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Background: COVID-19 pandemic still pose a substantial threat worldwide despite increasing vaccine availability. Patients with haematological malignancies have been shown to have increased risk of contracting COVID-19 and are more susceptible to develop severe illness from SARS-CoV- 2 infection. The immune response to vaccines is impaired in patients with haematological malignancy due to underlying disease or antineoplastic therapies. The monoclonal-antibody combination, Evusheld is composed of tixagevimab and cilgavimab, two neutralising antibodies against SARS-CoV- 2. It has been shown to be safe and have efficacy for the prevention of COVID-19. Our aim of study is to describe the incidence and outcome of breakthrough COVID-19 infection among patients who received Evusheld in our centre and analyse the factors that possibly increase the risk of breakthrough infection. Material(s) and Method(s): A retrospective review of all adult patients with haematological malignancy who received tixagevimab/ cilgavimab 150/150 mg injection in Hospital Pulau Pinang from 1 July 2022 to 31 August 2022 with a follow-up period to 30 November 2022 was conducted. Demographic data, clinical characteristics and outcome will be retrieved from patient's medical records. Data were analysed using Statistical Package for Social Sciences software (version 21.0). Result(s): A total of 96 patients (50 males and 46 females) received tixagevimab/cilgavimab injection during the study period with a median age of 61 years (range 19-82). Majority of them were diagnosed with multiple myeloma (42.7%), followed by lymphoma (33.3%) and leukaemia (24%). One third of them had history of therapy with monoclonal antibody and 20% had haematopoietic stem cell transplantation. No major adverse effects of tixagevimab/cilgavimab injection were noted among the study population. Of the 12 patients (12.5%) who had COVID-19 infection, all of them had mild infection;three were asymptomatic and six patients received Paxlovid antiviral therapy. The median time from tixagevimab/cilgavimab to the onset of COVID-19 infection was 35 days (range 5-97 days). The mean age of patients with breakthrough COVID-19 infection were older compared to those without breakthrough infection but was not statistically significant. The incidence of breakthrough COVID-19 infection was not affected by type of haematological malignancy, history of monoclonal antibody therapy or COVID-19 vaccination. Discussion and Conclusion(s): Our findings showed that tixagevimab/cilgavimab was safe and effective in preventing COVID-19- related morbidity and mortality among patients with haematological malignancy during the study period. However, the limitation is the lack of access to whole genome sequencing for detection of resistant variants for breakthrough infections.
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Evusheld is a combination injection of tixagevimab/cilgavimab for pre-exposure COVID-19 prophylaxis and was made available to UK private clinics from October 2022. NICE review is ongoing. Whilst efficacy analysis of Evusheld has focused on the risk-reduction of contracting COVID-19, anecdotal reports suggest additional psychological benefits from Evusheld, although supportive objective data are lacking. In this study, we used 4 well-established psychological health questionnaires to assess different psychological parameters (EQ5D-3 L quality of life (QoL) score, DSM5 Agoraphobia score, Duke's Social Support Index (DSSI) and the hospital anxiety and depression score (HADS)) in blood cancer patients treated with Evusheld at the Genesis Care (GC) Clinic, Cambridge. Patient data (pre-and post-Evusheld) were compared with a control group of GC blood cancer patients who had not received Evusheld. The study was approved by GC and all patients had consented to email contact. Questionnaire replies were anonymised and free-text comments were invited. Questionnaires were completed by 29/40 Evusheld and 54/100 control patients. With EQ5D, Evusheld did not impact mobility, self-care and pain/discomfort scores and patient/ control groups scored at similar levels. EQ5D scores for 'usual activities' and 'anxiety/depression' improved post-Evusheld (patients reporting 'normal activities' increased from 52% to 76% (control = 78%);patients reporting 'no anxiety/ depression' increased from 45% to 66% (control = 65%)). The mean global EQ5D QoL score improved post-Evusheld [69.4% to 72.9% (control = 75.7%)]. With the DSM5 agoraphobia score, Evusheld treatment improved agoraphobia parameters, reducing the mean score from 15.7 to 5.1 (control = 3.7;max = 40) with certain striking changes;72% of pretreatment patients avoided crowded situations all of/most of the time, reducing to 14% post-Evusheld (control = 11%). The DSSI score assessed social/work interactions with external household contacts and post-Evusheld the mean number of interactions over 3 weeks increased from 1.48 to 3.37 (control = 3.77). Pre-Evusheld, 52% of patients had no interactions outside their household, dropping to 20% in the 3 weeks post-Evusheld (control = 17%). Using the HADS 14-point analysis of depression and anxiety revealed on average that each parameter was 25.3% 'significantly improved' and 25.4% 'a little improved' post-Evusheld. Accepting limitations of a small study and potential biases associated with a self-funding patient cohort, Evusheld treatment broadly improved all psychological scores assessed. Free-text comments clearly indicate that Evusheld had a major positive impact on QoL/social mobility for specific patients. The Evusheld patients had higher baseline scores for social isolation, anxiety, depression and agoraphobia compared with control patients, yet Evusheld treatment appeared to improve these parameters to a level similar to control patients.
