EXPERIENCE IN THE USE OF NEUTRALIZING MONOCLONAL ANTIBODIES IN KIDNEY TRANSPLANT RECIPIENTS WITH COVID-19.

Therapy with neutralizing monoclonal antibodies (mAbs) is particularly relevant during COVID-19 outbreaks in patients at high risk of severe disease, including kidney transplant recipients (KTRs). Objective(s): to evaluate the efficacy and safety of neutralizing mAbs in KTRs with mild to moderate COVID-19. Materials and methods. The retrospective study included 99 KTRs who received inpatient treatment for COVID-19 between September 1 and December 31, 2021. Patients were 52.0 +/- 11.5 years old (M, 47.5%). Bamlanivimab/etesevimab combination drug at a dose of 700/1400 mg was used as mAbs. To evaluate the efficacy of mAbs therapy, two groups of patients were identified. Group 1 consisted of 33 KTRs who received mAbs as one of the therapy components, while group 2 consisted of 66 patients who received no mAbs. Discharge from the hospital or death was considered as the endpoint of follow-up. Results. In group 1, after the use of mAb, progression of pulmonary process was observed less frequently than in the control group with CT1-2 transformation to CT3-4 (9.1% vs. 30.3%, respectively, p < 0.01). Group 1 KTRs differed significantly from group 2 - lower need for ICU and ventilator care (6.1% vs. 27.3% and 3% vs. 19.8%, respectively). The groups were comparable by sex, age, body mass index, Charlson Comorbidity Index (CCI) and time after kidney transplant (KTx) at the onset of the disease and by aseline blood biochemistry parameter values at the time of hospitalization. Only C-reactive protein (CRP) and fibrinogen values were higher in the non-mAbs patients who were hospitalized later in the course of the disease (7.7 +/- 3.2 days versus 4.6 +/- 1.6 days in group 1, p < 0.001). The frequency of prescription of other therapies did not differ between the compared groups. Use of mAbs significantly reduced mortality from 19.7% in KTRs in group 2 to 3% in group 1 without adverse effect on graft function. Conclusion. The use of mAbs therapy in the early stages of COVID-19 in KTRs is safe, it prevents severe COVID-19, and reduces the incidence of adverse outcomes.Copyright © 2023 Russian Transplant Society. All rights reserved.

The use of neutralizing monoclonal antibodies against SARS-CoV-2 in hemodialysis patients

Patients with end-stage kidney disease undergoing hemodialysis have one of the highest COVID-19 mortality rates. The use of innovative methods capable of optimizing their treatment outcomes is important for clinical practice. Aims - to investigate the efficacy and safety of neutralizing monoclonal antibodies in COVID-19 patients treated with hemodialysis. Material and methods. We conducted a retrospective controlled single-center study with 102 COVID-19 patients on maintenance hemodialysis involved (M: 67;65.7%;W: 35;34.3%), aged 57.2+/-15.3 years. PCR-detected SARS-CoV-2 infection was diagnosed in all patients. Neutralizing monoclonal antibodies were administered to 69 patients, who formed the study group (group 1). The control group included 33 patients (group 2). The combination of bamlanevimab and etesevimab was the most frequent therapy used (in 59 patients). Results. In the course of the disease, group 1 patients, compared to those of group 2, had statistically significantly higher blood oxygen saturation values (94.2+/-5.7 vs 89.8+/-10.7);they required less frequent oxygen support (29.0 vs 54.5%) and ICU treatment (18.8 vs 48.5%), respectively. Fatal outcomes occurred in 4 (5.8%) of 69 patients who received neutralizing antibodies and in 6 (18.2%) of 33 patients who did not receive the therapy, p<0.05. Except for one patient, all other patients in both groups developed an unfavorable outcome due to progressive lung damage. However, only 4 of 6 (2/3) patients with progressive lung damage died in group 1, whereas the similar course of the disease proved fatal in all cases in group 2. Conclusion. The use of neutralizing monoclonal antibodies in hemodialysis patients is safe and effective when the drugs are administered early, the pulmonary process progression is insignificant and dominant SARSCoV-2 variants are sensitive to them.Copyright © 2022 Tomsk Polytechnic University, Publishing House. All rights reserved.

