#Antiviral activity of #ribavirin and #favipiravir against #human #astroviruses (J Clin Virol., abstract)

[Source: Journal of Clinical Virology, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 17 December 2019, 104247 / In Press, Journal Pre-proof / Short communication

Antiviral activity of ribavirin and favipiravir against human astroviruses

Andrew B Janowski a, Holly Dudley a, David Wang b,c

{a} Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA; {b} Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA; {c} Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

Received 18 October 2019, Revised 9 December 2019, Accepted 16 December 2019, Available online 17 December 2019.

DOI: https://doi.org/10.1016/j.jcv.2019.104247

 

Highlights

  • Ribavirin inhibits replication of astrovirus VA1 and classic human astrovirus 4.
  • Replication of astrovirus VA1 is reduced by favipiravir.
  • No significant cytotoxicity was detected for favipiravir or ribavirin.

 

Abstract

Background

Recent recognition of invasive astrovirus infections, including encephalitis and viremia in humans, have highlighted the need for effective anti-astrovirus therapeutics. However, there is a paucity of data regarding the in vitro activity of broad-spectrum RNA antivirals against astroviruses, including ribavirin and favipiravir.

Objectives

We quantified the EC50 values for ribavirin and favipiravir against two human astrovirus strains, astrovirus VA1 (VA1) and human astrovirus 4 (HAstV4).

Study Design

Caco-2 cells were infected with VA1 or HAstV4 in the presence of ribavirin or favipiravir (dose range 0.1-1000 μM), and the cells were maintained in media containing the drugs for 72 hours. Viral RNA was extracted and quantified by qRT-PCR. As a surrogate for cytotoxicity, cellular adenosine triphosphate (ATP) from each drug treatment was also measured.

Results

VA1 replication was inhibited 10-100-fold by both ribavirin (EC50 = 154μM) and favipiravir (EC50 = 246 μM). In contrast, ribavirin inhibited HAstV4 replication (EC50 = 268 μM) but favipiravir only reduced replication by 44% at the highest dose. Mild reductions in ATP (17-31%) was only observed at the highest concentration of ribavirin (1000 μM) and no significant decrease in ATP was detected for any concentration of favipiravir.

Conclusions

Ribavirin inhibited both human astrovirus species and favipiravir was only active against VA1. In the future, the in vivo efficacy of these drugs could be tested with development of an animal model of human astrovirus infection

Keywords: Astroviruses – astrovirus VA1 – classic human astrovirus – ribavirin – favipiravir – antiviral

© 2019 Elsevier B.V. All rights reserved.

Keywords: Antivirals; Ribavirin; Favipiravir; Astrovirus.

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Comparative effectiveness of combined #favipiravir and #oseltamivir #therapy versus oseltamivir monotherapy in critically ill patients with #influenza virus infection (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection

Yeming Wang, Guohui Fan, Alex Salam, Peter Horby, Frederick G Hayden, Cheng Chen, Jianguang Pan, Jing Zheng, Binghuai Lu, Liping Guo, Chen Wang, Bin Cao, CAP-China Network

The Journal of Infectious Diseases, jiz656, https://doi.org/10.1093/infdis/jiz656

Published: 11 December 2019

 

Abstract

Background

A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in pre-clinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza.

Methods

Data from two separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes includes rate of clinical improvement, defined as a decrease of 2 categories on a 7-category ordinal scale, and viral RNA detectability over time. Sub-hazard ratio (sHR) was estimated by Fine and Gray model for competing risks.

Results

In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on Day 14 occurred in the combination group was higher than in monotherapy group (62.5% vs 42.2%, p=0.0247). The adjusted sHR for combination therapy was 2.06 (95%CI: 1.3-3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than oseltamivir group (67.5% vs 21.9%, p<0.01). No significant differences were observed in mortality or other outcomes.

Conclusions

Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial.

Topic: influenza – combined modality therapy – critical illness – orthomyxoviridae – infection – oseltamivir – comparative effectiveness research – favipiravir

Issue Section: Major Article

This content is only available as a PDF.

