BMJ m3379 Full

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RAPID RECOMMENDATIONS
BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from http://www.bmj.com/ on 2 January 2023 by guest. Protected by copyright.
For numbered affiliations see end of
article.
Correspondence for this iteration to:
François Lamontagne
francois.lamontagne@usherbrooke.ca;
A living WHO guideline on drugs for covid-19
Miriam Stegemann
miriam.stegemann@charite.de. Arnav Agarwal, 1, 2, 3, * Bram Rochwerg, 1, 2, * François Lamontagne, 4, * Reed AC Siemieniuk, 1, 2, *
Additional material is published online Thomas Agoritsas, 1, 3, 5, * Lisa Askie, 6, * Lyubov Lytvyn, 1, * Yee-Sin Leo, 7 Helen Macdonald, 8, * Linan Zeng, 1,
only. To view please visit the journal *
online
Wagdy Amin, 9 André Ricardo Araujo da Silva, 10 Diptesh Aryal, 11 Fabian A Jaimes Barragan, 12
Cite this as: BMJ 2020;370:m3379 Frederique J Bausch, 13 Erlina Burhan, 14 Carolyn S Calfee, 15 Maurizio Cecconi, 16 Binila Chacko, 17
http://dx.doi.org/10.1136/bmj.m3379 Duncan Chanda, 18 Vu Quoc Dat, 19 An De Sutter, 20 Bin Du, 21 Stephen Freedman, 22 Heike Geduld, 23
Patrick Gee, 24 Matthias Gotte, 25 Nerina Harley, 26 Madiha Hashmi, 27 Beverley Hunt, 28 Fyezah Jehan, 29
Sushil K Kabra, 30 Seema Kanda, 31 Yae-Jean Kim, 32 Niranjan Kissoon, 33 Sanjeev Krishna, 34 Krutika Kuppalli, 6
Arthur Kwizera, 35 Marta Lado Castro-Rial, 6, * Thiago Lisboa, 36 Rakesh Lodha, 37 Imelda Mahaka, 38
Hela Manai, 39 Marc Mendelson, 40 Giovanni Battista Migliori, 41 Greta Mino, 42 Emmanuel Nsutebu, 43
Jacobus Preller, 6, * Natalia Pshenichnaya, 44 Nida Qadir, 45 Pryanka Relan, 6, * Saniya Sabzwari, 46
Rohit Sarin, 47 Manu Shankar-Hari, 48 Michael Sharland, 49 Yinzhong Shen, 50 Shalini S Ranganathan, 51
Joao P Souza, 52 Miriam Stegemann, 53 Ronald Swanstrom, 54 Sebastian Ugarte, 55 Tim Uyeki, 56
Sridhar Venkatapuram, 57 Dubula Vuyiseka, 58 Ananda Wijewickrama, 59 Lien Tran, 60, * Dena Zeraatkar, 1,
*
Jessica J Bartoszko, 1, * Long Ge, 1, 61, * Romina Brignardello-Petersen, 1, * Andrew Owen, 62, * Gordon Guyatt, 1,
2, a, *
Janet Diaz, 6, a, * Leticia Kawano-Dourado, 63 Michael Jacobs, 64, a Per Olav Vandvik3, 65, a, *
ABSTRACT UNDERSTANDING THE NEW RECOMMENDATIONS
UPDATES When moving from new evidence to updated
This is the twelfth version (eleventh update) of the recommendations, the Guideline Development Group
living guideline, replacing earlier versions (available (GDG) considered a combination of evidence
as data supplements). New recommendations will assessing relative benefits and harms, values and
be published as updates to this guideline. preferences, and feasibility issues.
CLINICAL QUESTION For remdesivir, new trial data were added to a
What is the role of drugs in the treatment of patients previous subgroup analysis and provided sufficiently
with covid-19? trustworthy evidence to demonstrate benefits in
CONTEXT patients with severe covid-19, but not critical
The evidence base for therapeutics for covid-19 is covid-19. The GDG considered benefits of remdesivir
evolving with numerous randomised controlled trials to be modest and of moderate certainty for key
(RCTs) recently completed and under way. The outcomes such as mortality and mechanical
emerging SARS-CoV-2 variants (such as omicron) and ventilation, resulting in a conditional
subvariants are also changing the role of recommendation.
therapeutics. This update provides updated For baricitinib, the GDG considered clinical trial
recommendations for remdesivir, addresses the use evidence (RECOVERY) demonstrating reduced risk of
of combination therapy with corticosteroids, death in patients already receiving corticosteroids
interleukin-6 (IL-6) receptor blockers, and janus and IL-6 receptor blockers. The GDG acknowledged
kinase (JAK) inhibitors in patients with severe or that the clinical trials were not representative of the
critical covid-19, and modifies previous world population and that the risk-benefit balance
recommendations for the neutralising monoclonal may be less advantageous, particularly in patients
antibodies sotrovimab and casirivimab-imdevimab who are immunosuppressed at higher risk of
in patients with non-severe covid-19. opportunistic infections (such as serious fungal, viral,
NEW OR UPDATED RECOMMENDATIONS or bacteria), those already deteriorating where less
aggressive or stepwise addition of
• Remdesivir: a conditional recommendation for its
immunosuppressive medications may be preferred,
use in patients with severe covid-19; and a
and in areas where certain pathogens such as HIV or
conditional recommendation against its use in
tuberculosis, are of concern. The panel anticipated
patients with critical covid-19.
that there would be situations where clinicians may
• Concomitant use of IL-6 receptor blockers
opt for less aggressive immunosuppressive therapy
(tocilizumab or sarilumab) and the JAK inhibitor
or to combine medications in a stepwise fashion in
baricitinib: these drugs may now be combined, in
patients who are deteriorating. The decision to
addition to corticosteroids, in patients with severe
combine the medications will depend on their
or critical covid-19.
availability, and the treating clinician's perception
• Sotrovimab and casirivimab-imdevimab: strong
of the risk-benefit balance associated with
recommendations against their use in patients with
combination immunosuppressive therapy, particularly
covid-19, replacing the previous conditional
in patient populations at risk of opportunistic
recommendations for their use.
the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379 1

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infections who may have been under-represented in clinical trials. encouraged by WHO to contextualise recommendations in a
When making a strong recommendation against the use of healthcare system to maximise impact.
monoclonal antibodies for patients with covid-19, the GDG FUTURE RECOMMENDATIONS
considered in vitro neutralisation data demonstrating that Recommendations on anticoagulation are planned for the next
sotrovimab and casirivimab-imdevimab evaluated in clinical trials update to this guideline.
have meaningfully reduced neutralisation activity of the currently Vaccines are linked to limiting hospitalisations, but limitations in
circulating variants of SARS-CoV-2 and their subvariants. There was global access and residual uncertainties remain regarding the
consensus among the panel that the absence of in vitro duration of protection following vaccination or natural infection,
neutralisation activity strongly suggests absence of clinical and their efficacy against emerging SARS-CoV-2 variants and
effectiveness of these monoclonal antibodies. However, there was subvariants. Therefore, the potential for drugs to treat people
also consensus regarding the need for clinical trial evidence in order infected with covid-19 remains of interest. This living guideline
to confirm clinical efficacy of new monoclonal antibodies that responds to emerging evidence from randomised controlled trials
reliably neutralise the circulating strains in vitro. Whether emerging (RCTs) on existing and new drug treatments for covid-19.
new variants and subvariants might be susceptible to sotrovimab,
More than 5000 trials investigating covid-19 interventions have
casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal
been registered or are ongoing (see section on emerging evidence1).
antibodies cannot be predicted.
Although most of these studies are small and of variable
PRIOR RECOMMENDATIONS
methodological quality, some large, international platform trials
• Recommended for patients with severe or critical covid-19—strong
have provided robust evidence. Such trials can also adapt their
recommendations for systemic corticosteroids; IL-6 receptor
design, recruitment strategies, and selection of interventions based
blockers (tocilizumab or sarilumab) in combination with
on new insights. Examples include ACCT, RECOVERY, WHO
corticosteroids; and baricitinib as an alternative to IL-6 receptor
SOLIDARITY, REMAP-CAP, and ACTIV, which recruit large numbers
blockers, in combination with corticosteroids.
of patients in many countries.2 -5 An overview of ongoing trials is
• Recommended for patients with non-severe covid-19 at highest
available from the Infectious Diseases Data Observatory, through
risk of hospitalisation—a strong recommendation for
their living systematic review of covid-19 clinical trial registrations1
nirmatrelvir/ritonavir; conditional recommendations for molnupiravir
and the World Health Organization (WHO) website
and remdesivir.
(https://www.covid-nma.com/dataviz/).
• Not recommended for patients with non-severe covid-19—a
conditional recommendation against systemic corticosteroids; a However, existing and emerging evidence demonstrates remaining
strong recommendation against convalescent plasma; a uncertainties concerning treatment effects for all outcomes of
recommendation against fluvoxamine, except in the context of a importance to patients. There is also a need for better evidence on
clinical trial; and a strong recommendation against colchicine. values and preferences of patients with covid-19. Moreover, the
• Not recommended for patients with non-severe covid-19 at low rapidly evolving evidence landscape requires trustworthy
risk of hospitalisation—a conditional recommendation against interpretation and expeditious clinical practice guidelines to inform
nirmatrelvir/ritonavir. clinicians and health care decision-makers.
• Not recommended for patients with severe or critical covid-19—a Several living network meta-analyses associated with this guideline
recommendation against convalescent plasma except in the context incorporate emerging trial data and allow for analysis of comparative
of a clinical trial; and a conditional recommendation against the effectiveness of multiple covid-19 treatments.6 7 Box 1 includes these
JAK inhibitors ruxolitinib and tofacitinib. network meta-analyses and other related publications. To inform
• Not recommended, regardless of covid-19 disease severity—a the living guidance, we also use additional relevant evidence on
strong recommendations against hydroxychloroquine and against safety, prognosis, and patient values and preferences related to
lopinavir/ritonavir; and a recommendation against ivermectin except covid-19 treatments.
in the context of a clinical trial.
ABOUT THIS GUIDELINE Box 1: Linked resources in this BMJ Rapid Recommendations cluster
This living guideline from the World Health Organization (WHO) Versions of this guidance
incorporates new evidence to dynamically update recommendations
• This article and infographic: Agarwal A, Rochwerg B, Siemieniuk RAC,
for covid-19 therapeutics. The GDG typically evaluates a therapy
et al. A living WHO guideline on drugs for covid-19 [Update 11]. BMJ
when the WHO judges sufficient evidence is available to make a
2020;370:m3379, doi:10.1136/bmj.m3379
recommendation. While the GDG takes an individual patient
• WHO PDF: World Health Organization. Therapeutics and COVID-19.
perspective in making recommendations, it also considers resource
implications, acceptability, feasibility, equity, and human rights. Living guideline. September 2022.
https://www.who.int/teams/health-care-readiness-clinical-unit/covid-
This guideline was developed according to standards and methods 19/therapeutics
for trustworthy guidelines, making use of an innovative process to
• MAGICapp (https://app.magicapp.org/#/guideline/nBkO1E)
achieve efficiency in dynamic updating of recommendations. The
methods are aligned with the WHO Handbook for Guideline ‐ Expanded version of the guideline, including methods, processes,
Development and according to a pre-approved protocol (planning and results with multi-layered recommendations, evidence
proposal) by the Guideline Review Committee (GRC). A box at the summaries, and decision aids for use on all devices
end of the article outlines key methodological aspects of the ‐ MATCH-IT interactive decision support incorporating multiple
guideline process. MAGIC Evidence Ecosystem Foundation provides treatment comparisons for recommended drugs in non-severe
methodological support, including the coordination of living covid-19 at highest risk of hospitalisation: https://magicevi-
systematic reviews with network meta-analyses to inform the dence.org/match-it/220404dist-covid-meds/
recommendations. The full version of the guideline is available Linked research
online in MAGICapp and in PDF, with a summary version here in The
BMJ. These formats should facilitate adaptation, which is strongly
2 the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379

