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Influenza A(H1N1)pdm09 genotypic drug resistance interpretation’s algorithm

Influenza A(H3N2) genotypic drug resistance interpretation’s algorithm

Influenza B genotypic drug resistance interpretation’s algorithm

1 Huang W, Cheng Y, Li X, Tan M, Wei H, Zhao X, Xiao N, Dong J, Wang D. 2018. Neuraminidase inhibitor susceptibility profile of human influenza viruses during the 2016-2017 influenza season in Mainland China. J Infect Chemother 24:729-733.
2 Lackenby A, Besselaar TG, Daniels RS, Fry A, Gregory V, Gubareva LV, Huang W, Hurt AC, Leang SK, Lee RTC, Lo J, Lollis L, Maurer-Stroh S, Odagiri T, Pereyaslov D, Takashita E, Wang D, Zhang W, Meijer A. 2018. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016-2017. Antiviral Res 157:38-46.
3 Gubareva LV, Besselaar TG, Daniels RS, Fry A, Gregory V, Huang W, Hurt AC, Jorquera PA, Lackenby A, Leang SK, Lo J, Pereyaslov D, Rebelo-de-Andrade H, Siqueira MM, Takashita E, Odagiri T, Wang D, Zhang W, Meijer A. 2017. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015-2016. Antiviral Res 146:12-20.
4 Samson M, Abed Y, Desrochers FM, Hamilton S, Luttick A, Tucker SP, Pryor MJ, Boivin G. 2014. Characterization of drug-resistant influenza virus A(H1N1) and A(H3N2) variants selected in vitro with laninamivir. Antimicrob Agents Chemother 58:5220-5228.
5 Baek YH, Song MS, Lee EY, Kim YI, Kim EH, Park SJ, Park KJ, Kwon HI, Pascua PN, Lim GJ, Kim S, Yoon SW, Kim MH, Webby RJ, Choi YK. 2015. Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. J Virol 89:287-299.
6 L’Huillier AG, Abed Y, Petty TJ, Cordey S, Thomas Y, Bouhy X, Schibler M, Simon A, Chalandon Y, van Delden C, Zdobnov E, Boquete-Suter P, Boivin G, Kaiser L. 2015. E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient. J Infect Dis doi:10.1093/infdis/jiv288.
7 Lloren KKS, Kwon JJ, Choi WS, Jeong JH, Ahn SJ, Choi YK, Baek YH, Song MS. 2019. In Vitro and In Vivo Characterization of Novel Neuraminidase Substitutions in Influenza A(H1N1)pdm09 Virus Identified Using Laninamivir-Mediated In Vitro Selection. J Virol 93(6):e01825-18.
8 Pizzorno A, Bouhy X, Abed Y, Boivin G. 2011. Generation and characterization of recombinant pandemic influenza A(H1N1) viruses resistant to neuraminidase inhibitors. J Infect Dis 203:25-31.
9 Tamura D, DeBiasi RL, Okomo-Adhiambo M, Mishin VP, Campbell AP, Loechelt B, Wiedermann BL, Fry AM, Gubareva LV. 2015. Emergence of Multidrug-Resistant Influenza A(H1N1)pdm09 Virus Variants in an Immunocompromised Child Treated With Oseltamivir and Zanamivir. J Infect Dis doi:10.1093/infdis/jiv245.
10 Kaminski MM, Ohnemus A, Staeheli P, Rubbenstroth D. 2013. Pandemic 2009 H1N1 influenza A virus carrying a Q136K mutation in the neuraminidase gene is resistant to zanamivir but exhibits reduced fitness in the guinea pig transmission model. J Virol 87:1912-1915.
11 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. Antimicrob Agents Chemother 57:1784-1789.
12 Meijer A, Rebelo-de-Andrade H, Correia V, Besselaar T, Drager-Dayal R, Fry A, Gregory V, Gubareva L, Kageyama T, Lackenby A, Lo J, Odagiri T, Pereyaslov D, Siqueira MM, Takashita E, Tashiro M, Wang D, Wong S, Zhang W, Daniels RS, Hurt AC. 2014. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012-2013. Antiviral Res 110:31-41.
13 Takashita E, Meijer A, Lackenby A, Gubareva L, Rebelo-de-Andrade H, Besselaar T, Fry A, Gregory V, Leang SK, Huang W, Lo J, Pereyaslov D, Siqueira MM, Wang D, Mak GC, Zhang W, Daniels RS, Hurt AC, Tashiro M. 2015. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013-2014. Antiviral Res 117:27-38.
