J Korean Med Sci.  2021 Mar;36(11):e83. 10.3346/jkms.2021.36.e83.

Clinical and Virologic Effectiveness of Remdesivir Treatment for Severe Coronavirus Disease 2019 (COVID-19) in Korea: a Nationwide Multicenter Retrospective Cohort Study

• Joo EJ
• Ko JH
• Kim SE
• Kang SJ
• Baek JH
• Heo EY
• Shi HJ
• Eom JS
• Choe PG
• Bae S
• Ra SH
• Kim DY
• Kim BN
• Kang YM
• Kim JY
• Chung JW
• Chang HH
• Bae S
• Cheon S
• Park Y
• Choi H
• Lee E
• Lee By
• Park JW
• Sohn Y
• Heo JY
• Kim SH
• Peck KR

• KMID: 2514055
• DOI: http://doi.org/10.3346/jkms.2021.36.e83

Abstract

Background
Remdesivir is widely used for the treatment of coronavirus disease 2019 (COVID-19), but controversies regarding its efficacy still remain.
Methods
A retrospective cohort study was conducted to evaluate the effect of remdesivir on clinical and virologic outcomes of severe COVID-19 patients from June to July 2020. Primary clinical endpoints included clinical recovery, additional mechanical ventilator (MV) support, and duration of oxygen or MV support. Viral load reduction by hospital day (HD) 15 was evaluated by calculating changes in cycle threshold (Ct) values.
Results
A total of 86 severe COVID-19 patients were evaluated including 48 remdesivirtreated patients. Baseline characteristics were not significantly different between the two groups. Remdesivir was administered an average of 7.42 days from symptom onset. The proportions of clinical recovery of the remdesivir and supportive care group at HD 14 (56.3% and 39.5%) and HD 28 (87.5% and 78.9%) were not statistically different. The proportion of patients requiring MV support by HD 28 was significantly lower in the remdesivir group than in the supportive care group (22.9% vs. 44.7%, P = 0.032), and MV duration was significantly shorter in the remdesivir group (average, 1.97 vs. 5.37 days; P = 0.017). Analysis of upper respiratory tract specimens demonstrated that increases of Ct value from HD 1–5 to 11–15 were significantly greater in the remdesivir group than the supportive care group (average, 10.19 vs. 5.36; P = 0.007), and the slope of the Ct value increase was also significantly steeper in the remdesivir group (average, 5.10 vs. 2.68; P = 0.007).
Conclusion
The remdesivir group showed clinical and virologic benefit in terms of MV requirement and viral load reduction, supporting remdesivir treatment for severe COVID-19.

Keyword

Remdesivir; Severe; COVID-19; Clinical; Virologic

Figure

• 

  Fig. 1 Population of the cohort study.COVID-19 = coronavirus disease 2019, MV = mechanical ventilation, URT = upper respiratory tract, LRT = lower respiratory tract, HD = hospital day, RT-PCR = real-time reverse-transcriptase polymerase chain reaction.aFor the calculation of cycle threshold value slopes, at least two-point values are required and patients with more than single point RT-PCR test result were included in the overall trend analysis; bPatients with RT-PCR test result at all of each fixed time point (HD, 1–5, 6–10, and 11–15) were included in the three time-point analysis.

• 

  Fig. 2 Comparisons of overall virologic response between treatment groups. Slopes of Ct values were calculated for individual patients using all available RT-PCR test results by HD 15 and compared between treatment groups (virologic analysis 1). Since at least two-point values are required for the calculation of slopes (using linear regression), patients with more than single point RT-PCR test result were included in this analysis.Ct = cycle threshold, RT-PCR = real-time reverse-transcriptase polymerase chain reaction, HD = hospital day.

• 

  Fig. 3 Comparisons of virologic response at three fixed time points. To evaluate viral load reduction along a controlled timeline, the first RT-PCR test results during each fixed time point (HD, 1–5, 6–10, and 11–15) were selected and compared between the two groups. Patients with RT-PCR test result at all of each fixed time point (HD, 1–5, 6–10, and 11–15) were included in the three time-point analysis. The slopes of Ct value increase (virologic analysis 2) and differences of Ct values from HD 1–5 to 11–15 (virologic analysis 3) were compared between the two groups.Ct = cycle threshold, RT-PCR = real-time reverse-transcriptase polymerase chain reaction, HD = hospital day.

Reference

1. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017; 9(396):eaal3653. PMID: 28659436.

2. 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):269–271. PMID: 32020029.

3. 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):1569–1578. PMID: 32423584.

4. 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(19):1813–1826. PMID: 32445440.

