A living WHO guideline on drugs for covid-19BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3379 (Published 04 September 2020) Cite this as: BMJ 2020;370:m3379
Visual summary of recommendation
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- Reed Siemieniuk, methods chair hydroxychloroquine12a,
- Bram Rochwerg, methods chair remdesivir and lopinavir-ritonavir, critical care physician12a,
- Thomas Agoritsas, internist, methodologist134*b,
- François Lamontagne, methods chair corticosteroids, critical care physician5*b,
- Yee-Sin Leo, clinical chair corticosteroids, infectious disease specialist6ab,
- Helen Macdonald, UK research editor7*,
- Arnav Agarwal, methodologist, internist8*,
- Linan Zeng, methodologist1*,
- Lyubov Lytvyn, methodologist1*,
- John Adabie Appiah, paediatric critical care physician9b,
- Wagdy Amin, chest physician10a,
- Yaseen Arabi, critical care physician11b,
- Lucille Blumberg, infectious disease physician12b,
- Erlina Burhan, chest physician13a,
- Frederique Jacquerioz Bausch, infectious disease physician14a,
- Carolyn S Calfee, intensive care physician15b,
- Bin Cao, chest physician16b,
- Maurizio Cecconi, critical care physician17ab,
- Duncan Chanda, infectious disease physician18a,
- Graham Cooke, infectious disease physician19b,
- Bin Du, critical care physician20a,
- Jake Dunning, infectious disease physician21b,
- Heike Geduld, emergency physician22ab,
- Patrick Gee, patient panel member23ab,
- Madiha Hashimi, critical care physician24a,
- David S Hui, chest physician25b,
- Sushil Kabra, paediatric chest physician26a,
- Seema Kanda, patient partner27ab,
- Leticia Kawano-Dourado, respiratory medicine physician28ab,
- Yae-Jean Kim, paediatric infectious disease physician29ab,
- Niranjan Kissoon, paediatric critical care physician30ab,
- Arthur Kwizera, critical care physician31ab,
- Jon Henrik Laake, critical care physician32b,
- Flavia R Machado, critical care physician33b,
- Imelda Mahaka, patient partner34a,
- Hela Manai, emergency physician35ab,
- Greta Mino, paediatric infectious disease physician36a,
- Emmanuel Nsutebu, infectious disease physician37a,
- Natalia Pshenichnaya, infectious disease physician38a,
- Nida Qadir, critical care physician39ab,
- Saniya Sabzwari, geriatrician40a,
- Rohit Sarin, chest physician41ab,
- Michael Sharland, infectious disease physician42a,
- Yinzhong Shen, infectious disease physician43ab,
- Shalini Sri Ranganathan, paediatric physician44a,
- Joao Souza, obstetrics and gynaecology physician45a,
- Sebastian Ugarte, intensive care physician46a,
- Sridhar Venkatapuram, ethicist47a,
- Vu Quoc Dat, infectious disease physician48a,
- Dubula Vuyiseka, patient partner49a,
- Miriam Stegemann, infectious disease physician50,
- Ananda Wijewickrama, infectious disease physician51a,
- Brittany Maguire, methodologist52*,
- Dena Zeraatkar, methodologist1*,
- Jessica Bartoszko, methodologist1*,
- Long Ge, methodologist153*,
- Romina Brignardello-Petersen, methodologist1*,
- Andrew Owen, clinical pharmacologist54*,
- Gordon Guyatt, methodologist12*,
- Janet Diaz, WHO lead, clinical team for covid-19 response55*c,
- Michael Jacobs, clinical chair remdesivir, hydroxychloroquine, and lopinavir-ritonavir, infectious disease specialist56ac,
- Per Olav Vandvik, methodologist, internist457*c
- 1Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- 2Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- 3Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
- 4MAGIC Evidence Ecosystem Foundation, Oslo, Norway
- 5Université de Sherbrooke, Centre de recherche due CHU de Sherbrooke, Quebec, Canada
- 6National Center for Infectious Diseases, Singapore
- 7The BMJ, London, UK
- 8Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- 9Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
- 10Ministry of Health and Population, Cairo, Egypt
- 11King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- 12National Institute for Communicable Diseases, South Africa
- 13Infection Division, Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia
- 14Geneva University Hospital, Switzerland
- 15University of California, San Francisco, USA
- 16China-Japan Friendship Hospital, Beijing, China
- 17Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center - IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy
- 18Adult Infectious Disease Centre, University Teaching Hospital, Lusaka, Zambia
- 19Imperial College London, London, UK
- 20Peking Union Medical College Hospital, Beijing, China
- 21Public Health England, UK
- 22Division of Emergency Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- 24Ziauddin University, Karachi, Pakistan
- 25Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, China
- 26All India Institute of Medical Sciences, New Delhi, India
