Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections DOI
Mohammed Nooruzzaman, Katherine Johnson, Ruchi Rani

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 18, 2024

Abstract We investigated the impact of antiviral treatment on emergence SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n=15). All received remdesivir and some also nirmatrelvir-ritonavir or monoclonal antibodies. Sequence analysis showed that nine carried viruses with mutations nsp12 (RNA dependent RNA polymerase), while four had nsp5 (3C protease) mutations. Infectious a double mutation (T169I) (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis patient treated nirmatrelvir-ritonavir. In vitro characterization confirmed its decreased sensitivity to nirmatrelvir, which overcome by combined treatment. Studies golden Syrian hamsters demonstrated efficient transmission contact animals. This study documents isolation carrying both nirmatrelvir demonstrates transmissibility vivo .

Language: Английский

Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections DOI Creative Commons
Mohammed Nooruzzaman, Katherine Johnson, Ruchi Rani

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 18, 2024

Language: Английский

Citations

16
The impact of remdesivir on SARS-CoV-2 evolution in vivo DOI Creative Commons
Ted Ling-Hu, Lacy M. Simons, Estefany Rios-Guzman

et al.

JCI Insight, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

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 diversification over time a hospitalized patients who did or not receive remdesivir. Whole genome sequencing was performed 98 paired specimens collected from 49 before after administration. Genetic divergence between significantly different what observed the drug. However, when comparing minority variants, several positions showed preferential treatment, which were associated with variants concern. Most notably, administration resulted strong selection for nonsynonymous mutation nsp12, G671S, previously enhanced viral fitness. This same found enriched second 143 inpatients compared to controls. Only one other implicated resistance (nsp12:V792I) be preferentially selected These data suggest that replicative fitness may presence antiviral therapy as an indirect means overcome selective pressure.

Language: Английский

Citations

0
An Update on SARS-CoV-2 Clinical Trial Results—What We Can Learn for the Next Pandemic DOI Open Access
Edi Dharmana, Juliane Brun, Michelle L. Hill

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 354 - 354

Published: Dec. 26, 2023

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance preparedness. Due to lack approved antiviral drugs effective against coronaviruses at start pandemic, world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials date, as well selected in vitro data directly acting antivirals, host-targeting and immunomodulatory drugs. Overall, repurposing efforts evaluating antivirals targeting other viral families were unsuccessful, whereas several led clinical improvement hospitalised patients with severe disease. In addition, accelerated drug discovery during progressed multiple novel efficacy, including small molecule inhibitors monoclonal antibodies. We argue that large-scale investment is required prepare for future pandemics; both develop an arsenal broad-spectrum beyond build worldwide trial networks can be rapidly utilised.

Language: Английский

Citations

8
In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants DOI Open Access
Lia Fiaschi,

Camilla Biba,

Ilenia Varasi

et al.

Published: Jan. 3, 2024

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection, however no clinical trial data are available and combined use direct acting antivirals (DAA) monoclonal antibodies (mAb) has been reported only anecdotally. To assess cooperative effects dual drug combinations vitro, we used a VERO E6 cell based vitro system with ancestral B.1 or highly divergent BQ.1.1 virus to test pairwise licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) active metabolite molnupiravir (EIDD-1931) as well combination RDV four mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested susceptible virus). According SynergyFinder 3.0 summary weighted scores, all had an additive effect. Within DAA/DAA combinations, paired scores variants were comparable. In post-hoc analysis weighting synergy by concentrations, several cases synergistic detected at specific both for RDV/mAb combinations. This was supported confirmation experiments showing more than linear shift effective concentration (IC50) increasing concentrations companion drug, although effect prominent but minimal null These results support which should further investigated animal models before introduction into clinic.

Language: Английский

Citations

2
In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants DOI Creative Commons
Lia Fiaschi,

Camilla Biba,

Ilenia Varasi

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 168 - 168

Published: Jan. 23, 2024

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection; however, no clinical trial data are available, and combined use direct-acting antivirals (DAA) monoclonal antibodies (mAb) has been reported only anecdotally. To assess cooperative effects dual drug combinations vitro, we used a VERO E6 cell-based vitro system with ancestral B.1 or highly divergent BQ.1.1 virus to test pairwise licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) active metabolite molnupiravir (EIDD-1931) as well combination RDV four mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested susceptible virus). According SynergyFinder 3.0 summary weighted scores, all had an additive effect. Within DAA/DAA combinations, paired scores variants were comparable. In post hoc analysis weighting synergy by concentrations, several cases synergistic detected at specific both for RDV/mAb combinations. This was supported confirmation experiments showing more than linear shift drug-effective concentration (IC50) increasing concentrations companion drug, although effect prominent minimal null These results support which should further investigated animal models before introduction into clinic.

Language: Английский

Citations

2
A Day in the Life of a Medical Microbiology Director: Navigating the Diverse Duties as a Clinical Conductor DOI
Karissa Culbreath, Peera Hemarajata,

Richard B. Thomson

et al.

Clinical Microbiology Newsletter, Journal Year: 2024, Volume and Issue: 47, P. 14 - 20

Published: July 1, 2024

Language: Английский

Citations

0
Limited Short-Term Evolution of SARS-CoV-2 RNA-Dependent RNA Polymerase under Remdesivir Exposure in Upper Respiratory Compartments DOI Creative Commons
Vladimir Novitsky, Curt G. Beckwith,

Kristin Carpenter‐Azevedo

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(10), P. 1511 - 1511

Published: Sept. 24, 2024

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood. Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled completed up to three visits, in which they provided specimens from four compartments. Near full-length genome sequences obtained viral RNA, standard lineage variant assignments performed, mutations RNA-dependent RNA polymerase (RdRp) region—the target gene—were detected compared between participants RDV, compartments, within versus a larger sequence dataset. statistical analysis used generalized linear mixed-effects model. Results: A total 139 37 out 44 (84%) participants. genotyping success varied ranged 42% oropharyngeal 67% nasopharyngeal showed improvement higher loads. No RdRp known be associated resistance identified, 34 at 32 amino acid positions that as RDV-associated, there was no evidence any associations exposure, compartment, time. At least 1 these all participants, some differed Conclusions: This study highlighted genomic stability hosts suggests lack over contributes our understanding dynamics.

Language: Английский

Citations

0
Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections DOI
Mohammed Nooruzzaman, Katherine Johnson, Ruchi Rani

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 18, 2024

Abstract We investigated the impact of antiviral treatment on emergence SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n=15). All received remdesivir and some also nirmatrelvir-ritonavir or monoclonal antibodies. Sequence analysis showed that nine carried viruses with mutations nsp12 (RNA dependent RNA polymerase), while four had nsp5 (3C protease) mutations. Infectious a double mutation (T169I) (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis patient treated nirmatrelvir-ritonavir. In vitro characterization confirmed its decreased sensitivity to nirmatrelvir, which overcome by combined treatment. Studies golden Syrian hamsters demonstrated efficient transmission contact animals. This study documents isolation carrying both nirmatrelvir demonstrates transmissibility vivo .

Language: Английский

Citations

0