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Therapeutic Effectiveness of Interferon Alpha 2B Treatment for COVID-19 Patient Recovery

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Therapeutic Effectiveness of Interferon Alpha 2B Treatment for COVID-19 Patient Recovery medRxiv preprint doi: https://doi.org/10.1101/2020.07.28.20157974; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Therapeutic effectiveness of interferon alpha 2b treatment for COVID-19 patient recovery Pereda R1, González D2, Rivero HB3, Rivero JC4, Pérez A5, López LR6, Mezquia N4, Venegas R7, Betancourt JR8, Domínguez RE9. 1 Intensive Medicine Department, Medical College of Havana. 23 Street 202, Vedado, Plaza de la Revolución, ZIP code 10400. Havana, Cuba. 2 Internal Medicine Department, Pedro Kouri Institute. Avenida Novia del Mediodía, KM 6 ½, La Lisa, ZIP code 11400, Havana, Cuba. 3 Internal Medicine Department, Enrique Cabrera General Hospital. Calzada de Aldabó 11117, Altahabana, Arroyo Naranjo, ZIP code 10800, Havana, Cuba. 4 Intensive Medicine Department, Miguel Enríquez Surgical Clinical Hospital. Ramón Pinto 202, 10 de octubre, ZIP code 10700, Havana, Cuba. 5 Intensive Medicine Department, Enrique Cabrera General Hospital. Calzada de Aldabó 11117 Corner E, Altahabana, Arroyo Naranjo, ZIP code 10800, Havana, Cuba. 6 Intensive Medicine Department, Juan Manuel Marquez Pediatric Hospital. Avenida 31, Marianao, ZIP code 11400, Havana, Cuba. 7 Intensive Medicine Department, Luis Díaz Soto Central Military Hospital. Ave Monumental km 2 ½ Eastern Havana, ZIP code 19130, Havana, Cuba. 8 Intensive Medicine Department, Manuel Piti Fajardo Surgical Clinical Military Hospital. New Abel Santa María, Santa Clara, ZIP code 50100, Villa Clara, Cuba. 9 Intensive Medicine Department, Octavio de la Concepcion y la Pedraja Military Hospital. Cornelio Porro Street 52, Camagüey, ZIP code 70200, Camagüey, Cuba. Corresponding author: Ricardo Pereda González Medical College of Havana. 23 Street 202, Vedado, Plaza de la Revolución, ZIP code 10400. Havana, Cuba. Email: [email protected] Running title: IFN-α2b treatment in COVID-19 Key words: interferon, COVID-19, SARS-Cov-2 NOTE: This preprint reports new research that has not been certified1 by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.07.28.20157974; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . ABSTRACT Background Effective antiviral treatments are required to contain the ongoing coronavirus disease 2019 (COVID-19) pandemic. A previous report in 814 patients COVID-19 positive in Cuba provided preliminary therapeutic efficacy evidence with interferon-α2b (IFN-α2b) from March 11 to April 14, 2020. This study, re-evaluates the contribution of IFN-α2b on the evolution of all patients, after 98 days of the epidemic, in a period from March 11 to June 17, 2020. Method A prospective observational study was implemented to monitor a therapeutic intervention with IFN-α2b used in the national protocol for COVID-19 attending in Cuba. Were included patients with positive throat swab specimens by real time RT-PCR who gave informed consent and had no contraindications for IFN treatment. Patients received therapy as per the Cuban COVID protocol that included a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN-α2b The primary endpoint was the proportion of patients discharged from hospital, secondary was the case fatality rate and several outcomes related to time variables were also evaluated. Results From March 11th until June 17th, 2295 patients had been confirmed SARS-CoV-2 positive in Cuba, 2165 were treated with Heberon® Alpha R and 130 received the approved protocol without IFN. The proportion of fully recovered patients was higher in the IFN-treated compared with non-IFN treated group. Prior IFN treatment decreases the likelihood of intensive care and increases the survival after severe or critical diseases. The benefits of IFN were significantly supported by time variables analyzed. Conclusions This second report confirm the preliminary evidences from first for the therapeutic effectiveness of IFNα-2b for SARS-Cov-2 infection and postulated that Heberon® Alpha R is the main component within the antiviral triad used as a therapeutic intervention in the Cuban protocol COVID-19. 