Keywords: Influenza A; Antivirals; SARI; Oseltamivir; Favipiravir.

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A meta-analysis of #clinical #studies conducted during the West #Africa #Ebola virus disease #outbreak confirms the need for randomized control groups (Sci Transl Med., abstract)

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

Sci Transl Med. 2019 Nov 27;11(520). pii: eaaw1049. doi: 10.1126/scitranslmed.aaw1049.

A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups.

Dodd LE1,2, Follmann D3, Proschan M3, Wang J4, Malvy D5,6, van Griensven J7, Ciglenecki I8, Horby PW9, Ansumana R10,11, Jiang JF12, Davey RT13, Lane HC14, Gouel-Cheron A3,15.

Author information: 1 Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. doddl@mail.nih.gov. 2 School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 3 Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 4 Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD, USA. 5 Inserm, UMR 1219, Université de Bordeaux, Bordeaux, France. 6 Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 7 Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium. 8 Operational Centre Geneva, Médecins Sans Frontières, 1211 Geneva, Switzerland. 9 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 10 Mercy Hospital Research Laboratory, Kulanda Town, Bo, Sierra Leone. 11 School of Community Health Sciences, Njala University, Bo, Sierra Leone. 12 Beijing Institute of Microbiology and Epidemiology, Beijing, China. 13 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 14 Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 15 Anesthesiology and Intensive Care Department, Hopital Bichat-Claude Bernard, Assistance Publique-Hopitaux de Paris, Paris, France.

 

Abstract

Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013-2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PMID: 31776287 DOI: 10.1126/scitranslmed.aaw1049

Keywords: Antivirals; Favipiravir; Serotherapy; ZMapp; Monoclonal antibodies; Ebola; West Africa.

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Reevaluation of the efficacy of #favipiravir against #rabies virus using in vivo imaging analysis (Antiviral Res., abstract)

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

Antiviral Res. 2019 Oct 28:104641. doi: 10.1016/j.antiviral.2019.104641. [Epub ahead of print]

Reevaluation of the efficacy of favipiravir against rabies virus using in vivo imaging analysis.

Yamada K1, Noguchi K2, Kimitsuki K3, Kaimori R3, Saito N3, Komeno T4, Nakajima N4, Furuta Y4, Nishizono A5.

Author information: 1 Research Promotion Institute, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan. 2 Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan; Department of Food Science and Technology, Minami Kyushu University, 5-1-2 Kirishima, Miyazaki City, Miyazaki, 880-0031, Japan. 3 Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan. 4 FUJIFILM Toyama Chemical Co.,Ltd, 2-4-1 Shimookui, Toyama City, Toyama, 930-8508, Japan. 5 Research Promotion Institute, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan; Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan. Electronic address: a24zono@oita-u.ac.jp.

 

Abstract

Rabies virus (RABV) is a highly neurotropic virus and the causative agent of rabies, an encephalitis with an almost 100% case-fatality rate that remains incurable after the onset of symptoms. Favipiravir (T-705), a broad-spectrum antiviral drug against RNA viruses, has been shown to be effective against RABV in vitro but ineffective in vivo. We hypothesized that favipiravir is effective in infected mice when RABV replicates in the peripheral tissues/nerves but not after virus neuroinvasion. We attempted to clarify this point in this study using in vivo bioluminescence imaging. We generated a recombinant RABV from the field isolate 1088, which expressed red firefly luciferase (1088/RFLuc). This allowed semiquantitative detection and monitoring of primary replication at the inoculation site and viral spread in the central nervous system (CNS) in the same mice. Bioluminescence imaging revealed that favipiravir (300 mg/kg/day) treatment commencing 1 h after intramuscular inoculation of RABV efficiently suppressed viral replication at the inoculation site and the subsequent replication in the CNS. However, virus replication in the CNS was not inhibited when the treatment began 2 days after inoculation. We also found that higher doses (600 or 900 mg/kg/day) of favipiravir could suppress viral replication in the CNS even when administration started 2 days after inoculation. These results support our hypothesis and suggest that a highly effective drug-delivery system into the CNS and/or the enhancement of favipiravir conversion to its active form are required to improve favipiravir treatment of rabies. Furthermore, the bioluminescence imaging system established in this study will facilitate the development of treatment for symptomatic rabies.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Favipiravir; In vivo bioluminescence imaging; Rabies virus; Red firefly luciferase

