Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial

Abstract

Type 1 Interferons (IFNs) have been associated with positive effects on Coronaviruses. Previous studies point towards the superior potency of IFNβ compared to IFNα against viral infections. We conducted a three-armed, individually-randomized, open-label, controlled trial of IFNβ1a and IFNβ1b, comparing them against each other and a control group. Patients were randomly assigned in a 1:1:1 ratio to IFNβ1a (subcutaneous injections of 12,000 IU on days 1, 3, 6), IFNβ1b (subcutaneous injections of 8,000,000 IU on days 1, 3, 6), or the control group. All three arms orally received Lopinavir/Ritonavir (400 mg/100 mg twice a day for ten days) and a single dose of Hydroxychloroquine 400 mg on the first day. Our utilized primary outcome measure was Time To Clinical Improvement (TTCI) defined as the time from enrollment to discharge or a decline of two steps on the clinical seven-step ordinal scale, whichsoever came first. A total of 60 severely ill patients with positive RT-PCR and Chest CT scans underwent randomization (20 patients to each arm). In the Intention-To-Treat population, IFNβ1a was associated with a significant difference against the control group, in the TTCI; (HR; 2.36, 95% CI 1.10–5.17, P-value = 0.031) while the IFNβ1b indicated no significant difference compared with the control; HR; 1.42, (95% CI 0.63–3.16, P-value = 0.395). The median TTCI for both of the intervention groups was five days vs. seven days for the control group. The mortality was numerically lower in both of the intervention groups (20% in the IFNβ1a group and 30% in the IFNβ1b group vs. 45% in the control group). There were no significant differences between the three arms regarding the adverse events. In patients with laboratory-confirmed SARS-CoV-2 infection, as compared with the base therapeutic regiment, the benefit of a significant reduction in TTCI was observed in the IFNβ1a arm. This finding needs further confirmation in larger studies.Trial Registration Number: ClinicalTrials.gov, NCT04343768. (Submitted: 08/04/2020; First Online: 13/04/2020) (Registration Number: NCT04343768).

Antibodies against type I interferon: detection and association with severe clinical outcome in COVID‐19 patients

“…Based on its antiviral properties, recombinant IFN‐I has been tested as therapy for severe COVID‐19, but the treatment showed little or no benefit. 7 , 8 Yet, the potential of such treatment may have been hindered by the presence of IFN‐I auto‐Abs in patient sera, and this question could therefore be revisited by determining the level of these Abs, for example using the ELISA method we used here. Moreover, patients could be treated with recombinant IFN‐I that is not targeted by auto‐Abs (e.g.…”

Nafamostat–Interferon-α Combination Suppresses SARS-CoV-2 Infection In Vitro and In Vivo by Cooperatively Targeting Host TMPRSS2

“…Our recent studies have highlighted the synergism of several compounds against SARS-CoV-2 in human lung epithelial Calu-3 cells, with IFNα-remdesivir and camostat-remdesivir combinations having the highest synergy scores [2,10,11]. In these studies, we were also able to show that camostat-remdesivir was effective against SARS-CoV-2 infection in human lung organoids, as well as that IFNα-remdesivir was effective in both human lung organoids and Syrian hamsters [10,11]. Furthermore, other studies have shown that combinations of IFNα with lopinavir-ritonavir-ribavirin as well as nafamostat with favipiravir are effective for treatment of patients infected with SARS-CoV-2 [12,13].…”

Commentary: Why Haven’t We Found an Effective Treatment for COVID-19?

“…Several studies have shown that timing of interferon administration is one decisive factor in COVID-19 (13)(14)(15)(16). A positive treatment effect can be achieved only if interferon is used early in the course of this disease.…”

“…However, the MTD of most interferon products currently available has still to be determined, in particular regarding long-term intravenous administration of interferon beta. In COVID-19, a lower dosage than the MTD (as well as the subcutaneous route for interferon beta) can be therapeutically effective only if synergistic effects are utilized, i.e., if interferon is used in combination with other antiviral agents, as demonstrated in some recent clinical studies (13)(14)(15)(16). Furthermore, relatively low doses can successfully be employed without concomitant administration of other antivirals if interferon is given by inhalation (17,18).…”