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1.
Future Microbiol ; 17: 411-416, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1742148

ABSTRACT

Aim: To evaluate the role and perceptions of trainees during the COVID-19 pandemic. Method: An online survey was designed to provide an insight into the significance of the COVID-19 pandemic on working conditions of infectious diseases and clinical microbiology trainees. Results: The main roles of trainees included management of patients hospitalized for COVID-19 (55%), research (53%) and diagnostic procedures (43%). The majority (82%) of trainees felt useful in managing the crisis. However, more than two-thirds felt more stressed and more tired compared with other rotations. Only 39% of the participants had access to psychological support. Conclusion: Due to the significant impact of the pandemic on infectious diseases and clinical microbiology trainees, further research should focus on their health and welfare in the post-pandemic period.


Subject(s)
COVID-19 , Communicable Diseases , COVID-19/epidemiology , Communicable Diseases/diagnosis , Communicable Diseases/epidemiology , Humans , Pandemics , Perception , SARS-CoV-2 , Surveys and Questionnaires
2.
J Antimicrob Chemother ; 2022 Mar 02.
Article in English | MEDLINE | ID: covidwho-1722504

ABSTRACT

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

3.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327725

ABSTRACT

Objectives: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. Methods We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity ( NCT04315948 , EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. Results The intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147;lopinavir/ritonavir-IFN-beta-1a, n=147;hydroxychloroquine, n=150;control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36);lopinavir/ritonavir-IFN-beta-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08);hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. Conclusion In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320595

ABSTRACT

Background: Patients who smoke and with preexisting comorbidities have a greater risk of developing severe coronavirus disease 2019 (COVID-19) and have a higher mortality rate. However, the number of deaths attributable to diabetes, hypertension, obesity, or smoking have never been estimated. We conducted a systematic literature review and meta-analysis of observational studies to investigate the association between diabetes, hypertension, body mass index (BMI) or smoking with the risk of death in patients with COVID-19.Methods: Relevant observational studies were identified by searches in the PubMed and Embase databases through October 29, 2020. Random-effects models were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). We further estimated the proportion of deaths attributable to these conditions. Certainty of evidence was assessed using the Cochrane methods and the GRADE framework. This study is registered with PROSPERO, CRD42020218115.Findings: A total of 186 studies representing 210,447 deaths among 1,304,587 patients with COVID-19 were included in this analysis. The SRR for death in COVID-19 patients was 1.54 (95% CI=1.44-1.64, I2=92%, n=145, low certainty) for diabetes and 1.42 (95% CI=1.30-1.54, I2=90%, n=127, low certainty) for hypertension compared to patients without each of these comorbidities. Regarding obesity, the SSR was 1.45 (95% CI=1.31-1.61, I2=91%, n=54, high certainty) for patients with BMI ≥30kg/m2 compared to those with BMI <30kg/m2 and 1.12 (95% CI=1.07-1.17, I2=68%, n=25) per 5 kg/m2 increase in BMI. There was evidence of a J-shaped non-linear dose-response relationship between BMI and mortality from COVID-19, with the nadir of the curve at a BMI of around 22-24, and a 1.5-2 fold increase in COVID-19 mortality with extreme obesity (BMI of 40-50). The SRR was 1.28 (95% CI=1.29-1.50, I2=74.0, n=28, low certainty) for ever, 1.29 (95% CI=1.03-1.62, I2=84%, n=19) for current and 1.26 (95% CI=1.11-1.42, I2=84%, n=14) for former smokers compared to never smokers. The proportion of deaths attributable to diabetes, hypertension, obesity, and smoking was 8%, 7%, 11%, and 2%, respectively.Interpretation: Our findings suggest that diabetes, hypertension, obesity and smoking are major contributors to COVID-19 mortality accounting for nearly 30% of COVID-19 deaths.Funding Statement: There was no funding source for this study.Declaration of Interests: We declare no competing interests.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320044

