Retrospective Analysis of a Real-Life Use of Tixagevimab–Cilgavimab plus SARS-CoV-2 Antivirals for Treatment of COVID-19
by
Nicolina Capoluongo
1,†, 
Annamaria Mascolo
2,3,†,
Francesca Futura Bernardi
4,
Marina Sarno
1,
Valentina Mattera
5,
Giusy di Flumeri
1,
Bruno Pustorino
1,
Micaela Spaterella
2,
Ugo Trama
4,
Annalisa Capuano
2,3,‡ and
Alessandro Perrella
1,*,‡
1
UOC Emerging Infectious Disease with High Contagiousness, AORN Ospedali dei Colli P.O. C Cotugno, 80131 Naples, Italy
2
Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Napoli, Italy
3
Department of Experimental Medicine—Section of Pharmacology “L. Donatelli”, University of Campania “Luigi Vanvitelli”, 81100 Napoli, Italy
4
Directorate-General for Health Protection, Campania Region, 80143 Naples, Italy
5
UOSD Pharmacovigilance, AORN Ospedali dei Colli P.O. C Cotugno, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors contributed equally to this work.
Pharmaceuticals 2023, 16(10), 1493; https://doi.org/10.3390/ph16101493
Submission received: 12 September 2023
/
Revised: 11 October 2023
/
Accepted: 17 October 2023
/
Published: 20 October 2023
(This article belongs to the Section Pharmacology)
Abstract
:Tixagevimab–cilgavimab is effective for the treatment of early COVID-19 in outpatients with risk factors for progression to severe illness, as well as for primary prevention and post-exposure prophylaxis. We aimed to retrospectively evaluate the hospital stay (expressed in days), prognosis, and negativity rate for COVID-19 in patients after treatment with tixagevimab–cilgavimab. We enrolled 42 patients who were nasal swab-positive for SARS-CoV-2 (antigenic and molecular)—both vaccinated and not vaccinated for COVID-19—hospitalized at the first division of the Cotugno Hospital in Naples who had received a single intramuscular dose of tixagevimab–cilgavimab (300 mg/300 mg). All patient candidates for tixagevimab–cilgavimab had immunocompromised immune systems either due to chronic degenerative disorders (Group A: 27 patients) or oncohematological diseases (Group B: 15 patients). Patients enrolled in group A came under our observation after 10 days of clinical symptoms and 5 days after testing positivite for COVID-19, unlike the other patients enrolled in the study. The mean stay in hospital for the patients in Group A was 21 ± 5 days vs. 25 ± 5 days in Group B. Twenty patients tested negative after a median hospitalization stay of 16 days (IQR: 18–15.25); of them, five (25%) patients belonged to group B. Therefore, patients with active hematological malignancy had a lower negativization rate when treated 10 days after the onset of clinical symptoms and five days after their first COVID-19 positive nasal swab.
1. Introduction
Antiviral therapies, when used alone, have been reported to not always be sufficient to change the course of the COronaVIrus Disease 2019 (COVID-19) [1], especially in frail patients. Therefore, identifying new therapeutic options to prevent or fight this disease in its early phase is essential [2].
Tixagevimab–cilgavimab is a long-acting monoclonal antibody combination of two Fc-modified human monoclonal antibodies obtained from patients who recovered from COVID-19. Tixagevimab and cilgavimab bind non-overlapping sites of the spike (S) glycoprotein of the Severe Acute Respiratory Syndrome COronaVirus-2 (SARS-CoV-2), the causative agent of COVID-19 [3]. The Fc region was modified to extend their half-life (to about 90 days) and reduce binding to the Fc receptor and C1q complement, minimizing the risk of increasing disease inflammation [4,5]. This extended half-life could also offer the advantage of long-term protection against symptomatic COVID-19, compared to the shorter half-lives of other anti-SARS-CoV-2 monoclonal antibodies (approximately 18–32 days) [6,7,8]. Tixagevimab–cilgavimab, by binding to different sites of the S protein, may also help to overcome the immune escape phenomenon and maintain effectiveness against SARS-CoV-2 variants [9]. Based on these beneficial properties, this combination was authorized in Europe for the treatment of early COVID-19 in outpatients (aged ≥ 12 years and weighed at least 40 kg) who do not require oxygen supplement therapy and have risk factors for progression to severe illness, as well as for pre-exposure prophylaxis to SARS-CoV-2 [10].
After marketing authorization, a randomized Phase 3 clinical trial was published. This trial compared tixagevimab–cilgavimab with a placebo in hospitalized COVID-19 patients receiving remdesivir and standard care, finding no improvement in the primary outcome (time to sustained recovery), but a good safety profile and a low mortality rate in the tixagevimab–cilgavimab group [11]. Moreover, little evidence has described the use of tixagevimab–cilgavimab in patients affected by hematological malignancies or impaired immune systems [12,13].
Although tixagevimab–cilgavimab seems to be an important therapeutic strategy for protecting people who cannot be vaccinated or who respond poorly to COVID-19 vaccines and for treating early COVID-19, based on the few pieces of real-world evidence available in frail patients, further research is needed to better define the therapeutic role of this medicine. Therefore, we decided to conduct a retrospective observational chart review to describe the use of tixagevimab–cilgavimab in patients affected by COVID-19 who are also affected by other comorbidities, such as hematological malignancies.