14 Takashita E, Daniels RS, Fujisaki S, Gregory V, Gubareva LV, Huang W, Hurt AC, Lackenby A, Nguyen HT, Pereyaslov D, Roe M, Samaan M, Subbarao K, Tse H, Wang D, Yen HL, Zhang W, Meijer A. 2020. Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018. Antiviral Res 175:104718.
15 Nguyen HT, Fry AM, Loveless PA, Klimov AI, Gubareva LV. 2010. Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. Clin Infect Dis 51:983-984.
16 Huang L, Cao Y, Zhou J, Qin K, Zhu W, Zhu Y, Yang L, Wang D, Wei H, Shu Y. 2014. A conformational restriction in the influenza A virus neuraminidase binding site by R152 results in a combinational effect of I222T and H274Y on oseltamivir resistance. Antimicrob Agents Chemother 58:1639-1645.
17 Govorkova EA, Takashita E, Daniels RS, Fujisaki S, Presser LD, Patel MC, Huang W, Lackenby A, Nguyen HT, Pereyaslov D, Rattigan A, Brown SK, Samaan M, Subbarao K, Wong S, Wang D, Webby RJ, Yen HL, Zhang W, Meijer A, Gubareva LV. 2022. Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018-2020. Antiviral Res 200:105281.
18 van der Vries E, Stelma FF, Boucher CA. 2010. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. N Engl J Med 363:1381-1382.
19 Eshaghi A, Patel SN, Sarabia A, Higgins RR, Savchenko A, Stojios PJ, Li Y, Bastien N, Alexander DC, Low DE, Gubbay JB. 2011. Multidrug-resistant pandemic (H1N1) 2009 infection in immunocompetent child. Emerg Infect Dis 17:1472-1474.
20 Pizzorno A, Abed Y, Bouhy X, Beaulieu E, Mallett C, Russell R, Boivin G. 2012. Impact of mutations at residue I223 of the neuraminidase protein on the resistance profile, replication level, and virulence of the 2009 pandemic influenza virus. Antimicrob Agents Chemother 56:1208-14.
21 Hurt AC, Lee RT, Leang SK, Cui L, Deng YM, Phuah SP, Caldwell N, Freeman K, Komadina N, Smith D, Speers D, Kelso A, Lin RT, Maurer-Stroh S, Barr IG. 2011. Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation. Euro Surveill 16.
22 Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin ME, Boivin G. 2009. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. N Engl J Med 361:2296-2297.
23 Okomo-Adhiambo M, Nguyen HT, Sleeman K, Sheu TG, Deyde VM, Garten RJ, Xu X, Shaw MW, Klimov AI, Gubareva LV. 2010. Host cell selection of influenza neuraminidase variants: implications for drug resistance monitoring in A(H1N1) viruses. Antiviral Res 85:381-388.
24 Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV. 2010. Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays. Antimicrob Agents Chemother 54:3671-3677.
25 Nguyen HT, Trujillo AA, Sheu TG, Levine M, Mishin VP, Shaw M, Ades EW, Klimov AI, Fry AM, Gubareva LV. 2012. Analysis of influenza viruses from patients clinically suspected of infection with an oseltamivir resistant virus during the 2009 pandemic in the United States. Antiviral Res 93:381-386.
26 Ikematsu H, Kawai N, Kashiwagi S. 2012. In vitro neuraminidase inhibitory activities of four neuraminidase inhibitors against influenza viruses isolated in the 2010-2011 season in Japan. J Infect Chemother 18:529-533.
27 Leang SK, Kwok S, Sullivan SG, Maurer-Stroh S, Kelso A, Barr IG, Hurt AC. 2014. Peramivir and laninamivir susceptibility of circulating influenza A and B viruses. Influenza Other Respir Viruses 8:135-139.
28 Takashita E, Fujisaki S, Kishida N, Xu H, Imai M, Tashiro M, Odagiri T, Influenza Virus Surveillance Group of J. 2013. Characterization of neuraminidase inhibitor-resistant influenza A(H1N1)pdm09 viruses isolated in four seasons during pandemic and post-pandemic periods in Japan. Influenza Other Respir Viruses 7:1390-1399.
29 Okomo-Adhiambo M, Sleeman K, Lysen C, Nguyen HT, Xu X, Li Y, Klimov AI, Gubareva LV. 2013. Neuraminidase inhibitor susceptibility surveillance of influenza viruses circulating worldwide during the 2011 Southern Hemisphere season. Influenza Other Respir Viruses 7:645-658.