Evaluation of adverse events of bamlanivimab, bamlanivimab/etesevimab used for COVID-19 based on FAERS database.

BACKGROUND: We study the adverse events (AEs) of bamlanivimab (BAM), bamlanivimab/etesevimab (BAM/ETE) to alert risk factors during coronavirus disease 2019 (COVID-19) treatment and provide references for drug safety. RESEARCH DESIGN AND METHODS: Extract AEs from the COVID-19 Emergency Use Authorization (EUA) FDA Adverse Event Reporting System (FAERS) Public Dashboard. Disproportionality analysis was performed to discover the potential risks of BAM and BAM/ETE. RESULTS: With COVID-19 drugs as the research background, the number of BAM/ETE signals is about half that of BAM, and 80% of signals overlap with BAM. Signals such as atrial fibrillation, tachycardia, and confusional state are present in BAM but not in BAM/ETE. With BAM and BAM/ETE as the research background, potential safety signals of BAM/ETE such as acute respiratory failure, hypersensitivity, and infusion-related reaction require long-term observation, especially acute respiratory failure which is not in the label. CONCLUSIONS: The AEs report on this study confirm most of the label information of BAM and BAM/ETE. BAM/ETE is relatively safe, while the risk signals such as acute respiratory failure and infusion-related reaction require to be monitored.

Effects of bamlanivimab alone or in combination with etesevimab on subsequent hospitalization and mortality in outpatients with COVID-19: a systematic review and meta-analysis.

Background: Coronavirus disease 2019 (COVID-19) has caused an enormous loss of life worldwide. The spike protein of the severe acute respiratory syndrome coronavirus 2 is the cause of its virulence. Bamlanivimab, a recombinant monoclonal antibody, has been used alone or in combination with etesevimab to provide passive immunity and improve clinical outcomes. A systematic review and meta-analysis was conducted to investigate the therapeutic effects of bamlanivimab with or without etesevimab (BAM/ETE) treatment. Methods: Our study was registered in PROSPERO (registry number CRD42021270206). We searched the following electronic databases, without language restrictions, until January 2023: PubMed, Embase, medRxiv, and the Cochrane database. A systematic review and meta-analysis was conducted based on the search results. Results: Eighteen publications with a total of 28,577 patients were identified. Non-hospitalized patients given bamlanivimab with or without etesevimab had a significantly lower risk of subsequent hospitalization (18 trials, odds ratio (OR): 0.37, 95% confidence interval (CI): [0.29-0.49], I2: 69%; p < 0.01) and mortality (15 trials, OR: 0.27, 95% CI [0.17-0.43], I2: 0%; p = 0.85). Bamlanivimab monotherapy also reduced the subsequent risk of hospitalization (16 trials, OR: 0.43, 95% CI [0.34-0.54], I2: 57%; p = 0.01) and mortality (14 trials, OR: 0.28, 95% CI [0.17-0.46], I2: 0%; p = 0.9). Adverse events from these medications were uncommon and tolerable. Conclusions: In this meta-analysis, we found the use of bamlanivimab with or without etesevimab contributed to a significantly-reduced risk of subsequent hospitalization and mortality in non-hospitalized COVID-19 patients. However, resistance to monoclonal antibodies was observed in COVID-19 variants, resulting in the halting of the clinical use of BAM/ETE. Clinicians' experiences with BAM/ETE indicate the importance of genomic surveillance. BAM/ETE may be repurposed as a potential component of a cocktail regimen in treating future COVID variants.