ABSTRACT

Background: All prevention efforts currently being implemented for COVID-19 are aimed at reducing the burden on strained health systems and human resources. There has been little research conducted to understand how SARS-CoV-2 has affected healthcare systems and professionals in terms of their work. Finding effective ways to share the knowledge and insight between countries, including lessons learned, is paramount to the international containment and management of the COVID-19 pandemic. The aim of this project is to compare the pandemic response to COVID-19 in Brazil, Canada, China, France, Japan, and Mali. This comparison will be used to identify strengths and weaknesses in the response, including challenges for health professionals and health systems. Methods: We will use a multiple case study approach with multiple levels of nested analysis. We chose these countries as they represent different continents and different stages of the pandemic. We will focus on several major hospitals and two public health interventions (contact tracing and testing). It is a multidisciplinary research approach that will use qualitative data through observations, document analysis, and interviews, as well as quantitative data based on disease surveillance data and other publicly available data. Given that the methodological approaches of the project are largely qualitative, the ethical risks are minimal. For the quantitative component, the data being used are publicly available. Discussion: We will deliver lessons learned based on a rigorous process and on strong evidence to enable operational-level insight for national and international stakeholders.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-304820

ABSTRACT

Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in patients with COVID-19 requiring oxygen and/or ventilator support.Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial in adults hospitalised with COVID-19 (DisCoVeRy, NCT04315948;EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care alone or in combination with intravenous remdesivir (200 mg on day 1, then 100 mg once-daily for 9 days or until discharge). Treatment assignation was performed via web-based randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 832 participants were included for the evaluation of remdesivir (control, n=418;remdesivir, n=414). There was no difference in the clinical status neither at day 15 between treatment groups (OR for remdesivir, 0.98, 95% CI, 0.77 to 1.25, P=0.85) nor at day 29. The proportion of deaths at day 28 was not significantly different between control (8.9%) and remdesivir (8.2%) treatment groups (OR for remdesivir, 0.93 95%CI 0.57 to 1.52, P=0.77). There was also no difference on SARS-CoV-2 viral kinetics (effect of remdesivir on viral load slope, -0.004 log10 cp/10,000 cells/day, 95% CI, -0.03 to 0.02, P=0.75). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups.Interpretation: The use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA.Trial Registration: DisCoVeRy, NCT04315948;EudraCT2020-000936-23Funding: European Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB;Belgian Health Care Knowledge Centre (KCE)Declaration of Interests: Dr. Costagliola reports grants and personal fees from Janssen, personal fees from Gilead, outside the submitted work. Dr. Mentré reports grants from INSERM Reacting (French Government), grants from Ministry of Health (French Government), grants from European Commission, during the conduct of the study;grants from Sanofi, grants from Roche, outside the submitted work. Dr. Hites reports grants from The Belgian Center for Knowledge (KCE), grants from Fonds Erasme-COVID-ULB, during the conduct of the study;personal fees from Gilead, outside the submitted work. Dr. Mootien reports non-financial support from GILEAD, outside the submitted work. Dr. Gaborit reports non-financial support from Gilead, non- financial support from MSD, outside the submitted work. Dr. Botelho-Nevers reports other from Pfizer, other from Janssen, outside the submitted work. Dr. Lacombe reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Dr. Wallet reports personal fees and non-financial support from Jazz pharmaceuticals, personal fees and non-financial support from Novartis, personal fees and nonPage financial support from Kite-Gilead, outside the submitted work. Dr. Kimmoun reports personal fees from Aguettan, personal fees from Aspen, outside the submitted work. Dr. Thiery reports personal fees from AMGEN, outside the submitted work. Dr. Burdet reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. Dr. Poissy reports personal fees from Gilead for lectures, outside the submitted work. Dr. Goehringer reports personal fees from G lead Sciences, non-financial support from Gilead Sciences, grants from Biomerieux, non-financial support from Pfizer, outside the submitted work. Dr. Peytavin reports personal fees from Gilead Sciences, personal fees from Merck France, personal fees from ViiV Healthcare, personal fees from TheraTechnologies, outside the submitted work. Dr. Danion reports personal fees from Gilead, outside the submitted work. Dr. Raffi reports personal fees from Gilead, personal fees from Janssen, personal fees from MSD, personal fees from Abbvie, personal fees from ViiV Healthcare, personal fees from Theratechnologies, personal fees from Pfizer, outside the submitted work. Dr. Gallien reports personal fees from Gilead, personal fees from Pfizer, personal fees from ViiV, personal fees from MSD, outside the submitted work;and has received consulting fee from Gilead in August 2020 to check the registration file of remdesivir for the French administration. Dr. Nseir reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomérieux, personal fees from BioRad, outside the submitted work. Dr. Lefèvre reports personal fees from Mylan, personal fees from Gilead, outside the submitted work. Dr. Guedj reports personal fees from Roche, outside the submitted work. Other authors have nothing to disclose.Ethics Approval Statement: The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744), and is sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France);it was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all included participants (or their legal representatives if unable to consent). The present analysis is based on the protocol v11.0 of December 12th, 2020.

