Effect of early #oseltamivir #treatment on #mortality in critically ill patients with different types of #influenza: a multi-season cohort study (Clin Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Clin Infect Dis. 2019 Feb 7. doi: 10.1093/cid/ciz101. [Epub ahead of print]

Effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study.

Lytras T1, Mouratidou E1,2, Andreopoulou A1, Bonovas S3,4, Tsiodras S1,5.

Author information: 1 Hellenic Centre for Disease Control and Prevention, Athens, Greece. 2 European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden. 3 Department of Biomedical Sciences, Humanitas University, Milan, Italy. 4 Humanitas Clinical and Research Center, Milan, Italy. 5 4th Department of Internal Medicine, Attikon University Hospital, University of Athens Medical School, Athens, Greece.

 

Abstract

BACKGROUND:

The available evidence on whether neuraminidase inhibitors reduce mortality in patients with influenza is inconclusive, and focuses solely on influenza A/H1N1pdm09. We assessed whether early oseltamivir treatment (≤48 hours from symptom onset) decreases mortality compared to late treatment in a large cohort of critically ill patients with influenza of all types.

METHODS:

The study included all adults with laboratory-confirmed influenza hospitalized in intensive care units (ICU) in Greece over eight seasons (2010-2011 to 2017-2018) and treated with oseltamivir. The association of early oseltamivir with mortality was assessed with log-binomial models, and a competing risks analysis estimating cause-specific and subdistribution hazards for death and discharge. Effect estimates were stratified by influenza type and adjusted for multiple covariates.

RESULTS:

1330 patients were studied, of whom 622 (46.8%) died in the ICU. Among patients with influenza A/H3N2, early treatment was associated with significantly lower mortality (Relative Risk 0.69, 95% CrI 0.49-0.94; subdistribution Hazard Ratio 0.58, 95% CrI 0.37-0.88). This effect was purely due to an increased cause-specific hazard for discharge, while the cause-specific hazard for death was not increased. Among survivors, the median length of ICU stay was shorter with early treatment by 1.8 days (95% CrI 0.5-3.5). No effect on mortality was observed for A/H1N1 and influenza B patients.

CONCLUSIONS:

Severely ill patients with suspected influenza should be promptly treated with oseltamivir, particularly when A/H3N2 is circulating. The efficacy of oseltamivir should not be assumed to be equal against all types of influenza.

PMID: 30753349 DOI: 10.1093/cid/ciz101

Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Antivirals; Oseltamivir.

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Annual #report on #influenza viruses received and tested by the #Melbourne #WHO CC for #Reference and Research on Influenza in 2016 (Commun Dis Intell (2018), abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Commun Dis Intell (2018). 2019 Feb 1;43. doi: 10.33321/cdi.2019.43.5.

Annual report on influenza viruses received and tested by the Melbourne WHO Collaborating Centre for Reference and Research on Influenza in 2016

Leung VK1, Deng YM1, Kaye M1, Leang SK1, Gillespie L1, Chow MK1.

Author information: 1 WHO Collaborating Centre for Reference and Research on Influenza

 

Abstract

As part of its role in the World Health Organization’s (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 4,247 human influenza positive samples during 2016. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties and also propagated in qualified cells and hens eggs for potential seasonal influenza vaccine virus candidates. In 2016, influenza A(H3) viruses predominated over influenza A(H1)pdm09 and B viruses, accounting for a total of 51% of all viruses analysed. The vast majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2016. However, phylogenetic analysis of a selection of viruses indicated that the majority of circulating A(H3) viruses had undergone some genetic drift relative to the WHO recommended strain for 2016. Of more than 3,000 samples tested for resistance to the neuraminidase inhibitors oseltamivir and zanamivir, six A(H1)pdm09 viruses and two B/Victoria lineage viruses showed highly reduced inhibition to oseltamivir.

© Commonwealth of Australia CC BY-NC-ND

PMID: 30739429

Keywords: Seasonal Influenza; Vaccines; Antivirals; Drugs Resistance; Australia.

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#AZT acts as an anti- #influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/ #H1N1 RNA dependent RNA #polymerase (J Comput Aided Mol Des., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Comput Aided Mol Des. 2019 Feb 9. doi: 10.1007/s10822-019-00189-w. [Epub ahead of print]

AZT acts as an anti-influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/H1N1 RNA dependent RNA polymerase.

Pagadala NS1,2,3,4.

Author information: 1 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 2 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 3 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 4 Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, T6G 2E1, Canada. nattu251@gmail.com.