30 Dapat C, Kondo H, Dapat IC, Baranovich T, Suzuki Y, Shobugawa Y, Saito K, Saito R, Suzuki H. 2013. Neuraminidase inhibitor susceptibility profile of pandemic and seasonal influenza viruses during the 2009-2010 and 2010-2011 influenza seasons in Japan. Antiviral Res 99:261-269.
31 Okomo-Adhiambo M, Nguyen HT, Abd Elal A, Sleeman K, Fry AM, Gubareva LV. 2014. Drug susceptibility surveillance of influenza viruses circulating in the United States in 2011-2012: application of the WHO antiviral working group criteria. Influenza Other Respir Viruses 8:258-265.
32 Kwon JJ, Choi WS, Jeong JH, Kim EH, Lee OJ, Yoon SW, Hwang J, Webby RJ, Govorkova EA, Choi YK, Baek YH, Song MS. 2018. An I436N substitution confers resistance of influenza A(H1N1)pdm09 viruses to multiple neuraminidase inhibitors without affecting viral fitness. J Gen Virol 99:292-302.
33 Ghedin E, Laplante J, DePasse J, Wentworth DE, Santos RP, Lepow ML, Porter J, Stellrecht K, Lin X, Operario D, Griesemer S, Fitch A, Halpin RA, Stockwell TB, Spiro DJ, Holmes EC, St George K. 2011. Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance. J Infect Dis 203:168-174.
34 Centers for Disease C, Prevention. 2009. Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis–North Carolina, 2009. MMWR Morb Mortal Wkly Rep 58:969-972.
35 Hurt AC, Chotpitayasunondh T, Cox NJ, Daniels R, Fry AM, Gubareva LV, Hayden FG, Hui DS, Hungnes O, Lackenby A, Lim W, Meijer A, Penn C, Tashiro M, Uyeki TM, Zambon M, Antivirals WHOCoPIAVRt. 2012. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis 12:240-248.
36 Abed Y, Baz M, Boivin G. 2006. Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds. Antivir Ther 11:971-976.
37 Choi W, Shin JY, Jeong HE, Jeong MJ, Kim SJ, Lee JY, Kang C. 2013. Generation and Characterization of Recombinant Influenza A(H1N1) Viruses Resistant to Neuraminidase Inhibitors. Osong Public Health Res Perspect 4:323-328.
38 Hurt AC, Holien JK, Parker M, Kelso A, Barr IG. 2009. Zanamivir-resistant influenza viruses with a novel neuraminidase mutation. J Virol 83:10366-10373.
39 Monto AS, McKimm-Breschkin JL, Macken C, Hampson AW, Hay A, Klimov A, Tashiro M, Webster RG, Aymard M, Hayden FG, Zambon M. 2006. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 50:2395-2402.
40 Hurt AC, Holien JK, Barr IG. 2009. In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses. Antimicrob Agents Chemother 53:4433-4440.
41 Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, Butler EN, Wallis TR, Klimov AI, Gubareva LV. 2008. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 52:3284-3292.
42 Mishin VP, Hayden FG, Gubareva LV. 2005. Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob Agents Chemother 49:4515-4520.
43 Boltz DA, Douangngeun B, Phommachanh P, Sinthasak S, Mondry R, Obert C, Seiler P, Keating R, Suzuki Y, Hiramatsu H, Govorkova EA, Webster RG. 2010. Emergence of H5N1 avian influenza viruses with reduced sensitivity to neuraminidase inhibitors and novel reassortants in Lao People’s Democratic Republic. J Gen Virol 91:949-959.
44 Hurt AC, Selleck P, Komadina N, Shaw R, Brown L, Barr IG. 2007. Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antiviral Res 73:228-231.
45 Kode SS, Pawar SD, Tare DS, Keng SS, Hurt AC, Mullick J. 2019. A novel I117T substitution in neuraminidase of highly pathogenic avian influenza H5N1 virus conferring reduced susceptibility to oseltamivir and zanamivir. Vet Microbiol 235:21-24.
46 Ilyushina NA, Seiler JP, Rehg JE, Webster RG, Govorkova EA. 2010. Effect of neuraminidase inhibitor-resistant mutations on pathogenicity of clade 2.2 A/Turkey/15/06 (H5N1) influenza virus in ferrets. PLoS Pathog 6:e1000933.
