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      Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza

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          Abstract

          Background

          Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.

          Methods

          We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.

          Results

          Viruses containing PA/I38X substitutions were identified 3–9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.

          Conclusions

          The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.

          Clinical Trial Registration

          NCT02954354.

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          Most cited references25

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          Neuraminidase inhibitors for influenza.

          Anne Moscona (2005)
          Article 0 comments Cited 284 times – based on 0 reviews     Review now
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            The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.

            Alexandre Dias, Denis Bouvier, Thibaut Crépin … (2009)
            The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs.
            Article 0 comments Cited 251 times – based on 0 reviews     Review now
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              Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States.

              Rick A. Bright, David K Shay, Bo Shu … (2006)
              The adamantanes, amantadine and rimantadine, have been used as first-choice antiviral drugs against community outbreaks of influenza A viruses for many years. Rates of viruses resistant to these drugs have been increasing globally. Rapid surveillance for the emergence and spread of resistant viruses has become critical for appropriate treatment of patients. To investigate the frequency of adamantane-resistant influenza A viruses circulating in the United States during the initial months of the 2005-2006 influenza season. Influenza isolates collected from 26 states from October 1 through December 31, 2005, and submitted to the US Centers for Disease Control and Prevention were tested for drug resistance as part of ongoing surveillance. Isolates were submitted from World Health Organization collaborating laboratories and National Respiratory and Enteric Virus Surveillance System laboratories. Using pyrosequencing and confirmatory assays, we identified viruses containing mutations within the M2 gene that are known to confer resistance to both amantadine and rimantadine. A total of 209 influenza A(H3N2) viruses isolated from patients in 26 states were screened, of which 193 (92.3%) contained a change at amino acid 31 (serine to asparagine [S31N]) in the M2 gene known to be correlated with adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same mutation. Drug-resistant viruses were distributed across the United States. The high proportion of influenza A viruses currently circulating in the United States demonstrating adamantane resistance highlights the clinical importance of rapid surveillance for antiviral resistance. Our results indicate that these drugs should not be used for the treatment or prophylaxis of influenza in the United States until susceptibility to adamantanes has been reestablished among circulating influenza A isolates.
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                Author and article information

                Journal
                Title: The Journal of Infectious Diseases
                Publisher: Oxford University Press (OUP)
                ISSN (Print): 0022-1899
                ISSN (Electronic): 1537-6613
                Publication date Created: July 16 2019
                Publication date (Electronic): July 16 2019
                Affiliations
                [1 ]Shionogi & Co., Ltd, Osaka, Japan
                [2 ]University of Virginia School of Medicine, Charlottesville
                [3 ]Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia
                [4 ]Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, the Netherlands
                [5 ]Hirotsu Clinic, Kawasaki, Japan
                [6 ]Department of Pediatrics, Keiyu Hospital, Yokohama, Japan
                [7 ]Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada
                [8 ]Shionogi Inc., Florham Park, New Jersey
                [9 ]Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
                Article
                DOI: 10.1093/infdis/jiz244
                PubMed ID: 31309975
                SO-VID: 32690a9f-38b2-4802-98e9-457e81a3d7e1
                Copyright © © 2019
                License:

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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