Assessing the evidence on remdesivir

We read with interest the Comment by Iwein Gyselinck and Wim Janssens concerning the recently published DisCoVeRy trial,1, 2 which concluded that given current evidence there is no reason to advocate remdesivir use outside clinical trials. Although we largely agree, the question remains whether there is still a need for additional trials, or whether already published and existing data are sufficient to conclude this.

At present, remdesivir has been tested in five large randomised trials in hospitalised patients.¹ With the exception of the ACTT-1 trial, which reported reduced time to recovery in patients with moderate COVID-19 and a median of 9 days between symptom onset and randomisation, most trials have failed to show significant benefit in mortality or disease progression.¹ Additionally, trials that evaluated viral endpoints did not find any effect on viral clearance with remdesivir.2, 3, 4 Notably, median time from symptom onset to randomisation was relatively long in most published trials. Treatment initiation at the tail of the viral phase could explain the lack of effect on viral clearance, and possibly the limited clinical effect.¹

Hence, testing remdesivir earlier in the disease course could be more relevant, and unpublished results from the PINETREE trial reported an 87% risk reduction for hospitalisation or death with a 3-day course of remdesivir compared with placebo.⁵ However, with the encouraging preliminary results of oral molnupiravir from the MOVe-OUT trial (NCT04575597), oral antivirals might be the preferred treatment option for outpatients, making intravenous alternatives less attractive.

Remdesivir could also be a candidate drug for carefully selected hospitalised patients, since the RECOVERY trial showed a survival benefit of the monoclonal antibody cocktail REGN-COV2 in seronegative patients.⁵ In seronegative individuals and immunocompromised patients in general, head-to-head comparisons between remdesivir and antiviral monoclonal antibodies could be an option. However, with emerging variants, testing combinations of monoclonal antibodies and other antivirals, including remdesivir, could be even more relevant, given the demonstrated effect of each compound.

Before moving ahead with new trials, it should be noted that the final report from the Solidarity trial is yet to be published. In our view, there is now an urgent need for an individual-level meta-analysis based on existing trials, including consolidated data from the Solidarity trial. Such a meta-analysis is planned and will hopefully clarify the role of remdesivir in hospitalised patients and help identify the potential need for additional trials.

This work is a collaboration within the EU-RESPONSE project, which has received funding from the EU Horizon 2020 Research and Innovation programme, under the grant number 101015736. MT has participated without pay in Eli Lilly's European advisory board. MH has received funding for the DisCoVeRy and COV-AID trials from the Federal Belgian Center for Knowledge and the joint Université Libre de Bruxelles-Fonds Erasme-COVID-19 projects. MH has also participated in Gilead's educational advisory board on invasive aspergillosis infections, is an editor of the Belgian Framingham's Journal on Infectious Diseases, and received support from Pfizer to attend the ECCMID 2021 congress. All other authors declare no competing interests.