CORD-19-Sentences  

CORD-19:0329e0f2e3b8ab0eabe2afe0e5214cc88c61080e JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-181 Sentence denotes Journal Pre-proof Favipiravir, an anti-influenza drug against life-threatening RNA virus infections Favipiravir, an anti-influenza drug against life-threatening RNA virus infections
T28156 0-181 Sentence denotes Journal Pre-proof Favipiravir, an anti-influenza drug against life-threatening RNA virus infections Favipiravir, an anti-influenza drug against life-threatening RNA virus infections
TextSentencer_T2 183-191 Sentence denotes Abstract
T94036 183-191 Sentence denotes Abstract
TextSentencer_T3 194-309 Sentence denotes Acyclovir enabled the first systemic antiviral therapy, and many antiviral agents have subsequently been developed.
T33176 194-309 Sentence denotes Acyclovir enabled the first systemic antiviral therapy, and many antiviral agents have subsequently been developed.
TextSentencer_T4 310-525 Sentence denotes Acyclovir targets herpes simplex virus and varicella-zoster infection, and individual antiviral agents target one viral infection caused by one virus or two viruses of the same family (Elion, 1982; Shiraki, , 2018 .
T88192 310-525 Sentence denotes Acyclovir targets herpes simplex virus and varicella-zoster infection, and individual antiviral agents target one viral infection caused by one virus or two viruses of the same family (Elion, 1982; Shiraki, , 2018 .
TextSentencer_T5 526-831 Sentence denotes Among antiviral agents, one of the unique features of favipiravir (T-705) is its broad spectrum activity toward RNA viruses, including influenza virus, rhinovirus, and respiratory syncytial virus, but not DNA viruses, as shown in Fig. 1 (Furuta, et al., 2002; Furuta, et al., 2005; Furuta, et al., 2009) .
T18718 526-831 Sentence denotes Among antiviral agents, one of the unique features of favipiravir (T-705) is its broad spectrum activity toward RNA viruses, including influenza virus, rhinovirus, and respiratory syncytial virus, but not DNA viruses, as shown in Fig. 1 (Furuta, et al., 2002; Furuta, et al., 2005; Furuta, et al., 2009) .
TextSentencer_T6 832-1149 Sentence denotes Favipiravir shows better efficacy in treating influenza infections than oseltamivir (Tamiflu) (Takahashi, et al., 2003; Tanaka, et al., 2017) , and its efficacy in treating pathogenic avian influenza A(H5N1) and oseltamivir-resistant viruses has been confirmed in animals (Kiso, et al., 2010; Sidwell, et al., 2007) .
T82684 832-1149 Sentence denotes Favipiravir shows better efficacy in treating influenza infections than oseltamivir (Tamiflu) (Takahashi, et al., 2003; Tanaka, et al., 2017) , and its efficacy in treating pathogenic avian influenza A(H5N1) and oseltamivir-resistant viruses has been confirmed in animals (Kiso, et al., 2010; Sidwell, et al., 2007) .
TextSentencer_T7 1150-1344 Sentence denotes Clinical trials of treatments for seasonal influenza have been performed in Japan and US, and favipiravir was approved as a treatment for novel or re-emerging influenza viruses in Japan in 2014.
T41609 1150-1344 Sentence denotes Clinical trials of treatments for seasonal influenza have been performed in Japan and US, and favipiravir was approved as a treatment for novel or re-emerging influenza viruses in Japan in 2014.
TextSentencer_T8 1345-1529 Sentence denotes Favipiravir is considered for administration to patients only when the government judges that this drug will be used as a countermeasure against novel or re-emerging influenza viruses.
T86764 1345-1529 Sentence denotes Favipiravir is considered for administration to patients only when the government judges that this drug will be used as a countermeasure against novel or re-emerging influenza viruses.
TextSentencer_T9 1530-1692 Sentence denotes The Japanese government and Taiwanese Centers for Disease Control (CDCs) decided to stockpile favipiravir for the people as a countermeasure for severe influenza.
T15387 1530-1692 Sentence denotes The Japanese government and Taiwanese Centers for Disease Control (CDCs) decided to stockpile favipiravir for the people as a countermeasure for severe influenza.
TextSentencer_T10 1693-1882 Sentence denotes Favipiravir has been submitted for additional indications for severe fever with thrombocytopenia syndrome (SFTS) based on clinical trials (Yasukawa, 2016) in addition to influenza in Japan.
T8362 1693-1882 Sentence denotes Favipiravir has been submitted for additional indications for severe fever with thrombocytopenia syndrome (SFTS) based on clinical trials (Yasukawa, 2016) in addition to influenza in Japan.
TextSentencer_T11 1883-2130 Sentence denotes against influenza viruses at the cell culture level was confirmed, the use of favipiravir as an anti-influenza drug was confirmed by analyzing its efficacy in animal models of influenza infection, as described below, which led to drug development.
T95147 1883-2130 Sentence denotes against influenza viruses at the cell culture level was confirmed, the use of favipiravir as an anti-influenza drug was confirmed by analyzing its efficacy in animal models of influenza infection, as described below, which led to drug development.
TextSentencer_T12 2131-2359 Sentence denotes Favipiravir was effective against other RNA viruses, poliovirus, rhinovirus, and respiratory syncytial virus but not effective against DNA viruses, herpes simplex virus-1, cytomegalovirus, and adenovirus (Furuta, et al., 2002) .
T85576 2131-2359 Sentence denotes Favipiravir was effective against other RNA viruses, poliovirus, rhinovirus, and respiratory syncytial virus but not effective against DNA viruses, herpes simplex virus-1, cytomegalovirus, and adenovirus (Furuta, et al., 2002) .
TextSentencer_T13 2360-2500 Sentence denotes Based on the antiviral activity toward four RNA viruses, we expected that favipiravir should be active against a broad range of RNA viruses.
T35361 2360-2500 Sentence denotes Based on the antiviral activity toward four RNA viruses, we expected that favipiravir should be active against a broad range of RNA viruses.
TextSentencer_T14 2501-2625 Sentence denotes Favipiravir has been evaluated and developed as a broad spectrum anti-RNA virus drug, including lethal RNA virus infections.
T63881 2501-2625 Sentence denotes Favipiravir has been evaluated and developed as a broad spectrum anti-RNA virus drug, including lethal RNA virus infections.
TextSentencer_T15 2626-2817 Sentence denotes The anti-RNA virus activity of favipiravir was analyzed at the cellular level, and efficacy studies were performed in animal models of human lethal RNA virus infections, as shown in Table 1 .
T49988 2626-2817 Sentence denotes The anti-RNA virus activity of favipiravir was analyzed at the cellular level, and efficacy studies were performed in animal models of human lethal RNA virus infections, as shown in Table 1 .
TextSentencer_T16 2818-3129 Sentence denotes Patients with an Ebola virus infection in West Africa in 2014 and patients with other RNA virus infections have been treated with favipiravir (Avigan®) based on the efficacy in human lethal RNA virus infections, clinical experience, efficacy in patients with seasonal influenza, and its licensure for human use.
T80590 2818-3129 Sentence denotes Patients with an Ebola virus infection in West Africa in 2014 and patients with other RNA virus infections have been treated with favipiravir (Avigan®) based on the efficacy in human lethal RNA virus infections, clinical experience, efficacy in patients with seasonal influenza, and its licensure for human use.
TextSentencer_T17 3130-3216 Sentence denotes We have identified two antipyretic steps in influenza infections, as shown in Fig. 2 .
T94460 3130-3216 Sentence denotes We have identified two antipyretic steps in influenza infections, as shown in Fig. 2 .
TextSentencer_T18 3217-3347 Sentence denotes Influenza infection and its replication in the epithelium of the upper respiratory tract induce levels in influenza-infected mice.
T51820 3217-3347 Sentence denotes Influenza infection and its replication in the epithelium of the upper respiratory tract induce levels in influenza-infected mice.
TextSentencer_T19 3348-3476 Sentence denotes Cinnamyl compounds regulate cytokine levels by modulating the amount of NF-κB (Kurokawa, et al., 2003; Kurokawa, et al., 1998) .
T94715 3348-3476 Sentence denotes Cinnamyl compounds regulate cytokine levels by modulating the amount of NF-κB (Kurokawa, et al., 2003; Kurokawa, et al., 1998) .
TextSentencer_T20 3477-3666 Sentence denotes Cinnamyl compounds and clarithromycin increase the levels of IL-12 on day 2 and IFN-γ on day 3 in the bronchoalveolar fluids of mice and decrease the area of pneumonia throughout the lungs.
T46086 3477-3666 Sentence denotes Cinnamyl compounds and clarithromycin increase the levels of IL-12 on day 2 and IFN-γ on day 3 in the bronchoalveolar fluids of mice and decrease the area of pneumonia throughout the lungs.
TextSentencer_T21 3667-3932 Sentence denotes The role of IL-12 on day 2 was confirmed through its direct nasal application, and nasal administration of IL-12 reduced the virus yield in the bronchoalveolar fluids from influenza-infected mice (Hama, et al., 2009; Kurokawa, et al., 2002; Tsurita, et al., 2001) .
T77909 3667-3932 Sentence denotes The role of IL-12 on day 2 was confirmed through its direct nasal application, and nasal administration of IL-12 reduced the virus yield in the bronchoalveolar fluids from influenza-infected mice (Hama, et al., 2009; Kurokawa, et al., 2002; Tsurita, et al., 2001) .
TextSentencer_T22 3933-4090 Sentence denotes Cinnamyl compounds that are mainly derived from medicinal herbs prevent the induction of fever in influenza-infected mice by decreasing the serum IL-1 level.
T41666 3933-4090 Sentence denotes Cinnamyl compounds that are mainly derived from medicinal herbs prevent the induction of fever in influenza-infected mice by decreasing the serum IL-1 level.
TextSentencer_T23 4091-4330 Sentence denotes In contrast, aspirin suppresses fever by inhibiting hypothalamic cyclooxygenase activity and prostaglandin E 2 production without affecting the high level of IL-1 (Kurokawa, et al., 1996a; Kurokawa, et al., 1996b; Kurokawa, et al., 1998) .
T96405 4091-4330 Sentence denotes In contrast, aspirin suppresses fever by inhibiting hypothalamic cyclooxygenase activity and prostaglandin E 2 production without affecting the high level of IL-1 (Kurokawa, et al., 1996a; Kurokawa, et al., 1996b; Kurokawa, et al., 1998) .
TextSentencer_T24 4331-4459 Sentence denotes We have determined two steps of antipyretic action by cinnamyl compounds and NSAIDs in the fever cascade in influenza infection.
T95031 4331-4459 Sentence denotes We have determined two steps of antipyretic action by cinnamyl compounds and NSAIDs in the fever cascade in influenza infection.
TextSentencer_T25 4460-4686 Sentence denotes Studies of the efficacy of favipiravir on influenza in animals ha ve been performed in our biosafety level 3 laboratory, and sterile and pyrogen-free distilled water for injections was used for drinking to ensure traceability.
T72935 4460-4686 Sentence denotes Studies of the efficacy of favipiravir on influenza in animals ha ve been performed in our biosafety level 3 laboratory, and sterile and pyrogen-free distilled water for injections was used for drinking to ensure traceability.
TextSentencer_T26 4687-4953 Sentence denotes As we have experience in conducting a pharmacological study for a famciclovir approval application in Japan, the efficacy and validation studies of favipiravir were conducted in mice and ferrets using the influenza infection system described above in our laboratory.
T28223 4687-4953 Sentence denotes As we have experience in conducting a pharmacological study for a famciclovir approval application in Japan, the efficacy and validation studies of favipiravir were conducted in mice and ferrets using the influenza infection system described above in our laboratory.
TextSentencer_T27 4954-4978 Sentence denotes Tsurita, et al., 2001 ).
T22927 4954-4978 Sentence denotes Tsurita, et al., 2001 ).
TextSentencer_T28 4979-5090 Sentence denotes Our animal model for influenza was used to study the efficacy of favipiravir in the influenza-infected animals.
T50214 4979-5090 Sentence denotes Our animal model for influenza was used to study the efficacy of favipiravir in the influenza-infected animals.
TextSentencer_T29 5091-5214 Sentence denotes As favipiravir was effective in cell culture, its effectiveness in animals infected with influenza virus must be confirmed.
T33913 5091-5214 Sentence denotes As favipiravir was effective in cell culture, its effectiveness in animals infected with influenza virus must be confirmed.
TextSentencer_T30 5215-5280 Sentence denotes We first observed the prevention of a lethal influenza infection.
T18312 5215-5280 Sentence denotes We first observed the prevention of a lethal influenza infection.
TextSentencer_T31 5281-5472 Sentence denotes Oral administration of favipiravir was significantly effective in alleviating influenza infection in mice (Furuta, et al., 2002) , and its efficacy was characterized under various conditions.
T71429 5281-5472 Sentence denotes Oral administration of favipiravir was significantly effective in alleviating influenza infection in mice (Furuta, et al., 2002) , and its efficacy was characterized under various conditions.
TextSentencer_T32 5473-5711 Sentence denotes We are convinced that favipiravir will be developed as an influenza drug for humans after the confirmation of its therapeutic activity in two species of animals, mice and ferrets, infected with influenza virus. (Takahashi, et al., 2003) .
T20025 5473-5711 Sentence denotes We are convinced that favipiravir will be developed as an influenza drug for humans after the confirmation of its therapeutic activity in two species of animals, mice and ferrets, infected with influenza virus. (Takahashi, et al., 2003) .
TextSentencer_T33 5712-5927 Sentence denotes Favipiravir and oseltamivir show similar efficacy in low-dose infections, but the efficacy of favipiravir as an influenza drug is clearly increased compared with oseltamivir in high-titer virus infections (Fig. 3) .
T98955 5712-5927 Sentence denotes Favipiravir and oseltamivir show similar efficacy in low-dose infections, but the efficacy of favipiravir as an influenza drug is clearly increased compared with oseltamivir in high-titer virus infections (Fig. 3) .
TextSentencer_T34 5928-6096 Sentence denotes Mice in the control group die on day 3 after a high-dose infection, and an oseltamivir treatment prolongs the survival period for three days but does not prevent death.
T74745 5928-6096 Sentence denotes Mice in the control group die on day 3 after a high-dose infection, and an oseltamivir treatment prolongs the survival period for three days but does not prevent death.
TextSentencer_T35 6097-6353 Sentence denotes The favipiravir treatment cures lethal infection, and all mice survive. ineffective in this model, favipiravir effectively improves survival in all cases, indicating the importance of administering a drug with a mechanism of action that reduces viral load.
T83134 6097-6353 Sentence denotes The favipiravir treatment cures lethal infection, and all mice survive. ineffective in this model, favipiravir effectively improves survival in all cases, indicating the importance of administering a drug with a mechanism of action that reduces viral load.
TextSentencer_T36 6354-6650 Sentence denotes TNF-α production is induced through recognition of the single-strand RNA or double-strand RNA of the influenza virus genome by Toll-like receptor-7/8 (Yang & Chen, 2012) or 3 (Diebold, et al., 2003; Guillot, et al., 2005; Poux, et al., 2019; Wong, et al., 2009) , respectively, in infected cells.
T74757 6354-6650 Sentence denotes TNF-α production is induced through recognition of the single-strand RNA or double-strand RNA of the influenza virus genome by Toll-like receptor-7/8 (Yang & Chen, 2012) or 3 (Diebold, et al., 2003; Guillot, et al., 2005; Poux, et al., 2019; Wong, et al., 2009) , respectively, in infected cells.
