 1) days after symptom onset, 2) days after hospital admission and 3) the disease stage/clinical appearance.

Here the following criteria are used to categorize the treatment starts:

Treatment Start Categories

Motivation to Use Interferon Treatments

Interferon treatment is also motivated by the observation that a dSARS-CoV-2 a major risk factor for severe disease is a disrupted interferon response [to cite].

References Topical IFN

Refs Topical IFN Alpha

Summary Yu

Yu J, Lu X, Tong L, Shi X, Ma J, Lv F, Wu J, Pan Q, Yang J, Cao H, Li L. Interferon‐α‐2b Aerosol Inhalation is Associated with Improved Clinical Outcomes in Patients with Coronavirus Disease‐2019. British Journal of Clinical Pharmacology. 2021 May 13.

Methods
Treatment

5 000 000 U of IFN-α-2b via aerosol inhalation twice daily.

Situation at Treatment Start

Grouped by time after symptom onset.

Characteristics at admission (patients with all symptom onsets included):

Group\Status Age Days of symptoms Temperature % Fever % Cough % Muscle ache % Fatigue Shortness of Breath
Intervention 48.06 (14.33) 4 (2–7) 37.93 (0.84) 692 (81.2%) 509 (59.7%) 86 (10.1%) 187 (22.0%) 37 (4.3%)
Control 49.73 (15.42) 5 (2–7) 37.82 (0.86) 417 (76.0%) 288 (52.5%) 54 (9.8%) 134 (24.4%) 49 (8.9%)
Outcomes
Settings

It is a retrospective study and there are differences in the medical characteristics and demographics of the patients across the groups. Examples of uneven grouping (Table 2 and Table S4 in the paper):

Results

“The risk probability for crude endpoints was lower in the IFN-α-2b group (3.8%) than in the non-IFN-α-2b group (9.3%, P < .001). After adjusting the confounding factors, IFN-α-2b therapy achieved a reduction of 64% in occurrence of endpoint events (hazard ratio, 0.36; 95% confidence interval [CI], 0.21–0.62).”

Outcome by time of Treatment start after symptom onset (Data from Table 2 and Table S4 in the paper):

Symptom onset to treatment start All treated 0 - 2 days 3 - 5 days 6 - 8 days 9 - 11 days >=12 days Control
Patients 852 208 279 206 109 50 549
Mechanical ventilation 25 2 8 10 3 2 35
ICU admission 23 2 6 7 5 3 40
Composite endpoint 32 2 9 12 6 3 51
Mechanical ventilation in % 2.9% 1.0% 2.9% 4.9% 2.8% 4.0% 6.4%
ICU admission in % 2.7% 1.0% 2.2% 3.4% 4.6% 6.0% 7.3%
Composite endpoint in % 3.8% 1.0% 3.2% 5.8% 5.5% 6.0% 9.3%
Reduction Mechanical ventilation 54% 85% 55% 24% 57% 37% 0%
Reduction ICU admission 63% 87% 70% 53% 37% 18% 0%
Reduction Composite endpoint 60% 90% 65% 37% 41% 35% 0%

// The data above are all unadjusted. The different patients cohorts don’t differ that much (Table 2 and S4) and accordingly the adjustments don’t change the overall interpretation (e.g. overall reduction of composite endpoint is 64% with adjustments in the paper and 60% without as in the table above.). The patients treated with later treatment starts had some increased risk factors both compared to those with earlier treatment starts and the control, thus the efficacies for the later stages are possibly underestimated without adjustments. The patients with early treatments had marginally reduced risk factors, thus a slight overestimation of efficacies is possible. // Patients characteristics are discussed in the sections above.

=> Efficacy of aerosolized IFN-α-2b is up to 90% if started within the first few days of symptom onset. Topical IFN-α-2b treatment is beneficial even in the later disease stage, however at much less than when started early.