2. Results
Forty-two patients were enrolled that had received tixagevimab–cilgavimab. All patients were affected by omicron SARS-CoV-2 variants and were hospitalized for causes other than COVID-19, mainly due to comorbidities. No patient complained of side effects related to the administration of tixagevimab–cilgavimab.
Of the 42 enrolled patients, 21 were female and 21 were male, with a median age of 71 years (Interquartile range, IQR: 78.5–59.0). Fifteen patients had oncohematological diseases (Group B); specifically, 11 patients were affected by active non-Hodgkin lymphoma (NHL) and four patients by chronic lymphocytic leukemia (CLL). A total of 27 patients were affected by chronic disorders (Group A), including cardiovascular disorders (n = 8), degenerative diseases (n = 7), solid tumors (n = 5), infections (n = 4), and autoimmune diseases (n = 3). Ten (37%) patients of group A were affected by more than one chronic disorder. The basal characteristics of these patients are shown in Table 1, while the underlying pathologies are in Table 2. Eleven (40.7%) patients of group A and 12 (80.0%) patients of group B were treated with remdesivir (Table 1). One patient in group B did not receive remdesivir treatment because she was discharged against the advice of the health care workers with oxygen therapy with a Venturi mask (during their short hospitalization, the patient presented a rapid worsening of respiratory function). Patients with NHL and CLL also had immunoglobulin deficiency. Two patients presented with sepsis upon admission to the hospital. One patient had legionella pneumonia. The enrolled patients presented a variegated pulmonary CT picture (Table 3).
Of the 42 enrolled patients, 16 patients were unvaccinated (12 patients for group A and 4 patients in group B). IL-6 levels were similar between groups. CRP at admission was higher in Group A compared to Group B (Table 1). Moreover, in stratifying CRP levels for remdesivir treatment, we found higher median levels for 5 mg remdesivir (Median: 20.5; IQR: 27.06–9.70, Figure 1).
The mean stay in hospital of patients in Group A was 21 ± 5 days vs. 25 ± 5 days in Group B. Twenty patients tested negative after a median of hospitalization stay of 16 days (IQR: 18–15.25); of them, five (25%) patients belonged to group B. Eight patients died from COVID-related respiratory failure—four for each group. Two patients in Group B presented with respiratory distress syndrome. Patients enrolled in our study and affected by CLL and NHL came to our observation 10 days after their first clinical symptoms, having tested positive for COVID-19 within 5 days of hospitalization—unlike the other patients enrolled in this study.
3. Discussion
Patients with COVID-19 at high risk of being hospitalized or of death—such as older adults, those with multiple comorbidities, or immunocompromised patients—need to be treated early [14,15,16,17]. Specifically, patients with an impaired immune system are at higher risk of prolonged or unresolved SARS-CoV-2 infection, which might also facilitate the development of new variants [18]. In fact, the presence of active malignancy as well as the type of hematological malignancy—together with age, the presence of comorbidities, length of stay in the Intensive Care Unit, and need for mechanical ventilation—are recognized risk factors for adverse outcomes in patients with COVID-19 and hematological malignancies [19].
In this study, we observed a similar mean hospital stay between patients treated with tixagevimab–cilgavimab affected by oncohematological tumors and those affected by chronic disorders, despite the higher negativization rate for those affected by chronic disorders (75%). Indeed, patients with hematologic malignancy are characterized by a more compromised immune response to SARS-CoV-2 and high mortality rates (about 34%) [19]. Moreover, hematologic patients can have an impaired response to COVID-19 vaccines by failing in the production of neutralizing and protective anti-S antibodies after a full vaccination cycle [20]. This poor response is common in patients with B cell tumors, such as in CLL [21]. Our hematologic patients mostly had a three-dose schedule of COVID-19 vaccines (n = 10; 66.7%). In the literature, the administration of tixagevimab–cilgavimab did not change the response to COVID-19 vaccines [22], but rather potentiated the pre-existing protection against SARS-CoV-2 infection—even in immunocompromised patients receiving full vaccination [23,24].
Moreover, the low negativization rate observed in patients with hematological tumors may also be due to a delayed start of treatment with tixagevimab–cilgavimab, since patients came to our observation only after 10 days of clinical symptoms in mean and 5 days after testing positive with a COVID-19 nasal swab. This may suggest the importance of early interception in frail patients, with a nasal swab for COVID19 being given when the patient is affected by flu-like symptoms, and then starting early treatment with tixagevimab–cilgavimab to have a higher probability of a good and effective clinical response to the therapy.
