Terapevticheskii arkhivTerapevticheskii arkhiv0040-36602309-5342LLC Obyedinennaya Redaktsiya3371910.26442/00403660.2019.11.000454Review ArticleReview of current and future directions of antiviral therapy of influenza and acute respiratory viral infections in RussiaPshenichnayaN Ynatalia-pshenichnaya@yandex.ruBulgakovaV A-VolchkovaE V-KarevaE N-SelkovaE P-GorodinV N-Federal State Budgetary Institution “National Medical Research Center for Phthisiopulmonology and Infectious Diseases”Federal State Autonomous Institution “National Medical Research Center for Children's Health”Federal State Autonomous Educational Institution of the High Education “Sechenov First Moscow State Medical University” (Sechenov University)Federal State Budgetary Educational Institution of the High Education “Pirogov Russian National Research Medical University” (Pirogov Medical University)Federal State Budgetary Educational Institution of the High Education “Pirogov Russian National Research Medical University” (Pirogov Medical University)Federal State Budgetary Institution of Science “Moscow Research Institute of Epidemiology and Microbiology” of Federal Service for Surveillance on Consumer Rights Protection and Human WellbeingKuban State Medical University (KubSMU)15112019911110510916042020Copyright © 2019, Consilium Medicum2019Aim: to determine the perspectives for the use of drugs with combined antiviral, anti - inflammatory and immunomodulatory activity on the basis of medical studies of existing antiviral drugs for the treatment of influenza and acute respiratory viral infections in Russia. Materials and methods. A brief review of the antiviral drugs used in Russia for the treatment of influenza and acute respiratory viral infections was conducted on the basis of 37 articles published in Scopus, Web of Science (WoS), and RSCI databases in the period from 1997 to 2018. Results. Resistance to neuraminidase inhibitors (oseltamivir, zanamivir), is slowly developing due to the mutations of the neuraminidase gene H275Y and Q136K. Most influenza A viruses remain resistant to adamantane antivirals. Repeated use of immunomodulators with indirect antiviral action leads to a hyporeactivity of the immune system and, subsequently, to a decrease in their effectiveness. Positive clinical and laboratory data in clinical trials were obtained using Enisamium iodide, a drug with combined action - direct antiviral, and immunomodulatory. Conclusion. According to the WHO strategy, the results of the review demonstrate the need for continued research of medications with combined antiviral and pathogenetic effects on the infectious process caused by influenza and acute respiratory viral infections.acute respiratory viral infectionsinfluenzaantiviralsimmunomodulatorsnonsteroid anti inflammatory drugsenisamium iodideNobazidострые респираторные вирусные инфекциигрипппротивовирусные препаратыиммуномодуляторыэнисамия йодиднобазит[Johnson N.P.A.S, Mueller J. Updating the accounts: global mortality of the 1918-1920 “Spanish” influenza pandemic. Bull Hist Med. 2002;76(1):105-15. doi:10.1353/bhm.2002.0022][Spreeuwenberg P, Kroneman M, Paget J. Reassessing the global mortality burden of the 1918 influenza pandemic. Am J Epidemiol. 2018;187(12):2561-7. doi:10.1093/aje/kwy191][Iuliano A.D, Roguski K.M, Chang H.H, Muscatello D.J, Palekar R, Tempia S, et al. Estimates of global seasonal influenza - associated respiratory mortality: a modelling study. Lancet. 