Abstract
Since 2020, COVID-19 pandemic has spread worldwide causing a huge number of cases and casualties. Among direct anti SARS-CoV-2 agents available for the treatment of COVID-19, only remdesivir and casirivimab/imdevimab have been approved for severe disease. As they act at different levels in blocking viral replication, it is theoretically possible to combine them. In this case series we describe tolerability, safety and effectiveness in a small group of 14 patients of the combination of casirivimab/imdevimab monoclonal antibodies with the polymerase inhibitor remdesivir for the treatment of severe COVID-19. We conducted a retrospective study among consecutive patients admitted to the Infectious Disease ward of the University of Naples (Italy) Hospital for COVID-19 that received the combination of casirivimab/imdevimab and remdesivir for the treatment of severe COVID-19 from the August 1, 2021 to the November 30, 2021. During the study period, 78 patients were admitted for severe COVID-19. Fourteen patients (18%) received the combination casirivimab/imdevimab and remdesivir. They were five males and nine females with a median age of 54 years. Eight patients had significant comorbidities; three patients were in the immediate post-partum period. No adverse drug reaction was observed. All patients except one improved clinical condition and respiratory parameters within seven days following the therapy. All patients were discharged in good conditions.
1. Introduction
Since COVID-19 became a pandemic, great scientific efforts have been made in order to produce an efficacious vaccine. As Pfizer-BioNTech and Moderna vaccines have demonstrated a 95% efficacy in preventing severe disease, the focus of physicians moved on other possible therapeutic approaches [1,2].
Albeit the remarkable effectiveness of vaccination, there is still a portion of population that is less likely to respond to vaccination due to various degrees of immunodepression [3]. Monoclonal antibodies have shown very promising results in individuals with mild COVID-19 to prevent the evolution towards more severe forms [[4], [5], [6]]. However, despite their potential, their use remains limited: several factors probably contribute to this phenomenon including cost, limited availability, and the narrow time frame in which they must be administered to keep their efficacy [[7], [8]]. Among anti SARS CoV-2 treatments available, only casirivimab/imdevimab and remdesivir are approved for the treatment of severe COVID-19.
It is noteworthy that the efficacy of neutralizing monoclonal antibodies in severe patients with COVID-19, depends on the serostatus for anti-spike antibodies. In fact, in the RECOVERY trial casirivimab/imdevimab in hospitalized patients demonstrated to reduce mortality only in patients without detectable anti-spike antibodies, with a higher prevalence of discharge alive within 28 days (64% vs. 58%) and a less frequent progression to use of ventilation (28 vs 32%) [9]. Those data should be confirmed in real life settings as the trial data comes from a patient population where only 8% had received at least one COVID-19 vaccine dose, and this is no longer the clinical reality in most countries worldwide, where vaccination rates are now much higher.
However, three other trials including the others monoclonal antibodies licensed in hospitalized patients [10,11] have been all terminated for futility [12]. Real-life data on monoclonal antibodies in severe COVID-19 are lacking.
To date, the only licensed direct antiviral treatment for severe COVID-19 is remdesivir. In these patients, remdesivir is associated with a reduced median time for recovery (10 days vs 15 days, p < 0.001), without a significant effect on mortality [13].
Viral replication cycle involves six steps: attachment, penetration, uncoating, nucleic acid replication, assembly, and release. The rationale of combining remdesivir and neutralizing monoclonal antibodies is that they interfere with two different stages in the replication cycle of SARS-CoV-2 virus. Monoclonal antibodies bind to the virus spike protein blocking the virus attachment and entry inside the host cell [ [14,15]]. The antiviral drug remdesivir acts by interfering with the RNA-dependent RNA polymerase and therefore blocking SARS CoV-2 RNA replication [16].
However, little is known regarding this combination. The main aim of our study was to assess safety and efficacy of combination of monoclonal antibodies and remdesivir for the treatment of severe COVID-19.
2. Materials and methods
We designed a retrospective study on consecutive patients admitted to the University of Naples Hospital (Italy) for SARS-CoV-2 infection with a severe COVID-19 (defined as patients with COVID-19 who needed a respiratory support) and treated with a combination of the antiviral drug remdesivir and the monoclonal antibodies casirivimab/imdevimab between the August 1, 2021 and the November 30, 2021.
We included consecutive patients with a diagnosis of SARS-CoV-2 infection by the means of PCR analysis of nasopharyngeal swab, who tested negative anti SARS-CoV-2 spike protein antibodies as this was a requirement for the administration of monoclonal antibodies in severe patients. Moreover, COVID-19 vaccination was not a contraindication to monoclonal antibodies administration.
The patients were evaluated for the onset of adverse events. Chest CT severity score was assessed according to Chung et al. score [17].
Remdesivir treatment was administered within ten days from symptoms onset, a single dose of 200mg I.V. was administered on day one, followed by 100 mg once day I.V. for the next four days. The combination of casirivimab (1200mg) and imdevimab (1200mg) was administered I.V. the same day of the first remdesivir infusion. All patients at the time of administration were receiving oxygen supplementation either with a nasal cannula or venturi mask. All patients received the usual standard of care in addition to remdesivir and monoclonal antibodies in fact all patients received low molecular weight heparin at intermediate dosage (50 UI/kg bis in die) and dexamethasone at standard dosage (6 mg i. v., progressively tapered).