Summary Zhou

Zhou Q, Chen V, Shannon CP, Wei X-S, Xiang X, Wang X, Wang Z-H, Tebbutt SJ, Kollmann TR and Fish EN (2020) Interferon-α2b Treatment for COVID-19. Front. Immunol. 11:1061. doi: 10.3389/fimmu.2020.01061

Methods

Summary Nan Wang

Wang N, Zhan Y, Zhu L, Hou Z, Liu F, Song P, Qiu F, Wang X, Zou X, Wan D, Qian X. Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients. Cell host & microbe. 2020 Sep 9;28(3):455-64.

Methods
Treatment
Situation at Treatment Start

Early start is defined as treatment start within 5 days of hospital admission and late start after 5 days. The ‘late group’ was both more severe at admission compared to the ‘early IFN’ and control and additionally the IFN treatment was initiated later than the ‘early IFN’ (Table 1 in the paper). E.g. the O2 Saturation by group at admission (not at treatment start [to confirm]):

O2 Saturation\Group Early IFN Control Late IFN
<90% 9 (4.2) 14 (6.9) 4 (15.4)
90–93% 41 (19) 35 (17.2) 7 (26.9)
> 93% 166 (76.9) 155 (76) 15 (57.7)
Results

=> 80% mortality reduction for an early treatment start.

Summary Liu

Liu H, Ruan Z, Yin Z, Wu D, Zhu H. Association of administration of IFN-α with mortality among patients hospitalized with coronavirus disease 2019. Future Virology. 2021 Mar;16(3):201-9.

Methods

“In this retrospec- tive study, 103 of 1555 hospitalized COVID-19 patients were treated with IFN-α, and the others matched through propensity score matching.”

Treatment
Results

Xu

Xu P, Huang J, Fan Z, Huang W, Qi M, Lin X, Song W, Yi L. Arbidol/IFN-α2b therapy for patients with corona virus disease 2019: a retrospective multicenter cohort study. Microbes and infection. 2020 May 1;22(4-5):200-5.

Chkihis

Chkhis A, Abdulrazzaq N, Mokhtar S, Al Jasmi A. Efficacy of High-Dose Nebulized Interferon α 2b in Severe COVID-19 Pneumonia. Turk Toraks Dergisi/Turkish Thoracic Journal. 2021 May 1;22(3).

Methods

about 60% reduction for ventilation

Summary Mordyk

Mordyk A.V., Ivanova O.G., Samsonov K.Yu., Sitnikova S.V., Zenkova L.A. Interferon alpha-2b in comprehensive treatment of patients with COVID-19. Infekc. bolezni (Infectious diseases). 2021; 19(1): 16–25. (In Russian). DOI: 10.20953/1729-9225-2021-1-16-25

Methods
Group\Status % Concomitant diseases, total % Arterial Hypertension % Allergy
Intervention 61 47 10
Control 50 41 4
Situation at Treatment Start
Group\Status % Dry Cough % Muscle ache % Fatigue Shortness of Breath 26-50% Lung Involvement in % 51-75% Lung Involvement in %
Intervention 56 83 100 77 59 19
Control 59 63 100 60 53 7
Results

Huang

Huang Y-Q, Tang S-Q, Xu X-L, Zeng Y-M, He X-Q, Li Y, Harypursat V, Lu Y-Q, Wan Y, Zhang L, Sun Q-Z, Sun N-N, Wang G-X, Yang Z-P and Chen Y-K (2020) No Statistically Apparent Difference in Antiviral Effectiveness Observed Among Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon- Alpha, and Ribavirin Plus Lopinavir/ Ritonavir Plus Interferon-Alpha in Patients With Mild to Moderate Coronavirus Disease 2019: Results of a Randomized, Open-Labeled Prospective Study. Front. Pharmacol. 11:1071. doi: 10.3389/fphar.2020.01071

Methods

“This was a single-center, randomized, open-labeled, prospective clinical trial. Eligible patients with mild to moderate COVID-19 were randomized into three groups: ribavirin (RBV) plus interferon-a (IFN-a), lopinavir/ritonavir (LPV/r) plus IFN-a, and RBV plus LPV/r plus IFN-a at a 1:1:1 ratio.”

Results

“The proportion of patients with SARS-CoV-2 nucleic acid negativity in the LPV/ r+IFN-a-treated group (61.1%) was higher than the RBV+ IFN-a-treated group (51.5%) and the RBV+LPV/r+IFN-a-treated group (46.9%) at day 14; however, the difference between these groups was calculated to be statistically insignificant.”