The effectiveness and safety of tixagevimab–cilgavimab as a pre-exposure prophylaxis against COVID-19 has been widely evaluated. A meta-analysis found that tixagevimab–cilgavimab prophylaxis may reduce the rate of SARS-CoV-2 infection (OR: 0.24; 95% CI: 0.15–0.40) and COVID-19 hospitalization (OR: 0.13; 95% CI: 0.07–0.24), and decrease the severity (OR: 0.13; 95% CI: 0.07–0.24) and mortality (OR: 0.17; 95% CI: 0.03–0.99) associated with COVID-19 [25]. Another meta-analysis evaluated the effectiveness of tixagevimab–cilgavimab prophylaxis in immunocompromised participants—including patients with hematological malignancies—confirming the overall clinical effectiveness of tixagevimab/cilgavimab in terms of hospitalization, intensive care admission, and mortality [26]. Both meta-analyses showed the efficacy and safety of tixagevimab–cilgavimab for preventing COVID-19. However, evidence of its efficacy as a post-exposure treatment has been more conflicting. A randomized, double-blind, Phase 3, placebo-controlled trial (ACTIVE-3 study) investigating the efficacy of tixagevimab–cilgavimab compared to placebo in patients treated with remdesivir and other standard therapies found no improvement in the primary outcome of time to sustained recovery with tixagevimab–cilgavimab, but it was safe and showed low mortality [11]. Another Phase 3 study (STORMCHASER study) evaluated treatment with tixagevimab/cilgavimab as a post-exposure prophylaxis against symptomatic COVID-19, finding no difference in the incidence of post-dose positive symptomatic COVID-19 compared to a placebo [27]. On the contrary, a Phase 3, randomized, double-blind, placebo-controlled trial (TACKLE study) demonstrated that tixagevimab/cilgavimab can prevent the development of severe COVID-19 by reducing the risk of severe COVID-19 or death by 50.5% (95% CI 14.6–71.3; p = 0.0096) and 66.9% (95% CI 31.1–84.1; 0.0017) in patients with mild or moderate COVID-19 who were symptomatic for less than 5 days, respectively [8]. In particular, this study suggested the efficacy of tixagevimab/cilgavimab in reducing COVID-19 progression and death in high-risk patients [8]. However, it should be highlighted that the most representative risk factors (>10%) were obesity, smoking, hypertension, diabetes, and lung diseases, while the immunocompromised state was underrepresented [8].
We observed a good safety profile for tixagevimab/cilgavimab, in accordance with the results of aforementioned clinical trials in which most events were found to be mild to moderate in severity, with a similar incidence in both the tixagevimab–cilgavimab and placebo groups [8,11,26]. In our study, all patients were affected by omicron variants. In this regard, in-vitro studies have shown the efficacy of tixagevimab/cilgavimab in neutralizing the BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4, and BA.5 omicron subvariants, with a potency within the half maximal inhibitory concentration (IC50) range of 4.0–806.0 ng/mL [28,29,30,31]. These results have also been reported in previous studies on the neutralizing activity of monoclonal antibodies for COVID-19 in the treatment of Omicron-infected patients; in particular, combining available mAbs could be an attractive option for targeting newly emerging SARS-CoV-2 variants [32,33].
The main limitation of our study was the small number of patients retrospectively enrolled and treated with tixagevimab–cilgavimab, which also hindered the execution of an adequate statistical analysis. Even so, we described our experience in the use of tixagevimab–cilgavimab in patients with chronic and oncohematological disorders, thus providing new data on the safety and efficacy of this therapy in frail patients affected by Omicron variants, and underlining the possible importance of starting early treatment.
4. Materials and Methods
In this observational retrospective chart review study, we enrolled patients who were nasal swab-positive for SARS-CoV-2 (Antigenic and molecular)—vaccinated or not for COVID-19—hospitalized at the first division of the Cotugno Hospital in Naples (UOC of Emerging and Highly Contagious Infectious Diseases), who had received an early therapeutic dose of tixagevimab–cilgavimab from 8 July 2022 to 10 January 2023. This treatment schedule was based on AIFA (Italian Agency for Drug) policy https://www.aifa.gov.it/-/aifa-autorizza-l-utilizzo-terapeutico-del-monoclonale-evusheld-per-il-trattamento-precoce-del-covid-19-in-soggetti-a-rischio-di-progressione, (accessed on 11 September 2023). Basically, patients received an intramuscular single dose of tixagevimab–cilgavimab of 300 mg/300 mg. Patients were divided into two groups: those affected by chronic disorders (Group A) and those affected by oncohematological diseases (Group B). Early treatment and the chronic disorders included were defined according to the Italian ministry of health classification (“Gestione domiciliare dei pazienti con infezione da SARS-CoV-2” aggiornamento del 10 febbraio 2022 in (sanitaria Dgdpsedp, ed), Ministero della Salute, Roma: (2022)—https://www.quotidianosanita.it/allegati/allegato3418644.pdf, accessed on 11 September 2023). Early recognition of positive patients was made possible according to Campania Region BigData SINFONIA [34] and the regional COVID-19 patients early enrolment treatment protocol (https://www.ordinemedicinapoli.it/upload/file/id-0-1657026671-piano%20regionale%20di%20contrasto%20al%20covid-19%20-%20luglio%202022.pdf, accessed on 11 September 2023).
The two groups were evaluated for their length of stay in hospital (expressed in days) and time elapsed to negativity for COVID-19 at follow-up. Patients’ venous blood samples were analyzed for immunoglobulins A (IgA), M (IgM), and G (IgG); C-reactive protein (CRP); procalcitonin; interleukine-6 (IL6); D-dimer; and fibrinogen, and were retrospectively evaluated during hospital admission every 48 h. High resolution CT scans of the chest (HR chest CT) at hospital admission and hospital discharge were performed too. Antigen testing for SARS-CoV2 on the nasal swab (Methodical: Chemiluminescence Enzyme ImmunoAssay) and viral RNA testing using four gene assays were used to follow-up SARS-CoV-2 evolution and negativizing.