- 27McMaster University (alumnus)
- 28Pulmonary Division, Heart Institute (InCor)- HCFMUSP, Medical School, University of Sao Paulo, São Paulo, Brazil and Research Institute, Hospital do Coração (HCor), São Paulo, Brazil
- 29Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea
- 30Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada
- 31Department of Anaesthesia and Critical Care, College of Health Sciences, Makerere University, Kampala, Uganda
- 32Critical Care and Emergencies, Rikshospitalet Medical Centre, Oslo, Norway
- 33Anesthesiology, Pain and Intensive Care, Federal University of São Paulo, Brazil
- 35Emergency Medical Services, Faculty of Medicine, Tunis, Tunisia
- 36Alcivar Hospital in Guayaquil, Ecuador
- 37Sheikh Shakhbout Medical City, Abu Dhabi
- 38Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
- 39Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- 40Aga Khan University, Karachi, Pakistan
- 41National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
- 42St. George’s University Hospital, UK
- 43Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- 44University of Colombo, Sri Lanka
- 45University of Sao Paulo, Brazil
- 46Faculty of Medicine Andres Bello University, Indisa Clinic, Santiago, Chile);
- 47King’s College, London, UK
- 48Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam
- 49University of Stellenbosch, South Africa
- 50Charite, Berlin, Germany
- 51Ministry of Health, Sri Lanka
- 52Infectious Diseases Data Observatory (IDDO), Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- 53Evidence Based Social Science Research Centre, School of Public Health, Lanzhou University, Lanzhou, China and the Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, China
- 54University of Liverpool, UK
- 55World Health Organization, Geneva, Switzerland
- 56Royal Free London NHS Foundation Trust
- 57Department of Health Economics and Health Management, Institute for Health and Society, University of Oslo, Oslo, Norway
- *. Not panel member; resource for methodology, systematic review, and content support
- aRemdesivir, hydroxychloroquine, and lopinavir-ritonavir panel member
- bCorticosteroid panel member
- cCo-senior author
- Correspondence to: Bram Rochwerg , Reed Siemieniuk , or Michael Jacobs
Clinical question What is the role of drug interventions in the treatment of patients with covid-19?
New recommendation The latest version of this WHO living guidance provides strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir in patients with covid-19 regardless of disease severity. These recommendations follow the publication of results from the WHO SOLIDARITY trial
Recommendations This guidance adds to recommendations for corticosteroids and remdesivir published in the previous versions, with no changes made in this update: (a) a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, (b) a conditional recommendation against systemic corticosteroids in patients with non-severe covid-19, (c) a conditional recommendation against remdesivir in hospitalised patients with covid-19.
How this guideline was created WHO has partnered with the non-profit Magic Evidence Ecosystem Foundation (MAGIC) for methodologic support, to develop and disseminate living guidance for covid-19 drug treatments, based on a living systematic review and network analysis. An international standing Guideline Development Group (GDG) of content experts, clinicians, patients, and methodologists produced recommendations following standards for trustworthy guideline development using the GRADE approach. No competing interests were identified for any panel member.
Understanding the new recommendation When moving from the to the strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir in patients with covid-19, the panel was informed by a living systematic review and network meta-analysis of 30 trials with 10 921 participants for hydroxychloroquine and seven trials with 7429 participants for lopinavir-ritonavir. The trials for both drugs included inpatients and outpatients. Moderate certainty evidence for both drugs demonstrated no reduction in mortality or need for mechanical ventilation. There was also low certainty of evidence for harm with both drugs, including diarrhoea and nausea/vomiting. The panel did not anticipate important variability when it comes to patient values and preferences. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and health care systems did not alter the recommendation.
Updates This is a living guideline. It replaces earlier versions (4 September and 20 November 2020) and supersedes the BMJ Rapid Recommendations on remdesivir published on 2 July 2020. The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline.
