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BMJ ; 370: m3379, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-2316359


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.

Adrenal Cortex Hormones/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , COVID-19 , Humans , Pandemics , SARS-CoV-2 , World Health Organization , COVID-19 Drug Treatment
Ann Intern Med ; 174(2): 283-284, 2021 02.
Article in English | MEDLINE | ID: covidwho-1553980
Clin Microbiol Infect ; 27(7): 1007-1010, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1141681


OBJECTIVES: To compare the gender distribution of clinical trial leadership in coronavirus disease 2019 (COVID-19) clinical trials. METHODS: We searched and retrieved all clinical trials on COVID-19 from 1 January 2020 to 26 June 2020. As a comparator group, we have chosen two fields that are not related to emerging infections and infectious diseases: and considered not directly affected by the pandemic: breast cancer and type 2 diabetes mellitus (T2DM) and included studies within the aforementioned study period as well as those registered in the preceding year (pre-study period: 1 January 2019 to 31 December 2019). Gender of the investigator was predicted using the application programming interface. The repository of the data sets used to collect and analyse the data are available at RESULTS: Only 27.8% (430/1548) of principal investigators among COVID-19-related studies were women, which is significantly different compared with 54.9% (156/284) and 42.1% (56/133) for breast cancer (p < 0.005) and T2DM (p < 0.005) trials over the same period, respectively. During the pre-study period, the proportion of principal investigators who were predicted to be women were 49.7% (245/493) and 44.4% (148/333) for breast cancer and T2DM trials, respectively, and the difference was not statistically significant when compared with results from the study period (p > 0.05). CONCLUSION: We demonstrate that less than one-third of COVID-19-related clinical trials are led by women, half the proportion observed in non-COVID-19 trials over the same period, which remained similar to the pre-study period. These gender disparities during the pandemic may not only indicate a lack of female leadership in international clinical trials and involvement in new projects but also reveal imbalances in women's access to research activities and funding during health emergencies.

COVID-19 , Leadership , Women , Breast Neoplasms , Clinical Trials as Topic/statistics & numerical data , Diabetes Mellitus, Type 2 , Female , Humans , Male , Research Personnel/statistics & numerical data , Sex Ratio , Sexism
Open Forum Infect Dis ; 8(2): ofaa658, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1010613


In this perspective, we discuss the importance of developing a vaccine to help curb transmission of severe acute respiratory syndrome coronavirus 2. The question remains: Once a safe and effective vaccine is developed, will the public be willing to get it? We present information from one of the first tracking polls to assess public attitudes and perceptions toward a possible coronavirus disease 2019 vaccine that suggests public hesitancy over a potential vaccine, concern regarding accelerating clinical trials, and unease over the vaccine approval process. Public health experts, government officials, advocates, and others in the scientific community should respect the signals of hesitancy and communicate sensitivity, applying lessons not only to how we message, but also in how we build this urgently needed vaccine if we are to have successful uptake once available.