Positivity tests for anti-spike antibodies were routinely performed, but did not exclude treatment with intramuscular tixagevimab–cilgavimab.
5. Conclusions
In conclusion, patients with active hematological malignancy are those with the worst prognosis for COVID-19, despite therapy with tixagevimab–cilgavimab and remdesivir when treated 10 days after the onset of clinical symptoms and five days after the first COVID-19-positive nasal swab.
These results, according to the new COVID-19 wave currently present in Europe and the USA [35], could be considered in the planning of strategies for early interception in frail patients, aiming to treat them as soon as possible with current antiviral and monoclonal antibodies. This could be made possible with the use of Big Data IT platforms and machine learning algorithms for early identification and direction towards treatment in patients positive for COVID-19, as in SINFONIA [34].
Therefore, it could be useful to encourage hematologists and patients with active hematological malignancies towards the early interception of COVID-19 and to start pharmacological treatment within 5 days after a positive nasal swab. Further studies with an adequate sample size are needed to better elucidate the efficacy and safety of tixagevimab–cilgavimab in patients with COVID-19 and those affected by chronic comorbidities or an impaired immune response.
Author Contributions
Conceptualization, A.P. and A.C.; methodology, A.C.; software, A.P.; validation, A.C. and A.P.; formal analysis, A.M. and N.C.; investigation, N.C., M.S. (Marina Sarno), G.d.F. and U.T.; resources, B.P. and N.C.; data curation, B.P. and A.M.; writing—original draft preparation, N.C., A.P. and A.M.; writing—review and editing, A.P., A.C. and F.F.B.; visualization, F.F.B., V.M. and M.S. (Micaela Spaterella); supervision, A.P. and A.C.; project administration, A.P. and A.C. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
According to the local legislation, a retrospective study does not require ethical approval. For the use of retrospective data, this study was conducted in accordance with the Declaration of Helsinki 1975 and its later amendments. All patients’ data were fully anonymized and were analyzed retrospectively.
Informed Consent Statement
For this type of study, formal consent was not required according to the current national established by the Italian Medicines Agency, and according to the Italian Data Protection Authority, neither ethical committee approval nor informed consent was required for anonymized data.
Data Availability Statement
Data is contained within the article.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Hammond, J.; Leister-Tebbe, H.; Gardner, A.; Abreu, P.; Bao, W.; Wisemandle, W.; Baniecki, M.; Hendrick, V.M.; Damle, B.; Simón-Campos, A.; et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19. N. Engl. J. Med. 2022, 386, 1397–1408. [Google Scholar] [CrossRef] [PubMed]
- UK NERVTAG: Antiviral Drug Resistance and the Use of Directly Acting Antiviral Drugs (DAAs) for COVID-19, 8 December 2021—GOV.UK. Available online: https://www.gov.uk/government/publications/nervtag-antiviral-drug-resistance-and-the-use-of-directly-acting-antiviral-drugs-daas-for-covid-19-8-december-2021/nervtag-antiviral-drug-resistance-and-the-use-of-directly-acting-antiviral-drugs-daas-for-covid-19-8-december-2021 (accessed on 3 May 2023).
- Dong, J.; Zost, S.J.; Greaney, A.J.; Starr, T.N.; Dingens, A.S.; Chen, E.C.; Chen, R.E.; Case, J.B.; Sutton, R.E.; Gilchuk, P.; et al. Genetic and Structural Basis for SARS-CoV-2 Variant Neutralization by a Two-Antibody Cocktail. Nat. Microbiol. 2021, 6, 1233–1244. [Google Scholar] [CrossRef] [PubMed]
- Loo, Y.M.; McTamney, P.M.; Arends, R.H.; Abram, M.E.; Aksyuk, A.A.; Diallo, S.; Flores, D.J.; Kelly, E.J.; Ren, K.; Roque, R.; et al. The SARS-CoV-2 Monoclonal Antibody Combination, AZD7442, Is Protective in Nonhuman Primates and Has an Extended Half-Life in Humans. Sci. Transl. Med. 2022, 14, eabl8124. [Google Scholar] [CrossRef]
- Oganesyan, V.; Damschroder, M.M.; Woods, R.M.; Cook, K.E.; Wu, H.; Dall’Acqua, W.F. Structural Characterization of a Human Fc Fragment Engineered for Extended Serum Half-Life. Mol. Immunol. 2009, 46, 1750–1755. [Google Scholar] [CrossRef] [PubMed]
- O’Brien, M.P.; Forleo-Neto, E.; Musser, B.J.; Isa, F.; Chan, K.-C.; Sarkar, N.; Bar, K.J.; Barnabas, R.V.; Barouch, D.H.; Cohen, M.S.; et al. Subcutaneous REGEN-COV Antibody Combination to Prevent COVID-19. N. Engl. J. Med. 2021, 385, 1184–1195. [Google Scholar] [CrossRef] [PubMed]
- Food and Drug Administration Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Bamlanivimab and Etesevimab. Available online: Chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fda.gov/media/145802/download (accessed on 3 May 2023).