Emergency Department-based monoclonal antibody therapy for patients with mild to moderate COVID-19

Objectives: To describe the implementation of an ED-based program to offer monoclonal antibody therapy to patients with mild-moderate COVID-19 disease. Background(s): Monoclonal antibody therapy (MOAB) has recently emerged as a treatment for mild to moderate COVID-19, potentially preventing those with underlying conditions from progressing to severe illness and hospitalization. Further, as EDs are the primary point of health care access for many at-risk individuals, offering MOAB in the ED may increase availability of treatment options for patients from traditionally underserved communities. Method(s): A retrospective chart review was conducted of patients 12 years and above who received treatment in our urban, academic, community hospital. Patients 12 years and older were screened for eligibility during ED visits or during follow-up calls providing positive test results. Staff was trained on specific consent, infusion, monitoring, and documentation procedures adherent to MOAB administration under the Emergency Use Authorization. Patients were contacted following MOAB and queried regarding symptom resolution and healthcare utilization. Data regarding patient demographics, ED course, and 7-day unscheduled visits were collected. Result(s): In this ongoing quality improvement initiative, from December 2020 to March 2021, there were 26,229 patient encounters at the pilot ED site. 84 patients were provided MOAB, 87% Bamlanivimab and 13% Bamlanivimab/Etesevimab. Patients had a mean age of 52.3 years (SD 24.4);21% were 12-17 years of age and 37% were >65 years old. 52% were male. 33% self-reported as Caucasian, 19% Black, 18% Asian/Pacific Islander, 21% as other, and 9% were unknown. 17% identified as Latinx. 19% of patients were insured by Medicaid, 36% Medicare, 39% commercially insured, and 6% were uninsured. Patients had symptoms a median of 3 days prior to MOAB. After age (46%), the most commonly reported eligibility criteria was obesity (20%), followed by hypertension (11%) and immunocompromised state (11%). 74% of infusions were administered during nights and weekends. No infusion reactions occurred. 8% returned to an ED within 7 days of MOAB, 5% were hospitalized. No patients required ICU admission or died. Conclusion(s): ED-based MOAB has been safely implemented and may be an effective treatment for patients with mild to moderate COVID-19. Health-system wide expansion of this program may provide opportunities to offer this life-saving therapy to underserved populations with poor access to care.Copyright © 2023

Endogenous antibody response to SARS-CoV-2 in patients who received monoclonal antibodies against COVID-19: A systematic review

Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.Copyright © 2022

Monoclonal antibody infusion reaction with bamlanivimab and etesevimab in a 5-year-old male with coronavirus disease 2019: a case report.

BACKGROUND: Bamlanivimab and etesevimab had been granted emergency use authorization in children under 12 years who are at risk of progression from mild/moderate coronavirus disease 2019 to severe disease and hospitalization. CASE REPORT: We report on a 5-year-old white male with preexisting conditions, predisposing him to severe disease, who developed hypoxia and flushing 3 minutes into his infusion, thus meeting the criteria for anaphylaxis. CONCLUSIONS: We believe this patient developed either an immunoglobulin E-mediated anaphylactic or a non-immunoglobulin E-mediated anaphylactoid reaction to bamlanivimab and etesevimab, which is an important possibility to consider on administration.

Monoclonal Antibody Use for Coronavirus Disease 2019 in Pediatric Patients: A Multicenter Retrospective Study.

Monoclonal antibodies for COVID-19 are authorized in high-risk patients aged ≥12 years, but evidence in pediatric patients is limited. In our cohort of 142 patients treated at seven pediatric hospitals between 12/1/20 and 7/31/21, 9% developed adverse events, 6% were admitted for COVID-19 within 30 days, and none received ventilatory support or died.