Readers note This is the third version (update 2) of the living guideline (BMJ 2020;370:m3379). When citing this article, please consider adding the update number and date of access for clarity.
This living guideline responds to emerging evidence from randomised controlled trials (RCTs) on existing and new drug treatments for covid-19. More than 2800 trials on covid-19 interventions have been registered or are ongoing (see section on emerging evidence1). Among these are large national and international platform trials (such as RECOVERY, WHO SOLIDARITY, and DISCOVERY) that recruit large numbers of patients, with a pragmatic and adaptive design.23 These platform trials are currently investigating and reporting on drugs such as antiviral monoclonal antibodies and immunomodulators. This rapidly evolving evidence landscape requires trustworthy interpretation and expeditious clinical practice guidelines to inform clinicians, patients, governments, ministries, and health administrators.
A living network meta-analysis associated with this guideline will incorporate new trial data as the evidence base increases and allow for analysis of comparative effectiveness of multiple covid-19 treatments.4 This network meta-analysis and other related publications are included in box 1. We will also use additional relevant evidence on long term safety, prognosis, and patient values and preferences related to covid-19 treatments to inform the living guidance.
Linked resources in this BMJ Rapid Recommendations cluster
Siemieniuk R, Rochwerg B, Agoritsas T, et al. A living WHO guideline on drugs for covid-19 [Update 2]. BMJ 2020;370:m3379, doi:10.1136/bmj.m3379
World Health Organization. Therapeutics and COVID-19. Living guideline. 17 Dec 2020. https://apps.who.int/iris/bitstream/handle/10665/337876/WHO-2019-nCoV-therapeutics-2020.1-eng.pdf
Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis [Update 2]. BMJ 2020;370:m2980, doi:10.1136/bmj.m2980
Preprint data for update 2 are available in the appendix of the WHO living guideline
Izcovich A, Siemieniuk RAC, Bartoszko JJ, et al. Adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomized trials. Preprint available at: https://www.medrxiv.org/content/10.1101/2020.11.16.20232876v1
Expanded version of the methods, processes, and results with multilayered recommendations, evidence summaries, and decision aids for use on all devices
What triggered this version of the guideline?
This third version of the WHO living guideline addresses the use of hydroxychloroquine and lopinavir-ritonavir in patients with covid-19. It follows the pre-print publication of the WHO SOLIDARITY trial on 15 October, 2020, fully published in the New England Journal of Medicine on 2 December 2020, reporting results on treatment with remdesivir, hydroxychloroquine, and lopinavir-ritonavir in hospitalised patients with covid-19.25 The role of these drugs in clinical practice has remained uncertain, with limited prior trial evidence. The WHO SOLIDARITY trial adds 11 266 randomised patients (2570 to remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir-ritonavir, and 6331 to usual care) and holds the potential to change practice.
In response to the release of SOLIDARITY data, the WHO Guideline Development Group (GDG) started with developing trustworthy recommendations on remdesivir (published 20 November 2020), and now provides recommendations on hydroxychloroquine and lopinavir-ritonavir. Hydroxychloroquine (and chloroquine) is an anti-inflammatory agent that works through blocking of toll-like receptors reducing dendritic cell activation. It is used to treat rheumatoid arthritis and systemic lupus erythematosus. Chloroquine is listed in the WHO Model List of Essential Medicines as an antimalarial, for use only for the treatment of Plasmodium vivax infection. It has an antiviral effect against many viruses in vitro, including SARS-CoV-2, but a clinically useful antiviral effect has not been shown for any viral infection. Lopinavir is a protease inhibitor antiretroviral agent commonly used in combination with ritonavir, which increases the serum concentration of lopinavir. This combination drug is used to treat and prevent HIV infection.
How to use this guideline
This is a living guideline, so the recommendations included here will be updated, and new recommendations will be added on other therapies for covid-19. The infographic provides a summary of the recommendations and includes links to the MAGICapp for more details on the evidence and rationale for the recommendation, as well as patient decision aids. Box 2 outlines key methodological aspects of the guideline process.
How this living guideline was created (see MAGICapp for full details https://app.magicapp.org/#/guideline/nBkO1E)
This guideline was developed by WHO and the MAGIC Evidence Ecosystem Foundation (MAGIC), with support from The BMJ. It is driven by an urgent need for trustworthy and living guidance to rapidly inform policy and practice worldwide during the covid-19 pandemic. WHO has partnered with MAGIC for their methodologic support in the development and dissemination of living guidance for covid-19 drug treatments, in the form of BMJ Rapid Recommendations, to provide patients, clinicians, and policy makers with up to date, evidence based, and user friendly guidelines.