TextSentencer_T37 6651-6844 Sentence denotes Influenza infection induces TNF-α production in mouse macrophage-derived P388D1 cells, and the suppressive effects of favipiravir and oseltamivir were compared in this P388D1 cell-based system.
T34980 6651-6844 Sentence denotes Influenza infection induces TNF-α production in mouse macrophage-derived P388D1 cells, and the suppressive effects of favipiravir and oseltamivir were compared in this P388D1 cell-based system.
TextSentencer_T38 6845-7016 Sentence denotes Favipiravir significantly suppresses the production of TNF-α in influenza virus-infected P388D1 cells compared with the active form of oseltamivir (Tanaka, et al., 2017) .
T26386 6845-7016 Sentence denotes Favipiravir significantly suppresses the production of TNF-α in influenza virus-infected P388D1 cells compared with the active form of oseltamivir (Tanaka, et al., 2017) .
TextSentencer_T39 7017-7261 Sentence denotes TNF-α appears first and disappears first in P338D1 cells among TNF-α, IL-1, and IL-6 (Kurokawa, et al., 2003) , and we observed a significant reduction in the levels of TNF-α in P388D1 cells and influenza-infected mice treated with favipiravir.
T60841 7017-7261 Sentence denotes TNF-α appears first and disappears first in P338D1 cells among TNF-α, IL-1, and IL-6 (Kurokawa, et al., 2003) , and we observed a significant reduction in the levels of TNF-α in P388D1 cells and influenza-infected mice treated with favipiravir.
TextSentencer_T40 7262-7658 Sentence denotes The antiviral activity of favipiravir has been attributed to a decrease in the pulmonary viral load and TNF-α level in the airways of influenza virus-infected mice compared with oseltamivir, and the reduction in the viral RNA load induced by favipiravir might have resulted in a reduction in TNF-α production and alleviation of lung pathogenesis (Damjanovic, et al., 2011; Tanaka, et al., 2017) .
T92366 7262-7658 Sentence denotes The antiviral activity of favipiravir has been attributed to a decrease in the pulmonary viral load and TNF-α level in the airways of influenza virus-infected mice compared with oseltamivir, and the reduction in the viral RNA load induced by favipiravir might have resulted in a reduction in TNF-α production and alleviation of lung pathogenesis (Damjanovic, et al., 2011; Tanaka, et al., 2017) .
TextSentencer_T41 7659-7803 Sentence denotes Based on these findings, the intracellular viral RNA is less recognized by intracellular Toll-like receptors and results in a decrease in drugs.
T42242 7659-7803 Sentence denotes Based on these findings, the intracellular viral RNA is less recognized by intracellular Toll-like receptors and results in a decrease in drugs.
TextSentencer_T42 7804-7927 Sentence denotes The viral hemagglutinin binds to sialic acid on the cell surface, and the viral particle is incorporated into the endosome.
T20989 7804-7927 Sentence denotes The viral hemagglutinin binds to sialic acid on the cell surface, and the viral particle is incorporated into the endosome.
TextSentencer_T43 7928-8146 Sentence denotes When the endosome is acidified and the pH decreases to a value of 5, which is characteristic of the late endosome, the structure of the hemagglutinin changes through a process mediated by the Matrix-2 (M2) ion channel.
T12085 7928-8146 Sentence denotes When the endosome is acidified and the pH decreases to a value of 5, which is characteristic of the late endosome, the structure of the hemagglutinin changes through a process mediated by the Matrix-2 (M2) ion channel.
TextSentencer_T44 8147-8291 Sentence denotes Then, the endosomal membrane and the viral envelope fuse, and the viral genome in the viral particle is released into the cytoplasm (uncoating).
T59003 8147-8291 Sentence denotes Then, the endosomal membrane and the viral envelope fuse, and the viral genome in the viral particle is released into the cytoplasm (uncoating).
TextSentencer_T45 8292-8425 Sentence denotes The viral genome and RdRp complex are transported to the nucleus where the transcription (replication) of viral RNA synthesis begins.
T77102 8292-8425 Sentence denotes The viral genome and RdRp complex are transported to the nucleus where the transcription (replication) of viral RNA synthesis begins.
TextSentencer_T46 8426-8703 Sentence denotes The synthesized RNA does not contain the Cap structure required for mRNA, and the Cap structure from the host mRNA is excised and transferred to the viral RNA by the Cap-dependent endonuclease of viral RdRp complex, resulting in the formation of the viral mRNA (Cap-snatching).
T80888 8426-8703 Sentence denotes The synthesized RNA does not contain the Cap structure required for mRNA, and the Cap structure from the host mRNA is excised and transferred to the viral RNA by the Cap-dependent endonuclease of viral RdRp complex, resulting in the formation of the viral mRNA (Cap-snatching).
TextSentencer_T47 8704-8770 Sentence denotes After the viral mRNA is produced, the viral protein is translated.
T30669 8704-8770 Sentence denotes After the viral mRNA is produced, the viral protein is translated.
TextSentencer_T48 8771-8877 Sentence denotes The viral proteins and RdRp-RNA complex form viral particles that subsequently bud from the cell membrane.
T4684 8771-8877 Sentence denotes The viral proteins and RdRp-RNA complex form viral particles that subsequently bud from the cell membrane.
TextSentencer_T49 8878-9060 Sentence denotes Hemagglutinin However, influenza A virus becomes resistant, even in an epidemic occurring in a closed facility, and the current influenza A viruses are not susceptible to amantadine.
T73921 8878-9060 Sentence denotes Hemagglutinin However, influenza A virus becomes resistant, even in an epidemic occurring in a closed facility, and the current influenza A viruses are not susceptible to amantadine.
TextSentencer_T50 9061-9165 Sentence denotes Favipiravir inhibits viral RNA synthesis, and therefore viral RNA is not produced in the infected cells.
T76418 9061-9165 Sentence denotes Favipiravir inhibits viral RNA synthesis, and therefore viral RNA is not produced in the infected cells.
TextSentencer_T51 9166-9425 Sentence denotes The NA inhibitors (NAIs) zanamivir, oseltamivir, peramivir, and laminamivir inhibit the NA activity of viral particles on the surface of the infected cell and the release of viral particles from the cell surface to other cells for the next round of infection.
T67649 9166-9425 Sentence denotes The NA inhibitors (NAIs) zanamivir, oseltamivir, peramivir, and laminamivir inhibit the NA activity of viral particles on the surface of the infected cell and the release of viral particles from the cell surface to other cells for the next round of infection.
TextSentencer_T52 9426-9539 Sentence denotes NAIs result in the accumulation of viral particles on the cell surface and inhibit the spread of virus infection.
T66496 9426-9539 Sentence denotes NAIs result in the accumulation of viral particles on the cell surface and inhibit the spread of virus infection.
TextSentencer_T53 9540-9599 Sentence denotes NAIs are currently the main choice of anti-influenza drugs.
T72110 9540-9599 Sentence denotes NAIs are currently the main choice of anti-influenza drugs.
TextSentencer_T54 9600-9653 Sentence denotes Cap-dependent endonuclease of the viral RdRp complex.
T37843 9600-9653 Sentence denotes Cap-dependent endonuclease of the viral RdRp complex.
TextSentencer_T55 9654-9857 Sentence denotes Baloxavir inhibits mRNA synthesis and subsequent viral protein synthesis, but genomic RNA without the Cap structure is synthesized by the incorporated RdRp-viral RNA complex in the presence of baloxavir.
T35630 9654-9857 Sentence denotes Baloxavir inhibits mRNA synthesis and subsequent viral protein synthesis, but genomic RNA without the Cap structure is synthesized by the incorporated RdRp-viral RNA complex in the presence of baloxavir.
TextSentencer_T56 9858-9921 Sentence denotes Favipiravir inhibits viral RNA synthesis as a chain terminator.
T28846 9858-9921 Sentence denotes Favipiravir inhibits viral RNA synthesis as a chain terminator.
TextSentencer_T57 9922-10270 Sentence denotes This inhibition of genomic RNA synthesis is the most important difference from other anti-influenza drugs, which substantially forms the pool of genomic RNA containing drug-resistant mutants There is a high probability that the resistant virus is already present in the virus that grew rapidly and in large quantities before the start of treatment.
T38178 9922-10270 Sentence denotes This inhibition of genomic RNA synthesis is the most important difference from other anti-influenza drugs, which substantially forms the pool of genomic RNA containing drug-resistant mutants There is a high probability that the resistant virus is already present in the virus that grew rapidly and in large quantities before the start of treatment.
TextSentencer_T58 10271-10409 Sentence denotes In addition, the viral RNA formed in the cells in patients treated with anti-influenza drugs serves as a source of drug-resistant viruses.
T96927 10271-10409 Sentence denotes In addition, the viral RNA formed in the cells in patients treated with anti-influenza drugs serves as a source of drug-resistant viruses.
TextSentencer_T59 10410-10539 Sentence denotes Subsequently, drug-resistant influenza viruses should appear more readily from the mutant genomic RNA pool during drug treatment.
T5169 10410-10539 Sentence denotes Subsequently, drug-resistant influenza viruses should appear more readily from the mutant genomic RNA pool during drug treatment.
TextSentencer_T60 10540-10737 Sentence denotes The replication cycle of influenza viruses is approximately 6 hours from entry to the production of new virus, and robust growth begins after infection at a rate of four replication cycles per day.
T19776 10540-10737 Sentence denotes The replication cycle of influenza viruses is approximately 6 hours from entry to the production of new virus, and robust growth begins after infection at a rate of four replication cycles per day.
TextSentencer_T61 10738-10919 Sentence denotes The course of influenza virus infection was analyzed in 56 different studies with 1,280 healthy participants after an experimental influenza virus infection (Carrat, et al., 2008) .
T31768 10738-10919 Sentence denotes The course of influenza virus infection was analyzed in 56 different studies with 1,280 healthy participants after an experimental influenza virus infection (Carrat, et al., 2008) .
TextSentencer_T62 10920-11127 Sentence denotes The A(H1N1) and A(H3N2) infections resulted in a substantial increase in viral shedding on the first day after experimental influenza virus infection, and they reached their maximum values on the second day.
T46530 10920-11127 Sentence denotes The A(H1N1) and A(H3N2) infections resulted in a substantial increase in viral shedding on the first day after experimental influenza virus infection, and they reached their maximum values on the second day.
TextSentencer_T63 11128-11180 Sentence denotes Fever was reported in 34.9% of infected individuals.
T9872 11128-11180 Sentence denotes Fever was reported in 34.9% of infected individuals.
TextSentencer_T64 11181-11344 Sentence denotes Systemic symptoms (fever, muscle aches, fatigue, and headache) peaked earlier, by day 2 after inoculation, and resolved faster than respiratory or nasal symp toms.
T16251 11181-11344 Sentence denotes Systemic symptoms (fever, muscle aches, fatigue, and headache) peaked earlier, by day 2 after inoculation, and resolved faster than respiratory or nasal symp toms.
TextSentencer_T65 11345-11660 Sentence denotes The presence of a preexisting antibody modified the mean duration of illness of 4.4 days in participants with pre-hemagglutinin inhibition titers of <1/8 compared with 1.0 day in participants with pre-hemagglutinin inhibition titers of >1/8 after the inoculation of a wild-type A(H1N1) virus (Doyle, et al., 1994) .
T44608 11345-11660 Sentence denotes The presence of a preexisting antibody modified the mean duration of illness of 4.4 days in participants with pre-hemagglutinin inhibition titers of <1/8 compared with 1.0 day in participants with pre-hemagglutinin inhibition titers of >1/8 after the inoculation of a wild-type A(H1N1) virus (Doyle, et al., 1994) .
TextSentencer_T66 11661-11914 Sentence denotes Influenza causes dry cough (90%), fever (83.8%), and headache (82.5%), J o u r n a l P r e -p r o o f Journal Pre-proof and immunocompromised patients exhibit a significantly longer length of illness with delayed virus clearance (Memoli, et al., 2014) .
T31961 11661-11914 Sentence denotes Influenza causes dry cough (90%), fever (83.8%), and headache (82.5%), J o u r n a l P r e -p r o o f Journal Pre-proof and immunocompromised patients exhibit a significantly longer length of illness with delayed virus clearance (Memoli, et al., 2014) .
TextSentencer_T67 11915-12133 Sentence denotes The mean durations of viral shedding in immunocompromised and non-immunocompromised patients are 19.4 and 6.38 days with median values of 8.0 and 5.0 days, respectively, indicating that viral replication persists for a
T14329 11915-12133 Sentence denotes The mean durations of viral shedding in immunocompromised and non-immunocompromised patients are 19.4 and 6.38 days with median values of 8.0 and 5.0 days, respectively, indicating that viral replication persists for a
TextSentencer_T68 12134-12181 Sentence denotes week after the disappearance of major symptoms.
T77625 12134-12181 Sentence denotes week after the disappearance of major symptoms.
TextSentencer_T69 12182-12289 Sentence denotes Preexisting immunity and immunocompetence are important in modifying the severity of symptoms of influenza.
T64031 12182-12289 Sentence denotes Preexisting immunity and immunocompetence are important in modifying the severity of symptoms of influenza.
TextSentencer_T70 12290-12452 Sentence denotes Seasonal influenza strains that are adapted to humans include A(H1N1), A(H3N2), and B influenza and cause seasonal epidemics of influenza among humans every year.
T88615 12290-12452 Sentence denotes Seasonal influenza strains that are adapted to humans include A(H1N1), A(H3N2), and B influenza and cause seasonal epidemics of influenza among humans every year.
TextSentencer_T71 12453-12700 Sentence denotes Seasonal influenza viruses mainly infect the epithelium of the upper respiratory tract because their hemagglutinins bind to their receptor, sialic acid linked to galactose by an alpha-2,6 linkage that is distributed in the upper respiratory tract.
T77895 12453-12700 Sentence denotes Seasonal influenza viruses mainly infect the epithelium of the upper respiratory tract because their hemagglutinins bind to their receptor, sialic acid linked to galactose by an alpha-2,6 linkage that is distributed in the upper respiratory tract.
TextSentencer_T72 12701-12865 Sentence denotes Although these strains cause epidemics every year, the susceptibility and severity of illness are modified by the degree of immunity of the host as described above.
T29440 12701-12865 Sentence denotes Although these strains cause epidemics every year, the susceptibility and severity of illness are modified by the degree of immunity of the host as described above.
TextSentencer_T73 12866-12979 Sentence denotes Novel influenza is derived from avian influenza A and is a source of concern as a cause of an influenza pandemic.
T83658 12866-12979 Sentence denotes Novel influenza is derived from avian influenza A and is a source of concern as a cause of an influenza pandemic.
TextSentencer_T74 12980-13199 Sentence denotes Avian influenza is divided into highly pathogenic avian influenza and low-pathogenicity avian influenza based on the molecular characteristics of the virus and their abilities to cause disease and mortality in chickens.
T45255 12980-13199 Sentence denotes Avian influenza is divided into highly pathogenic avian influenza and low-pathogenicity avian influenza based on the molecular characteristics of the virus and their abilities to cause disease and mortality in chickens.
TextSentencer_T75 13200-13348 Sentence denotes Both low-pathogenicity avian influenza and highly pathogenic avian influenza viruses have caused severe and lethal infections in humans (CDC, 2017).
T4062 13200-13348 Sentence denotes Both low-pathogenicity avian influenza and highly pathogenic avian influenza viruses have caused severe and lethal infections in humans (CDC, 2017).
TextSentencer_T76 13349-13627 Sentence denotes Since the novel influenza strain is transmitted in the original host bird, the avian receptor is sialic acid linked to galactose by an alpha-2,3 linkage, and this receptor is distributed in respiratory bronchioles and alveolar epithelial cells in humans (Shinya, et al., 2006) .