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The problem of prevention of coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory rheumatic diseases (IMRD) remains highly relevant. The presence of IRD is associated with a high risk of disease and severe course of COVID-19 during immunosuppressive treatment, primarily anti-B cell therapy with rituximab (RTX), and a low level of post-vaccination response in such patients. A new strategy for the prevention and treatment of COVID-19 are virus-neutralizing monoclonal antibodies to coronavirus;currently, combined long-acting monoclonal antibodies tixagevimab and cilgavimab (Evusheld) are registered for prevention in the world and the Russian Federation. . Tixagevimab and cilgavimab (TC) show neutralizing activity against SARS-CoV-2, including the Omicron strain, primarily its variants BA.4, BA.5, BA.2.75 ("Centaur"). Objective - to evaluate the efficacy and safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving RTX, based on a prospective observational study. Materials and methods. The main group included 86 patients with various IMRD receiving RTX: 50 of them had ANCA-associated systemic vasculitis (AAV), 15 - rheumatoid arthritis, 9 - Sjogren's syndrome (SS), 4 - IgG4-related disease, 3 - systemic lupus erythematosus (SLE), 3 - dermatomyositis (DM), 2 - systemic scleroderma (SSD). Median age was 59 (19-82) years;male: female ratio - 1:1,8. From March 26 to August 30 2022, patients received a single intramuscular injection of TC in a total dose of 300 mg, mainly after RTX (in 52% of cases, in 28% on the next day after RTX). The control group included 42 patients with AAV (median age - 45 (35-71) years;male: female ratio - 1:1), also treated with RTX, who did not receive pre-exposure prophylaxis of TC. The duration of observation was 7 months, until November 1 2022. At this time, 98% of confirmed cases of coronavirus in the Russian Federation were Omicron. A telephone and/or online survey of patient has been conducted to detect cases of COVID-19 and adverse reactions. Results. In the TC group, confirmed coronavirus infection have been detected in 17 (20%) patients (AAV - 10, SS - 3, SSD - 2, SLE - 1, DM - 1), with fever in 7 (8%), only in one case hospitalization was required (lung damage was not detected in computed tomography), in two cases, according to CT mild lung damage (CT 1-2), there were no deaths. Good TC's tolerability was noted, signs not associated with COVID-19 or progression of IMRD after administration of TC were observed in 8 (9%) patients (GPA - 3 MPA - 1, RA - 2, SLE - 1, IgG4-related disease - 1), adverse reactions definitely associated with the use of TC were not found. The most serious event not associated with coronavirus infection was the progression of polyneuropathy in a patient with RA. In the control group, 3 (7%) patients were diagnosed with COVID-19, one with severe lung injury (CT 3, pulmonary embolism) and death. Conclusions. The data of clinical studies and our own clinical experience evidence the effectiveness of the use of a combination of long-acting monoclonal antibodies TC (Evusheld), registered for indications for pre-exposure prophylaxis and treatment of COVID-19. Patients with IMRD treated with RTX have a favorable safety profile of TC. The introduction of virus-neutralizing monoclonal antibodies, a new drug class for the prevention and treatment of infectious diseases, opens significant prospects for improving the prognosis of patients with IRD.Copyright © 2023 Ima-Press Publishing House. All rights reserved.
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Background/Aims Immunocompromised patients have a reduced ability to generate antibodies after COVID-19 vaccination, and are at a high risk of SARSPOSTERS CoV-2 infection, complications and mortality. Tixagevimab/Cilgavimab (Evusheld) is a combination of two monoclonal antibodies which bind to the SARS-CoV-2 spike protein, preventing the virus entering human cells. Tixagevimab/Cilgavimab has been approved as COVID-19 prophylaxis for immunocompromised individuals, and is being used in over 32 different countries. The phase III PROVENT clinical trial found that high-risk participants prophylactically administered Tixagevimab/Cilgavimab had a significantly reduced risk of COVID- 19 infection after three and six months compared to controls. However, the PROVENT trial was conducted prior to the SARS-CoV- 2 Omicron wave, and did not include participants who had been previously vaccinated or infected. This systematic review provides an updated summary of the real-world clinical evidence of the efficacy of Tixagevimab/Cilgavimab for immunocompromised patients. The review reports breakthrough COVID-19 infections as its primary outcome. COVID-19-related hospitalisations, ITU admissions and mortality were included as secondary outcomes. Methods Two independent reviewers conducted electronic searches of PubMed and Medxriv, on 03/08/22 and 01/10/22. Clinical studies which reported the primary outcome of breakthrough COVID-19 infections after Tixagevimab/Cilgavimab administration were included. Clinical effectiveness was determined using the case-control clinical effectiveness methodology. Odds ratios and 95% confidence intervals (CI) between intervention and control groups were also calculated. The GRADE tool was used to assess the level of certainty for the primary outcome. Results 17 clinical studies were included in the review, with a total of 24,773 immunocompromised participants from across the world, of whom 10,775 received Tixagevimab/Cilgavimab. One randomised controlled trial, ten retrospective cohort studies (two of which were preprints) and six prospective cohort studies (one preprint) were included. The majority of studies reported clinical outcomes during the SARS-CoV-2 Omicron wave. Six studies compared a Tixagevimab/Cilgavimab intervention group to a control group. Reasons for participant immunocompromise included rheumatology patients treated with immunosuppressant drugs, transplant recipients and those with malignancies. Overall, the clinical effectiveness of prophylactic Tixagevimab/Cilgavimab against COVID- 19 breakthrough infection was 40.47% (CI 29.82-49.67;p<0.0001), COVID-19 hospitalisation- 69.23% (CI: 50.78-81.64;p<0.00001), ITU admission- 87.89% (CI: 47.12-98.66;p=0.0008), all-cause mortality- 81.29% (66.93-90.28;p<0.0001 and COVID-19-specifc mortality- 86.36% (CI:-6.21-99.70;p=0.0351). Conclusion There is a growing body of real-world evidence validating the original PROVENT phase III study regarding the clinical effectiveness of Tixagevimab/Cilgavimab as prophylaxis for immunocompromised groups, notably demonstrating effectiveness during the Omicron wave. This systematic review demonstrates the significant clinical effectiveness of prophylactic Tixagevimb/Cilgavimab at reducing COVID-19 infection, hospitalisation, ITU admission and mortality for immunosuppressed individuals. It is critically important that largerscale and better-controlled studies are performed to highlight the significant clinical benefit of prophylactic antibody treatment in immunocompromised groups.
