Effect of combination of interferon alpha-2b and interferon-gamma or interferon alpha-2b alone for elimination of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial

Abstract

Objectives: IFN-alpha2b and IFN-gamma combination has demonstrated favorable pharmacodynamics for genes underlying antiviral activity which might be involved in the defense of the organism from a SARS-CoV-2 infection. Considering this we conducted a randomized controlled clinical trial for efficacy and safety evaluation of subcutaneous IFN-alpha2b and IFN-gamma administration in patients positive to SARS-CoV-2. Methods: We enrolled 19-82 years-old inpatients at the Military Central Hospital Luis Diaz Soto, Havana, Cuba. They were hospitalized after confirmed diagnosis for SARS-CoV-2 RNA by real-time reverse transcription polymerase chain reaction. Patients were randomly assigned in a 1:1 ratio to receive either, subcutaneous treatment with a co-lyophilized combination of 3.0 MIU IFN-alpha2b and 0.5 MIU IFN-gamma (HeberFERON, CIGB, Havana, Cuba), twice a week for two weeks, or thrice a week intramuscular injection of 3.0 MIU IFN-alpha2b (Heberon Alpha R, CIGB, Havana, Cuba). Additionally, all patients received lopinavir-ritonavir 200/50 mg every 12 h and chloroquine 250 mg every 12 h (standard of care). The primary endpoints were the time to negativization of viral RNA and the time to progression to severe COVID-19, from the start of treatment. The protocol was approved by the Ethics Committee on Clinical Investigation from the Hospital and the Center for the State Control of Medicines, Equipment and Medical Devices in Cuba. Informed consent was obtained from each participant. Results: A total of 79 patients with laboratory-confirmed SARS-CoV-2 infection, including symptomatic or asymptomatic conditions, fulfilled the inclusion criteria and underwent randomization. Thirty-three subjects were assigned to the HeberFERON group, and 33 to the Heberon Alpha R group. Sixty-three patients were analyzed for viral negativization, of them 78.6% in the HeberFERON group negativized the virus after 4 days of treatment versus 40.6% of patients in the Heberon Alpha R groups (p=0.004). Time to reach the negativization of the SARS-CoV-2 measured by RT-PCR in real time was of 3.0 and 5.0 days for the HeberFERON and Heberon Alpha R groups, respectively. A significant improvement in the reduction of time for negativization was attributable to HeberFERON (p=0.0027, Log-rank test) with a Hazard Ratio of 3.2 and 95% CI of 1.529 to 6.948, as compared to Heberon Alpha R treated group. Worsening of respiratory symptoms was detected in two (6.6%) and one (3.3%) patients in HeberFERON and IFN-alpha2b groups, respectively. None of the subjects transit to severe COVID-19 during the study or the epidemiological follow-up for 21 more days. RT-PCR on day 14 after the start of the treatment was negative to SARS-CoV-2 in 100% and 91% of patients of the combination of IFNs and IFN-alpha2b, respectively. Negativization for HeberFERON treated patients was related to a significant increase in lymphocytes counts and an also significant reduction in CRP as early as 7 days after commencing the therapeutic schedule. All the patients in both cohorts recover by day 14 and were in asymptomatic condition and laboratory parameters return to normal values by day 14 after treatment initiation. Adverse events were identified in 31.5% of patients, 28.5% in the control group, and 34.4% in the HeberFERON group, and the most frequent were headaches (17.4%). Conclusions: In a cohort of 63 hospitalized patients between 19 to 82 years-old with positive SARS-CoV-2, HeberFERON significantly negativized the virus on day 4 of treatment when comparing with IFN-alpha2b. Heberon Alpha R also showed efficacy for the treatment of the viral infection. Both treatments were safe and positively impact on the resolution of the symptoms. None of the patients developed severe COVID-19. Key words: COVID-19, treatment, drug, virus negativization, antiviral, interferon combination, SARS CoV-2.

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

“…The remaining trial comparisons included: favipiravir versus umifenovir [33]; umifenovir versus lopinavir-ritonavir [40]; umifenovir versus standard care [40]; novaferon versus novaferon plus lopinavir-ritonavir [45]; novaferon plus lopinavir-ritonavir versus lopinavir-ritonavir [45]; novaferon versus lopinavir-ritonavir [45]; alpha lipotic acid versus placebo [46]; baloxavir marboxil versus favipavir [41]; baloxavir marboxil versus standard care [41]; triple combination of interferon beta-1b plus lopinavir-ritonavir plus ribavirin versus lopinavir-ritonavir [38]; remdesivir for 5 days versus remdesivir for 10 days [37]; high-flow nasal oxygenation versus standard bag-valve oxygenation [44]; hydroxychloroquine versus chloroquine [48]; chloroquine versus standard care [48]; high dosage chloroquine diphosphate versus low dosage chloroquine diphosphate [50]; hydroxychloroquine plus azithromycin versus standard care [54]; triple combination of darunavir plus cobicistat plus interferon alpha-2b versus interferon alpha-2b [117]; lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [61]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [61]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus lopinavir-ritonavir plus interferon alpha [61]; lincomycin versus azithromycin [62];, 99-mTc-methyl diphosphonate (99mTc-MDP) injection versus standard care [63]; interferon alpha-2b plus interferon gamma versus interferon alpha-2b [64]; telmisartan versus standard care [66]; avifavir 1800/800 versus avifavir 1600/600 [67]; dexamethasone plus aprepitant versus dexamethasone [69]; anti-C5a antibody versus standard care [70]; azvudine versus standard care [73]; human plasma-derived C1 esterase/kallikrein inhibitor versus standard care [72]; icatibant acetate versus standard care [72]; icatibant acetate versus human plasma-derived C1 esterase/kallikrein inhibitor [72]; pulmonary rehabilitation program versus isolation at home [71]; auxora (calcium release-activated calcium channel inhibitors) versus standard care [74]; umbilical cord stem cell infusion versus standard care [75]; vitamin C versus placebo [76]; sofosbuvir plus daclatasvir versus standard care [80]; sofosbuvir plus daclatasvir plus ribavirin versus hydroxychloroquine plus lopinavir-ritonavir with or without ribavirin [79]; interferon beta-1b versus standard care [81]; calcifediol versus standard care [84]; recombinant human granulocyte colony–stimulating factor versus standard care [85]; intravenous and/or nebulized electrolyzed saline w...…”

Interferon alpha-based combinations suppress SARS-CoV-2 infection in vitro and in vivo

“…A combination of IFNb1b, lopinavir–ritonavir, and ribavirin has been tested for treatment of hospitalized patients with COVID-19 in an open-label, randomized, phase 2 trial [16]. Similarly, IFNa2b and IFNg has also been evaluated in patients positive to SARS-CoV-2 [17]. Both treatments were shown to positively impact the resolution of the COVID-19 symptoms.…”

The Time Course of Therapeutic Interventions for Covid-19

“…In Cuba, a combination of interferon-α-2b and interferon γ on background therapy of LPV/r and chloroquine was successful in achieving viral clearance in 4 days in 78.6% of the patients compared to 40.6% of those receiving interferon-α-2b alone (53). A study of 81 hospitalized patients in Iran showed 28-day overall mortality significantly lower in an interferon β treated group than the control group (19% vs. 43.6% respectively, p = 0.015) (54).…”