Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
1.
BMJ ; 374: n2231, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438073

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a data supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).


Subject(s)
Antibodies, Viral/therapeutic use , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , SARS-CoV-2/immunology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , Bayes Theorem , COVID-19/immunology , Clinical Trials as Topic , Humans , Immunization, Passive , Network Meta-Analysis , Treatment Outcome
2.
BMJ ; 370: m3379, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-744846

ABSTRACT

UPDATES: This is the tenth version (ninth update) of the living guideline, replacing earlier versions, available as data supplements. New recommendations will be published as updates to this guideline. CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19? CONTEXT: The evidence base for therapeutics for covid-19 is evolving with numerous recently completed randomised controlled trials (RCTs). In this update the Guideline Development Group (GDG) developed new recommendations for patients with non-severe covid-19, concerning the use of nirmatrelvir/ritonavir (2 RCTs, 3100 participants) and remdesivir (5 RCTs, 2710 participants). We have also revised the structure of the guideline to accommodate for an increasing number of effective treatment options to choose between. NEW RECOMMENDATION: • Nirmatrelvir/ritonavir: a strong recommendation for its use in patients at highest risk of hospitalisation; and a conditional recommendation against its use in patients at low risk of hospitalisation. In the absence of trial data, no recommendation on nirmatrelvir/ritonavir was made in patients with severe or critical illness. • Remdesivir: a conditional recommendation for its use in patients at highest risk of hospitalisation. UNDERSTANDING THE NEW RECOMMENDATIONS: In patients with non-severe illness at highest risk of hospitalisation, the recommendations for treatment with nirmatrelvir/ritonavir and remdesivir reflect what the GDG considered to be important reductions in admission to hospital (moderate certainty) with little or no impact on mortality, mechanical ventilation, time to symptom resolution (low to very low certainty), and adverse effects leading to drug discontinuation (high certainty for nirmatrelvir/ritonavir, moderate certainty for remdesivir), though diarrhoea and altered taste were noted more often with nirmatrelvir/ritonavir. Several treatment alternatives are now available for patients with non-severe covid-19 at highest risk of hospitalisation. In the absence of direct comparisons in trials, indirect comparisons from the living network meta-analysis have been used to inform the use of one drug over another with a related mechanism of action. Choices will depend on availability of the drugs, routes of administration (only intravenous for remdesivir), duration of treatment, and time from onset of symptoms to starting treatment in the trials. The strong recommendation for nirmatrelvir/ritonavir reflects what the GDG considered to represent a superior choice over other treatment options for those with non-severe illness at highest risk; it may prevent more hospitalisations than the alternatives, has fewer harms than molnupiravir, and is easier to administer than intravenous options such as remdesivir and the monoclonal antibodies. For monoclonal antibodies, efficacy may depend on the given SARS-CoV-2 variant, with a less certain benefit seen with the omicron BA1-2 variant which is dominating in many regions. There are no clinical data on combination treatment, and currently the GDG advises against combining antivirals in the absence of supporting evidence. UPDATES TO PRIOR RECOMMENDATIONS: The conditional (weak) recommendation for remdesivir in patients with non-severe illness at highest risk of hospitalisation replaces a previous conditional recommendation against treatment with remdesivir in all patients with covid-19 regardless of disease severity. The recommendation for patients with severe or critical illness is being updated using new evidence. PRIOR RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19­a strong recommendation for systemic corticosteroids; a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab), in combination with corticosteroids; a strong recommendation for baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids; and a conditional recommendation for casirivimab-imdevimab, for those with seronegative status, (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant). • Recommended for patients with non-severe covid-19­conditional recommendations for those at highest risk of hospitalisation for molnupiravir; sotrovimab; and for casirivimab-imdevimab (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant). • Not recommended for patients with non-severe covid-19­a conditional recommendation against systemic corticosteroids; and a strong recommendation against convalescent plasma. • Not recommended for patients with severe or critical covid-19­a recommendation against convalescent plasma, except in the context of a clinical trial; and a conditional recommendation against ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity­a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; and a recommendation against ivermectin, except in the context of a clinical trial. ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates new recommendations on two drugs for covid-19 and updates existing recommendations. The GDG typically evaluates a therapy when WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , COVID-19 , Humans , Pandemics , SARS-CoV-2 , World Health Organization
3.
BMJ ; 370: m2980, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-691120

ABSTRACT

OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. CONCLUSION: Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is publicly available in the supplementary material. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiration, Artificial/statistics & numerical data , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Betacoronavirus/pathogenicity , COVID-19 , Centers for Disease Control and Prevention, U.S./statistics & numerical data , China/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/virology , Databases, Factual/statistics & numerical data , Drug Combinations , Evidence-Based Medicine/methods , Evidence-Based Medicine/statistics & numerical data , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Network Meta-Analysis , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Ritonavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Standard of Care , Treatment Outcome , United States/epidemiology
SELECTION OF CITATIONS
SEARCH DETAIL