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• Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19:

recommendations. The WHO considers multiple factors, including
the extent of available evidence, and whether and when additional
living systematic review and network meta-analysis [Update 4]. BMJ
2021;370:m2980, doi:10.1136/bmj.m2980 evidence might be anticipated, to make decisions. Other therapeutics
in progress for this WHO living guideline include therapeutic
‐ Updated evidence available online: https://www.covid19ln- anticoagulation.
ma.com/
• Siemieniuk RAC, Bartoszko JJ, Díaz Martinez JP, et al. Antibody and How to use this guideline and associated resources
cellular therapies for treatment of covid-19: a living systematic review This is a living guideline. The recommendations and evidence
and network meta-analysis. BMJ 2021;374:n2231, included here will be updated, and new recommendations will be
doi:10.1136/bmj.n2231 added for other treatments for covid-19. The infographic provides
• Zeraatkar D, Cusano E, Diaz Martinez JP, et al. Tocilizumab and a summary of the recommendations. Readers can find more detailed
sarilumab alone or in combination with corticosteroids for COVID-19: information in the full version of the WHO guideline (see box 1 for
a systematic review and network meta-analysis. medRxiv 2021; links to MAGICapp and the PDF version).
doi:10.1101/2021.07.05.21259867v1
• Izcovich A, Siemieniuk RAC, Bartoszko JJ, et al. Adverse effects of Who do the recommendations apply to?
remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used This guideline applies to all patients with covid-19.
for COVID-19: systematic review and meta-analysis of randomized Recommendations may differ based on the severity of covid-19,
trials. medRxiv 2020; doi:10.1101/2020.11.16.20232876v1 according to WHO severity definitions (box 2).8 These definitions
• Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline avoid reliance on access to healthcare to define patient subgroups.
on drugs to prevent covid-19. BMJ 2021;372:n526.
doi:10.1136/bmj.n526 Box 2: WHO definitions of illness severity for covid-19
• World Health Organization. Clinical management of COVID-19: interim
• Critical covid-19—Defined by the criteria for acute respiratory distress
guidance. 2020. https://www.who.int/publications/i/item/clinical-
management-of-covid-19 syndrome (ARDS), sepsis, septic shock, or other conditions that would
normally require the provision of life-sustaining therapies such as
• Wynants L, Van Calster B, Collins GS, et al. Prediction models for mechanical ventilation (invasive or non-invasive) or vasopressor
diagnosis and prognosis of covid-19: systematic review and critical therapy.
appraisal. BMJ 2020;369:m1328
• Severe covid-19—Defined by any of:
‐ Oxygen saturation <90% on room air*
What triggered this version of the guideline and what is
‐ Signs of pneumonia
coming next?
‐ Signs of severe respiratory distress (in adults, accessory muscle
This twelfth version of the WHO living guideline was triggered by
use, inability to complete full sentences, respiratory rate > 30
breaths per minute; and, in children, very severe chest wall
• The publication of a large RCT (RECOVERY), confirming the
indrawing, grunting, central cyanosis, or presence of any other
benefits of the JAK inhibitor baricitinib in patients with severe general danger signs including inability to breastfeed or drink,
or critical covid-19, also in patients receiving corticosteroids and lethargy, convulsions, or reduced level of consciousness).
IL-6 receptor blockers
• Non-severe covid-19—Defined as the absence of any criteria for severe
• The availability of data from in vitro SARS-CoV-2 neutralisation or critical covid-19.
assays, suggesting that monoclonal antibodies (sotrovimab and
*The Guideline Development Group (GDG) noted that the oxygen
casirivimab-imdevimab) are not effective for patients with
saturation threshold of 90% to define severe covid-19 was arbitrary and
non-severe covid-19 in the current stage of the pandemic with should be interpreted cautiously when defining illness severity. For
the predominant omicron variants example, clinicians must use their judgment to determine whether a low
New RCTs on the effects of remdesivir in patients with severe oxygen saturation is a sign of severity or is normal for a given patient
• with chronic lung disease. Similarly, clinicians may interpret a saturation
and critical covid-19.
of 90-94% on room air as abnormal in a patient with normal lungs, or as
an early sign of severe disease in a patient with a downward clinical
The WHO has a standing steering committee to evaluate possibilities
trajectory. Generally, in cases where there is any doubt, the GDG
for new drug recommendations and updates to existing drug suggested erring on the side of considering disease as severe.

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How to use the recommendations (GDG) considered a combination of the evidence regarding relative
benefits and harms, values and preferences, practical issues,
Selecting therapeutic agents
resource considerations, and feasibility and equity considerations
Over two years into the pandemic, there are several effective (box 3). The GDG notes that these issues have to be considered when
treatments to choose between. When moving from evidence to choosing between therapeutic agents, and when re-using or
recommendations for these drugs, the Guideline Development Group adapting the recommendations in national or local contexts.

PRACTICE
Box 3: Resources, access, and equity issues when choosing therapeutics that would most benefit from interventions; data regarding
emergence of resistance and efficacy against new variants; safety
Several drugs may be unavailable or impractical for use in some contexts. and efficacy in children and in immunocompromised, vaccinated,
Additional obstacles to access in low and middle income countries or pregnant patients and other specific subgroups of patients;
(LMICs) may include cost and availability, and limited access to services
optimal duration of therapies; head-to-head comparisons of
such as diagnostic testing and treatments within the first five days of
symptoms, which may further limit access to interventions. Health recommended treatments; and relative effectiveness of
inequities may be exacerbated if patients at higher risk receive the combination therapy.
intervention. See the full version of the guideline (box 1) for more
• For drugs recommended in severe or critical illness: safety and
information.
efficacy in children and in immunocompromised, vaccinated,
WHO aims to provide a stimulus to engage all possible mechanisms to
or pregnant patients and other specific subgroups of patients;
improve global access to diagnostic tests and effective interventions and
how countries can address such challenges; such as the integration of long term mortality and functional outcomes in covid-19
a covid-19 clinical care pathway and establishing services to offer survivors; and immunity and the risk of a subsequent infection,
intravenous treatments. which may affect the risk of death after 28 days.
At a time of drug shortage, it may be necessary to prioritise use through
clinical triage such as selecting patients with the highest baseline risk The recommendations
for mortality (for instance, those with critical illness over those with severe
Remdesivir (Update 11, published 16 September 2022)
illness), in whom the absolute benefit of treatment is greatest. Other
suggestions for prioritisation, which lack direct evidence, include focusing Overview
on patients with an actively deteriorating clinical course and avoiding
treatment in patients with established multi-organ failure (in whom the Remdesivir was developed for treatment of hepatitis C virus
benefit is likely to be small). infection, and was also studied in Ebola and Marburg virus
infections before being repurposed for SARS-CoV-2. Remdesivir is
Some therapies can be used in combination (such as those for severe a nucleoside analogue which interacts with the SARS-CoV-2
or critical covid-19) while others are to be used as alternatives. polymerase to elicit delayed chain termination during RNA genome
Recommended combinations of treatments are based on direct synthesis; its mechanism of action is further described in the full
comparisons from trials demonstrating additional benefit, such as version of the guideline (box 1). Resistance to remdesivir has been
adding the JAK inhibitor baricitinib to IL-6 receptor blockers and reported in vitro and in a case report, but the clinical significance
to systemic corticosteroids in patients with severe or critical covid-19. of these observations remain unclear.
An interactive decision support tool incorporates multiple treatment Update—An initial conditional (weak) recommendation was made
comparisons to inform the use of one drug over another with related on 20 November 2020, suggesting not to use remdesivir for patients
mechanisms of action for patients with non-severe covid-19 at with covid-19 regardless of illness severity. This was based on data
highest risk of hospitalisation: https://magicevidence.org/match- from the four RCTs available at the time, with 7333 participants
it/220404dist-covid-meds/. hospitalised for covid-19. In the tenth iteration of the guideline, a
new recommendation was made for the use of remdesivir for patients
Identifying patients with non-severe illness at highest risk of with non-severe illness. In this twelfth iteration of the guideline,
hospitalisation new recommendations for patients with severe or critical covid-19
Several recommendations for therapeutics in patients with are provided, given new trial data providing sufficiently trustworthy
non-severe covid-19 apply only to those at highest risk of evidence for a subgroup effect demonstrating modest benefit in
hospitalisation, defined as beyond 10% risk of being hospitalised patients with severe, but not critical, covid-19.
for covid-19. These patients should achieve what the GDG agreed Evidence-The clinical evidence underpinning the recommendations
would represent what most patients would value as an important (focused on the benefits and short-term harms from trial data) is
benefit: a 6% absolute reduction in hospital admission (see box on outlined in box 4. Evidence in severe and critical illness are
how this guideline was created). Reliably identifying those at highest presented separately, based on new data providing sufficiently
risk is challenging because of the changing global context, with
trustworthy evidence for a subgroup effect demonstrating modest
evolution of the virus and patterns of vaccination, thus raising the benefit in patients with severe, but not critical covid-19.
importance of validation of models to local contexts. A living
systematic review of 232 risk prediction models for covid-19, recently Box 4: Remdesivir data for severe or critical covid-19 (https://app.mag-
updated, identified two promising risk prediction tools before icapp.org/#/guideline/nBkO1E/rec/noRNGw and https://app.magi-
circulation of the omicron variant: these tools concur that typical capp.org/#/guideline/nBkO1E/rec/nJBG6y)
characteristics of people at highest risk include older age, The living network meta-analysis for remdesivir was informed by five
immunosuppression, and/or presence of chronic diseases, with trials, which enrolled 7643 patients with severe or critical covid-19. All
lack of vaccination as an additional risk factor.9 trials were published in peer-reviewed journals, and none included
children or pregnant women. See more trial details in appendix 12 on
Uncertainties
bmj.com.
Uncertainties exist regarding covid-19 therapeutics and emerging For patients with severe covid-19, remdesivir possibly reduces mortality
evidence which may both inform clinical decision-making as well (odds ratio (OR) 0.89 (95% confidence interval (CI) 0.78 to 1.02); absolute
as future research. The recommendations therefore need to be used difference 13 fewer deaths per 1000 patients (95% CI 26 fewer to 2 more);
in light of these uncertainties. Specific uncertainties are listed with low certainty), probably reduces the need for mechanical ventilation (OR
the relevant drug, but many uncertainties are common across 0.87 (0.77 to 0.99); absolute difference 14 fewer per 1000 patients (24
fewer to 1 fewer); moderate certainty), and probably has little or no impact
therapeutics:
on time to symptom improvement (absolute difference 0.7 fewer days
(1.8 fewer to 0.6 more); moderate certainty).
• For drugs recommended in non-severe illness: the lack of
accurate clinical prediction guides to establish the individual For patients with critical covid-19, remdesivir possibly has little or no
effect on mortality (OR 1.15 (0.89 to 1.51); absolute difference 34 more
patient risk of hospitalisation in order to best identify patients

