The association of antiviral drugs with COVID-19 morbidity: The retrospective analysis of a nationwide COVID-19 cohort
Cenk Babayigit, Nurdan Kokturk, Seval Kul, Pelin Duru Cetinkaya, Sibel Atis Nayci, Serap Argun Baris, Oguz Karcioglu, Pinar Aysert, Ilim Irmak, Aycan Akbas Yuksel, Yonca Sekibag, Oya Baydar Toprak, Emel Azak, Sait Mulamahmutoglu, Caglar Cuhadaroglu, Aslihan Demirel, Bugra Kerget, Burcu Baran Ketencioglu, Hasan Selcuk Ozger, Gulcihan Ozkan, Zeynep Ture, Begum Ergan, Vildan Avkan Oguz, Oguz Kilinc, Merve Ercelik, Tansu Ulukavak Ciftci, Ozlem Alici, Esra Nurlu Temel, Ozlem Ataoglu, Asena Aydin, Dilek Cetiner Bahcetepe, Yusuf Taha Gullu, Fusun Fakili, Figen Deveci, Neslihan Kose, Muge Meltem Tor, Gulsah Gunluoglu, Sedat Altin, Teyfik Turgut, Tibel Tuna, Onder Ozturk, Oner Dikensoy, Pinar Yildiz Gulhan, Ilknur Basyigit, Hasim Boyaci, Ipek Kivilcim Oguzulgen, Sermin Borekci, Bilun Gemicioglu, Firat Bayraktar, Osman Elbek, Ismail Hanta, Hacer Kuzu Okur, Gulseren Sagcan, Oguz Uzun, Metin Akgun, Goksel Altinisik, Berna Dursun, Ebru Cakir Edis, Erkmen Gulhan, Fusun Oner Eyuboglu, Okkes Gultekin, Yavuz Havlucu, Metin Ozkan, Aysin Sakar Coskun, Abdullah Sayiner, A Fuat Kalyoncu, Oya Itil, Hasan Bayram
Frontiers in Medicine, doi:10.3389/fmed.2022.894126
Furthermore, favipiravir was associated with increased risks of ICU admission (OR [95% CI]: 3.02 [1.70-5.35]; p = 0.001) and invasive mechanical ventilation requirement (OR [95% CI]: 2.94 [1.28-6.75]; p = 0.011).
Conclusion: Our findings demonstrated that antiviral drugs including lopinavir, ritonavir, and favipiravir were associated with negative clinical outcomes such as increased risks for lengthy hospital stay, ICU admission, and invasive mechanical ventilation requirement. Therefore, repurposing such agents without proven clinical evidence might not be the best approach for COVID-19 treatment.
Ethics statement The studies involving human participants were reviewed and approved by Institutional Review Board of Gazi University Faculty of Medicine, Ankara, Turkey (356/22.05.2020). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
Author contributions CB, NKk, HBa, OI, FO, AS, ASC, BD, and AK designed the study. CB, NKk, PC, SAB, OKa, PA, II, AAk, YS, OB, EA, SM, CC, AD, BK, BB, HO, GO, ZT, BE, VA, OKi, ME, TU, OAl, EN, OAt, AAy, DC, YG, FF, FD, NKs, MT, GG, SA, TeT, TiT, OO, OD, PY, IB, HBo, IO, SB, BG, FB, OE, IH, HK, GS, OU, MA, GA, BD, EC, EG, OG, YH, MO, and ASC collected the data. SK and SAN analyzed the data. CB, NKk, SK, and HBa searched the literature and wrote the manuscript. CB, NKk, SK, SAB, PC, and HBa edited and revised manuscript according to journal's instructions. CB, NKk, SK, PC, SAB, and HBa edited and controlled the final version of the manuscript. All authors approved the final version of the manuscript.
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BH declared a shared affiliation with the authors, II and AK to the handling editor at the time of review.
Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of..