Standards, methods, and processes for living and trustworthy guidance
The panel produced the recommendations following standards for trustworthy guideline development using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, in compliance with the WHO Handbook for Guideline Development 2nd Edition,6 the Institute of Medicine, and the Guideline International Network (G-I-N).7 Details are provided in the WHO guideline (link to website) and MAGICapp (https://app.magicapp.org/#/guideline/nBkO1E).
Selection and support of the panel
For the hydroxychloroquine and lopinavir-ritonavir recommendation, WHO convened an international guideline development panel with 28 individuals, of whom 24 were content experts (clinicians, methodologists, scientists) and four were patients who survived covid-19. The methods chair (methodological expertise) and a clinical chair (content expertise) guided the panel discussions. Panel members were invited by WHO, after consultation with the methods chair and MAGIC, with the aim of achieving gender, geography, expertise, and patient representation balance in the panel. No relevant conflict of interest was identified for any panel member.
As recommended by the WHO handbook, the panel aimed to create a recommendation based on consensus but elected, at the beginning of the first panel meeting, to call a vote if a consensus could not be reached. Before discussions started, the panel determined that a simple majority would provide the direction of the recommendation and that 80% would be required to make a strong recommendation.
Guideline perspective, outcomes, and values and preferences
The target audience for this guidance consists primarily of clinicians, but secondarily of patients and healthcare decision makers. The panel considered an individual patient perspective but also took account of contextual factors (such as resources, feasibility, acceptability, equity) to accommodate global re-use and adaptation for countries and healthcare systems.
During a pandemic, access to healthcare may vary over time and between different countries. The panel defined covid-19 by clinical severity, and mutually exclusive definitions are provided in box 3.
There were insufficient published data to provide the GDG with an informative systematic review of studies describing patients’ experiences or values and preferences on treatment decisions for covid-19 drug treatments. The GDG therefore relied on their own judgments of what well informed patients would value after carefully balancing the benefits, harms, and burdens of treatment and their subsequent treatment preferences. The GDG included four patient representatives who had lived experience with covid-19.
The GDG agreed that the following values and preferences would be representative of those of typical well informed patients:
Mortality would be the outcome most important to patients, followed by need and duration of mechanical ventilation, time to clinical improvement, and serious intervention-related adverse events
Most patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on the outcomes listed above. This was particularly so when evidence suggested treatment effects, if they exist, are small and the possibility of important harm remains.
In an alternative situation with larger benefits and less uncertainty regarding both benefits and harms, more patients would be inclined to choose the intervention.
The GDG acknowledged, however, that values and preferences are likely to vary. There will be patients inclined to use a treatment in which evidence has not excluded important benefit, particularly when the underlying condition is potentially fatal. On the other hand, there will be those who have a high threshold of likely benefit before they will choose the intervention.
Sources of evidence
To create recommendations, the panel relied on evidence synthesised in a living network meta-analysis led by MAGIC.4 While the investigators responsible for the meta-analyses rate the certainty of the evidence, this is re-assessed independently by the guideline panel.
Derivation of absolute effects for drug treatments
The control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, was identified by the remdesivir GDG panel as representing the most relevant source of evidence to make the baseline risk estimates for the outcomes of mortality and mechanical ventilation. The rationale for selecting the WHO SOLIDARITY trial was to reflect the overall prognosis of the global population for which the WHO guideline recommendations are made. In view of the study designs, the GDG determined that for other outcomes using the median or mean of all patients randomised to usual care across the included studies would provide the most reliable estimate of baseline risk.
Of note, baseline risks, and thus absolute effects, may vary significantly geographically and over time. As such, users of this guideline may prefer estimating absolute effects by using local event rates.
Who do the recommendations apply to?
The guideline for covid-19 therapeutics applies to all patients with covid-19. For some drugs (such as corticosteroids), recommendations may differ based on the severity of covid-19 disease. The GDG elected to use the WHO severity definitions based on clinical indicators, adapted from WHO covid-19 severity categorisation (see box 3).8 These definitions avoid reliance on access to healthcare to define patient subgroups. The infographic illustrates these three disease severity groups and key characteristics to apply in practice.