- Montgomery, H.; Hobbs, F.D.R.; Padilla, F.; Arbetter, D.; Templeton, A.; Seegobin, S.; Kim, K.; Campos, J.A.S.; Arends, R.H.; Brodek, B.H.; et al. Efficacy and Safety of Intramuscular Administration of Tixagevimab–Cilgavimab for Early Outpatient Treatment of COVID-19 (TACKLE): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Respir. Med. 2022, 10, 985–996. [Google Scholar] [CrossRef]
- Keam, S.J. Tixagevimab + Cilgavimab: First Approval. Drugs 2022, 82, 1001. [Google Scholar] [CrossRef]
- Europea Medicine Agency Evusheld: EPAR—Product Information. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/evusheld (accessed on 13 April 2023).
- Ginde, A.A.; Paredes, R.; Murray, T.A.; Engen, N.; Grandits, G.; Vekstein, A.; Ivey, N.; Mourad, A.; Sandkovsky, U.; Gottlieb, R.L.; et al. Tixagevimab-Cilgavimab for Treatment of Patients Hospitalised with COVID-19: A Randomised, Double-Blind, Phase 3 Trial. Lancet. Respir. Med. 2022, 10, 972–984. [Google Scholar] [CrossRef]
- Wang, Y.; Zheng, J.; Zhu, K.; Xu, C.; Wang, D.; Hou, M. The Effect of Tixagevimab-Cilgavimab on Clinical Outcomes in Patients with COVID-19: A Systematic Review with Meta-Analysis. J. Infect. 2023, 86, e15–e17. [Google Scholar] [CrossRef]
- Lafont, E.; Pere, H.; Lebeaux, D.; Cheminet, G.; Thervet, E.; Guillemain, R.; Flahault, A. Targeted SARS-CoV-2 Treatment Is Associated with Decreased Mortality in Immunocompromised Patients with COVID-19. J. Antimicrob. Chemother. 2022, 77, 2688–2692. [Google Scholar] [CrossRef]
- Dougan, M.; Nirula, A.; Azizad, M.; Mocherla, B.; Gottlieb, R.L.; Chen, P.; Hebert, C.; Perry, R.; Boscia, J.; Heller, B.; et al. Bamlanivimab plus Etesevimab in Mild or Moderate COVID-19. N. Engl. J. Med. 2021, 385, 1382–1392. [Google Scholar] [CrossRef]
- Hippisley-Cox, J.; Coupland, C.A.C.; Mehta, N.; Keogh, R.H.; Diaz-Ordaz, K.; Khunti, K.; Lyons, R.A.; Kee, F.; Sheikh, A.; Rahman, S.; et al. Risk Prediction of COVID-19 Related Death and Hospital Admission in Adults after COVID-19 Vaccination: National Prospective Cohort Study. BMJ 2021, 374, n2244. [Google Scholar] [CrossRef]
- Agrawal, U.; Katikireddi, S.V.; McCowan, C.; Mulholland, R.H.; Azcoaga-Lorenzo, A.; Amele, S.; Fagbamigbe, A.F.; Vasileiou, E.; Grange, Z.; Shi, T.; et al. COVID-19 Hospital Admissions and Deaths after BNT162b2 and ChAdOx1 NCoV-19 Vaccinations in 2·57 Million People in Scotland (EAVE II): A Prospective Cohort Study. Lancet. Respir. Med. 2021, 9, 1439–1449. [Google Scholar] [CrossRef]
- Antonelli, M.; Penfold, R.S.; Merino, J.; Sudre, C.H.; Molteni, E.; Berry, S.; Canas, L.S.; Graham, M.S.; Klaser, K.; Modat, M.; et al. Risk Factors and Disease Profile of Post-Vaccination SARS-CoV-2 Infection in UK Users of the COVID Symptom Study App: A Prospective, Community-Based, Nested, Case-Control Study. Lancet. Infect. Dis. 2022, 22, 43–55. [Google Scholar] [CrossRef]
- Kemp, S.A.; Collier, D.A.; Datir, R.P.; Ferreira, I.A.T.M.; Gayed, S.; Jahun, A.; Hosmillo, M.; Rees-Spear, C.; Mlcochova, P.; Lumb, I.U.; et al. SARS-CoV-2 Evolution during Treatment of Chronic Infection. Nature 2021, 592, 277–282. [Google Scholar] [CrossRef] [PubMed]
- Langerbeins, P.; Hallek, M. COVID-19 in Patients with Hematologic Malignancy. Blood 2022, 140, 236–252. [Google Scholar] [CrossRef] [PubMed]
- Griffiths, E.A.; Segal, B.H. Immune Responses to COVID-19 Vaccines in Patients with Cancer: Promising Results and a Note of Caution. Cancer Cell 2021, 39, 1045–1047. [Google Scholar] [CrossRef] [PubMed]
- Greenberger, L.M.; Saltzman, L.A.; Senefeld, J.W.; Johnson, P.W.; DeGennaro, L.J.; Nichols, G.L. Antibody Response to SARS-CoV-2 Vaccines in Patients with Hematologic Malignancies. Cancer Cell 2021, 39, 1031–1033. [Google Scholar] [CrossRef] [PubMed]