Drug repurposing against SARS-CoV-2: A review based on principal reports

Despite the measures taken and the molecular advances for the development of new agents for the control of SARS-CoV-2 infection, there is still insufficient development of an effective treatment. The objective of the review was to de-scribe the clinical studies and reported articles on drugs used as possible therapeutic agents for COVID-19 and the main conclusions on their reuse. A non-systematic review through PubMed, ScienceDirect, and clinical trials at ClinicalTrials. gov on original articles and case report in English and Span-ish that will report information on COVID-19 treatment and its main conclusions. Articles that were not relevant or that did not mention updated information to that reported in other articles were excluded. A total of 99 bibliographic references were included. COVID-19 appears as a multisystemic disease with variable clinical symptoms. Since no specific treatment is yet known, multiple drugs have been proposed that attack the different pathways of SARS-CoV-2. For severe disease in patients who require hospitalization and oxygen support, the use of remdesivir, dexamethasone, or tocilizumab is recommended if there are patient conditions that apply to use them. The use of ivermectin, colchicine, lopinavir/ritonavir, hydroxy-chloroquine, and chloroquine have not reported benefits that surpass adverse effects.

Monoclonal Antibody Therapy for COVID-19: A Retrospective Observational Study at a Regional Hospital.

BACKGROUND: Monoclonal antibodies represent one option for treatment of COVID-19 early after infection. Although large clinical trials have been successfully conducted, real world data are needed to obtain a realistic assessment of the assumed effect on hospitalization rates. METHODS: For this retrospective, observational study, clinical data were collected in 2021 from outpatients (402) as well as hospitalized patients (350) receiving monoclonal antibodies Bamlanivimab, Casirivimab/Imdevimab or Etesevimab/Bamlanivimab. These data were compared with data from a control group of patients not receiving antibodies because admission to the hospital was too late for this therapy. RESULTS: Both groups showed a comparable spectrum of risk factors. Due to the late hospitalization of control patients, a higher frequency of severe symptoms, such as fever, dyspnea, syncope and lower viral load, were observed. CRP and leukocytes counts were also higher in the untreated group. Most importantly, hospitalization time was significantly shorter and the number of deaths was also lower in the treated group. CONCLUSIONS: Apparently, the application of anti-SARS-CoV-2 antibodies reduced the work load of our hospital as shown by the shorter hospitalization time and lower number of COVID-19-related deaths.

Pharmacological treatment of COVID-19: an opinion paper.

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.

Evolution of Anti-SARS-CoV-2 Therapeutic Antibodies.

Since the first COVID-19 reports back in December of 2019, this viral infection caused by SARS-CoV-2 has claimed millions of lives. To control the COVID-19 pandemic, the Food and Drug Administration (FDA) and/or European Agency of Medicines (EMA) have granted Emergency Use Authorization (EUA) to nine therapeutic antibodies. Nonetheless, the natural evolution of SARS-CoV-2 has generated numerous variants of concern (VOCs) that have challenged the efficacy of the EUA antibodies. Here, we review the most relevant characteristics of these therapeutic antibodies, including timeline of approval, neutralization profile against the VOCs, selection methods of their variable regions, somatic mutations, HCDR3 and LCDR3 features, isotype, Fc modifications used in the therapeutic format, and epitope recognized on the receptor-binding domain (RBD) of SARS-CoV-2. One of the conclusions of the review is that the EUA therapeutic antibodies that still retain efficacy against new VOCs bind an epitope formed by conserved residues that seem to be evolutionarily conserved as thus, critical for the RBD:hACE-2 interaction. The information reviewed here should help to design new and more efficacious antibodies to prevent and/or treat COVID-19, as well as other infectious diseases.

Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern.

