The impact of remdesivir on SARS-CoV-2 evolution in vivo
Ted Ling-Hu, Lacy M. Simons, Estefany Rios-Guzman, Alexandre Machado Carvalho, Maria Francesca R. Agnes, Arghavan Alisoltanidehkordi, Egon A. Ozer, Ramon Lorenzo-Redondo, Judd F. Hultquist
Ted Ling-Hu, Lacy M. Simons, Estefany Rios-Guzman, Alexandre Machado Carvalho, Maria Francesca R. Agnes, Arghavan Alisoltanidehkordi, Egon A. Ozer, Ramon Lorenzo-Redondo, Judd F. Hultquist
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Research Article COVID-19 Therapeutics

The impact of remdesivir on SARS-CoV-2 evolution in vivo

Abstract

The impact of remdesivir on SARS-CoV-2 diversity and evolution in vivo has remained unclear. In this single-center, retrospective cohort study, we assessed SARS-CoV-2 diversification and diversity over time in a cohort of hospitalized patients who did or did not receive remdesivir. Whole-genome sequencing was performed on 98 paired specimens collected from 49 patients before and after remdesivir administration. The genetic divergence between paired specimens was not significantly different in this cohort compared with that in a control group of patients who did not receive the drug. However, when we focused on minority variants, several positions showed preferential diversification after remdesivir treatment, some of which were associated with specific variants of concern. Most notably, remdesivir administration resulted in strong selection for a nonsynonymous mutation in nsp12, G671S, previously associated with enhanced viral fitness. This same mutation was found to be enriched in a second cohort of 143 inpatients with specimens collected after remdesivir administration compared with controls. Only one other mutation previously implicated in remdesivir resistance (nsp12:V792I) was found to be preferentially selected for after remdesivir administration. These data suggest that SARS-CoV-2 variants with enhanced replicative fitness may be selected for in the presence of antiviral therapy as an indirect means to overcome this selective pressure.

Authors

Ted Ling-Hu, Lacy M. Simons, Estefany Rios-Guzman, Alexandre Machado Carvalho, Maria Francesca R. Agnes, Arghavan Alisoltanidehkordi, Egon A. Ozer, Ramon Lorenzo-Redondo, Judd F. Hultquist

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Figure 4

Identification of nucleotide positions with significantly altered genetic diversity after remdesivir administration.

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Identification of nucleotide positions with significantly altered geneti...
(A) Mutational frequency at positions in nsp12 previously implicated in remdesivir resistance relative to the Wuhan-Hu-1 reference genome in pre and post specimens from each cohort. Nucleotide and amino acid positions are shown below. Box-and-whisker plots represent the median (center line) and first/third quartiles (box), with tails extending 1.5 times the IQR. Only specimens with greater than 1% mutational frequency at a given position are shown (positions that were not detected are indicated as “ND”). (B) Stacked bar plot illustrating the number of patients in each cohort that exhibited a change in Shannon entropy at a given position in paired specimens. To be shown, at least 4 patients in either cohort had to have an increase in Shannon entropy from 0 (i.e., diversification) or decrease to 0 (i.e., purification). (C) Heatmap of mutational frequency at positions identified in B by lineage (reported as percentage of total SARS-CoV-2 sequences per variant in the GISAID database [accessed January 4, 2024]). (D) Shannon entropy in pre and post specimens from each cohort at 3 nucleotide positions that had significant changes following remdesivir administration. Box-and-whisker plots represent the median (center line) and first/third quartiles (box), with tails extending 1.5 times the IQR. Significantly changing positions in the remdesivir cohort were identified using a linear mixed-effects model (specified below the graph) controlling for time between paired specimens, viral load, and within-patient variability for each patient. P values were adjusted for FDR using the Benjamini-Hochberg method; differences at positions with an adjusted P value less than 0.1 were considered significant.