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Background/Aims Since the COVID-19 outbreak the rheumatology community have been concerned about the risk of SARS-CoV-2 infection in patients prescribed immunosuppressing medications. Data suggests that patients receiving Rrtuximab are at increased risk of developing severe outcomes from COVID-19 (1). In our unit all patients receiving rituximab were selected to receive a targeted vaccination and booster programme with all patients receiving at least 2 vaccinations and up to 3 booster vaccinations. We studied the efficacy of the COVID-19 vaccines in rituximab patients, by checking the the Roche Elecsys Anti-SARS-CoV-2-S (Spike) IgG/IgM total antibody levels post vaccination. Our aim was to assess the vaccination response in patients receiving rituximab and to offer advice on continued shielding or alternatively passive immunization with tixagevimab/cilgavimab in those patients who did not mount a response. Methods Taking 39 patients currently on rituximab therapy, we measured Anti- SARS-CoV-2-S (Spike) antibody levels post vaccination. We recorded whether the test was positive or negative, and the numerical result. We recorded rituximab dates of administration and dates of vaccines. We also recorded diagnosis, co-prescribed DMARDs, immunoglobulin levels, white cell and lymphocyte counts. We took record of whether or not the patient subsequently contracted COVID-19, required a hospital admission, ICU or died. Results Of our 39 patients, 21 had Anti-SARS-CoV-2-S (Spike) antibody levels checked. Of these patients, 7 (33%) had a negative spike protein result. Of the patients with a positive result, 8 (38%) had an antibody level between 0-250U/ML, and only 6 (28.6%) had a level >250U/ML (The manufacturer advises that a level above 0.8U/ML is a positive result). Of patients with a negative result, 1 patient had received 3 vaccines, 5 patients had received 4, and 1 patient had 5. All of the patients had received a vaccine >4 weeks prior to receiving the drug. Two patients were co-prescribed Belimumab, 3 were co-prescribed low-dose methotrexate and 2 were not on additional disease modifying agents. The diagnoses of these patients were, 2 patients with SLE, 4 with SPRA, and 1 MPO Vasculitis. There were no significant findings in lymphocyte count, white cell count or immunoglobulin levels. Conclusion These findings suggest that our current COVID-19 vaccination and booster programme may not provide adequate response in patients receiving rituximab therapy. Despite this being a small cohort, these results show that 33% of patients have not mounted a vaccine response and this is concerning. We suggest that vaccine response should be checked in all patients receiving rituximab therapy and those patients who do not mount a vaccine response should be offered passive immunity and advised of possible additional risks regarding COVID-19 exposure.
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Introduction/Aim: Rates of hospitalisation and death from COVID-19 in lung transplant (LTx) recipients vary internationally. We aimed to assess risk factors for this in an Australian cohort. Method(s): We performed a retrospective cohort study of all LTx recipients between January 2020 and September 2022. LTx recipients with COVID-19 were included. Baseline characteristics and treatments were recorded. Multivariate logistic regression was performed to identify risk factors associated with hospitalisation and death. Result(s): 128/387 (33%) recipients tested positive to SARS-CoV-2 during the study period, 97.6% during the Omicron waves with 40(31.3%) requiring hospitalisation and 10 (7.8%) died. The median (IQR) recipient age was 50.6 (22-77). The cohort was of Caucasian ethnicity 105 (82%), 48% were female with high vaccination rates (98.4%). Chronic lung allograft dysfunction (CLAD) was present in 48 (37.5%). 103 (80.5%) of patients received early SARS-CoV-2 treatment with either Sotrovimab 84(65%), Molnupirivir 50(39%) or combination 31(24%). 25 patients (19.5%) received no early treatment. All hospitalised patients received Remdesivir and Dexamethasone as per local treatment protocols. Regarding risk of hospitalisation, multivariate analysis showed that recipient age (1-unit change OR 1.04 95% CI 1.01-1.07 p = 0.019) was associated with an increased risk, whereas Molnupiravir was protective (OR 0.32 95% CI 0.13-0.80 p = 0.02). In univariable analysis, increasing age (1-unit change, OR 1.07 95% CI 1.02-1.129 p = 0.01) and severe disease (OR 9.95 95% CI 2.58-38.32 p =< 0.001) were associated with an increased risk of death. Male gender, non-Caucasian ethnicity, CLAD, CKD stage 3-5 were correlated with death with weak association. Conclusion(s): Recipient age is a significant risk factor for both hospitalisation and death, and older patients with COVID-19 should be monitored closely during COVID-19 illness. Molnupirivir is protective against hospitalisation, with Sotrovimab having a weak association. Further analysis of the protective effect of pre-exposure prophylaxis with emerging therapies such as Evusheld would be helpful to fully evaluate the currently available early disease therapies in Australia.