T13040 13349-13627 Sentence denotes Since the novel influenza strain is transmitted in the original host bird, the avian receptor is sialic acid linked to galactose by an alpha-2,3 linkage, and this receptor is distributed in respiratory bronchioles and alveolar epithelial cells in humans (Shinya, et al., 2006) .
TextSentencer_T77 13628-13946 Sentence denotes Although the name of the influenza virus is common to both seasonal influenza and J o u r n a l P r e -p r o o f Journal Pre-proof novel influenza, a new subtype of influenza causes severe influenza in humans because it is a completely new subtype of virus, and humans have neither a history of infection nor immunity.
T39272 13628-13946 Sentence denotes Although the name of the influenza virus is common to both seasonal influenza and J o u r n a l P r e -p r o o f Journal Pre-proof novel influenza, a new subtype of influenza causes severe influenza in humans because it is a completely new subtype of virus, and humans have neither a history of infection nor immunity.
TextSentencer_T78 13947-14105 Sentence denotes Seasonal influenza mainly infects the upper respiratory tract, while novel influenza causes pneumonia, mainly due to an infection of the pulmonary epithelium.
T82703 13947-14105 Sentence denotes Seasonal influenza mainly infects the upper respiratory tract, while novel influenza causes pneumonia, mainly due to an infection of the pulmonary epithelium.
TextSentencer_T79 14106-14237 Sentence denotes Furthermore, unlike the presence of a certain level of immunity to seasonal influenza, immunity does not exist for novel influenza.
T29814 14106-14237 Sentence denotes Furthermore, unlike the presence of a certain level of immunity to seasonal influenza, immunity does not exist for novel influenza.
TextSentencer_T80 14238-14405 Sentence denotes Therefore, the severity of the infection appears to be caused by a prolonged virus growth period and the affinity for the pulmonary epithelium (Shinya, et al., 2006) .
T69667 14238-14405 Sentence denotes Therefore, the severity of the infection appears to be caused by a prolonged virus growth period and the affinity for the pulmonary epithelium (Shinya, et al., 2006) .
TextSentencer_T81 14406-14645 Sentence denotes As described above, novel influenza causes severe diseases, particularly pneumonia, compared to seasonal influenza, and the mortality rate is 53.5% (483/903) for A(H5N1) (Lai, et al., 2016) and 34% (47/137) for A(H7N9) (Li, et al., 2014) .
T20489 14406-14645 Sentence denotes As described above, novel influenza causes severe diseases, particularly pneumonia, compared to seasonal influenza, and the mortality rate is 53.5% (483/903) for A(H5N1) (Lai, et al., 2016) and 34% (47/137) for A(H7N9) (Li, et al., 2014) .
TextSentencer_T82 14646-14724 Sentence denotes Oseltamivir, an NAI, has been the treatment of choice for influenza infection.
T20159 14646-14724 Sentence denotes Oseltamivir, an NAI, has been the treatment of choice for influenza infection.
TextSentencer_T83 14725-15023 Sentence denotes The emergence of a resistant virus (after day 1) was detected in 43/1,207 (3.56%) oseltamivir-treated influenza A-infected patients, with a higher frequency observed in 1-to 5-year-olds (11.8%) than in children aged > 5 years (1.4%), and viral clearance occurred in 8-10 days (Lina, et al., 2018) .
T12434 14725-15023 Sentence denotes The emergence of a resistant virus (after day 1) was detected in 43/1,207 (3.56%) oseltamivir-treated influenza A-infected patients, with a higher frequency observed in 1-to 5-year-olds (11.8%) than in children aged > 5 years (1.4%), and viral clearance occurred in 8-10 days (Lina, et al., 2018) .
TextSentencer_T84 15024-15193 Sentence denotes The overall incidence of an oseltamivir-resistant virus was 10 of 182 (5.5%) (Whitley, et al., 2001) and 9 of 50 (18%) (Kiso, et al., 2004) oseltamivir-treated children.
T67488 15024-15193 Sentence denotes The overall incidence of an oseltamivir-resistant virus was 10 of 182 (5.5%) (Whitley, et al., 2001) and 9 of 50 (18%) (Kiso, et al., 2004) oseltamivir-treated children.
TextSentencer_T85 15194-15272 Sentence denotes Oseltamivir-resistant influenza appears and becomes dominant during treatment.
T58 15194-15272 Sentence denotes Oseltamivir-resistant influenza appears and becomes dominant during treatment.
TextSentencer_T86 15273-15389 Sentence denotes Another concern is the prevalence of oseltamivir-resistant strains that was observed during the 2008 to 2009 season.
T5309 15273-15389 Sentence denotes Another concern is the prevalence of oseltamivir-resistant strains that was observed during the 2008 to 2009 season.
TextSentencer_T87 15390-15627 Sentence denotes Oseltamivir-resistant seasonal A(H1N1) viruses possessing an NA H275Y substitution spread globally, 12.3% (142/1,155) in the US (Dharan, et al., 2009 ), 64% in South Africa, Oceania and SE Asia (Hurt, et al., 2009) , and 20.1% in Europe.
T75432 15390-15627 Sentence denotes Oseltamivir-resistant seasonal A(H1N1) viruses possessing an NA H275Y substitution spread globally, 12.3% (142/1,155) in the US (Dharan, et al., 2009 ), 64% in South Africa, Oceania and SE Asia (Hurt, et al., 2009) , and 20.1% in Europe.
TextSentencer_T88 15628-15863 Sentence denotes In particular, a prevalence of 67% (184/272) was observed in Norway, with a gradual increase observed in Europe from approximately 0% in week 19 to 56% in week 40 (Meijer, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2009).
T59937 15628-15863 Sentence denotes In particular, a prevalence of 67% (184/272) was observed in Norway, with a gradual increase observed in Europe from approximately 0% in week 19 to 56% in week 40 (Meijer, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2009).
TextSentencer_T89 15864-15984 Sentence denotes Thus, once the oseltamivir-resistant virus has adapted to humans, it will become or replace an epidemic virus worldwide.
T65273 15864-15984 Sentence denotes Thus, once the oseltamivir-resistant virus has adapted to humans, it will become or replace an epidemic virus worldwide.
TextSentencer_T90 15985-16219 Sentence denotes Single-dose baloxavir is superior to the placebo in alleviating influenza symptoms and to both oseltamivir and placebo in reducing the viral load 1 day after initiation in patients with uncomplicated influenza (Hayden, et al., 2018) .
T12375 15985-16219 Sentence denotes Single-dose baloxavir is superior to the placebo in alleviating influenza symptoms and to both oseltamivir and placebo in reducing the viral load 1 day after initiation in patients with uncomplicated influenza (Hayden, et al., 2018) .
TextSentencer_T91 16220-16390 Sentence denotes The emergence of baloxavir-resistant mutants with PA/I38X substitutions occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and phase 3 trials, respectively.
T23430 16220-16390 Sentence denotes The emergence of baloxavir-resistant mutants with PA/I38X substitutions occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and phase 3 trials, respectively.
TextSentencer_T92 16391-16682 Sentence denotes Patients with a substitution at position I38 in the viral polymerase acidic protein (PA/I38X) of the baloxavir-resistant virus exhibited sustained alleviation and virus clearance, and baloxavir-resistant viruses were not cross-resistant to favipiravir and oseltamivir (Omoto, et al., 2018) .
T54627 16391-16682 Sentence denotes Patients with a substitution at position I38 in the viral polymerase acidic protein (PA/I38X) of the baloxavir-resistant virus exhibited sustained alleviation and virus clearance, and baloxavir-resistant viruses were not cross-resistant to favipiravir and oseltamivir (Omoto, et al., 2018) .
TextSentencer_T93 16683-16871 Sentence denotes Baloxavir-resistant viruses were identified after 3-9 days in 9.7% (36/370) of baloxavir-treated immunocompetent adults and adolescents (Uehara, et al., 2019) . (Takashita, et al., 2016) .
T72660 16683-16871 Sentence denotes Baloxavir-resistant viruses were identified after 3-9 days in 9.7% (36/370) of baloxavir-treated immunocompetent adults and adolescents (Uehara, et al., 2019) . (Takashita, et al., 2016) .
TextSentencer_T94 16872-17068 Sentence denotes Although the number of cases is limited, 57 pairs might be sufficient to detect a virus resistant to the current anti-influenza drug, suggesting that favipiravir-resistant mutants will not appear.
T87974 16872-17068 Sentence denotes Although the number of cases is limited, 57 pairs might be sufficient to detect a virus resistant to the current anti-influenza drug, suggesting that favipiravir-resistant mutants will not appear.
TextSentencer_T95 17069-17328 Sentence denotes Favipiravir alone may maintain its efficacy from the beginning to the end of an influenza pandemic without replacement by resistant strains for J o u r n a l P r e -p r o o f which the effectiveness of drugs is reduced during treatment or during the pandemic.
T5505 17069-17328 Sentence denotes Favipiravir alone may maintain its efficacy from the beginning to the end of an influenza pandemic without replacement by resistant strains for J o u r n a l P r e -p r o o f which the effectiveness of drugs is reduced during treatment or during the pandemic.
TextSentencer_T96 17329-17401 Sentence denotes An influenza pandemic is a global outbreak of a novel influenza A virus.
T12355 17329-17401 Sentence denotes An influenza pandemic is a global outbreak of a novel influenza A virus.
TextSentencer_T97 17402-17564 Sentence denotes Pandemics occur when novel influenza A viruses emerge that are able to infect people easily and spread from person to person in an efficient and sustained manner.
T42026 17402-17564 Sentence denotes Pandemics occur when novel influenza A viruses emerge that are able to infect people easily and spread from person to person in an efficient and sustained manner.
TextSentencer_T98 17565-17743 Sentence denotes Two decades have elapsed since an avian influenza case was reported in Hong Kong in 1997, and a decade has elapsed since the most recent influenza pandemic that occurred in 2009.
T83058 17565-17743 Sentence denotes Two decades have elapsed since an avian influenza case was reported in Hong Kong in 1997, and a decade has elapsed since the most recent influenza pandemic that occurred in 2009.
TextSentencer_T99 17744-17985 Sentence denotes Sporadic cases of A(H5N1) and A(H7N9) influenza infections have been accumulating, and we must prepare for these strains or other novel influenza strains that might progress to an influenza pandemic and spread globally, such as A(H1N1)pdm09.
T74760 17744-17985 Sentence denotes Sporadic cases of A(H5N1) and A(H7N9) influenza infections have been accumulating, and we must prepare for these strains or other novel influenza strains that might progress to an influenza pandemic and spread globally, such as A(H1N1)pdm09.
TextSentencer_T100 17986-18324 Sentence denotes Influenza pandemics can cause severe pneumonia, Favipiravir is significantly more effective in treating mice with severe influenza infections characterized by a high viral load than oseltamivir (Takahashi, et al., 2003) , and a J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir-resistant virus does not emerge during treatment.
T40289 17986-18324 Sentence denotes Influenza pandemics can cause severe pneumonia, Favipiravir is significantly more effective in treating mice with severe influenza infections characterized by a high viral load than oseltamivir (Takahashi, et al., 2003) , and a J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir-resistant virus does not emerge during treatment.
TextSentencer_T101 18325-18526 Sentence denotes This outstanding feature of favipiravir as an anti-influenza drug has been exploited in treating patients with severe influenza in combination with oseltamivir in China (Cao, 2018; Wang et al., 2019) .
T61669 18325-18526 Sentence denotes This outstanding feature of favipiravir as an anti-influenza drug has been exploited in treating patients with severe influenza in combination with oseltamivir in China (Cao, 2018; Wang et al., 2019) .
TextSentencer_T102 18527-18661 Sentence denotes Favipiravir and oseltamivir combination therapy accelerated clinical recovery compared to oseltamivir monotherapy in severe influenza.
T87983 18527-18661 Sentence denotes Favipiravir and oseltamivir combination therapy accelerated clinical recovery compared to oseltamivir monotherapy in severe influenza.
TextSentencer_T103 18662-18915 Sentence denotes The dose of favipiravir used in the study mentioned above was 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 9 days, and the approved favipiravir dose in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days.
T46037 18662-18915 Sentence denotes The dose of favipiravir used in the study mentioned above was 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 9 days, and the approved favipiravir dose in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days.
TextSentencer_T104 18916-19032 Sentence denotes The viral replication period is 6 days or longer for seasonal influenza (Lina, et al., 2018; Memoli, et al., 2014) .
T29901 18916-19032 Sentence denotes The viral replication period is 6 days or longer for seasonal influenza (Lina, et al., 2018; Memoli, et al., 2014) .
TextSentencer_T105 19033-19175 Sentence denotes When drug administration is stopped during the virus replication period or when resistant strains appear, virus replication and fever relapse.
T19110 19033-19175 Sentence denotes When drug administration is stopped during the virus replication period or when resistant strains appear, virus replication and fever relapse.
TextSentencer_T106 19176-19428 Sentence denotes Thus, 10 days of administration may be required for severe influenza or novel influenza. whether the next pandemic will occur are difficult to determine, but researchers are currently concerned about the A(H5N1) and A(H7N9) strains with high lethality.
T4093 19176-19428 Sentence denotes Thus, 10 days of administration may be required for severe influenza or novel influenza. whether the next pandemic will occur are difficult to determine, but researchers are currently concerned about the A(H5N1) and A(H7N9) strains with high lethality.
TextSentencer_T107 19429-19550 Sentence denotes When these strains adapt to humans and become pandemic, their pathogenicity may be milder, similar to previous pandemics.
T79263 19429-19550 Sentence denotes When these strains adapt to humans and become pandemic, their pathogenicity may be milder, similar to previous pandemics.
TextSentencer_T108 19551-19670 Sentence denotes If an influenza pandemic causes severe disease, it may cause substantial damage to human health and social dysfunction.
T4156 19551-19670 Sentence denotes If an influenza pandemic causes severe disease, it may cause substantial damage to human health and social dysfunction.
TextSentencer_T109 19671-19739 Sentence denotes The need for pandemic countermeasures is an important consideration.
T84871 19671-19739 Sentence denotes The need for pandemic countermeasures is an important consideration.
TextSentencer_T110 19740-19904 Sentence denotes Favipiravir has a broad spectrum of activity toward RNA viruses, including life-threatening RNA viruses, and exhibits efficacy in animal models of these infections.
T52351 19740-19904 Sentence denotes Favipiravir has a broad spectrum of activity toward RNA viruses, including life-threatening RNA viruses, and exhibits efficacy in animal models of these infections.
TextSentencer_T111 19905-19989 Sentence denotes Table 1 summarizes the efficacy of favipiravir in animal models of human infections.
T30219 19905-19989 Sentence denotes Table 1 summarizes the efficacy of favipiravir in animal models of human infections.
TextSentencer_T112 19990-20270 Sentence denotes Based on the efficacy in animal models, it ha s been used to treat humans with diseases such as Ebola virus infection (Bai, et al., 2016; Jacobs, et al., 2015; Sissoko, et al., 2016) , Lassa fever (Raabe, et al., 2017) , norovirus (Ruis, et al., 2018) , and rabies (Baker, 2017) .
T91397 19990-20270 Sentence denotes Based on the efficacy in animal models, it ha s been used to treat humans with diseases such as Ebola virus infection (Bai, et al., 2016; Jacobs, et al., 2015; Sissoko, et al., 2016) , Lassa fever (Raabe, et al., 2017) , norovirus (Ruis, et al., 2018) , and rabies (Baker, 2017) .
