Turkiye Klinikleri Cardiovascular Sciences

.: ORIGINAL RESEARCH
Impact of Adding Favipiravir to Hydroxychloroquine and Azithromycin Treatment on QTc Interval in COVID-19
Hidroksiklorokin ve Azitromisin Tedavisine Favipiravirin Eklenmesinin COVID-19'da QTc Aralığı Üzerindeki Etkisi
İdris Buğra ÇERİK a, Hatun ÖZTÜRK ÇERİK b, Ahmet DOĞAN c, Seçkin DERELİ d , Osman BEKTAŞ d, Yasemin KAYA e
aDepartment of Cardiology, Sivas Cumhuriyet University Faculty of Medicine, Sivas, TURKEY
bClinic of Infectious Diseases and Clinical Microbiology, Sivas Numune Hospital, Sivas, TURKEY
cClinic of Infectious Diseases and Clinical Microbiology, Ordu State Hospital, Ordu, TURKEY
dDepartment of Cardiology, Ordu University Faculty of Medicine, Ordu, TURKEY
eDepartment of Internal Medicine, Ordu University Faculty of Medicine, Ordu, TURKEY
Turkiye Klinikleri J Cardiovasc Sci. 2021;33(1):15-21
doi: 10.5336/cardiosci.2020-80082
Article Language: EN
Full Text
ABSTRACT
 Objective: The Coronavirus disease-2019 (COVID-19) pandemic has caused the death of many people worldwide. Treatment protocol had to be developed as soon as possible so drug combinations, whose reliability has not been fully disclosed, have started to be used. In this study, we aimed to evaluate the effect of azithromycin (AZT), hydroxychloroquine (HCQ), and favipiravir (FVR) combination on the corrected QT (QTc) interval. Material and Methods: Eighty-four consecutive COVID 19 patients were enrolled in the study. All patients received AZT and HCQ, however, FVR was added to the combination in 32 patients with severe pneumonia at the beginning. ECG characteristics of all patients before treatment and on the fifth day of treatment were compared. Results: There was no significant difference between the HCQ+AZT group (n=52) and HCQ+AZT+FVR groups (n=32) in terms of baseline clinical characteristics. QTc interval significantly prolonged on the fifth day of treatment in the HCQ+AZT group (413,75±30,13; 440,27±36,11 p 500 ms was detected after the treatment, four patients in the HCQ+AZT+FVR group and three patients in the HCQ+AZT group. Conclusion: We observed that FVR caused more prolongation in the QTc interval when used with the combination of HCQ+AZT. We recommend that patients who receive this treatment be monitored more closely for QTc.

Keywords: Azithromycin; COVID-19; favipiravir; hydroxychloroquine; QT interval
ÖZET
 Amaç: Koronavirüs hastalığı-2019 [coronavirus disease-2019 (COVID-19)], dünya çapında birçok ölüme neden olan bir pandemiye yol açtı. Tedavi protokolünün bir an önce geliştirilmesi gerektiğinden, güvenilirliği tam olarak tanımlanmamış ilaç kombinasyonlarının kullanılmasına neden oldu. Bu çalışmada, azitromisin (AZT), hidroksiklorokin (HCQ) ve favipiravirin (FVR) kombinasyonunda düzeltilmiş QT (QTc) aralığı üzerindeki etkisini değerlendirmeyi amaçladık. Gereç ve Yöntemler: Çalışmaya, 84 ardışık COVID-19 hastası dâhil edildi. Tüm hastalara AZT ve HCQ verildi, ancak başlangıçta şiddetli pnömonili 32 hastada kombinasyona FVR eklendi. Tüm hastaların tedavi öncesi ve tedavinin 5. gününde elektrokardiyografi özellikleri karşılaştırıldı. Bulgular: HCQ+AZT grubu (n=52) ile HCQ+AZT+FVR grupları (n=32) arasında başlangıç klinik özellikleri açısından anlamlı fark yoktu. QTc aralığı, tedavinin 5. gününde HCQ+AZT grubunda (413,75±30,13 msn; 440,27±36,11 msn p500 msn ölçüldü, bu hastaların 4'ü HCQ+AZT+FVR grubunda ve 3'ü HCQ+AZT grubundaydı. Sonuç: Çalışmamızda, HCQ+AZT kombinasyonu ile kullanıldığında FVR'nin, QTc aralığında daha fazla uzamaya neden olduğunu gözlemledik. Bu tedaviyi alan hastaların, QTc için daha yakından izlenmesi gerektiği kanaatindeyiz.

