1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), became known to the general public at the end of 2019 when it was first detected and identified in Wuhan, China. Due to the rapid spread of the virus, the World Health Organization (WHO) first declared a public health emergency of international concern at the end of January 2020, followed by the pandemic declaration in mid-March 2020. At the same time, the scientific response to COVID-19 was unprecedented, with a high volume of research focusing on viral biology, diagnostics, clinical aspects of infection, preventive measures, and the development of vaccines and treatment options 1,2. Since developing novel drugs against new viral diseases is time-consuming, the primary focus encompassed repurposed drugs 3,4. However, prior to the COVID-19 pandemic, remdesivir (RDV), a non-canonical nucleotide, was developed as a broad-spectrum antiviral drug that terminates RNA replication through inhibition of the RNA-dependent RNA polymerase of RNA viruses of several families, including Coronaviridae, Paramyxoviridae, and Filoviridae5,6. Based on clinical evidence, RDV was authorized in June 2020 by European Medicine Agency to treat COVID-19 in adults and adolescents (> 12 years with weight ≥ 40 kg) who require oxygen therapy. It can also be used in adults who do not require oxygen supplementation but represent a high-risk group for severe COVID-197.
Since RNA viruses are characterized by a very high mutation rate, SARS-CoV-2 is continuously subject to adaptive evolution8. This results in the emergence of genetic variants that which WHO designates as variants of concern (VOCs) and which, through a comparative evaluation, have been found to reveal one or more of the following impacts at a degree of global public health significance: increased transmissibility, increased virulence, or decreased effectiveness of preventive and treatment measures, including vaccines and therapeutics 9.  So far, five lineages have been classified as VOCs: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). In Europe, three of them played a significant role in the COVID-19 pandemic: (i) Alpha, which was active in the first quarter of 2021, (ii) Delta, which dominated through June and December 2021 and (ii) Omicron, which has been a dominant lineage since early 2022 and continues to evolve with numerous subvariants identified.
Due to accumulated nonsynonymous mutations, they have impacted, to a different degree, the effectiveness of several therapeutics, particularly anti-spike monoclonal antibodies 10. However, antivirals that target other SARS-COV-2 sites than spike protein, including RDV, are less prone to be subject to resistance11,12. However, the evolution of SARS-CoV-2 has also led to a rise of mutations in the sequence encoding RNA-dependent RNA polymerase, targeted by RDV 13. There is also experimental evidence that resistance to RDV could emerge in clinical settings and under RDV-selective pressure 14. Moreover, the emergence of de novo mutations of RDV resistance has been observed in treated immunocompromised patients 15,16. These findings stress the continuous need to monitor and compare the effectiveness of RDV against various SARS-CoV-2 variants. While there isin vitro evidence that RDV remains active against the Omicron variant at a level comparable to that against the Delta variant, a confirmation of this in a clinical setting is scarce17,18.
This real-world study was designed to assess whether RDV treatment of patients hospitalized during the period of dominance of the Omicron variant retained the efficacy achieved during the dominance of the Delta variant. Therefore, during both periods of the COVID-19 pandemic, the clinical course and outcomes of patients treated with RDV were compared with those not receiving any antiviral treatment.