=> Additional lopinavir/ritonavir or ribavirin or both had no much effect on the viral load clearance.

Meng

Meng, Z., Wang, T., Li, C., Chen, X., Li, L., Qin, X., … & Luo, J. (2020). An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area. MedRxiv.

Study Population

Refs Topical IFN Beta

Summary Monk

Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, Gabbay FJ, Davies DE, Holgate ST, Ho LP, Clark T. 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. The Lancet Respiratory Medicine. 2021 Feb 1;9(2):196-206

Methods
Outcome\Group IFN beta-1a (48) control (49)
Recover (OSCI<=1) on Day 14 21(44%) 11(22%)
Recover (OSCI<=1) on Day 28 28 (58%) 17 (35%)
Severe disease on Day 16 (OSCI>=5) 6 (13%) 11 (22%)
Deaths 0 of 48 3 of 49

=>

  • About 50% reduction in severe disease despite the treatment start was quite late with a median symptom duration of 10 days. 3 deaths without IFN and 0 with IFN indicates a death rate reduction >=70%.
  • The probability to be recovered was about two times higher in the IFN group from day 5 to day 28.
Adverse Events

“SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven [15%] patients in the SNG001 group and five [10%] in the placebo group). There were three deaths in the placebo group and none in the SNG001 group.”

Comments

” The optimal route and specific type of interferon might depend on the stage of disease, the spread of viral infection beyond the lung, and the ease of administration in different clinical settings.”

Summary Khamis

Khamis F, Al Naabi H, Al Lawati A, Ambusaidi Z, Al Sharji M, Al Barwani U, Pandak N, Al Balushi Z, Al Bahrani M, Al Salami I, Al-Zakwani I. Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia. International Journal of Infectious Diseases. 2021 Jan 1;102:538-43

Methods
Treatment
Results

Refs Topical IFN-K

Summary Fu Pilot

Fu, W., Liu, Y., Xia, L., Li, M., Song, Z., Hu, H., … & Lu, H. (2020). A clinical pilot study on the safety and efficacy of aerosol inhalation treatment of IFN-κ plus TFF2 in patients with moderate COVID-19. EClinicalMedicine, 25, 100478.

// basis for the follow up trial

Summary Fu Trial

Fu W, Liu Y, Liu L, Hu H, Cheng X, Liu P, Song Z, Zha L, Bai S, Xu T, Yuan S. An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19. EClinicalMedicine. 2020 Oct 1;27:100547.

Methods
Treatment

“In addition, both proteins (5 mg TFF2 plus 2 mg IFN-k) were dissolved in 5 mL sterilized water, and the combination aerosol was delivered to the patient for 20 -30 min by a nasal mask driven by a medical compressed air atomizer (YUWELL, 403M). The aerosol inhalation treatment started from the first day of hospitalization and was administered 6 times every 24 h.”

Situation at Treatment Start

Patients with peripheral capillary oxygen saturation (SpO2) was > 94% on room air at screening and moderate pneumonia.

Medical Analysis of Treatment Effects
Outcomes
Results

Both the average time for the primary endpoint negative viral RNA conversion and the secondary endpoint improvement in lung CTs were shorter in the treatment group:

Fu Trial IFN K effects

=> Nearly 50% reduction for the average time to viral clearance, about 25% reduced time for CT improvement and about 25% reduced hospital stay.

Notes:

Refs Systemic IFN

Refs Subcutaneous IFN Alpha

Pandit

Pandit A, Bhalani N, Bhushan BS, Koradia P, Gargiya S, Bhomia V, Kansagra K. Efficacy and safety of pegylated interferon alfa-2b in moderate COVID-19: A phase II, randomized, controlled, open-label study. International Journal of Infectious Diseases. 2021 Apr 1;105:516-21.

follow up phase 3 trial is by Bhushan et al

Bhushan

Bhushan SB, Wanve S, Koradia P, Bhomia V, Soni P, Chakraborty S, Khobragade A, Joshi S, Mendiratta SK, Kansagra KK, Parihar A. Efficacy and safety of pegylated interferon-α2b in moderate COVID-19: a phase 3, randomized, comparator-controlled, open-label study. International Journal of Infectious Diseases. 2021 Oct 1;111:281-7.