References
Antoniou, Dilaveris, Manolakou, Galanakos, Magkas et al., QT prolongation and malignant arrhythmia: How serious a problem?, Eur Cardiol,
doi:10.15420/ecr.2017:16:1Arshad, Kilgore, Chaudhry, Jacobsen, Wang et al., Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19, Int J Infect Dis,
doi:10.1016/j.ijid.2020.06.099Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of Covid-19-final report, N Engl J Med,
doi:10.1056/NEJMoa2007764Bernal, Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, N Engl J Med,
doi:10.1056/NEJMoa2116044Catteau, Dauby, Montourcy, Bottieau, Hautekiet et al., Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: A nationwide observational study of 8075 participants, Int J Antimicrob Agents
Chan, Lai, Chu, Tsui, Tam et al., Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: A multicentre retrospective matched cohort study, Hong Kong Med J
Chinello, Petrosillo, Pittalis, Biava, Ippolito et al., Cardiac safety of off-label COVID-19 drug therapy: A review and proposed monitoring protocol, Eur Heart J Acute Cardiovasc Care,
doi:10.1177/2048872620922784Choy, Wong, Kaewpreedee, Sia, Chen et al., None
Covid, 19 Risk and Treatments (Corist) Collaboration. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study, Eur J Intern Med
Doi, Hibino, Hase, Yamamoto, Kasamatsu et al., A prospective, randomized, open-label trial of early versus late favipiravir therapy in hospitalized patients with COVID-19, Antimicrob Agents Chemother,
doi:10.1128/AAC.01897-20Fiolet, Guihur, Rebeaud, Mulot, Peiffer-Smadja et al., Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): A randomised clinical trial, Clin Microbiol Infect,
doi:10.1016/S0140-6736(20)31862-6Food, Coronavirus (COVID-19) update: FDA Authorizes additional oral antiviral for treatment of COVID-19 in certain adults
Gao, Tian, Yang, Wei, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends,
doi:10.1097/CM9.0000000000000819Geleris, Sun, Platt, Zucker, Baldwin et al., Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2012410Guner, Hasanoglu, Kayaaslan, Aypak, Akinci et al., Comparing ICU admission rates of mild/moderate COVID-19 patients treated with hydroxychloroquine, favipiravir, and hydroxychloroquine plus favipiravir, J Infect Public Health,
doi:10.14744/nci.2021.60420Ivashchenko, Dmitriev, Vostokova, Azarova, Blinow et al., AVIFAVIR for treatment of patients with moderate coronavirus disease 2019 (COVID-19): Interim results of a phase II/III multicenter randomized clinical trial, Clin Infect Dis,
doi:10.1093/cid/ciaa1176Karim, Repurposed antiviral drugs for covid-19 -interim WHO solidarity trial results, N Engl J Med,
doi:10.1056/NEJMx200021Kokturk, Babayigit, Kul, Cetinkaya, Nayci et al., The predictors of COVID-19 mortality in a nationwide cohort of Turkish patients, Respir Med,
doi:10.1016/j.rmed.2021.106433Manabe, Kambayashi, Akatsu, Kudo, Ghanei et al., Favipiravir for the treatment of patients with COVID-19: A systematic review and meta-analysis, Br MC Infect Dis,
doi:10.1186/s12879-021-06164-xMitjà, Corbacho-Monné, Ubals, Tebé, Peñafiel et al., Hydroxychloroquine for early treatment of adults with mild Covid-19: A randomized-controlled trial, Clin Infect Dis,
doi:10.1093/cid/ciaa1009Pan, Peto, Henao-Restrepo, Preziosi, Sathiyamoorthy, None
Ranieri, Rubenfeld, Thompson, Ferguson, classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European league against rheumatism/American College of rheumatology/paediatric rheumatology international trials organisation collaborative initiative, Ann Rheum Dis,
doi:10.1378/chest.101.6.1644Remdesivir, Cao, Wang, Wen, Liu et al., A trial of lopinavirritonavir in adults hospitalized with severe covid-19, Antiviral Res,
doi:10.1056/NEJMc2008043Rice, Janj, Kokturk, Kul, Cetinkaya et al., In defence of evidence-based medicine for the treatment of COVID-19 acute respiratory distress syndrome,
doi:10.1513/AnnalsATS.202004-325IPRosenberg, Dufort, Udo, Wilberschied, Kumar et al., Association of treatment with hydroxychloroquine or azithromycin with inhospital mortality in patients with COVID-19 in New York state, JAMA,
doi:10.1001/jama.2020.8630Soltane, Elmaaty, Tantawy, Antar, Yahya, Coronavirus disease (COVID-19) control between drug repurpising and vaccination: A comprehensive overview, Vaccines,
doi:10.3390/vaccines9111317Spinner, Gottlieb, Criner, López, Cattelan et al., FDA approves first treatment for COVID-19
Sun, Deng, Chen, Huang, Huang et al., Incidence of adverse drug reactions in COVID-19 patients in China: An active monitoring study by hospital pharmacovigilance system, Clin Pharmacol Ther,
doi:10.1002/cpt.1866Viladomiu, Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A Randomized clinical trial, Ann Intern Med,
