The place for remdesivir in COVID-19 treatment
Authors: Barnaby Young, Thuan Tong Tan, Yee Sin Leo
Journal: The Lancet Infectious Diseases (2020)

Finding antivirals that reduce mortality from severe respiratory viral infections has proven challenging. Phase 3 trials of baloxavir and pimodivir for severe influenza were unsuccessful (NCT03684044 and NCT03376321). Lopinavir–ritonavir and hydroxychloroquine are not efficacious in treating COVID-19.1RECOVERY Collaborative GroupLopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2020; 396: 1345-1352Summary Full Text Full Text PDF PubMed Scopus (486) Google Scholar, 2RECOVERY Collaborative GroupEffect of hydroxychloroquine in hospitalized patients with Covid-19.N Engl J Med. 2020; (published online October 8.)https://doi.org/10.1056/NEJMoa2022926Google Scholar Interim results from the WHO-led, open-label, randomised SOLIDARITY trial3WHO Solidarity trial consortiumRepurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results.medRxiv. 2020; (published online October 15.) (preprint)https://doi.org/10.1101/2020.10.15.20209817Google Scholar of patients with COVID-19 report that 301 (11·0%) of 2743 patients analysed who received remdesivir and 303 (11·2%) of 2708 patients analysed who received standard care died by day 28 (Kaplan-Meier rate ratio [RR] 0·95, 95% CI 0·81–1·11; p=0·50). Final results from the ACTT-1 study4Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4997) Google Scholar sponsored by the National Institute of Allergy and Infectious Diseases are broadly similar: this randomised, placebo-controlled trial of patients with COVID-19 reported a 29-day mortality of 11·4% in 541 individuals assigned remdesivir and 15·2% in 521 assigned placebo (hazard ratio [HR] 0·73, 95% CI 0·52–1·03).4Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4997) Google Scholar The characteristic immunopathology of COVID-19 might explain these disappointing results. An initial phase of intense viral replication progresses to respiratory failure at day 8–9 in severe infections due to the host inflammatory response.5Tay MZ Poh CM Rénia L MacAry PA Ng LFP The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. 2020; 20: 363-374Crossref PubMed Scopus (2927) Google Scholar Although severe acute respiratory syndrome coronavirus 2 is still detectable during the hyperinflammatory phase, viral concentrations are substantially lower in this phase than in the first week of illness.6Weiss A Jellingsø M Sommer MOA Spatial and temporal dynamics of SARS-CoV-2 in COVID-19 patients: a systematic review and meta-analysis.EBioMedicine. 2020; 58102916Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar Suppressing hyperinflammation with corticosteroids was shown to be efficacious at reducing mortality in the RECOVERY trial, with the greatest benefit among those requiring mechanical ventilation (mortality 29·3% in the dexamethasone group vs 41·4% in the usual care group; RR 0·64, 95% CI 0·51–0·81).7RECOVERY Collaborative GroupDexamethasone in hospitalized patients with Covid-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Google Scholar This natural history suggests a window of opportunity for antivirals before fulminant inflammation sets in. In the SOLIDARITY trial,3WHO Solidarity trial consortiumRepurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results.medRxiv. 2020; (published online October 15.) (preprint)https://doi.org/10.1101/2020.10.15.20209817Google Scholar there was a trend towards reduced mortality with remdesivir among patients requiring low-flow or high-flow oxygen at baseline, but not among those requiring mechanical ventilation at baseline, albeit without reaching statistical significance (12·2% in the remdesivir group vs 13·8% in the control group; RR 0·85, 95% CI 0·66–1·09). Among the subset of patients in the ACTT-1 trial4Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4997) Google Scholar requiring oxygen supplementation but not high-flow oxygen or ventilatory support, remdesivir had a significant mortality benefit (4·0% in the remdesivir group vs 12·7% in the control group; HR 0·30, 95% CI 0·14–0·64). Although the credibility of post-hoc subgroup analysis is questionable, the concordant results suggests this finding is not due to chance. Rather than mortality, the primary endpoint for the ACTT-1 