7.
Médecine et Maladies Infectieuses Formation ; 1(1):13-23, 2022.
Article in French | EuropePMC | ID: covidwho-1678933

ABSTRACT

Les thérapeutiques en cours d’évaluation pour la COVID-19 interviennent à différents stades de la maladie. Alors que la prophylaxie à large échelle en population générale fait désormais appel à la vaccination, des molécules antivirales sont en cours d’évaluation pour la prophylaxie post-exposition, dont les anticorps monoclonaux, notamment chez les patients à haut risque d’évolution vers une forme sévère de COVID-19. La phase précoce de la maladie, symptomatique ou non, pourrait bénéficier d'une stimulation de l'immunité antivirale naturelle, comme les interférons de type 1 ou de l'administration de traitements antiviraux, et notamment les anticorps monoclonaux. À une phase plus avancée de la maladie, la corticothérapie a montré un bénéfice sur la mortalité chez des patients en hospitalisation conventionnelle ou en réanimation nécessitant un support en oxygène. Malgré de nombreux échecs de traitements antiviraux, des molécules antivirales ainsi que des thérapies ciblées anti-inflammatoires sont encore en cours d’évaluation.

9.
M�decine et Maladies Infectieuses Formation ; 2022.
Article in English | ScienceDirect | ID: covidwho-1633994

ABSTRACT

Résumé Les thérapeutiques en cours d’évaluation pour la COVID-19 interviennent à différents stades de la maladie. Alors que la prophylaxie à large échelle en population générale fait désormais appel à la vaccination, des molécules antivirales sont en cours d’évaluation pour la prophylaxie post-exposition, dont les anticorps monoclonaux, notamment chez les patients à haut risque d’évolution vers une forme sévère de COVID-19. La phase précoce de la maladie, symptomatique ou non, pourrait bénéficier d'une stimulation de l'immunité antivirale naturelle, comme les interférons de type 1 ou de l'administration de traitements antiviraux, et notamment les anticorps monoclonaux. À une phase plus avancée de la maladie, la corticothérapie a montré un bénéfice sur la mortalité chez des patients en hospitalisation conventionnelle ou en réanimation nécessitant un support en oxygène. Malgré de nombreux échecs de traitements antiviraux, des molécules antivirales ainsi que des thérapies ciblées anti-inflammatoires sont encore en cours d’évaluation. There are different therapeutics options to treat COVID-19 at different stages of the disease. While large-scale prophylaxis in the general population now relies on vaccination, antiviral molecules such as monoclonal antibodies are being evaluated for post-exposure prophylaxis, particularly in patients at high risk of severe forms of COVID-19. The early phase of the disease, whether symptomatic or not, could benefit from stimulation of natural antiviral immunity such as type 1 interferons and/or from the administration of antiviral treatments including monoclonal antibodies. In more advanced stages of the disease, corticosteroid therapy has shown a benefit on mortality in hospitalized patients requiring oxygen support. Despite numerous disappointments of antiviral treatments, antiviral molecules are still being evaluated as well as targeted anti-inflammatory therapies.

12.
Anaesth Crit Care Pain Med ; 41(1): 100998, 2022 02.
Article in English | MEDLINE | ID: covidwho-1561582

Subject(s)
COVID-19 , SARS-CoV-2 , Humans
14.
Future Microbiol ; 16: 687-695, 2021 07.
Article in English | MEDLINE | ID: covidwho-1511960

ABSTRACT

Trainees represent the medical practice of tomorrow. Interactions and collaborations at the early stage in career will strengthen the future of our specialties, clinical microbiology and infectious diseases. Trainee networks at the national level help access the best education and career opportunities. The aim of this collaborative white paper between the Trainee Association of European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and four national trainee networks is to discuss the motivation for building such networks and offer guidance for their creation and sustainability even during a health crisis.


