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Resistance - Animal Studies

Many mammalian models (mice, ferrets, guinea pigs, cotton rats, golden hamsters, and nonhuman primates) are used to study antiviral efficacy and monitor the virulence and transmission potential of resistant influenza viruses (Mifsud et al., 2018). Such animal models provide controllable experimental sample sizes to analyse a wide range of antiviral compounds with different regimens and facilitate study of the parameters that may be associated with infection and disease progression (e.g., morbidity, involvement in lung function, and immune responses). The ferret is a well-established model for influenza research because of its natural susceptibility to infection, human-like distribution of sialic acid receptors in the respiratory tract, and manifestation of influenza symptoms similar to that in humans, including fever, sneezing, coughing, lethargy, and weight loss (Belser et al., 2018). A guinea pig model was developed as an alternative to the ferret model for human influenza virus transmission studies (Lowen et al., 2006).

Belser JA, Barclay W, Barr I, Fouchier RAM, Matsuyama R, Nishiura H, Peiris M, Russell CJ, Subbarao K, Zhu H, Yen HL. Ferrets as models for influenza virus transmission studies and pandemic risk assessments. Emerg Infect Dis. 2018; 24(6):965–971.

Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P. The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci U S A. 2006; 103:9988–9992.

Mifsud EJ, Tai CM, Hurt AC. Animal models used to assess influenza antivirals. Expert Opin Drug Discov. 2018; 13(12):1131–1139.

 

Neuraminidase Inhibitors (Oseltamivir, Zanamivir, Peramivir, and Laninamivir)

Pharmacokinetics
The four neuraminidase inhibitors (NAIs) approved for human clinical use are delivered either orally (oseltamivir and peramivir) or via inhalation (zanamivir and laninamivir). Oseltamivir is the predominant NAI used clinically. The prodrug oseltamivir phosphate (OSE) is rapidly cleaved into active oseltamivir carboxylate by esterases in the gastrointestinal tract, liver, and blood (McClellan and Perry, 2001). To achieve the same area-under-the-curve pharmacokinetic profile of orally administered OSE in humans (75 mg, twice daily) in mice requires administration of 20 mg/kg per day (e.g.,10 mg/kg, twice daily) (Ward et al. 2005). Intravenous, intramuscular, or intraperitoneal delivery in mice and subsequent pharmacokinetic analyses suggest that peramivir has a long half-life (>24 h) (Bantia et al, 2006). Administering 5.08 mg/kg of OSE every 12 h for 5 days in ferrets results in an equivalent median area-under-the-plasma concentration–time curve from 0 to 12 h (i.e., 3220 mg × h/mL) as that of the steady state observed in humans (Reddy et al, 2015). Zanamivir is readily bioavailable after intravenous, intraperitoneal, or intranasal, but not oral, administration. After intranasal administration of the ester prodrug laninamivir octanoate in mice (0.5 μmol/kg), it is distributed from the airway space into the lungs, and laninamivir remains detectable in the lungs at 24 h post dosing (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid (Koyama et al., 2013).
 
Efficacy
Therapeutic and prophylactic NAI regimens were evaluated in mice infected with seasonal influenza A(H1N1)pdm09, A(H3N2), and B viruses (Pascua et al., 2017; Smee and Barnard, 2013); newly emerging A(H7N9) viruses; and highly pathogenic A(H5N1) viruses (Baranovich et al., 2014; Yen et al., 2005). Early initiation of drug administration, ideally within 48 h after the onset of symptoms, remains the primary obstacle for successful NAI therapy. Various antiviral agents have been studied in combination with NAIs (e.g., amantadine, rimantadine, ribavirin, human IFN-α, plant extracts, and T-705) for different subtypes of influenza viruses (Govorkova and Webster, 2010), including the highly pathogenic A(H5N1) viruses (Marathe et al., 2016). Immunocompromised mice have been used to evaluate treatment options for influenza A and B viral infections (Ison et al, 2006; Marathe et al. 2017; Pascua et al., 2017). OSE is efficacious in mice against infection with recombinant viruses bearing the 1918 influenza hemagglutinin (HA), NA, and M gene segments (Tumpey et al., 2002). It is also effective in preventing severe disease in macaques infected with the fully reconstructed 1918 influenza virus but vulnerable to viral escape through emergence of resistant mutants, especially if given in a treatment regimen (Feldmann et al., 2019).
 