The patients were followed up for 28 days until discharge.
No sequencing for viral variant determination was performed.
Written informed consent was obtained from the patients for the publication of the collection of their clinical data. This study was approved by the Ethical Committee of “Federico II and Cardarelli Hospital” of Naples, Italy.
3. Results
During the study period in our COVID facility, 78 patients were hospitalized. Among these, 44 patients (56.4%) were treated with the combination of Casirivimab/Imdevimab according to the indications provided by AIFA (Italian Medicines Agency): patients within the first ten days from symptoms onset, presence of a radiologic evidence of pneumonia, needing for oxygen supplementation, negative serology (IgG) for SARS-CoV-2 spike protein.
Of these 44 patients, 14 (31.8%) received remdesivir in addition to casirivimab/Imdevimab and they were all included in the analysis of this study.
They were five males and nine females with median age of 54 (34–61) years.
Four patients require oxygen supplementation via low flow nasal cannula at the time of casirivimab/imdevimab and remdesivir infusion, 9 patients were given oxygen via a venturi mask (FiO2 35–60%) and one patient was receiving oxygen via a non-rebreather mask (FiO2 80%). Two of these infections were breakthrough infections as they occur after a full vaccination cycle.
Eight patients (53.3%) had significant comorbidities (among those: peripheral artery disease, chronic heart failure, diabetes and obesity) (Table 1). Regarding the three patients in post-partum period, delivery occurred in the day just before the administration of remdesivir and casirivimab/imdevimab. All these three patients were already vaccinated against COVID-19.
Table 1.
Characteristic of included patients (n = 14 patients).
| N | 14 |
|---|---|
| Age (years) | 54; 34 -61 |
| Male sex | 5 (35%) |
| CT severity score (median; IQR) | 9 (6–12) |
| Charlson (median; IQR) | 1 (0–3) |
| Relevant medical conditions | |
| Peripheral artery disease | 2 (14%) |
| Chronic heart failure | 1(7%) |
| Puerperium | 3(21%) |
| Chronic cerebrovascular disease | 1(7%) |
| Diabetes | 2(14%) |
| Obesity | 2(14%) |
| Prior vaccination against COVID-19 | 4 (28%) |
| Type of Vaccine | |
| Pfizer-BioNTech | 3 (21%) |
| AstraZeneca | 1(7%) |
| Time between vaccination and symptoms onset (days; min - max) | 137; (4–177) |
| Hospital stay (days) | 16.5 (13–21.5) |
| Type of ventilation | |
| Low-flow ventilation | 4(28%) |
| Venturi mask, | 9(65%) |
| Non-rebreather mask | 1(7%) |
| Need for non-invasive ventilation support | |
| yes | 1(7%) |
| No | 13(93%) |
Continuous variables are expressed as median (interquartile range [IQR]). Qualitative variables are given in number and percentage.
All enrolled patients received a radiologic diagnosis of interstitial pneumonia. CT severity score was calculated for 12 of the 14 patients (85.7%) included in the study. Median CT severity score was 9 (IQR 6–12).
No adverse drug reaction was recorded during the administration of either remdesivir casirivimab/imdevimab. All patients had improved clinical conditions and respiratory parameters within seven days following the therapy, except for one patient, who needed non-invasive ventilation support.
During the study period we recorded a substantial improvement in inflammatory markers, in detail the median C reactive protein decreased from 3,04mg/dl at baseline tov 0,35mg/dl at discharge, other laboratory data are given in Table 2.
Table 2.
Main laboratory parameters of the included patients.
| baseline | 72h | 7 days | discharge | |
|---|---|---|---|---|
| white blood cells (10^3/μL) | 5,84(3825–7,84) | 7,33(6055–8955) | 8,15(6595–9845) | 8,43(7205–9,99) |
| neutrophils (cell/μL) | 4775(2455–6,78) | 5,72(4,15–6605) | 5,33(4,58–7655) | 4,84(4345–6945) |
| lymphocytes (cell/μL) | 0,895(0,6825–1085) | 1,32(0,925–1,51) | 1,48(1225–1,83) | 2,14(1885–2,55) |
| C reactive protein (mg/dL) | 3,04(2–9,8) | 1865(1245–3215) | 1605(1335–3,2125) | 0,35(0,275–0645) |
| AST (I·U.) | 32(24,25–47) | 25(20–46,5) | 25(20–30) | 22(16–26,5) |
| ALT (I·U.) | 27(18,25–38) | 16,5(12,5–26,5) | 29(22–57) | 32(18,25–52) |
| LDH (I·U.) | 351,5(233,75–405) | 240(197,5–393) | 252(212,25–343,25) | 230(181,5–254,25) |
Continuous variables are expressed as median (interquartile range [IQR]).
All the patients recovered from COVID-19 and were discharged alive in a median time of 16,5 days (IQR 13–21,5 days).
4. Discussion
In our case series we showed efficacy and safety of a combination treatment of casirivimab/imdevimab and remdesivir for the treatment of severe COVID-19.