Background: Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies according to the variant of concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. Methods: The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of early treatments with bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with mild-to-moderate SARS-CoV-2 infection. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was coronavirus disease 2019 (COVID-19) progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. Results: Overall, 319 patients were included. Among 141 patients infected with Delta, no COVID-19 progression was recorded, and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.90). Among 170 patients infected with Omicron (80.6% BA.1 and 19.4% BA.1.1), two COVID-19 progressions were recorded, both in the bamlanivimab/etesevimab group, and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared with the bamlanivimab/etesevimab and casirivimab/imdevimab groups (HR 0.53 and HR 0.45, 95% CI 0.36-0.77 and 95% CI 0.30-0.67, p<0.01). Conclusions: Our data suggest that, among adult outpatients with mild-to-moderate SARS-CoV-2 infection due to Omicron BA.1 and BA.1.1, early treatment with sotrovimab reduces the time to recovery compared with casirivimab/imdevimab and bamlanivimab/etesevimab. In the same population, early treatment with casirivimab/imdevimab may maintain a role in preventing COVID-19 progression. The generalisability of trial results is substantially limited by the early discontinuation of the trial and firm conclusions cannot be drawn. Funding: This trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 101016167. Clinical trial number: NCT05205759.

Lung Ultrasound Is Useful for Evaluating Lung Damage in COVID-19 Patients Treated with Bamlanivimab and Etesevimab: A Single-Center Pilot Study.

Background and Objectives: COVID-19 induces massive systemic inflammation. Researchers have spent much time and effort finding an excellent and rapid image tool to evaluate COVID-19 patients. Since the pandemic's beginning, lung ultrasound (LUS) has been identified for this purpose. Monoclonal antibodies (mAb) were used to treat mild patients and prevent respiratory disease worsening. Materials and Methods: We evaluated 15 Caucasian patients with mild COVID-19 who did not require home oxygen, treated with Bamlanivimab and Etesevimab (Group 1). A molecular nose-throat swab test confirmed the diagnosis. All were office patients, and nobody was affected by respiratory failure. They were admitted to receive the single-day infusion of mAb treatment in agreement with the Italian Drug Agency (AIFA) rules for approval. LUS was performed before the drug administration (T0) and after three months (T1). We compared LUS at T1 in other outpatients who came for follow-up and were overlapping at the time of diagnosis for admittance criteria to receive mAb (Group 2). Results: Our COVID-19 outpatients reported no hospitalization in a follow-up visit after recovery. All patients became SARS-CoV-2 negative within one month since T0. LUS score at T0 was 8.23 ± 6.46. At T1 we found a significant decrease in Group 1 LUS score (5.18 ± 4.74; p < 0.05). We also found a significant decrease in the LUS score of Group 1 T1 compared to Group2 T1 (5.18 ± 4.74 vs 7.82 ± 5.21; p < 0.05). Conclusion: Early treatment of the SARS-CoV-2 virus effectively achieves a better recovery from disease and reduces lung involvement after three months as evaluated with LUS. Despite extrapolation to the general population may be done with caution, based on our data this ultrasound method is also effective for evaluating and following lung involvement in COVID-19 patients.

A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection.

Antiviral therapies are integral in the fight against SARS-CoV-2 (i.e. severe acute respiratory syndrome coronavirus 2), the causative agent of COVID-19. Antiviral therapeutics can be divided into categories based on how they combat the virus, including viral entry into the host cell, viral replication, protein trafficking, post-translational processing, and immune response regulation. Drugs that target how the virus enters the cell include: Evusheld, REGEN-COV, bamlanivimab and etesevimab, bebtelovimab, sotrovimab, Arbidol, nitazoxanide, and chloroquine. Drugs that prevent the virus from replicating include: Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, and Kaletra. Drugs that interfere with protein trafficking and post-translational processing include nitazoxanide and ivermectin. Lastly, drugs that target immune response regulation include interferons and the use of anti-inflammatory drugs such as dexamethasone. Antiviral therapies offer an alternative solution for those unable or unwilling to be vaccinated and are a vital weapon in the battle against the global pandemic. Learning more about these therapies helps raise awareness in the general population about the options available to them with respect to aiding in the reduction of the severity of COVID-19 infection. In this 'A Guide To' article, we provide an in-depth insight into the development of antiviral therapeutics against SARS-CoV-2 and their ability to help fight COVID-19.

