key: cord-0849698-hww1qo0y
authors: Tortajada, Cecilia; Añón, Sol; Ortiz, María Milagros; Andreu‐Ballester, Juan Carlos; Flores, Juan
title: Interferon β‐1b for patients with moderate to severe COVID‐19 in the inflammatory phase of the disease
date: 2021-04-15
journal: J Med Virol
DOI: 10.1002/jmv.26976
sha: d2792f2545797ef0f7f3d5a0d3f73f5b4708eeed
doc_id: 849698
cord_uid: hww1qo0y

nan

Register: CTA-ARA-2020-04.

In our Health Department, the interim guidelines for management of COVID-19 were developed by a committee of experts following the guidelines issued by the Spanish Ministry of Health. These guidelines included the use of IFNβ-1b (Betaferon®, Bayer AG) 250 μg subcutaneously every 48 h for a maximum of 14 days. Patients could also receive tocilizumab and methylprednisolone or dexamethasone. As antiviral therapy, patients received hydroxychloroquine, with or without azithromycin, and/or lopinavir/ritonavir. Data were recorded from patients' electronic medical records, including demographics, comorbidities, chest radiography, SatO2, laboratory values, other therapies received for COVID-19, and outcome. Patients were assessed to fit in one of the categories of the WHO's Eight-category scale for clinical improvement, based on oxygen support requirement, 8 at admission and at days 7 and 21 (see Table legend ). If a given patient was discharged before reaching the 21st day of hospitalization, and there were not electronic register of a new readmission or medical visit, the patient was considered to have at day 21 the same category as that at discharge. The primary composite endpoint of the study was admission to ICU or in-hospital death. The secondary endpoint was time to clinical improvement. Improvement was defined as two points decrease in the WHO's Eight-category scale or live discharge from the hospital, whichever occurred first. Descriptive analysis was performed to compare baseline characteristics of patients who received IFNβ-1b and those who did not. We used Kaplan-Meier analysis and log-rank test for survival analysis between both groups. The hazard ratio (HR) and 95% confidence interval (CI) for clinical improvement and the composite endpoint death or ICU admission were estimated by the Cox proportional hazards model and were adjusted for propensity score index and confounding variables. P-values were two-sided and values < 0.05 were considered statistically significant. Statistical analysis was performed using the Statistical Package for Social Science (SPSS 19.0 Inc.).

Of 287 eligible patients evaluated for study inclusion, 46 were excluded because laboratory confirmation of SARS-CoV-2 infection by RT-PCR was negative, 126 were excluded because SatO2 was not lower than 92%, and 10 were excluded because of a terminal disease.

From the remaining 105 patients included in our analysis, 28 of them received INFβ-1b. In the IFNβ-1b group, Table 1 (Table 1) .

Among all patients, cumulative survival incidence in IFNβ-1b versus control group was 92% (95% CI, 100-82) and 51% (95% CI, 68-34), respectively, p = .002 ( Figure 1A ). HR for death or ICU admission was 0.06 (95% CI, 0.01-0.34), p = .001. Median time to clinical improvement was not significantly different between groups: (7) 6. ICU and ventilation 0 0 7. Ventilation and additional organ support The results of this study showed that IFNβ-1b, when given in the inflammatory phase of the disease, is associated with reduction in mortality and ICU admission in COVID-19 hospitalized patients that require oxygen support, while time to reach clinical response did not change.

Along the same lines, some real-world setting studies have been recently published. 9-11 IFNα-2b significantly reduced elevated blood levels of inflammatory markers. 5 IFNβ−1a combined with the standard antiviral treatment have shown efficacy in reducing mortality. 9

IFNβ-1b, in severe patients, was effective in shortening the time to clinical improvement and in decreasing admission to ICU, although it could not offer an estimation of the survival benefit. 11 Recent data from the WHO SOLIDARITY trial 12 which repurposes IFN as an antiviral drug, exclude a mortality reduction among these patients.

However, a caveat of the Solidarity trial is that the time from symptom onset to IFN initiation is not available.

Severe COVID-19 has two phases, an initial viral replication phase followed by an inflammatory phase. It has been proposed that the window of opportunity for antiviral treatment should be no longer than 1 week from symptom onset. 1 

Dexamethasone in Hospitalized Patients with COVID-19-Preliminary Report. 2020

Corticosteroids for COVID-19 patients requiring oxygen support? Yes, but not for everyone: effect of corticosteroids on mortality and intensive care unit admission in patients with COVID-19 according to patients' oxygen requirements

Dysregulation of type I interferon responses in COVID-19

Clinical improvement was defined as two points decrease in the WHO's Eight-category scale or live discharge from the hospital, whichever occurs first. Not discharged patients (censored patients) died. Cox regression was adjusted for propensity score index for interferon use, oxygen requirements (patients requiring noninvasive mechanical ventilation [NIMV], high flow nasal cannula or FiO 2 > 0.40, or patients requiring supplemental oxygen with FiO2 < 0.40) and corticosteroids. To calculate the propensity score index, sex, age, diabetes, hypertension, obesity, CURB-65 at admission, and C-reactive protein were included

Interferon-α2b treatment for COVID-19

Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study

Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study

COVID-19 Therapeutic Trial Synopsis

A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe COVID-19

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

Interferon β-1b in treatment of severe COVID-19: a randomized clinical trial

Repurposed antiviral drugs for COVID-19-interim. WHO Solidarity trial results (version posted October 15