Browsing by Subject "Antiviral Agents"

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    Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial
    (AMA, 2021-06-03) Cohen, Myron S.; Nirula, Ajay; Mulligan, Mark J.; Novak, Richard M.; Marovich, Mary; Yen, Catherine; Stemer, Alexander; Mayer, Stockton M.; Wohl, David; Brengle, Blair; Montague, Brian T.; Frank, Ian; McCulloh, Russell J.; Fichtenbaum, Carl J.; Lipson, Brad; Gabra, Nashwa; Ramirez, Julio A.; Thai, Christine; Chege, Wairimu; Gomez Lorenzo, Margarita M.; Sista, Nirupama; Farrior, Jennifer; Clement, Meredith E.; Brown, Elizabeth R.; Custer, Kenneth L.; Van Naarden, Jacob; Adams, Andrew C.; Schade, Andrew E.; Dabora, Matan C.; Knorr, Jack; Price, Karen L.; Sabo, Janelle; Tuttle, Jay L.; Klekotka, Paul; Shen, Lei; Skovronsky, Daniel M.; IU School of Medicine-Northwest
    Importance Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. Objective To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. Design, Setting, and Participants Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. Interventions Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). Main Outcomes and Measures The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase–polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. Results The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; odds ratio, 0.43 [95% CI, 0.28-0.68]; P < .001; absolute risk difference, −6.6 [95% CI, −10.7 to −2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). Conclusions and Relevance Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy.
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    Ethics guide for health care practitioners: working under conditions of an influenza pandemic. Plan, Prepare, Practice [Pocket version].
    (2009-12-01T18:49:23Z) Indiana University Center for Bioethics; Indiana State Department of Health
    The Ethics Toolkit is designed to assist health care providers in carrying out their ethical responsibilities of caring for patients and families within the clinical environment during an influenza pandemic. In particular, the Toolkit is designed to give practical input on key issues facing health care practitioners, specifically: Altered Standards of Care; Vaccine and Antiviral Provision; Triage; and Workforce Management. Other issues are discussed in the Toolkit, but receive less comprehensive attention. The input for each of these issues is based on an Ethical Framework that provides a reasoned basis for decision making. In addition to this pocket-sized version, a 16 page, full-sized, color brochure is also available. Likewise, a separate, single sheet, "Patient Guide" (page 15) is available.
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    Ethics guide for health care practitioners: working under conditions of an influenza pandemic. Plan, prepare, practice.
    (2009-12-01T18:37:50Z) Indiana University Center for Bioethics; Indiana State Department of Health
    The Ethics Toolkit is designed to assist health care providers in carrying out their ethical responsibilities of caring for patients and families within the clinical environment during an influenza pandemic. In particular, the Toolkit is designed to give practical input on key issues facing health care practitioners, specifically: Altered Standards of Care; Vaccine and Antiviral Provision; Triage; and Workforce Management. Other issues are discussed in the Toolkit, but receive less comprehensive attention. The input for each of these issues is based on an Ethical Framework that provides a reasoned basis for decision making. In addition to this full sized, 16 page color brochure, the Toolkit is also available in a pocket-sized version. Likewise, a separate, single sheet, "Patient Guide" (page 15) is available.