Methods
Treatment

PEG IFN-α2b (1 μg/kg subcutaneous injection, single dose) + standard care for both groups

Situation at Treatment Start

moderate pneumonia, respiratory rate ≥24 breaths/min, SpO2 90–94%

Outcome

“The primary endpoint was a two-point improvement in clinical status on Day 11, measured by the World Health Organization’s seven-point ordinal scale.”

Measuring
Results

Pereda

Therapeutic effectiveness of interferon alpha 2b treatment for COVID-19 patient recovery

Method

=> The study indicates a mortality reduction by 75% for an early started systemic IFN alpha 2b treatment.

Bo Wang

Wang B, Li D, Liu T, Wang H, Luo F, Liu Y. Subcutaneous injection of IFN alpha-2b for COVID-19: an observational study. BMC infectious diseases. 2020 Dec;20(1):1-6.

Methods

Frankel

Frankel AE, Reddy R, DeSuza KR, Deeb K, Carlin AF, Smith D, Xie Y, Naik E, Silver RT, Hasselbalch HC. Response to pegylated interferon in a COVID‐19–positive elderly woman with primary myelofibrosis treated with ruxolitinib. Clinical case reports. 2021 Apr;9(4):2228-35.

Refs Systemic IFN Beta

WHO Solidarity Trial Consortium

WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results. New England journal of medicine. 2021 Feb 11;384(6):497-511

The subgroup analyses give some hints in which situations the medication could be useful and in which they could be harmful.

Methods
Treatment
Outcome

in-hospital mortality regardless of time point.

Results

=>

  • As observed by other studies systemic IFN has an adverse effect at severe disease stages.
  • If Subcutaneous IFN treatment started when no oxygen support was needed, the death rate decreased by roughly 20%.

Refs Subcutaneous IFN Beta

Summary Hung

Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, Ng YY, Lo J, Chan J, Tam AR, Shum HP. 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. The Lancet. 2020 May 30;395(10238):1695-704.

Methods
Treatment

=> all IFN doses within the first 7 days of symptoms. Later doses were omitted.

Situation at Treatment Start

Baseline Status:

Group\Status Age Days of symptoms % Fever % Chills % Cough % Myalgia % Malaise
Intervention 51 5 (4–7) 70 (81%) 13 (15%) 45 (52%) 10 (12%) 19 (22%)
Control 52 4 (3–8) 32 (78%) 6 (15%) 23 (56%) 8 (20%) 5 (12%)
Outcome

“The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population.”

Assessment of Progression

“Daily nasopharyngeal swab, posterior oropharyngeal saliva, throat swab, stool or rectal swabs, and urine if available, were obtained until discharge, for quantification of viral load and genetic mutation testing (appendix pp 20–23).”

Findings

all results left side table 3 (Table 2 and Figure 2: not all have IFN since some post day 7)

  • Average days to negative in post. saliva for the IFN group: 6·0 (2·0–7·0) and control: 8·5 (5·3–11·8) (Table 3)
  • Days to SOFA 0: 3 days for IFN and 7 for control (Table 3).
  • Days in hospital: IFN: 8 (6–12·5) and control: 15 (9–16)
Adverse Events

” Adverse events included self-limited nausea and diarrhoea with no difference between the two groups.”

=> -50% duration to SOFA==0 (3 days instead of 7) and -50% days in hospital (8 instead of 15)

Summary Kalil

Kalil AC, Mehta AK, Patterson TF, Erdmann N, Gomez CA, Jain MK, Wolfe CR, Ruiz-Palacios GM, Kline S, Pineda JR, Luetkemeyer AF. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial. The Lancet Respiratory Medicine. 2021 Oct 18.