2 medRxiv preprint doi: https://doi.org/10.1101/2020.07.28.20157974; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . INTRODUCTION The coronavirus disease 2019 (COVID-19) emerged in China in December 20191. The responsible virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to a distinct classification from the human severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV)2. The clinical spectrum of COVID-19 varies from asymptomatic infection or mild symptoms to severe acute respiratory illness and death3. According to the COVID-19 situation report issued by World Health Organization (WHO) on 11th July 2020, COVID-19 pandemic affects more than 213 countries around the world with more than 12 million cases have been diagnosed and over 556 thousand patients have died4. Effective antiviral treatments are required to contain the epidemics; several candidates are already being investigated, including type 1 interferon (IFN-α/)5. At present, a RNA-dependent RNA polymerases (RdRp), remdesivir, is the first medicine against covid-19 approved in the European Union, mainly based on preliminary data from a trial published in the New England Journal of Medicine and limited to patients with severe disease6. Remdesivir has also been approved for emergency use in severely ill patients in the United States (US), India, and South Korea and has received full approval in Japan7. Favipiravir8, an anti-influenza medication that also is an RdRp inhibitor, was approved for medical use in Russia using a generic version named Avifavir. IFN-α, a member of the first line of natural antiviral defense activates the innate immune response against the virus and the mechanism of inhibition of viral replication9. After COVID-19 outbreak, a strong anti-SARS-CoV-2 activity in cultured cells has been reported for IFN-α, demonstrating its therapeutic potency for COVID-1910. Guidelines issued by the expert committee of WHO identified IFN-α2b as a potential antiviral for the treatment and prevention of COVID-1911. Early on in the 3 medRxiv preprint doi: https://doi.org/10.1101/2020.07.28.20157974; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . outbreak, the Chinese government recommended the use of IFN-α for the treatment of COVID- 1912. Several ongoing clinical studies evaluating IFN-α2b for the treatment of COVID-19 are registered at clinicaltrials.gov13 and already provided clinical evidences for therapeutic efficacy14. Heberon® Alpha R is a human recombinant IFN-α2b formulation produced by the Center for Genetic Engineering and Biotechnology, Havana, Cuba, with demonstrated antiviral efficacy and a proven safety profile over 34 years15 and is one of the drugs used in the Cuban protocol16 for the management of COVID-19. A prospective observational study was implemented to monitor therapeutic interventions used in the national protocol for COVID-19 attending in Cuba. The preliminary results in 814 patients included from March 11 to April 14, 2020 was reported previously17 and here we reanalyze the evolution of all patients COVID-19 positive in Cuba and report the efficacy of IFN-α2b after 98 days of the epidemic, a period from March 11 to June 17, 2020. MATERIALS AND METHODS Patients Two groups of individuals were admitted to the hospital, according to the case classification criteria defined in the Cuban protocol: 1) people with suspected COVID-19 due to clinical respiratory symptoms, such as fever, fatigue, cough, headache, shortness of breath and nasal discharge in the last 14 days; 2) subjects who had contact with a patient with confirmed or suspected COVID-19 infection and were followed up for 14 days for possible infection. Each patient had to declare their date of symptom onset. Persons, with or without symptoms, were considered COVID-19 confirmed based on SARS-CoV-2 detected by real time polymerase chain reaction (RT-PCR). 4 medRxiv preprint doi: https://doi.org/10.1101/2020.07.28.20157974; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Treatment Individuals below age 50 without comorbidities and suspected COVID-19 started treatment at day of hospital admission. A combination of oseltamivir 75 mg every 12 hours for five days, azithromycin 500 mg daily for 3 days and IFN-α2b human recombinant (Heberon® Alpha R) by intramuscular injection 3 million IU 3 times per week, for 4 weeks were prescribed. Once individuals were COVID-19 confirmed patients, lopinavir/ritonavir (LPV/RTV) (250 mg, one capsule b.i.d. (500 mg/day) for 30 days and chloroquine (CQ) 150 mg, one tablet twice a day (300 mg/day) for 10 days were introduced and oseltamivir and azithromycin leave off. People with suspected COVID-19 in age 50 or older with or without comorbidities and subjects below age 50 with comorbidities were considered high-risk patient and antiviral treatment initiated directly with LPV/RTV + CQ + IFN-α2b.
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