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Background: Tixagevimab(Txg)/cilgavimab (Cgv) was given emergency use authorization (EUA) to provide passive immunity against COVID-19(CoV) for immunocompromised (IC) pts who may not mount an adequate response to CoV vaccination [1]. Recipients of allogeneic hematopoietic cell transplant (Allo-HCT) are amongst the most IC. Due to high risk of mortality and complications of CoV in this population, Txg/ Cgv was used as pre-exposure prophylaxis (PrEP) under EUA without prior study. Our study aims to assess efficacy and adverse events (AE) of Txg/Cgv administration in this cohort of patients to help guide future practice. Method(s): We retrospectively investigated Allo-HCT recipients who received Txg/Cgv as PrEP. Data were gathered including changes in blood counts, incidence of graft-vs-host-disease (GVHD), history of prior CoV infection and vaccination status. Pts who developed CoV infection after PrEP were assessed for supplemental oxygen(O2) need and hospitalization. Data cutoff date was 9/30/2022. Result(s): A total of 18 Allo-HCT recipients received Txg/Cgv. Table 1 summarizes patient and transplant characteristics. Thirteen (72.2%) pts received 2 doses of 150mg of Txg / Cgv, while 4 pts received 1 dose of 300mg, and one patient received one dose of 150mg. Median time to first dose was 213 days [range 22-3660] post-transplant. Two pts had lab confirmed CoV, one at 24 days post dosing and the 2nd patient at 22 days post dose. Neither required supplemental O2;one was hospitalized for fever. Prior to dosing, 44.4% (8/18) of pts had GVHD. (Table Presented) (Figure Presented) (Figure Presented) Of these, 62.5% (5/8) had no changes in the severity of their GVHD. Two of 8 (25%) pts with pre-existing chronic GVHD had a flare of symptoms. Two (25%) had improvement of GVHD. Two pts developed new onset acute GVHD following Txg/Cgv administration, one requiring 1mg/kg prednisone and the other topical steroids (2/18, 11%). Figure 1 summarizes GVHD patterns observed. Hematologic parameters did not change significantly, see Figure 2. None of the pts reported any subjective AE following dosing. Summary: Txg/Cgv was found to be safe and effective for Allo-HCT pts, without significant toxicity. Two patients had new onset GVHD and 2 patients had progressive GVHD. Whether there is a true association between Txg/Cgv and development of GVHD should be investigated in a larger cohort and then investigated for possible underlying mechanisms.Copyright © 2023 American Society for Transplantation and Cellular Therapy
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BACKGROUND: SARS-CoV-2 infection, which causes COVID-19, has impacted the entire world due to its extensive and rapid spread. In the last two years, more than 412 million cases have been confirmed, with more than 5.8 million deaths, as of February 14, 2022. OBJECTIVE(S): Integrate a series of recommendations based on the best level of evidence in prevention, diagnosis and treatment of SARS-CoV-2 infection, including its new variants. METHODOLOGY: Review of different international guidelines and recent articles published in peer-reviewed journals. Issue recommendations based on the level of evidence and degree of confirmation established by the guidelines of the National Institute for Health and Care Excellence (NICE). The authors analyzed the selected articles and, based on their experience, summarized the most relevant to meet the objectives of these recommendations. RESULT(S): 200 articles were found, of which only 124 were selected that met the requirements to identify the level of evidence and degree of recommendation. CONCLUSION(S): Prevention through vaccination continues to be the best tool to establish protection mechanisms against the virus and substantially reduce hospitalizations and associated mortality. Although homologous vaccination is still the accepted reference pattern, the efficacy of heterologous schemes to avoid hospitalization and mortality must be considered. Monoclonal experiments, such as sotrovimab, have activity against the Omicron variant and the AZD7442 molecule that have shown high efficacy in preventing symptomatic COVID-19 in pre- and post-exposure conditions.Copyright © 2022 Comunicaciones Cientificas Mexicanas S.A. de C.V.. All rights reserved.
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Background: SARS-CoV-2 Omicron sublineages exhibit evolving escape to in vitro neutralization by monoclonal antibodies (mAbs), with an unclear impact on in vivo treatment response. Our aim is to assess the impact of SARS-Cov-2 variants on the decline of viral load (VL) after treatment with 3 different drugs approved in EU for the early treatment of patients with mild-moderate COVID-19. Method(s): Post-hoc analysis from MONET (EudraCT: 2021-004188-28), phase 4 open-label RCT to assess efficacy of 500 mg intravenous sotrovimab (SOT), 600 mg intramuscular tixagevimab/cilgavimab (TIX/CIL) and oral 5-days course of NMV/r 300/100 mg BID, in non-hospitalized high-risk patients (pts) with early COVID-19. Pts' features were analyzed as binary variables by Chi-squared test. SARS-Cov-2 VL in nasopharyngeal swabs was carried out at randomization (1d) and at day 7 (7d) by cycle threshold value (Ct). Variant sequencing was performed at 1d. Ct variation was assessed by mixed effect log-linear model including random intercept at pts' level, log of Ct as independent variable, time, arm, viral variant as dependent variables, and interaction between time and arm. Multiple comparisons were adjusted by Bonferroni. Result(s): Among the 320 pts included between 4 Mar and 16 Nov, 2022, 108 (33.75%) received NMV/r, 103 (32.19%) TIX/CIL, and 109 (34.06%) SOT. Main characteristics were balanced across arms. Most of the pts were infected either with BA.2 (N=194;60.63%) or BA.4/BA.5 (N=100;31.25%) (Fig1A). VL at 1d was similar across the arms. In contrast, mean 7d VL was significantly lower in pts receiving NMV/r than in those receiving TIX/ CIL or SOT (P< 0.001) No significant VL variation was observed between the mAb arms (Fig1B). The analysis of the impact of viral variants suggests that while VL was significantly affected by variants (P=0.034), the superior effect of NMV/r over mAbs was homogeneous across all variant groups (P=0.290 for interaction) (Fig1C). Conclusion(s): Our study provides for the first time strong in vivo evidence that, when used against Omicron lineages, NMV/r exerts a stronger antiviral effect than mAbs. These results confirm previous in vitro evidence suggesting that mAbs may not retain neutralizing activity against all Omicron sublineages and provide preliminary information on how to use VL variation as a surrogate marker of efficacy. Further studies are needed to investigate whether the superior virologic activity of NMV/r over mAbs is confirmed for newly emerging variants, including BQ.1.1 or XBB.
