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.