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 (400mg/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)

Differential roles of interferons in innate responses to mucosal viral infections

“…Much of the current research focus has been on type I IFN, which is used clinically for other diseases and restricts SARS-CoV-2 [148]. Indeed, preliminary phase 2 studies investigating the efficacy of type I IFN in preventing or ameliorating COVID-19 have been promising: data from randomized controlled trials support this type of therapy, including results with IFN-β, which resulted in a shorter length of positive infection or a shorter time to clinical improvement in COVID-19 patients, relative to therapy devoid of IFN-β (NCT04276688 i , NCT04343768 ii ) [149,150]. An additional phase 2 randomized controlled study has demonstrated that inhaled, nebulized IFN-β1a contributes to an improvement in breathlessness for hospitalized patients (NCT04385095 iii ) [151].…”

RIG-I-induced innate antiviral immunity protects mice from lethal SARS-CoV-2 infection

“…Other studies have proposed stimulation of the innate immune system as an approach for SARS-CoV-2 treatment. Notably, recombinant PEG-IFNa2 42 , PEG-IFNb 43 or PEG-interferon lambda 44 treatment were shown to accelerate the recovery of COVID-19 patients in phase II trials. However, 3pRNA offers the additional advantage that the entire physiological spectrum of type I and III interferons are induced and that the anti-viral immune expression profile is broader than the one induced by type I IFN alone 28 .…”

Current status of therapeutic alternatives for COVID-19: A narrative review

“…Other investigated antiviral agents Although many potential antiviral agents have been investigated so far in RCTs, including darunavir/cobicistat, umifenovir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, ribavirin, nitazoxanide, and various interferon-based regimens, these studies have serious limitations [29,[54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69]. Until the results of ongoing trials evaluating these agents are available, the use of these drugs for the treatment of COVID-19 should be limited to randomized controlled trials.…”