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Background: Omicron subvariants questioned the efficacy of the approved therapies for the early COVID-19. In vitro data show that remdesivir (RDV), molnupiravir (MLN), and nirmatrelvir/ritonavir (NMV/r) all retained activity against all sub-lineages, while poor neutralizing activity was observed for Sotrovimab (SOT) and Tixagevimab/cilgavimab (TIX/CIL). No data about the risk of clinical failure or even in vivo antiviral activity are available. Method(s): Single-center observational comparison study enrolling all consecutive patients (pts) seen for care with a confirmed SARS-CoV-2 Omicron diagnosis and who met the AIFA criteria for eligibility for treatment with RDV, MLN, NMV/r, TIX/CIL, or SOT. Treatment allocation was subject to drug availability, time from symptoms onset, and comorbidities. Nasopharyngeal swab (NPS) VL was measured on day 1 (D1) and D7 and was expressed by log2 cycle threshold (CT) scale. Comparisons between treatment groups were made by Chi-square, and Wilcoxon paired tests. Primary endpoint was D1-D7 VL variation. Potential decrease in VL and average treatment effect (ATE) were calculated from fitting marginal linear regression models weighted for calendar month of drug initiation, duration of symptoms, and immunodeficiency using NMV/r as the comparator trial arm. Result(s): A total of 971 pts received treatments (SOT 321, MLN 231, NMV/r 211, TIX/CIL 70, and RDV 138): female 457 (47%), median age 67 yrs (IQR 56-78), 93% vaccinated;12% with negative baseline serology. At D1, median time from symptoms onset was 3 days (IQR 2,4). 379 (39%) pts were infected with BA.1, 215 (22%) with BA.2, 372 with BA.4/5 (38%), and 5 with BQ.1 (0,5%). D1 mean viral load was 4.02 log2. Adjusted analysis (ATE) showed that NMV/r significantly reduced VL compared to all the other drugs in pts infected with all sublineages, (Fig.1A-B) while less evidence for a difference vs. TIX/CIL was seen in those infected with BA.2 (p=0.05) (Fig.1 C-D). Conclusion(s): In this analysis of in vivo early VL reductions, NMV/r appears to be the drug showing the greatest antiviral activity, regardless of the underlying subvariant, perhaps with the exception of TIX/CIL in people infected with BA.2 for which there was less evidence for a difference. In the Omicron era, due to the high prevalence of vaccinated people and in absence of clinical events, VL is one of the possible alternative endpoints which guarantees adequate statistical power. Fig 1 SARS-CoV-2 RNA levels at D1 and D7 in patients treated with Nirmatrelvir/ ritonavir, Sotrovimab, Molnupiravir, Remdesivir, and Tixagevimab/cilgavimab. Dot-plots showing the comparison of viral loads detected at D1 and D7 and the variation of RNA levels observed between the two time-points by intervention in (A) all patients treated with Nirmatrelvir/ritonavir (n=211), Sotrovimab (n=321), or Molnupiravir (n=231), or Remdesivir (n=138), or Tixagevimab/ cilgavimab (n=136);(C) patients with Omicron BA.2 infection treated with Nirmatrelvir/ritonavir (n=58), Sotrovimab (n=81), or Molnupiravir (n=21), or Remdesivir (n=37), or Tixagevimab/cilgavimab (n=18);(D) patients with Omicron BA.4/5 infection treated with Nirmatrelvir/ritonavir (n=102), Sotrovimab (n=92), or Molnupiravir (n=110), or Remdesivir (n=16), or Tixagevimab/cilgavimab (n=52). Viral RNA levels are expressed as log2 CT values. The horizontal dashed line represents the limit of detection (CT: 40.0), values >=40 are considered negative. Mean of log2 CT values, and SD are shown in the graph. Statistical analysis of the differences in viral loads by intervention as compared to Nirmatrelvir/ritonavir was performed by Mann-Whitney test. Potential decrease in VL and average treatment effect (ATE) were calculated from fitting marginal linear regression models weighted for calendar month of drug initiation, duration of symptoms, and immunodeficiency using NMV/r as the comparator trial arm. Results are shown (B) for patients infected with all Omicron sublineages and (D) for those infected with Omicron BA.2 sublineage.
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Background: Antivirals and monoclonal antibodies (mAbs) were approved for early treatment of COVID-19 based on data from trials conducted in unvaccinated people before the Omicron era. The comparative effectiveness of different treatments is unknown. We present the results of the interim analysis of MONET trial (EudraCT: 2021-004188-28). Method(s): In this ongoing multicenter, open-label, phase 4 trial, we randomly assigned, in a 1:1:1 ratio, non-hospitalized patients with early symptomatic Covid-19 (<=5 days after symptoms onset) and >=1 risk factor for disease progression, to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TIX/CIL) or oral 5-days course of NMV/r 300/100 mg BID. Primary outcome was hospitalization or death for any cause within 29 days after randomization, reported as cumulative incidence per 100 (95% CI), and P-value calculated by Fisher's exact test. Inflammatory marker (CRP, d-dimer, and neutrophils-to-lymphocytes ratio) and antibody level (serum anti-S IgG and anti-N IgG) analysed by mixed linear regression with random intercept and P-values for time trend calculated by ANOVA-style test with Bonferroni correction. Result(s): Prespecified interim analysis, including 400 patients (SOT =133, TIX/ CIL=130, NMV/r=137) enrolled from Mar 4 to Nov 16, 2022 (Fig.1A). Overall, 5 pts (3/5 immunosuppressed) had disease progression leading to hospitalization [1.25% (95% CI 0.4%-2.89%)], 1 in SOT (0.75%, 95% CI 0.01%-4.1%), 4 in TIX/CIL (3.08%, 95% CI 0.84%-7.69%) and none in NMV/r arm (P=0.030). No deaths or ICU admissions were observed. Among the hospitalized pts, 3 were infected with BA.2 (1 SOT, 2 TIX/CIL), one with BA.4/5, and one BQ.1.1 (both TIX/ CIL). No serious adverse events and no kidney or liver toxicity were reported. Temporal trend of inflammation markers was similar in the three arms, and their estimates are shown in Fig.1B. Kinetics of antibody was reported in Fig.1C. The plot shows a rapid increase of anti-S in both mAb arm and a linear increase of IgG in the NMV/r arm. Anti-N IgG kinetics was similar in the three arms. Conclusion(s): By these data the overall cumulative risk of clinical failure in mild Covid-19 occurring in the Omicron era is low. The hypothesis that differences in clinical progression among the three arms could be related to different activity against the Omicron subvariant observed in vitro should be further investigated. Type of treatment does not seem to influence the development of the natural antibody response.
