COVID-19: Antiviral Therapy

Abstract

The cases reported in Wuhan province in China in December 2020 spread all over the world within a few months, and the SARS-CoV-2 infection pandemic was declared by the World Health Organization (WHO) on March 11, 2020. Since the first cases were seen, some drugs used in clinical practice have been repurposed and started to be used in the treatment of COVID-19. Many articles on the subject have been published without peer review, and a serious information pollution has emerged. As of the date the pandemic was declared in the world, the first patient with coronavirus infection was reported in our country. Repurposed agents like hydroxychloroquine, favipiravir and remdesivir have been used in treatment for antiviral effects in accordance with the Ministry of Health's Coronavirus Guideline and international literature in our country. Recently, monoclonal antibodies have started to take place in clinical practice. In this article, the drugs used in the antiviral treatment of SARS-CoV-2 infection during the pandemic process are reviewed.

Keywords

• covid
• therapy
• antiviral

COVID-19: Antiviral Tedavi

Abstract

Aralık 2020’de Çin’de Wuhan eyaletinde bildirilen vakalar birkaç ay içinde tüm dünyaya yayılmış ve 11 Mart 2020’de Dünya Sağlık Örgütü (DSÖ) tarafından SARS-CoV-2 enfeksiyonu pandemisi ilan edilmiştir. İlk vakaların görülmeye başlanmasından itibaren klinik pratikte kullanılan bazı ilaçlar yeniden konumlandırılarak COVID-19 tedavisinde kullanılmaya başlanmıştır. Konuyla ilgili çok sayıda makale hakem değerlendirmesi olmadan yayınlanmış, ciddi bir bilgi kirliliği ortaya çıkmıştır. Dünyada pandemi ilan edildiği tarih itibariyle ülkemizde de ilk koronavirüs enfeksiyonu olan hasta bildirilmiştir. Ülkemizde Sağlık Bakanlığı Koronavirüs Rehberi doğrultusunda yeniden konumlandırılan ajanlar antiviral etki amacıyla tedavide kullanılmıştır. Hidroksiklorokin, favipiravir ve remdesivir kullanılan antiviral ajanlardır. Son zamanlarda monoklonal antikorlar klinik pratikte yer almaya başlamıştır. Bu yazıda SARS-CoV-2 enfeksiyonunun antiviral tedavisinde pandemi sürecinde kullanılan ilaçlar gözden geçirilmiştir.

Keywords

• covid
• tedavi
• antiviral

References

1. 1. Fragkou PC, Belhadi D, Peiffer-Smadja N Moschopoulos CD, Lescure FX, Janocha H, et al. Review of trials currently testing treatment and prevention of COVID-19. CMI 2020;26(8):988-98.
2. 2. T.C. Sağlık Bakanlığı Halk Sağlığı Genel Müdürlüğü COVID-19 Erişkin Hasta Tedavisi. [Internet]. [cited 22 March 2021] Available from: https://covid19.saglik.gov.tr/Eklenti/39061/0/covid-19rehberieriskinhastatedavisipdf.pdf.
3. 3. Siddigi J, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. Heart Lung Transplant 2020;39(5):405-7.
4. 4. Liu J, Chen H, Tang K, Guo Y. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect 2020 Mar 4. doi: 10.1016/j.jinf.2020.02.028
5. 5. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020;30(3):269-71.
6. 6. Lu CC, Chen MY Wan-Shin L, Chang YL. Potential therapeutic agents against COVID-19: What we know so far. J Chin Med Assoc 2020;83(6):534-6. doi: 10.1097/JCMA.0000000000000318
7. 7. Yao X, Ye F, Zhang Z, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020;40:(5):416-37.
8. 8. Barlow A, Landolf KM, Barlow B, Yeung SYA, Heavner JJ, Claassen CW, et al. Review of emerging pharmacotherapy for the reatment of coronavirus disease 2019. Pharmacotherapy 2020. doi: 10.1002/ phar.2398