doi:10.7326/M20-5752Wang, Cao, Zhang, Xinglou, Jia et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Wu, Chen, Cai, Xia, Zhou et al., Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.0994Yousefi, Valizadeh, Ghaffari, Vahedi, Karbalaei et al., A global treatment for coronaviruses including COVID-19, J Cell Physiol,
doi:10.1002/jcp.29785Özlüşen, Kozan, Akcan, Kalender, Yaprak et al., Effectiveness of favipiravir in COVID-19: A live systematic review, Eur J Clin Microbiol Infect Dis,
doi:10.1007/s10096-021-04307-1{ 'indexed': {'date-parts': [[2022, 8, 31]], 'date-time': '2022-08-31T07:42:07Z', 'timestamp': 1661931727547},
'reference-count': 52,
'publisher': 'Frontiers Media SA',
'license': [ { 'start': { 'date-parts': [[2022, 8, 31]],
'date-time': '2022-08-31T00:00:00Z',
'timestamp': 1661904000000},
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'abstract': '<jats:sec><jats:title>Background and objectives</jats:title><jats:p>Although several '
'repurposed antiviral drugs have been used for the treatment of COVID-19, only a few such as '
'remdesivir and molnupiravir have shown promising effects. The objectives of our study were to '
'investigate the association of repurposed antiviral drugs with COVID-19 '
'morbidity.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Patients '
'admitted to 26 different hospitals located in 16 different provinces between March 11–July '
'18, 2020, were enrolled. Case definition was based on WHO criteria. Patients were managed '
'according to the guidelines by Scientific Board of Ministry of Health of Turkey. Primary '
'outcomes were length of hospitalization, intensive care unit (ICU) requirement, and '
'intubation.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We '
'retrospectively evaluated 1,472 COVID-19 adult patients; 57.1% were men (mean age = 51.9 ± '
'17.7years). A total of 210 (14.3%) had severe pneumonia, 115 (7.8%) were admitted to ICUs, '
'and 69 (4.7%) were intubated during hospitalization. The median (interquartile range) of '
'duration of hospitalization, including ICU admission, was 7 (5–12) days. Favipiravir '
'(<jats:italic>n</jats:italic> = 328), lopinavir/ritonavir (<jats:italic>n</jats:italic> = '
'55), and oseltamivir (<jats:italic>n</jats:italic> = 761) were administered as antiviral '
'agents, and hydroxychloroquine (HCQ, <jats:italic>n</jats:italic> = 1,382) and azithromycin '
'(<jats:italic>n</jats:italic> = 738) were used for their immunomodulatory activity. '
'Lopinavir/ritonavir (β [95% CI]: 4.71 [2.31–7.11]; <jats:italic>p</jats:italic> = 0.001), '
'favipiravir (β [95% CI]: 3.55 [2.56–4.55]; <jats:italic>p</jats:italic> = 0.001) and HCQ (β '
'[95% CI]: 0.84 [0.02–1.67]; <jats:italic>p</jats:italic> = 0.046) were associated with '
'increased risk of lengthy hospital stays. Furthermore, favipiravir was associated with '
'increased risks of ICU admission (OR [95% CI]: 3.02 [1.70–5.35]; <jats:italic>p</jats:italic> '
'= 0.001) and invasive mechanical ventilation requirement (OR [95% CI]: 2.94 [1.28–6.75]; '
'<jats:italic>p</jats:italic> = '
'0.011).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings '
'demonstrated that antiviral drugs including lopinavir, ritonavir, and favipiravir were '
'associated with negative clinical outcomes such as increased risks for lengthy hospital stay, '
'ICU admission, and invasive mechanical ventilation requirement. Therefore, repurposing such '
'agents without proven clinical evidence might not be the best approach for COVID-19 '
'treatment.</jats:p></jats:sec>',
'DOI': '10.3389/fmed.2022.894126',
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'author': 'Catteau',
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'associated with reduced mortality: Findings from the observational '
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'author': 'Geleris',
'year': '2020',
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'author': 'Mitjà',
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'volume': '323',
'author': 'Rosenberg',
'year': '2020',
'journal-title': 'JAMA.'},
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'year': '2022',
'journal-title': 'Guideline for treatment of adult patients with covid-19.'},
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'doi-asserted-by': 'publisher',
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'volume': '101',
'author': 'Bone',
'year': '1992',
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'doi-asserted-by': 'crossref',
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'complicating systemic juvenile idiopathic arthritis: A European league '
'against rheumatism/American College of rheumatology/paediatric '
'rheumatology international trials organisation collaborative '
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'volume': '75',
'author': 'Ravelli',
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