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    The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion
    (American Society for Microbiology, 2015-09-15) Yan, Ran; Zhao, Xuesen; Cai, Dawei; Liu, Yuanjie; Block, Timothy M.; Guo, Ju-Tao; Guo, Haitao; Microbiology and Immunology, School of Medicine
    Interferon alpha (IFN-α) is an approved medication for chronic hepatitis B therapy. Besides acting as an immunomodulator, IFN-α elicits a pleiotropic antiviral state in hepatitis B virus (HBV)-infected hepatocytes, but whether or not IFN-α impedes the late steps of the HBV life cycle, such as HBV secretion, remains elusive. Here we report that IFN-α treatment of HepAD38 cells with established HBV replication selectively reduced HBV virion release without altering intracellular viral replication or the secretion of HBV subviral particles and nonenveloped capsids. In search of the interferon-stimulated gene(s) that is responsible for the reduction of HBV virion release, we found that tetherin, a broad-spectrum antiviral transmembrane protein that inhibits the egress of a variety of enveloped viruses, was highly induced by IFN-α in HepAD38 cells and in primary human hepatocytes. We further demonstrated that the expression of full-length tetherin, but not the C-terminal glycosylphosphatidylinositol (GPI) anchor-truncated form, inhibited HBV virion egress from HepAD38 cells. In addition, GPI anchor-truncated tetherin exhibited a dominant-negative effect and was incorporated into the liberated virions. We also found colocalization of tetherin and HBV L protein at the intracellular multivesicular body, where the budding of HBV virions takes place. In line with this, electron microscopy demonstrated that HBV virions were tethered in the lumen of the cisterna membrane under tetherin expression. Finally, knockdown of tetherin or overexpression of dominant negative tetherin attenuated the IFN-α-mediated reduction of HBV virion release. Taken together, our study suggests that IFN-α inhibits HBV virion egress from hepatocytes through the induction of tetherin. IMPORTANCE: Tetherin is a host restriction factor that blocks the egress of a variety of enveloped viruses through tethering the budding virions on the cell surface with its membrane anchor domains. Here we report that interferon directly and selectively inhibits the secretion of HBV virions, but not subviral particles or nonenveloped capsids, through the induction of tetherin in hepatocyte-derived cells. The antiviral function of tetherin requires the carboxyl-terminal GPI anchor, while the GPI anchor deletion mutant exhibits dominant negative activity and attaches to liberated HBV virions. Consistent with the fact that HBV is an intracellular budding virus, microscopy analyses demonstrated that the tethering of HBV virions occurs in the intracellular cisterna and that tetherin colocalizes with HBV virions on the multivesicular body, which is the HBV virion budding site. Our study not only expands the antiviral spectrum of tetherin but also sheds light on the mechanisms of interferon-elicited anti-HBV responses.
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    Interferon-inducible ribonuclease ISG20 inhibits hepatitis B virus replication through directly binding to the epsilon stem-loop structure of viral RNA
    (PLOS, 2017-04-11) Liu, Yuanjie; Nie, Hui; Mao, Richeng; Mitra, Bidisha; Cai, Dawei; Yan, Ran; Guo, Ju-Tao; Block, Timothy M.; Mechti, Nadir; Guo, Haitao; Microbiology and Immunology, School of Medicine
    Hepatitis B virus (HBV) replicates its DNA genome through reverse transcription of a viral RNA pregenome. We report herein that the interferon (IFN) stimulated exoribonuclease gene of 20 KD (ISG20) inhibits HBV replication through degradation of HBV RNA. ISG20 expression was observed at basal level and was highly upregulated upon IFN treatment in hepatocytes, and knock down of ISG20 resulted in elevation of HBV replication and attenuation of IFN-mediated antiviral effect. The sequence element conferring the susceptibility of HBV RNA to ISG20-mediated RNA degradation was mapped at the HBV RNA terminal redundant region containing epsilon (ε) stem-loop. Furthermore, ISG20-induced HBV RNA degradation relies on its ribonuclease activity, as the enzymatic inactive form ISG20D94G was unable to promote HBV RNA decay. Interestingly, ISG20D94G retained antiviral activity against HBV DNA replication by preventing pgRNA encapsidation, resulting from a consequence of ISG20-ε interaction. This interaction was further characterized by in vitro electrophoretic mobility shift assay (EMSA) and ISG20 was able to bind HBV ε directly in absence of any other cellular proteins, indicating a direct ε RNA binding capability of ISG20; however, cofactor(s) may be required for ISG20 to efficiently degrade ε. In addition, the lower stem portion of ε is the major ISG20 binding site, and the removal of 4 base pairs from the bottom portion of ε abrogated the sensitivity of HBV RNA to ISG20, suggesting that the specificity of ISG20-ε interaction relies on both RNA structure and sequence. Furthermore, the C-terminal Exonuclease III (ExoIII) domain of ISG20 was determined to be responsible for interacting with ε, as the deletion of ExoIII abolished in vitro ISG20-ε binding and intracellular HBV RNA degradation. Taken together, our study sheds light on the underlying mechanisms of IFN-mediated HBV inhibition and the antiviral mechanism of ISG20 in general.
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    Patient guide: Questions and answers about Altered Standards of Care. Plan, prepare, practice.
    (2009-12-01T18:57:14Z) Indiana State Department of Health; Indiana University Center for Bioethics
    This patient guide address the following questions: What is an influenza (flu) pandemic? What are Altered Standards of Care? Will vaccines ("flu shot") and antiviral medicines work? and How will my family and I get vaccines and antiviral medicine? In addition to this patient guide, see the related: "Ethics guide for health care practitioners: working under conditions of an influenza pandemic. Plan, Prepare, Practice."