Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1)

Hedskog, Charlotte; Rodriguez, Lauren; Roychoudhury, Pavitra; Huang, Meei‐Li; Jerome, Keith R.; Hao, Linhui; Ireton, Reneé C.; Li, Jiani; Perry, Jason K.; Han, Dong; Greninger, Alexander L.; Gale, Michael; Porter, Danielle

doi:10.1093/infdis/jiad270

Cited by 11 publications

(2 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly in the ACTT-1 study, only 2 participants had an emergence of substitutions associated with low-level reduced remdesivir susceptibility (V792I and C799F; ≤3.4-fold change in EC 50 compared with wildtype and associated with reduced fitness). Notably, clinical recovery was similar between participants with and without emergent Nsp12 substitutions in the RDV arm, suggesting no impact on clinical outcome [ 34 ]. Rare cases of the prolonged shedding of SARS-CoV-2 have been described in older or immunocompromised patients [ 35 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Hedskog,

Spinner,

Protzer

et al. 2024

Viruses

Self Cite

View full text Add to dashboard Cite

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

show abstract

Section: Discussionmentioning

confidence: 99%

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Hedskog,

Spinner,

Protzer

et al. 2024

Viruses

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is a viral replication inhibitor recommended in non-hospitalized adult people [ 4 ]. The use of these three drugs is very controversial, and the FDA has remodulated their administration several times, especially due to the appearance of various side effects and resistant strains [ 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Fusion Peptide Conjugated to a Tetravalent Dendrimer Selectively Inhibits Viral Infection

Zannella,

Chianese,

Monti

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

Fusion is a key event for enveloped viruses, through which viral and cell membranes come into close contact. This event is mediated by viral fusion proteins, which are divided into three structural and functional classes. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein belongs to class I fusion proteins, characterized by a trimer of helical hairpins and an internal fusion peptide (FP), which is exposed once fusion occurs. Many efforts have been directed at finding antivirals capable of interfering with the fusion mechanism, mainly by designing peptides on the two heptad-repeat regions present in class I viral fusion proteins. Here, we aimed to evaluate the anti-SARS-CoV-2 activity of the FP sequence conjugated to a tetravalent dendrimer through a classical organic nucleophilic substitution reaction (SN2) using a synthetic bromoacetylated peptide mimicking the FP and a branched scaffold of poly-L-Lysine functionalized with cysteine residues. We found that the FP peptide conjugated to the dendrimer, unlike the monomeric FP sequence, has virucidal activity by impairing the attachment of SARS-CoV-2 to cells. Furthermore, we found that the peptide dendrimer does not have the same effects on other coronaviruses, demonstrating that it is selective against SARS-CoV-2.

show abstract

SARS-CoV-2 Resistance to Small Molecule Inhibitors

Lopez,

Hasan,

Havranek

et al. 2024

Curr Clin Micro Rpt

View full text Add to dashboard Cite

Purpose of the Review SARS-CoV-2 undergoes genetic mutations like many other viruses. Some mutations lead to the emergence of new Variants of Concern (VOCs), affecting transmissibility, illness severity, and the effectiveness of antiviral drugs. Continuous monitoring and research are crucial to comprehend variant behavior and develop effective response strategies, including identifying mutations that may affect current drug therapies. Recent Findings Antiviral therapies such as Nirmatrelvir and Ensitrelvir focus on inhibiting 3CLpro, whereas Remdesivir, Favipiravir, and Molnupiravir target nsp12, thereby reducing the viral load. However, the emergence of resistant mutations in 3CLpro and nsp12 could impact the efficiency of these small molecule drug therapeutics. Summary This manuscript summarizes mutations in 3CLpro and nsp12, which could potentially reduce the efficacy of drugs. Additionally, it encapsulates recent advancements in small molecule antivirals targeting SARS-CoV-2 viral proteins, including their potential for developing resistance against emerging variants.

show abstract

Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1)

Cited by 11 publications

References 46 publications

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

SARS-CoV-2 Fusion Peptide Conjugated to a Tetravalent Dendrimer Selectively Inhibits Viral Infection

SARS-CoV-2 Resistance to Small Molecule Inhibitors

Contact Info

Product

Resources

About