9. 9. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020;16:155-66.
10. 10. Nakayama T, Sugano Y, Yokokawa T, Nagai T, Matsuyama TA, Ohta-Ogo K, et al. Clinical impact of the presence of macrophages in endomyocardial biopsies of patients with dilated cardiomyopathy. Eur J Heart Fail 2017;19(4):490-8.
11. 11. Hoffmann H, Mösbauer K, Hofmann-Winkler H, Kaul A, Kleine-Weber H, Krüger N, et al. Chloroquine does not inhibit infection of human lung cells with SARS-cov-2. Nature 2020;585(7826):588-90. https://doi.org/10.1038/s41586-020-2575-3
12. 12. Maisonnasse, P., Guedi J, Contreas V, Behillil S, Solas C, Marlin R, et al. Hydroxychloroquineuse against SARS-cov-2 infection in non-human primates. Nature 2020;585(7826):584-7 https://doi.org/10.1038/ s41586-020-2558-4
13. 13. Letter to Dr Rick Bright re: request for Emergency Use Authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 coronavirus disease. Published March 28, 2020. . [Internet]. [cited 22 March 2021] Available from: https://www.fda.gov/media/136534/download
14. 14. Tecen-Yücel K, Kara E, Demirkan K, Ünal S. Covid-19 tedavisinde hidroksiklorokin kullanımı. FLORA 2020;25(3):283-91.
15. 15. Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 1996;(Supp 1):S11-5.
16. 16. Stokkermans TJ, Goyal A, Bansal P, Trichonas G. Chloroquine And Hydroxychloroquine Toxicity. Treasure Island (FL): StatPearls Publishing LLC, 2020.
17. 17. Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ 2020;369:m1432
18. 18. RECOVERY Collaborative Group, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multicentre, randomized, controlled trial. N Engl J Med. 2020 Nov 19;383(21):2030-2040. doi: 10.1056/NEJMoa2022926.
19. 19. WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, et al. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results N Engl J Med. 2021;384(6):497-511. doi: 10.1056/NEJMoa2023184.
20. 20. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. 2020;383(21):2041-2052. doi: 10.1056/NEJMoa2019014
21. 21. Tang W, Cao Z, Han M, Wang Z, Chen J, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial BMJ. 2020 May 14;369:m1849. doi: 10.1136/bmj.m1849.
22. 22. Abd-Elsalam S, Esmail ES, Khalaf M, Abdo EF, Mohammed A. Medhat MA, Abd El Ghafar MS, et al. Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study. Am J Trop Med Hyg. 2020103(4):1635-1639. doi: 10.4269/ajtmh.20-0873.
23. 23. Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann Intern Med. 2020;173(8):623-631. doi: 10.7326/M20-4207.
24. 24. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19 A Randomized Clinical Trial. JAMA. 2020;324(21):2165-2176. doi:10.1001/jama.2020.22240
25. 25. Lyngbakken MN, Berdal JE, Eskesen A, Kvale D, Olsen IC, Rueegg CS. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun 2020;11(5284) https://doi.org/10.1038/s41467-020-19056-6
26. 26. Mitjà O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias a, et al. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clinical Infectious Diseases 2020; https://doi.org/10.1093/cid/ciaa100929
27. 27. Chen Z, Hu J, Zhang Z, Jiang S, Han S et al. Efficacy of hydrochlroquine in patients with COVID-19: Results of a randomized trial; 2020: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2
28. 28. Huang M, Tang T, Pang P, Li M, Ma R, Lu J, et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol. 2020;12(4):322-325. doi: 10.1093/jmcb/mjaa014.
29. 29. Chen L, Zhang ZY, Fu JG, Feng ZP, Zhang SZ, Han QY, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. Medrxiv preprint doi: https://doi.org/10.1101/2020.06.19.20136093.t