WHO definitions of disease severity for covid-19
Critical covid-19—Defined by the criteria for acute respiratory distress syndrome (ARDS), sepsis, septic shock, or other conditions that would normally require the provision of life sustaining therapies such as mechanical ventilation (invasive or non-invasive) or vasopressor therapy.
Severe covid-19—Defined by any of:
Oxygen saturation <90% on room air*
Respiratory rate >30 breaths per minute in adults and children >5 years old, ≥60 breaths/min in children <2 months old, ≥50 in children 2-11 months old, and ≥40 in children 1-5 years old
Signs of severe respiratory distress (accessory muscle use, inability to complete full sentences, and, in children, very severe chest wall indrawing, grunting, central cyanosis, or presence of any other general danger signs).
Non-severe covid-19—Defined as absence of any signs of severe or critical covid-19.
*The panel noted that the oxygen saturation threshold of 90% to define severe covid-19 was arbitrary and should be interpreted cautiously when defining disease severity. For example, clinicians must use their judgment to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient with chronic lung disease. Similarly, a saturation >90-94% is abnormal, and can be an early sign of severe disease, if the patient is on a downward trend. Generally, if there is any doubt, the panel suggested erring on the side of considering the illness as severe.
The recommendation addressing hydroxychloroquine was informed by results from a systematic review and network meta-analysis that pooled data from 30 RCTs with 10 921 participants. Of note, none of the included RCTs enrolled children or adolescents under the age of 19 years. Given this, the applicability of this recommendation to children is currently uncertain.
Understanding the recommendation on hydroxychloroquine
We recommend against using hydroxychloroquine or chloroquine in addition to usual care for the treatment of patients with covid-19, regardless of disease severity or duration of symptoms (strong recommendation).
Balance of benefit and harm—Hydroxychloroquine and chloroquine probably do not reduce mortality or mechanical ventilation and may not reduce duration of hospitalisation. The evidence does not exclude the potential for a small increased risk of death and mechanical ventilation with hydroxychloroquine. The effect on other less important outcomes—including time to symptom resolution, admission to hospital, and duration of mechanical ventilation—remains uncertain.
Hydroxychloroquine may increase the risk of diarrhoea and nausea or vomiting, a finding consistent with evidence from its use in other conditions. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension, and acute kidney injury, especially in settings where healthcare resources are limited. Whether and to what degree hydroxychloroquine increases the risk of cardiac toxicity, including life threatening arrhythmias, when used in patients with covid-19 is uncertain.
Subgroup analyses indicated no effect modification based on severity of illness (comparing either critical versus severe/non-severe or non-severe versus critical/severe) or age (comparing those aged <70 years versus those ≥70 years). Further, the cumulative dose and predicted Day 3 serum trough concentrations (lowest predicted blood concentration on Day 3) did not modify the effect for any outcome. Therefore, we assumed similar effects in all subgroups. Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients with patients early in the disease course for early treatment (that is, as early as one day in outpatient setting). The GDG also noted the challenges in capturing this variable in large platform trials. The GDG panel therefore felt that the evidence applies to all patients with covid-19.
We also reviewed evidence comparing the use of hydroxychloroquine plus azithromycin versus hydroxychloroquine alone. There was no evidence that the addition of azithromycin modified the effect of hydroxychloroquine for any outcome (very low certainty).
Values and preferences—Applying the agreed values and preferences (box 2), the GDG inferred that almost all well informed patients would not want to receive hydroxychloroquine given the evidence suggesting there was probably no effect on mortality or need for mechanical ventilation and that there was a risk of adverse events including diarrhoea and nausea/vomiting. The panel did not expect there would be much variation among patients in values and preferences when it came to this intervention.
Resource implications, feasibility, equity, and human rights—Hydroxychloroquine and chloroquine are relatively inexpensive and are already widely available, including in low income settings. Despite this, the panel felt that almost all patients would choose not to use hydroxychloroquine or chloroquine because the harms outweigh the benefits. Although the cost may be low per patient, the GDG panel raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe covid-19 and other supportive care interventions.
The recommendation addressing lopinavir-ritonavir was informed by the same systematic review and network meta-analysis, but in this case including seven RCTs with 7429 participants. None of the included RCTs enrolled children or adolescents under the age of 19 years, so the applicability of this recommendation to children is uncertain.