Subject(s)
Education, Medical/organization & administration , Infectious Disease Medicine/education , Microbiology/education , Humans
15.
J Antimicrob Chemother ; 76(Supplement_3): iii20-iii27, 2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1493833

ABSTRACT

BACKGROUND: Virus-associated respiratory infections are in the spotlight with the emergence of SARS-CoV-2 and the expanding use of multiplex PCR (mPCR). The impact of molecular testing as a point-of-care test (POCT) in the emergency department (ED) is still unclear. OBJECTIVES: To compare the impact of a syndromic test performed in the ED as a POCT and in the central laboratory on length of stay (LOS), antibiotic use and single-room assignment. METHODS: From 19 November 2019 to 9 March 2020, adults with acute respiratory illness seeking care in the ED of a large hospital were enrolled, with mPCR performed with a weekly alternation in the ED as a POCT (week A) or in the central laboratory (week B). RESULTS: 474 patients were analysed: 275 during A weeks and 199 during B weeks. Patient characteristics were similar. The hospital LOS (median 7 days during week A versus 7 days during week B, P = 0.29), the proportion of patients with ED-LOS <1 day (63% versus 60%, P = 0.57) and ED antibiotic prescription (59% versus 58%, P = 0.92) were not significantly different. Patients in the POCT arm were more frequently assigned a single room when having a positive PCR for influenza, respiratory syncytial virus and metapneumovirus [52/70 (74%) versus 19/38 (50%) in the central testing arm, P = 0.012]. CONCLUSIONS: Syndromic testing performed in the ED compared with the central laboratory failed to reduce the LOS or antibiotic consumption in patients with acute respiratory illness, but was associated with an increased single-room assignment among patients in whom a significant respiratory pathogen was detected.


Subject(s)
COVID-19 , Point-of-Care Systems , Adult , Emergency Service, Hospital , Humans , Length of Stay , Point-of-Care Testing , SARS-CoV-2
16.
BMJ Open ; 11(10): e052777, 2021 10 25.
Article in English | MEDLINE | ID: covidwho-1484033

ABSTRACT

OBJECTIVES: We conducted a systematic literature review and meta-analysis of observational studies to investigate the association between diabetes, hypertension, body mass index (BMI) or smoking with the risk of death in patients with COVID-19 and to estimate the proportion of deaths attributable to these conditions. METHODS: Relevant observational studies were identified by searches in the PubMed, Cochrane library and Embase databases through 14 November 2020. Random-effects models were used to estimate summary relative risks (SRRs) and 95% CIs. Certainty of evidence was assessed using the Cochrane methods and the Grading of Recommendations, Assessment, Development and Evaluations framework. RESULTS: A total of 186 studies representing 210 447 deaths among 1 304 587 patients with COVID-19 were included in this analysis. The SRR for death in patients with COVID-19 was 1.54 (95% CI 1.44 to 1.64, I2=92%, n=145, low certainty) for diabetes and 1.42 (95% CI 1.30 to 1.54, I2=90%, n=127, low certainty) for hypertension compared with patients without each of these comorbidities. Regarding obesity, the SSR was 1.45 (95% CI 1.31 to 1.61, I2=91%, n=54, high certainty) for patients with BMI ≥30 kg/m2 compared with those with BMI <30 kg/m2 and 1.12 (95% CI 1.07 to 1.17, I2=68%, n=25) per 5 kg/m2 increase in BMI. There was evidence of a J-shaped non-linear dose-response relationship between BMI and mortality from COVID-19, with the nadir of the curve at a BMI of around 22-24, and a 1.5-2-fold increase in COVID-19 mortality with extreme obesity (BMI of 40-45). The SRR was 1.28 (95% CI 1.17 to 1.40, I2=74%, n=28, low certainty) for ever, 1.29 (95% CI 1.03 to 1.62, I2=84%, n=19) for current and 1.25 (95% CI 1.11 to 1.42, I2=75%, n=14) for former smokers compared with never smokers. The absolute risk of COVID-19 death was increased by 14%, 11%, 12% and 7% for diabetes, hypertension, obesity and smoking, respectively. The proportion of deaths attributable to diabetes, hypertension, obesity and smoking was 8%, 7%, 11% and 2%, respectively. CONCLUSION: Our findings suggest that diabetes, hypertension, obesity and smoking were associated with higher COVID-19 mortality, contributing to nearly 30% of COVID-19 deaths. TRIAL REGISTRATION NUMBER: CRD42020218115.