47 Le MT, Wertheim HF, Nguyen HD, Taylor W, Hoang PV, Vuong CD, Nguyen HL, Nguyen HH, Nguyen TQ, Nguyen TV, Van TD, Ngoc BT, Bui TN, Nguyen BG, Nguyen LT, Luong ST, Phan PH, Pham HV, Nguyen T, Fox A, Nguyen CV, Do HQ, Crusat M, Farrar J, Nguyen HT, de Jong MD, Horby P. 2008. Influenza A H5N1 clade 2.3.4 virus with a different antiviral susceptibility profile replaced clade 1 virus in humans in northern Vietnam. PLoS One 3:e3339.
48 Hurt AC, Lowther S, Middleton D, Barr IG. 2010. Assessing the development of oseltamivir and zanamivir resistance in A(H5N1) influenza viruses using a ferret model. Antiviral Res 87:361-366.
49 Naughtin M, Dyason JC, Mardy S, Sorn S, von Itzstein M, Buchy P. 2011. Neuraminidase inhibitor sensitivity and receptor-binding specificity of Cambodian clade 1 highly pathogenic H5N1 influenza virus. Antimicrob Agents Chemother 55:2004-2010.
50 Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KH, Pham ND, Ngyen HH, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y. 2005. Avian flu: isolation of drug-resistant H5N1 virus. Nature 437:1108.
51 Nguyen HT, Nguyen T, Mishin VP, Sleeman K, Balish A, Jones J, Creanga A, Marjuki H, Uyeki TM, Nguyen DH, Nguyen DT, Do HT, Klimov AI, Davis CT, Gubareva LV. 2013. Antiviral susceptibility of highly pathogenic avian influenza A(H5N1) viruses isolated from poultry, Vietnam, 2009-2011. Emerg Infect Dis 19:1963-1971.
52 Earhart KC, Elsayed NM, Saad MD, Gubareva LV, Nayel A, Deyde VM, Abdelsattar A, Abdelghani AS, Boynton BR, Mansour MM, Essmat HM, Klimov A, Shuck-Lee D, Monteville MR, Tjaden JA. 2009. Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt. J Infect Public Health 2:74-80.
53 Creanga A, Hang NLK, Cuong VD, Nguyen HT, Phuong HVM, Thanh LT, Thach NC, Hien PT, Tung N, Jang Y, Balish A, Dang NH, Duong MT, Huong NT, Hoa DN, Tho ND, Klimov A, Kapella BK, Gubareva L, Kile JC, Hien NT, Mai LQ, Davis CT. 2017. Highly Pathogenic Avian Influenza A(H5N1) Viruses at the Animal-Human Interface in Vietnam, 2003-2010. J Infect Dis 216:S529-S538.
54 Zurcher T, Yates PJ, Daly J, Sahasrabudhe A, Walters M, Dash L, Tisdale M, McKimm-Breschkin JL. 2006. Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro. J Antimicrob Chemother 58:723-732.
55 Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV. 2010. Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance. Antimicrob Agents Chemother 54:1834-1841.
56 Tamura D, Sugaya N, Ozawa M, Takano R, Ichikawa M, Yamazaki M, Kawakami C, Shimizu H, Uehara R, Kiso M, Kawakami E, Mitamura K, Kawaoka Y. 2011. Frequency of drug-resistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors. Clin Infect Dis 52:432-437.
57 Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. 2006. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series. J Infect Dis 193:760-764.
58 Simon P, Holder BP, Bouhy X, Abed Y, Beauchemin CA, Boivin G. 2011. The I222V neuraminidase mutation has a compensatory role in replication of an oseltamivir-resistant influenza virus A/H3N2 E119V mutant. J Clin Microbiol 49:715-717.
59 Tamura D, Nguyen HT, Sleeman K, Levine M, Mishin VP, Yang H, Guo Z, Okomo-Adhiambo M, Xu X, Stevens J, Gubareva LV. 2013. Cell culture-selected substitutions in influenza A(H3N2) neuraminidase affect drug susceptibility assessment. Antimicrob Agents Chemother 57:6141-6146.
60 Hurt AC, Besselaar TG, Daniels RS, Ermetal B, Fry A, Gubareva L, Huang W, Lackenby A, Lee RT, Lo J, Maurer-Stroh S, Nguyen HT, Pereyaslov D, Rebelo-de-Andrade H, Siqueira MM, Takashita E, Tashiro M, Tilmanis D, Wang D, Zhang W, Meijer A. 2016. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014-2015. Antiviral Res 132:178-185.
