77 SH O R T C O M M U N IC A T IO N ISSN 2413-6077. IJMMR 2020 Vol. 6 Issue 2 dOI 10.11603/IJMMR.2413-6077.2020.2.11485 FAVIPIRAVIR AND DEXAMETHASONE IN MANAGEMENT OF SARS-COV2 INFECTION (PILOT STUDy) M. Latief1, O. Shafi2, Z. Hassan3, *F. Abbas4 1 – GANDHI MEDICAL COLLEGE AND HOSPITAL, HyDERABAD, INDIA 2 – FLUSHING HOSPITAL MEDICAL CENTER NEW YORK, USA 3 – GOVERNMENT MEDICAL COLLEGE, BARAMULLA, INDIA 4 – PATHOLOGy DIVISION GOVERNMENT MEDICAL COLLEGE, SRINAGAR, INDIA Background. The clinical presentation of Coronavirus disease 19 (COVID-19) varies from mild symptoms to severe illness including multiorgan dysfunction. Favipiravir is an antiviral agent which has been previously used for treatment of influenza and was recently approved for treatment of mild to moderate COVID-19 in India. Objective. The Objective of this study was to assess the role of Favipiravir and Dexamethasone in patients with COVID-19. Methods. A total of 17 patients were included in this observational study. The included patients were RT-PCR for SARS-Cov-2 positive with increased inflammatory markers. All patients received Antiviral therapy, Anticoagulation (Enoxaparin 0.4mg subcutaneous twice daily), Steroids (Dexamethasone 8mg daily for 5days and 4mg daily for 5 days). Viral clearance (time to RT-PCR negative), time to defervescence after antiviral therapy, time to become independent of Oxygen support was studied. Results. Fever, myalgias, dry cough and dyspnea were the commonest presentation of COVID-19. All of our patients had lymphopenia. In our study 11 (64.7%) patients had bilateral ground glass opacities on CT chest while 6 had consolidation in addition to ground glass opacities. In two patients, who required non-invasive ventilation, Favipiravir was stopped and these patients received Remdesivir for a total of 5 days. In patients who received Favipiravir only, the Median time to RT-PCR negative, defervescence and oxygen independence was 8,3 and 6 days respectively. Conclusion. Our observational study demonstrated improvement in the majority of patients with COVID-19 with use of Favipiravir. Additional studies are needed to compare the efficiency of Favipiravir with Remdesivir. KEyWoRdS: SARS-CoV-2; Favipiravir; Remdesivir; COVID-19. *Corresponding Author: Farhat Abbas, Senior Resident, Patho- logy Division Government Medical College, Srinagar, 190011, India. E-mail: farahabbas.m@gmail.com International Journal of Medicine and Medical Research 2020, Volume 6, Issue 2, p. 77-81 copyright © 2020, TNMU, All Rights Reserved M. latief et al. Introduction COVID-19 or coronavirus disease 2019, is a novel illness caused by recently discovered severe acute respiratory syndrome coronavirus 2 (SaRS-CoV-2). The virus was first identified in Wuhan, a city in the Hubei province of China in December 2019 and has since rapidly spread into a global pandemic causing considerable morbidity and mortality worldwide [1, 2]. The disease is classified as either mild to moderate di sease (with no or mild symptoms up to mild pneu monia), severe disease (with hypoxia, dysp nea or >50% lung involvement on imaging within 48 hours), or critical illness (with respi- ratory failu re, multiorgan dysfunction or shock) [3-6]. However, the vast majority (around 80 to 85%) of infections result in a mild to moderate illness [7]. The ideal therapies for management of COVID-19 are still under investigation. Favipi- ravir is an antiviral agent which has been pre- viously used for treatment of influenza and was recently approved for treatment of mild to moderate COVID-19 in India [8, 9]. It has shown promise in an early non-randomized open label clinical trial in patients with non-severe disease, where use of Favipiravir was associated with faster rates of viral clearance (median time to clearance 4 versus 11 days) and more frequent radiographic improvement (in 91 versus 62 per cent by day 14) compared with lopinavir- ritonavir [10]. Other robust studies are under- way to assess the utility of Favipiravir in the ma nagement of COVID-19. We describe our early experience with the use of Favipiravir in patients with COVID-19. Methods A total of 17 patients were included in this observational study. The included patients were RT-PCR positive for SARS-CoV-2 with increased inflammatory markers. Clinical Characteristics 78 SH O R T C O M M U N IC A T IO N ISSN 2413-6077. IJMMR 2020 Vol. 6 Issue 2 of the patient population was studied. The inflammatory markers done in all patients