 

Abstract

To develop potent drugs that inhibit the activity of influenza virus RNA dependent RNA polymerase (RdRp), a set of compounds favipiravir, T-705, T-1105 and T-1106, ribavirin, ribavirin triphosphate viramidine, 2FdGTP (2′-deoxy-2′-fluoroguanosine triphosphate) and AZT-TP (3′-Azido-3′-deoxy-thymidine-5′-triphosphate) were docked with a homology model of IAV RdRp from the A/PR/8/34/H1N1 strain. These compounds bind to four pockets A-D of the IAV RdRp with different mechanism of action. In addition, AZT-TP also binds to the PB1 catalytic site near to the tip of the priming loop with a highest ΔG of - 16.7 Kcal/mol exhibiting an IC50 of 1.12 µM in an in vitro enzyme transcription assay. This shows that AZT-TP mainly prevents the incorporation of incoming nucleotide involved in initiation of vRNA replication. Conversely, 2FdGTP used as a positive control binds to pocket-B at the end of tunnel-II with a highest ΔG of - 16.3 Kcal/mol inhibiting chain termination with a similar IC50 of 1.12 µM. Overall, our computational results in correlation with experimental studies gives information for the first time about the binding modes of the known influenza antiviral compounds in different models of vRNA replication by IAV RdRp. This in turn gives new structural insights for the development of new therapeutics exhibiting high specificity to the PB1 catalytic site of influenza A viruses.

KEYWORDS: Catalytic site; Docking; Nucleotide triphosphates; RNA dependent RNA polymerase

PMID: 30739239 DOI: 10.1007/s10822-019-00189-w

Keywords: Influenza A; H1N1; Antivirals; AZT; Ribavirin; Favipiravir.

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#Filovirus #Virulence in #Interferon α/β and γ Double Knockout Mice, and #Treatment with #Favipiravir (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Feb 3;11(2). pii: E137. doi: 10.3390/v11020137.

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir.

Comer JE1,2,3,4, Escaffre O5, Neef N6, Brasel T7,8,9, Juelich TL10, Smith JK11, Smith J12, Kalveram B13, Perez DD14, Massey S15, Zhang L16, Freiberg AN17,18,19,20.

Author information: 1 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 2 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 3 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 4 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 5 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. olescaff@utmb.edu. 6 Experimental Pathology Laboratories, Inc., Sterling, VA 20167, USA. nneef@7thwavelabs.com. 7 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 8 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 9 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 10 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. tljuelic@utmb.edu. 11 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jeksmith@UTMB.EDU. 12 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jensmit1@utmb.edu. 13 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. bkkalver@utmb.edu. 14 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. dadperez@tamu.edu. 15 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. chmassey@utmb.edu. 16 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. lihzhang@utmb.edu. 17 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 18 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 19 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 20 Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu.

 

Abstract

The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10-1 pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 10² pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.

KEYWORDS: Ebola virus; filovirus; interferon receptor knockout; mouse

PMID: 30717492 DOI: 10.3390/v11020137 Free full text

Keywords: Filovirus; Ebola; Marburg; Ebola Bundibugyo; Tai Forest Virus; Favipiravir; Antivirals; Animal models.

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Evaluating Promising #Investigational #Medical #Countermeasures: #Recommendations in the Absence of #Guidelines (Health Secur., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Health Secur. 2019 Feb 6. doi: 10.1089/hs.2018.0092. [Epub ahead of print]

Evaluating Promising Investigational Medical Countermeasures: Recommendations in the Absence of Guidelines.

Bhadelia N1, Sauer L2, Cieslak TJ3, Davey RT4, McLellan S5, Uyeki TM6, Kortepeter MG7; National Ebola Training and Education Center’s Special Pathogens Research Network (SPRN)’s Medical Countermeasures Working Group.

Collaborators (12): Akers M, Dierberg K, Eiras D, Evans J, Figueroa E, Kraft C, Kratochvil C, Martins K, Measer G, Mehta A, Hu-Primmer J, Risi G.

Author information: 1 Nahid Bhadelia, MD, MA, is Medical Director, Special Pathogens Unit, Section of Infectious Diseases, Boston University School of Medicine, Boston, MA. 2 Lauren Sauer, MS, is Assistant Professor, Director of Research, Johns Hopkins Biocontainment Unit, Department of Emergency Medicine, Johns Hopkins Medicine, Baltimore, MD. 3 Theodore J. Cieslak, MD, MPH, is Associate Professor, Department of Epidemiology, University of Nebraska College of Public Health, Omaha, NE. 4 Richard T. Davey, MD, is Deputy Clinical Director, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD. 5 Susan McLellan, MD, MPH, is Medical Director, Biocontainment Treatment Unit, Division of Infectious Diseases, University of Texas Medical Branch at Galveston, TX. 6 Timothy M. Uyeki, MD, MPH, MPP, is Chief Medical Officer, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA. 7 Mark G. Kortepeter, MD, MPH, is Professor, Department of Epidemiology, University of Nebraska College of Public Health, Omaha, NE.