PRACTICE
person and their healthcare provider while discussing whether the

deaths per 1000 patients (27 fewer to 101 more); low certainty) and need
potential benefit justifies the potential risk to the mother and fetus.
for mechanical ventilation (OR 0.97 (0.61 to 1.54); absolute difference 7
fewer per 1000 patients (96 fewer to 100 more); low certainty), and has See MAGICapp for additional guidance.
an uncertain effect on time to symptom improvement (absolute difference Practical issues—Remdesivir is administered as one intravenous
0.4 more days (4.3 fewer to 8.7 more); very low certainty). Overall, the infusion daily over 10 consecutive days. The recommended dose is
drug was well tolerated, and adverse events were rare.
200 mg intravenously on day 1, followed by 100 mg intravenously
Planned subgroup analyses for age, chronic conditions, serological status,
on days 2 to 10. Shorter regimens of five days are described in the
vaccination status, need for non-invasive ventilation at baseline, and
timing of initiation of therapy were precluded by lack of available data.
smaller trials, and local practices may vary. Administration should
be as early as possible in the time course of the disease. Patients
See MAGICapp for details about the evidence and certainty ratings, and
additional details regarding pre-specified subgroup analyses. with severe liver or kidney disease warrant additional caution. See
MAGICapp for additional guidance.
Recommendation1: For patients with severe covid-19, we suggest Resource implications, acceptability, feasibility, equity, and human
treatment with remdesivir (weak or conditional rights—Given the intravenous administration of remdesivir daily
recommendation). over 10 days, this is more easily done for hospitalised patients with
Understanding the recommendation severe disease, as opposed to the outpatient setting. Obstacles to
access in low and middle income countries due to cost, feasibility,
When moving from evidence to the conditional recommendation and availability are of concern (see box 3 for more details).
to use remdesivir in patients with severe covid-19, the GDG
emphasised the benefits on survival and reduction in need for Recommendation 2: For patients with critical covid-19, we
invasive mechanical ventilation, and the likelihood of little or no suggest not to use remdesivir (weak or conditional
serious adverse events attributable to the drug. The GDG recommendation).
acknowledged that some serious adverse events may not have been Understanding the recommendation
accurately captured during the relatively short follow-up period in
the included trials. Of note, although the GDG has recommended When moving from evidence to the conditional recommendation
for other antiviral drugs in patients with non-severe illness, not to use remdesivir in patients with critical covid-19, the GDG
remdesivir is the only one with a recommendation for use in patients emphasised the lack of benefit on survival or other patient-important
with severe covid-19. outcomes as demonstrated in the subgroup analysis judged to be
of moderate credibility. The GDG recognised there is ongoing
The GDG did not anticipate important variability in patient values uncertainty, and there may still be a subset of patients who would
and preferences, although the low certainty of evidence and ongoing benefit (for example, immunocompromised, persistent viraemia),
uncertainty in effect contributed to the conditional recommendation. but there is insufficient evidence to make recommendations specific
There was insufficient trial level data to examine subgroups based to these subsets of critical patients.
on age or to consider patients requiring non-invasive ventilation
(those on bilevel ventilation or high flow nasal cannula) as a The GDG did not anticipate important variability in patient values
separate subgroup of interest. and preferences, although the low certainty of evidence and ongoing
uncertainty in effect contributed to the conditional recommendation.
When making the recommendation for treatment with remdesivir, There was insufficient trial level data to examine subgroups based
the GDG carefully considered the credibility of subgroup findings on age, or to consider patients requiring non-invasive ventilation
based on severity of disease, where remdesivir demonstrated a (those on bilevel ventilation or high flow nasal cannula) as a
possible survival benefit in patients with severe covid-19, while separate subgroup of interest.
possibly having no impact on mortality in patients with critical
covid-19. The GDG used the ICEMAN tool to assess the credibility Balance of benefits and harms—Low certainty evidence suggests
of subgroup effects, and ultimately decided the credibility of the remdesivir possibly has little or no effect on mortality and need for
observed subgroup finding based on severity of illness was mechanical ventilation, and an uncertain effect on time to symptom
moderate, therefore warranting separate recommendations for each, improvement. The drug is well tolerated, and adverse events are
while recognising residual uncertainties (see MAGICapp for full rare.
details regarding ICEMAN assessments). Values and preferences—The GDG inferred that the majority of well
Balance of benefits and harms—There was low certainty evidence informed patients with critical covid-19 would choose not to receive
suggesting remdesivir possibly reduces mortality, and moderate remdesivir due to little or no impact on patient-important outcomes.
certainty evidence suggesting probable reduction in need for The GDG anticipated little variation in values and preferences
mechanical ventilation with probably little or no impact on time to between patients for this intervention.
symptom improvement. The drug is well tolerated, and adverse Applicability, practical issues, resource implications, acceptability,
events are rare. feasibility, equity, and human rights—Similar issues exist as for
Values and preferences—The GDG inferred that the majority of well patients with severe illness. Such considerations are less relevant
informed patients with severe covid-19 would choose to receive for patients with critical illness, given the weak or conditional
remdesivir due to the possible reduction in mortality and need for recommendation against use.
mechanical ventilation and the safety of the drug. The GDG Recommendation 3: We suggest treatment with remdesivir for
anticipated little variation in values and preferences between patients with non-severe covid-19, conditional to those at highest
patients for this intervention. risk of hospitalisation (conditional or weak recommendation).
Applicability—Insufficient evidence exists to inform a Understanding the recommendation
recommendation around use in children. Decisions regarding its
use in pregnant or breastfeeding women should, in the absence of The GDG emphasised the benefits of decreased need for
trials enrolling such participants, be made between the pregnant hospitalisation, along with little or no serious adverse effects

PRACTICE
attributable to the drug. Feasibility, costs, access, and complexity are three of at least nine JAK inhibitors. Their inherent differences,
of administration were also carefully considered and led to the as well as variation in dosing and administration and
conditional recommendation for use only in patients at highest risk pharmacokinetics, limit class-wide recommendations, and the GDG
of hospitalisation. decided to make separate recommendations for individual drugs.
Balance of benefits and harms—In highest risk patients with Update—The existing strong recommendation concerning baricitinib
non-severe illness, moderate certainty evidence showed that for patients with severe or critical covid-19 was updated by the GDG
remdesivir probably provides an important reduction in hospital in this twelfth version of the living guideline. This follows the
admissions and may have little or no effect on mortality. The impact availability of new clinical trial evidence for baricitinib administered
of remdesivir on mechanical ventilation and time to symptom in combination with corticosteroids and IL-6 receptor blockers
resolution is very uncertain. Treatment probably does not increase suggesting that the incremental survival benefit afforded by
the likelihood of serious adverse effects leading to drug baricitinib exists even among patients also treated with
discontinuation. corticosteroids and IL-6 receptor blockers.10
Values and preferences—The GDG inferred that almost all well Evidence—For patients with covid-19, data were derived from four
informed patients with a low risk of hospitalisation would decline trials that enrolled 10 815 inpatients for baricitinib, two trials that
remdesivir, and only those at highest risk would choose to receive enrolled 475 inpatients for ruxolitinib, and one trial that enrolled
treatment. 289 inpatients for tofacitinib. See MAGICapp for detailed description
of the mechanism of action, evidence, and subgroup analyses
Applicability—Only one included trial enrolled children (aged ≥12
underpinning the recommendation (https://app.magi-
years) with small numbers included; the applicability of this
capp.org/#/guideline/nBkO1E/rec/E5AOaN).
recommendation to children therefore remains uncertain. In the
absence of trial data for children aged <12 years with weight <40 Recommendation 1: We recommend treatment with baricitinib
kg, the use of remdesivir in these children is not recommended. for patients with severe or critical covid-19 (strong
Uncertainty also remains with regard to administration of remdesivir recommendation).
to pregnant or lactating women. The decision regarding use should
Understanding the recommendation
be made between the pregnant individual and their healthcare
provider while discussing whether the potential benefit justifies In this update, the GDG confirmed the existing strong
the potential risk to the mother and fetus. recommendation to use baricitinib in patients with severe or critical
covid-19. This update was based on additional data from 8156
The GDG also had concerns regarding whether the drug would retain
patients enrolled in the RECOVERY trial, which confirmed a survival
efficacy against emerging variants of concern, such as omicron BA-1
benefit (now high certainty evidence) and other benefits, with little
or BA-2. Surveillance is needed for SARS-CoV-2 strains with reduced
or no serious adverse events, of a drug that may be administered
susceptibility to remdesivir, and further research is needed to
easily.10 The GDG acknowledged that some serious adverse events,
examine the role of combination therapy in severely
such as fungal infections, may not have been accurately captured
immunocompromised patients. In the absence of further data, the
during the relatively short follow-up period in the included trials.
GDG did not have reason to believe the activity against known
Because of different mechanisms of action, the GDG considered
variants would be diminished.
baricitinib separately from other JAK inhibitors.
Practical issues—Remdesivir is administered via intravenous
Costs and access remain important considerations, and the GDG
infusion as a three-day regimen, in keeping with the large trials
recognises that this recommendation could exacerbate health
informing the recommendation; 200 mg is administered
inequities. This strong recommendation further strengthens the
intravenously on day 1, followed by 100 mg given intravenously on
impetus to address these concerns and maximise access across
days 2 and 3. Administration should be as early as possible in the
regions and countries. The GDG did not anticipate important
course of the disease, with monitoring for allergic, infusion related,
variability in patient values and preferences, and judged that other
or other adverse outcomes. In the included studies, remdesivir was
contextual factors would not alter the recommendation.
administered within seven days of disease onset. Additional
considerations regarding practical issues are summarised in The GDG had previously made a strong recommendation for use of
MAGICapp. IL-6 receptor blockers (tocilizumab and sarilumab) or baricitinib as
alternative agents administered in addition to corticosteroids for
Resource implications, acceptability, feasibility, equity, and human
patients with severe or critical covid-19. The GDG had elected to
rights—The infusion schedule represents a feasibility challenge in
refrain from recommending the combination of these three
the outpatient settings. Furthermore, remdesivir is unlikely to be
immunosuppressive drugs until clear evidence of incremental
available for all individuals who, given the option, would choose
benefit emerged. The RECOVERY trial has now provided this
to receive the treatment. See box 3 for concerns about costs,
evidence, demonstrating that combining corticosteroids, IL-6
availability, and health inequities.
receptor blockers, and baricitinib provides incremental survival
Janus kinase (JAK) inhibitors (Update 11, published 16 September benefit.10 In RECOVERY, 2659 patients received baricitinib along
2022) with corticosteroids and IL-6 receptor blockers. The effect of
baricitinib in this subgroup was consistent with the beneficial effect
Overview
of baricitinib in patients who were not treated with IL-6 receptor
JAK inhibitors inhibit intracellular signalling in response to blockers.10
numerous interleukins, interferons, colony stimulating factors, and
Although these three immunosuppressive drugs are recommended
hormones. As a consequence, they interfere with many cellular
and may be administered jointly, the panel anticipated that there
responses, including antiviral responses, angiotensin-converting
would be situations where clinicians may opt for less aggressive
enzyme 2 (ACE2) expression, T cell function and differentiation,
immunosuppressive therapy or choose to combine medications in
and macrophage activation. Baricitinib, ruxolitinib, and tofacitinib
a stepwise fashion in patients who are deteriorating. However, since