Methods
Treatment

“Hospitalised patients received up to four doses of either 44 μg interferon beta-1a or matched normal saline placebo administered subcutaneously every other day. The dose chosen was based on the bioavailability of interferon beta- 1a, which is approximately 30% after subcutaneous administration, with peak serum concentrations being reached with in several hours of receiving a dose.Serum concentrations of interferon beta-1a typically peak 3–15 h after intramuscular administration. Interferon beta-1a is excreted by hepatic and renal pathways. All hospitalised patients also received intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days. All patients received standard supportive care by the trial site hospital, including glucocorticoids, but other experimental treatments for COVID-19 were prohibited.”

Results

=> Subcutaneous IFN beta-1a has an adverse effect on patients with an ordinal score of 6 at treatment start. The treatment showed no benefit for patients at ordinal score scales 4 or 5.

Davoudi-Monfared

Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, Kazemzadeh H, Yekaninejad MS. A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe COVID-19. Antimicrobial agents and chemotherapy. 2020 Aug 20;64(9):e01061-20.

Setting
Treatment

“Each 44-microgram/ml (12 million IU/ml) dose of interferon beta-1a (ReciGen, CinnaGen Co., Iran) was subcutaneously injected three times weekly for two consecutive weeks.” // medications in Table 3; of note Corticosteroid were given to 62% of IFN treated while only to 44% in the control

Situation at Treatment Start

Symptoms at baseline (from Table 1 in the paper):

Group\Status Symptoms in days % cough % fever % dyspnea % myalgia
IFN Group 8.3 88 71 69 38
Control 6.57 64 51 69 51
Results

=> accounting the 4 dead dropouts from FIG 1 which likely belong to the late IFN group, late IFN seems to have an adverse effect. In the early/mid IFN group on the other hand, the death rates seems to be around 10% (inferred from OR 13.5 and control group death rate) which indicates a mortality reduction of 75%.

Darazam April 20

Darazam IA, Shokouhi S, Pourhoseingholi MA, Irvani SS, Mokhtari M, Shabani M, Amirdosara M, Torabinavid P, Golmohammadi M, Hashemi S, Azimi A. Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial. Scientific reports. 2021 Apr 13;11(1):1-1.

Methods

Unlike in most other studies, in this study, treatment with subcutaneous IFN beta-1a/b reduced the mortality and improved the clinical state even for severely sick patients. //The trial was carried out in early 2020 when hospitals were at their limits in many locations around the world, thus a possible bias could have occurred: e.g. since the IFN investigator team provided additional support to the standard care team, could be a factor for the better outcome in the intervention groups.

Darazam June 21

Darazam IA, Hatami F, Rabiei MM, Pourhoseingholi MA, Shabani M, Shokouhi S, Mardani M, Moradi O, Gharehbagh FJ, Mirtalaee N, Negahban H. An investigation into the beneficial effects of high-dose interferon beta 1-a, compared to low-dose interferon beta 1-a in severe COVID-19: The COVIFERON II randomized controlled trial. International Immunopharmacology. 2021 Oct 1;99:107916.

Methods and Treatment

“The intervention group was treated with high-dose IFN-β 1a (Recigen) (Subcutaneous injections of 88 μg (24 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally) and the control group was treated with low-dose IFN-β 1a (Recigen) (Subcutaneous injections of 44 μg (12 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally).”

Situation at Treatment Start

All patients with oxygen support and mostly saturation below 90%.

Results

“Median Time To Clinical Improvement (TTIC) for cases treated with low-dose IFN-β1a was shorter than that for cases treated with high-dose IFN-β1a (6 vs 10 days; P = 0.018). The mortality rates in intervention and control group were 41% and 36.5%, respectively.”

=> in severely sick patients, the dose increase of IFN-beta1a had adverse effects.

Seyfi

Seyfi S, Latifi K, Zavareh MS, Ezoji K, Mohammadnia-Afrozi M. Comparing the Outcomes of Treatment with INF-β 1-a (interferon beta-1a) and IFN-β 1-b (interferon beta-1b) among COVID-19 Inpatients. International Immunopharmacology. 2021 Oct 15:108241.

Methods

“Methods: In this study, we retrospectively evaluated the clinical treatment outcomes of 100 patients with COVID- 19 who received IFN-β 1-a and IFN-β 1-b during their hospitalization period.”