TextSentencer_T113 20271-20441 Sentence denotes Notably, as a broad spectrum anti-RNA virus drug, favipiravir has been submitted for additional indications for SFTS in Japan, based on clinical trials (Yasukawa, 2016) .
T4018 20271-20441 Sentence denotes Notably, as a broad spectrum anti-RNA virus drug, favipiravir has been submitted for additional indications for SFTS in Japan, based on clinical trials (Yasukawa, 2016) .
TextSentencer_T114 20442-20768 Sentence denotes The broad spectrum of activity of favipiravir toward RNA viruses has been reviewed, including anti-RNA virus activity in vitro and in vivo in animal models (Delang, Abdelnabi, prophylaxis (PEP) was shown in a mouse model (Smither, et al., 2014) and a therapeutic mouse model of Ebola virus disease (Oestereich, et al., 2014) .
T99677 20442-20768 Sentence denotes The broad spectrum of activity of favipiravir toward RNA viruses has been reviewed, including anti-RNA virus activity in vitro and in vivo in animal models (Delang, Abdelnabi, prophylaxis (PEP) was shown in a mouse model (Smither, et al., 2014) and a therapeutic mouse model of Ebola virus disease (Oestereich, et al., 2014) .
TextSentencer_T115 20769-20990 Sentence denotes Treatment with favipiravir from 6 to 13 days after lethal infection with Ebola virus cured all mice when the treatment was started at the initiation of liver damage (elevation of AST and ALT) and virus detection in blood.
T66796 20769-20990 Sentence denotes Treatment with favipiravir from 6 to 13 days after lethal infection with Ebola virus cured all mice when the treatment was started at the initiation of liver damage (elevation of AST and ALT) and virus detection in blood.
TextSentencer_T116 20991-21142 Sentence denotes However, the administration of favipiravir from 8 to 14 days prolonged survival, but four of five mice died when the liver damage and viremia advanced.
T2072 20991-21142 Sentence denotes However, the administration of favipiravir from 8 to 14 days prolonged survival, but four of five mice died when the liver damage and viremia advanced.
TextSentencer_T117 21143-21415 Sentence denotes Early treatment with favipiravir was effective, but when the disease is advanced, including liver damage, the efficacy in prolonging survival is limited to one of five mice, indicating that treatment should be started before liver damage progresses to irreversible levels.
T39204 21143-21415 Sentence denotes Early treatment with favipiravir was effective, but when the disease is advanced, including liver damage, the efficacy in prolonging survival is limited to one of five mice, indicating that treatment should be started before liver damage progresses to irreversible levels.
TextSentencer_T118 21416-21607 Sentence denotes Thus, favipiravir may be able to cure an Ebola virus infection in the early phase of infection, but the curative activity of favipiravir may be limited in patients with an advanced infection.
T66867 21416-21607 Sentence denotes Thus, favipiravir may be able to cure an Ebola virus infection in the early phase of infection, but the curative activity of favipiravir may be limited in patients with an advanced infection.
TextSentencer_T119 21608-21812 Sentence denotes The dose of favipiravir used to treat a human with an Ebola virus infection is 6,000 mg on the first day and 2,400 mg/day on days 1-9 for a total of 27,600 mg when administered for both PEP and treatment.
T51064 21608-21812 Sentence denotes The dose of favipiravir used to treat a human with an Ebola virus infection is 6,000 mg on the first day and 2,400 mg/day on days 1-9 for a total of 27,600 mg when administered for both PEP and treatment.
TextSentencer_T120 21813-22108 Sentence denotes Four of eight health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, were administered PEP with favipiravir alone or favipiravir with other anti-Ebola agents and did not develop Ebola virus disease (Jacobs, et al., 2015) .
T67948 21813-22108 Sentence denotes Four of eight health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, were administered PEP with favipiravir alone or favipiravir with other anti-Ebola agents and did not develop Ebola virus disease (Jacobs, et al., 2015) .
TextSentencer_T121 22109-22350 Sentence denotes Although the needle stick had not been confirmed to result in infection, the probability of infection was high based on previous observations, and PEP was considered effective, as observed in PEP using a mouse model (Smither, et al., 2014 ).
T82877 22109-22350 Sentence denotes Although the needle stick had not been confirmed to result in infection, the probability of infection was high based on previous observations, and PEP was considered effective, as observed in PEP using a mouse model (Smither, et al., 2014 ).
TextSentencer_T122 22351-22492 Sentence denotes An Ebola study conducted in Guinea included 126 patients, and 111 were analyzed and compared with 540 patients as a historical control group.
T9211 22351-22492 Sentence denotes An Ebola study conducted in Guinea included 126 patients, and 111 were analyzed and compared with 540 patients as a historical control group.
TextSentencer_T123 22493-22759 Sentence denotes Favipiravir treatment reduced the mortality rate in the low viral load group to 33% compared with the historical control group that was not treated with favipiravir, but this reduction in the mortality rate was not statistically significant (Sissoko, et al., 2016) .
T84037 22493-22759 Sentence denotes Favipiravir treatment reduced the mortality rate in the low viral load group to 33% compared with the historical control group that was not treated with favipiravir, but this reduction in the mortality rate was not statistically significant (Sissoko, et al., 2016) .
TextSentencer_T124 22760-22822 Sentence denotes An Ebola study conducted in Sierra Leone (Bai, et al., 2016) .
T53090 22760-22822 Sentence denotes An Ebola study conducted in Sierra Leone (Bai, et al., 2016) .
TextSentencer_T125 22823-23218 Sentence denotes During the 2014 epidemic of Ebola virus infection in West Africa, patients who were treated without favipiravir in the period before preparation for favipiravir treatment were classified as historical controls, and the therapeutic efficacy of favipiravir was compared between the patient group treated with favipiravir and the historical patient group in the two clinical trials described above.
T72132 22823-23218 Sentence denotes During the 2014 epidemic of Ebola virus infection in West Africa, patients who were treated without favipiravir in the period before preparation for favipiravir treatment were classified as historical controls, and the therapeutic efficacy of favipiravir was compared between the patient group treated with favipiravir and the historical patient group in the two clinical trials described above.
TextSentencer_T126 23219-23468 Sentence denotes Randomized placebo-controlled trials are desirable for confirming therapeutic effects in clinical trials, but the placebo group has an ethical problem of not being able to receive an effective drug that can recover fatal infections in animal models.
T76245 23219-23468 Sentence denotes Randomized placebo-controlled trials are desirable for confirming therapeutic effects in clinical trials, but the placebo group has an ethical problem of not being able to receive an effective drug that can recover fatal infections in animal models.
TextSentencer_T127 23469-23763 Sentence denotes The studies were conducted to compare the effectiveness of favipiravir treatment between patients who were not treated in the period prior to the start of drug administration as the historical control patient group and those who were treated with favipiravir after the clinical study was ready.
T22598 23469-23763 Sentence denotes The studies were conducted to compare the effectiveness of favipiravir treatment between patients who were not treated in the period prior to the start of drug administration as the historical control patient group and those who were treated with favipiravir after the clinical study was ready.
TextSentencer_T128 23764-23917 Sentence denotes The number of patients is limited, and favipiravir has been used as an emergency or compassionate treatment for Lassa fever, norovirus, and rabies cases.
T90780 23764-23917 Sentence denotes The number of patients is limited, and favipiravir has been used as an emergency or compassionate treatment for Lassa fever, norovirus, and rabies cases.
TextSentencer_T129 23918-24015 Sentence denotes This review focuses on human administration in terms of the broad spectrum of RNA virus activity.
T6849 23918-24015 Sentence denotes This review focuses on human administration in terms of the broad spectrum of RNA virus activity.
TextSentencer_T130 24016-24151 Sentence denotes Therefore, favipiravir has been positioned as a valuable anti-influenza drug and a broad spectrum anti-RNA drug, as listed in Table 1 .
T54301 24016-24151 Sentence denotes Therefore, favipiravir has been positioned as a valuable anti-influenza drug and a broad spectrum anti-RNA drug, as listed in Table 1 .
TextSentencer_T131 24152-24390 Sentence denotes Favipiravir has been used in human therapy for Ebola hemorrhagic fever (Jacobs, et al., 2015; Sissoko, et al., 2016) , Lassa fever (Raabe, et al., 2017) , norovirus (Ruis, et al., 2018) , rabies (Baker, 2017) , and SFTS (Yasukawa, 2016) .
T89622 24152-24390 Sentence denotes Favipiravir has been used in human therapy for Ebola hemorrhagic fever (Jacobs, et al., 2015; Sissoko, et al., 2016) , Lassa fever (Raabe, et al., 2017) , norovirus (Ruis, et al., 2018) , rabies (Baker, 2017) , and SFTS (Yasukawa, 2016) .
TextSentencer_T132 24391-24487 Sentence denotes Some treatments were used in emergencies, and some were used in the setting of a clinical trial.
T44432 24391-24487 Sentence denotes Some treatments were used in emergencies, and some were used in the setting of a clinical trial.
TextSentencer_T133 24488-24805 Sentence denotes In addition, combination therapy of favipiravir with the other existing therapies is also an option and favipiravir and oseltamivir combination therapy showed accelerated clinical recovery J o u r n a l P r e -p r o o f compared to oseltamivir monotherapy in severe influenza in China (Cao, 2018; Wang et al., 2019) .
T63322 24488-24805 Sentence denotes In addition, combination therapy of favipiravir with the other existing therapies is also an option and favipiravir and oseltamivir combination therapy showed accelerated clinical recovery J o u r n a l P r e -p r o o f compared to oseltamivir monotherapy in severe influenza in China (Cao, 2018; Wang et al., 2019) .
TextSentencer_T134 24806-25056 Sentence denotes The antiviral activity (EC 50 ) of favipiravir against influenza and Ebola viruses is different from the range of 0.014-0.55 μg/mL in medium without adenosine and guanosine and 10 μg/mL, respectively (Furuta, et al., 2002; Oestereich, et al., 2014) .
T58897 24806-25056 Sentence denotes The antiviral activity (EC 50 ) of favipiravir against influenza and Ebola viruses is different from the range of 0.014-0.55 μg/mL in medium without adenosine and guanosine and 10 μg/mL, respectively (Furuta, et al., 2002; Oestereich, et al., 2014) .
TextSentencer_T135 25057-25248 Sentence denotes Addition of 10 x EC 50 (63.7 μM) of adenine, guanine, adenosine, guanosine, and inosine in the assay medium abolishes the anti-influenza virus activity of favipiravir (Furuta, et al., 2005) .
T76846 25057-25248 Sentence denotes Addition of 10 x EC 50 (63.7 μM) of adenine, guanine, adenosine, guanosine, and inosine in the assay medium abolishes the anti-influenza virus activity of favipiravir (Furuta, et al., 2005) .
TextSentencer_T136 25249-25567 Sentence denotes The intracellular concentration of ATP is 1-9 mM in various tissues (Beis & Newsholme, 1975 The approved favipiravir dose for influenza in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days, and the dose for Ebloa virus infection is 6,000 mg on the first day and 2,400 mg/day on days 1-9.
T77974 25249-25567 Sentence denotes The intracellular concentration of ATP is 1-9 mM in various tissues (Beis & Newsholme, 1975 The approved favipiravir dose for influenza in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days, and the dose for Ebloa virus infection is 6,000 mg on the first day and 2,400 mg/day on days 1-9.
TextSentencer_T137 25568-25845 Sentence denotes The antiviral concentration of favipiravir in influenza is achieved in the lung epithelium by diffusion from the blood, and in the case of Ebola virus infection, direct perfusion of blood reaches target tissues, vascular endothelial cells, hematopoietic cells, and hepatocytes.
T9824 25568-25845 Sentence denotes The antiviral concentration of favipiravir in influenza is achieved in the lung epithelium by diffusion from the blood, and in the case of Ebola virus infection, direct perfusion of blood reaches target tissues, vascular endothelial cells, hematopoietic cells, and hepatocytes.
TextSentencer_T138 25846-25981 Sentence denotes Differences in the two factors between antiviral concentrations and target cells do not appear to be significantly reflected in dosage.
T18990 25846-25981 Sentence denotes Differences in the two factors between antiviral concentrations and target cells do not appear to be significantly reflected in dosage.
TextSentencer_T139 25982-26072 Sentence denotes Intravenous preparations are being prepared to improve oral administration of favipiravir.
T16724 25982-26072 Sentence denotes Intravenous preparations are being prepared to improve oral administration of favipiravir.
TextSentencer_T140 26073-26121 Sentence denotes J o u r n a l P r e -p r o o f Journal Pre-proof
T50309 26073-26121 Sentence denotes J o u r n a l P r e -p r o o f Journal Pre-proof
TextSentencer_T141 26122-26272 Sentence denotes Favipiravir inhibits viral RdRp by terminating elongation at the incorporation site as a chain terminator (Jin, et al., 2013; Sangawa, et al., 2013) .
T44264 26122-26272 Sentence denotes Favipiravir inhibits viral RdRp by terminating elongation at the incorporation site as a chain terminator (Jin, et al., 2013; Sangawa, et al., 2013) .
TextSentencer_T142 26273-26416 Sentence denotes Favipiravir functions as a purine analogue, as expected from the chemical structure, and it is incorporated instead of guanosine and adenosine.
T51718 26273-26416 Sentence denotes Favipiravir functions as a purine analogue, as expected from the chemical structure, and it is incorporated instead of guanosine and adenosine.
TextSentencer_T143 26417-26700 Sentence denotes Favipiravir terminates elongation after the incorporation of a single favipiravir molecule (Sangawa, et al., 2013) and after the incorporation of two consecutive favipiravir molecules (Jin, et al., 2013) , and the synthesis of this complementary viral RNA strand cannot be completed.
T19813 26417-26700 Sentence denotes Favipiravir terminates elongation after the incorporation of a single favipiravir molecule (Sangawa, et al., 2013) and after the incorporation of two consecutive favipiravir molecules (Jin, et al., 2013) , and the synthesis of this complementary viral RNA strand cannot be completed.
TextSentencer_T144 26701-26882 Sentence denotes In contrast, the anti-RNA virus drug ribavirin is incorporated into the replicating strand, which further elongates and accumulates mismatched nucleotides at the incorporated sites.
T26494 26701-26882 Sentence denotes In contrast, the anti-RNA virus drug ribavirin is incorporated into the replicating strand, which further elongates and accumulates mismatched nucleotides at the incorporated sites.
TextSentencer_T145 26883-27114 Sentence denotes Base pairing with ribavirin in the complementary strand during replication, transcription, and translation of the RNA strand causes mismatched base pairing, the production of nonfunctional proteins, and a loss of viral infectivity.
T92928 26883-27114 Sentence denotes Base pairing with ribavirin in the complementary strand during replication, transcription, and translation of the RNA strand causes mismatched base pairing, the production of nonfunctional proteins, and a loss of viral infectivity.
TextSentencer_T146 27115-27320 Sentence denotes Accumulated mutations (mismatched nucleotides) cause the replicated viruses to lose their replicative capability, which is known as "lethal mutagenesis" (Vignuzzi, Stone, & Andino, 2005) , as shown in Fig.
T53261 27115-27320 Sentence denotes Accumulated mutations (mismatched nucleotides) cause the replicated viruses to lose their replicative capability, which is known as "lethal mutagenesis" (Vignuzzi, Stone, & Andino, 2005) , as shown in Fig.
TextSentencer_T147 27322-27445 Sentence denotes RdRp that affect ribavirin incorporation are produced, drug-resistant viruses can be selected in the presence of ribavirin.
