Outcomes of Bebtelovimab Therapy in Patients With Solid Organ Transplantation With Mild and Moderate COVID-19.

Solid organ transplant recipients (SOTRs) are at greater risk of poorer outcomes from coronavirus disease 2019 (COVID-19) as compared to the general population. Because of significant drug-drug interactions between nirmatrelvir-ritonavir and immunosuppressive agents as well as logistical challenges of outpatient administration of remdesivir, anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) monoclonal antibodies (mAbs) had been the mainstay of outpatient treatment of COVID-19 among SOTRs, with bamlanivimab, casirivimab-imdevimab, and sotrovimab having been previously granted emergency use authorization by the Food and Drug Administration (FDA). The challenge with the ongoing use of these monoclonal antibodies is the loss of efficacy against emerging variants of SARS-CoV-2. Bebtelovimab, which retained efficacy against early subvariants of Omicron, was granted emergency use authorization by the Food and Drug Administration when Omicron BA.4 and BA.5 became the predominant variants in the United States. However, the study based on which bebtelovimab was authorized by the FDA did not include SOTRs. The only available safety and efficacy data on these patients are from retrospective studies. In our retrospective analysis of 62 SOTRs who received bebtelovimab infusion between May 11, 2022, and October 11, 2022, 28 had a kidney transplant, 18 had a liver transplant, 10 had a heart transplant, and six had multi-organ transplants (liver/kidney: 4, heart/kidney: 2). None of the patients reported infusion-associated adverse reaction. Only one (1.6%) patient developed progression of COVID-19, requiring subsequent treatment with remdesivir, steroids, and oxygen supplementation. The rate of need for intensive care and death from COVID-19 during the 30-day follow-up period was 0%.

Covid-19 for the Primary Care Clinician: Current Recommendations—Don't Blink!

The chapter will discuss the outpatient assessment of the patient with possible Covid-19. The outpatient provider's tasks are the following: Appropriately identify those who are sick enough to warrant inpatient treatment. Recognize those patients who are at high risk for progression to severe Covid-19 based on risk factors and to guide them toward interruptive therapy with antibody infusion or inhibitors of viral replication. Advise about testing, treatment, isolation/quarantine, and follow-up care including vaccination guidelines. Patients with post-acute sequelae of Covid-19 (Long Covid) are also usually under the aegis of the primary care provider. The post-acute course of Covid-19 is described, and the assessment and management of these patients are discussed. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Initiating Home Parenteral Nutrition Therapy in a Patient at High Risk of Refeeding Syndrome After COVID-19 Infection

Background: An emerging finding about COVID-19 is its effect on nutrition and weight loss. The COVID-19 symptoms of fatigue, altered taste or smell, and lack of appetite are well known. But COVID-19 may have a more profound effect on clinical nutrition status. Two recent studies have identified that approximately one-third of ambulatory COVID-19 patients are at risk of experiencing weight loss >= 5% (Anker, et al;di Filippo, et al). The case study presented here discusses home start total parenteral nutrition (TPN) in a patient recently diagnosed with COVID-19 at high risk for refeeding syndrome. Method(s): N/A Results: Case Study: A 92-year-old patient was diagnosed with COVID-19 on June 8, 2022. Over the next week, she was hospitalized twice to manage symptoms of acute mental status changes, lethargy, aphasia, hypotension, and loss of appetite. The patient received nirmatrelvir/ritonavir, remdesivir, and bebtelovimab to treat COVID-19 at different times between June 9, 2022, and June 18, 2022. She remained COVID positive and continued to deteriorate clinically. On June 20, 2022, the patient began receiving 24/7 homecare, including intravenous (IV) fluids of dextrose 5% in normal saline (D5NS) 1000 mL daily for three days. She continued to experience loss of appetite and had no bowel movement for 3 days. On June 23, 2022, she was referred to this specialty infusion provider to initiate TPN therapy in the home setting. The patient's BMI was 18.2 kg/m2. Lab results revealed potassium 3.0 mmol/L, phosphate 1.6 mg/dL, and magnesium 1.6 mg/dL. High risk of refeeding syndrome was identified by the level of hypophosphatemia and hypokalemia. The specialty infusion provider's registered dietitian recommended to discontinue D5NS and begin NS with added potassium, phosphate, and magnesium. Thiamine 200mg daily was added to prevent Wernicke's encephalopathy. The patient's clinical status and lab values were monitored closely each day until her electrolyte levels stabilized (Table 1). Home TPN therapy was initiated on June 28, 2022, with <10% dextrose and 50% calorie requirement with 85% protein and 1.0 g/kg lipids. Three-day calorie count and nutrition education were performed four days post TPN initiation. Oral intake met only 25% of estimated needs. Over several days, theTPN formula was gradually increased to goal calories and the infusion cycle was slowly decreased. The following week, the patient's oral intake improved to 60%-75% of estimated needs. Her constipation resolved, and she showed improvement in functional status and mobility. Her appetite drastically improved when the TPN was cycled. Another three-day calorie count was performed when TPN calories reached goals. Oral intake demonstrated 100% estimated calorie and protein needs. TPN therapy was ultimately discontinued on July 14, 2022. As of September 30, 2022, the patient has stabilized at her pre-COVID weight of 45 kg with full recovery of appetite, function, and cognition. Discussion(s): The ASPEN Consensus Recommendations for Refeeding Syndrome (da Silva, et al) describe the repletion of electrolyte levels before introducing calories to prevent end-organ damage associated with refeeding syndrome (respiratory muscle dysfunction, decreased cardiac contractility, cardiac arrhythmias, and encephalopathy). Conclusion(s): This case study highlights the successful initiation of home TPN therapy in a patient at high risk of refeeding syndrome post COVID-19 infection. Although home start TPN and the risk of refeeding syndrome are not new concepts, they must be considered in the setting of COVID-19. Given the effects COVID-19 has on taste, smell, and appetite and the recent finding that one-third of patients with COVID infection may experience weight loss of >= 5%, nutrition support and patient education are vital components of overall patient care. (Figure Presented).

