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      Remdesivir for the Treatment of Covid-19 — Final Report

      research-article
        , M.D. , , M.D., M.P.H., , Ph.D., , M.D., , M.D., , M.D., M.P.H., , M.D., , M.D., M.P.H., , M.D., , M.D., M.P.H., , M.D., M.P.H., , M.D., , M.D., M.P.H., , M.D., , M.D., , M.D., , M.D., Ph.D., , M.D., , M.D., M.P.H., , Ph.D.,   , M.B., B.S., , M.D., Ph.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., M.P.H., , M.D., , Ph.D., , Ph.D., , Ph.D., , M.D., M.P.H., , M.S., , M.P.H., M.B.A., , Ph.D., , M.D., M.P.H., , M.D., , M.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_9Keyword part (keyword): Global HealthKeyword part (code): 18_11Keyword part (keyword): Influenza , 18, Infectious Disease, Keyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_9Keyword part (keyword): Global HealthKeyword part (code): 18_11Keyword part (keyword): Influenza , 18_1, Infectious Disease General, 18_6, Viral Infections, 18_9, Global Health, 18_11, Influenza
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          Abstract

          Background

          Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.

          Methods

          We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

          Results

          A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).

          Conclusions

          Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)

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          Most cited references6

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          Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

          Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.
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            Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

            Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.
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              Is Open Access

              Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

              ABSTRACT Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs in vitro and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC50) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC50. The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS-CoV resulted in the same in vitro resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                08 October 2020
                : NEJMoa2007764
                Affiliations
                From the National Institute of Allergy and Infectious Diseases, National Institutes of Health (J.H.B., K.M.T., L.E.D., S.N., H.C.L.), and the Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences (T.H.B.), Bethesda, the Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick (T. Bonnett), and Emmes, Rockville (M.G., M.M.) — all in Maryland; Emory University, Atlanta (A.K.M.); Montefiore Medical Center–Albert Einstein College of Medicine (B.S.Z.) and NYU Langone Health and NYC Health and Hospitals–Bellevue (K.D.), New York; University of Nebraska Medical Center, Omaha (A.C.K., M.G.K.); Massachusetts General Hospital, Boston (E.H.), and University of Massachusetts Medical School, Worcester (R.W.F.); University of Washington, Seattle (H.Y.C.), and Evergreen Health Medical Center, Kirkland (D.L.C.) — both in Washington; University of California, San Francisco, San Francisco (A.L.), Cedars–Sinai Medical Center, Los Angeles (V.T.), University of California, Irvine, Irvine (L.H.), University of California, San Diego, La Jolla (D.A.S.), and Gilead Sciences, Foster City (A.O.) — all in California; University of Minnesota (S.K.) and University of Minnesota School of Public Health and INSIGHT (J.D.N.), Minneapolis; University of Texas Health San Antonio, University Health System, and the South Texas Veterans Health Care System, San Antonio (T.F.P.), and Baylor College of Medicine, Houston (R.L.A.); Hospital Germans Trias i Pujol and irsiCaixa AIDS Research Institute, Badalona, Spain (R.P.); University of Pennsylvania, Philadelphia (W.R.S.); Medical School, National and Kapodistrian University of Athens, Athens (G.T.); National Center for Infectious Diseases–Tan Tock Seng Hospital–Lee Kong Chian School of Medicine–Yong Loo Lin School of Medicine, Singapore, Singapore (D.C.L.); the National Center for Global Health and Medicine Hospital, Tokyo (N.O.); Seoul National University Hospital, Seoul, South Korea (M.O.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (G.M.R.-P.); the Department of Infectious Diseases, Amager Hvidovre Hospital–University of Copenhagen, Hvidovre (T. Benfield), and Rigshospitalet, Department of Infectious Diseases (CHIP) and INSIGHT, Copenhagen (J.L.) — both in Denmark; University Hospital of Cologne, Cologne, Germany (G.F.); Vanderbilt University Medical Center, Nashville (C.B.C.); and University College London, MRC Clinical Trials Unit at UCL and INSIGHT, London (A.G.B., S.P.).
                Author notes
                Address reprint requests to Dr. Beigel at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Ln., Rm. 7E60, MSC 9826, Rockville, MD 20892-9826, or at jbeigel@ 123456niaid.nih.gov .
                [*]

                A complete list of members of the ACTT-1 Study Group is provided in the Supplementary Appendix, available at NEJM.org.

                Author information
                http://orcid.org/0000-0002-4879-4941
                http://orcid.org/0000-0002-6489-6294
                http://orcid.org/0000-0003-0324-0205
                http://orcid.org/0000-0001-9509-1045
                Article
                NJ202010083831902
                10.1056/NEJMoa2007764
                7262788
                32445440
                a890cbca-2c26-45ad-bfc1-7b24a5930477
                Copyright © 2020 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, FundRef http://dx.doi.org/10.13039/100006492;
                Funded by: National Cancer Institute, FundRef http://dx.doi.org/10.13039/100000054;
                Award ID: HHSN261200800001E
                Award ID: HHSN261201500003I
                Funded by: National Institute of Allergy and Infectious Diseases, FundRef http://dx.doi.org/10.13039/100000060;
                Award ID: UM1AI148450
                Award ID: UM1AI148452
                Award ID: UM1AI148573
                Award ID: UM1AI148575
                Award ID: UM1AI148576
                Award ID: UM1AI148684
                Award ID: UM1AI148685
                Award ID: UM1AI148689
                Categories
                Original Article
                Custom metadata
                2020-10-08T17:00:00-04:00
                2020
                10
                08
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