T93343 27322-27445 Sentence denotes RdRp that affect ribavirin incorporation are produced, drug-resistant viruses can be selected in the presence of ribavirin.
TextSentencer_T148 27446-27843 Sentence denotes Favipiravir treatment increases the frequency of transition (Delang, et al., 2014; Goldhill, et al., 2019; Vanderlinden, et al., 2016) and transversion (Baranovich, et al., 2013) in viral genomes, and these mutations are hypothesized to be caused by favipiravir, resulting in lethal mutagenesis (Baranovich, et al., 2013; Delang, et al., 2014; Goldhill, et al., 2019; Vanderlinden, et al., 2016) .
T66997 27446-27843 Sentence denotes Favipiravir treatment increases the frequency of transition (Delang, et al., 2014; Goldhill, et al., 2019; Vanderlinden, et al., 2016) and transversion (Baranovich, et al., 2013) in viral genomes, and these mutations are hypothesized to be caused by favipiravir, resulting in lethal mutagenesis (Baranovich, et al., 2013; Delang, et al., 2014; Goldhill, et al., 2019; Vanderlinden, et al., 2016) .
TextSentencer_T149 27844-28189 Sentence denotes We observed a transition of influenza virus and poliovirus in cultures treated with favipiravir but did not assess the frequency because we were unable to J o u r n a l P r e -p r o o f Journal Pre-proof compare the transition rate with the proper antiviral agents with similar mechanisms as a control Daikoku, Yoshida, Okuda, & Shiraki, 2014) .
T37407 27844-28189 Sentence denotes We observed a transition of influenza virus and poliovirus in cultures treated with favipiravir but did not assess the frequency because we were unable to J o u r n a l P r e -p r o o f Journal Pre-proof compare the transition rate with the proper antiviral agents with similar mechanisms as a control Daikoku, Yoshida, Okuda, & Shiraki, 2014) .
TextSentencer_T150 28190-28258 Sentence denotes Ribavirin is known to cause lethal mutagenesis, as shown in Fig. 5 .
T74153 28190-28258 Sentence denotes Ribavirin is known to cause lethal mutagenesis, as shown in Fig. 5 .
TextSentencer_T151 28259-28426 Sentence denotes Ribavirin is incorporated into the elongating RNA strand, resulting in the production of multiple mismatches that lead to lethal mutagenesis (Vignuzzi, et al., 2005) .
T3244 28259-28426 Sentence denotes Ribavirin is incorporated into the elongating RNA strand, resulting in the production of multiple mismatches that lead to lethal mutagenesis (Vignuzzi, et al., 2005) .
TextSentencer_T152 28427-28630 Sentence denotes Favipiravir inhibits RNA synthesis through chain termination, and this inhibitory mechanism more consistently explains the observations reported than a mechanism similar to ribavirin, as described below.
T89150 28427-28630 Sentence denotes Favipiravir inhibits RNA synthesis through chain termination, and this inhibitory mechanism more consistently explains the observations reported than a mechanism similar to ribavirin, as described below.
TextSentencer_T153 28631-28824 Sentence denotes Favipiravir-4-ribofuranosyl-5'-triphosphate (RTP) has a higher affinity for the RdRp of influenza virus than GTP and functions as a chain terminator (Jin, et al., 2013; Sangawa, et al., 2013) .
T15667 28631-28824 Sentence denotes Favipiravir-4-ribofuranosyl-5'-triphosphate (RTP) has a higher affinity for the RdRp of influenza virus than GTP and functions as a chain terminator (Jin, et al., 2013; Sangawa, et al., 2013) .
TextSentencer_T154 28825-29014 Sentence denotes Favipiravir-RTP and ribavirin TP inhibit the RdRp activity in a dose-dependent manner, with 50% inhibitory concentrations (IC 50 s) of 0.14 and 2.4 μM, respectively (Furuta, et al., 2005) .
T67227 28825-29014 Sentence denotes Favipiravir-RTP and ribavirin TP inhibit the RdRp activity in a dose-dependent manner, with 50% inhibitory concentrations (IC 50 s) of 0.14 and 2.4 μM, respectively (Furuta, et al., 2005) .
TextSentencer_T155 29015-29123 Sentence denotes The RdRp activity was determined by measuring the incorporation of labeled GTP in the elongating RNA strand.
T4228 29015-29123 Sentence denotes The RdRp activity was determined by measuring the incorporation of labeled GTP in the elongating RNA strand.
TextSentencer_T156 29124-29287 Sentence denotes Favipiravir-RTP has a higher affinity for RdRp than GTP, and when incorporated, favipiravir-RTP stops the elongation of the RNA strand in which it is incorporated.
T50104 29124-29287 Sentence denotes Favipiravir-RTP has a higher affinity for RdRp than GTP, and when incorporated, favipiravir-RTP stops the elongation of the RNA strand in which it is incorporated.
TextSentencer_T157 29288-29435 Sentence denotes This termination prevents the incorporation of radioactivity, and thus favipiravir-RTP exhibits high inhibitory activity and a low IC 50 (0.14 μM).
T75404 29288-29435 Sentence denotes This termination prevents the incorporation of radioactivity, and thus favipiravir-RTP exhibits high inhibitory activity and a low IC 50 (0.14 μM).
TextSentencer_T158 29436-29659 Sentence denotes On the other hand, ribavirin induces competitive inhibition with GTP, and incorporation results in mismatch mutations; the strand continues to elongate and incorporate labeled GTP without stopping at the incorporation site.
T39918 29436-29659 Sentence denotes On the other hand, ribavirin induces competitive inhibition with GTP, and incorporation results in mismatch mutations; the strand continues to elongate and incorporate labeled GTP without stopping at the incorporation site.
TextSentencer_T159 29660-29786 Sentence denotes Thus, ribavirin has a high IC 50 value (2.4 μM) because its RNA strand is further elongated by incorporating radiolabeled GTP.
T1013 29660-29786 Sentence denotes Thus, ribavirin has a high IC 50 value (2.4 μM) because its RNA strand is further elongated by incorporating radiolabeled GTP.
TextSentencer_T160 29787-29907 Sentence denotes Therefore, its ability to inhibit enzyme activity becomes weaker, and it displays a higher IC 50 value than favipiravir.
T22563 29787-29907 Sentence denotes Therefore, its ability to inhibit enzyme activity becomes weaker, and it displays a higher IC 50 value than favipiravir.
TextSentencer_T161 29908-30094 Sentence denotes Furthermore, a marked decrease in the amount of the viral genome has been observed in favipiravir-treated cultures compared with ribavirin-treated cultures (Vanderlinden, et al., 2016) .
T10889 29908-30094 Sentence denotes Furthermore, a marked decrease in the amount of the viral genome has been observed in favipiravir-treated cultures compared with ribavirin-treated cultures (Vanderlinden, et al., 2016) .
TextSentencer_T162 30095-30386 Sentence denotes Favipiravir is incorporated into the viral genome and terminates elongation, resulting in shorter genome sizes and the marked loss of the viral genome in favipiravir-treated cultures J o u r n a l P r e -p r o o f Journal Pre-proof (Rocha-Pereira, et al., 2012; Vanderlinden, et al., 2016) .
T35442 30095-30386 Sentence denotes Favipiravir is incorporated into the viral genome and terminates elongation, resulting in shorter genome sizes and the marked loss of the viral genome in favipiravir-treated cultures J o u r n a l P r e -p r o o f Journal Pre-proof (Rocha-Pereira, et al., 2012; Vanderlinden, et al., 2016) .
TextSentencer_T163 30387-30481 Sentence denotes These observations are consistently explained by the chain termination induced by favipiravir.
T99007 30387-30481 Sentence denotes These observations are consistently explained by the chain termination induced by favipiravir.
TextSentencer_T164 30482-30681 Sentence denotes Proofreading activity mediated by enzymes such as the 3'-5' exonuclease of herpesvirus DNA polymerase removes the terminal mismatched base and corrects the base pairing during the elongation process.
T67759 30482-30681 Sentence denotes Proofreading activity mediated by enzymes such as the 3'-5' exonuclease of herpesvirus DNA polymerase removes the terminal mismatched base and corrects the base pairing during the elongation process.
TextSentencer_T165 30682-30826 Sentence denotes Viral RdRp lacks proofreading activity and is unable to complete the elongation step when favipiravir-RTP is incorporated as a chain terminator.
T95250 30682-30826 Sentence denotes Viral RdRp lacks proofreading activity and is unable to complete the elongation step when favipiravir-RTP is incorporated as a chain terminator.
TextSentencer_T166 30827-30945 Sentence denotes Coronavirus has been reported to expresses a 3'-to-5'exoribonuclease and its proofreading function among RNA viruses .
T29710 30827-30945 Sentence denotes Coronavirus has been reported to expresses a 3'-to-5'exoribonuclease and its proofreading function among RNA viruses .
TextSentencer_T167 30946-31116 Sentence denotes Acyclovir causes chain termination at the incorporated site during the elongation of herpes simplex virus and varicella-zoster virus DNA and prevents viral DNA synthesis.
T28144 30946-31116 Sentence denotes Acyclovir causes chain termination at the incorporated site during the elongation of herpes simplex virus and varicella-zoster virus DNA and prevents viral DNA synthesis.
TextSentencer_T168 31117-31253 Sentence denotes However, the incorporated acyclovir is removed by the proofreading activity of viral DNA polymerase, and viral DNA elongation continues.
T94978 31117-31253 Sentence denotes However, the incorporated acyclovir is removed by the proofreading activity of viral DNA polymerase, and viral DNA elongation continues.
TextSentencer_T169 31254-31736 Sentence denotes Therefore, the sequence containing the guanosine homopolymeric string (G-string) in the genome is the target of the incorporation and removal of acyclovir, and the incorporation of guanosine followed by repeated corrections by the proofreading machinery create a hot spot of mutations in G-strings of our laboratory and clinical acyclovir-resistant isolates (Akahoshi, et al., 2017; Daikoku, et al., 2016; Ida, et al., 1999; Shimada, et al., 2007; Talarico, Phelps, & Biron, 1993) .
T1288 31254-31736 Sentence denotes Therefore, the sequence containing the guanosine homopolymeric string (G-string) in the genome is the target of the incorporation and removal of acyclovir, and the incorporation of guanosine followed by repeated corrections by the proofreading machinery create a hot spot of mutations in G-strings of our laboratory and clinical acyclovir-resistant isolates (Akahoshi, et al., 2017; Daikoku, et al., 2016; Ida, et al., 1999; Shimada, et al., 2007; Talarico, Phelps, & Biron, 1993) .
TextSentencer_T170 31737-32053 Sentence denotes Penciclovir (famciclovir) and ganciclovir (valganciclovir), which are guanosine analogues, function as an anti-herpes simplex virus and varicella-zoster virus agent and anti-cytomegalovirus agent, respectively, with mechanisms similar to acyclovir, but they do not induce mutations or have hot spots in the G-string.
T14268 31737-32053 Sentence denotes Penciclovir (famciclovir) and ganciclovir (valganciclovir), which are guanosine analogues, function as an anti-herpes simplex virus and varicella-zoster virus agent and anti-cytomegalovirus agent, respectively, with mechanisms similar to acyclovir, but they do not induce mutations or have hot spots in the G-string.
TextSentencer_T171 32054-32216 Sentence denotes These compounds do not prevent elongation at the incorporation site but are incorporated, and elongation pauses at normal nucleotides after the incorporated site.
T67498 32054-32216 Sentence denotes These compounds do not prevent elongation at the incorporation site but are incorporated, and elongation pauses at normal nucleotides after the incorporated site.
TextSentencer_T172 32217-32534 Sentence denotes Therefore, mutations associated with proofreading do not occur in the G-string, and this J o u r n a l P r e -p r o o f difference in the mode of chain termination and proofreading activity causes a lower mutation frequency in subjects treated with penciclovir and ganciclovir than in subjects treated with acyclovir.
T40687 32217-32534 Sentence denotes Therefore, mutations associated with proofreading do not occur in the G-string, and this J o u r n a l P r e -p r o o f difference in the mode of chain termination and proofreading activity causes a lower mutation frequency in subjects treated with penciclovir and ganciclovir than in subjects treated with acyclovir.
TextSentencer_T173 32535-32766 Sentence denotes If favipiravir induces mismatches as a mutagen, favipiravir should allow elongation after its incorporation into the elongating RNA strand and induce mismatches at the favipiravir-incorporated sites in the new complementary strand.
T74657 32535-32766 Sentence denotes If favipiravir induces mismatches as a mutagen, favipiravir should allow elongation after its incorporation into the elongating RNA strand and induce mismatches at the favipiravir-incorporated sites in the new complementary strand.
TextSentencer_T174 32767-32856 Sentence denotes This possibility is inconsistent with the mechanism of favipiravir as a chain terminator.
T97219 32767-32856 Sentence denotes This possibility is inconsistent with the mechanism of favipiravir as a chain terminator.
TextSentencer_T175 32857-33080 Sentence denotes Thus, the increased mutation rates observed in response to favipiravir treatment are unlikely to be due to the incorporation of favipiravir into viral RNA followed by elongation, similar to ribavirin or acyclovir (Fig. 5) .
T66105 32857-33080 Sentence denotes Thus, the increased mutation rates observed in response to favipiravir treatment are unlikely to be due to the incorporation of favipiravir into viral RNA followed by elongation, similar to ribavirin or acyclovir (Fig. 5) .
TextSentencer_T176 33081-33215 Sentence denotes Favipiravir is unlikely to induce mismatches upon its incorporation into the RNA strand and transitions in the influenza virus genome.
T18053 33081-33215 Sentence denotes Favipiravir is unlikely to induce mismatches upon its incorporation into the RNA strand and transitions in the influenza virus genome.
TextSentencer_T177 33216-33437 Sentence denotes The increased rate of transition mutations observed after favipiravir treatment is presumed to be due to the biased nucleotide pool induced by the increase in the level of favipiravir-RTP and the properties of viral RdRp.
T6233 33216-33437 Sentence denotes The increased rate of transition mutations observed after favipiravir treatment is presumed to be due to the biased nucleotide pool induced by the increase in the level of favipiravir-RTP and the properties of viral RdRp.
TextSentencer_T178 33438-33572 Sentence denotes A biased nucleotide pool is a major factor that promotes polymerase-induced mutation synthesis (Wheeler, Rajagopal, & Mathews, 2005) .
T89514 33438-33572 Sentence denotes A biased nucleotide pool is a major factor that promotes polymerase-induced mutation synthesis (Wheeler, Rajagopal, & Mathews, 2005) .
TextSentencer_T179 33573-33715 Sentence denotes Influenza RdRp complex is composed of PB1, PB2, and PA and requires four nucleotides, ATP, GTP, CTP, and UTP, as substrates for RNA synthesis.
T50845 33573-33715 Sentence denotes Influenza RdRp complex is composed of PB1, PB2, and PA and requires four nucleotides, ATP, GTP, CTP, and UTP, as substrates for RNA synthesis.
TextSentencer_T180 33716-33967 Sentence denotes Influenza RdRp incorporates mismatched nucleotides in a primer-extension-based misincorporation assay in the presence of completely biased nucleotide pools consisting of only three nucleotides instead of all four nucleotides (Aggarwal, et al., 2010) .
T52168 33716-33967 Sentence denotes Influenza RdRp incorporates mismatched nucleotides in a primer-extension-based misincorporation assay in the presence of completely biased nucleotide pools consisting of only three nucleotides instead of all four nucleotides (Aggarwal, et al., 2010) .
TextSentencer_T181 33968-34126 Sentence denotes Even if one of the four nucleotides is missing, its absence is compensated by other nucleotides, and the RNA strand continues to elongate, causing mismatches.