Update on COVID-19 Therapy in Pediatric Age.

With the extension of the COVID-19 pandemic, the large use of COVID-19 vaccines among adults and the emergence of SARS-CoV-2 variants means that the epidemiology of COVID-19 in pediatrics, particularly among younger children, has substantially changed. The prevalence of pediatric COVID-19 significantly increased, several severe cases among children were reported, and long-COVID in pediatric age was frequently observed. The main aim of this paper is to discuss which types of treatment are presently available for pediatric patients with COVID-19, which of them are authorized for the first years of life, and which are the most important limitations of COVID-19 therapy in pediatric age. Four different antivirals, remdesivir (RVD), the combination nirmatrelvir plus ritonavir (Paxlovid), molnupiravir (MPV), and the monoclonal antibody bebtelovimab (BEB), are presently approved or authorized for emergency use for COVID-19 treatment by most of the national health authorities, although with limitations according to the clinical relevance of disease and patient's characteristics. Analyses in the literature show that MPV cannot be used in pediatric age for the risk of adverse events regarding bone growth. The other antivirals can be used, at least in older children, and RDV can be used in all children except in neonates. However, careful research on pharmacokinetic and clinical data specifically collected in neonates and children are urgently needed for the appropriate management of pediatric COVID-19.

Antiviral Treatment of Coronavirus Disease-2019 Pneumonia.

Direct acting antivirals and monoclonal antibodies reduce morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 infection. Persons at higher risk for disease progression and hospitalized patients with coronavirus disease-2019 (COVID-19) benefit most from available therapies. Following an emphasis on inpatient treatment of COVID-19 during the early pandemic, several therapeutic options were developed for outpatients with COVID-19. Additional clinical trials and real-world studies are needed to keep pace with the evolving pandemic.

Deep Mutational Scanning to Predict Escape from Bebtelovimab in SARS-CoV-2 Omicron Subvariants.

The major concern with COVID-19 therapeutic monoclonal antibodies is the loss of efficacy against continuously emerging variants of SARS-CoV-2. To predict antibody efficacy against future Omicron subvariants, we conducted deep mutational scanning (DMS) encompassing all single mutations of the receptor-binding domain of the BA.2 strain utilizing an inverted infection assay with an ACE2-harboring virus and library spike-expressing cells. In the case of bebtelovimab, which preserves neutralization activity against BA.2 and BA.5, a broad range of amino acid substitutions at K444, V445, and G446, and some substitutions at P499 and T500, were indicated to achieve the antibody escape. Among subvariants with current rises in case numbers, BA2.75 with G446S partially evaded neutralization by bebtelovimab, while complete evasion was observed in XBB with V445P and BQ.1 with K444T. This is consistent with the DMS results against BA.2, highlighting the potential of DMS as a predictive tool for antibody escape.