Results

“Mortality rate was also estimated as 10% among IFN-β 1-a recipients and 14% among IFN-β 1-b recipients, which was not statistically significant (p = 0.190). ICU hospitalization rate for the IFN-β 1-a recipients and IFN-β 1-b recipients was 26% and 36%, respectively.”

=> beta 1-a seems better than beta 1-b regarding mortality and ICU

Estebanez

Estebanez M, Ramirez-Olivencia G, Mata T, Marti D, Gutierrez C, De Dios B, Herrero MD, Roel A, Martinez Y, Aguirre A, Nicolas FA. Clinical evaluation of IFN beta1b in COVID-19 pneumonia: a retrospective study. MedRxiv. 2020 Jan 1.

Refs IFN Lambda

Summary Jagannathan

Jagannathan P, Andrews JR, Bonilla H, Hedlin H, Jacobson KB, Balasubramanian V, Purington N, Kamble S, de Vries CR, Quintero O, Feng K. Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nature communications. 2021 Mar 30;12(1):1-0.

Methods
Group\Status Age BMI Days since symptom onset Baseline SARS-2 IgG+ Viral load CT value
Trial 37 (18–66) 27.6 4 (3–6) 21 (35.0%) 4.2 (3.3–5.5) 30.9(26.4–33.8)
Control 34 (20–71) 28.5 5 (3–5) 28 (46.7%) 4.7 (3.2–5.5) 29.3(26.4–34.3)
  • Quite low viral loads/high Ct values. Some randomness is excepted due to PCR accuracy/sensitivity.
  • Seropositivity quite high already which possibly ameliorates IFN effects and indicates that some patients are already in the recovery phase.
Outcomes
  1. Duration of detectable oropharyngeal viral load.
  2. duration of symptoms.
Results

“In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39).”

=> Nearly 50% seropositivity in the control group, suggests the patients are in the recovery phase, which is consistent with the vanishing viral loads.

Summary Feld

Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, Borgia SM, Boggild AK, Powis J, McCready J, Tan DH. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial. The Lancet Respiratory Medicine. 2021 May 1;9(5):498-510.

Methods
Treatment

Single subcutaneous injection of peginterferon lambda 180 μg or placebo

Situation at Treatment Start
Group\Status Age BMI Days since symptom onset Baseline SARS-2 IgG+ Viral load
Trial 48 (30–53) 27·3 (5·2) 4·3 (1·7) 0/27 6·16 (3·14)
Control 39 (33–55) 26·1 (4·2) 4·7 (1·7) 5/24 (21%) 4·87 (3·68)
Results

=> Viral load declined faster in interferon lambda group. Overall symptoms and respiratory symptoms declined somewhat slower in the IFN group. // start of treatment is around viral load peak of control group => some inflammatory effects possible.

Adverse Events

“Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group.”

Refs IFN Reviews and Overviews

Refs General IFN Treatment

Sodeifian

Sodeifian F, Nikfarjam M, Kian N, Mohamed K, Rezaei N. The role of type I interferon in the treatment of COVID‐19. J Med Virol. 2021;1‐19. https://doi.org/10.1002/jmv.27317

Wong

Wong CK, Wan EY, Luo S, Ding Y, Lau EH, Ling P, Hu X, Lau EC, Wong J, Zheng X, Cowling BJ. Clinical outcomes of different therapeutic options for COVID-19 in two Chinese case cohorts: A propensity-score analysis. EClinicalMedicine. 2021 Feb 1;32:100743.

Refs IFN Alpha Review

Nakhlband

Nakhlband A, Fakhari A, Azizi H. Interferon‐alpha position in combating with COVID‐19: A systematic review. Journal of Medical Virology. 2021 Jun 8.

Refs IFN Beta Review

Kumar

Kumar S, Saurabh MK, Narasimha VL, Maharshi V. Efficacy of Interferon-β in Moderate-to-Severe Hospitalised Cases of COVID-19: A Systematic Review and Meta-analysis. Clinical Drug Investigation. 2021 Oct 23:1-0.

Includes 8 studies:

Refs IFN other Viruses

Refs IFN other CoVs