Very low levels of remdesivir resistance in SARS-COV-2 genomes after 18 months of massive usage during the COVID19 pandemic: A GISAID exploratory analysis

Abstract

Massive usage of antiviral compounds during a pandemic creates an ideal ground for emergence of resistant strains. Remdesivir, a broad-spectrum inhibitor of the viral RNA-dependent RNA polymerase (RdRp), was extensively prescribed under emergency use authorization during the first 18 months of the COVID19 pandemic, before randomized controlled trials showed poor efficacy in hospitalized patients. RdRp mutations conferring resistance to remdesivir are well known from in vitro studies, and the huge SARS-CoV-2 sequencing effort during the ongoing COVID19 pandemic represents an unprecedented opportunity to assess emergence and fitness of antiviral resistance in vivo . We mined the GISAID database to extrapolate the frequency of remdesivir escape mutations. Our analysis reveals very low levels of remdesivir resistance worldwide despite massive usage.

Remdesivir and GS-441524 retain antiviral activity against Delta, Omicron, and other emergent SARS-CoV-2 variants

“…The sequence analysis presented here and by others (22, 42) have found the nsp12 gene, encoding the RNA dependent RNA polymerase, of variants to be remarkably stable over the last 2 years. Only two substitutions, P323L (among all variants) and G671S (in the Delta variant) have an observed prevalence >15% among sequenced variant isolates (Supplemental Table 2).…”

“…Nsp12 mutations selected through in vitro passaging that are known to confer RDV resistance in coronaviruses (19, 35) are noticeably lacking from the sequence analysis of clinical samples. These mutations were observed in <0.001% of sequences analyzed, indicating that despite the widely prevalent use of RDV to treat COVID-19 in >10 million hospitalized patients over the course of the pandemic, emergence of RDV-resistant viruses is rare (42). However, with the recent expansion of RDV indication to treat COVID-19 earlier in the course of viral infection through outpatient use (11, 12) or potential future use of orally bioavailable prodrugs of GS- 441524, a sustained surveillance for emergence of resistance will need to continue.…”

Genetic surveillance of SARS-CoV-2 Mpro reveals high sequence and structural conservation prior to the introduction of protease inhibitor Paxlovid

“…However, at present, nirmatrelvir has yet to be deployed on a mass scale. Following FDA approval of remdesivir, its widespread usage in hospitals for the first year and a half of the COVID-19 pandemic has permitted analyses of known resistance mutations in viral isolates under remdesivir selection (57). Therefore, as more sampled viral isolates undergo nirmatrelvir selection, and as more sequences become available in GISAID, our analysis workflow is prepared to detect the emergence of potential escape mutations.…”

Omicron Genetic and Clinical Peculiarities That May Overturn SARS-CoV-2 Pandemic: A Literature Review

“…However, new evidence on remdesivir intracellular signalling pathways is currently emerging as the possible implications on herpesviruses (HHV8 and EBV) reactivation [66]. Notwithstanding, a very low level of overall remdesivir resistance is described [67].…”