2018;391(10127):1285-300. doi:10.1016/ S0140-6736(17)33293-2][Global influenza strategy 2019-2030. Geneva: World Health Organization, 2019. https://apps.who.int/iris/bitstream/handle/10665/311184/ 9789241515320-eng.pdf?ua=1 [Accessed 20.07.2019]][О состоянии санитарно - эпидемиологического благополучия населения в Российской Федерации в 2018 году: Государственный доклад. М.: Федеральная служба по надзору в сфере защиты прав потребителей и благополучия человека, 2019:254 с.][Руженцова Т.А. Протививорусные ЛС и иммуномодуляторы в терапии ОРВИ. Путеводитель врачебных назначений. Бионика Медиа. 2017;5.][Shinahara W, Takahashi E, Sawabuchi T, Arai M, Hirotsu N, Takasaki Y, et al. Immunomodulator clarithromycin enhances mucosal and systemic immune responses and reduces re - infection rate in pediatric patients with influenza treated with antiviral neuraminidase inhibitors: a retrospective analysis. PloS ONE. 2013;8(7):e70060. doi:10.1371/journal.pone.0070060][Sheu T.G, Fry A.M, Garten R.J, Deyde V.M, Shwe T, Bullion L, et al. Dual resistance to adamantanes and oseltamivir among seasonal influenza A (H1N1) viruses: 2008-2010. J Infectious Diseases. 2011;203(1):13-7. doi:10.1093/inf dis/jiq005][Spencer S, Nguyen H, Elal A.A, Laplante J, St George K, Fry A.M, et al. Surveillance for Oseltamivir-Resistant Influenza A (H1N1) pdm09 Virus Infections During 2016-2017 and 2017-2018, United States. In Open Forum Infectious Diseases. 2018;5(Suppl 1):S267. doi:10.1093/ofid/ofy210.752][Bragstad K, Hungnes O, Litleskare I, Nyrerød H.C, Dorenberg D.H, Hauge S.H. Community spread and late season increased incidence of oseltamivir - resistant influenza A (H1N1) viruses in Norway 2016. Influenza and other respiratory viruses. 2019;13(4):372-81. doi:10.1111/irv.12637][Hurt A.C, Holien J.K, Parker M, Kelso A, Barr I.G. Zanamivir - resistant influenza viruses with a novel neuraminidase mutation. J Virology. 2009; 83(20):10366-73. doi:10.1128/JVI.01200-09][Kiatboonsri S, Kiatboonsri C, Theerawit P. Fatal respiratory events caused by zanamivir nebulization. Clinical infectious diseases. 2009;50(4):620. doi:10. 1086/650176][Dong G, Peng C, Luo J, Wang C, Han L, Wu B. Adamantane - resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations. PloS ONE. 2015;10(3):e0119115. doi:10.1371/journal.pone.01 19115][Shiraishi K, Mitamura K, Sakai-Tagawa Y, Goto H, Sugaya N, Kawaoka Y. High frequency of resistant viruses harboring different mutations in amantadine - treated children with influenza. J Infectious Diseases. 2003;188(1):57-61. doi: 10.1086/375799][Булгакова В.А., Поромов А.А., Грекова А.И., Пшеничная Н.Ю., Селькова Е.П., Львов Н.И., Малеев, В.В. Фармакоэпидемиологическое исследование течения гриппа и других ОРВИ в группах риска. Терапевтический архив. 2017;89(1):62-71. doi:10.17116/terarkh201789162-71][Ратникова Л. И. Применение нового отечественного противовирусного препарата в этиотропной терапии гриппа. Экспериментальная и клиническая фармакология. 2018;81(3):24-7.][Ramos I, Fernandez-Sesma A. Modulating the innate immune response to influenza A virus: potential therapeutic use of anti - inflammatory drugs. Frontiers in immunology. 2015;(6):361. doi:10.3389/fimmu.2015.00361][Бухтiарова Т.А. Амiзон - новий неопiоїдний анальгетик з протизапальними, жарознижуючими та iнтерфероногенними властивостями. Лiки. 1997;3:69.][Фролов А.Ф., Фролов В.