Real-life data of patients treated with this combination are lacking. The pivotal RECOVERY trial showed a reduced mortality in patients treated with casirivimab and indevimab versus usual care [9] among seronegative patients. Among the patients receiving the monoclonal antibodies combination, 380 patients were also on remdesivir and their mortality was 20%, while 1253 were not given remdesivir and their mortality was 26%. However, the purpose of the above-mentioned study was not to assess the benefit of casirivimab and indevimab and remdesivir in combination.
In our case series there were no deaths despite prognostic factors of worse outcome were present in 9 of the 14 patients at admission. Among those factors, heart disease, obesity, and diabetes, were present in a total of 5 of our patients, are comorbidities that strongly correlate with a high mortality.
Three of the 14 patients were women in immediate post-partum period. In detail the combination remdesivir and casirivimab/imdevimab was administered just after delivery, as remdesivir is not allowed for use during pregnancy.
In this setting it is noteworthy that the outcome of pregnant women tends to be worse than that of similarly aged female adults [18]. Moreover, an increased rate of pre-term birth has been observed [18]. In particular, the severity of COVID-19 in pregnancy seems to increase in case of infection by the delta variant of SARS-CoV-2 [19,20]. In our case series we did not perform sequencing of viral RNA, however, according to Italian National Institute of Health, the prevalence of delta variant in the study period was over 90% (8% was due to unrecognized variants, less than 1% to kappa and alpha variants) [21]. Moreover, it is to be noted that the first case of omicron variant was diagnosed in Italy on November 27, 2021 in a traveler returning from Africa [22], at that time there was only one patient already on follow-up so there is very little chance that any of our subject was infected by Omicron. Albeit in very small numbers, we confirmed the effectiveness and safety of the combination remdesivir, casirivimab and Imdevimab also in this subset of patients.
We acknowledge that our study has several limitations. First of all, the lack of a control group and the small sample size cannot draw strong conclusion and recommendations. However, this is the first real life experience in severe COVID with high percentage of patients with risk factors for worse outcome so that other studies can start from our results to evaluate efficacy in larger cohorts. We decided not to compare treated patients to the ones who did not receive the combination Casirivimab/Imdevimab + remdesivir as these latter patients had positive serology for spike protein of SARS-CoV-2. As more variants arise, the drugs object of this study, in particular the monoclonal antibodies casirivimab/imdevimab that, like all monoclonal antibodies are highly selective, could lose their efficacy. However, the concept of combining monoclonal antibodies with remdesivir or other antiviral drugs against SARS CoV-2 still remains valid as it could simultaneously led to a synergistic interaction with a rise in the therapeutic efficacy and could even hypothetically prevent the rising of new variants.
5. Conclusions
In conclusion, the association of casirivimab/imdevimab and remdesivir combination was well tolerated. Moreover, in our cohort, despite the numerous risk factors associated with a poor prognosis, all patients with a severe COVID-19 treated with this combination fully recovered. We underline that the mortality rate in our cohort is favorable when compared with that of patients with a similar comorbidity profile. Based on our results, studies designed to evaluate efficacy and safety of the combination of monoclonal antibodies and remdesivir in treating severe forms of COVID-19 are needed.
Author contribution statement
All authors listed have significantly contributed to the investigation, development and writing of this article.
Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability statement
Data will be made available on request.
Declaration of interest’s statement
The authors declare the following conflict of interests: Ivan Gentile: Consultant for Gilead Sciences, received departmental grants from Gilead Sciences.
Additional information
No additional information is available for this paper.
Funding: This research received no external funding
Conflicts of Interest: Ivan Gentile: Consultant for Gilead Sciences, received departmental grants from Gilead Sciences.
Acknowledgments
Federico II COVID team: Luigi Ametrano, Francesco Beguinot, Giuseppe Castaldo, Letizia Cattaneo, Maria Carmela Domenica Conte, Mariarosaria Cotugno, Alessia d’Agostino, Ivana D’Alterio, Giovanni Di Filippo, Isabella Di Filippo, Antonio Di Fusco, Nunzia Esposito, Mariarosaria Faella, Lidia Festa, Maria Foggia, Maria Elisabetta Forte, Ludovica Fusco, Antonella Gallicchio, Ivan Gentile, Agnese Giaccone, Anna Iervolino, Carmela Iervolino, Antonio Iuliano, Amedeo Lanzardo, Federica Licciardi, Matteo Lorito, Simona Mercinelli, Fulvio Minervini, Giuseppina Muto, Mariano Nobile, Biagio Pinchera, Giuseppe Portella, Laura Reynaud, Alessia Sardanelli, Marina Sarno, Nicola Schiano Moriello, Maria Michela Scirocco, Fabrizio Scordino, Riccardo Scotto, Stefano Mario Susini, Anastasia Tanzillo, Grazia Tosone, Maria Triassi, Emilia Trucillo, Annapaola Truono, Ilaria Vecchietti, Giulio Viceconte, Riccardo Villari, Emilia Anna Vozzella, Emanuela Zappulo, Irene Zotta, Giulia Zumbo
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data will be made available on request.