were Interlekin-6, Ferritin, C-Reactive protein, Lactate dehydrogenase (LDH), D-Dimer. The other investigations done in all the included patients were Complete Blood count, Liver Function and Kidney Function tests, Urine examination, Blood Cultures, Serum procalcitonin. Ultrasound ab- do men, Xray Chest and High-Resolution com- puted tomography Chest. All patients received Antiviral therapy, Anticoagulation (Enoxaparin 0.4mg SC twice daily), Steroids (Dexamethasone 8mg daily for 5days and 4mg daily for 5 days). Viral clearance (time to RT-PCR negative), time to defervescence after antiviral therapy, time to become independent of Oxygen support and development of any complication during hos- pital stay was studied. Patients requiring me- cha nical ventilation at presentation to hospital were not included in this study. Results Out of 17 patients, there were 7 females and 10 male patients. The mean age of patients was 43.88±14.62 and mean Body mass index (BMI) was 23.54±1.62 kg/m2. All had high grade fever and myalgias, while 9 (52.9%) patients had dry cough on presentation. 5 patients complained of sore throat and shortness of breath was seen in 9 patients (table 1). There were 4 patients with known Diabetes mellitus and 3 of them were hypertensive as well. Rest of the patients did not have any underlying comorbidity. However, in two pa- tients, who developed new onset hyperglycemia during steroid course, were found to have Hba1c in Prediabetic range. Out of 17 patients, 11 (64.7%) patients had bilateral ground glass opacities on CT chest while 6 had consolidation in addition to ground glass opacities. All of our patients had Absolute Lymphocyte count (ALC) below 1500 while 4 patients had severe lym- phopenia (aLC<1000 cells). The inflammatory markers and biochemical parameters are shown in table 2. In our study, 10 patients had mild trans- aminitis before Favipiravir and 3 developed self-limiting transaminitis after Favipiravir, 4 had normal Liver function test throughout. Two patient had acute kidney injury (AKIN class 1) that resolved during hospital stay. Blood culture was sterile in all the patients and Serum pro- calcitonin was negative in all the patients. Nine patients required oxygen support. Among them 7 were on oxygen support via Nasal Canula and 2 patients required non-invasive ventilation (NIV) during hospital stay. Favipiravir was given at a dose of 1800 mg twice on day 1 and sub- sequently 800 mg twice daily from day 2-10. In two patients, who required NIV Favipiravir was stopped, and these patients received Remdesivir for a total of 5 days. In patients who received Favipiravir only, the median time to RT-PCR negative, defervescence and oxygen inde pen- dence was 8,3 and 6 days respectively. There was no thrombocytopenia, bleeding bacterial sepsis in our patient population. There was no mortality in our study population. Discussion The optimal management of patients with COVID-19 is rapidly evolving based on extensive ongoing research. Initial studies have suggested a clinical benefit with Remdesivir (antiviral agent) and a mortality benefit with the use of glucocorticoids. Remdesivir, a nucleotide ana- logue, has in vitro activity against SARS-CoV-2 [11]. Although more data from comparati- ve, randomized trials are emerging [12, 13], available reports suggest there is likely some clinical benefit to Remdesivir prompting emer- gency use authorization by the FDA for severe COVID-19 in hospitalized children and adults [14]. Remdesivir needs to be administered intra venously and should be avoided in patients with transaminitis (aLT ≥5 times normal) or in Table 1. Clinical features of patient population Clinical feature n (%) Fever 17 (100) Myalgia 17 (100) Cough 9 (52.9) Sore throat 5 (29.4) Vomiting 2 (11.7) Dyspnea 9 (52.9) Epigastric discomfort 1 (0.05) Table 2. Biochemical parameters and inflammatory markers Parameter Mean±SD Hemoglobin (g/dL) 13.08±1.83 Platelet (lac/ µL) 3.4±0.71 ferritin (µg/L) 615.41±307.03 ALT (IU/L) 111.5±35.7 Absolute lymphocyte count 1180±213.2 Bilirubin (mg/dL) 0.92±0.23 Triglyceride (mg/dL) 125.4±21.01 d-dimer (ng/ µL) 566.13±207.92 LDH (U/L) 615±187.06 iL 6 (pg/µL) 80.58±98.06 M. latief et al. 79 SH O R T C O M M U N IC A T IO N ISSN 2413-6077. IJMMR 2020 Vol. 6 Issue 2 patients with an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2. It should also not be coadministered with hydroxy chlo- roquine or chloroquine due to potential drug interactions. The use