М. Эффективность Амизона в лечении и профилактике вирусных инфекций (к 10-летию применения препарата в клинической практике). Український медичний часопис. 2005;49(5)-ІХ/Х: 75-80.][Исаков В.А., Охапкина Е.А., Евграфов В.Д. Эффективность амизона в терапии и профилактике ОРВИ. Медицинский форум. 2015.][Boltz D, Peng X, Muzzio M, Dash P, Thomas P, Mehta R, Margitich V. Antiviral activity of enisamium against influenza viruses in differentiated normal human bronchial epithelial cells. In III antivirus congress. Amsterdam, October 2014:12-14.][Cocking D, Cinatl J, Boltz D.A, Peng X, Johnson W, et al. Antiviral effect of a derivative of isonicotinic acid enisamium iodide (FAV00A) against influenza virus. Acta virologica. 2018;62(2):191-5. doi: 10.4149/av_2018_2 11][Денисова А.Р., Максимов М.Л. Острые респираторные вирусные инфекции: этиология, диагностика, современный взгляд на лечение. РМЖ. Медицинское обозрение. 2018;1(II):99-103.][Фролов А.Ф., Фролов В.М., Бухтиарова Т.А., Даниленко В.Ф. Клинические аспекты применения Амизона. Украинский медицинский журнал. 2004;39(1):69-74.][Нобазит, инструкция по применению. Интернет - ресурс. http://www.grls.rosminzdrav. ru/Grls_View_v2.aspx?routingGuid=fd084d2c-63a4-4360-bb5b-281e98c9c241 &t=2d3c9fcf-1833-4c0e-8c37-82b0f568fa4d [Accessed 20.07.2019].][Мельникова Т.И., Деева Э.Г., Амосова И.В., Оксамитная Е.Г., Маргитич В.М. Клиническая эффективность Амизона в терапии гриппа и других острых респираторных вирусных инфекций. Здоров’я Украiни. 2013;17:40-1.][Сенцова Т.Б., Ревякина В.А., Ворожко И.В., Кириллова О.О., Моносова О.Ю. Современные аспекты применения иммуномодуляторов в лечении и профилактике респираторных вирусных инфекций у детей. Вопросы практической педиатрии. 2011;6(5):100-4.][Исаков Д.В., Исаков В.А., Алексеева Е.А. Иммуномодуляторы в терапии и профилактике респираторных и герпесвирусных инфекций. Клиническая фармакология и терапия. 2018;27(5):76-85.][Савенкова М.С, Савенков М.П, Афанасьева А.А, Абрамова Н.А. Возможности противовирусной и иммуномодулирующей терапии в лечении гриппа, ОРВИ, герпесвирусных инфекций. Пульмонология. 2015; (5):83-93.][Li W, Moltedo B, Moran T.M. Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of γδ T-cells. J Virology. 2012;86(22):12304-12. doi:10.1128/JVI.01269-12][Killip M.J, Fodor E, Randall R.E. Influenza virus activation of the interferon system. Virus research. 2015;209:11-22. doi:10.1016/j.virusres.2015.02.003][Taylor R.T, Bresnahan W.A. Human cytomegalovirus immediate - early 2 gene expression blocks virus - induced beta interferon production. J Virology. 2005;79(6):3873-7. doi:10.1128/JVI.79.6.3873-3877.2005][Minamitani T, Iwakiri D, Takada K. Adenovirus virus - associated RNAs induce type I interferon expression through a RIG-I-mediated pathway. J Virology. 2011;85(8):4035-40. doi:10.1128/JVI.02160-10][Hermodsson S. Inhibition of interferon by an infection with parainfluenza virus type 3 (PIV-3). J Virology. 1963;20(2):333-43. doi:10.1016/0042-6822(63) 90123-5][Peng T, Kotla S, Bumgarner R.E, Gustin K.E. Human rhinovirus attenuates the type I interferon response by disrupting activation of interferon regulatory factor 3. J Virology. 2006;80(10):5021-31. doi:10.1128/JVI.80.10.5021-5031. 2006][Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25+ CD4+ regulatory T-cells through GITR breaks immunological self - tolerance. Nature immunology. 2002;3(2):135.][Интерфероногены: перспективы клинического применения: Руководство для врачей. Под ред. М.Г. Романцова. М., СПб., 1998:38 с.]