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Background: At the end of 2021, concomitantly with the beginning of Omicron variant circulation, pre-exposure prophylaxis with the dual monoclonal long-acting monoclonal antibodies tixagevimab/cilgavimab became available in France to protect patients non-responding or non-eligible to SARS-CoV-2 vaccination at risk of severe COVID-19. Method(s): This study included patients who received tixagevimab/cilgavimab for pre-exposure prophylaxis independently of vaccination status or previous SARS-CoV-2 infection. This prophylaxis strategy was implemented at the Bichat-Claude Bernard University Hospital, Paris since December 2021 Last date of follow-up was November 1st, 2022. Incident SARS-CoV-2 infections were detected based on positive RT-PCR result and/or anti-nucleocapsid antibodies seroconversion. Severe COVID-19 was defined as an infection leading to an hospitalization requiring oxygenotherapy and/or high dose corticotherapy. Result(s): Among the 275 patients who received a tixagevimab/cilgavimab preexposure prophylaxis, 55% (n=153) were solid organ transplant recipients (50% lung, 46% kidney, 4% heart transplants), 42% (n=116) had an autoimmune disease, and 3% (n=6) had other indications. 51% (n=141) of all patients received rituximab. No severe adverse event of tixagevimab/cilgavimab was observed. Incident SARS-CoV-2 infection was diagnosed in 67 patients (24%). Among them, 59% (n=40) were solid organ transplant recipients, 36% (n=24) had an autoimmune disease and overall 52% had received rituximab. For the 56 patients whose infection date was available, the median delay between the last infusion of tixagevimab/cilgavimab and SARS-CoV-2 infection was 62 days (IQR=[30-97]). During the study period, 57% of incident infections occurred between December 17th, 2021 and May 31st, 2022, when BA.1 and BA.2 were the major Omicron sublineages in France, and 43% between June 1st, 2022 and November 2022 1st, a period during which BA.4 and BA.5 were predominant in France. Severe COVID-19 occurred in 6 patients out of 67 (9%);5 were solid organ transplant recipients and 3 received rituximab. No death due to COVID-19 was reported. Conclusion(s): Overall, 76% of patients receiving pre-exposure prophylaxis with tixagevimab/cilgavimab had no incident SARS-CoV-2 infection during the study period. Severe COVID-19 was observed in 9% of infected patients. These results suggest a potential protective effect in-vivo of tixagevimab/cilgavimab during the study period despite the circulation of different Omicron sublineages.
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Background: Within the ACTIV-2/A5401 platform (NCT04518410), the safety and efficacy of tixagevimab/cilgavimab (T/C), an anti-SARS-CoV-2 monoclonal antibody combination, was studied in outpatients with COVID-19. Intravenous (IV) and intramuscular (IM) administration of T/C were assessed. Method(s): Non-hospitalized adults >=18 years enrolled within 10 days of positive SARS-CoV-2 test and symptom onset. Participants at higher risk of disease progression were eligible for IV T/C 300mg (150mg each component) or placebo;all were eligible for IM T/C 600mg (300mg each) administered to the lateral thigh or placebo. Co-primary outcomes were: time to symptom improvement through day 28;nasopharyngeal (NP) SARS-CoV-2 RNA below lower limit of quantification (LLoQ) on days 3, 7 or 14;and treatment emergent Grade >=3 adverse events. Result(s): Between February and May 2021, 223 participants (106 T/C, 117 placebo) initiated study intervention and were included in the IM analysis and 114 participants (58 T/C, 56 placebo) in the IV analysis;the IV study was stopped early for administrative reasons. Both studies enrolled 45% Latinx;the IM and IV populations included 12% and 19% Black participants, 49% and 59% female sex at birth, and median age was 39 and 44 years, respectively, all of which were balanced between active vs placebo for each. Median (IQR) days from symptom onset at enrollment was 6 (4, 7). There were no differences in time to symptom improvement comparing IM T/C to placebo (median 8 (IQR 7, 12) vs 10 (8, 13) days;p=0.35) or IV T/C to placebo (11 (9, 15) vs 10 (7, 15) days;p=0.71). A significantly greater proportion (80%) in the IM T/C arm had NP SARS-CoV-2 RNA below LLoQ at day 7 compared to placebo (65%), but not days 3 or 14, overall p=0.003 across visits. Secondary and post-hoc analyses revealed antiviral effects within the smaller IV study. There was no difference in Grade >=3 AEs with either administration route. Fewer participants were hospitalized who received T/C vs placebo (4 vs 7 in IM group;0 vs 4 in IV group), neither group reaching statistical significance. Conclusion(s): Tixagevimab/cilgavimab administered IM or IV was well-tolerated and demonstrated antiviral activity and a trend towards fewer hospitalizations, but did not change time to symptom improvement in mild-to-moderate COVID-19 compared to placebo. Monoclonal antibodies administered intramuscularly to the thigh may present a valuable alternative for early SARSCoV-2 infection. Virologic Outcomes of Tixagevimab/Cilgavimab treatment 600mg IM (panels A and B) or 300mg IV (panels C and D) versus placebo.