PRACTICE
the drugs have not undergone direct comparisons, the GDG felt that Recommendation 2: We suggest not to use ruxolitinib or
clinicians should choose between baricitinib and IL-6 receptor tofacitinib for patients with severe or critical covid-19
blockers on the basis of experience and comfort using the drugs, (conditional or weak recommendation).
local institutional policies, route of administration (baricitinib is
oral; IL-6 receptor blockers are intravenous), and cost.
Low to very low certainty evidence for mortality and duration of
Balance of benefits and harms—In patients with severe or critical
mechanical ventilation and a possible increase in serious adverse
illness, baricitinib reduces mortality (high certainty), and probably
events, particularly for tofacitinib, drove the weak recommendation
reduces duration of mechanical ventilation and hospital length of
not to use ruxolitinib or tofacitinib in patients with severe or critical
stay (both moderate certainty). Treatment probably results in little
covid-19. Clinicians should consider using ruxolitinib or tofacitinib
or no increase in serious adverse events leading to drug
only if neither baricitinib nor IL-6 receptor blockers (tocilizumab
discontinuation (moderate certainty). Some serious adverse events
or sarilumab) are available. The GDG emphasised the need for more
such as severe infections which may arise from immunosuppressive
trial evidence to better inform the recommendations; this is
therapy like baricitinib may not have been accurately captured
anticipated through ongoing trials for these JAK inhibitors.
during the relatively short follow-up in the included trials. This risk
may vary in different parts of the world according to the local Benefits and harms—Low to very low certainty evidence from small
prevalence of infections such as tuberculosis. This risk may also be trials failed to demonstrate benefits for mortality or duration of
less pertinent, given the short course of baricitinib used for the mechanical ventilation, and suggested tofacitinib may increase
treatment of covid-19. adverse events leading to drug discontinuation. When more evidence
is available, the GDG acknowledged that these drugs may prove to
Subgroup analyses were undertaken for JAK inhibitors as a class
have similar benefits as baricitinib.
(rather than on individual drugs) and revealed no evidence of a
subgroup effect on relative risk in younger (<70 years old) versus Values and preferences—Most well informed patients would decline
older patients, those with critical versus severe covid-19, those ruxolitinib or tofacitinib. However, a minority might choose to
receiving or not receiving corticosteroids at baseline, and those receive one or the other drug if neither baricitinib nor IL-6 receptor
receiving or not receiving remdesivir or IL-6 blockers at baseline. blockers are available, given that the possibility of benefit has not
been excluded and a class effect of JAK inhibitors might exist.
Values and preferences—The GDG inferred that almost all well
informed patients with severe or critical covid-19 would choose to Applicability—None of the included RCTs enrolled children;
receive baricitinib due to the likely reduction in mortality, and therefore, the applicability of this recommendation to children
moderate certainty evidence of little or no increase in serious adverse remains uncertain. Uncertainty also remains with regards to the
events. The GDG anticipated little variation in values and administration of ruxolitinib or tofacitinib to pregnant or lactating
preferences between patients for this intervention. women.
Applicability—None of the included RCTs for baricitinib enrolled Practical issues—Both drugs are administered orally twice daily as
children, or pregnant or lactating women; therefore, the applicability tablets and can be dispersed in water or administered via nasogastric
of this recommendation to these groups remains uncertain. The tube.
GDG did not have reason to believe that patients in these groups The GDG referred to treatment regimens in the included trials,
with covid-19 would respond differently; decisions regarding the available via MAGICapp, in the absence of other available
use of JAK inhibitors in these groups should be guided by discussion information. If ruxolitinib or tofacitinib is administered, like with
between the individual and their healthcare provider. IL-6 receptor blockers, it should be given with systemic
Practical issues—Baricitinib is administered orally once daily as corticosteroids; specific timing during hospitalisation or in the
tablets; it can be crushed, dispersed in water, or given via a context of the course of illness is not specified.
nasogastric tube. Based on trials informing the recommendation, Resource implications, equity, and human rights—Efforts to ensure
the recommended dose is 4 mg daily orally in adults with normal access to drugs should focus on those that are currently
renal function for a duration of 14 days or until hospital discharge, recommended.
whichever is first. The optimal duration of treatment is unknown.
Specific uncertainties, emerging evidence, and future research
Dose adjustments may be needed for patients with leucopenia, renal
(for all JAK inhibitors)
impairment, or hepatic impairment, all of which should be
monitored during treatment, and for patients taking strong organic • Safety and efficacy of combination therapy of baricitinib with
anion transporter 3 (OAT3) inhibitors such as probenecid, where corticosteroids and IL-6 receptor blockers on longer term
drug interactions warrant dose reductions. outcomes
Baricitinib, like IL-6 receptor blockers, should be initiated at the • Safety and efficacy in areas where certain infections (such as
same time as systemic corticosteroids; there are currently no data HIV infection, tuberculosis, and some fungal infections) are
to suggest that specific timing during hospitalisation or the course endemic
of illness is beneficial.
• Impact of tofacitinib and ruxolitinib relative to that of baricitinib.
See MAGICapp for more information regarding practical issues.
Sotrovimab (Update 11, published 16 September 2022)
Resource implications, feasibility, equity, and human
rights—Compared with some other candidate treatments for covid-19, Overview
baricitinib is expensive. The recommendation does not take into Sotrovimab is a single human monoclonal antibody that binds to
account cost effectiveness. See box 3 for related considerations. As a highly conserved epitope in the SARS-CoV-2 spike protein,
baricitinib is administered orally once daily, hospitalised patients preventing the virus from entering cells.
should find it easy to accept this treatment.

PRACTICE
Update—An updated recommendation concerning sotrovimab for and feasibility, such as limited production, intravenous
patients with non-severe covid-19 was published in the twelfth administration, and requirement for expertise to offer such treatment
version of the living guideline. Previously, a conditional while oral antiviral therapies are available.
recommendation was provided for patients with non-severe covid-19
at highest risk of hospitalisation. Following the emergence of the
currently circulating SARS-CoV-2 variants and subvariants (such Efficacy and safety for severe or critical seronegative covid-19
as omicron) now dominating covid-19 worldwide, and availability
•
patients
of evidence showing sotrovimab lacks related in vitro neutralisation
activity, the GDG made a strong recommendation against the use Casirivimab-imdevimab (neutralising monoclonal antibodies)
of sotrovimab. See MAGICapp for detailed description of the (Update 11, published 16 September 2022)
mechanism of action, detailed in vitroneutralisation activity data,
Overview
and rationale underpinning the recommendation
(https://app.magicapp.org/#/guideline/nBkO1E/rec/LA69PM). Casirivimab and imdevimab are two fully human antibodies
(REGN10933 and REGN10987) that bind to the SARS-CoV-2 spike
Recommendation: We recommend not to use sotrovimab for protein and have demonstrated antiviral activity in animal models.
patients with non-severe covid-19 (strong recommendation). It has been postulated that administration of a combination of
Understanding the recommendation casirivimab and imdevimab might have differential effects in
patients who have produced their own anti-SARS-CoV-2 spike
Although previous clinical trial evidence available via the LNMA
protein antibodies (hereafter seropositive) compared with those
remains accurate,7 the panel concluded that it is no longer
who have not (hereafter seronegative); it was hypothesised that
applicable to covid-19 caused by the SARS-CoV-2 variants that are
effects might be larger for, or restricted to, seronegative individuals
currently circulating globally. The panel surmised that the likelihood
who have not yet mounted an effective natural antibody response.
of covid-19 caused by former variants was extremely low and that,
accordingly, evidence of sotrovimab’s clinical effectiveness for Update
covid-19 was inexistent. An updated recommendation concerning the neutralising antibodies
Of note, the panel applied the same rationale to the recommendation casirivimab-imdevimab for patients with covid-19 was published
for casirivimab-imdevimab. in this twelfth version of the WHO living guideline. Previously, a
conditional recommendation was provided for patients with
The GDG agreed that large, high quality clinical trials generally
non-severe covid-19 at highest risk of hospitalisation, and for
provide the best evidence of clinical effectiveness for therapeutic
patients with severe or critical illness with seronegative status.
interventions. The GDG also continues to base its recommendations
Following the emergence of the currently circulating SARS-CoV-2
strictly on critically important outcomes. From the perspective of
variants and subvariants (such as omicron) now dominating
clinical guidelines, mechanistic studies and surrogate outcomes
worldwide, and availability of in vitro data showing lack of
are useful to identify candidate therapies for clinical trials but are
neutralisation activity, the GDG made a strong recommendation
of no use in the evaluation of clinical effectiveness. The panel
against the use of casirivimab-imdevimab for all patients with
concluded that the emerging evidence demonstrating that
covid-19. See MAGICapp for detailed description of the mechanism
sotrovimab did not neutralise current variants in vitro would have
of action, detailed in vitro neutralisation activity data, and rationale
justified not launching clinical trials and now renders the results
of previous trials inapplicable. In vitro assays were deemed sufficient
capp.org/#/guideline/nBkO1E/section/LG5NRE).
to rule out a clinical effect. Notwithstanding, proof of potent in vitro
neutralisation would not be sufficient to confirm clinical Recommendation: We recommend not to use
effectiveness. Therefore, the GDG will only consider making casirivimab-imdevimab for patients with covid-19, regardless of
recommendations for new monoclonal antibodies once they have illness severity (strong recommendation).
been rigorously evaluated in clinical trials. Understanding the recommendation
Balance of benefits and harms—There was consensus among the Although previous clinical trial evidence available via the LNMA
panel that it is highly unlikely that the clinical effectiveness of remains accurate,7 the GDG concluded that it is no longer applicable
sotrovimab would persist in the absence of adequate in vitro to covid-19 caused by the SARS-CoV-2 variants that are currently
neutralisation of the circulating variants. Accordingly, the panel circulating globally. The panel surmised that the likelihood of
concluded that the evidence upon which hinged the previous covid-19 caused by former variants was extremely low and that,
recommendation was no longer applicable. accordingly, evidence of casirivimab-imdevimab clinical
Values and preferences—The GDG inferred that, in the absence of effectiveness for covid-19 was inexistent.
compelling evidence of clinical effectiveness for the currently Of note, the panel applied the same rationale to the recommendation
circulating SARS-CoV-2 variants, almost all well informed patients for sotrovimab.
would not choose to receive sotrovimab.
The GDG agreed that large, high quality clinical trials generally
Applicability—Given the updated recommendation against provide the best evidence of clinical effectiveness for therapeutic
treatment, issues pertaining to applicability were felt to be less interventions. The GDG also continues to base its recommendations
relevant. strictly on predefined patient-important outcomes. From the
Practical issues—Given the updated recommendation against perspective of clinical practice guidelines, mechanistic studies and
treatment, related practical issues were felt to be less relevant. surrogate outcomes are useful to identify candidate therapies for
clinical trials but are of no use in the evaluation of clinical
Resource implications, equity, human rights, acceptability, and
effectiveness. The panel concluded that the emerging evidence
feasibility—The strong recommendation against the use of
demonstrating that casirivimab-imdevimab did not neutralise
sotrovimab is further supported by their challenges with availability