61 Dapat C, Suzuki Y, Saito R, Kyaw Y, Myint YY, Lin N, Oo HN, Oo KY, Win N, Naito M, Hasegawa G, Dapat IC, Zaraket H, Baranovich T, Nishikawa M, Saito T, Suzuki H. 2010. Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs. Emerg Infect Dis 16:493-496.
62 Yen HL, Hoffmann E, Taylor G, Scholtissek C, Monto AS, Webster RG, Govorkova EA. 2006. Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses. J Virol 80:8787-8795.
63 Mishin VP, Sleeman K, Levine M, Carney PJ, Stevens J, Gubareva LV. 2014. The effect of the MDCK cell selected neuraminidase D151G mutation on the drug susceptibility assessment of influenza A(H3N2) viruses. Antiviral Res 101:93-6.
64 Richard M, Ferraris O, Erny A, Barthelemy M, Traversier A, Sabatier M, Hay A, Lin YP, Russell RJ, Lina B. 2011. Combinatorial effect of two framework mutations (E119V and I222L) in the neuraminidase active site of H3N2 influenza virus on resistance to oseltamivir. Antimicrob Agents Chemother 55:2942-2952.
65 Abed Y, Baz M, Boivin G. 2009. A novel neuraminidase deletion mutation conferring resistance to oseltamivir in clinical influenza A/H3N2 virus. J Infect Dis 199:180-183.
66 Tamura D, Okomo-Adhiambo M, Mishin VP, Guo Z, Xu X, Villanueva J, Fry AM, Stevens J, Gubareva LV. 2015. Application of a seven-target pyrosequencing assay to improve the detection of neuraminidase inhibitor-resistant Influenza A(H3N2) viruses. Antimicrob Agents Chemother 59:2374-2379.
67 Carr J, Ives J, Kelly L, Lambkin R, Oxford J, Mendel D, Tai L, Roberts N. 2002. Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res 54:79-88.
68 Yen HL, Herlocher LM, Hoffmann E, Matrosovich MN, Monto AS, Webster RG, Govorkova EA. 2005. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother 49:4075-4084.
69 Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, Hayden FG, Sugaya N, Kawaoka Y. 2004. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 364:759-765.
70 McCauley JW, et al. 2017. Report prepared for the WHO annual consultation on the composition of influenza vaccine for the Southern Hemisphere 2018. Accessed 2023-05-07: https://www.crick.ac.uk/sites/default/files/2018-07/crick_sh2017_vcm_report_to_post.pdf
71 Hussain S, Daniels RS, Wharton SA, Howell S, Halai C, Kunzelmann S, Whittaker L, McCauley JW. 2021. Reduced sialidase activity of influenza A(H3N2) neuraminidase associated with positively charged amino acid substitutions. J Gen Virol 102: doi 10.1099/jgv.0.001648.
72 Baz M, Abed Y, McDonald J, Boivin G. 2006. Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child. Clin Infect Dis 43:1555-1561.
73 Sleeman K, Mishin VP, Guo Z, Garten RJ, Balish A, Fry AM, Villanueva J, Stevens J, Gubareva LV. 2014. Antiviral susceptibility of variant influenza A(H3N2)v viruses isolated in the United States from 2011 to 2013. Antimicrob Agents Chemother 58:2045-2051.
74 Gubareva LV, Sleeman K, Guo Z, Yang H, Hodges E, Davis CT, Baranovich T, Stevens J. 2017. Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins. J Infect Dis 216:S566-S574.
75 Marjuki H, Mishin VP, Chesnokov AP, Jones J, De La Cruz JA, Sleeman K, Tamura D, Nguyen HT, Wu HS, Chang FY, Liu MT, Fry AM, Cox NJ, Villanueva JM, Davis CT, Gubareva LV. 2015. Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan. J Infect Dis 211:249-257.
76 Tang J, Gao R, Liu L, Zhang S, Liu J, Li X, Fang Q, Feng Z, Xu C, Huang W, Wang D. 2021. Substitution of I222L-E119V in neuraminidase from highly pathogenic avian influenza H7N9 virus exhibited synergistic resistance effect to oseltamivir in mice. Sci Rep 11:16293.
77 Hai R, Schmolke M, Leyva-Grado VH, Thangavel RR, Margine I, Jaffe EL, Krammer F, Solorzano A, Garcia-Sastre A, Palese P, Bouvier NM. 2013. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun 4:2854.