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Introduction: B-cell-depleting therapies may affect the development of a protective immune response following vaccination against SARS-CoV-2. It is important to have a different strategy for creating immunity. Evusheld (tixagevimab co-packaged with cilgavimab) is currently approved by the FDA under an emergency use authorization (EUA) for use in patients who are not able to mount an immune response to the COVID-19 vaccines. No study has been undertaken to evaluate its efficacy in people with MS. The objective of this study was to evaluate whether Evusheld (tixagevimab co-packaged with cilgavimab) affects the antibody response to SARS-CoV-2 following an existing attenuated response to the vaccines against SARS-CoV-2. Material(s) and Method(s): This was a single-center cohort study performed at Methodist Hospitals in Merrillville, IN, USA. It included patients with multiple sclerosis treated with ocrelizumab and ofatumumab. Patients had already received the mRNA vaccinations against SARS-CoV-2 and had demonstrated an attenuated response on antibody testing. All participants received 150mg of Evusheld (tixagevimab co-packaged with cilgavimab). Antibody levels were measured at least two weeks following Evusheld injections. Result(s): All patients (100%) developed the highest level of antibodies possible at least two weeks following Evusheld injections. Conclusion(s): In this study, patients with MS who had an attenuated antibody response to the COVID-19 vaccines due to exposure to b-cell depleters now had the highest antibody response possible after receiving Evusheld. This is important as it provides a different strategy for protection against COVID-19.Copyright © 2022
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Rationale: The FDA granted an emergency use authorization for tixagevimab/ cilgavimab in December 2021 for COVID-19 pre-exposure prophylaxis for individuals that are moderate to severely immunocompromised and has since recommended repeat dosing every 6 months. Given its novelty and resultant hesitation for use among some physicians and patients, our study aimed to observe safety and efficacy of tixagevimab/ cilgavimab, including against one of the newest variants, Omicron BA.5, among our patient population with immunodeficiencies 6 months post-administration via a telephone survey. We hypothesized that adverse outcomes would be minimal and COVID-19 incidence and severity would lessen following tixagevimab/cilgavimab administration. Methods: The Atrium Health Wake Forest Baptist Allergy, Asthma, and Immunology department recruited 15 patients with immunodeficiencies receiving immunoglobulin replacement and tixagevimab/ cilgavimab in March 2022 for a prospective cohort study. A telephone survey was conducted 6 months later regarding tixagevimab/ cilgavimab adverse effects and incidence/severity of COVID infection before and after administration. Results: Two patients experienced minor adverse effects (fatigue, bruising) following tixagevimab/ cilgavimab administration. No severe reactions were reported. Two patients required hospitalization for severe COVID-19 infection prior to tixagevimab/cilgavimab administration, whereas 0 patients required hospitalization for COVID-19 in the 6 months following administration. Four of 5 patients that had COVID-19 following administration had not yet received the bivalent Omicron booster vaccine and 2 had received no COVID-19 vaccines. Conclusions: Tixagevimab/ cilgavimab is associated with minor adverse effects and reduction of COVID-19 severity, albeit perhaps not associated with diminished incidence of newest COVID-19 strains, in a prospective, population-based cohort.
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Rationale: Tixagevimab-cilgavimab is a combination of two monoclonal antibodies against SARS-CoV-2. In December 2021, the FDA issued emergency use authorization for intramuscular injection of tixagevimab-cilgavimab for prophylaxis against SARS-CoV-2 in immunocompromised patients. Shortly thereafter, our clinic distributed tixagevimab-cilgavimab to patients with Common Variable Immunodeficiency (CVID). To our knowledge, no prior study has looked at effects of this monoclonal antibody combination on CVID patients. Methods: 47 patients with CVID were offered tixagevimab-cilgavimab. 23 chose to receive prophylaxis. Comparative outcomes of treatment and non-treatment groups examined: occurrence of SARS-CoV-2 infection, severity of SARS-CoV-2 infection, and other non-SARS-CoV-2 infections. Results: 70% were female;mean age 49. 23 patients received tixagevimab-cilgavimab and 24 did not receive prophylaxis. In the tixagevimab-cilgavimab group, all were vaccinated for SARS-CoV-2 and 22 were receiving immunoglobulin replacement. In the cohort that did not receive prophylaxis, 21 were vaccinated, and all received immunoglobulin replacement. In the prophylaxis group one patient was infected with SARS-CoV-2, no patients required emergency care, and 7 patients had non- SARS-CoV-2 infection. In the group that did not receive prophylaxis 2 patients tested positive for SARS-CoV-2, one patient required emergency care due to SARS-CoV-2 disease severity, and four patients had a non-SARS-CoV-2 infection. None of the results showed statistical significance. Conclusions: Although there is preliminary evidence that tixagevimab-cilgavimab can be protective against SARS-CoV-2 in immunocompromised individuals, our data suggests that this benefit may be blunted in CVID patients on immunoglobulin replacement. The additional benefit of tixagevimab-cilgavimab in immunocompromised patients already receiving replacement therapy requires further exploration.
