title: Combinations of Oseltamivir and T-705 Extend the Treatment Window for Highly Pathogenic Influenza A(H5N1) Virus Infection in Mice.
abstract: Current anti-influenza therapy depends on administering drugs soon after infection, which is often impractical. We assessed whether combinations of oseltamivir (a neuraminidase inhibitor) and T-705 (a nonspecific inhibitor of viral polymerases) could extend the window for treating lethal infection with highly pathogenic A(H5N1) influenza virus in mice. Combination therapy protected 100% of mice, even when delayed until 96 h postinoculation. Compared to animals receiving monotherapy, mice receiving combination therapy had reduced viral loads and restricted viral spread in lung tissues, limited lung damage, and decreased inflammatory cytokine production. Next-generation sequencing showed that virus populations in T-705-treated mice had greater genetic variability, with more frequent transversion events, than did populations in control and oseltamivir-treated mice, but no substitutions associated with resistance to oseltamivir or T-705 were detected. Thus, combination therapy extended the treatment window for A(H5N1) influenza infection in mice and should be considered for evaluation in a clinical setting.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
authors.forename: Bindumadhav M
authors.initials: BM
authors.lastname: Marathe
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
authors.forename: Sook-San
authors.initials: SS
authors.lastname: Wong
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Roche Pharma Research and Early Development, Infectious Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Fernando
authors.initials: F
authors.lastname: Garcia-Alcalde
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
authors.affiliation: Roche Pharma Research and Early Development, Infectious Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D053124:Influenza A Virus, H5N1 Subtype; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053139:Oseltamivir / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000577:Amides; D011719:Pyrazines; D053139:Oseltamivir; C462182:favipiravir