T74140 33968-34126 Sentence denotes Even if one of the four nucleotides is missing, its absence is compensated by other nucleotides, and the RNA strand continues to elongate, causing mismatches.
TextSentencer_T182 34127-34286 Sentence denotes Therefore, even in the absence of a mutagen, mismatches should occur during RNA synthesis under biased nucleotide pool conditions as if the mutagen is present.
T11526 34127-34286 Sentence denotes Therefore, even in the absence of a mutagen, mismatches should occur during RNA synthesis under biased nucleotide pool conditions as if the mutagen is present.
TextSentencer_T183 34287-34535 Sentence denotes Influenza RdRp displays a significantly higher fidelity than human immunodeficiency virus-1 reverse transcriptase and T7 RNA polymerase and an equivalent or higher fidelity than murine leukemia virus reverse transcriptase (Aggarwal, et al., 2010) .
T35079 34287-34535 Sentence denotes Influenza RdRp displays a significantly higher fidelity than human immunodeficiency virus-1 reverse transcriptase and T7 RNA polymerase and an equivalent or higher fidelity than murine leukemia virus reverse transcriptase (Aggarwal, et al., 2010) .
TextSentencer_T184 34536-35024 Sentence denotes The mutation frequency of influenza RdRp is 7.06 x 10 -4 nucleotides in wild-type H3N2 virus (Cheung, et al., 2014 ) and > 7.26 x 10 -5 nucleotides deduced from 108 sequenced clones of an average of 849 bases from the database (Drake, 1993) , and these values are much larger than those of herpesvirus DNA polymerases with proofreading activity at the levels of 1.38 x 10 -7 per nucleotide (Lee, et al., 2015) to 3 x 10 -9 substitutions per site per year (McGeoch, Dolan, & Ralph, 2000) .
T9569 34536-35024 Sentence denotes The mutation frequency of influenza RdRp is 7.06 x 10 -4 nucleotides in wild-type H3N2 virus (Cheung, et al., 2014 ) and > 7.26 x 10 -5 nucleotides deduced from 108 sequenced clones of an average of 849 bases from the database (Drake, 1993) , and these values are much larger than those of herpesvirus DNA polymerases with proofreading activity at the levels of 1.38 x 10 -7 per nucleotide (Lee, et al., 2015) to 3 x 10 -9 substitutions per site per year (McGeoch, Dolan, & Ralph, 2000) .
TextSentencer_T185 35025-35129 Sentence denotes These results indicate the low fidelity of the RdRp activity of influenza lacking proofreading activity.
T61222 35025-35129 Sentence denotes These results indicate the low fidelity of the RdRp activity of influenza lacking proofreading activity.
TextSentencer_T186 35130-35329 Sentence denotes Jurkat cells exposed to 500 μM guanosine for 24 h show an increase in GTP pools to 600% of the control and a decrease in ATP to 40% of the control (Batiuk, Schnizlein-Bick, Plotkin, & Dagher, 2001) .
T89915 35130-35329 Sentence denotes Jurkat cells exposed to 500 μM guanosine for 24 h show an increase in GTP pools to 600% of the control and a decrease in ATP to 40% of the control (Batiuk, Schnizlein-Bick, Plotkin, & Dagher, 2001) .
TextSentencer_T187 35330-35519 Sentence denotes Thus, the intracellular condition of biased nucleotide pools alone is sufficient to increase the ratios of mismatched transition mutations without treatment with mutagens such as ribavirin.
T35533 35330-35519 Sentence denotes Thus, the intracellular condition of biased nucleotide pools alone is sufficient to increase the ratios of mismatched transition mutations without treatment with mutagens such as ribavirin.
TextSentencer_T188 35520-35700 Sentence denotes Ribavirin reduces GTP levels by inhibiting inosine monophosphate dehydrogenase, but favipiravir has little effect on GTP levels (Furuta, et al., 2005; Vanderlinden, et al., 2016) .
T35101 35520-35700 Sentence denotes Ribavirin reduces GTP levels by inhibiting inosine monophosphate dehydrogenase, but favipiravir has little effect on GTP levels (Furuta, et al., 2005; Vanderlinden, et al., 2016) .
TextSentencer_T189 35701-35943 Sentence denotes As a guanosine analogue, extracellular favipiravir may bias the nucleotide pools, and favipiravir-RTP competes with GTP or ATP, resulting in an increase in the transition mutations, although data are not available to support this speculation.
T38095 35701-35943 Sentence denotes As a guanosine analogue, extracellular favipiravir may bias the nucleotide pools, and favipiravir-RTP competes with GTP or ATP, resulting in an increase in the transition mutations, although data are not available to support this speculation.
TextSentencer_T190 35944-36158 Sentence denotes An observed increase in the transition frequency is presumed to be due to the low fidelity of RdRp of influenza virus and misincorporation of nucleotides by the biased nucleotide pools in favipiravir-treated cells.
T27726 35944-36158 Sentence denotes An observed increase in the transition frequency is presumed to be due to the low fidelity of RdRp of influenza virus and misincorporation of nucleotides by the biased nucleotide pools in favipiravir-treated cells.
TextSentencer_T191 36159-36364 Sentence denotes Favipiravir is a chain terminator without direct mutagenic activity but increases the number of mismatches in the genome due to the induction of biased nucleotide pools in the favipiravir-treated cultures.
T30632 36159-36364 Sentence denotes Favipiravir is a chain terminator without direct mutagenic activity but increases the number of mismatches in the genome due to the induction of biased nucleotide pools in the favipiravir-treated cultures.
TextSentencer_T192 36365-36385 Sentence denotes Journal Pre-proof 7.
T52841 36365-36385 Sentence denotes Journal Pre-proof 7.
TextSentencer_T193 36386-36415 Sentence denotes Favipiravir-resistant mutants
T49349 36386-36415 Sentence denotes Favipiravir-resistant mutants
TextSentencer_T194 36416-36962 Sentence denotes We have isolated a herpes simplex virus resistant to acyclovir, phosphonoacetic acid, and foscarnet, a varicella-zoster virus resistant to acyclovir, penciclovir, foscarnet, and vidarabine, and a cytomegalovirus resistant to ganciclovir, foscarnet, and mizoribine by culturing the virus in the presence of these antiviral agents (Ida, et al., 2000; Ida, et al., 1999; Kamiyama, Kurokawa, & Shiraki, 2001; Kuramoto, et al., 2010; Kurosaki, et al., 2004; Miwa, et al., 2005; Mori, et al., 1988; Shiraki, Ogino, Yamanishi, & Takahashi, 1983 , 1985 .
T92276 36416-36962 Sentence denotes We have isolated a herpes simplex virus resistant to acyclovir, phosphonoacetic acid, and foscarnet, a varicella-zoster virus resistant to acyclovir, penciclovir, foscarnet, and vidarabine, and a cytomegalovirus resistant to ganciclovir, foscarnet, and mizoribine by culturing the virus in the presence of these antiviral agents (Ida, et al., 2000; Ida, et al., 1999; Kamiyama, Kurokawa, & Shiraki, 2001; Kuramoto, et al., 2010; Kurosaki, et al., 2004; Miwa, et al., 2005; Mori, et al., 1988; Shiraki, Ogino, Yamanishi, & Takahashi, 1983 , 1985 .
TextSentencer_T195 36963-37065 Sentence denotes These resistant viruses replace the virus population in the presence of drug in vitro and in patients.
T9618 36963-37065 Sentence denotes These resistant viruses replace the virus population in the presence of drug in vitro and in patients.
TextSentencer_T196 37066-37254 Sentence denotes The emergence and replacement of resistant strains occurs in the herpetic lesions in immunocompromised individuals when a lesion with viral growth is treated for at least one or two weeks.
T44731 37066-37254 Sentence denotes The emergence and replacement of resistant strains occurs in the herpetic lesions in immunocompromised individuals when a lesion with viral growth is treated for at least one or two weeks.
TextSentencer_T197 37255-37448 Sentence denotes An oseltamivir-or baloxavir marboxil (baloxavir)-resistant virus has emerged in patients with seasonal influenza during treatment, and the isolated virus has been replaced by a resistant virus.
T67764 37255-37448 Sentence denotes An oseltamivir-or baloxavir marboxil (baloxavir)-resistant virus has emerged in patients with seasonal influenza during treatment, and the isolated virus has been replaced by a resistant virus.
TextSentencer_T198 37449-37518 Sentence denotes A subsequent new infection by the resistant virus has been confirmed.
T59592 37449-37518 Sentence denotes A subsequent new infection by the resistant virus has been confirmed.
TextSentencer_T199 37519-37756 Sentence denotes Therefore, we investigated the possibility that a favipiravir-resistant virus appeared in cultured cells while influenza virus was growing in the presence of favipiravir and that the proliferating virus was replaced by a resistant virus.
T48729 37519-37756 Sentence denotes Therefore, we investigated the possibility that a favipiravir-resistant virus appeared in cultured cells while influenza virus was growing in the presence of favipiravir and that the proliferating virus was replaced by a resistant virus.
TextSentencer_T200 37757-38102 Sentence denotes We tried to isolate favipiravir-resistant influenza virus and poliovirus from 28 and 10 25 cm 2 flasks, respectively, after independent cultures in the presence of increasing concentrations of favipiravir for a month, but no resistant virus was isolated (Daikoku, et al., J o u r n a l P r e -p r o o f Journal Pre-proof Daikoku, et al., 2014) .
T57863 37757-38102 Sentence denotes We tried to isolate favipiravir-resistant influenza virus and poliovirus from 28 and 10 25 cm 2 flasks, respectively, after independent cultures in the presence of increasing concentrations of favipiravir for a month, but no resistant virus was isolated (Daikoku, et al., J o u r n a l P r e -p r o o f Journal Pre-proof Daikoku, et al., 2014) .
TextSentencer_T201 38103-38184 Sentence denotes Then, we decided to deny the possibility of replacement with the resistant virus.
T57158 38103-38184 Sentence denotes Then, we decided to deny the possibility of replacement with the resistant virus.
TextSentencer_T202 38185-38363 Sentence denotes Spontaneous mutation rates of the influenza virus RdRp complex and poliovirus 3D RdRp are both approximately 1 x 10 -4 (Cheung, et al., 2014; Drake, 1993; Gubareva & Fry, 2019) .
T21521 38185-38363 Sentence denotes Spontaneous mutation rates of the influenza virus RdRp complex and poliovirus 3D RdRp are both approximately 1 x 10 -4 (Cheung, et al., 2014; Drake, 1993; Gubareva & Fry, 2019) .
TextSentencer_T203 38364-38656 Sentence denotes Titers of influenza virus and poliovirus in the culture reach approximately 10 8 viral particles/mL in 5 mL of media in a 25 cm 2 flask, and their genomes contain approximately 13,600 and 7,500 base pairs, respectively, stochastically indicating 10 4 alterations per nucleotide in the genome.
T93126 38364-38656 Sentence denotes Titers of influenza virus and poliovirus in the culture reach approximately 10 8 viral particles/mL in 5 mL of media in a 25 cm 2 flask, and their genomes contain approximately 13,600 and 7,500 base pairs, respectively, stochastically indicating 10 4 alterations per nucleotide in the genome.
TextSentencer_T204 38657-38826 Sentence denotes Therefore, every type of mutant should be generated during replication, and continuous cultivation for a month might increase the favipiravir-resistant virus population.
T80750 38657-38826 Sentence denotes Therefore, every type of mutant should be generated during replication, and continuous cultivation for a month might increase the favipiravir-resistant virus population.
TextSentencer_T205 38827-39032 Sentence denotes If favipiravir induces mutations more frequently than natural processes, mutants resistant to favipiravir should be isolated easily, and the culture should be replaced by the favipiravir-resistant mutants.
T27119 38827-39032 Sentence denotes If favipiravir induces mutations more frequently than natural processes, mutants resistant to favipiravir should be isolated easily, and the culture should be replaced by the favipiravir-resistant mutants.
TextSentencer_T206 39033-39339 Sentence denotes We isolated susceptibility variants of influenza virus and poliovirus in the cultures treated with favipiravir for a month and identified nucleotide substitutions (mutations) in their RdRp genes, but these mutations were not related to resistance or mutations common to favipiravir Daikoku, et al., 2014) .
T16608 39033-39339 Sentence denotes We isolated susceptibility variants of influenza virus and poliovirus in the cultures treated with favipiravir for a month and identified nucleotide substitutions (mutations) in their RdRp genes, but these mutations were not related to resistance or mutations common to favipiravir Daikoku, et al., 2014) .
TextSentencer_T207 39340-39503 Sentence denotes Therefore, theoretical resistant mutants should be generated but are unable to replicate or replicate with reduced fidelity to replace the entire virus population.
T19064 39340-39503 Sentence denotes Therefore, theoretical resistant mutants should be generated but are unable to replicate or replicate with reduced fidelity to replace the entire virus population.
TextSentencer_T208 39504-39761 Sentence denotes The favipiravir-resistant mutant replicates as an artificially generated clone but does not become dominant among the entire virus population that grows in the presence of favipiravir (Abdelnabi, et al., 2017; Delang, et al., 2014; Goldhill, et al., 2019) .
T88734 39504-39761 Sentence denotes The favipiravir-resistant mutant replicates as an artificially generated clone but does not become dominant among the entire virus population that grows in the presence of favipiravir (Abdelnabi, et al., 2017; Delang, et al., 2014; Goldhill, et al., 2019) .
TextSentencer_T209 39762-39883 Sentence denotes Our results are consistent with the absence of a resistant virus in the entire virus population treated with favipiravir.
T21264 39762-39883 Sentence denotes Our results are consistent with the absence of a resistant virus in the entire virus population treated with favipiravir.
TextSentencer_T210 39884-39997 Sentence denotes Many laboratories have attempted to isolate favipiravir-resistant influenza viruses but have not been successful.
T35177 39884-39997 Sentence denotes Many laboratories have attempted to isolate favipiravir-resistant influenza viruses but have not been successful.
TextSentencer_T211 39998-40239 Sentence denotes Recently, mutants of influenza virus (Goldhill, et al., 2018) and chikungunya virus (Abdelnabi, et al., 2017; Delang, et al., 2014) that are less susceptible to J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir have been reported.
T80809 39998-40239 Sentence denotes Recently, mutants of influenza virus (Goldhill, et al., 2018) and chikungunya virus (Abdelnabi, et al., 2017; Delang, et al., 2014) that are less susceptible to J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir have been reported.
TextSentencer_T212 40240-40472 Sentence denotes Mutated sequences of these viruses have been detected in cultures treated with favipiravir, and reverse-engineered viruses showed favipiravir resistance with altered RdRp activity related to the fidelity and reduced growth property.
T31275 40240-40472 Sentence denotes Mutated sequences of these viruses have been detected in cultures treated with favipiravir, and reverse-engineered viruses showed favipiravir resistance with altered RdRp activity related to the fidelity and reduced growth property.
TextSentencer_T213 40473-40717 Sentence denotes The K229R mutation in motif F of the PB1 gene was observed in the virus population cultivated in the presence of favipiravir, and a virus with the K229R mutation was created by reverse engineering and confirmed as a favipiravir-resistant virus.
T22158 40473-40717 Sentence denotes The K229R mutation in motif F of the PB1 gene was observed in the virus population cultivated in the presence of favipiravir, and a virus with the K229R mutation was created by reverse engineering and confirmed as a favipiravir-resistant virus.
TextSentencer_T214 40718-40838 Sentence denotes However, the virus was artificially produced and grown as a clone and is not considered a dominant virus in the culture.