THE PANDEMIC'S FUNGAL REVENGE: COVID-19 ASSOCIATED PULMONARY ASPERGILLOSIS (CAPA)

SESSION TITLE: Pathologies of the Post-COVID-19 World SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Since the start of the COVID-19 pandemic, COVID-19 Associated Pulmonary Aspergillosis (CAPA) has been on the rise. This superinfection, if not properly identified and treated, has shown to increase mortality up to 67% in COVID-19 patients. We are presenting a late presentation of CAPA after 4-month of COVID-19 infection and treated successfully. CASE PRESENTATION: A 57-year-old female patient with past medical history type 2 diabetes mellitus, hypertension and cardiomyopathy in addition to COVID-19 pneumonia treated for months ago with azithromycin, Bamlanivimab/Etesevimab, and Dexamethasone who presents to the hospital with massive hemoptysis and shortness of breath requiring intubation and mechanical ventilation. There was no reported history of recent travel, smoking, alcohol, or illicit drug use. Physical exam showed diminished lung sounds at the right lower lobe. Her labs showed mild leukocytosis, lactic acidosis and negative COVID-19 PCR. CT scan showed dense consolidation on right lower lobe consistent with lobar pneumonia and centrilobular ground glass opacities in the right upper lobe. Bronchoscopy showed complete obstruction of right bronchus intermedius and minimal blood clots in LLL. BAL respiratory culture, fungal smear, acid fast bacilli were non-diagnostic and negative for malignancy. Patient continued to have hemoptysis and bronchoscopy was repeated with negative cytology and cultures. The patient continued to have hemoptysis and she was transferred to tertiary center were bronchoscopy was repeated and confirmed right bronchus intermedius stenosis, blood clots, and suspicious right mainstem nodules with mucosal lesion. Biopsy results from bronchoscopy came back positive for the morphologic features of Aspergillus species. The patient was started on voriconazole with significant improvement in her symptoms. DISCUSSION: The recent literature of COVID-19 suggest association between COVID infection and invasive pulmonary Aspergillosis. COVID-19 virus causes damage in the airway epithelium and enable aspergillus to invade the pulmonary tract leading to serious infections with Aspergillus. It has also been known that Aspergillus infections are associated with diabetes mellitus and immune suppression which can be precipitated by steroid use and other treatments for COVID-19 infection like IL-6 inhibitors. Here in our patient with help of tissue biopsy we diagnosed CAPA, started treatment early and treated successfully. CONCLUSIONS: CAPA can be difficult to diagnose and needs high index of suspicion in the appropriate clinical scenario when dealing with post COVID respiratory complaints like hemoptysis. Bronchoalveolar lavage alone without tissue biopsy might miss the diagnosis in the context of invasive aspergillosis like the scenario we observed in our case. Doing tissue biopsy through bronchoscopy might add more clinical benefit when Aspergillus infections are suspected. Reference #1: Chih-Cheng Lai, Weng-Liang Yu, COVID-19 associated with pulmonary aspergillosis: A literature review, https://doi.org/10.1016/j.jmii.2020.09.004 DISCLOSURES: No relevant relationships by Haytham Adada No relevant relationships by Mahmoud Amarna No relevant relationships by Rishika Bajaj No relevant relationships by Camelia Chirculescu No relevant relationships by Sonia Dogra No relevant relationships by Azad Patel

Dual Monoclonal Antibodies on Sars-Cov-2 Alpha and Delta Variants: Clinical and Virological Efficacy.