Fitness and transmissibility of resistance variants
The effects of NAI resistance–associated NA substitutions on the fitness and transmissibility of influenza viruses may vary depending on several factors: location of the mutation substitution (catalytic or framework residue), NA type/subtype, viral genetic background, existence of permissive secondary NA mutations, degree of NA functional loss, and an appropriate functional NA–HA balance (Govorkova, 2013). While multiple amino acid substitutions have been reported to be associated with reduced susceptibility to NAIs (WHO), the NA-H275Y substitution (N1 numbering) has been one of the most clinically significant because seasonal A(H1N1) variants with the NA-H275Y substitution were spread globally in the 2007–2008 influenza season. No other variant has caused such extensive spread among humans. The fitness of the influenza A(H1N1)pdm09 virus carrying the NA-H275Y substitution was extensively evaluated in a ferret model, with controversial results reported. Some studies demonstrated that the pathogenicity and transmissibility of the NAI-resistant virus was comparable to those of its wild-type (WT) counterpart in a ferret model (Kiso et al., 2010; Seibert et al., 2010; Memoli et al., 2011). Others showed that the A(H1N1)pdm09 oseltamivir-resistant H275Y variant was not efficiently transmitted between ferrets by the respiratory droplet route (Duan et al., 2010; Panilla et al., 2012). A pair of permissive secondary NA substitutions (V241I and N369K) confers robust fitness in recent A(H1N1)pdm09 viruses with the NA-H275Y substitution, suggesting that these viruses are more permissive to the acquisition of the NA-H275Y substitution than were earlier A(H1N1)pdm09 viruses (Butler et al., 2014).

Influenza A(H1N1)pdm09 viruses with the NA-S247N substitution exhibit reduced respiratory-droplet transmissibility in guinea pigs, and H275Y/S247N double-mutant variants exhibit more efficient transmission than do WT viruses (Seirbert et al., 2012). The NAI resistance–associated markers, including the H275Y substitution, found in oseltamivir-treated patients infected with highly pathogenic influenza A(H5N1) viruses causes different fitness loss, although loss of NA function may not reduce viral virulence because of extremely efficient viral replication (Ilyushina et al, 2010; Kiso et al., 2011).

Other commonly observed NA amino acid substitutions that are associated with reduced susceptibility to NAIs in clinical specimens include the E119G and R292K substitutions, which confer resistance to oseltamivir and peramivir in a N2 background. In a direct-contact transmission model, a recombinant A(H3N2) virus carrying an NA-E119V is transmissible among ferrets, whereas the A(H3N2) virus carrying the R292K is not (Yen et al., 2005). Studies in a ferret model with A(H1N1)pdm09 influenza viruses with zanamivir resistance–associated NA substitutions demonstrated that E119G causes reversion to the susceptible phenotype (E119), indicative of decreased fitness of resistant viruses (Pizzorno et al., 2013). The R292K substitution was also identified in patients infected with A(H7N9) viruses after receiving NAI treatment. Replication of the A(H7N9) virus with an R292K substitution is decreased in the upper respiratory tract of ferrets, but the virus does transmit to naïve contacts (Yen et al., 2014). The influenza A(H7N9) virus with the R292K substitution is not appreciably attenuated and can transmit to guinea pigs via the aerosol route (Hai et al., 2013).

 

Bantia S, Arnold CS, Parker CD, Upshaw R, Chand, P. Anti-influenza virus activity of peramivir in mice with single intramuscular injection. Antiviral Res. 2006; 69, 39–45.

Baranovich T, Burnham AJ, Marathe BM, Armstrong J, Guan Y, Shu Y, Peiris JMS, Webby RJ, Webster RG, and Govorkova EA. The neuraminidase inhibitor oseltamivir is effective against A/Anhui/1/2013 (H7N9) influenza virus in a mouse model of acute respiratory distress syndrome. J Infect Dis. 2014; 209(9):1343–1353.

Butler J, Hooper KA, Petrie S, Lee R, Maurer-Stroh S, Reh L, Guarnaccia T, Baas C, Xue L, Vitesnik S, Leang SK, McVernon J, Kelso A, Barr IG, McCaw JM, Bloom JD, Hurt AC. Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses. PLoS Pathog. 2014; 10(4):e1004065.

Duan S, Boltz DA, Seiler P, Li J, Bragstad K, Nielsen LP, Webby RJ, Webster RG, Govorkova EA. Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets. PLoS Pathog. 2010; 6(7):e1001022.

Feldmann F, Kobasa D, Embury-Hyatt C, Grolla A, Taylor T, Kiso M, Kakugawa S, Gren J, Jones SM, Kawaoka Y, Feldmann H. Oseltamivir is effective against 1918 influenza virus infection of macaques but vulnerable to escape. mBio 2019; 10:e02059-19.