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SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Much has been learned about the immune dysregulation and release of pro-inflammatory cytokines since the emergence of the COVID-19 pandemic.1 Patients with interstitial lung disease are often on immunosuppressive agents, such as rituximab, which is a B-cell depleting agent. There has been a large retrospective cohort study showing that rituximab therapy was the only immunosuppressive medication with a trend towards in-hospital death.2 We present a case of COVID-19 in a patient on rituximab with ANCA vasculitis. CASE PRESENTATION: A 51-year-old male, never smoker, with ANCA positive vasculitis (positive MPO and PR3) and interstitial lung disease (on 4-5L of oxygen) presented to the hospital with nausea and fever for 2 days and was found to have a positive SARS-CoV-2 PCR. At the time of presentation, he was on rituximab 1000 mg x 2 doses every 6 months with last infusion one month prior to presentation, azathioprine 150 mg daily, prednisone 15 mg daily, nintedanib 100 mg BID, and IVIG monthly. Spirometry showed FVC of 1.60L/37% predicted and an FEV1 1.28L/39% predicted. Patient had 2 COVID vaccinations and one booster (all Pfizer mRNA), the latter 3 months prior to presentation. On admission, he was saturating at 55% on 4L and placed on 15L non-rebreather;he was afebrile, normotensive, and with a pulse of 110 BPM. Exam was notable for a cough, wheezing, and tachypnea. Lab work was notable for positive SARS-COV-2 PCR, a total white blood cell count of 5.3x103 uL, and a normal hemoglobin and platelet count. He had a CO2 of 34, normal creatinine, and no transaminitis. Lactate dehydrogenase (LDH) was elevated at 318 U/L, and lactate was elevated at 3.5 mmol/L. His chest x-ray on admission demonstrated patchy filling opacities and low lung volumes. He received dexamethasone, remdesivir, and the monoclonal antibodies casirivimab and imdevimab (REGEN-COV) on the first day of admission. Patient also received his monthly IVIG dose inpatient. After a week, he was weaned back to his home oxygen and symptomatically back to baseline. Most recent PFTs on the same outpatient immunosuppressive regimen as prior to admission are unchanged. Patient received two doses of preventative monoclonal antibodies (EVUSHELD) 3 months after admission. DISCUSSION: Here we discuss a case of a patient with severe COVID-19 pneumonia requiring inpatient hospitalization despite three COVID mRNA vaccinations, likely secondary to difficulty in mounting an immune response to the vaccinations given his use of immunosuppressive medications. This is also an example of the early use of monoclonal antibodies in an inpatient with long term preservation of his underlying lung function.3 CONCLUSIONS: We recommend counseling and close observation of patients on rituximab due to risk of severe COVID-19 infection as well the use of preventative monoclonal antibodies (EVUSHELD). Reference #1: Jamal M, Bangash HI, Habiba M, Lei Y, Xie T, Sun J, Wei Z, Hong Z, Shao L, Zhang Q. Immune dysregulation and system pathology in COVID-19. Virulence. 2021 Dec;12(1):918-936. doi: 10.1080/21505594.2021.1898790. PMID: 33757410;PMCID: PMC7993139. Reference #2: Andersen, K. M., Bates, B. A., Rashidi, E. S., Olex, A. L., Mannon, R. B., Patel, R. C., Singh, J., Sun, J., Auwaerter, P. G., Ng, D. K., Segal, J. B., Garibaldi, B. T., Mehta, H. B., Alexander, G. C., Haendel, M. A., & Chute, C. G. (2022). Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: A retrospective cohort study using data from the National COVID Cohort Collaborative. The Lancet Rheumatology, 4(1), e33–e41. https://doi.org/10.1016/S2665-9913(21)00325-8 Reference #3: Weinreich, D. M., Sivapalasingam, S., Norton, T., Ali, S., Gao, H., Bhore, R., Xiao, J., Hooper, A. T., Hamilton, J. D., Musser, B. J., Rofail, D., Hussein, M., Im, J., Atmodjo, D. Y., Perry, C., Pan, C., Mahmood, A., Hosain, R., Davis, J. D., Yancopoulos, G. D. (2021). Regen-cov antibody combination and outcomes in outpatients with covid-19. New England Journal of Medicine, 385(23), e81. https://doi.org/10.1056/NEJMoa2108163 DISCLOSURES: Advisory Committee Member relationship with Genentech Please note: 2019-2022 Added 06/06/2022 by Ayodeji Adegunsoye, value=Consulting fee Advisory Committee Member relationship with Boehringer Ingelheim Please note: 2018-2022 Added 06/06/2022 by Ayodeji Adegunsoye, value=Consulting fee Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: 2018-2022 Added 06/06/2022 by Ayodeji Adegunsoye, value=Honoraria Consultant relationship with Genentech Please note: 2018-2020 by Ayodeji Adegunsoye, value=Consulting fee Removed 06/06/2022 by Ayodeji Adegunsoye No relevant relationships by Cathryn Lee No relevant relationships by Kavitha Selvan PI relationship with Boehringer-Ingelheim Please note: >$100000 by Mary Strek, value=Grant/Research Support PI relationship with Galapagos Please note: $70,000-100,00 by Mary Strek, value=Grant/Research Support Endpoint Adjudication Committee Member relationship with Fibrogen Please note: $1-$1000 by Mary Strek, value=Honoraria No relevant relationships by Rachel Strykowski
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The FDA has approved tirzepatide (Mounjaro - Lilly), a peptide hormone with activity at both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, to improve glycemic control in adults with type 2 diabetes. Tirzepatide, which is injected subcutaneously once weekly, is the fi rst dual GIP/GLP-1 receptor agonist to become available in the US. Selective GIP receptor agonists are not available in the US;GLP-1 receptor agonists have been available for years. Copyright © 2022, Medical Letter Inc.. All rights reserved.