Understanding the recommendation on lopinavir-ritonavir
We recommend against using lopinavir-ritonavir in addition to usual care for the treatment of patients with covid-19 regardless of disease severity (strong recommendation).
Balance of benefit and harm—The GDG panel found a lack of evidence that lopinavir-ritonavir improved patient-important outcomes such as reduced mortality, need for mechanical ventilation, time to clinical improvement, and others. For mortality and need for mechanical ventilation, this was based on moderate certainty evidence; for the other outcomes, low or very low certainty evidence.
There was low certainty evidence that lopinavir-ritonavir may increase the risk of diarrhoea and nausea or vomiting, a finding consistent with the indirect evidence evaluating its use in patients with HIV infection. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension, and acute kidney injury, especially in settings where healthcare resources are limited. There was an uncertain effect on viral clearance and acute kidney injury.
Subgroup analysis indicated no effect modification based on severity of illness (comparing either critical versus severe/non-severe or non-severe versus critical/severe) or age (comparing those aged <70 years versus those ≥70 years). As there was no evidence of a statistical subgroup effect, we did not formally evaluate credibility. Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients with patients early in the disease course. The GDG panel therefore felt that the evidence applies to all patients with covid-19.
Values and preferences—Applying the agreed values and preferences (box 2), the GDG inferred that almost all well informed patients would not want to receive lopinavir-ritonavir given that the evidence suggested there was probably no effect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea or vomiting. The panel did not expect there would be much variation in values and preferences between patients for this intervention.
Resource implications, feasibility, equity, and human rights—Although the cost of lopinavir-ritonavir is not as high as some other investigational drugs for covid-19 and the drug is generally available in most healthcare settings, the GDG raised concerns about opportunity costs and the importance of not drawing attention and resources away from best supportive care or the use of corticosteroids in severe covid-19.
Remdesivir (published 20 November 2020)
The recommendation addressing remdesivir was informed by results from a systematic review and network meta-analysis that pooled data from four randomised trials with 7333 participants hospitalised for covid-19.291011 Of note, none of the included RCTs enrolled children or adolescents under the age of 19 years, and, although older people were included in the trials, their outcomes were not reported separately. Also, there is no pharmacokinetic or safety data on remdesivir for children. Given this, the applicability of this recommendation to children is currently uncertain. The WHO guideline publication and MAGICapp provides details about the evidence, such as characteristics of trials, subgroup analyses performed, and underlying panel discussions to inform recommendations (see box 1 for links).
Understanding the recommendation on remdesivir
We suggest against administering remdesivir in addition to usual care for the treatment of patients hospitalised with covid-19 regardless of disease severity (weak or conditional recommendation).
When moving from evidence to the conditional recommendation against the use of remdesivir for patients with covid-19, the panel emphasised the evidence of possibly no effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes, albeit of low certainty; it also noted the anticipated variability in patient values and preferences and other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity (see below).
Importantly, given the low certainty evidence for these outcomes, the panel concluded that the evidence did not prove that remdesivir has no benefit; rather, there is no evidence based on currently available data that it does improve patient-important outcomes. Especially given the costs and resource implications associated with remdesivir, but consistent with the approach that should be taken with any new drug, the panel felt the responsibility should be on demonstrating evidence of efficacy, which is not established by the currently available data.
Balance of benefit and harm—The GDG panel found a lack of evidence that remdesivir improved outcomes that matter to patients such as reduced mortality, need for mechanical ventilation, time to clinical improvement, and others. There was no evidence of increased risk of serious adverse events in patients receiving remdesivir, at least from the included trials. Further pharmacovigilance is required to confirm this, as serious adverse events are commonly underreported and rare events would be missed, even in large RCTs.
Data from the network meta-analysis indicated that a subgroup of people with non-critical disease might benefit from remdesivir. However, the panel judged the credibility in this subgroup analysis to be insufficient to make subgroup recommendations.12 Important factors influencing this decision included a lack of a priori hypothesised direction of subgroup effect by trial investigators, little or no previously existing supportive evidence for the subgroup finding, and relatively arbitrary cut points used to examine the subgroups of interest. The overall low certainty evidence for the benefits and harms of remdesivir, driven by risk of bias and imprecision limitations, also contributed to the judgment (see WHO guidance and MAGICapp linked from box 1 for full details). The panel highlighted that, despite the conditional recommendation against remdesivir, they support further enrolment into RCTs evaluating remdesivir, especially to provide higher certainty of evidence for specific subgroups of patients. The panel had a priori requested analyses of other important subgroups of patients, including children and older people, but there were no data to address these groups specifically.