PRACTICE
current variants in vitro would have justified not launching clinical substantial pharmacological interactions. In the largest trial,
trials and now renders the results of previous trials inapplicable. markedly more patients discontinued treatment in the fluvoxamine
In vitro assays were deemed sufficient to rule out a clinical effect. group than in the placebo group. Acknowledging that its evaluation
Notwithstanding, proof of potent in vitro neutralisation would not of the certainty of the evidence may differ from other published
be sufficient to confirm clinical effectiveness. Therefore, the GDG meta-analyses, GDG members pointed out that early stopping due
will only consider making recommendations for new monoclonal to apparent benefit may have biased the results of the largest trial.
antibodies once they have been rigorously evaluated in clinical They argued that, although the stopping rules were pre-specified,
trials. the decision to stop the trial was based on the effect estimate on a
composite outcome of questionable importance; meanwhile the
Balance of benefits and harms—There was consensus among the
number of important events was lower and vulnerable to bias. The
panel that it is highly unlikely that the clinical effectiveness of
GDG also raised concerns regarding the uncertain applicability of
casirivimab-imdevimab would persist in the absence of adequate
this trial conducted in a single country.
in vitro neutralisation of the circulating variants. Accordingly, the
panel concluded that the evidence upon which hinged the previous Values and preferences—The GDG inferred that almost all well
recommendations was no longer applicable. informed patients would choose not to receive fluvoxamine therapy
for covid-19 based on available evidence. The GDG did not believe
Values and preferences—The GDG inferred that, in the absence of
that other considerations, such as feasibility, acceptability, equity,
compelling evidence of clinical effectiveness for the currently
and cost, would affect this specific recommendation. Specifically,
circulating SARS-CoV-2 variants, almost all well informed patients
the GDG did not consider the potential role of fluvoxamine as an
would not choose to receive casirivimab-imdevimab.
antidepressant for this guideline of medications for covid-19.
Applicability—Given the updated recommendation against
Applicability—None of the included studies enrolled children, and
treatment, issues pertaining to applicability were felt to be less
the applicability of this recommendation to children is therefore
relevant.
uncertain. However, the GDG did not see a reason to assume that
Practical issues—Given the updated recommendation against children with covid-19 would respond any differently to treatment
treatment, related practical issues were felt to be less relevant. with fluvoxamine.
Resource implications, acceptability, feasibility, equity, and human Practical issues—The GDG made a recommendation against using
rights—The strong recommendation against the use of fluvoxamine for treatment of patients with covid-19 outside the
casirivimab-imdevimab is further supported by their challenges setting of a clinical trial, and therefore practical considerations are
with availability and feasibility, such as limited production, less relevant for this drug.
intravenous administration and requirement for expertise to offer
such treatment while oral options are available.
rights—Fluvoxamine is relatively inexpensive compared with other
Specific uncertainties, emerging evidence, and future research drugs used for covid-19, and widely available, including in low
No specific uncertainties: see uncertainties section in “How to use income settings. Its use would risk diverting attention and resources
this guideline” (above) away from interventions that are more likely to provide a benefit.
Specific uncertainties, emerging evidence, and future research—The
Fluvoxamine (Update 10, published 14 July 2022)
current evidence does not justify using fluvoxamine to treat covid-19.
Overview However, the recommendation does not imply that fluvoxamine is
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) proven to be ineffective. Decisions to further investigate the effects
approved as an antidepressant. It increases concentrations of of fluvoxamine for covid-19 will likely hinge on how stakeholders
serotonin in the synaptic cleft. Indirect evidence from non-covid-19 perceive the opportunity cost of investigating the effects of
disease models have suggested possible anti-inflammatory fluvoxamine over other candidate therapies. The GDG discussions
properties, and mechanistic studies have suggested host-directed highlighted the following knowledge gaps:
antiviral properties. There are currently no published preclinical
• What are the effects of fluvoxamine in patients who have a
studies that directly demonstrate a mechanism in covid-19.
combination of non-severe covid-19 that is at risk of deteriorating
Evidence—For patients with non-severe covid-19, data were derived and significant symptoms of anxiety?
from three trials that enrolled 2208 non-hospitalised patients. See
• What are the side effects of fluvoxamine therapy in patients with
MAGICapp for detailed description of the mechanism of action,
non-severe covid-19 at risk of deteriorating?
evidence, and subgroup analyses underpinning the recommendation
(https://app.magicapp.org/#/guideline/nBkO1E/rec/jmYxpV). • What proportion of patients with non-severe covid-19 at risk of
deteriorating would be ineligible due to risk of pharmacological
Recommendation 1: For patients with non-severe covid-19, we interactions?
recommend not to use fluvoxamine, except in the context of a
clinical trial (recommended only in a research setting). The GDG surmised that, in the future, investigators would have to
Understanding the recommendation carefully consider whether fluvoxamine could still be compared
with placebo or no treatment given that effective treatments are
Insufficient evidence of benefit, coupled with a lack of a clear available. If the rationale to further investigate fluvoxamine is its
mechanism of action and known drug interactions, drove the advantageous cost and availability, non-inferiority designs may be
recommendation against use in clinical care. considered.
Balance of benefits and harms—There was low to moderate certainty
evidence suggesting little or no effect on hospitalisation, mortality,
or mechanical ventilation, and an absence of reliable data on serious
adverse effects attributable to the drug. Fluvoxamine is known for

PRACTICE
Colchicine (Update 10, published 14 July 2022) Nirmatrelvir/ritonavir (Update 9, published 22 April 2022)
Overview Overview
Colchicine is an anti-inflammatory drug used to treat gout, recurrent Nirmatrelvir is a SARS-CoV protease inhibitor which prevents viral
pericarditis, familial Mediterranean fever, and other inflammatory replication. Nirmatrelvir/ritonavir is administered orally in
conditions. Proposed mechanisms for its anti-inflammatory effect combination with ritonavir, a HIV protease inhibitor, which boosts
include a reduction in neutrophil chemotaxis, inflammasome its pharmacokinetics. Through its impact on metabolism and
signalling inhibition, and decreased production of cytokines such clearance, ritonavir is a perpetrator of many drug-drug interactions
as interleukin 1b. No published animal models evaluating colchicine during active treatment and possibly for several days after treatment
in SARS-CoV-2 infection are published at the time of guideline completion. While these may be more easily managed with short
publication. durations of treatment, twice daily administration involves doubling
ritonavir dose relative to most modern antiretroviral regimens.
Evidence—For patients with non-severe covid-19, data were derived
from 10 trials that enrolled 17 914 non-hospitalised patients. See The antiviral effect of nirmatrelvir has been demonstrated through
MAGICapp for detailed description of the mechanism of action, in vitro animal studies and human models.11 -13 Nirmatrelvir retains
evidence, and subgroup analyses underpinning the recommendation activity against the omicron BA1 variant in vitro, but clinical data
are currently unavailable.14 There remains uncertainty regarding
Recommendation 1: For patients with non-severe covid-19, we
risk of emergence of resistance; in vitro studies have suggested
recommend against treatment with colchicine (strong
acquired mutations in the protease sequence may significantly
recommendation).
reduce nirmatrelvir activity, though variably so depending on type
Understanding the recommendation and number of mutations.11
The lack of benefits on hospitalisations, mortality, and mechanical Evidence—For patients with non-severe covid-19, data were derived
ventilation, combined with possible harms and toxicity, drove the from two trials (EPIC-SR and EPIC-HR) that enrolled 3100
strong recommendation against the use of colchicine in patients non-hospitalised patients. See MAGICapp for detailed description
with non-severe covid-19. of the mechanism of action, evidence, and subgroup analyses
Balance of benefits and harms—In patients with non-severe covid-19, underpinning the recommendations (https://app.magi-
colchicine has little or no impact on mortality or mechanical capp.org/#/guideline/nBkO1E/rec/LwrMyv and https://app.magi-
ventilation (moderate certainty). It is unclear whether it affects capp.org/#/guideline/nBkO1E/rec/Lrvo3R).
hospitalisations or adverse effects leading to drug discontinuation. Recommendation 1: For patients with non-severe covid-19 at
The GDG discussed the risk of drug interactions and colchicine's highest risk of hospitalisation, we recommend treatment with
narrow therapeutic window, particularly in patients with or at risk nirmatrelvir/ritonavir (strong recommendation).
of hepatic and renal failure. Colchicine toxicity can be severe and
sometimes fatal. The planned subgroup analyses for colchicine
versus standard care did not show different relative effects for Only a minority of patients who are at highest risk are likely to
disease severity or age (children, adults, older adults), with no data achieve sufficient benefit in reduced admission to hospital.
reported from illness onset. Nirmatrelvir/ritonavir likely represents a superior choice for these
patients because it may have greater efficacy in preventing
Values and preferences—The GDG inferred that almost all well
hospitalisation than available alternatives, has fewer concerns with
informed patients would choose not to receive colchicine.
respects to harms than molnupiravir, and is easier to administer
Applicability—The applicability of this recommendation to children than intravenous remdesivir and antibodies.
is currently uncertain because none of the included studies enrolled
Balance of benefits and harms—Beyond the important benefits in
children. However, the GDG did not consider that children with
reducing hospital admission in patients at highest risk of hospital
covid-19 would respond any differently to treatment with colchicine.
admission, treatment may have little or no impact on mortality;
Practical issues—The GDG made a strong recommendation against data regarding effects on time to symptom resolution or mechanical
using colchicine for treatment of patients with non-severe covid-19, ventilation are limited. Treatment does not increase the likelihood
and therefore practical considerations are less relevant. of serious adverse effects leading to drug discontinuation, though
Resource implications, acceptability, feasibility, equity, and human diarrhoea and altered taste were noted to occur more often with
rights—These considerations did not affect this specific treatment relative to placebo. The GDG also acknowledged the
recommendation. Although colchicine is relatively inexpensive paucity of information related to emergence of resistance.
compared with other drugs used for covid-19, and widely available, Values and preferences—The GDG inferred that almost all well
including in low income settings, the evidence does not justify the informed patients at highest risk of hospitalisation would choose
use of colchicine for non-severe covid-19 anywhere. Although the to receive nirmatrelvir/ritonavir.
cost of colchicine may be low, the GDG raised concerns regarding
Applicability—Given included RCTs enrolled only non-pregnant
the risk of diverting attention and resources away from interventions
adults, the GDG concluded that nirmatrelvir/ritonavir should not
that are more likely to provide a benefit.
be offered to children or to breastfeeding or pregnant women with
Specific uncertainties, emerging evidence, and future research—The covid-19.
GDG considered it unlikely that future studies would identify
Practical issues—As per the large trials informing the
subgroups of patients who would benefit from colchicine.
recommendation, nirmatrelvir/ritonavir is administered as 300
mg/100 mg orally every 12 hours for five days. Administration should
be as early as possible in the course of the disease. In the included
studies, nirmatrelvir/ritonavir was administered within five days