Govorkova EA and Webster RG. Combination chemotherapy for influenza. Viruses 2010; 2, 1510–1529.

Govorkova EA. Consequences of resistance: in vitro fitness, in vivo infectivity, and transmissibility of oseltamivir-resistant influenza A viruses. Influenza Other Respir Viruses. 2013; Suppl 1:50–57.

Hai R, Schmolke M, Leyva-Grado VH, Thangavel RR, Margine I, Jaffe EL, Krammer F, Solórzano A, García-Sastre A, Palese P, Bouvier NM. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun. 2013; 4:2854.

lyushina NA, Seiler JP, Rehg JE, Webster RG, Govorkova EA. Effect of neuraminidase inhibitor-resistant mutations on pathogenicity of clade 2.2 A/Turkey/15/06 (H5N1) influenza virus in ferrets. PLoS Pathog. 2010; 6:e1000933.

Ison MG, Mishin VP, Braciale TJ, Hayden FG, Gubareva LV. Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection. J Infect Dis. 2006; 193:765–772.

Kiso M, Shinya K, Shimojima M, Takano R, Takahashi K, Katsura H, Kakugawa S, Le MT, Yamashita M, Furuta Y, Ozawa M, Kawaoka Y. Characterization of oseltamivir-resistant 2009 H1N1 pandemic influenza A viruses. PLoS Pathog. 2010; 6(8):e1001079.

Kiso M, Ozawa M, Le MT, Imai H, Takahashi K, Kakugawa S, Noda T, Horimoto T, Kawaoka Y. Effect of an asparagine-to-serine mutation at position 294 in neuraminidase on the pathogenicity of highly pathogenic H5N1 influenza A virus. J Virol. 2011; 85(10):4667–4672.

Koyama K, Nakai D, Takahashi M, Nakai N, Kobayashi N, Imai T, Izumi T. Pharmacokinetic mechanism involved in the prolonged high retention of laninamivir in mouse respiratory tissues after intranasal administration of its prodrug laninamivir octanoate. Drug Metab Dispos. 2013; 41(1):180–187.

Memoli MJ, Davis AS, Proudfoot K, Chertow DS, Hrabal RJ, Bristol T, Taubenberger JK. Multidrug-resistant 2009 pandemic influenza A(H1N1) viruses maintain fitness and transmissibility in ferrets. J Infect Dis. 2011; 203(3):348–357.

Marathe BM, Mostafa HH, Vogel P, Pascua PNQ, Jones JC, Russell CJ, Webby RJ, Govorkova EA. A pharmacologically immunosuppressed mouse model for assessing influenza B virus pathogenicity and oseltamivir treatment. Antiviral Res. 2017; 148:20–31.

Marathe BM, Wong SS, Vogel P, Garcia-Alcalde F, Webster RG, Webby RJ, Najera I, and Govorkova EA. Combinations of oseltamivir and T-705 extend the treatment window for highly pathogenic influenza A(H5N1) virus infection in mice. Sci Rep, 2016; 6:26742.

McClellan K and Perry CM. Oseltamivir: a review of its use in influenza. Drugs. 2001; 61(2):263–283.

Pascua PNQ, Mostafa HH, Marathe BM, Vogel P, Russell CJ, Webby RJ, and Govorkova EA. Pathogenicity and peramivir efficacy in immunocompromised murine models of influenza B virus infection. Sci Rep. 2017; 7(1):7345.

Pinilla LT, Holder BP, Abed Y, Boivin G, Beauchemin CA. The H275Y neuraminidase mutation of the pandemic A/H1N1 influenza virus lengthens the eclipse phase and reduces viral output of infected cells, potentially compromising fitness in ferrets. J Virol. 2012; 86(19):10651–10660.

Pizzorno A, Abed Y, Rheaume C, Bouhy X, Boivin G. 2013. Evaluation of recombinant 2009 pandemic influenza A (H1N1) viruses harboring zanamivir resistance mutations in mice and ferrets. Antimicrobial Agents Chemother. 2013; 57(4):1784–1789.

Reddy MB, Yang KH, Rao G, Rayner CR, Nie J, Pamulapati C, Marathe BM, Forrest A, and Govorkova EA. Oseltamivir population pharmacokinetics in the ferret: model application for pharmacokinetic/pharmacodynamic study design. PLoS One. 2015; 10(10):e0138069.

Seibert CW, Kaminski M, Philipp J, Rubbenstroth D, Albrecht RA, Schwalm F, Stertz S, Medina RA, Kochs G, García-Sastre A, Staeheli P, Palese P. Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models. J Virol. 2010; 84(21):11219–11226.