of dexamethasone (oral or intravenous) provided a mortality benefit at 28 days in hospitalised patients with COVID-19 compared to usual care alone as per a preli mi- nary report of the RECOVERY trial, a large ran- domized open-label study in the United King- dom [15]. however, no benefit was reported among patients who did not require either oxygen or ventilatory support; with a statistically non-significant trend towards higher mortality (17.8 versus 14 percent, RR 1.19, 95% CI 0.91- 1.55). Also, there remain uncertainties in this preliminary report, as the baseline mortality rate in this report was higher than that from some other trials. Thus, the absolute mortality benefit in other settings may not be as high as observed in this trial. Addi tionally, adverse effects (including secondary infections) were not reported in the preliminary report. Another antiviral agent which is being in vestigated for its use in patients with COVID-19 is a purine nucleoside analogue, Favipiravir. It selectively in hibits RNA dependent RNA polymerase (RdRP), an enzyme needed for RNA viral repli- cation within human cells, by getting incorpo- rated instead of guanine and adenine [8]. The drug is converted into its active phosphorylated form intracellularly and subsequently is re- cognized as a substrate by the viral RdRP. The incorporation of a single molecule of the active form of Favipiravir terminates the elongation of viral RNA [8]. Favipiravir is known to have a broad spectrum of activity towards RNA viruses (like influenza, bunyavirus, arenavirus, flavivirus, and filoviruses causing hemorrhagic fever) including activity against oseltamivir- and za- namivir-resistant influenza viruses [8, 16]. Wang et al studied the in vitro antiviral efficiency of several drugs including Favipiravir against SARS-CoV-2, reporting that Favipiravir reduced the viral infection, albeit at higher concentra- tions half-maximal effective concentration (EC50) = 61.88 μm, half-cytotoxic concentration (CC50) > 400 μm, selectivity index (Si) > 6.46 [11]. Pertinently, in a previous study evaluating the efficiency of favipiravir against Ebola virus, even with a high EC50 value in Vero E6 cells of 67 μm, the antiviral agent demonstrated 100% in vivo effectiveness in protecting mice against Ebola virus; suggesting that further clinical studies could better evaluate the in vivo respon- se of this antiviral nucleoside [17]. Early clinical studies of Favipiravir for COVID-19 have been promising. A non-rando- mized open-label study by Cai et al. reported a significant reduction in time taken for viral clearance in COVID-19 patients treated with Favipiravir compared to historical controls who had received lopinavir/ritonavir [10]. This study from China involved administration of Favi- piravir (1600 mg orally twice daily on day 1 follo wed by 600 mg orally twice daily on days 2–14) in patients with mild to moderate CoVid-19. Patients ≥75 years old, those having severe or critical COVID-19, chronic liver disease or end-stage renal disease were excluded from the study. in addition to a significant reduction (p < 0.001) in median time to viral clearance in the Favipiravir arm (4 days; IQR = 2.5–9) com- pared with the historical lopinavir/ritonavir arm (11 days; IQR = 8–13), the vast majority of pa- tients (91.4%) in the former group had radio- graphic improvement versus 62.2% in the latter group at 14 days. There was a significantly lower rate of adverse events in patients receiving Favipiravir (11.4% versus 55.6%; P < 0.01). In our study those patients who received Favipiravir only, the median time to RT-PCR negative, defervescence and oxygen independence was 8,3 and 6 days respectively. Chen et al conducted a prospective multicenter randomized open label study comparing outcomes in adult COVID-19 patients after administration of Umi- fenovir versus Favipiravir in addition to conven- tional therapy [18]. In their preprint article, they report a statistically non-significant (p=0.1396, difference of recovery rate: 0.0954; 95% Ci: -0.0305 to 0.2213) higher clinical recovery rate at Day 7 in the Favipiravir group (61.2%) compared to the Umifenovir group (51.6%). also, the favipiravir group had significantly shorter latencies to relief in pyrexia (difference: 1.70 days, P<0.0001) and cough (difference: 1.75 days, P<0.0001). They reported only mild and manageable side effects from the use of Favipiravir. Although there is a paucity of high- grade evidence for the