30. 30. Mega TA, Feyissa TM, Bosho DD, Goro KK, Negera GZ. The Outcome of Hydroxychloroquine in Patients Treated for COVID-19: Systematic Review and Meta-Analysis. Can Respir J 2020;4312519. doi: 10.1155/2020/4312519.
31. 31. Chandrasekar VT, Venkatesalu B, Patel HK, Spadaccini M, Jacob Manteuffel J, et al. Systematic review and meta‐analysis of effectiveness of treatment options against SARS‐CoV‐2 infection J Med Virol. 2021;93(2):775-785. doi: 10.1002/jmv.26302.
32. 32. Das RR, Behera B, Mishra B, Naik SS. Effect of Chloroquine and Hydroxychloroquine on COVID‑19 Virological Outcomes: An Updated Meta‑Analysis. Indian J Med Microbiol 2020;38:265-76.
33. 33. Das S, Bhowmick S, Tiwari S, Sen S. An Updated Systematic Review of the Therapeutic Role of Hydroxychloroquine in Coronavirus Disease-19 (COVID-19). Clin Drug Investig. 2020 (7):591-601. doi: 10.1007/s40261-020-00927-1
34. 34. Elavarasi A, Prasad M, Seth T, Sahoo RK, Madan K, Nischal N, et al. Chloroquine and Hydroxychloroquine for the Treatment of COVID-19: a Systematic Review and Meta-analysis. J Gen Intern Med 35(11):3308–14 DOI: 10.1007/s11606-020-06146-w
35. 35. Maraolo AE, Grossi A. Safety of hydroxychloroquine for treatment or prevention of SARS‐CoV‐2 infection: A rapid systematic review and meta‐analysis of randomized clinical trials. Immun Inflamm Dis. 2021;9(1):31-6. doi: 10.1002/iid3.374.
36. 36. Hong TS, Gonzalez J, Nahass RG, Brunetti L. Impact of Hydroxychloroquine on Mortality in Hospitalized Patients with COVID-19: Systematic Review and Meta-Analysis. Pharmacy 2020;8(4):208. doi: 10.3390/pharmacy8040208.
37. 37. Pathak SK, Salunke AA, Thivari P, Pandey A, Nandy K, Ratna HVK, et al. No benefit of hydroxychloroquine in COVID-19: Results of Systematic Review and Meta-Analysis of Randomized Controlled Trials Diabetes Metab Syndr. 2020;14(6):1673-80. doi: 10.1016/j.dsx.2020.08.033.
38. 38. Shamshirian A, Hessami A, Heydari K, Alizadeh-Navaei R, Ebrahimzadeh MA, Yip GW, et al. The Role of Hydroxychloroquine in COVID-19 Treatment: A Systematic Review and Meta-Analysis. Ann Acad Med Singap 2020;49:789-800 DOI: 10.47102/annals-acadmedsg.2020370
39. 39. Singh AK, Singh A, Singh R, Misra A. Hydroxychloroquine in patients with COVID-19: A Systematic Review and meta-analysis. Diabetes Metab Syndr 2020;14:589-96
40. 40. Ullah W, Abdullah HM, Roomi S, Sattar Y, Almas T,Gowda SN,et al. Safety and Efficacy of Hydroxychloroquine in COVID-19: A Systematic Review and Meta-Analysis. J Clin Med Res. 2020;12(8):483-491. doi: 10.14740/jocmr4233.2(8
41. 41. Zang Y, Han X, He M, Shi J, Li Y. Hydroxychloroquine use and progression or prognosis of COVID-19:a systematic review and meta-analysis. Naunyn Schmiedebergs Arch Pharmacol. 2020:1–8. doi: 10.1007/s00210-020-01964-5. 483-491
42. 42. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Eng J Med 2020;383:517-25.
43. 43. Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebe C, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med 2021;384:417-27. DOI: 10.1056/NEJMoa2021801
44. 44. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine [Internet] [cited 20 March 2021]. Available from: https://www.fda.gov/media/138945/download
45. 45. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. [Internet] [cited 20 March 2021]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
46. 46. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446-54.
47. 47. Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 2014;105:17-21.