trial4Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4997) Google Scholar was time to clinical recovery, defined as either discharge from hospital or continued hospitalisation without the need for supplemental oxygen or ongoing medical care. Median time to recovery improved from 15 days (95% CI 13–18) for those given placebo to 10 days (9–11) for those given remdesivir (RR 1·29, 95% CI 1·12–1·49). In subgroup analyses, the reduction in time to recovery was only statistically significant in patients randomly assigned 10 days or fewer from symptom onset. Similarly, in a prematurely terminated trial of remdesivir in China, patients with COVID-19 and symptom duration of 10 days or less who received remdesivir clinically improved faster than did those who received placebo (HR 1·52, 95% CI 0·95–2·43).8Wang Y Zhang D Du G et al.Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.Lancet. 2020; 395: 1569-1578Summary Full Text Full Text PDF PubMed Scopus (2521) Google Scholar No comparable recovery rate data are available from the SOLIDARITY trial.3WHO Solidarity trial consortiumRepurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results.medRxiv. 2020; (published online October 15.) (preprint)https://doi.org/10.1101/2020.10.15.20209817Google Scholar So, what currently is the role of remdesivir in COVID-19 treatment? For patients with mild or moderately severe COVID-19 and no need for respiratory support, remdesivir does not offer significant benefit at day 28 and its use is not recommended.9Spinner CD Gottlieb RL Criner GJ et al.Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.JAMA. 2020; 324: 1048-1057Crossref PubMed Scopus (918) Google Scholar For individuals at high risk of hyperinflammation who are diagnosed early during illness (≤10 days) and require supplemental oxygen, remdesivir shortens the time to recovery and reduces the risk of progression. This clinically important endpoint is cost-effective in some health-care settings.10Campbell JD Whittington MD Rind DM Pearson SD Alternative pricing models for remdesivir and other potential treatments for COVID-19.https://icer-review.org/material/covid-19-second-assessment-updateDate: Nov 10, 2020Date accessed: November 12, 2020Google Scholar The risks and benefits of remdesivir in patients presenting with severe COVID-19 who require high-flow oxygen or mechanical ventilation are uncertain. Adverse event reporting from the ACTT-14Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4997) Google Scholar trial and the paper by Yeming Wang and colleagues8Wang Y Zhang D Du G et al.Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.Lancet. 2020; 395: 1569-1578Summary Full Text Full Text PDF PubMed Scopus (2521) Google Scholar indicate that there is a low risk of remdesivir causing harm, but knowing whether it has any additive effect in combination with corticosteroids is crucial. Studies of investigational agents, such as immunomodulators and monoclonal antibodies, in critically ill patients should also examine the effects of combination therapies with remdesivir by use of a placebo-controlled design. Further assessment of the effects of remdesivir on the inflammatory response and virological dynamics would be useful to define its role. Virological data from the ACTT-1 trial4Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4997) Google Scholar are eagerly awaited as there was no difference in the decline in viral titres between remdesivir and placebo in the study by Wang and colleagues.8Wang Y Zhang D Du G et al.Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.Lancet. 2020; 395: 1569-1578Summary Full Text Full Text PDF PubMed Scopus (2521) Google Scholar Optimism surrounding forthcoming results from phase 3 COVID-19 vaccine trials should not deflect from the search for an effective therapeutic. Findings from the impressive SOLIDARITY trial3WHO Solidarity trial consortiumRepurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results.medRxiv. 2020; (published online October 15.) (preprint)https://doi.org/10.1101/2020.10.15.20209817Google Scholar demand a re-examination of remdesivir, but in the context of other high-quality studies. For now, remdesivir is an important COVID-19 treatment option only in selected patient groups. BY reports personal fees from Sanofi Pasteur and Roche outside the submitted work. All other authors declare no competing interests.