key: cord-1054399-dnewyjry authors: Pereda, R.; Gonzalez, D.; Rivero, H.; Rivero, J.; Perez, A.; Lopez, L. d. R.; Mezquia, N.; Venegas, R.; Betancourt, J.; Dominguez, R. title: Therapeutic effectiveness of interferon-alpha2b against COVID-19: the Cuban experience date: 2020-06-09 journal: nan DOI: 10.1101/2020.05.29.20109199 sha: 61dc63719d62de13c09548192538d45995c23d81 doc_id: 1054399 cord_uid: dnewyjry Background Effective therapies are needed to control the SARS-Cov-2 infection pandemic and reduce mortality associated with COVID-19. Several clinical studies have provided evidence for the antiviral effects of type I interferons (IFNs) in patients with respiratory coronaviruses. This study assessed the therapeutic efficacy of IFN-alpha 2b in patients infected with SARS-CoV-2 during the first month after the outbreak began in Cuba. Method This multicenter prospective observational study was conducted in 16 hospitals in 8 Cuban provinces. Participants were patients with confirmed SARS-CoV-2 infection detected from 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 administration of IFN-alpha 2b (Heberon Alpha R, Center for Genetic Engineering and Biotechnology, Havana), 3 times per week, for 2 weeks. The primary endpoint was the proportion of patients discharged from hospital (without clinical and radiological symptoms and non-detectable virus by RT-PCR). The secondary endpoint was the case fatality rate (CFR), defined as the number of confirmed deaths divided by the number of confirmed cases. Results From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba, 761 (93.4%) were treated with Heberon Alpha R and 53 received the approved protocol without IFN treatment. The proportion of fully recovered patients was higher in the IFN-treated compared with non-IFN treated group (95.4% vs 26.1%, p<0.01). The CFR for all patients was 2.95%, and for those patients who received IFN-alpha 2b the CFR was reduce to 0.92. The estimated global CFR is 6.34% and 4.05% for the Americas reported by WHO and PAHO, respectively. In this study, 82 patients (10.1%) required intensive care and, of these, 42 (5.5%) were treated with IFN. Conclusions This report provides preliminary evidence for the therapeutic effectiveness of IFN alpha-2b for COVID-19 and suggests that the use of Heberon Alpha R may contribute to complete recovery. The clinical spectrum of COVID-19 varies from asymptomatic infection to mild symptoms to severe acute respiratory illness and death 1, 2 . There is an urgent need for antiviral drugs to effectively treat this disease. Due to their antiviral properties and known mechanisms of action, type I interferons (IFN-α/) present as candidate broad spectrum antivirals for global virus outbreaks 3 . In a recent clinical study, evidence was provided that IFN-α2b treatment accelerated viral clearance from the airways and reduced circulating levels of the inflammatory biomarkers IL-6 and CRP in COVID-19 cases 4 . In previous coronavirus epidemics in 2002 (SARS-CoV) and 2012 (MERS-CoV), evidence was provided that coronaviruses encode in their genome factors that specifically block an IFN response, including preventing the activation of MyD88 associated with IFN production and STAT1, associated with IFN signaling 3 . Notably, for both outbreaks, evidence was provided for the antiviral effects of type I IFNs, suggesting that IFN treatment can override the inhibitory effects of coronaviruses 5, 6 . In the absence of a vaccine, a number of candidate antivirals are currently under consideration around the globe. Remdesivir is considered the most promising 7 ; it functions by inhibiting the activity of RNA-dependent RNA polymerases (RdRp). Case studies describing the use of remdesivir for COVID-19 have been reported 8, 9 . Ongoing randomized, controlled clinical trials will evaluate the safety and antiviral efficacy of remdesivir in patients with mild to moderate or severe COVID-19 (NCT04292899, NCT04292730, NCT04257656, NCT04252664, NCT04280705). Favipiravir, an anti-influenza medication that also is an RdRp inhibitor is under investigation for COVID-19, but to date, clinical data suggest limited efficacy 10 . The HIV protease inhibitor lopinavir/ritonavir (LPV/RTV) has seen disappointing outcomes in COVID-19 patients 11 , this despite evidence for LPV/RTV plus ribavirin being effective in vitro against SARS-CoV 12 . The antiviral activities of chloroquine 13 and hydroxychloroquine 14 against SARS-Cov-2, prompted further evaluation in clinical studies, where early data suggest that they may contribute to inhibition of pneumonia exacerbation and shortening of disease course 15 . Guidelines issued by the expert committee of the World Health Organization (WHO) identified IFN-α2b as a potential antiviral for the treatment and prevention of COVID-19 16 . Early on in the outbreak, the Chinese government recommended the use of IFN-α for the treatment of COVID-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 9, 2020. 