78 Sleeman K, Guo Z, Barnes J, Shaw M, Stevens J, Gubareva LV. 2013. R292K substitution and drug susceptibility of influenza A(H7N9) viruses. Emerg Infect Dis 19:1521-1524.
79 Brown SK, Tseng YY, Aziz A, Baz M, Barr IG. 2022. Characterization of influenza B viruses with reduced susceptibility to influenza neuraminidase inhibitors. Antiviral Res 200:105280.
80 Fujisaki S, Takashita E, Yokoyama M, Taniwaki T, Xu H, Kishida N, Sato H, Tashiro M, Imai M, Odagiri T. 2012. A single E105K mutation far from the active site of influenza B virus neuraminidase contributes to reduced susceptibility to multiple neuraminidase-inhibitor drugs. Biochem Biophys Res Commun 429:51-56.
81 Farrukee R, Leang SK, Butler J, Lee RT, Maurer-Stroh S, Tilmanis D, Sullivan S, Mosse J, Barr IG, Hurt AC. 2015. Influenza viruses with B/Yamagata- and B/Victoria-like neuraminidases are differentially affected by mutations that alter antiviral susceptibility. J Antimicrob Chemother 70:2004-2012.
82 Jackson D, Barclay W, Zurcher T. 2005. Characterization of recombinant influenza B viruses with key neuraminidase inhibitor resistance mutations. J Antimicrob Chemother 55:162-169.
83 Sheu TG, Deyde VM, Garten RJ, Klimov AI, Gubareva LV. 2010. Detection of antiviral resistance and genetic lineage markers in influenza B virus neuraminidase using pyrosequencing. Antiviral Res 85:354-360.
84 Burnham AJ, Baranovich T, Marathe BM, Armstrong J, Webster RG, Govorkova EA. 2014. Fitness costs for Influenza B viruses carrying neuraminidase inhibitor-resistant substitutions: underscoring the importance of E119A and H274Y. Antimicrob Agents Chemother 58:2718-2730.
85 Barnett JM, Cadman A, Burrell FM, Madar SH, Lewis AP, Tisdale M, Bethell R. 1999. In vitro selection and characterisation of influenza B/Beijing/1/87 isolates with altered susceptibility to zanamivir. Virology 265:286-295.
86 Baranovich T, Vongphrachanh P, Ketmayoon P, Sisouk T, Chomlasack K, Khanthamaly V, Nguyen HT, Mishin VP, Marjuki H, Barnes JR, Garten RJ, Stevens J, Wentworth DE, Gubareva LV. 2017. Antiviral Drug-Resistant Influenza B Viruses Carrying H134N Substitution in Neuraminidase, Laos, February 2016. Emerg Infect Dis 23:686-690.
87 Fage C, Abed Y, Checkmahomed L, Venable MC, Boivin G. 2019. In Vitro Properties and Virulence of Contemporary Recombinant Influenza B Viruses Harboring Mutations of Cross-Resistance to Neuraminidase Inhibitors. Viruses 11, 6; doi:10.3390/v11010006.
88 Fujisaki S, Imai M, Takashita E, Taniwaki T, Xu H, Kishida N, Yokoyama M, Sato H, Tashiro M, Odagiri T. 2013. Mutations at the monomer-monomer interface away from the active site of influenza B virus neuraminidase reduces susceptibility to neuraminidase inhibitor drugs. J Infect Chemother 19:891-895.
89 Gubareva LV, Webster RG, Hayden FG. 2001. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother 45:3403-3408.
90 Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG. 1998. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 178:1257-1262.
91 Sleeman K, Sheu TG, Moore Z, Kilpatrick S, Garg S, Fry AM, Gubareva LV. 2011. Influenza B viruses with mutation in the neuraminidase active site, North Carolina, USA, 2010-11. Emerg Infect Dis 17:2043-2046.
92 Hurt AC, Iannello P, Jachno K, Komadina N, Hampson AW, Barr IG, McKimm-Breschkin JL. 2006. Neuraminidase inhibitor-resistant and -sensitive influenza B viruses isolated from an untreated human patient. Antimicrob Agents Chemother 50:1872-1874.
93 Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Ichikawa M, Kimura K, Kiso M, Shimizu H, Kawakami C, Koike K, Mitamura K, Kawaoka Y. 2007. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA 297:1435-1442.