- Nkolola, J.P.; Yu, J.; Wan, H.; Chang, A.; McMahan, K.; Anioke, T.; Jacob-Dolan, C.; Powers, O.; Ye, T.; Chandrashekar, A.; et al. A Bivalent SARS-CoV-2 Monoclonal Antibody Combination Does Not Affect the Immunogenicity of a Vector-Based COVID-19 Vaccine in Macaques. Sci. Transl. Med. 2022, 14, eabo6160. [Google Scholar] [CrossRef] [PubMed]
- Bar, D.Z.; Atkatsh, K.; Tavarez, U.; Erdos, M.R.; Gruenbaum, Y.; Collins, F.S. Biotinylation by Antibody Recognition—A Method for Proximity Labeling. Nat. Methods 2017, 15, 127–133. [Google Scholar] [CrossRef]
- Conte, W.L.; Golzarri-Arroyo, L. Tixagevimab and Cilgavimab (Evusheld) Boosts Antibody Levels to SARS-CoV-2 in Patients with Multiple Sclerosis on b-Cell Depleters. Mult. Scler. Relat. Disord. 2022, 63, 103905. [Google Scholar] [CrossRef] [PubMed]
- Soeroto, A.Y.; Yanto, T.A.; Kurniawan, A.; Hariyanto, T.I. Efficacy and Safety of Tixagevimab-Cilgavimab as Pre-Exposure Prophylaxis for COVID-19: A Systematic Review and Meta-Analysis. Rev. Med. Virol. 2023, 33, e2420. [Google Scholar] [CrossRef] [PubMed]
- Suribhatla, R.; Starkey, T.; Ionescu, M.C.; Pagliuca, A.; Richter, A.; Lee, L.Y.W. Systematic Review and Meta-Analysis of the Clinical Effectiveness of Tixagevimab/Cilgavimab for Prophylaxis of COVID-19 in Immunocompromised Patients. Br. J. Haematol. 2023, 201, 813–823. [Google Scholar] [CrossRef]
- Levin, M.J.; Ustianowski, A.; Thomas, S.; Templeton, A.; Yuan, Y.; Seegobin, S.; Houlihan, C.F.; Menendez-Perez, I.; Pollett, S.; Arends, R.H.; et al. AZD7442 (Tixagevimab/Cilgavimab) for Post-Exposure Prophylaxis of Symptomatic Coronavirus Disease 2019. Clin. Infect. Dis. 2023, 76, 1247–1256. [Google Scholar] [CrossRef] [PubMed]
- Iketani, S.; Liu, L.; Guo, Y.; Liu, L.; Chan, J.F.W.; Huang, Y.; Wang, M.; Luo, Y.; Yu, J.; Chu, H.; et al. Antibody Evasion Properties of SARS-CoV-2 Omicron Sublineages. Nature 2022, 604, 553–556. [Google Scholar] [CrossRef]
- VanBlargan, L.A.; Errico, J.M.; Halfmann, P.J.; Zost, S.J.; Crowe, J.E.; Purcell, L.A.; Kawaoka, Y.; Corti, D.; Fremont, D.H.; Diamond, M.S. An Infectious SARS-CoV-2 B.1.1.529 Omicron Virus Escapes Neutralization by Therapeutic Monoclonal Antibodies. Nat. Med. 2022, 28, 490–495. [Google Scholar] [CrossRef]
- Zhou, T.; Wang, L.; Misasi, J.; Pegu, A.; Zhang, Y.; Harris, D.R.; Olia, A.S.; Talana, C.A.; Yang, E.S.; Chen, M.; et al. Structural Basis for Potent Antibody Neutralization of SARS-CoV-2 Variants Including B.1.1.529. Science 2022, 376, eabn8897. [Google Scholar] [CrossRef]
- Tuekprakhon, A.; Nutalai, R.; Dijokaite-Guraliuc, A.; Zhou, D.; Ginn, H.M.; Selvaraj, M.; Liu, C.; Mentzer, A.J.; Supasa, P.; Duyvesteyn, H.M.E.; et al. Antibody Escape of SARS-CoV-2 Omicron BA.4 and BA.5 from Vaccine and BA.1 Serum. Cell 2022, 185, 2422–2433.e13. [Google Scholar] [CrossRef]
- Das, N.C.; Chakraborty, P.; Bayry, J.; Mukherjee, S. In Silico Analyses on the Comparative Potential of Therapeutic Human Monoclonal Antibodies Against Newly Emerged SARS-CoV-2 Variants Bearing Mutant Spike Protein. Front. Immunol. 2022, 12, 782506. [Google Scholar] [CrossRef]
- Das, N.C.; Chakraborty, P.; Bayry, J.; Mukherjee, S. Comparative Binding Ability of Human Monoclonal Antibodies against Omi. cron Variants of SARS-CoV-2: An In Silico Investigation. Antibodies 2023, 12, 17. [Google Scholar] [CrossRef]
- Perrella, A.; Bisogno, M.; D’Argenzio, A.; Trama, U.; Coscioni, E.; Orlando, V. Risk of SARS-CoV-2 Infection Breakthrough among the Non-Vaccinated and Vaccinated Population in Italy: A Real-World Evidence Study Based on Big Data. Healthcare 2022, 10, 1085. [Google Scholar] [CrossRef] [PubMed]
- Available online: https://www.ecdc.europa.eu/en/news-events/epidemiological-update-covid-19-transmission-eueea-sars-cov-2-variants-and-public (accessed on 1 August 2023).
