To the editor,
We sincerely thank Dr Dauby for his comments [1].
The effectiveness of remdesivir was assessed in large randomized controlled trials (RCTs). The ACTT-1 trial showed a reduction in time to clinical improvement and, in a subgroup analysis, a mortality benefit in patients requiring supplemental oxygen but not ventilation [2]. Conversely, the SOLIDARITY trial showed no mortality benefit with the use of remdesivir [3].
In the ESCMID coronavirus disease 2019 (COVID-19) treatment guidelines, the efficacy of remdesivir in the treatment of patients with COVID-19 not receiving ventilation was assessed in five RCTs enrolling 6400 patients, showing a relative risk (RR) of mortality of 0.76 (95% CI, 0.57–1.02) [4].
There are possible explanations for the conflicting results of available RCTs. First, the trials had different primary endpoints and thus varied in design, sample size, and power. In addition, the timing between symptom onset and the beginning of treatment was poorly assessed in the aforementioned trials. This is particularly important for antivirals because these drugs might be effective during the initial phase of infection [5]. This hypothesis might be confirmed by the fact that the drug is active in patients who do not require ventilation and by a recent randomized, placebo-controlled trial enrolling 562 outpatients with COVID-19 assigned in a 1:1 ratio to receive remdesivir or placebo. The primary endpoint (COVID-19–related hospitalization or death from any cause) occurred in two patients (0.7%) in the remdesivir group and 15 (5.3%) in the placebo group (hazard ratio: 0.13; 95% CI, 0.03–0.59; p = 0.008) [6]. Possible cardiac side effects emerged in postmarketing studies [7]. However, in patients receiving remdesivir and monitored with daily electrocardiogram, none showed bradycardia, symptomatic bradycardia, or significant corrected QT prolongation leading to drug discontinuation [8].
Taking together the data on the efficacy and safety of remdesivir, the panel believed that the benefits outweigh the harms in a situation in which there are no other licensed antivirals for the treatment of COVID-19 at the moment [4].
The ESCMID COVID-19 treatment guideline is a living document, which means that we have planned updates to review previous recommendations and propose new treatments as soon as novel data become available.
Lastly, we would like to offer a reminder that the ESCMID policies establish a public consultation phase. During this phase, researchers, colleagues, and experts are invited to evaluate the document and propose any improvement or modification [9].
Transparency declaration
The authors have no conflicts of interest to disclose. No external funding was received for this letter.
Editor: L. Leibovici
References
- 1.Dauby N. Re: 'ESCMID COVID-19 living guidelines: drug treatment and clinical management' by Bartoletti et al. Clin Microbiol Infect. 2022;28:616. doi: 10.1016/j.cmi.2021.11.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Beigel J.H., Tomashek K.M., Dodd L.E., Mehta A.K., Zingman B.S., Kalil A.C., et al. Remdesivir for the treatment of COVID-19–Final report. N Engl J Med. 2020;383:1813–1826. doi: 10.1056/NEJMoa2007764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pan H., Peto R., Henao-Restrepo A.M., Preziosi M.P., Sathiyamoorthy V., Abdool Karim Q., et al. WHO Solidarity Trial Consortium Repurposed antiviral drugs for COVID-19–Interim WHO solidarity trial results. N Engl J Med. 2021;384:497–511. doi: 10.1056/NEJMoa2023184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bartoletti M., Azap O., Barac A., Bussini L., Ergonul O., Krause R., et al. ESCMID COVID-19 living guidelines: drug treatment and clinical management. Clin Microbiol Infect. 2021;S1198–743X doi: 10.1016/j.cmi.2021.11.007. 0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Goncalves A., Bertrand J., Ke R.A., Comets E., de Lamballerie X., Malvy D., et al. Timing of antiviral treatment initiation is critical to reduce SARS-CoV-2 viral load. CPT Pharmacometrics Syst Pharmacol. 2020;9:509–514. doi: 10.1002/psp4.12543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gottlieb R.L., Vaca C.E., Paredes R., Mera J., Webb B.J., Perez G., et al. Early remdesivir to prevent progression to severe COVID-19 in outpatients. N Engl J Med. 2021 doi: 10.1056/NEJMoa2116846. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Jung S.Y., Kim M.S., Li H., Lee K.H., Koyanagi A., Solmi M., et al. Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database. Clin Transl Sci. 2021 doi: 10.1111/cts.13168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Brunetti N.D., Poliseno M., Bottalico I.F., Centola A., Montemurro L., Sica S., et al. Safety and heart rate changes in COVID-19 patients treated with remdesivir. Int J Infect Dis. 2021;112:254–257. doi: 10.1016/j.ijid.2021.09.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.European Society of Clinical Microbiology and Infectious Diseases. ESCMID manual for clinical practice guidelines and other guidance documents [Internet]. 2020 [cited 2021 December 18]. Available from: www.escmid.org/fileadmin/src/media/PDFs/Guidelines/Guideline_Manual_Version_2.pdf.