Subject(s)
COVID-19 , Diabetes Mellitus , Hypertension , Body Mass Index , Humans , SARS-CoV-2 , Smoking
17.
Clin Microbiol Infect ; 28(2): 202-221, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1482510

ABSTRACT

BACKGROUND: Vaccines are critical cost-effective tools to control the coronavirus disease 2019 (COVID-19) pandemic. However, the emergence of variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may threaten the global impact of mass vaccination campaigns. AIMS: The objective of this study was to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness and impact of the variants of concern for 19 COVID-19 vaccines. SOURCES: References for this review were identified through searches of PubMed, Google Scholar, BioRxiv, MedRxiv, regulatory drug agencies and pharmaceutical companies' websites up to 22nd September 2021. CONTENT: Overall, all COVID-19 vaccines had a high efficacy against the original strain and the variants of concern, and were well tolerated. BNT162b2, mRNA-1273 and Sputnik V after two doses had the highest efficacy (>90%) in preventing symptomatic cases in phase III trials. mRNA vaccines, AZD1222, and CoronaVac were effective in preventing symptomatic COVID-19 and severe infections against Alpha, Beta, Gamma or Delta variants. Regarding observational real-life data, full immunization with mRNA vaccines and AZD1222 seems to effectively prevent SARS-CoV-2 infection against the original strain and Alpha and Beta variants but with reduced effectiveness against the Delta strain. A decline in infection protection was observed at 6 months for BNT162b2 and AZD1222. Serious adverse event rates were rare for mRNA vaccines-anaphylaxis 2.5-4.7 cases per million doses, myocarditis 3.5 cases per million doses-and were similarly rare for all other vaccines. Prices for the different vaccines varied from $2.15 to $29.75 per dose. IMPLICATIONS: All vaccines appear to be safe and effective tools to prevent severe COVID-19, hospitalization, and death against all variants of concern, but the quality of evidence greatly varies depending on the vaccines considered. Questions remain regarding a booster dose and waning immunity, the duration of immunity, and heterologous vaccination. The benefits of COVID-19 vaccination outweigh the risks, despite rare serious adverse effects.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2
19.
Lancet Infect Dis ; 22(2): 209-221, 2022 02.
Article in English | MEDLINE | ID: covidwho-1428619

ABSTRACT

BACKGROUND: The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. METHODS: DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir-ritonavir, lopinavir-ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77-1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). INTERPRETATION: No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. FUNDING: European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/therapy , Standard of Care , Adenosine Monophosphate/therapeutic use , Aged , Alanine/therapeutic use , COVID-19/drug therapy , COVID-19/mortality , Europe , Extracorporeal Membrane Oxygenation , Female , Hospitalization , Humans , Male , Middle Aged , Oxygen/administration & dosage , Respiration, Artificial
20.
Viruses ; 13(8)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367917

ABSTRACT

An Emergency Use Authorization was issued in the United States and in Europe for a monoclonal antibody monotherapy to prevent severe COVID-19 in high-risk patients. This study aimed to assess the risk of emergence of mutations following treatment with a single monoclonal antibody. Bamlanivimab was administered at a single dose of 700 mg in a one-hour IV injection in a referral center for the management of COVID-19 in France. Patients were closely monitored clinically and virologically with nasopharyngeal RT-PCR and viral whole genome sequencing. Six patients were treated for a nosocomial SARS-CoV-2 infection, all males, with a median age of 65 years and multiple comorbidities. All patients were infected with a B.1.1.7 variant, which was the most frequent variant in France at the time, and no patients had E484 mutations at baseline. Bamlanivimab was infused in the six patients within 4 days of the COVID-19 diagnosis. Four patients had a favorable outcome, one died of complications unrelated to COVID-19 or bamlanivimab, and one kidney transplant patient treated with belatacept died from severe COVID-19 more than 40 days after bamlanivimab administration. Virologically, four patients cleared nasopharyngeal viral shedding within one month after infusion, while two presented prolonged viral excretion for more than 40 days. The emergence of E484K mutants was observed in five out of six patients, and the last patient presented a Q496R mutation potentially associated with resistance. CONCLUSIONS: These results show a high risk of emergence of resistance mutants in COVID-19 patients treated with monoclonal antibody monotherapy.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/complications , Comorbidity , Drug Resistance, Viral/genetics , France , Humans , Male , Middle Aged , Mutation , SARS-CoV-2/drug effects , Severity of Illness Index
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