T18788 40718-40838 Sentence denotes However, the virus was artificially produced and grown as a clone and is not considered a dominant virus in the culture.
TextSentencer_T215 40839-40944 Sentence denotes A K229R mutation in P1 shows reduced polymerase activity and acquired P653L in the PA during replication.
T74260 40839-40944 Sentence denotes A K229R mutation in P1 shows reduced polymerase activity and acquired P653L in the PA during replication.
TextSentencer_T216 40945-41083 Sentence denotes The acquisition of the additional PA P653L mutation restores the polymerase activity and favipiravir resistance (Goldhill, et al., 2018) .
T61300 40945-41083 Sentence denotes The acquisition of the additional PA P653L mutation restores the polymerase activity and favipiravir resistance (Goldhill, et al., 2018) .
TextSentencer_T217 41084-41374 Sentence denotes The K291R mutation in the F1 motif of the RdRp (nsP4) in chikungunya virus is less susceptible to favipiravir, displays a reduced growth property and acquired an additional Y543C mutation in the helicase-protease (nsP2) during passages in the absence of favipiravir (Delang, et al., 2014) .
T27490 41084-41374 Sentence denotes The K291R mutation in the F1 motif of the RdRp (nsP4) in chikungunya virus is less susceptible to favipiravir, displays a reduced growth property and acquired an additional Y543C mutation in the helicase-protease (nsP2) during passages in the absence of favipiravir (Delang, et al., 2014) .
TextSentencer_T218 41375-41613 Sentence denotes The corresponding K-to-R substitution (K159R) of the chikungunya virus K291R mutation was introduced in the coxsackievirus B3 RdRp, but the engineered virus with the K159R mutation in RdRp was a nonviable virus (Abdelnabi, et al., 2017) .
T52878 41375-41613 Sentence denotes The corresponding K-to-R substitution (K159R) of the chikungunya virus K291R mutation was introduced in the coxsackievirus B3 RdRp, but the engineered virus with the K159R mutation in RdRp was a nonviable virus (Abdelnabi, et al., 2017) .
TextSentencer_T219 41614-41741 Sentence denotes The replication competence of the K159R variant is restored by the additional acquisition of an A239G substitution in the RdRp.
T12341 41614-41741 Sentence denotes The replication competence of the K159R variant is restored by the additional acquisition of an A239G substitution in the RdRp.
TextSentencer_T220 41742-41884 Sentence denotes The variant virus with the K159R and K291R mutations is more susceptible to favipiravir and exhibited lower fidelity than the wild-type virus.
T87796 41742-41884 Sentence denotes The variant virus with the K159R and K291R mutations is more susceptible to favipiravir and exhibited lower fidelity than the wild-type virus.
TextSentencer_T221 41885-42094 Sentence denotes A common feature of less susceptible viruses is high fidelity of RdRp that may distinguish favipiravir-RTP and GTP and replicate in the presence of favipiravir by avoiding the incorporation of favipiravir-RTP.
T95400 41885-42094 Sentence denotes A common feature of less susceptible viruses is high fidelity of RdRp that may distinguish favipiravir-RTP and GTP and replicate in the presence of favipiravir by avoiding the incorporation of favipiravir-RTP.
TextSentencer_T222 42095-42478 Sentence denotes Since their proliferative ability is not high, clones that are less susceptible to favipiravir grow well alone or are not viable, but an additional alteration that modulates RdRp activity restores the replication capability and the susceptibility to favipiravir (Abdelnabi, et al., 2017; Delang, et al., 2014; Goldhill, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2019).
T22724 42095-42478 Sentence denotes Since their proliferative ability is not high, clones that are less susceptible to favipiravir grow well alone or are not viable, but an additional alteration that modulates RdRp activity restores the replication capability and the susceptibility to favipiravir (Abdelnabi, et al., 2017; Delang, et al., 2014; Goldhill, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2019).
TextSentencer_T223 42479-42625 Sentence denotes Favipiravir-resistant mutants of influenza virus have been created by reverse-engineering and replicate as a clone with a reduced growth property.
T16652 42479-42625 Sentence denotes Favipiravir-resistant mutants of influenza virus have been created by reverse-engineering and replicate as a clone with a reduced growth property.
TextSentencer_T224 42626-42799 Sentence denotes Therefore, this virus is unlikely to replace the entire growing virus population when it is produced during favipiravir treatment, as has been observed in many laboratories.
T11816 42626-42799 Sentence denotes Therefore, this virus is unlikely to replace the entire growing virus population when it is produced during favipiravir treatment, as has been observed in many laboratories.
TextSentencer_T225 42800-43093 Sentence denotes Two highly pathogenic A(H5N1) influenza viruses from chicken and Muscovy duck and one H3 influenza virus from ruddy turnstone and two swine (H1N1) origin influenza viruses possess the PB1-V43I mutation that may result in a high-fidelity RdRp but has not been confirmed (Cheung, et al., 2014) .
T47296 42800-43093 Sentence denotes Two highly pathogenic A(H5N1) influenza viruses from chicken and Muscovy duck and one H3 influenza virus from ruddy turnstone and two swine (H1N1) origin influenza viruses possess the PB1-V43I mutation that may result in a high-fidelity RdRp but has not been confirmed (Cheung, et al., 2014) .
TextSentencer_T226 43094-43247 Sentence denotes Thus, researchers should consider the possibility of changes in the susceptibility to favipiravir when these types of influenza viruses cause a pandemic.
T22735 43094-43247 Sentence denotes Thus, researchers should consider the possibility of changes in the susceptibility to favipiravir when these types of influenza viruses cause a pandemic.
TextSentencer_T227 43248-43420 Sentence denotes Antiviral susceptibility was examined in 57 pairs of influenza viruses isolated from patients before and after the administration of favipiravir in phase 3 clinical trials.
T5119 43248-43420 Sentence denotes Antiviral susceptibility was examined in 57 pairs of influenza viruses isolated from patients before and after the administration of favipiravir in phase 3 clinical trials.
TextSentencer_T228 43421-43519 Sentence denotes No viruses displayed reduced susceptibility to favipiravir, although two of 20 paired A(H1N1)pdm09
T95968 43421-43519 Sentence denotes No viruses displayed reduced susceptibility to favipiravir, although two of 20 paired A(H1N1)pdm09
TextSentencer_T229 43520-43727 Sentence denotes isolates, one of 17 paired A(H3N2) isolates and one of 20 paired B viruses possessed amino acid substitutions in the RdRp subunits PB1, PB2 and PA after favipiravir administration (Takashita, et al., 2016) .
T18827 43520-43727 Sentence denotes isolates, one of 17 paired A(H3N2) isolates and one of 20 paired B viruses possessed amino acid substitutions in the RdRp subunits PB1, PB2 and PA after favipiravir administration (Takashita, et al., 2016) .
TextSentencer_T230 43728-43892 Sentence denotes These amino acid substitutions in the RdRp had nothing to do with the susceptibility of favipiravir and seemed to have occurred regardless of favipiravir treatment.
T10041 43728-43892 Sentence denotes These amino acid substitutions in the RdRp had nothing to do with the susceptibility of favipiravir and seemed to have occurred regardless of favipiravir treatment.
TextSentencer_T231 43893-44201 Sentence denotes This trial was a limited clinical study to assess the emergence of favipiravir-resistant virus, but the appearance of oseltamivir or baloxavir resistance might be observed in clinical trials of influenza treatment with oseltamivir and baloxavir with a similar number of patients, as described in Section 4.3.
T12291 43893-44201 Sentence denotes This trial was a limited clinical study to assess the emergence of favipiravir-resistant virus, but the appearance of oseltamivir or baloxavir resistance might be observed in clinical trials of influenza treatment with oseltamivir and baloxavir with a similar number of patients, as described in Section 4.3.
TextSentencer_T232 44202-44555 Sentence denotes The lack of the emergence and replacement of resistant viruses during favipiravir treatment in vitro and in humans indicates that the same effectiveness of favipiravir is expected to be maintained from the beginning to the end of the J o u r n a l P r e -p r o o f Journal Pre-proof influenza pandemic and that all patients could be treated effectively.
T43461 44202-44555 Sentence denotes The lack of the emergence and replacement of resistant viruses during favipiravir treatment in vitro and in humans indicates that the same effectiveness of favipiravir is expected to be maintained from the beginning to the end of the J o u r n a l P r e -p r o o f Journal Pre-proof influenza pandemic and that all patients could be treated effectively.
TextSentencer_T233 44556-44669 Sentence denotes Causes of death from severe infections may be liver failure, renal failure, respiratory failure and encephalitis.
T56991 44556-44669 Sentence denotes Causes of death from severe infections may be liver failure, renal failure, respiratory failure and encephalitis.
TextSentencer_T234 44670-44891 Sentence denotes Ebola virus infection seemed to be difficult for patients when they had the chance of infection or fever after infection, and the amount of virus was used as an indicator of the time of infection (Sissoko, et al., 2016) .
T9927 44670-44891 Sentence denotes Ebola virus infection seemed to be difficult for patients when they had the chance of infection or fever after infection, and the amount of virus was used as an indicator of the time of infection (Sissoko, et al., 2016) .
TextSentencer_T235 44892-44990 Sentence denotes Renal function represented by creatinine levels was found to be an important factor for prognosis.
T41903 44892-44990 Sentence denotes Renal function represented by creatinine levels was found to be an important factor for prognosis.
TextSentencer_T236 44991-45183 Sentence denotes The factor that determines survival and death rate with favipiravir treatment seems to be residual organ function at the start of treatment in fatal infections caused by cytotoxic RNA viruses.
T74890 44991-45183 Sentence denotes The factor that determines survival and death rate with favipiravir treatment seems to be residual organ function at the start of treatment in fatal infections caused by cytotoxic RNA viruses.
TextSentencer_T237 45184-45319 Sentence denotes The residual function necessary for the recovery of each organ can be estimated from the indication criteria for organ transplantation.
T47548 45184-45319 Sentence denotes The residual function necessary for the recovery of each organ can be estimated from the indication criteria for organ transplantation.
TextSentencer_T238 45320-45511 Sentence denotes One of the criteria for lung function for lung transplant patients is a forced expiratory volume in 1 second (FEV1) less than 25-30% (Maurer, Frost, Estenne, Higenbottam, & Glanville, 1998) .
T13616 45320-45511 Sentence denotes One of the criteria for lung function for lung transplant patients is a forced expiratory volume in 1 second (FEV1) less than 25-30% (Maurer, Frost, Estenne, Higenbottam, & Glanville, 1998) .
TextSentencer_T239 45512-45678 Sentence denotes Concerning renal function, hemodialysis starts when renal function falls to 10-15%, and death occurs within one to several weeks when dialysis is stopped (NKF, 2019).
T65016 45512-45678 Sentence denotes Concerning renal function, hemodialysis starts when renal function falls to 10-15%, and death occurs within one to several weeks when dialysis is stopped (NKF, 2019).
TextSentencer_T240 45679-45913 Sentence denotes Concerning liver function, the donor 's liver is left as a residual liver volume of at least 30% of the total liver volume to ensure hepatic graft with excellent results and low donor morbidity (Pomfret, Pomposelli, & Jenkins, 2001) .
T17659 45679-45913 Sentence denotes Concerning liver function, the donor 's liver is left as a residual liver volume of at least 30% of the total liver volume to ensure hepatic graft with excellent results and low donor morbidity (Pomfret, Pomposelli, & Jenkins, 2001) .
TextSentencer_T241 45914-46008 Sentence denotes It is important to begin treatment before losing the recoverable function of the target organ.
T62948 45914-46008 Sentence denotes It is important to begin treatment before losing the recoverable function of the target organ.
TextSentencer_T242 46009-46131 Sentence denotes Since pneumonia is the main cause of death by influenza, it may progress to some extent even after the start of treatment.
T33104 46009-46131 Sentence denotes Since pneumonia is the main cause of death by influenza, it may progress to some extent even after the start of treatment.
TextSentencer_T243 46132-46440 Sentence denotes Time from illness onset to oseltamivir treatment in avian influenza A(H7N9) virus infection is 6 days (5-9 days), and time from illness onset to the development of acute respiratory distress syndrome (ARDS) is 7 days (5-9 days) (Li, et al., 2014) , indicating the importance of early diagnosis and treatment.
T3238 46132-46440 Sentence denotes Time from illness onset to oseltamivir treatment in avian influenza A(H7N9) virus infection is 6 days (5-9 days), and time from illness onset to the development of acute respiratory distress syndrome (ARDS) is 7 days (5-9 days) (Li, et al., 2014) , indicating the importance of early diagnosis and treatment.
TextSentencer_T244 46441-46732 Sentence denotes In Ebola virus infection, other than the direct cause of death related to bleeding such as hemorrhagic shock, the degree of liver dysfunction and renal dysfunction seems to be related to survival and death rate as seen in an animal model treated with favipiravir (Oestereich, et al., 2014) .
T46985 46441-46732 Sentence denotes In Ebola virus infection, other than the direct cause of death related to bleeding such as hemorrhagic shock, the degree of liver dysfunction and renal dysfunction seems to be related to survival and death rate as seen in an animal model treated with favipiravir (Oestereich, et al., 2014) .
TextSentencer_T245 46733-46793 Sentence denotes SFTS is mainly caused by tick bites and develops with fever.
T89596 46733-46793 Sentence denotes SFTS is mainly caused by tick bites and develops with fever.
TextSentencer_T246 46794-46856 Sentence denotes Liver and renal dysfunction in SFTS may be the cause of death.
T93466 46794-46856 Sentence denotes Liver and renal dysfunction in SFTS may be the cause of death.
TextSentencer_T247 46857-47028 Sentence denotes In Yamaguchi Prefecture, where the first patient was found in Japan, dermatologists who have examined tick bites monitor the development of SFTS to enable early treatment.
T2906 46857-47028 Sentence denotes In Yamaguchi Prefecture, where the first patient was found in Japan, dermatologists who have examined tick bites monitor the development of SFTS to enable early treatment.
TextSentencer_T248 47029-47206 Sentence denotes Favipiravir has been developed as an anti-influenza drug with efficacy against severe infections caused by a high viral load and was approved as an anti-influenza drug in Japan.
T53431 47029-47206 Sentence denotes Favipiravir has been developed as an anti-influenza drug with efficacy against severe infections caused by a high viral load and was approved as an anti-influenza drug in Japan.
TextSentencer_T249 47207-47312 Sentence denotes Favipiravir is contraindicated in pregnant women due to its teratogenicity and embryotoxicity in animals.
T9891 47207-47312 Sentence denotes Favipiravir is contraindicated in pregnant women due to its teratogenicity and embryotoxicity in animals.
TextSentencer_T250 47313-47438 Sentence denotes Subsequent stockpiling of doses for 2 million people has been performed as a countermeasure against novel influenza in Japan.
T63825 47313-47438 Sentence denotes Subsequent stockpiling of doses for 2 million people has been performed as a countermeasure against novel influenza in Japan.
TextSentencer_T251 47439-47600 Sentence denotes Favipiravir has been used to treat lethal infections in humans because its efficacy has been confirmed in a wide range of animal models of lethal RNA infections.
T78015 47439-47600 Sentence denotes Favipiravir has been used to treat lethal infections in humans because its efficacy has been confirmed in a wide range of animal models of lethal RNA infections.
TextSentencer_T252 47601-47678 Sentence denotes Severe human RNA infections are sporadic, and the number of cases is limited.
T49183 47601-47678 Sentence denotes Severe human RNA infections are sporadic, and the number of cases is limited.