PRACTICE
of disease onset. Through its impact on metabolism and clearance, highest risk of hospitalisation (conditional or weak
ritonavir is a perpetrator of many drug-drug interactions, warranting recommendation).
serious consideration by clinicians. The Liverpool covid-19 drug
interaction checker may constitute a valuable tool for management
of drug interactions with nirmatrelvir/ritonavir.15 Additional Only a minority of patients who are at highest risk are likely to
considerations regarding practical issues are summarised in achieve sufficient benefit. Especially given the safety concerns
MAGICapp. related to molnupiravir, the WHO and the GDG recognise the need
to mitigate risks, both for individual patients and at the population
level.
rights—Nirmatrelvir/ritonavir is unlikely to be available for all
individuals who, given the option, would choose to receive the Balance of benefits and harms—Molnupiravir probably provides
treatment. benefits on admission to hospital and time to symptom resolution
(both moderate certainty) and may have a small effect on mortality
Recommendation 2: For patients with non-severe covid-19 at (low certainty), without an increase in short term adverse effects
low risk of hospitalisation, we suggest no nirmatrelvir/ritonavir (high certainty). Absolute benefits depend on the prognosis of the
(conditional or weak recommendation). individual patient. The GDG also considered potential long term
Understanding the recommendation harms of molnupiravir, including risk of malignancy based on
preclinical data (very low certainty), in what they ultimately
Most patients with non-severe covid-19 at low risk of hospitalisation
considered to be a close balance between benefits and harms.
will experience trivial benefits with use of nirmatrelvir/ritonavir.
The GDG inferred that most such patients would be uninterested in Values and preferences—The GDG inferred that almost all well
taking the drug for these trivial benefits. However, there are likely informed patients with a low risk of hospitalisation would decline
to be an appreciable number of individuals who place a high value molnupiravir, and only those at highest risk would choose to receive
on very small reductions in the risk of hospitalisation and would treatment.
thus choose to use nirmatrelvir/ritonavir; therefore, a conditional
Applicability—
(rather than a strong) recommendation was made. The benefits and
harms and other factors the GDG considered are comprehensively Children. Due to evidence of impact on growth plate thickness
described in the full version of the guideline (see box 1).
•
and decreased bone formation in some animal studies,
Specific uncertainties, emerging evidence, and future research molnupiravir should not be used in children.
(across disease severities) • Pregnancy, breastfeeding, and conception. Since molnupiravir
No drug-specific uncertainties: see broadly applicable uncertainties elicited embryo-fetal lethality and teratogenicity in offspring
section in “How to use this guideline” (above). when given to pregnant animals, it should not be used in
pregnant or breastfeeding women. If pregnancy status is unclear,
Molnupiravir (Update 8, published 01 March 2022) one should perform a pregnancy test before starting molnupiravir
Overview treatment. Women and people who can get pregnant should be
counselled regarding reducing the risk of conception (such as
Molnupiravir is an antiviral administered orally. It was re-purposed using birth control) during treatment and for at least four days
as an antiviral for covid-19 because it inhibits replication of after the last dose of molnupiravir.
SARS-CoV-2 with an in vitro potency broadly similar to
remdesivir.16 17 This inhibitory effect has been shown in animal • Uncertainty remains regarding consequences to children
studies, both at higher and lower doses, with possibly greater conceived by fathers receiving or having recently received
efficacy when combined with favipiravir (compared with either drug molnupiravir, and whether spermatogenesis may be especially
alone).18 -20 The drug is active against alpha and beta variants in prone to mutagenic effects. Men who might father a child should
vivo based on studies in hamsters and human cell models, and delta use birth control during treatment and for at least three months
and omicron variants in vitro (no data in vivo).21 -23 In vitro and after the last dose of molnupiravir.
animal studies have suggested the possibility of carcinogenesis; no Mitigation strategies at the population level include active
human data with long term follow-up are available regarding this.
•
sequence monitoring of SARS-CoV-2 detected in clinical
There is also residual uncertainty regarding other long term harms; respiratory samples for patients receiving therapy and active
the efficacy of the drug against variants, particularly those with pharmacovigilance programmes.
higher replication or transmission rates; the possibility of a selective
pressure for resistant mutations at an individual level, with the Practical issues—As per large trials informing the recommendation,
potential to spread at a population level; and the emergence of new molnupiravir is dosed as 800 mg orally every 12 hours for five days.
variants related to random mutagenesis arising from molnupiravir’s Administration should be as early as possible in the course of the
mechanism of action. These issues are comprehensively described disease. In the included studies, molnupiravir was administered
in the full version of the guideline (see box 1). within five days of symptom onset.
Evidence—For patients with non-severe covid-19, data were derived Resource implications, feasibility, equity, and human
from six trials that enrolled 4827 patients, of which the LNMA team rights—Molnupiravir is unlikely to be available for all individuals
had access to data for 4796 patients. See MAGICapp for detailed who, given the option, would choose to receive the treatment.
description of the mechanism of action, evidence, and subgroup
analyses underpinning the recommendation (https://app.magi-
capp.org/#/guideline/nBkO1E/rec/E85WNb). Need for clinical data to investigate safety and applicability
•
Recommendation 1: We suggest treatment with molnupiravir concerns (including in children, lactating or pregnant women,
for patients with non-severe covid-19, conditional to those at and men; and long term impact on mutagenesis and cancer risk).

PRACTICE
Convalescent plasma (Update 6, published 6 December 2021) anti-SARS-CoV-2 antibodies, collection of donor plasma, storage of
plasma, transportation of plasma to recipient location, and
Overview
administration of plasma. These resources and feasibility issues are
Treatment with convalescent plasma involves the transfer of compounded for those with non-severe illness, who are most often
endogenously produced neutralising antibodies present within the outpatients. Also, this process is costly and time consuming. Given
plasma from previously infected and recovered patients into patients the number of patients with non-severe illness and the low event
with active infection. The concentrations (titre) of neutralising rate in this subgroup of patients, mobilising the use of convalescent
antibodies present within convalescent plasma are highly variable plasma on a large scale would be of questionable feasibility.
between donors, and various methodologies to measure antibody
levels are available. Recommendation 2: We recommend not to use convalescent
plasma for patients with severe or critical covid-19, except in the
Evidence—Data were derived from 16 trials enrolling 16 236 patients context of a clinical trial (recommended only in research settings).
across illness severities, of which four RCTs with 1602 patients
informed estimates for outcomes in non-severe illness. See
MAGICapp for detailed description of the mechanism of action, Given relative benefits and harms, the GDG agreed further research
evidence, and subgroup analyses underpinning the recommendation addressing these patient-important outcomes would be valuable
(https://app.magicapp.org/#/guideline/nBkO1E/section/LG5NRE). for patients with severe or critical illness. A recommendation to use
a drug only in the setting of clinical trials is appropriate when there
Recommendation 1: We recommend not to use convalescent
is low certainty evidence, and future research has potential to reduce
plasma for patients with non-severe covid-19 (strong
uncertainty about the effects of the intervention, and for doing so
recommendation).
at a reasonable cost.
Balance of benefits and harms—In patients with severe or critical
The GDG noted that, although not demonstrated in the evidence covid-19, convalescent plasma may not result in an important impact
summary, there remains a potential for harms with blood product on mortality, mechanical ventilation, time to symptom
transfusion. Most importantly, given there was no benefit improvement, length of hospital stay, or ventilator-free days (all
demonstrated for any of the critical or important outcomes for low or very low certainty). Convalescent plasma probably does not
non-severe covid-19, the GDG did not see any justification for the result in important increases in risks of transfusion-related acute
resources (including time and cost) that would be associated with lung injury, transfusion-associated circulatory overload (both
administration of convalescent plasma. moderate certainty), or allergic reactions (low certainty). However,
Balance of benefits and harms—In patients with non-severe illness, there is always potential for harms with blood product transfusions.
convalescent plasma does not have an important impact on mortality Values and preferences—Applying the agreed values and
(high certainty). Convalescent plasma probably does not affect preferences, the GDG inferred that almost all well informed patients
mechanical ventilation (moderate certainty). There were no data would choose against receiving convalescent plasma outside the
evaluating the risk of hospitalisation with convalescent plasma; research setting.
the impact is therefore very uncertain. Convalescent plasma
probably does not result in important increases in risks of Specific uncertainties, emerging evidence, and future research
transfusion-related acute lung injury, transfusion-associated Effects of high titre convalescent plasma on mortality and other
circulatory overload (both moderate certainty), or allergic reactions
•
patient-important outcomes.
(low certainty).
• Effects in patients with seronegative antibody status.
Values and preferences—Applying the agreed values and
preferences, the GDG inferred that almost all well informed patients Interleukin-6 (IL-6) receptor blockers (Update 4, published 6 July
with non-severe covid-19 would choose against receiving 2021)
convalescent plasma.
Overview
Acceptability and applicability—Although blood transfusion is
IL-6 receptor blockers tocilizumab and sarilumab are monoclonal
acceptable to most, there is a subset of the population who will not
antibodies approved for use in rheumatoid arthritis. Elevated IL-6
accept allogenic blood transfusions. There are also regulatory
concentrations are associated with severe outcomes in covid-19,
challenges in most jurisdictions related to blood product
including respiratory failure and death. IL-6 receptor blockers
transfusions. The included RCTs enrolled non-pregnant women and
antagonise membrane-bound and soluble forms of the IL-6 receptor,
men. The GDG did not have reason to believe that children or
blocking the cytokine’s activation and regulation of the immune
pregnant women with covid-19 would respond any differently to
response to infection.
treatment with convalescent plasma; the GDG therefore inferred
that children and pregnant women should not receive the Update—WHO has made a strong recommendation for JAK
intervention either. inhibitors, specifically baricitinib, in patients with severe or critical
covid-19. As per guidance updated in this twelfth iteration of the
Practical issues—Issues include, though are not limited to, the
guideline, an IL-6 receptor blocker and baricitinib may now be given
identification and recruitment of potential donors, collection of
as combination therapy (see discussion for JAK inhibitors above).
plasma, storage and distribution of plasma, and infusion of
convalescent plasma into recipients. Evidence—In addition to the linked network meta-analysis, this
recommendation was also informed by an independent prospective
Resource implications, feasibility, equity, and human rights—The
meta-analysis from the WHO Rapid Evidence Appraisal for covid-19
GDG noted that convalescent plasma use is associated with
group.24 The network meta-analysis included 30 RCTs with 10 618
significant resource requirements, including identification of
participants, and these data were used by the GDG for all outcomes
potential donors, testing of donors to ensure adequate titres of
other than mortality. We used the prospective meta-analysis for