Values and preferences—The panel inferred that most patients would be reluctant to use remdesivir given that the evidence left high uncertainty regarding effects on mortality and the other prioritised outcomes. This was particularly so as any beneficial effects of remdesivir, if they do exist, are likely to be small, and the possibility of important harm remains. The panel acknowledged, however, that values and preferences are likely to vary, and there will be patients and clinicians who choose to use remdesivir given that the evidence has not excluded the possibility of benefit.
Resource implications, feasibility, equity, and human rights—A novel therapy typically requires higher certainty evidence of important benefits than is currently available for remdesivir, preferably supported wherever possible by cost-effectiveness analysis. In the absence of this information, the GDG raised concerns about opportunity costs and the importance of not drawing attention and resources away from best supportive care or the use of corticosteroids in severe covid-19. It was noted that, currently, remdesivir is administered only by the intravenous route and global availability is limited.
Practical issues—Its use is contraindicated in those with liver dysfunction (ALT >5 times normal at baseline) or renal dysfunction (eGFR <30 mL/minute). To date, it can only be administered intravenously, and it has relatively limited availability.
Corticosteroids (published 4 September 2020)
On 17 July 2020 the panel reviewed evidence from eight RCTs (7184 patients)1314151617 evaluating systemic corticosteroids versus usual care in treatment of covid-19, seven of which reported mortality data by subgroup of illness severity. Mortality data from one trial, GLUCOCOVID, were not incorporated in the summary of finding for mortality because the mortality outcome data were not available by subgroup. The panel did not consider transdermal or inhaled administration of corticosteroids, high dose or long term regimens, or prophylaxis. The panel did not reach consensus on recommendation 1, which required a vote. The second recommendation was made by consensus. The WHO guideline publication and MAGICapp provides details about the evidence, such as characteristics of trials, subgroup analyses performed, and underlying panel discussions to inform recommendations (see box 1 for link).
Understanding the recommendations on corticosteroids
Recommendation 1: We recommend systemic corticosteroids rather than no systemic corticosteroids for the treatment of patients with severe and critical covid-19 (strong recommendation)
Who does it apply to? This recommendation applies to patients with severe and critical covid-19. The panel judged that all or almost all fully informed patients with severe covid-19 would choose to take systemic corticosteroids. The recommendation should apply to patients with severe and critical covid-19 even if they cannot be hospitalised or receive oxygen because of resource limitations.
The applicability of the recommendation is less clear for populations that were under-represented in the considered trials, such as children, patients with tuberculosis, and those who are immunocompromised. In considering potential contraindications to short term systemic corticosteroids in such patients, clinicians must determine if they warrant depriving a patient of a potentially lifesaving therapy. Clinicians should exercise caution in use of corticosteroids in patients with diabetes or underlying immunocompromise. The panel was confident that clinicians using these guidelines would be aware of additional potential side effects and contraindications to systemic corticosteroid therapy, which may vary geographically in function of endemic microbiological flora.
Balance of benefit and harm—Ultimately, the panel made its recommendation on the basis of the moderate certainty evidence of a 28 day mortality reduction of 8.7% in the critically ill and 6.7% reduction in patients with severe covid-19 who were not critically ill. Systemic corticosteroids compared with no corticosteroid therapy probably reduce the risk of 28 day mortality in critically ill patients with covid-19 (moderate certainty evidence; relative risk 0.80 (95% confidence interval 0.70 to 0.91); absolute effect estimate 87 fewer deaths per 1000 patients (95% CI 124 fewer to 41 fewer)). In patients with severe covid-19, systemic corticosteroids also probably reduce the risk of death (moderate certainty evidence; relative risk 0.80 (0.70 to 0.92); absolute effect estimate 67 fewer deaths per 1000 patients (100 fewer to 27 fewer)). The effects of systemic corticosteroids on other outcomes are described in the summary of findings.