TextSentencer_T253 47679-47855 Sentence denotes In patients with these infections, favipiravir has been used for urgent and life-saving purposes because there is no standard effective treatment, rather than to show efficacy.
T86447 47679-47855 Sentence denotes In patients with these infections, favipiravir has been used for urgent and life-saving purposes because there is no standard effective treatment, rather than to show efficacy.
TextSentencer_T254 47856-48087 Sentence denotes Clinical trials have been performed to compare historical control patients and patients treated with favipiravir for Ebola virus infection (Bai, et al., 2016; Jacobs, et al., 2015; Sissoko, et al., 2016) and SFTS (Yasukawa, 2016) .
T3607 47856-48087 Sentence denotes Clinical trials have been performed to compare historical control patients and patients treated with favipiravir for Ebola virus infection (Bai, et al., 2016; Jacobs, et al., 2015; Sissoko, et al., 2016) and SFTS (Yasukawa, 2016) .
TextSentencer_T255 48088-48203 Sentence denotes Subsequently, favipiravir has been submitted for additional indications based on clinical trials for SFTS in Japan.
T84281 48088-48203 Sentence denotes Subsequently, favipiravir has been submitted for additional indications based on clinical trials for SFTS in Japan.
TextSentencer_T256 48204-48412 Sentence denotes The establishment of a placebo group that does not receive an effective drug in a le thal animal model is a challenging problem to confirm the efficacy of favipiravir by a randomized placebo-controlled trial.
T60046 48204-48412 Sentence denotes The establishment of a placebo group that does not receive an effective drug in a le thal animal model is a challenging problem to confirm the efficacy of favipiravir by a randomized placebo-controlled trial.
TextSentencer_T257 48413-48760 Sentence denotes As an example of this situation, PEP of human immunodeficiency J o u r n a l P r e -p r o o f Journal Pre-proof virus has been performed to protect against needle sticks or occupational exposures and has become a standard procedure in the guideline due to its prophylactic effect as a result of many years of implementation (Kuhar, et al., 2013) .
T74999 48413-48760 Sentence denotes As an example of this situation, PEP of human immunodeficiency J o u r n a l P r e -p r o o f Journal Pre-proof virus has been performed to protect against needle sticks or occupational exposures and has become a standard procedure in the guideline due to its prophylactic effect as a result of many years of implementation (Kuhar, et al., 2013) .
TextSentencer_T258 48761-48936 Sentence denotes Since children died of avian influenza A(H5N1) in Hong Kong in 1997 (Ku & Chan, 1999 , concern has been expressed about novel influenza pandemics, such as A(H5N1) and A(H7N9).
T84359 48761-48936 Sentence denotes Since children died of avian influenza A(H5N1) in Hong Kong in 1997 (Ku & Chan, 1999 , concern has been expressed about novel influenza pandemics, such as A(H5N1) and A(H7N9).
TextSentencer_T259 48937-49164 Sentence denotes An influenza pandemic consisting of a global outbreak of influenza A(H1N1)pdm09 virus occurred in 2009, and although the pathogenicity of this virus was milder than A(H5N1) and A(H7N9), it caused a pandemic and health problems.
T58769 48937-49164 Sentence denotes An influenza pandemic consisting of a global outbreak of influenza A(H1N1)pdm09 virus occurred in 2009, and although the pathogenicity of this virus was milder than A(H5N1) and A(H7N9), it caused a pandemic and health problems.
TextSentencer_T260 49165-49318 Sentence denotes Although there was immunity against influenza A(H1N1)pdm09 among the elderly, it caused health problems for young people and a substantial social impact.
T83147 49165-49318 Sentence denotes Although there was immunity against influenza A(H1N1)pdm09 among the elderly, it caused health problems for young people and a substantial social impact.
TextSentencer_T261 49319-49652 Sentence denotes As a next candidate for a pandemic influenza, avian influenza, such as A(H5N1) or A(H7N9), causes a severe infection and pneumonia due to the prolonged viral replication caused by the lack of immunity and its tropism to the pulmonary epithelium with a high mortality rate (Lai, et al., 2016; Li, et al., 2014; Shinya, et al., 2006) .
T70872 49319-49652 Sentence denotes As a next candidate for a pandemic influenza, avian influenza, such as A(H5N1) or A(H7N9), causes a severe infection and pneumonia due to the prolonged viral replication caused by the lack of immunity and its tropism to the pulmonary epithelium with a high mortality rate (Lai, et al., 2016; Li, et al., 2014; Shinya, et al., 2006) .
TextSentencer_T262 49653-49864 Sentence denotes The ability to predict whether a pandemic will occur remains challenging, but a necessary strategy appears to be to stockpile vaccines and anti-influenza drugs for novel influenza strains to cope with pandemics.
T21776 49653-49864 Sentence denotes The ability to predict whether a pandemic will occur remains challenging, but a necessary strategy appears to be to stockpile vaccines and anti-influenza drugs for novel influenza strains to cope with pandemics.
TextSentencer_T263 49865-50177 Sentence denotes The specific features and mechanism of action of favipiravir and the fact that favipiravir alone does not produce resistant viruses among anti-influenza drugs suggests that Influenza infection induces interferon (IFN) production that subsequently induces interleukin (IL)-1 production to act on the hypothalamus.
T76912 49865-50177 Sentence denotes The specific features and mechanism of action of favipiravir and the fact that favipiravir alone does not produce resistant viruses among anti-influenza drugs suggests that Influenza infection induces interferon (IFN) production that subsequently induces interleukin (IL)-1 production to act on the hypothalamus.
TextSentencer_T264 50178-50274 Sentence denotes Next, cyclooxygenase is expressed to induce prostaglandin (PG)E 2 production and generate fever.
T50395 50178-50274 Sentence denotes Next, cyclooxygenase is expressed to induce prostaglandin (PG)E 2 production and generate fever.
TextSentencer_T265 50275-50448 Sentence denotes Cinnamyl compounds from medicinal herbs, anti-IFN antibody, anti-IL-1 antibody, and nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin) act at each step of this process.
T9233 50275-50448 Sentence denotes Cinnamyl compounds from medicinal herbs, anti-IFN antibody, anti-IL-1 antibody, and nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin) act at each step of this process.
TextSentencer_T266 50449-50609 Sentence denotes Cinnamyl compounds and NSAIDs inhibit the induction of IFN and cyclooxygenase activity, respectively, in the fever cascade to work as antipyretics in influenza.
T1479 50449-50609 Sentence denotes Cinnamyl compounds and NSAIDs inhibit the induction of IFN and cyclooxygenase activity, respectively, in the fever cascade to work as antipyretics in influenza.
TextSentencer_T267 50610-50876 Sentence denotes Regarding pneumonia, IL-12 and IFN-γ production are induced in the bronchoalveolar fluid (BALF) on the second and third day of infection, respectively, and an increase in IL-12 levels reduces the viral load in the BALF and the area of pneumonia throughout the lungs.
T11822 50610-50876 Sentence denotes Regarding pneumonia, IL-12 and IFN-γ production are induced in the bronchoalveolar fluid (BALF) on the second and third day of infection, respectively, and an increase in IL-12 levels reduces the viral load in the BALF and the area of pneumonia throughout the lungs.
TextSentencer_T268 50877-51066 Sentence denotes indicates inhibitory action. (NA) on the surface of the virus particle, and the virus particle is released from the surface of the infected cell and proceeds to the next round of infection.
T10506 50877-51066 Sentence denotes indicates inhibitory action. (NA) on the surface of the virus particle, and the virus particle is released from the surface of the infected cell and proceeds to the next round of infection.
TextSentencer_T269 51067-51239 Sentence denotes Amantadine blocks uncoating by inhibiting acidification mediated by the M2 protein in the virus particle in late endosome, and thus the infection is unable to be completed.
T23962 51067-51239 Sentence denotes Amantadine blocks uncoating by inhibiting acidification mediated by the M2 protein in the virus particle in late endosome, and thus the infection is unable to be completed.
TextSentencer_T270 51240-51379 Sentence denotes Favipiravir inhibits viral RNA synthesis by terminating chain elongation at its incorporated site, and no new RNA is generated in the cell.
T97440 51240-51379 Sentence denotes Favipiravir inhibits viral RNA synthesis by terminating chain elongation at its incorporated site, and no new RNA is generated in the cell.
TextSentencer_T271 51380-51531 Sentence denotes Baloxavir marboxil prevents Cap-snatching, and the viral mRNA is not produced, resulting in a failure to produce viral proteins and infectious viruses.
T89789 51380-51531 Sentence denotes Baloxavir marboxil prevents Cap-snatching, and the viral mRNA is not produced, resulting in a failure to produce viral proteins and infectious viruses.
TextSentencer_T272 51532-51583 Sentence denotes Genomic RNA is synthesized and remains in the cell.
T16002 51532-51583 Sentence denotes Genomic RNA is synthesized and remains in the cell.
TextSentencer_T273 51584-51736 Sentence denotes NA inhibitors block the cleavage of the sialic acid-HA bond in the virus on the surface of infected cells and prevent the spread of the viral infection.
T52550 51584-51736 Sentence denotes NA inhibitors block the cleavage of the sialic acid-HA bond in the virus on the surface of infected cells and prevent the spread of the viral infection.
TextSentencer_T274 51737-51779 Sentence denotes NA inhibitors allow genomic RNA synthesis.
T25735 51737-51779 Sentence denotes NA inhibitors allow genomic RNA synthesis.
TextSentencer_T275 51780-51873 Sentence denotes Favipiravir inhibits viral RNA synthesis, while baloxavir and NAIs allow viral RNA synthesis.
T7019 51780-51873 Sentence denotes Favipiravir inhibits viral RNA synthesis, while baloxavir and NAIs allow viral RNA synthesis.
TextSentencer_T276 51874-52060 Sentence denotes Although viral spread is inhibited by baloxavir and NAIs, viral RNA is synthesized, and the pool of genomic RNA serves as a rich source of resistant viruses. indicates inhibitory action.
T26645 51874-52060 Sentence denotes Although viral spread is inhibited by baloxavir and NAIs, viral RNA is synthesized, and the pool of genomic RNA serves as a rich source of resistant viruses. indicates inhibitory action.
TextSentencer_T277 52061-52102 Sentence denotes Chain termination and lethal mutagenesis.
T15425 52061-52102 Sentence denotes Chain termination and lethal mutagenesis.
TextSentencer_T278 52103-52195 Sentence denotes Favipiravir is converted to favipiravir-RTP and incorporated into the elongating RNA strand.
T3162 52103-52195 Sentence denotes Favipiravir is converted to favipiravir-RTP and incorporated into the elongating RNA strand.
TextSentencer_T279 52196-52351 Sentence denotes Then, chain elongation stops at the site of favipiravir incorporation, and elongation does not proceed because favipiravir functions as a chain terminator.
T66657 52196-52351 Sentence denotes Then, chain elongation stops at the site of favipiravir incorporation, and elongation does not proceed because favipiravir functions as a chain terminator.
TextSentencer_T280 52352-52620 Sentence denotes This RNA-favipiravir (-RdRp) J o u r n a l P r e -p r o o f complex will not be repaired by the proofreading enzyme and would be disposed of as unnecessary RNA, resulting in the extinction of the viral genome (Rocha-Pereira, et al., 2012; Vanderlinden, et al., 2016) .
T28006 52352-52620 Sentence denotes This RNA-favipiravir (-RdRp) J o u r n a l P r e -p r o o f complex will not be repaired by the proofreading enzyme and would be disposed of as unnecessary RNA, resulting in the extinction of the viral genome (Rocha-Pereira, et al., 2012; Vanderlinden, et al., 2016) .
TextSentencer_T281 52621-52733 Sentence denotes Ribavirin is incorporated into the elongating RNA strand, and viral RdRp continues to elongate until completion.
T82063 52621-52733 Sentence denotes Ribavirin is incorporated into the elongating RNA strand, and viral RdRp continues to elongate until completion.
TextSentencer_T282 52734-52876 Sentence denotes Next, the RNA strand with multiple ribavirin incorporation sites further incorporates ribavirin or serves as mRNA for viral protein synthesis.
T11823 52734-52876 Sentence denotes Next, the RNA strand with multiple ribavirin incorporation sites further incorporates ribavirin or serves as mRNA for viral protein synthesis.
TextSentencer_T283 52877-53101 Sentence denotes The incorporation of ribavirin in the viral RNA causes the mismatch of base pairs (transition mutation), and translation of this RNA causes mutations in the amino acid sequence of the protein, resulting in impaired function.
T30792 52877-53101 Sentence denotes The incorporation of ribavirin in the viral RNA causes the mismatch of base pairs (transition mutation), and translation of this RNA causes mutations in the amino acid sequence of the protein, resulting in impaired function.
TextSentencer_T284 53102-53224 Sentence denotes Viral proteins with impaired function fail to replicate or produce infectious viral particles, and viral infection ceases.
T52489 53102-53224 Sentence denotes Viral proteins with impaired function fail to replicate or produce infectious viral particles, and viral infection ceases.
TextSentencer_T285 53225-53330 Sentence denotes Thus, lethal mutagenesis terminates viral infection through a different mechanism than chain termination.
T57450 53225-53330 Sentence denotes Thus, lethal mutagenesis terminates viral infection through a different mechanism than chain termination.
TextSentencer_T286 53331-54247 Sentence denotes J o u r n a l P r e -p r o o f (Bai, et al., 2016; Bixler, et al., 2018; Jacobs, et al., 2015; Oestereich, Ludtke, et al., 2014; Sissoko, et al., 2016; Smither, et al., 2014) Severe fever with thrombocytopenia syndrome (SFTS) caused by a virus infection 12-30% b (Gowen, Westover, Miao, et al., 2017a; Tani, et al., 2016; Yasukawa, 2016) Severe influenza (Cao, 2018; Wang et al., 2019) Lassa virus infection 1% a , severe cases 15% a (Gowen, Westover, Sefing, et al., 2017b; Mendenhall, et al., 2011; Oestereich, et al., 2016; Raabe, et al., 2017; Safronetz, et al., 2015) Rabies Approximately 100% a, b (Baker, 2017; Yamada, Noguchi, Komeno, Furuta, & Nishizono, 2015) Norovirus infection 50,000 deaths/year b (Arias, Thorne, & Goodfellow, 2014; Ruis, et al., 2018) Avian influenza A(H5N1) 52.8% (Sep 9, 2019) a Favipiravir is effective against influenza in animals and humans and has J o u r n a l P r e -p r o o f
T86793 53331-54247 Sentence denotes J o u r n a l P r e -p r o o f (Bai, et al., 2016; Bixler, et al., 2018; Jacobs, et al., 2015; Oestereich, Ludtke, et al., 2014; Sissoko, et al., 2016; Smither, et al., 2014) Severe fever with thrombocytopenia syndrome (SFTS) caused by a virus infection 12-30% b (Gowen, Westover, Miao, et al., 2017a; Tani, et al., 2016; Yasukawa, 2016) Severe influenza (Cao, 2018; Wang et al., 2019) Lassa virus infection 1% a , severe cases 15% a (Gowen, Westover, Sefing, et al., 2017b; Mendenhall, et al., 2011; Oestereich, et al., 2016; Raabe, et al., 2017; Safronetz, et al., 2015) Rabies Approximately 100% a, b (Baker, 2017; Yamada, Noguchi, Komeno, Furuta, & Nishizono, 2015) Norovirus infection 50,000 deaths/year b (Arias, Thorne, & Goodfellow, 2014; Ruis, et al., 2018) Avian influenza A(H5N1) 52.8% (Sep 9, 2019) a Favipiravir is effective against influenza in animals and humans and has J o u r n a l P r e -p r o o f