effectiveness of Favi- piravir in COVID-19, the in vitro activity and benefits seen in early studies strongly suggest the potential for using Favipiravir in SARS-CoV-2 infection. Our observational study demonstrated improvement in the majority of patients with COVID-19 with use of Favipiravir. Conclusions Ease of oral administration and a profile of mild adverse effects are advantages of Favi- piravir. Further evidence from well-designed M. latief et al. 80 SH O R T C O M M U N IC A T IO N ISSN 2413-6077. IJMMR 2020 Vol. 6 Issue 2 randomized controlled trials should enable clinicians to better understand the role of Favipiravir in the management of the ongoing coronavirus pandemic. Additional studies are needed to compare the efficiency of favipiravir compared to Remdesivir. Conflicts of Interest authors declare no conflict of interest. Funding No funding was received for this study. Acknowledgements We would love to thank Dr. Summyia Farooq of Pathology Division GMC Srinagar for helping us during this study. Author Contributions Muzamil Latief, Obeid Shafi – concep tuali- zation, methodology, formal analysis, writing – original draft, writing – reviewing and editing; Muzamil Latief, Zhahid Hassan, Farhat Abbas – data curation, writing – reviewing and editing; Muzamil Latief, Obeid Shafi, Farhat Abbas – investigation, formal analysis. ФАВІПІРАВІР ТА ДЕКСАМЕТАЗОН У ЛІКУВАННІ SARS-COV2 ІНФЕКЦІЇ (пілотне дослідження) M. Latief1, O. Shafi2, Z. Hassan3, *F. Abbas4 1 – GANDHI MEDICAL COLLEGE AND HOSPITAL, HyDERABAD, INDIA 2 – FLUSHING HOSPITAL MEDICAL CENTER NEW YORK, USA 3 – GOVERNMENT MEDICAL COLLEGE, BARAMULLA, INDIA 4 – PATHOLOGy DIVISION GOVERNMENT MEDICAL COLLEGE, SRINAGAR, INDIA Вступ. клінічна картина коронавірусної хвороби (COVID-19) варіює від легкого перебігу до тяжких проявів з поліорганною дисфункцією. противірусний засіб фавіпіравір, який раніше застосовувався для лікування грипу, нещодавно був схвалений для лікування COVID-19 легкого та середнього ступеня тяжкості в індії. Мета. Завданням цього дослідження – оцінка ефективності фавіпіравіру та дексаметазону при COVID-19. Методи. у пілотне дослідження було включено 17 пацієнтів, у яких були позитивні плр тести до SARS-CoV-2 та підвищені маркери запалення. усі пацієнти отримували противірусну терапію, антикоагулянт (еноксапарин 0,4 мг підшкірно двічі на день), глюкокортикостероїди (дексаметазон 8 мг щодня протягом 5 днів та 4 мг щодня протягом 5 днів). досліджувалися такі показники: тривалість перебігу хвороби до негативних результатів плр тесту, час нормалізації температури на тлі противірусної терапії, швидкість відновлення самостійного дихання. Результати. лихоманка, міалгія, сухий кашель та задишка були найпоширенішими симптомами COVID-19. у всіх пацієнтів була лімфопенія. при проведенні комп’ютерної томографії грудної клітки, у 11 (64,7%) пацієнтів було знайдено симптом «матового скла», тоді як у 6 спостерігалися і симптом «матового скла» і ущільнення. у двох пацієнтів, яким була потрібна неінвазивна вентиляція, фавіпіравір було відмінено, і ці пацієнти отримували ремдесевір протягом 5 днів. у пацієнтів, які отримували лише фавіпіравір, медіана часу до негативного значення плр тесту, швидкість повернення температури до нормальної та швидкість відновлення самостійного дихання становила 8,3 та 6 днів відповідно. Висновок. наше пілотне дослідження продемонструвало тенденцію до покращення у більшості пацієнтів із COVID-19 при застосуванні фавіпіравіру. Головні обмеження – мала кількість спостережень, та необхідність проведення додаткових досліджень для порівняння ефективності фавіпіравіру та ремдесевіру . КЛЮЧОВІ СЛОВА: SARS-CoV-2; фавіпіравір; ремдесевір; COVID-19. Information about the authors Muzamil Latief, DM Resident, Nephrology Division Gandhi Medical College and Hospital, Secunderabad, India oRCid 0000-0002-2267-6322, e-mail: muzamillatief.b@gmail.com Obeid Shafi, Chief Resident, Flushing Hospital Medical Center, New York, USA oRCid 0000-0003-2669-199X, e-mail: obeidshafi@gmail.com Zhahid Hassan, Consultant, Government Medical College, Baramulla, India oRCid 0000-0003-3724-8387, e-mail: xahid6676@yahoo.co.in Farhat Abbas, Senior Resident, Pathology Division Government Medical College, Srinagar, India oRCid 0000-0003-1922-4752, email: farahabbas.m@gmail.com M. latief et al. 81 SH O R T C O M M U N IC A T IO N ISSN 2413-6077. IJMMR 2020 Vol. 6 Issue 2 References 1. World Health Organization. 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