Figure 1.
PCR levels according to remdesivir treatment (10 mg, 5 mg, or no treatment).
Table 1.
The demographic, laboratory, and clinical characteristics of the 42 patients with COVID-19 receiving tixagevimab–cilgavimab. Group A: patients affected by chronic disorders; Group B: patients affected by oncohematological disorders.
Table 1.
The demographic, laboratory, and clinical characteristics of the 42 patients with COVID-19 receiving tixagevimab–cilgavimab. Group A: patients affected by chronic disorders; Group B: patients affected by oncohematological disorders.
| A (N = 27) | B (N = 15) | Overall (N = 42) | |
|---|---|---|---|
| Age | |||
| Mean (SD) | 66.8 (18.2) | 69.9 (10.1) | 68.0 (15.6) |
| Median [Min, Max] | 71.0 [35.0, 98.0] | 73.0 [49.0, 88.0] | 71.0 [35.0, 98.0] |
| Missing | 2 (7.4%) | 0 (0%) | 2 (4.8%) |
| Gender | |||
| F | 15 (55.6%) | 6 (40.0%) | 21 (50.0%) |
| M | 12 (44.4%) | 9 (60.0%) | 21 (50.0%) |
| CRP | |||
| Mean (SD) | 16.3 (12.6) | 25.3 (30.9) | 19.3 (20.5) |
| Median [Min, Max] | 16.1 [0.0200, 44.9] | 13.2 [4.70, 94.0] | 14.8 [0.0200, 94.0] |
| Missing | 7 (25.9%) | 5 (33.3%) | 12 (28.6%) |
| IL6 | |||
| Mean (SD) | 176 (509) | 36.6 (28.6) | 116 (387) |
| Median [Min, Max] | 19.0 [3.20, 2030] | 27.7 [3.10, 96.3] | 22.9 [3.10, 2030] |
| Missing | 11 (40.7%) | 3 (20.0%) | 14 (33.3%) |
| D-Dimer | |||
| Mean (SD) | 1880 (1910) | 521 (477) | 1400 (1680) |
| Median [Min, Max] | 1030 [220, 6890] | 290 [103, 1470] | 776 [103, 6890] |
| Missing | 5 (18.5%) | 3 (20.0%) | 8 (19.0%) |
| Fibrinogen | |||
| Mean (SD) | 539 (254) | 493 (107) | 527 (221) |
| Median [Min, Max] | 554 [179, 1140] | 451 [387, 666] | 519 [179, 1140] |
| Missing | 14 (51.9%) | 10 (66.7%) | 24 (57.1%) |
| Procalcitonin | |||
| Mean (SD) | 2.57 (5.82) | 0.788 (2.54) | 1.92 (4.91) |
| Median [Min, Max] | 0.940 [0.0200, 26.6] | 0.0500 [0.0200, 8.86] | 0.140 [0.0200, 26.6] |
| Missing | 6 (22.2%) | 3 (20.0%) | 9 (21.4%) |
| IgA | |||
| Mean (SD) | 247 (124) | 124 (135) | 196 (140) |
| Median [Min, Max] | 235 [35.0, 519] | 78.5 [11.0, 495] | 156 [11.0, 519] |
| Missing | 10 (37.0%) | 3 (20.0%) | 13 (31.0%) |
| IgM | |||
| Mean (SD) | 125 (133) | 29.4 (11.5) | 95.5 (119) |
| Median [Min, Max] | 73.0 [29.0, 580] | 25.5 [21.0, 53.0] | 62.5 [21.0, 580] |
| Missing | 9 (33.3%) | 7 (46.7%) | 16 (38.1%) |
| IgG | |||
| Mean (SD) | 953 (413) | 631 (315) | 822 (404) |
| Median [Min, Max] | 991 [245, 1780] | 662 [149, 1290] | 771 [149, 1780] |
| Missing | 8 (29.6%) | 2 (13.3%) | 10 (23.8%) |
| Antiviral therapy | |||
| Remdesivir (10 mg) | 4 (14.8%) | 9 (60.0%) | 13 (31.0%) |
| Remdesivir (5 mg) | 7 (25.9%) | 3 (20.0%) | 10 (23.8%) |
| No treatment | 11 (40.7%) | 1 (6.7%) | 12 (28.6%) |
| Molnupiravir | 1 (3.7%) | 0 (0%) | 1 (2.4%) |
| Missing | 4 (14.8%) | 2 (13.3%) | 6 (14.3%) |
| COVID-19 vaccine | |||
| Not vaccinated | 12 (44.4%) | 4 (26.7%) | 16 (38.1%) |
| Two doses | 5 (18.5%) | 1 (3.7%) | 6 (14.3%) |
| Three doses | 8 (29.6%) | 10 (66.7%) | 18 (42.8%) |
| Four doses | 2 (7.4%) | - | 2 (4.8%) |
C-reactive protein (CRP); Interleukin-6 (IL6); Standard deviation (SD).
Table 2.