Overall, the panel has high certainty that the adverse effects when considered together are sufficiently limited in importance and frequency and suggested that corticosteroids administered in these doses for 7-10 days are not associated with an increased risk of adverse events, beyond likely increasing the incidence of hyperglycaemia (moderate certainty evidence; absolute effect estimate 46 more per 1000 patients (23 more to 72 more)) and hypernatraemia (moderate certainty evidence; 26 more per 1000 patients (13 more to 41 more)). In contrast with new agents proposed for covid-19, clinicians have a vast experience of systemic corticosteroids, and the panel was reassured by their overall safety profile.
Values and preferences—The panel took an individual patient perspective to values and preferences but, given the burden of the pandemic for healthcare systems globally, also placed a high value on resource allocation and equity. The benefits of corticosteroids on mortality was deemed of critical importance to patients, with little or no anticipated variability in their preference to be offered treatment if severely ill from covid-19.
Resource implications, feasibility, equity, and human rights—Systemic corticosteroids are low cost, easy to administer, and readily available globally.18 Dexamethasone and prednisolone are among the most commonly listed medicines in national essential medicines lists; listed by 95% of countries. Accordingly, systemic corticosteroids are among a relatively small number of interventions for covid-19 that have the potential to reduce inequities and improve equity in health. Those considerations influenced the strength of this recommendation.
Acceptability—The ease of administration, the relatively short duration of a course of systemic corticosteroid therapy, and the generally benign safety profile of systemic corticosteroids administered for up to 7-10 days led the panel to conclude that the acceptability of this intervention was high.
Recommendation 2: We suggest not to use corticosteroids in the treatment of patients with non-severe covid-19 (weak or conditional recommendation)
Who does it apply to? This recommendation applies to patients with non-severe disease regardless of their hospitalisation status. The panel noted that patients with non-severe covid-19 would not normally require acute care in hospital or respiratory support, but in some jurisdictions these patients may be hospitalised for isolation purposes only, in which case they should not be treated with systemic corticosteroids. Several specific circumstances were considered.
Systemic corticosteroids should not be stopped for patients with non-severe covid-19 who are already treated with systemic corticosteroids for other reasons (such as patients with chronic obstructive pulmonary disease or chronic autoimmune disease).
If the clinical condition of patients with non-severe covid-19 worsens (that is, increase in respiratory rate, signs of respiratory distress or hypoxaemia) they should receive systemic corticosteroids (see recommendation 1).
Pregnancy: antenatal corticosteroid therapy may be administered for pregnant women at risk of preterm birth from 24 to 34 weeks’ gestation when there is no clinical evidence of maternal infection and adequate childbirth and newborn care are available. In cases where the woman presents with mild or moderate covid-19, the clinical benefits of antenatal corticosteroid might outweigh the risks of potential harm to the mother. In this situation, the balance of benefits and harms for the woman and the preterm newborn should be discussed with the woman to ensure an informed decision, as this assessment may vary depending on the woman’s clinical condition, her wishes and those of her family, and available healthcare resources.
Endemic infections that may worsen with corticosteroids should be considered. For example, for Strongyloides stercoralis hyperinfection associated with corticosteroid therapy, diagnosis or empiric treatment may be considered in endemic areas if steroids are used.
Balance of benefit and harm—Systemic corticosteroids may increase the risk of 28 day mortality (low certainty evidence; relative risk 1.22 (95% CI 0.93 to 1.61); absolute effect estimate 39 more per 1000 patients (95% CI 12 fewer to 107 more)). The certainty of the evidence for this specific subgroup was downgraded due to serious imprecision (that is, the evidence does not allow to rule out a mortality reduction) and risk of bias due to lack of blinding. The effects of systemic corticosteroids on other outcomes are described in the summary of findings (infographic and links to MAGICapp).
Values and preferences—The weak or conditional recommendation was driven by likely variation in patient values and preferences. The panel judged that most individuals with non-severe illness would decline systemic corticosteroids. However, many may want them after shared decision making with their treating physician.
Resource implications, feasibility, equity, and human rights—To help guarantee access to systemic corticosteroids for patients with severe and critical covid-19, it is reasonable to avoid their administration to patients who, given the current evidence, do not seem to derive any benefit from this intervention
Uncertainties, emerging evidence, and future research
The guideline recommendations for covid-19 therapeutics demonstrate remaining uncertainties concerning treatment effects for all outcomes of imp