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A living WHO guideline on drugs for covid-19
Agarwal, Arnav; Rochwerg, Bram; Lamontagne, François; Siemieniuk, Reed Ac; Agoritsas, Thomas; Askie, Lisa; Lytvyn, Lyubov; Leo, Yee-Sin; Macdonald, Helen; Zeng, Linan; Amin, Wagdy; da Silva, André Ricardo Araujo; Aryal, Diptesh; Barragan, Fabian AJ; Bausch, Frederique Jacquerioz; Burhan, Erlina; Calfee, Carolyn S; Cecconi, Maurizio; Chacko, Binila; Chanda, Duncan; Dat, Vu Quoc; De Sutter, An; Du, Bin; Freedman, Stephen; Geduld, Heike; Gee, Patrick; Gotte, Matthias; Harley, Nerina; Hashimi, Madiha; Hunt, Beverly; Jehan, Fyezah; Kabra, Sushil K; Kanda, Seema; Kim, Yae-Jean; Kissoon, Niranjan; Krishna, Sanjeev; Kuppalli, Krutika; Kwizera, Arthur; Lado Castro-Rial, Marta; Lisboa, Thiago; Lodha, Rakesh; Mahaka, Imelda; Manai, Hela; Mendelson, Marc; Migliori, Giovanni Battista; Mino, Greta; Nsutebu, Emmanuel; Preller, Jacobus; Pshenichnaya, Natalia; Qadir, Nida.
  • Agarwal A; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  • Rochwerg B; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • Lamontagne F; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • Siemieniuk RA; Not panel member; resource for methodology, systematic review, and content support
  • Agoritsas T; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  • Askie L; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • Lytvyn L; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Leo YS; ivermectin and IL-6 receptor blocker panel member
  • Macdonald H; Université de Sherbrooke, Centre de recherche due CHU de Sherbrooke, Quebec, Canada
  • Zeng L; Not panel member; resource for methodology, systematic review, and content support
  • Amin W; Corticosteroid panel member
  • da Silva ARA; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  • Aryal D; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • Barragan FAJ; Not panel member; resource for methodology, systematic review, and content support
  • Bausch FJ; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Burhan E; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  • Calfee CS; Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  • Cecconi M; MAGIC Evidence Ecosystem Foundation, Oslo, Norway
  • Chacko B; Not panel member; resource for methodology, systematic review, and content support
  • Chanda D; Corticosteroid panel member
  • Dat VQ; World Health Organization, Geneva, Switzerland
  • De Sutter A; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  • Du B; Not panel member; resource for methodology, systematic review, and content support
  • Freedman S; National Center for Infectious Diseases, Singapore
  • Geduld H; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Gee P; Corticosteroid panel member
  • Gotte M; ivermectin and IL-6 receptor blocker panel member
  • Harley N; The BMJ, London, UK
  • Hashimi M; Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center - IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy
  • Hunt B; Not panel member; resource for methodology, systematic review, and content support
  • Jehan F; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  • Kabra SK; Not panel member; resource for methodology, systematic review, and content support
  • Kanda S; Ministry of Health and Population, Cairo, Egypt
  • Kim YJ; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Kissoon N; ivermectin and IL-6 receptor blocker panel member
  • Krishna S; Fluminense Federal University, Brazil
  • Kuppalli K; Mediciti Hospital, Nepal
  • Kwizera A; Antioquia University Medellin, Colombia
  • Lado Castro-Rial M; Geneva University Hospital, Switzerland
  • Lisboa T; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Lodha R; ivermectin and IL-6 receptor blocker panel member
  • Mahaka I; Infection Division, Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia
  • Manai H; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Mendelson M; ivermectin and IL-6 receptor blocker panel member
  • Migliori GB; University of California, San Francisco, USA
  • Mino G; Corticosteroid panel member
  • Nsutebu E; ivermectin and IL-6 receptor blocker panel member
  • Preller J; Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center - IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy
  • Pshenichnaya N; Remdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
  • Qadir N; Corticosteroid panel member
BMJ ; 370: m3379, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-2316359
ABSTRACT
UPDATES This is the twelfth version (eleventh 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 randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19. NEW OR UPDATED

RECOMMENDATIONS:

• Remdesivir a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use. UNDERSTANDING THE NEW

RECOMMENDATIONS:

When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted. PRIOR

RECOMMENDATIONS:

• Recommended for patients with severe or critical covid-19­strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation­a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19­a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation­a conditional recommendation against nirmatrelvir/ritonavir. • 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 the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity­a strong recommendations against hydroxychloroquine and 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 evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the 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. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future

recommendations:

Recommendations on anticoagulation are planned for the next update to this guideline.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Adrenal Cortex Hormones / Coronavirus Infections / Betacoronavirus Type of study: Experimental Studies / Prognostic study / Randomized controlled trials / Reviews / Systematic review/Meta Analysis Topics: Variants Limits: Humans Language: English Journal: BMJ Journal subject: Medicine Year: 2020 Document Type: Article Affiliation country: Bmj.m3379

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Adrenal Cortex Hormones / Coronavirus Infections / Betacoronavirus Type of study: Experimental Studies / Prognostic study / Randomized controlled trials / Reviews / Systematic review/Meta Analysis Topics: Variants Limits: Humans Language: English Journal: BMJ Journal subject: Medicine Year: 2020 Document Type: Article Affiliation country: Bmj.m3379