Monoclonal antibodies for the treatment of COVID-19 infection in children.

INTRODUCTION: Monoclonal antibodies (mAbs) have been authorized for the treatment of COVID-19 in pediatric populations, however, there is a lack of evidence for their use in these populations. AREAS COVERED: We outline the evidence of mAbs for COVID-19, discuss their use in the treatment of COVID-19 infection for pediatric patients, and consider alternative treatment options and challenges to COVID-19 drug approvals. EXPERT OPINION: Limited evidence exists for the safety and efficacy of mAbs to treat COVID-19 in children as new variants emerge. In rare pediatric outpatient settings, such as profound immunodeficiency or severe pulmonary disease, the benefits of antiviral treatment for COVID-19 likely outweigh the relatively small risks. However, for the great majority of pediatric patients, mAb treatment is likely not indicated. Small molecule antiviral therapies are another potential treatment for COVID-19 in children in an outpatient setting, though neither mAb nor small molecule antiviral treatments have significant supporting evidence in children and developing a strong evidence base for these decisions will be challenging if not impractical. Ultimately, these decisions are likely to be made at the level of individual cases using expert opinion as the primary guiding principle.

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.

Convergent Evolution in SARS-CoV-2 Spike Creates a Variant Soup from Which New COVID-19 Waves Emerge.

The first 2 years of the COVID-19 pandemic were mainly characterized by recurrent mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 emerging independently across different variants of concern (Alpha, Beta, Gamma, and Delta). Such homoplasy is a marker of convergent evolution. Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and refocus antibody-mediated therapeutic efforts on polyclonal preparations that are less likely to allow for viral immune escape.

The Concomitant Use of Melatonin and Bebtelovimab as a Treatment Strategy for Omicron and Future Variants of Concern

The number of hospitalizations and fatalities brought on by COVID-19 has considerably grown since the World Health Organization proclaimed the disease as a global pandemic. New combination therapy is required to lessen the risk of COVID-19 progression during this time when the danger of transmission rises as new Omicron sub -variants arise. In this situation, it is critical to boost the immune system to combat highly inflammatory conditions like the cytokine storm brought on by COVID-19. Furthermore, if administered early in COVID-19 illness, monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 can minimize the chance of hospitalization. LY-CoV1404 (bebtelovimab) is one of these mAbs that has recently gained prominence due to its ability to effectively neutralize the SARS-CoV-2 virus and protect binding to spike proteins of several variants including B.1.1.529 (Omicron) and its subvariants (BA.1, BA.1.1, and BA.2) with various essential receptor binding domain (RBD) mutations. This brief review emphasizes the advantages of combining melatonin with bebtelovimab, which has been demonstrated to be the most effective SARS-CoV-2 neutralizing monoclonal antibody against the Omicron variant in the management of COVID-19. This study suggests that the combination therapy for Omicron sub -variants is beneficial and could be regarded as adjuvant therapy for COVID-19 disease.

Comparable Outcomes for Bebtelovimab and Ritonavir-Boosted Nirmatrelvir Treatment in High-Risk Patients With Coronavirus Disease-2019 During Severe Acute Respiratory Syndrome Coronavirus 2 BA.2 Omicron Epoch.

The effectiveness of bebtelovimab in real-world settings has not been assessed. In this retrospective cohort study of 3607 high-risk patients, bebtelovimab was used more commonly than nirmatrelvir-ritonavir for treatment of coronavirus disease 2019 (COVID-19) among older patients, immunosuppressed patients, and those with multiple comorbid conditions. Despite its use in patients with multiple comorbid conditions, the rate of progression to severe disease after bebtelovimab (1.4% [95% confidence interval, 1.2%-1.7%]) was not significantly different from that for nirmatrelvir-ritonavir treatment (1.2% [.8%-1.5%]). Our findings support the emergency use authorization of bebtelovimab for treatment of COVID-19 during the Omicron epoch dominated by BA.2 and subvariants.

Bebtelovimab for High-Risk Outpatients With Early COVID-19 in a Large US Health System.

There are limited data for the clinical efficacy of bebtelovimab in preventing severe coronavirus disease 2019. Among outpatients unable to take nirmatrelvir-ritonavir at a large health system, 10 of 377 (2.7%) patients who received bebtelovimab and 17 of 377 (4.5%) matched untreated patients were hospitalized or died. The 43% observed risk reduction with bebtelovimab was not statistically significant (P = 0.14).