5. Kalligeros M, Tashima KT, Mylona EK, Rybak N, Flanigan TP, Farmakiotis D, et al. Remdesivir use compared with supportive care in hospitalized patients with severe COVID-19: a single-center experience. Open Forum Infect Dis. 2020; 7(10):ofaa319. PMID: 33117850.

6. Olender SA, Perez KK, Go AS, Balani B, Price-Haywood EG, Shah NS, et al. Remdesivir for severe COVID-19 versus a cohort receiving standard of care. Clin Infect Dis. Forthcoming. 2020.

7. WHO Solidarity Trial Consortium. Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results. N Engl J Med. 2021; 384(6):497–511. PMID: 33264556.

8. Lee C, Ahn MY, Byeon K, Choi JP, Hahm C, Kim H, et al. Clinical experience with use of remdesivir in the treatment of severe acute respiratory syndrome coronavirus 2: a case series. Infect Chemother. 2020; 52(3):369–380. PMID: 32757500.

9. Yoo JH. Uncertainty about the efficacy of remdesivir on COVID-19. J Korean Med Sci. 2020; 35(23):e221. PMID: 32537956.

10. Sung HK, Kim JY, Heo J, Seo H, Jang YS, Kim H, et al. Clinical course and outcomes of 3,060 patients with coronavirus disease 2019 in Korea, January-May 2020. J Korean Med Sci. 2020; 35(30):e280. PMID: 32743995.

11. Ministry of Health and Welfare. Supplying Remdesivir for the treatment of COVID-19. Updated 2020. Accessed February 16, 2021. http://www.mohw.go.kr/react/al/sal0301vw.jsp?PAR_MENU_ID=04&MENU_ID=0403&page=1&CONT_SEQ=355233.

12. Huh HJ, Hong KH, Kim TS, Song SH, Roh KH, Lee H, et al. Surveillance of coronavirus disease 2019 (COVID-19) testing in clinical laboratories in Korea. Ann Lab Med. 2021; 41(2):225–229. PMID: 33063685.

13. Ko JH, Lim JU, Choi JY, Oh HS, Yoo H, Jhun BW, et al. Early cidofovir administration might be associated with a lower probability of respiratory failure in treating human adenovirus pneumonia: a retrospective cohort study. Clin Microbiol Infect. 2020; 26(5):646.e9–646.e14.

14. Shah DP, Ghantoji SS, Shah JN, El Taoum KK, Jiang Y, Popat U, et al. Impact of aerosolized ribavirin on mortality in 280 allogeneic haematopoietic stem cell transplant recipients with respiratory syncytial virus infections. J Antimicrob Chemother. 2013; 68(8):1872–1880. PMID: 23572228.

15. Boikos C, Caya C, Doll MK, Kraicer-Melamed H, Dolph M, Delisle G, et al. Safety and effectiveness of neuraminidase inhibitors in situations of pandemic and/or novel/variant influenza: a systematic review of the literature, 2009-15. J Antimicrob Chemother. 2017; 72(6):1556–1573. PMID: 28204554.

16. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19. N Engl J Med. 2021; 384(3):238–251. PMID: 33332778.

17. 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(3):229–237. PMID: 33113295.

18. 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(7824):273–276. PMID: 32516797.

19. Kim SB, Huh K, Heo JY, Joo EJ, Kim YJ, Choi WS, et al. Interim guidelines on antiviral therapy for COVID-19. Infect Chemother. 2020; 52(2):281–304. PMID: 32342676.

20. Kim JW, Kim EJ, Kwon HH, Jung CY, Kim KC, Choe JY, et al. Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019. Korean J Intern Med. 2021; 36(Suppl 1):S253–S263. PMID: 32536150.

21. RECOVERY Collaborative Group. Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020; 383(21):2030–2040. PMID: 33031652.

22. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020; 382(25):2411–2418. PMID: 32379955.

23. 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; 382(19):1787–1799. PMID: 32187464.

24. Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med. 2021; 384(7):610–618. PMID: 33406353.

25. Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med. Forthcoming. 2021.

26. Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med. 2021; 384(7):619–629. PMID: 33232588.

27. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020; 395(10238):1695–1704. PMID: 32401715.

28. Hoang T, Anh TT. Treatment options for severe acute respiratory syndrome, middle east respiratory syndrome, and coronavirus disease 2019: a review of clinical evidence. Infect Chemother. 2020; 52(3):317–334. PMID: 32869558.

29. Im JH, Nahm CH, Baek JH, Kwon HY, Lee JS. Convalescent plasma therapy in coronavirus disease 2019: a case report and suggestions to overcome obstacles. J Korean Med Sci. 2020; 35(26):e239. PMID: 32627442.

30. Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, et al. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020; 35(14):e149. PMID: 32281317.