 

Abstract

Emerging and re-emerging infectious diseases pose growing global public health threats. However, research on and development of medical countermeasures (MCMs) for such pathogens is limited by the sporadic and unpredictable nature of outbreaks, lack of financial incentive for pharmaceutical companies to develop interventions for many of the diseases, lack of clinical research capacity in areas where these diseases are endemic, and the ethical dilemmas related to conducting scientific research in humanitarian emergencies. Hence, clinicians providing care for patients with emerging diseases are often faced with making clinical decisions about the safety and effectiveness of experimental MCMs, based on limited or no human safety, preclinical, or even earlier product research or historical data, for compassionate use. Such decisions can have immense impact on current and subsequent patients, the public health response, and success of future clinical trials. We highlight these dilemmas and underscore the need to proactively set up procedures that allow early and ethical deployment of MCMs as part of clinical trials. When clinical trials remain difficult to deploy, we present several suggestions of how compassionate use of off-label and unlicensed MCMs can be made more informed and ethical. We highlight several collaborations seeking to address these gaps in data and procedures to inform future clinical and public health decision making.

KEYWORDS: Drug development; Ebola; Emerging infectious diseases; Ethics; Medical countermeasures; Outbreaks

PMID: 30724616 DOI: 10.1089/hs.2018.0092

Keywords: Infectious Diseases; Emerging Diseases; Antivirals; Vaccines.

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#Influenza virus #polymerase #inhibitors in #clinical development (Curr Opin Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Curr Opin Infect Dis. 2019 Feb 4. doi: 10.1097/QCO.0000000000000532. [Epub ahead of print]

Influenza virus polymerase inhibitors in clinical development.

Hayden FG1, Shindo N2.

Author information: 1 Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA. 2 Health Emergencies Program, World Health Organization, Geneva, Switzerland.

 

Abstract

PURPOSE OF REVIEW:

We review antivirals inhibiting subunits of the influenza polymerase complex that are advancing in clinical development.

RECENT FINDINGS:

Favipiravir, pimodivir, and baloxavir are inhibitory in preclinical models for influenza A viruses, including pandemic threat viruses and those resistant to currently approved antivirals, and two (favipiravir and baloxavir) also inhibit influenza B viruses. All are orally administered, although the dosing regimens vary. The polymerase basic protein 1 transcriptase inhibitor favipiravir has shown inconsistent clinical effects in uncomplicated influenza, and is teratogenic effects in multiple species, contraindicating its use in pregnancy. The polymerase basic protein 2 cap-binding inhibitor pimodivir displays antiviral effects alone and in combination with oseltamivir in uncomplicated influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Single doses of the polymerase acidic protein cap-dependent endonuclease inhibitor baloxavir are effective in alleviating symptoms and rapidly inhibiting viral replication in otherwise healthy and higher risk patients with acute influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Combinations of newer polymerase inhibitors with neuraminidase inhibitors show synergy in preclinical models and are currently undergoing clinical testing in hospitalized patients.

SUMMARY:

These new polymerase inhibitors promise to add to the clinical management options and overall control strategies for influenza virus infections.

PMID: 30724789 DOI: 10.1097/QCO.0000000000000532

Keywords: Antivirals; Drugs Resistance; Influenza A; Pandemic Influenza; Favipiravir; Pimodivir; Baloxavir.

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Beyond Members of the #Flaviviridae Family, #Sofosbuvir Also Inhibits #Chikungunya Virus Replication (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Beyond Members of the Flaviviridae Family, Sofosbuvir Also Inhibits Chikungunya Virus Replication

André C. Ferreira, Patrícia A. Reis, Caroline S. de Freitas, Carolina Q. Sacramento, Lucas Villas Bôas Hoelz, Mônica M. Bastos, Mayara Mattos, Natasha Rocha,Isaclaudia Gomes de Azevedo Quintanilha, Carolina da Silva Gouveia Pedrosa, Leticia Rocha Quintino Souza, Erick Correia Loiola, Pablo Trindade, Yasmine Rangel Vieira,Giselle Barbosa-Lima, Hugo C. de Castro Faria Neto, Nubia Boechat, Stevens K. Rehen, Karin Brüning, Fernando A. Bozza, Patrícia T. Bozza, Thiago Moreno L. Souza

DOI: 10.1128/AAC.01389-18

 

ABSTRACT

Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir than were hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg of body weight/day and prevented mortality in a neonate mouse model at 40- and 80-mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Alphavirus; Chikungunya fever; Antivirals; Sofosbuvir.

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