PRACTICE
mortality because it included additional data that was unpublished Finally, sarilumab is not indicated for use in children; therefore,
at the time. The prospective meta-analysis pooled data from 22 RCTs there could be a preference for tocilizumab in this subgroup.
with 10 156 participants.24 See MAGICapp for detailed description
of the mechanism of action, evidence, and subgroup analyses
underpinning the recommendation (https://app.magi- Safety data, including nosocomial infections.
capp.org/#/guideline/nBkO1E/section/LG5NRE).
•
• Immunity and the risk of subsequent infection, which may affect
Recommendation: We recommend treatment with IL-6 receptor the risk of death after 28 days.
blockers (tocilizumab or sarilumab) for patients with severe or
critical covid-19 (strong recommendation). • Outcomes by different IL-6 receptor blocker dosing, and optimal
timing of drug initiation.
Ivermectin (Update 3, published 31 March 2021)
Of note, corticosteroids have previously been strongly recommended
in patients with severe or critical covid-19, and we recommend that Overview
patients meeting these severity criteria should now receive both Ivermectin is an antiparasitic agent that interferes with nerve and
corticosteroids and IL-6 receptor blockers, possibly with baricitinib muscle function of helminths through binding glutamate-gated
as combination therapy (see above). chloride channels. The treatment is relatively inexpensive and
Balance of benefits and harms— IL-6 receptor blockers reduce accessible internationally. We currently lack persuasive evidence
mortality and need for mechanical ventilation (both high certainty), of a mechanism of action for ivermectin in covid-19; any observed
and may reduce durations of mechanical ventilation and clinical benefit would be unexplained.
hospitalisation (both low certainty). We are aware of a few new, relatively small trials published since
There was uncertainty about the risk of serious adverse effects (very our recommendation was made, and that one key trial has since
low certainty). There may be little or no increased risk of bacterial been retracted, given concerns about research fraud.25 26 However,
infections. However, the GDG had some concerns that, given the the updated evidence summary from the living network
short term follow-up of most trials and the challenges associated meta-analysis is consistent with our previous recommendation.
with accurately capturing adverse events such as bacterial or fungal This updated evidence summary will be fully considered by the
infections, that the evidence summary may under-represent the GDG in an upcoming iteration of the guideline.
risks of treatment with IL-6 receptor blockers. Furthermore, the Evidence—The living systematic review and network meta-analysis
trials of IL-6 receptor blockers that inform this recommendation pooled data from 16 trials with 2407 participants. Of the included
were mostly performed in high-income countries, where the risk of trials, 75% examined patients with non-severe illness, and 25%
infectious complications may be less than in some other parts of included patients with both severe and non-severe illness. See
the world; the generalisability of the data on these adverse events MAGICapp for detailed description of the mechanism of action,
is therefore unclear. evidence, and subgroup analyses underpinning the recommendation
Values and preferences—The GDG inferred that almost all well (https://app.magicapp.org/#/guideline/nBkO1E/section/LG5NRE).
informed patients with severe or critical covid-19 infection would
Recommendation: We recommend not to use ivermectin for
want to receive IL-6 receptor blockers, given the reduction in
patients with covid-19, regardless of illness severity, except in
mortality and mechanical ventilation, despite low certainty around
the context of a clinical trial (recommended only in research
evidence for serious adverse events. A minority of the GDG felt that
settings).
a significant proportion of patients might decline the intervention
due to the uncertainties around harms, and taking into account the Understanding the recommendation
small reduction in mortality. Very low certainty evidence was a critical factor in the
Applicability—None of the included RCTs enrolled children or recommendation.
pregnant women. Although this resulted in uncertain applicability, Balance of benefits and harms—Certainty of evidence for mortality
the GDG did not have reason to believe that children or pregnant was deemed very low, despite a point estimate and confidence
women with COVID-19 would respond any differently to treatment interval that seemed to suggest benefit with ivermectin; similar
with IL-6 receptor blockers. judgments were made for other outcomes, including mechanical
Practical issues—IL-6 receptor blockers require intravenous ventilation, hospital admission, duration of hospitalisation, and
administration but only require one, or at most two, doses. See viral clearance.
MAGICapp for practical information, including considerations if Ivermectin may have little or no effect on time to clinical
IL-6 receptor blockers are considered in children and pregnant improvement (low certainty) and may increase the risk of adverse
women. events leading to drug discontinuation (low certainty). A
Resource implications, acceptability, feasibility, equity, and human recommendation to only use a drug in the setting of clinical trials
rights—Compared with other treatments for covid-19, IL-6 receptor is appropriate when there is very low certainty evidence, and when
blockers are expensive and may be inaccessible. The future research has large potential for reducing uncertainty about
recommendation does not consider cost effectiveness. Given limited the effects of the intervention and at a reasonable cost.
availability of the drug, one may consider the relative effects (odds Subgroup analyses indicated no effect modification based on dose.
ratio 0.87) for reduction in mortality with IL-6 receptor blockers We were unable to examine subgroups based on age or severity of
result in 28 fewer deaths per 1000 patients (95% confidence interval illness due to insufficient trial data. Therefore, we assumed similar
9 to 47 fewer deaths) in critically ill patients, compared with 12 fewer effects across all subgroups.
deaths per 1000 patients (4 to 19 fewer deaths) in severely ill
patients. Values and preferences—The GDG inferred that almost all well
informed patients would not want to receive ivermectin, given

PRACTICE
available evidence left a very high degree of uncertainty in effects modified the effect of hydroxychloroquine for any outcome (very
on critical outcomes and the possibility of harms, such as adverse low certainty).
events associated with treatment.
Applicability—None of the included trials enrolled children or preferences, the GDG inferred that almost all well informed patients
pregnant women; the applicability of the evidence to these would not want to receive hydroxychloroquine.
subgroups is therefore uncertain, though there is no rationale to
Applicability—None of the included trials enrolled children or
suggest they would respond differently.
adolescents; the applicability to this subgroup is therefore uncertain.
Resource implications, feasibility, equity, and human
rights—Although the cost of ivermectin may be low per patient, the
rights—Hydroxychloroquine and chloroquine are relatively
GDG raised concerns about diverting attention and resources away
inexpensive compared with other drugs used for covid-19 and are
from care likely to provide a benefit, such as corticosteroids in
already widely available, including in low-income settings. Although
patients with severe covid-19, and other supportive care
the cost may be low per patient, the GDG raised concerns about
interventions. Also, use of ivermectin for covid-19 would divert
diverting attention and resources away from care likely to provide
supply away from pathologies for which it is clearly indicated,
a benefit such as corticosteroids in patients with severe covid-19
potentially contributing to drug shortages, especially for helminth
and other supportive care interventions.
control and elimination programmes. If corticosteroids are used in
the treatment of covid-19, empiric treatment with ivermectin may Specific uncertainties, emerging evidence, and future research
still be considered in strongyloidiasis-endemic areas, albeit not for Although some uncertainty remains, the GDG felt that further
treatment of covid-19 itself. research was unlikely to uncover a subgroup of patients who would
Specific uncertainties, emerging evidence, and future research benefit from hydroxychloroquine on the most important outcomes
(mortality, mechanical ventilation) given the consistent results in
No specific uncertainties: see uncertainties section in “How to use
trials across illness severity and location.
this guideline” (above).
Lopinavir-ritonavir (Update 2, published 17 December 2020)
Hydroxychloroquine (Update 2, published 17 December 2020)
Evidence—The recommendation was informed by data from seven
Evidence—The recommendation addressing hydroxychloroquine
RCTs with 7429 participants. See MAGICapp for detailed description
was informed by results from the living network meta-analysis,
of the evidence and subgroup analyses underpinning the
pooling data from 30 RCTs with 10 921 participants. See MAGICapp
recommendation (https://app.magicapp.org/#/guide-
for detailed description of the evidence and subgroup analyses
line/nBkO1E/section/EgylxL).
capp.org/#/guideline/nBkO1E/section/j197zj). Recommendation: We recommend not to use lopinavir-ritonavir
for patients with covid-19, regardless of illness severity (strong
Recommendation: We recommend not to use
recommendation).
hydroxychloroquine or chloroquine for patients with covid-19,
regardless of illness severity (strong recommendation). Balance of benefits and harms— Lopinavir-ritonavir probably has
little or no effect on mortality and mechanical ventilation (both
moderate certainty); effects on time to clinical improvement and
Balance of benefits and harms—Hydroxychloroquine and other patient-important outcomes were uncertain (low or very low
chloroquine probably do not reduce mortality or mechanical certainty). Treatment probably increases the risk of diarrhoea and
ventilation (both moderate certainty) and may have no effect on nausea or vomiting (both moderate certainty), a finding consistent
duration of hospitalisation (low certainty). The evidence does not with the indirect evidence evaluating its use in patients with HIV
exclude the potential for a small increased risk of death and infection. Diarrhoea and vomiting may increase the risk of
mechanical ventilation with hydroxychloroquine. The effect on hypovolaemia, hypotension, and acute kidney injury, especially in
other less important outcomes, including time to symptom settings where healthcare resources are limited. There was an
resolution, admission to hospital, and viral clearance, remains uncertain effect on viral clearance and acute kidney injury.
uncertain.
Subgroup analysis indicated no effect modification based on severity
Hydroxychloroquine may increase the risk of diarrhoea and nausea of illness or age. As there was no evidence of a statistical subgroup
or vomiting (both low certainty), a finding consistent with evidence effect, we did not formally evaluate credibility. Although the trials
from its use in other conditions. Diarrhoea and vomiting may did not report subgroup effects by time from symptom onset, many
increase the risk of hypovolaemia, hypotension, and acute kidney of the trials enrolled patients early in the illness course. The GDG
injury, especially in settings where healthcare resources are limited. therefore felt that the evidence applies to all patients with covid-19.
Whether and to what degree hydroxychloroquine increases the risk
of cardiac toxicity, including life-threatening arrhythmias, when
preferences, the GDG inferred that almost all well informed patients
used in patients with covid-19 is uncertain (very low certainty).
would not want to receive lopinavir-ritonavir given that the evidence
Subgroup analyses indicated no effect modification based on suggested there was probably no effect on mortality or need for
severity of illness, age, cumulative dose, or predicted day 3 serum mechanical ventilation and there was a risk of adverse events
trough concentrations. Therefore, we assumed similar effects in all including diarrhoea and nausea or vomiting.
subgroups.
Resource implications, feasibility, equity, and human rights—Although
We also reviewed evidence comparing the use of the cost of lopinavir-ritonavir is not as high as some other
hydroxychloroquine plus azithromycin versus hydroxychloroquine investigational drugs for covid-19 and the drug is generally available
alone. There was no evidence that the addition of azithromycin in most healthcare settings, the GDG raised concerns about
opportunity costs and the importance of not drawing attention and