Seibert CW, Rahmat S, Krammer F, Palese P, Bouvier NM. Efficient transmission of pandemic H1N1 influenza viruses with high-level oseltamivir resistance. J Virol. 2012; 86:5386–5389.

Smee DF and Barnard DL. Methods for evaluation of antiviral efficacy against influenza virus infections in animal models. Methods Mol Biol. 2013; 1030:407–425.

Tumpey TM, García-Sastre A, Mikulasova A, Taubenberger JK, Swayne DE, Palese P, Basler CF. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc Natl Acad Sci U S A 2002; 99:13849–13854.

Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005; 55:5–21.

Yen H-L, Herlocher LM, Hoffmann E, Matrosovich MN, Monto AS, Webster RG, and Govorkova EA. Neuraminidase inhibitor–resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents and Chemother. 2005; 49(10):4075–4084.

Yen H-L, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Inf Dis. 2005; 192(4):665–672.

Yen HL, Zhou J, Choy KT, Sia SF, Teng O, Ng IH, Fang VJ, Hu Y, Wang W, Cowling BJ, Nicholls JM, Guan Y, Peiris JS. The R292K mutation that confers resistance to neuraminidase inhibitors leads to competitive fitness loss of A/Shanghai/1/2013 (H7N9) influenza virus in ferrets. J Infect Dis. 2014; 210(12):1900–1908.

 

Polymerase Acidic Inhibitor (Baloxavir Marboxil)

Pharmacokinetics
Baloxavir marboxil (BXM) is rapidly hydrolyzed by the serine esterase acrylacetamide deacetylase into the active form baloxavir acid (BXA). A phase 1 study showed that the maximum serum concentration (Cmax) of BXA can be achieved in 3.5 h post dosing, with a half-life ranging from 49 to 91 h (Koshimichi et al., 2018). Limited data are available regarding the pharmacokinetics of BXM and BXA in different animal models. After oral BXM treatment at 15 or 50 mg/kg twice daily for 1 day in BALB/c mice, BXA plasma concentrations may reach a Cmax comparable to that in humans (Noshi et al., 2017).
 
Efficacy
Efficacy of BXM against influenza A and B viruses has been tested with different regimens in the mouse model. Compared to the twice daily, 5-day regimen required for NAIs, BXM treatment may confer full protection against a lethal challenge of influenza A or B viruses with a single-day treatment at 0.5 to 5 mg/kg twice daily or 5 to 50 mg/kg twice daily, respectively (Fukao et al., 2019b). In addition, BXM is highly effective against A(H7N9) viruses in the mouse model (Taniguchi et al., 2019 and Kiso et al. 2019a). Mice receiving single-day BXM treatment at 5 to 50 mg/kg twice daily exhibit a 100% survival rate against both low-pathogenic or highly pathogenic A(H7N9) viruses. In contrast, mice receiving oseltamivir at 5 mg/kg twice daily for 5 days exhibit a 0% to 30% survival rate (Taniguchi et al., 2019; Kiso et al. 2019a). In immunocompromised nude mice challenged with a lethal dose of mouse-adapted A/California/04/2009 (H1N1)pdm09 influenza virus, BXM at 10 mg/kg day once daily for 28 days prolonged the median survival time to 49 days, in comparison to a median survival time of 5 days in the nontreated group (Kiso et al., 2019b). Delayed BXM treatment starting at 72 h post-infection or BXM in combination with oseltamivir starting at 96 h post-infection confers 100% protection against a lethal challenge of A/PR/8/1934 virus, whereas 0% of mice receiving standard oseltamivir treatment survive (Fukao et al., 2019a; Fukao et al., 2019b).
 
Fitness and transmissibility of resistance variants
Resistant variants with amino acid substitutions at PA residue 38 (I38T, I38M, or I38F) have been detected in influenza A and B viruses isolated from patients who received BXM treatment (Omoto et al., 2018; Hayden et al. 2018, Uehara et al., 2020). Among these variants, the I38T substitution imparts the greatest fold change in the 50% effective concentration of BXA for both influenza A and B viruses (Omoto et al., 2018; Koszalka et al., 2019). In addition, A(H3N2) variants with the I38T substitution occur in patients who have not received BXM treatment, suggesting the possibility of human-to-human transmission of the resistant strains (Takashita et al., 2019a; Takashita et al., 2019b). I38X variants exhibit variable replicative in vitro fitness, depending on the viral genetic background or the specific amino acid substitution that was introduced (Omoto et al., 2018; Chesnokov et al., 2020). In vivo, the pathogenic potential of the I38T substitution in A(H1N1)pdm09 or A(H3N2) viruses is comparable to that of counterpart WT viruses in hamsters, mice, and ferrets. Furthermore, the respiratory droplet transmissibility of I38T variants are comparable to that of their WT counterparts in A(H1N1)pdm09 or A(H3N2) genetic backgrounds (Imai et al., 2020). Experiments in which ferrets were inoculated with a mixture of A(H3N2) WT and I38T or I38M revealed that the WT virus has a marginal advantage in fitness over the I38T or I38M variants over time (Chesnokov et al., 2020).