Monoclonal antibodies (MAbs) targeting the Spike glycoprotein of SARS-CoV-2 is a key strategy to prevent severe COVID-19. Here, the efficacy of two monoclonal antibody bitherapies against SARS-CoV-2 was assessed on 92 patients at high risk of severe COVID-19 between March and October 2021 (Bichat-Claude Bernard Hospital, Paris, France). Nine patients died despite appropriate management. From 14 days following treatment initiation, we observed a slower viral load decay for patients treated with the bitherapy Bamlanivimab/Etsevimab compared to the Casirivimab/Imdevimab association therapy (P = 0.045). The emergence of several mutations on the Spike protein known to diminish antiviral efficacy was observed from 1 to 3 weeks after infusion. The Q493R mutation was frequently selected, located in a region of joint structural overlap by Bamlanivimab/Etsevimab antibodies. Despite that this study was done on former SARS-CoV-2 variants (Alpha and Delta), the results provide new insights into resistance mechanisms in SARS-CoV-2 antibodies neutralization escape and should be considered for current and novel variants. IMPORTANCE Monoclonal antibody bitherapies (MAbs) are commonly prescribed to treat severe SARS-CoV-2-positive patients, and the rapid growth of resistance mutation emergence is alarming globally. To explore this issue, we conducted both clinical and genomic analyses of SARS-CoV-2 in a series of patients treated in 2021. We first noticed that the two dual therapies prescribed during the study had different kinetics of viral load decay. Rapidly after initiation of the treatments, resistance mutations emerged in the interface between the MAbs and the target Spike glycoprotein, demonstrating the importance to continuously screen the viral genome during treatment course. Taken together, the results highlight that viral mutations may emerge under selective pressure, conferring a putative competitive advantage, and could rapidly spread, as observed for the Omicron variant.

SARS-CoV-2 coronavirus: Pathogenesis, Pharmacotherapy and Treatment with Monoclonal Antibodies

The COVID-19 disease first appeared in 2019 and has spread widely. The SARS-CoV-2 virus that causes it is a member of the coronavirus family and is rapidly transmitted, primarily by droplets. In the disease, there is increased secretion of pro-inflammatory cytokines. There are several diagnostic methods, with RNA-qPCR-based detection being the most important and reliable. Vaccination is required to prevent the disease. COVID-19 Vaccines use viral vectors, the mRNA of the virus, certain subunits of the virus such as spike protein (S), and the inactivated virus itself. Some drugs that have been used for other diseases can be used for treatment, but one promising avenue is the use of monoclonal antibodies. Neutralizing monoclonal antibodies primarily target the SARS-CoV-2 spike protein (S). Most monoclonal antibodies have been identified to recognize the S1 fragment of SARS-CoV2. The receptor binding domain (RBD) in the S1 subunit is the most important target for SARS-CoV-2 because monoclonal antibodies can block the interaction of RBD and ACE2 of the receptor. If anti-SARSCoV-2 mAbs are used, treatment should be initiated as soon as possible after receiving a positive diagnostic result and within 10 days of symptom onset. Currently, three monoclonal antibody products are approved for COVID-19, namely bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab. Understanding their pharmacokinetics and pharmacodynamics is essential for selecting the right antibody, dose and treatment regimen for the target indication. In this context, this study provides a comprehensive overview of the pharmacology, pharmacokinetics and dosing regimens of monoclonal antibodies against SARS-CoV-2 virus.

Prescription of Anti-Spike Monoclonal Antibodies in COVID-19 Patients with Resistant SARS-CoV-2 Variants in Italy.

Anti-Spike monoclonal antibodies have been considered a promising approach to COVID-19 therapy. Unfortunately, the advent of resistant lineages jeopardized their effectiveness and prompted limitations in their clinical use. Change in the dominant variant can be fast to such an extent that, in the absence of timely medical education, prescribers can keep using these drugs for relatively long periods even in patients with resistant variants. Therefore, many patients could have been exposed to drugs with unlikely benefits and probable risks. We show here that about 20% of bamlanivimab+etesevimab, 30% of casirivimab+imdevimab, and 30% of sotrovimab courses were administered in Italy during periods in which a fully resistant variant was dominant. Additionally, for monoclonal antibody cocktails, the vast majority of usage occurred against variants for which one of the mAbs within the cocktail was ineffective. Given the high costs of these drugs and their potential side effects, it would be important to consider a frequent review of the appropriateness of these drugs and timely communication when the benefit/risk balance is no longer favorable.