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      Interferon β-1a for the treatment of Ebola virus disease: A historically controlled, single-arm proof-of-concept trial

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          Abstract

          To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD). Based on our in vitro evidence of antiviral activity of interferon (IFN)-ß activity against Ebola virus, we conducted a single arm clinical study in Guinea to evaluate the safety and therapeutic efficacy of IFN β-1a treatment for EVD. Nine individuals infected with Ebola virus were treated with IFN β-1a and compared retrospectively with a matched cohort of 21 infected patients receiving standardized supportive care only during the same time period at the same treatment unit. Cognizant of the limitations of having treated only 9 individuals with EVD, the data collected are cautiously considered. When compared to supportive care only, IFN β-1a treatment seemed to facilitate viral clearance from the blood and appeared associated with earlier resolution of disease symptoms. Survival, calculated from the date of consent for those in the trial and date of admission from those in the control cohort, to the date of death, was 19% for those receiving supportive care only, compared to 67% for those receiving supportive care plus IFN β-1a. Given the differences in baseline blood viremia between the control cohort and the IFN-treated cohort, an additional 17 controls were included for a subset analysis, from other treatment units in Guinea, matched with the IFN-treated patients based on age and baseline blood viremia. Subset analyses using this expanded control cohort suggests that patients without IFN β-1a treatment were ~ 1.5–1.9 fold more likely to die than those treated. Viewed altogether the results suggest a rationale for further clinical evaluation of IFN β-1a.

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          Most cited references13

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          Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections.

          A passive immunization strategy for treating Ebola virus infections was evaluated using BALB/ c mice, strain 13 guinea pigs, and cynomolgus monkeys. Guinea pigs were completely protected by injection of hyperimmune equine IgG when treatment was initiated early but not after viremia had developed. In contrast, mice were incompletely protected even when treatment was initiated on day 0, the day of virus inoculation. In monkeys treated with one dose of IgG on day 0, onset of illness and viremia was delayed, but all treated animals died. A second dose of IgG on day 5 had no additional beneficial effect. Pretreatment of monkeys delayed onset of viremia and delayed death several additional days. Interferon-alpha2b (2 x 10(7) IU/kg/day) had a similar effect in monkeys, delaying viremia and death by only several days. Effective treatment of Ebola infections may require a combination of drugs that inhibit viral replication in monocyte/macrophage-like cells while reversing the pathologic effects (e.g., coagulopathy) consequent to this replication.
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            Cytokine and chemokine expression in humans infected with Sudan Ebola virus.

            The size and duration of the 2000 outbreak of Sudan Ebola virus (SEBOV) infection in Uganda made it possible to collect serial serum samples from 87 patients (53 survivors and 34 nonsurvivors). Surprisingly, the levels of tumor necrosis factor- alpha and interferon (IFN)- gamma , which had been found to be increased in patients with fatal Zaire Ebola virus infection, were not increased in any of the patients with SEBOV infection. The levels of interleukin (IL)-1 beta , IFN- gamma -inducible protein-10, and RANTES (regulated on activation, normally T cell-expressed and -secreted) were higher in samples from all patients with SEBOV infection than in control samples from healthy hospital staff members, but their levels did not differ between those who survived and those who did not. The levels of IFN- alpha were significantly higher in surviving patients with SEBOV infection, whereas the levels of IL-6, IL-8, IL-10, and macrophage inflammatory protein-1 beta were higher in patients with fatal SEBOV infections.
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              The yin and yang of viruses and interferons

              Interferons (IFNs)-α/β are critical effectors of the innate immune response to virus infections. Through activation of the IFN-α/β receptor (IFNAR), they induce expression of IFN-stimulated genes (ISGs) that encode antiviral proteins capable of suppressing viral replication and promoting viral clearance. Many highly pathogenic viruses have evolved mechanisms to evade an IFN response and the balance between the robustness of the host immune response and viral antagonistic mechanisms determines whether or not the virus is cleared. Here, we discuss IFNs as broad-spectrum antivirals for treatment of acute virus infections. In particular, they are useful for treatment of re-emerging virus infections, where direct-acting antivirals (DAAs) have limited utility due to DAA-resistant mutations, and for newly emerging virus strains in which the time to vaccine availability precludes vaccination at the onset of an outbreak.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 February 2017
                2017
                : 12
                : 2
                : e0169255
                Affiliations
                [1 ]Sustainable Health Foundation (FOSAD), Conakry, Guinea
                [2 ]Center of Excellence for Training on Research and Priority Diseases (CEFORPAG), Conakry, Guinea
                [3 ]Sanofi Genzyme, Cambridge, Massachusetts, United Staes of America
                [4 ]Infectious Disease Ward, National Donka Hospital, Conakry, Guinea
                [5 ]Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany
                [6 ]Department of Biostatistics, University Health Network, Toronto, Canada
                [7 ]Toronto General Research Institute, University Health Network, Toronto, Canada
                [8 ]Department of Immunology, University of Toronto, Toronto, Canada
                Azienda Ospedaliera Universitaria di Perugia, ITALY
                Author notes

                Competing Interests: No sources of commercial funding were provided to support this study. DPB received salary support from Biogen. DPB is presently employed by Sanofi Genzyme, but this employment began after the conclusion of this study. Neither Biogen nor Sanofi Genzyme had a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. These affiliations do not alter our adherence to all PLOS ONE policies on sharing data and materials.

                • Conceptualization: ENF MKK.

                • Formal analysis: ENF MP.

                • Funding acquisition: ENF.

                • Investigation: MKK FAT MSS AC AAB DM AB M3C IK AAR AHB ENF.

                • Methodology: ENF MKK DPB MP.

                • Project administration: ENF MKK.

                • Resources: SG.

                • Supervision: ENF MKK.

                • Validation: ENF MKK SG.

                • Visualization: ENF.

                • Writing – original draft: ENF DPB MP.

                • Writing – review & editing: MKK ENF.

                ¶ Full author list provided in Acknowledgments.

                Article
                PONE-D-16-30273
                10.1371/journal.pone.0169255
                5321269
                28225767
                f2dbdb0a-e50e-4f36-a35d-6ee608e06621
                © 2017 Konde et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 August 2016
                : 13 December 2016
                Page count
                Figures: 3, Tables: 3, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000032, Institute of Infection and Immunity;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Award ID: 666100
                Award Recipient : Stephan Gunther
                This study was supported by a Canadian Institutes of Health Research (Institute of Infection & Immunity) grant to ENF. The funder provided support in the form of salaries for authors [MKK, FAT, MSS, AC, AAB, IK, DM, AB, AAR], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. In addition support was provided by The European Mobile Laboratory (EMLab), a technical partner of the WHO Emerging and Dangerous Pathogens Laboratory Network (EDPLN), and the Global Outbreak Alert and Response Network (GOARN). The work of EMLab was carried out in the context of the projects EVIDENT (Ebola virus disease: correlates of protection, determinants of outcome, and clinical management) that received funding from the European Union’s Horizon 2020 research and innovation program under grant agreements no. 666100, and in the context of service contract IFS/2011/272-372 funded by Directorate-General for International Cooperation and Development. Both Agreement no. 666100 and IFS/2011/272-372 funding support had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Categories
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                Biology and Life Sciences
                Biochemistry
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                Interferons
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