Chesnokov A, Patel MC, Mishin VP, De La Cruz JA, Lollis L, Nguyen HT, Dugan V, Wentworth DE, Gubareva LV. Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir. J Infect Dis. 2020; 221(3):367-371.

Imai M, Yamashita M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Kiso M, Murakami J, Yasuhara A, Takada K, Ito M, Nakajima N, Takahashi K, Lopes TJS, Dutta J, Khan Z, Kriti D, van Bakel H, Tokita A, Hagiwara H, Izumida N, Kuroki H, Nishino T, Wada N, Koga M, Adachi E, Jubishi D, Hasegawa H, Kawaoka Y. Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets. Nat Microbiol. 2020; 5(1):27-33.

Fukao K, Noshi T, Yamamoto A, Kitano M, Ando Y, Noda T, Baba K, Matsumoto K, Higuchi N, Ikeda M, Shishido T, Naito A. Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. J Antimicrob Chemother. 2019a; 74(3):654-662.

Fukao K, Ando Y, Noshi T, Kitano M, Noda T, Kawai M, Yoshida R, Sato A, Shishido T, Naito A. Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models. PLoS One. 2019b; 14(5):e0217307.

Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A; Baloxavir Marboxil Investigators Group. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018; 379(10):913-923.

Kiso M, Yamayoshi S, Furusawa Y, Imai M, Kawaoka Y. Treatment of highly pathogenic H7N9 virus-infected mice with baloxavir marboxil. Viruses. 2019a; 11(11). pii:E1066.

Kiso M, Yamayoshi S, Murakami J, Kawaoka Y. Baloxavir marboxil treatment of nude mice infected with influenza A virus. J Infect Dis. 2019b; pii:jiz665.

Koshimichi H, Ishibashi T, Kawaguchi N, Sato C, Kawasaki A, Wajima T. Safety, tolerability, and pharmacokinetics of the novel anti-influenza agent baloxavir marboxil in healthy adults: phase I study findings. Clin Drug Investig. 2018; 38:1189-1196.

Koszalka P, Tilmanis D, Roe M, Vijaykrishna D, Hurt AC. Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012-2018. Antiviral Res. 2019; 164:91-96.

Noshi T, Sato K, Ishibashi T, Ando Y, Ueda H, Oka R, Kawai M, Yoshida R, Sato A, Shishido T, Naito A. Pharmacokinetic and pharmacodynamic analysis of S-033188/S-033447, a novel inhibitor of influenza virus cap-dependent endonuclease, in mice infected with influenza A virus. In 27th European Congress of Clinical Microbiology and Infectious Diseases. 2017.

Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, Kawaguchi K, Uehara T, Shishido T, Naito A, Cusack S. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep. 2018; 8(1):9633.

Takashita E, Kawakami C, Ogawa R, Morita H, Fujisaki S, Shirakura M, Miura H, Nakamura K, Kishida N, Kuwahara T, Ota A, Togashi H, Saito A, Mitamura K, Abe T, Ichikawa M, Yamazaki M, Watanabe S, Odagiri T. Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019a. Euro Surveill. 2019; 24(12):1.

Takashita E, Ichikawa M, Morita H, Ogawa R, Fujisaki S, Shirakura M, Miura H, Nakamura K, Kishida N, Kuwahara T, Sugawara H, Sato A, Akimoto M, Mitamura K, Abe T, Yamazaki M, Watanabe S, Hasegawa H, Odagiri T. Human-to-human transmission of influenza A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019b. Emerg Infect Dis. 2019; 25(11):2108-2111.

Taniguchi K, Ando Y, Nobori H, Toba S, Noshi T, Kobayashi M, Kawai M, Yoshida R, Sato A, Shishido T, Naito A, Matsuno K, Okamatsu M, Sakoda Y, Kida H. Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Sci Rep. 2019; 9(1):3466.

Uehara T, Hayden FG, Kawaguchi K, Omoto S, Hurt AC, De Jong MD, Hirotsu N, Sugaya N, Lee N, Baba K, Shishido T, Tsuchiya K, Portsmouth S, Kida H. Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza. J Infect Dis. 2020; 221(3):346-355.

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