Pathologies of COVID-19 patients treated with tixagevimab–cilgavimab.
| Diseases | Group A | Group B |
|---|---|---|
| Cardiovascular disorders (n = 8) | ||
| Hypertensive cardiopathy | 3 | - |
| Atrial fibrillation | 2 | - |
| Arterial hypertension | 1 | - |
| Ischemic cardiopathy | 1 | - |
| Stroke | 1 | - |
| Degenerative diseases (n = 7) | ||
| Wagner syndrome | 1 | - |
| Alzheimer’s disease | 4 | - |
| Multiple sclerosis | 1 | - |
| Creutzfeldt-Jakob disease | 1 | - |
| Solid tumors (n = 5) | ||
| Lung carcinoma | 4 | - |
| Breast carcinoma | 1 | - |
| Infections (n = 4) | ||
| Cirrhosis HBV related | 1 | - |
| Cryptococcal meningitis | 1 | - |
| HIV | 2 | - |
| Autoimmune disorders (n = 3) | ||
| Autoimmune gastritis | 1 | - |
| Rheumatoid arthritis | 1 | - |
| Magic Syndrome | 1 | - |
| Other (n = 5) | ||
| Iatrogenic marrow aplasia | 1 | - |
| Chronic kidney disease | 4 | - |
| Oncohematological diseases (n = 15) | ||
| Chronic lymphocytic leukemia | - | 4 |
| Non-Hodgkin lymphoma | - | 11 |
Table 3.
HR chest CT scan of 42 patients with SARS-CoV-2 infection before treatment with tixagevimab-cilgavimab.
Table 3.
HR chest CT scan of 42 patients with SARS-CoV-2 infection before treatment with tixagevimab-cilgavimab.
| Group A |
| Patient 2: GGO + consolidation |
| Patient 3: 7/20 + acinetobacter multi-drug-resistant |
| Patient 4: 15/20 |
| Patient 7: 5/20 |
| Patient 14: GGO |
| Patient 15: GGO + effusion |
| Patient 16: 9/20 |
| Patient 18: GGO + thickening |
| Patient 19: GGO + effusion |
| Patient 20: Not available |
| Patient 21: GGO + thickening |
| Patient 23: no pneumonia |
| Patient 24: GGO |
| Patient 27: GGO + thickening |
| Patient 28: GGO |
| Patient 29: 13/20 |
| Patient 30: Not available |
| Patient 31: 7/20 |
| Patient 32: GGO + thickening |
| Patient 33: GGO |
| Patient 34: no pneumonia |
| Patient 35: Not available |
| Patients 36: Not available |
| Patient 37: GGO + thickening + effusion |
| Patient 38: Not available |
| Patient 39: GGO + thickening + effusion |
| Patient 40: GGO + thickening |
| Group B |
| Patient 1: GGO + Legionella infection |
| Patient 5: 13/20 |
| Patient 6: areoles |
| Patient 8: Not available |
| Patient 9: GGO |
| Patient 10: 18/25 |
| Patient 11: 12/20 |
| Patient 12: GGO |
| Patient 13: GGO + consolidation + effusion |
| Patient 17: GGO + thickening |
| Patient 22: cerebral edema, no pneumonia |
| Patient 25: GGO |
| Patient 26: GGO + consolidation |
| Patient 41: 4/20 + thickening |
| Patient 42: bilateral GGO |
Ground-glass opacity (GGO).
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Capoluongo, N.; Mascolo, A.; Bernardi, F.F.; Sarno, M.; Mattera, V.; di Flumeri, G.; Pustorino, B.; Spaterella, M.; Trama, U.; Capuano, A.; et al. Retrospective Analysis of a Real-Life Use of Tixagevimab–Cilgavimab plus SARS-CoV-2 Antivirals for Treatment of COVID-19. Pharmaceuticals 2023, 16, 1493. https://doi.org/10.3390/ph16101493
AMA Style
Capoluongo N, Mascolo A, Bernardi FF, Sarno M, Mattera V, di Flumeri G, Pustorino B, Spaterella M, Trama U, Capuano A, et al. Retrospective Analysis of a Real-Life Use of Tixagevimab–Cilgavimab plus SARS-CoV-2 Antivirals for Treatment of COVID-19. Pharmaceuticals. 2023; 16(10):1493. https://doi.org/10.3390/ph16101493
Chicago/Turabian StyleCapoluongo, Nicolina, Annamaria Mascolo, Francesca Futura Bernardi, Marina Sarno, Valentina Mattera, Giusy di Flumeri, Bruno Pustorino, Micaela Spaterella, Ugo Trama, Annalisa Capuano, and et al. 2023. "Retrospective Analysis of a Real-Life Use of Tixagevimab–Cilgavimab plus SARS-CoV-2 Antivirals for Treatment of COVID-19" Pharmaceuticals 16, no. 10: 1493. https://doi.org/10.3390/ph16101493
APA StyleCapoluongo, N., Mascolo, A., Bernardi, F. F., Sarno, M., Mattera, V., di Flumeri, G., Pustorino, B., Spaterella, M., Trama, U., Capuano, A., & Perrella, A. (2023). Retrospective Analysis of a Real-Life Use of Tixagevimab–Cilgavimab plus SARS-CoV-2 Antivirals for Treatment of COVID-19. Pharmaceuticals, 16(10), 1493. https://doi.org/10.3390/ph16101493
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