STUDY OF CLINICAL AND PATHOGENETIC EFFECTS OF ANTI-VIRAL DRUG BASED ON FAVIPIRAVIR IN COMORBID PATIENTS WITH COVID-19 AT THE OUTPATIENT STAGE OF TREATMENT

In many ways, arterial hypertension and obesity determine the likelihood of a severe course and lethal outcomes in COVID-19. This fact justifies the expediency of an early use of drugs with a direct antiviral action, the analysis of their efficacy not only in the acute, but also in the postcovid period.

The aim of the research was to analyze the outpatient cards and case histories of the COVID-19 patients to study the effect of the early (up to the 5^th day after the onset of the first symptoms of the disease) use of the drug based on favipiravir, on the frequency of patients’ hospitalizations with arterial hypertension and obesity, as well as to determine the cytokine status characteristics of this patient category in the postcovid period.

Materials and methods. “An open prospective comparative study of the “Areplivir^®” (favipiravir) efficacy in the debut of COVID-19 in comorbid patients” was carried out in the Republic of Mordovia (the analysis of the hospitalizations frequency and blood levels of M-CSF, EPO in 218 patients, in terms of the use of the antiviral preparation).

Results. According to the results of the analysis, it was found out that, despite the presence of comorbid conditions that increase the risk of developing a severe course of COVID-19, i.e. obesity and essential arterial hypertension, in the group of patients taking favipiravir, the need for hospitalization was twice as low (p < 0.05), in relation to the comparison group. The analysis of the cytokine status revealed that in the postcovid period, in the group that took the drug based on favipiravir at the outpatient stage, the average level of M-CSF was significantly lower (p> 0.05), and EPO was higher (p> 0.05) than in the patients from the group “without antiviral drugs at the outpatient stage”. Indirectly, according to the previously obtained data, that acts as a potential marker for reducing the risk of long-term cardiovascular complications of COVID-19.

Conclusion. This study showed that an early prescription of favipiravir contributes to a decrease in the rate of COVID-19 patients’ hospitalization even against the background of concomitant hypertension and obesity, due to a decrease in the likelihood of moderate and severe courses of the disease, and also leads to an earlier objective and subjective recovery. The results demonstrated a high potential benefit of an early favipiravir use in the novel coronavirus infection and in the prevention of postcovid complications.

1. Anka AU, Tahir MI, Abubakar SD, Alsabbagh M, Zian Z, Hamedifar H, Sabzevari A, Azizi G. Coronavirus disease 2019 (COVID-19): An overview of the immunopathology, serological diagnosis and management. Scand J Immunol. 2021 Apr;93(4):e12998. DOI: 10.1111/sji.12998.

2. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; the Northwell COVID-19 Research Consortium, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 May 26;323(20):2052–9. DOI: 10.1001/jama.2020.6775.

3. Mitrani RD, Dabas N, Goldberger JJ. COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm. 2020 Nov;17(11):1984–90. DOI: 10.1016/j.hrthm.2020.06.026.

4. Radaeva OA, Simbirtsev AS, Selezneva NM, Iskandyarova MS. Serum macrophage colony-stimulating factor levels in patients with essential hypertension after SARS-CoV-2 infection. Russ J Immunol. 2020;23(4):429–36. Russian. DOI: 10.46235/1028-7221-430-SMC.

5. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, Liao X, Gu Y, Cai Q, Yang Y, Shen C, Li X, Peng L, Huang D, Zhang J, Zhang S, Wang F, Liu J, Chen L, Chen S, Wang Z, Zhang Z, Cao R, Zhong W, Liu Y, Liu L. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020 Oct;6(10):1192–8. DOI: 10.1016/j.eng.2020.03.007.

6. Ongoing Living Update of COVID-19 Therapeutic Options: Summary of Evidence. Rapid: Review, 27 May 2021. Pan American Health Organization, – 241 рр. Available from: https://iris.paho.org/bitstream/handle/10665.2/52719/PAHOIMSEIHCOVID1921018_eng.pdf?sequence=45&isAllowed=y.

7. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Ju L, Zhang J, Wang X. Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial. Front Pharmacol. 2021 Sep 2;12:683296. DOI: 10.3389/fphar.2021.683296.

8. Goyal A, Cardozo-Ojeda EF, Schiffer JT. Potency and timing of antiviral therapy as determinants of duration of SARS-CoV-2 shedding and intensity of inflammatory response. Sci Adv. 2020 Nov 20;6(47):eabc7112. DOI: 10.1126/sciadv.abc7112.

9. Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, Patil S, Barkate H. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021 Jan;102:501-8. DOI: 10.1016/j.ijid.2020.10.069.

10. Pilkington V, Pepperrell T, Hill A. A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic? J Virus Erad. 2020 Apr 30;6(2):45–51. DOI: 10.1016/S2055-6640(20)30016-9.

11. Balykova LA, Pavelkina VF, Shmyreva NV, Pyataev NA, Selezneva NM, Shepeleva OI, Almyasheva RZ. Efficacy and safety of some etiotropic therapeutic schemes for treating patients with novel coronavirus infection (COVID-19). Pharmacy & Pharmacology. 2020;8(3):150–9. DOI: 10.19163/2307-9266-2020-8-3-150-159.