94 Escuret V, Frobert E, Bouscambert-Duchamp M, Sabatier M, Grog I, Valette M, Lina B, Morfin F, Ferraris O. 2008. Detection of human influenza A (H1N1) and B strains with reduced sensitivity to neuraminidase inhibitors. J Clin Virol 41:25-28.
95 Escuret V, Collins PJ, Casalegno JS, Vachieri SG, Cattle N, Ferraris O, Sabatier M, Frobert E, Caro V, Skehel JJ, Gamblin S, Valla F, Valette M, Ottmann M, McCauley JW, Daniels RS, Lina B. 2014. A Novel I221L Substitution in Neuraminidase Confers High-Level Resistance to Oseltamivir in Influenza B Viruses. J Infect Dis doi:10.1093/infdis/jiu244.
96 Pascua PNQ, Marathe BM, Bisen S, Webby RJ, Govorkova EA. 2020. Influenza B viruses from different genetic backgrounds are variably impaired by neuraminidase inhibitor resistance- associated substitutions. Antiviral Res 173:104669.
97 Wang D, Sleeman K, Huang W, Nguyen HT, Levine M, Cheng Y, Li X, Tan M, Xing X, Xu X, Klimov AI, Gubareva LV, Shu Y. 2013. Neuraminidase inhibitor susceptibility testing of influenza type B viruses in China during 2010 and 2011 identifies viruses with reduced susceptibility to oseltamivir and zanamivir. Antiviral Res 97:240-244.
98 Carr S, Ilyushina NA, Franks J, Adderson EE, Caniza M, Govorkova EA, Webster RG. 2011. Oseltamivir-resistant influenza A and B viruses pre- and postantiviral therapy in children and young adults with cancer. Pediatr Infect Dis J 30:284-288.
99 Anonymous. 2012. Meetings of the WHO working group on surveillance of influenza antiviral susceptibility – Geneva, November 2011 and June 2012. Wkly Epidemiol Rec 87:369-374.

References PAI (Polymerase Acidic inhibitors)
1 Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, Kawaguchi K, Uehara T, Shishido T, Naito A, Cusack S. 2018. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep 8:9633.
2 Hashimoto T, Baba K, Inoue K, Okane M, Hata S, Shishido T, Naito A, Wildum S, Omoto S. 2021. Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil. Influenza Other Respir Viruses 15:389-395.
3 Ince WL, Smith FB, O’Rear JJ, Thomson M. 2020. Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil. J Infect Dis 222:957-961.
4 Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, Hashimoto T, Ishida K, Kushima Y, Hattori K, Kawai M, Yoshida R, Kobayashi M, Yoshinaga T, Sato A, Okamatsu M, Sakoda Y, Kida H, Shishido T, Naito A. 2018. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res 160:109-117.
5 Takashita E, Morita H, Ogawa R, Nakamura K, Fujisaki S, Shirakura M, Kuwahara T, Kishida N, Watanabe S, Odagiri T. 2018. Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil. Front Microbiol 9:3026.
6 Takizawa N, Momose F. 2022. A novel E198K substitution in the PA gene of influenza A virus with reduced susceptibility to baloxavir acid. Arch Virol 167:1565-1570.
7 Gubareva LV, Mishin VP, Patel MC, Chesnokov A, Nguyen HT, De La Cruz J, Spencer S, Campbell AP, Sinner M, Reid H, Garten R, Katz JM, Fry AM, Barnes J, Wentworth DE. 2019. Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons. Euro Surveill 24.
8 Takashita E, Daniels RS, Fujisaki S, Gregory V, Gubareva LV, Huang W, Hurt AC, Lackenby A, Nguyen HT, Pereyaslov D, Roe M, Samaan M, Subbarao K, Tse H, Wang D, Yen HL, Zhang W, Meijer A. 2020. Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018. Antiviral Res 175:104718.
9 Govorkova EA, Takashita E, Daniels RS, Fujisaki S, Presser LD, Patel MC, Huang W, Lackenby A, Nguyen HT, Pereyaslov D, Rattigan A, Brown SK, Samaan M, Subbarao K, Wong S, Wang D, Webby RJ, Yen HL, Zhang W, Meijer A, Gubareva LV. 2022. Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018-2020. Antiviral Res 200:105281.
10 Jones JC, Zagribelnyy B, Pascua PNQ, Bezrukov DS, Barman S, Okda F, Webby RJ, Ivanenkov YA, Govorkova EA. 2022. Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission. PLoS Pathog 18:e1010698.
