Should remdesivir be recommended in France in the early stage of COVID-19.

COVID-19 due to SARS-CoV-2, has become a raging pandemic. Remdesivir, an RNA-dependent RNA polymerase (RdRP) inhibitor, was the first antiviral drug to be approved for SARS-CoV-2 in the United States (Beigel et al., 2020) and Europe (European Medicine Agency, 2020) and affects the hospital length of stay but not mortality (Goldman et al., 2020). The Solidarity and Discovery trials did not find a clinical benefit from the use of remdesivir in COVID-19 treatment (Ader et al., 2021, Consortium et al., 2021). However, most patients included in these trials who were admitted to the hospital for COVID-19 were symptomatic for >7 days and required oxygen support at a time where the inflammatory process is predominant and antiviral drugs are less efficient. The authors of the Discovery study limited their conclusion to symptomatic patients who were hospitalised for >7 days and required oxygen support. Note that numerous guidelines still include remdesivir in their strategies, such as the Infectious Diseases Society of America guideline for hospitalised patients with noncritical COVID-19 (IDSA, 2021) and the new European (European Society of Clinical Microbiology and Infectious Diseases) guidelines with conditional recommendations for patients with mild or severe COVID-19 (Bartoletti et al., 2021). Thus far, French recommendations summarised in the Coordination Opérationnelle Risque Epidémique et Biologique (COREB) guidelines do not include remdesivir, and the French Haute Autorité de Santé did not recommend the refund of remdesivir for hospitalised patients in September 2020.

Remdesivir (GS-5734) has potent in vitro activity against a range of RNA viruses, including MERS-CoV, SARS-CoV-1, and SARS-CoV-2, and previous studies highlighted the potential benefit in terms of length of hospitalisation and trends in the reduction of mortality (Bartoletti et al., 2021, Infectious Diseases Society of America [IDSA, 2021]). Remdesivir has renal and hepatic toxicity and must be regularly monitored, but the Discovery trial did not find significant differences in the occurrence of serious adverse events between the remdesivir and placebo groups (Ader et al., 2021), and these events are less frequent during the 5-day course regimen now recommended. More recently a 3-day course of remdesivir demonstrated efficacy and safety in treating high-risk nonhospitalised patients with COVID-19 (Hill et al., 2021). Interestingly, independent of clinical trials, in vivo activity of remdesivir is described in profoundly immunosuppressed patients with persistent viremia and chronic viral phase, which is responsible for persistent clinical symptoms. Sepulcri et al. reported a case of persistent viremia in a patient with mantle cell lymphoma who underwent treatment with rituximab, bendamustine, and cytarabine with consequent lymphopenia and hypogammaglobulinemia. Viremia was positive in 3 out of 4 COVID-19 clinical relapses and cleared after remdesivir treatment (Sepulcri et al., 2021). We reported a similar case in a 76-year-old woman with B-cell immunodeficiency who presented with severe protracted COVID-19 and persistent SARS-CoV-2 viremia and where remdesivir appeared efficient in clearing viremia during drug administration (Martinot et al., 2021). Remdesivir alone was in fact not efficient by itself in the treatment of heavily immunosuppressed patients with relapses after resolution of treatment and in our cases the emergence of a mutation in RdRP, which was responsible for drug resistance. However, in immunocompetent or less immunosuppressed patients, antiviral action provided by drugs, such as remdesivir, could be of high interest, especially in the earlier stage of COVID-19. Highly efficient drugs acting during this viral phase are still lacking, and the emergence of the delta virus with higher viral loads than precedent variants (Blanquart et al., 2021) underscores the need for antiviral agents, and we could hypothesise that antiviral drugs, in conjunction to the efficient immune system, could lead to a quick clearance of these high viral loads and diminish the secondary inflammatory cascade. Physicians are regularly confronted by hospitalised patients with severe COVID-19 despite an early stage (onset of symptoms < 1 week) oxygen requirement, which is associated with a low C-reactive protein level and low cycle threshold (Ct) (real-time polymerase chain reaction) in relation to a high viral load. Based on the French guidelines, these patients are frequently treated by dexamethasone alone and thus could benefit from antiviral treatments, such as remdesivir. Monoclonal antibodies, such as casirivimab and imdevimab, are efficient antiviral agents are now proposed as an early treatment for older patients and patients with comorbidities without oxygen requirement or in case of severe cases but a negative anti-spike serology (Bartoletti et al., 2021, IDSA, 2021). However, the generalisation of vaccination in the French population modified the position of monoclonal antibodies. The fifth wave is marked by an increasing rate of old patients (aged > 65 years) and patients with comorbidities with positive anti-spike serology associated with low Ct and mild and moderate or severe clinical symptoms for which monoclonal antibodies do not appear like an evident choice. New antivirals, molnupiravir and paxlovid, are promising drugs but only at a very early stage of the disease and up to date with unknown availability in France. Therefore, remdesivir should be re-evaluated in the French guidelines, especially in the earlier stage of COVID-19. Ongoing clinical trials in early stages, in special subpopulations, such as vaccinated patients, would be of great interest to assess the exact position of such treatments in the therapeutics arsenal against COVID-19.

Declaration of Competing Interest

The authors have no conflicts of interest to report.