48. 48. Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, et al. Experimental treatment with favipiravir for Ebola Virus Disease (the JIKI Trial): A historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med. 2016;13(3):e1001967.
49. 49. Bouazza N, Treluyer J-M, Foissac F, Mentré F, Taburet A-M, Guedj J, et al. Favipiravir for children with Ebola. The Lancet. 2015;385(9968):603-4.
50. 50. Choy KT. Wong AY, Kaewpreedee P, Sia SF, Chen D Pui K, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-cov-2 replication in vitro. Antiviral Research 2020;178:104786. Doi: 10.1016/j.antiviral.2020.104786
51. 51. Shannon, A., Selisko, B., Le, N.T.T, Huchting, J., Touret, F., Piorkowski, G., et al. Favipiravir strikes the SARS-cov-2 at its Achilles heel, the RNA polymerase Nat Commun. 2020;11(1):4682. doi: 10.1038/s41467-020-18463-z.
52. 52. Toyama Chemicals. Summary of Product Characteristics of Avigan. [Internet] [cited 17 Dec 2020]. Available from: https://www.cdc.gov.tw/File/Get/ht8jUiB_MI-aKnlwstwzvw,
53. 53. Madelain V, Nguyen TH, Olivo A, de Lamballerie X, Guedj J, Taburet AM, et al. Ebola Virus infection: Review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials. Clin Pharmacokinet. 2016;55(8):907-23.
54. 54. Kaya E, İnkaya AÇ, Demirkan K, Ünal S. COVID-19 Tedavisinde Favipiravir Kullanımı. FLORA 2021;26(1):1-11. doi: 10.5578/flora.20219901
55. 55. Rattanaumpawan P, Jirajariyavej S, Lerdlamyong K, Palavutitotai N, Saiyarin J. Real-world Experience with Favipiravir for Treatment of COVID-19 in Thailand: Results from a Multi-center Observational Study. Medrxiv preprint doi: https://doi.org/10.1101/2020.06.24.201332492020
56. 56. Kumagai Y, Murakawa Y, Hasunuma T, Aso M, Yuji W, Sakurai T, et al. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015;53(10):866-74.
57. 57. Pharmaceuticals and Medical Devices Agency. Report on the Deliberation Results Avigan, Japan. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau. [Internet] [cited 17 Dec 2020]. Available from: www.pmda.go.jp/files/000210319.pdf.
58. 58. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering (Beijing). 2020;6(10):1192-8.
59. 59. Kocayiğit H, Özmen Süner K, Tomak Y, Demir G, Yaylacı S, Dheir H, et al. Observational study of the effects of Favipiravir vs Lopinavir/Ritonavir on clinical outcomes in critically Ill patients with COVID-19. J Clin Pharm Ther. 2021;46(2):454-459. doi: 10.1111/jcpt.13305.
60. 60. Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, et al. AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis 2020; ciaa1176. doi: 10.1093/cid/ciaa1176.
61. 61. Chen C, Huang J, Cheng Z, Zhang Y, Cheng Z et al. (2020). Favipiravir versus arbidol for COVID-19: a randomized clinical trial [online]. Medrxiv preprint doi:https://doi.org/10.1101/2020.03.17.20037432
62. 62. Fu D, Cao R, Zhao L, Li W, Zhong W, Wen J. Oral favipiravir for patients with delayed SARS-CoV-2 viral RNA clearance: a case series. Critical Care. 2020;24(1):578.
63. 63. Yamamura H, Matsuura H, Nakagawa J, Fukuoka H, Domi H, Chujoh S. Effect of favipiravir and an anti-inflammatory strategy for COVID-19. Critical Care 2020;24(1):413.
64. 64. Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, et al. A prospective, randomized, open-label trial of early versus late favipiravir in hospitalized patients with COVID-19. Antimicrobial Agents and Chemotherapy. 2020;64(12):e01897-20.
