Frequent Emergence of Resistance Mutations Following Complex Intra-Host Genomic Dynamics in SARS-CoV-2 Patients Receiving Sotrovimab

Palomino-Cabrera, Rosalía; Tejerina, Francisco; Molero-Salinas, Andrea; Ferris, María; Veintimilla, Cristina; Catalán, Pilar; Macias, Gabriela Rodríguez; Alonso, Roberto; Muñoz, Patricia; Viedma, Darío García de; Pérez‐Lago, Laura; Alcalá, Luís; Aldámiz, Teresa; Álvarez‐Uría, Ana; Bermúdez, Elena; Bouza, Emilio; Buenestado‐Serrano, Sergio; Burillo, Almudena; Carrillo, Raquel; Cercenado, Emilia; Cobos, Alejandro; Díez, Cristina; Escribano, Pilar; Estévez, Agustín; Fanciulli, Chiara; Galar, Alicia; García, María del Mar Román; Gijón, Paloma; Guillén, Helmuth; Guinea, Jesús; Herránz, Marta; Irigoyen, Álvaro; Kestler, Martha; López, Juan Carlos; Machado, Marina; Marín, Mercedes; Martín‐Rabadán, Pablo; Montilla, Pedro; Padilla, Belén; Palomo, M.J.; Pérez‐Granda, María Jesús; Peñas-Utrilla, Daniel; Pérez, Leire; Reigadas, Elena; Rincón, Cristina; Rodríguez, Belén; Rodríguez, Sara; Rodríguez‐Grande, Cristina; Rojas, Adriana; Ruiz‐Serrano, María Jesús; Sánchez, Carlos; Sanchez, M. Cantero; Sanz-Pérez, Amadeo; Serrano, Julia; Valerio, Maricela; Veintimilla, Mª Cristina; Vesperinas, Lara; Vicente, Teresa; Villa, Sofía de la

doi:10.1128/aac.00266-23

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…A total of 12 case series have reported an incidence of sotrovimab treatment-emergent resistance; this resistance has ranged from 16 to 100%, with an overall incidence of 33% (146 out of 439 reported cases [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]). In comparison, in series with dual anti-Spike mAbs, treatment-emergent resistance ranged from 0% to 50% [ 35 ] ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

Focosi,

Casadevall,

Franchini

et al. 2024

Viruses

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Among the anti-Spike monoclonal antibodies (mAbs), the S-309 derivative sotrovimab was the most successful in having the longest temporal window of clinical use, showing a high degree of resiliency to SARS-CoV-2 evolution interrupted only by the appearance of the BA.2.86* variant of interest (VOI). This success undoubtedly reflects rational selection to target a highly conserved epitope in coronavirus Spike proteins. We review here the efficacy of sotrovimab against different SARS-CoV-2 variants in outpatients and inpatients, discussing both randomized controlled trials and real-world evidence. Although it could not be anticipated at the time of its development and introduction, sotrovimab’s use in immunocompromised individuals who harbor large populations of variant viruses created the conditions for its eventual demise, as antibody selection and viral evolution led to its eventual withdrawal due to inefficacy against later variant lineages. Despite this, based on observational and real-world data, some authorities have continued to promote the use of sotrovimab, but the lack of binding to newer variants strongly argues for the futility of continued use. The story of sotrovimab highlights the power of modern biomedical science to generate novel therapeutics while also providing a cautionary tale for the need to devise strategies to minimize the emergence of resistance to antibody-based therapeutics.

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Section: Resultsmentioning

confidence: 99%

Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

Focosi,

Casadevall,

Franchini

et al. 2024

Viruses

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“…The increased within-host microevolution described for SARS-CoV-2 in immunosuppressed patients, could lead to the random emergence of resistance mutations that can be selected for once the antiviral drug is present, as we noted previously for sotrovimab. 6 In eight other patients, we identified different mutations at low frequencies (10.94%-30.6%; Table 1); one of them (H163Y), mapping close to the nirmatrelvir catalytic site.…”

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confidence: 93%

“…a Day 0 corresponds to the day for nirmatrelvir/ritonavir administration. Roberto Alonso 1,2,6 Patricia Muñoz 1,2,6,7…”

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confidence: 99%

No emergence of resistance mutations in COVID‐19 patients receiving nirmatrelvir/ritonavir

Palomino‐Cabrera,

Tejerina,

Molero‐Salinas

et al. 2023

Journal of Medical Virology

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To the Editor, Nirmatrelvir/ritonavir is a combination antiviral drug for the treatment of COVID-19 in high-risk patients prone to severe disease that reduces the likelihood of hospitalization and mortality. [1][2][3][4] It is administered orally and should be taken for 5 days, within 5 days of symptom onset. 5 Different to other COVID-19 treatments, 6 there are few longitudinal genomic analyses of the emergence of nirmatrelvir resistance in clinical samples. Most of the evidence for resistance mutations for this drug comes from in silico, in vitro, and ex vivo studies and they are located in the residues S144, M165, E166, H172, and Q192 of the Mpro gene. [7][8][9][10] The compensatory mutations, T21I and L50F, have been found to offset the effects of substitutions in E166, restoring the cell growth kinetics. 10 Recently, mutations in Mpro (E166V/L50V and E166A/V) have been identified in two immunocompromised patients undergoing prolonged treatment, leading to therapeutic failures. 11,12 The aim of our study was to evaluate the emergence of nirmatrelvir/ritonavir resistance mutations in the clinical setting, in a longitudinal analysis of 60 patients who received it at our institution (April-October 2022), and had ≥1 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal positive specimen (C t < 32), 3-13 days after starting treatment. Whole-genome sequencing was performed as described elsewhere. 6 The sequences

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Sotrovimab

2024

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Frequent Emergence of Resistance Mutations Following Complex Intra-Host Genomic Dynamics in SARS-CoV-2 Patients Receiving Sotrovimab

Abstract: The emergence of the Omicron variant of SARS-CoV-2 represented a challenge to the treatment of COVID-19 using monoclonal antibodies. Only Sotrovimab maintained partial activity, allowing it to be used in high-risk patients infected with the Omicron variant.

Cited by 5 publications

References 14 publications

Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

No emergence of resistance mutations in COVID‐19 patients receiving nirmatrelvir/ritonavir

Sotrovimab

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