RESUMO
In vitro selection of remdesivir-resistant SARS-CoV-2 revealed the emergence of a V166L substitution, located outside of the polymerase active site of the nsp12 protein, after 9 passages. V166L remained the only nsp12 substitution after 17 passages at a final concentration of 10 {micro}M RDV, conferring a 2.3-fold increase in EC50. When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC50 was observed, indicating a high in vitro barrier to RDV resistance.
RESUMO
Genetic variation of SARS-CoV-2 has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern or interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies. Remdesivir (RDV, VEKLURY(R)) is a nucleoside analog prodrug and the first FDA-approved antiviral treatment of COVID-19. Here we present a comprehensive antiviral activity assessment of RDV and its parent nucleoside, GS-441524, against 10 current and former SARS-CoV-2 VOC/VOI clinical isolates by nucleoprotein ELISA and plaque reduction assay. Delta and Omicron variants remained susceptible to RDV and GS-441524, with EC50 values 0.31 to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC50 values ranging from 0.15 to 2.3-fold of the observed EC50 values against WA1. Analysis of nearly 6 million publicly available variant isolate sequences confirmed that Nsp12, the RNA-dependent RNA polymerase (RdRp) target of RDV and GS-441524, is highly conserved across variants with only 2 prevalent changes (P323L and G671S). Using recombinant viruses, both RDV and GS-441524 retained potency against all viruses containing frequent variant substitutions or their combination. Taken together, these results highlight the conserved nature of SARS-CoV-2 Nsp12 and provide evidence of sustained SARS-CoV-2 antiviral activity of RDV and GS-441524 across the tested variants. The observed pan-variant activity of RDV supports its continued use for the treatment of COVID-19 regardless of the SARS-CoV-2 variant.
RESUMO
BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) provides a minimally invasive alternative to resuscitative thoracotomy. The high morbidity associated with prolonged aortic occlusion has given rise to the concept of partial REBOA (pREBOA). We evaluated the novel use of the GORE Tri-Lobe Balloon Catheter (GORE) as a functional pREBOA catheter and compared it with existing REBOA and pREBOA techniques in a porcine hemorrhagic shock model. MATERIALS AND METHODS: Fifteen male Yorkshire swine were subjected to hemorrhagic shock with zone 1 aortic occlusion via standard REBOA techniques or a partial occlusion approach using a prototype pREBOA or GORE catheter. Continuous invasive monitoring was performed and laboratory values were analyzed every 30 min. RESULTS: One animal from the GORE cohort was excluded because of early demise from nonstudy factors. Survival to 120 mins was comparable between all study groups: REBOA resulting in 40% survival, pREBOA 60%, and Gore 50% (P = 0.685). No differences in lactate, base deficit, and pH between the cohorts were demonstrated at all measured time points; however, trends toward more physiologic values were appreciated in the GORE and pREBOA cohorts. Urine output was significantly improved during the course of the study in the GORE cohort (8.77 mL/kg) versus REBOA (5.46 mL/kg) and pREBOA (4.48 mL/kg) (P = 0.001). CONCLUSIONS: The GORE Tri-Lobe Balloon Catheter represents a potentially viable and commercially available alternative device for pREBOA that may achieve survivable hemorrhage control while preventing lethal reperfusion injury. Further studies should be performed after instrument refinement with larger study populations to confirm this potential.