PMID: 31672666 DOI: 10.1016/j.antiviral.2019.104641

Keywords: Antivirals; Favipiravir; Rabies; Neuroinvasion.

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Severe fever with thrombocytopenia syndrome (#SFTS) treated with a novel #antiviral medication, #favipiravir (T-705) (Infection, abstract)

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

Infection. 2019 Oct 31. doi: 10.1007/s15010-019-01364-9. [Epub ahead of print]

Severe fever with thrombocytopenia syndrome (SFTS) treated with a novel antiviral medication, favipiravir (T-705).

Song R1, Chen Z2, Li W3.

Author information: 1 Center of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, 100015, Beijing, People’s Republic of China. 2 Center of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, 100015, Beijing, People’s Republic of China. zhccmu@sina.com. 3 Cancer Center, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, 100015, Beijing, People’s Republic of China. vision988@126.com.

 

Abstract

BACKGROUND:

Severe fever and thrombocytopenia syndrome (SFTS) is an acute illness with a high mortality (16.2-29.1%). Unfortunately, there is no specific cure or vaccine for SFTS.

METHODS:

In this open-label study, two patients with SFTS were treated with favipiravir, a new antiviral drug.

RESULTS:

Patients had a sustainable virologic, immunologic and symptomatic recovery.

CONCLUSIONS:

Favipiravir may be a prosiming drug for the treatment of SFTS.

KEYWORDS: Favipiravir; SFTS; Severe fever and thrombocytopenia syndrome

PMID: 31673977 DOI: 10.1007/s15010-019-01364-9

Keywords: Antivirals; Favipiravir; SFTS.

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#Growth activation of #influenza virus by #trypsin and effect of T-705 (#favipiravir) on trypsin-optimized growth condition (Acta Virol., abstract)

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

Acta Virol. 2019;63(3):309-315. doi: 10.4149/av_2019_311.

Growth activation of influenza virus by trypsin and effect of T-705 (favipiravir) on trypsin-optimized growth condition.

Daikoku T, Okuda T, Kawai M, Morita N, Tanaka T, Takemoto M, Fukuda Y, Takahashi K, Nomura N, Shiraki K.

 

Abstract

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071 was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia.

Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.

PMID: 31507197 DOI: 10.4149/av_2019_311

Keywords: Influenza A; H1N1; H3N2; Antivirals; Favipiravir; Oseltamivir.

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Susceptibility of #Influenza A, B, C, and D Viruses to #Baloxavir (Emerg Infect Dis., abstract)

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

Volume 25, Number 10—October 2019 / Dispatch

Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir

Vasiliy P. Mishin, Mira C. Patel, Anton Chesnokov, Juan De La Cruz, Ha T. Nguyen, Lori Lollis, Erin Hodges, Yunho Jang, John Barnes, Timothy Uyeki, Charles T. Davis, David E. Wentworth, and Larisa V. Gubareva

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (V.P. Mishin, M.C. Patel, A. Chesnokov, J. De La Cruz, H.T. Nguyen, L. Lollis, E. Hodges, Y. Jang, J. Barnes, T. Uyeki, C.T. Davis, D.E. Wentworth, L.V. Gubareva); Battelle Memorial Institute, Atlanta (M.C. Patel, J. De La Cruz, H.T. Nguyen, L. Lollis)

 

Abstract

Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2–98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors.

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Favipiravir; Baloxavir; Influenza A; Influenza B; Influenza C; Influenza D; H1N1pdm09; H3N2; H7N9.

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