11 Takashita E, Abe T, Morita H, Nagata S, Fujisaki S, Miura H, Shirakura M, Kishida N, Nakamura K, Kuwahara T, Mitamura K, Ichikawa M, Yamazaki M, Watanabe S, Hasegawa H, Influenza Virus Surveillance Group of J. 2020. Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment. Antiviral Res 180:104828.
12 Jones JC, Rovito SW, Penaflor MK, Webby RJ, Govorkova EA. 2022. Influenza A virus polymerase acidic protein E23R substitution is a marker of reduced susceptibility to baloxavir. Antiviral Res 204:105369.
13 Sato M, Takashita E, Katayose M, Nemoto K, Sakai N, Fujisaki S, Hashimoto K, Hosoya M. 2021. Detection of Variants With Reduced Baloxavir Marboxil and Oseltamivir Susceptibility in Children With Influenza A During the 2019-2020 Influenza Season. J Infect Dis 224:1735-1741.
14 Koszalka P, Tilmanis D, Roe M, Vijaykrishna D, Hurt AC. 2019. Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012-2018. Antiviral Res 164:91-96.
15 Jones JC, Pascua PNQ, Fabrizio TP, Marathe BM, Seiler P, Barman S, Webby RJ, Webster RG, Govorkova EA. 2020. Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility. Proc Natl Acad Sci U S A 117:8593-8601.
16 Chesnokov A, Patel MC, Mishin VP, De La Cruz JA, Lollis L, Nguyen HT, Dugan V, Wentworth DE, Gubareva LV. 2020. Replicative Fitness of Seasonal Influenza A Viruses With Decreased Susceptibility to Baloxavir. J Infect Dis 221:367-371.
17 Hickerson BT, Adams SE, Barman S, Miller L, Lugovtsev VY, Webby RJ, Ince WL, Donnelly RP, Ilyushina NA. 2022. Pleiotropic Effects of Influenza H1, H3, and B Baloxavir-Resistant Substitutions on Replication, Sensitivity to Baloxavir, and Interferon Expression. Antimicrob Agents Chemother 66:e0000922.
18 Kiso M, Yamayoshi S, Murakami J, Kawaoka Y. 2020. Baloxavir Marboxil Treatment of Nude Mice Infected With Influenza A Virus. J Infect Dis 221:1699-1702.
19 Sato M, Takashita E, Katayose M, Nemoto K, Sakai N, Hashimoto K, Hosoya M. 2020. Detection of Variants With Reduced Baloxavir Marboxil Susceptibility After Treatment of Children With Influenza A During the 2018-2019 Influenza Season. J Infect Dis 222:121-125.
20 Checkmahomed L, M’Hamdi Z, Carbonneau J, Venable MC, Baz M, Abed Y, Boivin G. 2020. Impact of the Baloxavir-Resistant Polymerase Acid I38T Substitution on the Fitness of Contemporary Influenza A(H1N1)pdm09 and A(H3N2) Strains. J Infect Dis 221:63-70.
21 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. 2020. Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets. Nat Microbiol 5:27-33.
22 Takashita E, Kawakami C, Morita H, Ogawa R, Fujisaki S, Shirakura M, Miura H, Nakamura K, Kishida N, Kuwahara T, Mitamura K, Abe T, Ichikawa M, Yamazaki M, Watanabe S, Odagiri T, Influenza Virus Surveillance Group of J. 2019. Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018. Euro Surveill 24.
23 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. 2019. 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 2019. Euro Surveill 24.
24 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. 2019. Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019. Emerg Infect Dis 25:2108-2111.
25 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. 2020. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis 221:346-355.
26 Yano T, Ochiai H, Akachi S, Matsumura Y. 2020. Polymerase Acidic Subunit I38T Mutant Influenza A(H3N2) Virus Isolated from a Pediatric Patient without Prior Baloxavir Marboxil Treatment in Mie Prefecture (November 2018). Jpn J Infect Dis 73:383-385.
27 Abed Y, Fage C, Checkmahomed L, Venable MC, Boivin G. 2020. Characterization of contemporary influenza B recombinant viruses harboring mutations of reduced susceptibility to baloxavir marboxil, in vitro and in mice. Antiviral Res 179:104807.
28 Pascua PNQ, Jones JC, Webby RJ, Govorkova EA. 2022. Effect of E23G/K, F36V, N37T, E119D, and E199G polymerase acidic protein substitutions on the replication and baloxavir susceptibility of influenza B viruses. Antiviral Res 208:105455.