19 . Herein, we report the first results of the use of Heberon ® Alpha R as part of the Cuban protocol 20 for the management of COVID-19. A multicenter, prospective, observational study was conducted, that included all patients in Cuba Patients with confirmed SARS-CoV-2 infection, who gave informed consent and had no contraindications for IFN treatment described in the product information sheet, received therapy as approved in the Cuban COVID protocol. Namely, a combination of antivirals and intramuscular Heberon ® Alpha R (IFN-α2b, liquid formulation) administration. Antivirals used were lopinavir/ritonavir (Kaletra) (250 mg, one capsule b.i.d. (500 mg/day) for 30 days and chloroquine 150 mg, one tablet twice a day (300 mg/day) for 10 days. IFN treatment was administered by intramuscular injection 3 million IU 3 times per week, for 2 weeks. To treat pediatric cases, the three drugs were adjusted for age and weight or body surface (i.e. IFN: 100.000 IU/Kg). Patients with contraindications or who did not consent to receive IFN were treated with the Cuban protocol lacking IFN, i.e. only lopinavir/ritonavir and chloroquine. For those cases whose disease progressed to become severe and critical, requiring ICU support, treatment with Heberon ® Alpha R was stopped. Addition of Heberon ® Alpha R to the Cuban protocol was approved by the Cuban National Regulatory Authority, CECMED, which maintained surveillance of the scientific evidence All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 9, 2020. . https://doi.org/10.1101/2020.05.29.20109199 doi: medRxiv preprint Data presented are from patient medical records provided by the Cuban Ministry of Public Health, in accordance with the policies established for an investigation in a pandemic scenario. A qualitative real time polymerase chain reaction (RT-PCR) for SARS-CoV-2 was performed. Throat swab specimens from the upper respiratory tract of patients were placed into collection tubes prefilled with 150 μL of virus preservation solution, and total RNA was extracted using Hematological and biochemical profiles were assessed at admission and every 72 hours using routine clinical laboratory procedures. The primary endpoint was the proportion of patients discharged from hospital (i.e. discharge criteria were the absence of clinical and radiological symptoms and non-detectable virus, as determined by 2 consecutive PCR(-)s at least 24 hours apart. The secondary endpoint was the case fatality rate, (CFR), defined as the number of confirmed deaths divided by the number of confirmed cases. Descriptive statistics were used to estimate the measures of central tendency and dispersion (media and extreme values) in demographic characteristics. The association between qualitative variables was analyzed using contingency tables. For the comparison of proportions the Fisher exact test calculator was used. The odds ratio (OR) was applied as a measure of association between treatments and outcomes. The non-parametric Mann-Whitney U test was used for comparing independents samples. All confirmed patients with COVID-19 in Cuba during the period March 11 th to April 14 th 2020 were included in this study. The Cuban protocol 20 for clinical management of COVID-19 was initiated on March 11 th , 2020, concomitant with the diagnosis of the first three patients in the country. By All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 9, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 9, 2020. . https://doi.org/10.1101/2020.05.29.20109199 doi: medRxiv preprint p<0.01). According to the Odds Ratio estimation, an individual treated with Heberon ® Alpha R had a 58.7 times greater advantage to achieve recovery. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 9, 2020. . https://doi.org/10.1101/2020.05.29.20109199 doi: medRxiv preprint 8 since those critical patients not treated with IFN (48.6%) did not survive, compared to 21.9% of the IFN-treated patient who did survive (p<0.05). In this study the median age was higher in those patients that did not receive IFN. Despite this, data analysis revealed that age was not a variable that negated the effects of IFN treatment. Notably, the CFR of COVID-19 by age was consistent with data from other countries that suggest that the elderly are at greater risk for severe disease and death 13 . In our study, 22 of the 24 (91.7%) fatalities, were older than 44.3 years and 19 (79.2%) were older than 55 years. There were more deaths among males: 16 males compared with 8 females. Our data indicate that the estimated CFR in males with comorbidities is higher for individuals above the age of 45 years: 16.5 times greater likelihood of death. Irrespective of age, CFRs for those with comorbidities is much higher (87.5% vs 0.52%). In our study cohort, 7 (1.8%) of those under 45 years of age and 47 (11.4%) older had co-morbidities. Those individuals with comorbidities died: 21 (38.9%), compared to those with no co-morbidity 3 (0.39%). Elderly age and arterial hypertension represented the major risk predictors for death; in patients over 55 years, this increased from 4.9% to 38.9%. The lower incidence of comorbidities in the IFN-treated patients may have contributed to their 4.34-fold greater survival advantage compared with those had not been treated with IFN (Table 1 ). However, this advantage disappears in the subgroup of 28 patients with high blood pressure. High blood pressure was a comorbidity in 27 (32.9%) of the 82 patients who required intensive care. After adjusting for demographic characteristics, the IFN-related CFR was affected by comorbidity (p=1 x 10 -4 ) and age (p=0.02) and remained significant regardless of sex (p=0.29). The limitations of this open, non-randomized observational study include unbalanced demographics between treatment arms of unequal size. Nevertheless, the purpose of this study was to rapidly evaluate if inclusion of IFN-α2b at the doses and therapeutic regimen employed, offered a therapeutic benefit to COVID-19 cases. Recent publications suggest that treatment with chloroquine 16 or lopinavir/ritonavir 11 may offer little therapeutic benefit in COVID-19. With this information, we postulate that IFN treatment is likely the active antiviral in the regimen employed. Regardless of the identified limitations, therefore, our findings suggest that IFN-α2b treatment may be effective for the treatment of COVID-19 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 9, 2020. . https://doi.org/10.1101/2020.05.29.20109199 doi: medRxiv preprint The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Clinical presentation and course of COVID-19 Global virus outbreaks: interferons as 1st responders Interferon-α2b treatment for COVID-19 Interferon alfacon-1plus corticosteroids in severe acute respiratory syndrome Interferon-ß and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays Treatment options for COVID-19: The reality and challenges Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. medRxiv. Preprint posted March 9 Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) A Review A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19 Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Clinical management of severe acute respiratory infection when novel coronavirus ( 2019-nCoV) infection is suspected: interim guidance Chinese Guidelines Related to Novel Coronavirus Pneumonia A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19 Cuban interferon alpha-2b. Thirty years as an effective and safe drug Portal of the Cuban Health Network. (w.d.). Cuban Protocol against COVID 19. Ministry of Public Health Ministry of Public Health Closing part of the day April 14 at 12 midnight Coronavirus disease (COVID-2019) situation reports-85 Cumulative suspected and confirmed COVID-19 cases reported by countries and territories in the Americas Pan American Health Organization The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted June 9, 2020. . https://doi.org/10.1101/2020.05.29.20109199 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted June 9, 2020. . https://doi.org/10.1101/2020.05.29.20109199 doi: medRxiv preprint