12. Hassanipour S, Arab-Zozani M, Amani B, Heidarzad F, Fathalipour M, Martinez-de-Hoyo R. The efficacy and safety of Favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep. 2021 May 26;11(1):11022. DOI: 10.1038/s41598-021-90551-6.

13. Manabe T, Kambayashi D, Akatsu H, Kudo K. Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis. 2021 May 27;21(1):489. DOI: 10.1186/s12879-021-06164-x.

14. Hanna CR, Blyth KG, Burley G, Carmichael S, Evans C, Hinsley S, Ibrahim Khadra I, Saye Khoo S, Lewsley LA, Jones RR, Sharma R, Taladriz-Sender A, Thomson EC, Scott JT. Glasgow Early Treatment Arm Favirpiravir (GETAFIX) for adults with early stage COVID-19: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):935. DOI: 10.1186/s13063-020-04891-1.

15. Brown LK, Freemantle N, Breuer J, Dehbi HM, Chowdhury K, Jones G, Ikeji F, Ndoutoumou A, Santhirakumar K, Longley N, Checkley AM, Standing JF, Lowe DM. Early antiviral treatment in outpatients with COVID-19 (FLARE): a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Mar 8;22(1):193. DOI: 10.1186/s13063-021-05139-2.

16. Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, Mutoh Y, Homma Y, Terada M, Ogawa T, Kashizaki F, Yokoyama T, Koba H, Kasahara H, Yokota K, Kato H, Yoshida J, Kita T, Kato Y, Kamio T, Kodama N, Uchida Y, Ikeda N, Shinoda M, Nakagawa A, Nakatsumi H, Horiguchi T, Iwata M, Matsuyama A, Banno S, Koseki T, Teramachi M, Miyata M, Tajima S, Maeki T, Nakayama E, Taniguchi S, Lim CK, Saijo M, Imai T, Yoshida H, Kabata D, Shintani A, Yuzawa Y, Kondo M. A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01897–20. DOI: 10.1128/AAC.01897-20.

17. Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, Wang T, Sun Q, Ming Z, Zhang L, Ge J, Zheng L, Zhang Y, Wang H, Zhu Y, Zhu C, Hu T, Hua T, Zhang B, Yang X, Li J, Yang H, Liu Z, Xu W, Guddat LW, Wang Q, Lou Z, Rao Z. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020 May 15;368(6492):779–82. DOI: 10.1126/science.abb7498.

18. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020 May;209:107512. DOI: 10.1016/j.pharmthera.2020.107512.

19. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449–63. DOI: 10.2183/pjab.93.027.

20. Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018 May;153:85–94. DOI: 10.1016/j.antiviral.2018.03.003.

21. Udwadiaa ZF, Singh P, Barkateb H, Patilb S, Rangwalab S, Pendseb A, Kadamb J, Wuc W, Caractad CF, Tandonb M. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Intern J Infn Diseas. 2021;103:62–71. DOI: 10.1016/j.ijid.2020.11.142.

22. Radaeva OA, Simbirtsev AS, Kostina JA. The change in the circadian rhythm of macrophage colony-stimulating factor content in the blood of patients with essential hypertension. Cytokine X. 2019 Aug 23;1(3):100010. DOI: 10.1016/j.cytox.2019.100010.

23. Yağcı S, Serin E, Acicbe Ö, Zeren Mİ, Odabaşı MS. The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19. Int J Lab Hematol. 2021 Jul;43 Suppl 1:142–51. DOI: 10.1111/ijlh.13479.

24. Johnson CS, Cook CA, Furmanski P. In vivo suppression of erythropoiesis by tumor necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO). Exp Hematol. 1990 Feb;18(2):109–13.

25. Kassir R. Risk of COVID-19 for patients with obesity. Obes Rev. 2020 Jun;21(6):e13034. DOI: 10.1111/obr.13034.

26. Zhirnov O.P., Chernyshova AI. Favipiravir: the hidden threat of mutagenic action. J Microbiol Epidemiol & Immunobiol. 2021; 98(2):213–20. DOI: https://doi.org/10.36233/0372-9311-114.

27. Tam DNT, Qarawi TA, Luu NM, Turnage M, Tran L, Tawfik GM, Le HNM, Nguyen TH, Tatsuo I, Kyoshi K, Kenji H. Favipiravir and its potentials in COVID-19 pandemic: An update. Asian Pac. J. Trop. Med. 2021;14(10):433–9. DOI: 10.4103/1995-7645.329005.

28. Kocayiğit H, Özmen Süner K, Tomak Y, Gürkan D, Selçuk Y, Hamad D, Ertuğrul G, Ali Fuat E. 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):454-9. DOI: 10.1111/jcpt.13305.

29. Tsang HF, Chan LWC, Cho WCS, Yu ACS, Yim AKY, Chan AKC, Ng LPW, Wong YKE, Pei XM, Li MJW, Wong SC. An update on COVID-19 pandemic: the epidemiology, pathogenesis, prevention and treatment strategies. Expert Rev Anti Infect Ther. 2021 Jul;19(7):877–88. DOI: 10.1080/14787210.2021.1863146.

30. Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, Kadam J, Wu W, Caracta CF, Tandon M. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis. 2021 Feb;103:62–71. DOI: 10.1016/j.ijid.2020.11.142.

31. Vankadari N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int J Antimicrob Agents. 2020 Aug;56(2):105998. DOI: 10.1016/j.ijantimicag.2020.105998.