Remdesivir and COVID-19
Authors: Lei-Yun Wang, Jia-Jia Cui, Qian-Ying Ouyang, Yan Zhan, Cheng-Xian Guo, Ji-Ye Yin
Journal: The Lancet (2020)

In a Chinese clinical trial by Yeming Wang and colleagues,1Wang 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 (2504) Google Scholar 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 Administration2US Food & Drug AdministrationCoronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatmentDate: May 1, 2020Date accessed: May 12, 2020Google Scholar and approved in Japan3Reynolds I Japan approves Gilead's remdesivir to treat COVID-19 cases.https://www.bloomberg.com/news/articles/2020-05-07/japan-set-to-approve-remdesivir-for-coronavirus-on-thursdayDate: May 7, 2020Date accessed: September 23, 2020Google Scholar for patients with severe COVID-19 on the basis of preliminary phase 3 trial results.4Beigel JG Tomashek KM Dodd LE et al.Remdesivir for the treatment of COVID-19—a preliminary report.N Engl J Med. 2020; (published online May 22.) (2020)https://doi.org/10.1056/NEJMoa2007764Crossref Scopus (4958) Google Scholar We find it puzzling that the discrepancy of results between China and the USA is merely justified by different study designs. Genetic factors can influence drugs' efficacy and toxicity. Therefore, it is reasonable to seek answers from the genetic backgrounds of patients with COVID-19 and of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China and the USA. From the GnomAD database, we collected: 9977 genomes from east Asia that represented Chinese people; and 64 603 genomes from Europeans, 17 720 from Latinx, and 12 487 from African Americans, which represented the three majority ethnicities in the USA.5Karczewski KJ Francioli LC Tiao J et al.The mutational constraint spectrum quantified from variation in 141 456 humans.Nature. 2020; 581: 434-443Crossref PubMed Scopus (4813) Google Scholar Genetic diversity was found in seven pharmacogenes that mainly related to pharmacokinetics and pharmacodynamics of remdesivir.6Wishart DS Feunang YD Guo AC et al.DrugBank 5.0: a major update to the DrugBank database for 2018.Nucleic Acids Res. 2018; 46: D1074-D1082Crossref PubMed Scopus (4852) Google Scholar Notably, the mutation frequency of CYP2D6 (rs1065852) in east Asia (57·7%) was much greater than that of the American ethnicities (12·3–21·7%), whereas the mutation frequency of SLCO1B3 (rs60140950) showed the opposite result (appendix). Meanwhile, we also collected 432 SARS-CoV-2 samples from China and 2754 SARS-CoV-2 samples from the USA using an online database.7Zhao WM Song SH Chen ML et al.The 2019 novel coronavirus resource.Yi Chuan. 2020; 42: 212-221PubMed Google Scholar The frequency of potential functional variations such as p.P4715L (c.14144C>T) in polyprotein 1ab, which is the target of remdesivir, were largely different in the genomes from the USA (63·0%) and China (11·2%). These variations could generate the efficacy discrepancy of remdesivir among these clinical trials. Similar to remdesivir, ethnic diversity was also found in pharmacogenes related to other drugs, such as chloroquine, in COVID-19 treatment. In summary, pharmacogenomic studies for COVID-19 therapy seem to be needed urgently. J-YY and C-XG report grants from the National Natural Science Foundation of China (81773823, 81974511), and the National Science and Technology Major Project of China (2017ZX09304014, 2019ZX09201–002–006, 2020ZX09201010). All other authors declare no competing interests. Download .pdf (.36 MB) Help with pdf files Supplementary appendix 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-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-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-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 the first published placebo-controlled trial of remdesivir for treating severe COVID-19, Yeming Wang and colleagues1 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. Full-Text PDF