Remdesivir and COVID-19
Authors: Matthew J Glaus, Serena Von Ruden
Journal: The Lancet (2020)

In the first published placebo-controlled trial of remdesivir for treating severe COVID-19, Yeming Wang and colleagues1Wang 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 were unable to attain their primary endpoint of time to clinical improvement. Although admittedly underpowered due to early trial termination, remdesivir did not appear to affect rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA load decline and mortality when compared with placebo. Given these disappointing findings, we are left to wonder if a lack of clinically significant outcomes in placebo-controlled trials could have been predicted. By inhibiting early coronavirus life cycle in vitro2Agostini ML Andres EL Sims AC et al.Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease.MBio. 2018; 9: 1-15Crossref Scopus (1026) Google Scholar and in animal models,3Sheahan TP Sims AC Graham RL et al.Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.Sci Transl Med. 2017; 9: 1-10Crossref Scopus (1199) Google Scholar, 4De wit E Feldmann F Cronin J et al.Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection.Proc Natl Acad Sci USA. 2020; 117: 6771-6776Crossref PubMed Scopus (667) Google Scholar remdesivir might require initiation before the peak viral replication, which is not feasible in the clinical human presentation of COVID-19. In cell cultures exposed to murine coronavirus, early remdesivir initiation substantially decreased viral titres compared with control.2Agostini ML Andres EL Sims AC et al.Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease.MBio. 2018; 9: 1-15Crossref Scopus (1026) Google Scholar However, this treatment effect was completely lost when initiation occurred just 8 h after infection. In another study, mice administered early remdesivir relative to inoculation with SARS-CoV had substantially reduced lung damage compared with untreated cohorts, an effect that was lost when initiation was delayed by 2 days after inoculation.3Sheahan TP Sims AC Graham RL et al.Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.Sci Transl Med. 2017; 9: 1-10Crossref Scopus (1199) Google Scholar The need for early treatment has been identified in additional animal models,4De wit E Feldmann F Cronin J et al.Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection.Proc Natl Acad Sci USA. 2020; 117: 6771-6776Crossref PubMed Scopus (667) Google Scholar as Wang and colleagues1Wang 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 confirm, with remdesivir initiation following peak viral replication being unable to affect disease severity or mortality. With in vitro and animal evidence suggesting remdesivir is optimally suited for viral prophylaxis or immediately following viral inoculation, why would there have been any reason to expect a different outcome in humans, where SARS-CoV-2 has a median incubation period of 4 days?5Guan WJ Ni ZY Hu Y et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20405) Google Scholar We declare no competing interests. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trialIn this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Full-Text PDF Remdesivir and COVID-19I commend Yeming Wang and colleagues1 on their study in the difficult time of the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Full-Text PDF Remdesivir and COVID-19The Panel on Antiretroviral Guidelines for Adults and Adolescents with HIV and the American Association for the Study of Liver Diseases guidelines for hepatitis C virus treatment suggest that combination therapy for severe acute respiratory syndrome coronavirus 2 infection will outperform single drugs. Yeming Wang and colleagues1 reported that the hazard of 28-day clinical improvement for 158 patients with severe COVID-19 randomly assigned to remdesivir was 1·2 times (95% CI 0·9 to 1·8) the hazard of patients randomly assigned to placebo, but the 28-day mortality in both these groups was similar. Full-Text PDF Remdesivir and COVID-19 – Authors' replyWe thank the clinicians and researchers around the world for their comprehensive interpretation of the results of our randomised controlled trial of remdesivir for COVID-19.1 They shared valuable thoughts from different perspectives according to related evidence from in vitro and animal models, and pharmacogenomic studies. A suggestion was made for subgroup analyses by concomitant lopinavir-ritonavir use. Concerns for not reaching the predetermined sample size in our study were also expressed. These comments are appreciated and helpful for future conduct and interpretation of COVID-19 therapy studies. Full-Text PDF Remdesivir and COVID-19In a Chinese clinical trial by Yeming Wang and colleagues,1 remdesivird did not show significant benefits for patients with severe COVID-19. Shortly after their study was published, remdesivir was authorised in the USA by the US Food & Drug Administration2 and approved in Japan3 for patients with severe COVID-19 on the basis of preliminary phase 3 trial results.4 We find it puzzling that the discrepancy of results between China and the USA is merely justified by different study designs. Full-Text PDF