Synergistic Activity of Remdesivir-Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report

  • Viruses. 2023 Jul 19;15(7):1577. doi: 10.3390/v15071577.
Anna Gidari  1  2 ,  Samuele Sabbatini  3 ,  Elisabetta Schiaroli  1 ,  Sabrina Bastianelli  1 ,  Sara Pierucci  1 ,  Chiara Busti  1 ,  Lavinia Maria Saraca  2 ,  Luca Capogrossi  1 ,  Maria Bruna Pasticci  1  2 ,  Daniela Francisci  1
Affiliations
  • 1. Department of Medicine and Surgery, Clinic of Infectious Diseases, "Santa Maria della Misericordia" Hospital, University of Perugia, 06123 Perugia, Italy.
  • 2. Clinic of Infectious Diseases, "Santa Maria" Hospital, Terni, 05100 Terni, Italy.
  • 3. Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06123 Perugia, Italy.
PMID: 37515263 DOI: 10.3390/v15071577
Abstract

Background: This study aims to investigate the activity of the remdesivir-nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination.

Methods: A Vero E6 cell-based Infection assay was used to investigate the in vitro activity of the remdesivir-nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic.

Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical-radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative.

Conclusions: Remdesivir-nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

Keywords
COVID-19; SARS-CoV-2; antiviral; immunosuppressed; nirmatrelvir; remdesivir; synergy; variant.
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