Synergistic Activity of Remdesivir–Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report
Anna Gidari,
Samuele Sabbatini,
Elisabetta Schiaroli,
Sabrina Bastianelli,
Sara Pierucci,
Chiara Busti,
Lavinia Maria Saraca,
Luca Capogrossi,
Maria Bruna Pasticci,
Daniela Francisci
Affiliations
Anna Gidari
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Samuele Sabbatini
Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06123 Perugia, Italy
Elisabetta Schiaroli
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Sabrina Bastianelli
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Sara Pierucci
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Chiara Busti
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Maria Bruna Pasticci
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
Daniela Francisci
Department of Medicine and Surgery, Clinic of Infectious Diseases, “Santa Maria della Misericordia” Hospital, University of Perugia, 06123 Perugia, Italy
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.