65. 65. Agostini ML, Andres EL, Sims AC, Graham RL Sheahan TP, Lu X, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio 2018;9(2):e00221-18; DOI: 10.1128/mBio.00221-18
66. 66. Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature 2020;585 273–6. https://doi.org/10.1038/s41586-020-2423-5
67. 67. National Health Institute COVID-19 Treatment Guidelines. [Internet] [cited 22 March 2021]. Available from: www.pmda.go.jp/files/000210319.pdf.
68. 68. The Sanford Guide to Antimicrobial Therapy 2021 App Version 4.2.15. Gilbert DN, Chambers HF, Saag, MS., Pavia, AT, Black D, Boucher H, Freedman DO, Kim K, Schwarz BS (Editors). Last content update: 24 Mar 2021.
69. 69. Adamsick ML, Gandhi RG, Bidell MR, Elshaboury RH, Bhattacharyya RP, Kim AY. Remdesivir in Patients with Acute or Chronic Kidney Disease and COVID-19. J Am Soc Nephrol. 2020;(7):1384-6. doi: 10.1681/ASN.2020050589.
70. 70. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al . Remdesivir for the Treatment of Covid-19 — Final Report N Engl J Med 2020;383:1813-26 doi: 10.1056/NEJMoa2007764
71. 71. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Lancet. 2020;395(10236):1569-78. doi: 10.1016/S0140-6736(20)31022-9.
72. 72. Spinner CD, Gottlieb RL, Criner GJ, Lopez JRA, Cattelan AM, Viladomiu AS, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patient With Moderate COVID-19 A Randomized Clinical Trial. JAMA. 2020;324(11):1048-57. doi: 10.1001/jama.2020.16349.
73. 73. European Medicines Agency. First COVID-19 treatment recommended for EU authorisation [Internet] [cited 22 March 2021]. Available from https://www.ema.europa.eu/en/documents/press-release/first-covid-19-treatment recommended-eu-authorisation_en.pdf
74. 74. Discovery Stops Testing Remdesivir Against Covid-19 For Lack Of Evidence Of İts Efficacy. [Internet] [cited 22 March 2021]. Available from: Https://Presse.İnserm.Fr/En/Discovery-Stops-Testing-Remdesivir-Against-Covid-19-For-Lack-Of-Evidence-Of-İts-Efficacy/42034/
75. 75. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, et al. Infectious Diseases Society of America 2021; Version 4.1.1. [Internet] [cited 20 March 2021]. Available from: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/.
76. 76. WHO recommends against the use of remdesivir in COVID-19 patients [Internet] [cited 22 March 2021] Available from: https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients
77. 77. ACTIV-3/TICO LY-CoV555 Study Group, Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, Sandkovsky U, et al. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med 2021;384:905-14. doi: 10.1056/NEJMoa2033130.
78. 78. Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of Bamlanivimab as Monotherapy or in Combination with Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19 A Randomized Clinical Trial. JAMA. 2021;325(7):632–644. doi:10.1001/jama.2021.0202
79. 79. Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2021; 384:229-237. DOI: 10.1056/NEJMoa2029849
80. 80. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Bamlanivimab and Etesevimab. [Internet] [cited 22 March 2021] Available from: https://www.fda.gov/media/145802/download.
81. 81. Wang P, Wang M, Yu J, Cerutti G, Nair MS, Huang Y, et al. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization bioRxiv 2021.03.01.433466; doi: https://doi.org/10.1101/2021.03.01.433466
82. 82. U.S. Food And Drug Administration Fact Sheet For Health Care Provıders: Emergency Use Authorızatıon (Eua) Of Casırıvımab And Imdevımab. [Internet] [cited 22 March 2021] Available from: https://www.fda.gov/media/143892/download.