Anahtar Kelimeler: Azitromisin; COVID-19; favipiravir; hidroksiklorokin; QTc aralığı
REFERENCES:
  1. 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 Res. 2020;30(3):269-71.[Crossref] [PubMed] [PMC] 
  2. Choi Y, Lim HS, Chung D, Choi JG, Yoon D. Risk evaluation of azithromycin-induced QT prolongation in real-world practice. Biomed Res Int. 2018;14;2018:1574806.[Crossref] [PubMed] [PMC] 
  3. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949.[Crossref] [PubMed] [PMC] 
  4. Mzayek F, Deng H, Mather FJ, Wasilevich EC, Liu H, Hadi CM, et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials. 2007;5;2(1):e6.[Crossref] [PubMed] [PMC] 
  5. van den Broek MPH, Möhlmann JE, Abeln BGS, Liebregts M, van Dijk VF, van de Garde EMW, et al. Chloroquine-induced QTc prolongation in COVID-19 patients. Neth Heart J. 2020;28(7-8):406-9.[Crossref] [PubMed] [PMC] 
  6. Tomcsányi J, Tomcsányi K. [Hazard of acquired long QT syndrome during coronavirus pandemic. focus on hydroxychloroquine]. Orv Hetil. 2020;1;161(17):689-91.[PubMed] 
  7. Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease-2019 (COVID-19). JAMA Cardiol. 2020;1;5(9):1036-41. Erratum in: JAMA Cardiol. 2020;1;5(9):1071.[Crossref] [PubMed] [PMC] 
  8. Monzani A, Genoni G, Scopinaro A, Pistis G, Kozel D, Secco GG, et al. QTc evaluation in COVID-19 patients treated with chloroquine/hydroxychloroquine. Eur J Clin Invest. 2020;50(6):e13258.[Crossref] [PubMed] [PMC] 
  9. Saleh M, Gabriels J, Chang D, Soo Kim B, Mansoor A, Mahmood E, et al. Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol. 2020;13(6):e008662.[Crossref] [PubMed] [PMC] 
  10. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;17;323(11):1061-9.[Crossref] [PubMed] [PMC] 
  11. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446-54.[Crossref] [PubMed] [PMC] 
  12. 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.[Crossref] [PubMed] [PMC] 
  13. Chinello P, Petrosillo N, Pittalis S, Biava G, Ippolito G, Nicastri E, et al. QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis. 2017;11(12):e0006034.[Crossref] [PubMed] [PMC] 
  14. 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.[Crossref] [PubMed] 
  15. TC. Sağlık Bakanlığı COVID-19 Bilgilendirme Sayfası [Internet]. Erişkin Hasta Tedavisi. © 2021 T.C. Sağlık Bakanlığı. Available from: Access date 20 May 2020.[Link] 
  16. World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. WHO (COVID-19) Homepage. Available from: Access date: 16 November 2020.[Link] 
  17. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;7;382(19):1787-99.[PubMed] [PMC] 
  18. Cao YC, Deng QX, Dai SX. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: an evaluation of the evidence. Travel Med Infect Dis. 2020;35:101647.[Crossref] [PubMed] [PMC] 
  19. Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: the reality and challenges. J Microbiol Immunol Infect. 2020;53(3):436-43.[Crossref] [PubMed] [PMC] 
  20. Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter W, et al. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004;19;484(1):41-8.[Crossref] [PubMed] 
  21. Naksuk N, Lazar S, Peeraphatdit TB. Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol. Eur Heart J Acute Cardiovasc Care. 2020;9(3):215-21.[Crossref] [PubMed] [PMC] 
  22. Isbister GK, Dawson A, Whyte IM. Hydroxychloroquine overdose: a prospective case series. Am J Emerg Med. 2002;20(4):377-8.[Crossref] [PubMed] 
  23. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila). 2006;44(2):173-5.[Crossref] [PubMed] 
  24. Panoulas VF, Toms TE, Douglas KM, Sandoo A, Metsios GS, Stavropoulos-Kalinoglou A, et al. Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: an association driven by high inflammatory burden. Rheumatology (Oxford). 2014;53(1):131-7.[Crossref] [PubMed] 
  25. Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 treatment. Circulation. 2020;16;141(24):e906-e7.[Crossref] [PubMed] 
  26. Van Laecke S. Hypomagnesemia and hypermagnesemia. Acta Clin Belg. 2019;74(1):41-7.[Crossref] [PubMed] 
  27. Wilders R, Verkerk AO. Long QT syndrome and sinus bradycardia-a mini review. Front Cardiovasc Med. 2018;3;5:106.[Crossref] [PubMed] [PMC] 

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