PRACTICE
resources away from best supportive care or the use of corticosteroids in such patients, clinicians must determine if they
corticosteroids in severe covid-19. 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 GDG
Although some uncertainty remains, the GDG felt that further was confident that clinicians using these guidelines would be aware
research was unlikely to uncover a subgroup of patients who would of additional potential side effects and contraindications to systemic
benefit from lopinavir-ritonavir on the most important outcomes corticosteroid therapy, which may vary geographically in function
(mortality, mechanical ventilation) given the consistent results in of endemic microbiological flora.
trials across illness severity and location.
Acceptability and practical issues—The ease of administration, the
Systemic corticosteroids (Original publication, published 4 relatively short duration of a course of systemic corticosteroid
September 2020) therapy, and the generally benign safety profile of systemic
Evidence—The GDG reviewed evidence from eight RCTs (7184 corticosteroids administered for up to 7-10 days led the GDG to
patients) evaluating systemic corticosteroids versus usual care in conclude that the acceptability of this intervention was high.
treatment of covid-19, seven of which reported mortality data by Practical issues are summarised in detail on MAGICapp.
subgroup of illness severity. Mortality data from one trial, Resource implications, feasibility, equity, and human rights—Systemic
GLUCOCOVID, were not incorporated in the summary of finding for corticosteroids are low cost, easy to administer, and readily available
mortality because the mortality outcome data were not available globally. Dexamethasone and prednisolone are among the most
by subgroup. See MAGICapp for detailed description of the evidence commonly listed medicines in national essential medicines lists;
and subgroup analyses underpinning the recommendation and listed by 95% of countries. Accordingly, systemic corticosteroids
practical information on how to administer systemic corticosteroids are among a relatively small number of interventions for covid-19
(https://app.magicapp.org/#/guideline/nBkO1E/section/nByvRL). that have the potential to reduce inequities and improve equity in
Update—Whereas the recommendations remain unchanged, the health. Those considerations influenced the strength of this
evidence summary available via MAGICapp for corticosteroids was recommendation.
updated before the fifth iteration of the living guideline. The baseline Recommendation 2: We suggest not to use systemic
risk estimates for mortality are now based on the WHO SOLIDARITY corticosteroids for patients with non-severe covid-19 (conditional
trial (as for other drugs in this guideline)4 rather than the initial or weak recommendation).
ISARIC cohort study that likely overestimates current mortality risks
Balance of benefits and harms—Systemic corticosteroids may
at the global level.27 This update was also needed to inform the
increase the risk of 28-day mortality (low certainty).
baseline risk for mortality in the evidence summary informing the
strong recommendation for IL-6 inhibitors in addition to standard Values and preferences—The conditional recommendation was
care for patients with severe or critical covid-19, where driven by likely variation in patient values and preferences. The
corticosteroids provide a relative reduction in mortality by 21%. GDG judged that most individuals with non-severe illness would
decline systemic corticosteroids. However, many may want them
Recommendation 1: We recommend treatment with systemic
after shared decision making with their treating physician.
corticosteroids for patients with severe or critical covid-19 (strong
recommendation). Applicability—Several specific circumstances were considered.
Balance of benefits and harms—Ultimately, the GDG made its Systemic corticosteroids should not be stopped for patients with
recommendation on the basis of a 28-day mortality reduction of
•
non-severe covid-19 who are already treated with systemic
3.4% in severe or critical covid-19 combined (moderate certainty). corticosteroids for other reasons (such as patients with chronic
Systemic corticosteroids probably reduce the need for mechanical obstructive pulmonary disease or chronic autoimmune disease).
ventilation (moderate certainty).
• If the clinical condition of patients with non-severe covid-19
Overall, the GDG has reasonable certainty that the adverse effects, worsens (that is, increase in respiratory rate, signs of respiratory
when considered together, are sufficiently limited in importance distress or hypoxaemia) they should receive systemic
and frequency, and suggested that corticosteroids administered in corticosteroids (see recommendation 1).
these doses for 7-10 days are not associated with an increased risk
of adverse events, beyond likely increasing the incidence of • Pregnancy: antenatal corticosteroid therapy may be administered
hyperglycaemia and hyponatremia (both moderate certainty). In for pregnant women at risk of preterm birth from 24 to 34 weeks’
contrast with new agents proposed for covid-19, clinicians have gestation when there is no clinical evidence of maternal infection
vast experience administering systemic corticosteroids, and the and adequate childbirth and newborn care are available. In cases
GDG was reassured by their overall safety profile. where the woman presents with mild or moderate covid-19, the
clinical benefits of antenatal corticosteroid might outweigh the
Values and preferences—The GDG took an individual patient risks of potential harm to the mother. In this situation, the
perspective to values and preferences but, given the burden of the balance of benefits and harms for the woman and the preterm
pandemic for healthcare systems globally, also placed a high value newborn should be discussed with the woman to ensure an
on resource allocation and equity. The benefits of corticosteroids informed decision, as this assessment may vary depending on
on mortality were deemed of critical importance to patients, with the woman’s clinical condition, her wishes and those of her
little or no anticipated variability in their preference to be offered family, and available healthcare resources.
treatment if severely ill from covid-19.
• Endemic infections that may worsen with corticosteroids should
Applicability—Applicability is less clear for populations that were be considered. For example, for Strongyloides stercoralis
under-represented in the considered trials, such as children, patients hyper-infection associated with corticosteroid therapy, diagnosis
with tuberculosis, and those who are immunocompromised. In or empiric treatment may be considered in endemic areas if
considering potential contraindications to short term systemic steroids are used.

PRACTICE
Resource implications, feasibility, equity, and human rights—To help Sources of evidence
guarantee access to systemic corticosteroids for patients with severe
To create recommendations, the GDG relied on evidence synthesised in
or critical covid-19, it is reasonable to avoid their administration to
two living network meta-analyses coordinated by MAGIC.6 7
patients who, given the current evidence, do not seem to derive any Derivation of absolute effects for drug treatments
benefit from this intervention.
For patients with non-severe illness, we used the median of the control
Specific uncertainties, emerging evidence, and future research arm of the RCTs that contributed to the evidence. For patients with severe
or critical illness, the GDG identified the control arm of the WHO
Remaining uncertainties include effects on: SOLIDARITY trial, performed across a wide variety of countries and
geographical regions, as representing the most relevant source of
• Patients with non-severe covid-19 (that is, pneumonia without evidence for baseline risk estimates for mortality and mechanical
hypoxaemia). ventilation.4 Systemic corticosteroids now represent standard of care in
Immunity and the risk of a subsequent infection, which may patients with severe or critical covid-19 (see strong recommendation
• issued by WHO in September 2020). Therefore, the baseline risk estimates
affect the risk of death after 28 days.
in the evidence summaries for JAK inhibitors, convalescent plasma and
• By different steroid preparation, dosing, and optimal timing of IL-6 receptor blockers were adjusted for treatment effects of
drug initiation. corticosteroids for the outcome of mortality and mechanical ventilation.4
For other outcomes, we used the median of the control arm of the RCTs
How this living guideline was created (see MAGICapp for full details that contributed to the evidence. Baseline risks, and thus absolute effects,
https://app.magicapp.org/#/guideline/nBkO1E) may vary significantly geographically and over time. Thus, users of this
guideline may prefer estimating absolute effects by using local event
Standards, methods, and processes for living and trustworthy guidance rates. Recommended combinations of treatments are based on direct
The Guideline Development Group (GDG) produced the recommendations comparisons from trials demonstrating additional benefit, such as adding
following standards for trustworthy guideline development using the baricitinib or interleukin-6 receptor blockers to systemic corticosteroids
GRADE (Grading of Recommendations Assessment, Development and in patients with severe or critical covid-19. In patients with non-severe
Evaluation) approach, in compliance with the WHO Handbook for covid-19 the absence of direct comparisons from RCTs necessitate indirect
Guideline Development 2nd Edition,28 the Institute of Medicine, and the comparisons from the living network meta-analysis to inform judgments
Guideline International Network (G-I-N).29 made about alternative treatment options.
Selection and support of the GDG
WHO convened a Guideline Development Group (GDG) with content How patients were involved in the creation of this article
experts (clinicians, methodologists, scientists) and patients who
previously had covid-19. The methods chair (methodological expertise) The GDG included four patients who previously had covid-19. Their
and a clinical chair (content expertise) guided the GDG discussions. GDG perspectives were crucial in considering the values and preferences
members were invited by WHO, with the aim of achieving gender, associated with the various treatments.
geography, expertise, and patient representation balance as well as
relevant technical and clinical expertise. The WHO technical unit collected AUTHOR AFFILIATIONS
and managed declarations of interests (DOIs) and found no GDG member, 1
chair, or systematic review team member to have a conflict of interest. Department of Health Research Methods, Evidence and Impact, McMaster University,
The GDG aimed to create a recommendation based on consensus with a Hamilton, Ontario, Canada
provision for voting that proved unnecessary for this recommendation. 2
Co-chairs were not eligible to vote in this setting. For recommendations Department of Medicine, McMaster University, Hamilton, Ontario, Canada
revised or added in the current iteration, there was no need for voting. 3
Guideline perspective, outcomes, and values and preferences MAGIC Evidence Ecosystem Foundation, Oslo, Norway
The target audience for this guidance consists of clinicians, patients, 4
and healthcare decision makers. The GDG defined covid-19 by clinical Université de Sherbrooke, Centre de recherche due CHU de Sherbrooke, Quebec,
severity (box 2). The GDG considered an individual patient perspective, Canada
but also took account of contextual factors (such as resources, feasibility, 5
acceptability, and equity) to accommodate global re-use and adaptation Division of General Internal Medicine & Division of Clinical Epidemiology, University
for countries and healthcare systems, and to recognise system challenges Hospitals of Geneva, Geneva, Switzerland
in implementing recommendations. 6
There were insufficient published data to provide the GDG with an World Health Organization, Geneva, Switzerland
evidence-based description of patient experiences, or values and 7
preferences regarding treatment decisions for covid-19 drug treatments. National Center for Infectious Diseases, Singapore
The GDG therefore relied on their own judgments of what well informed 8
patients would value after carefully balancing the benefits, harms, and , London, UK
burdens of treatment. These judgments on values and preferences were 9
also informed through the experiences of former patients with covid-19, Ministry of Health and Population, Cairo, Egypt
represented in the GDG. 10
Fluminense Federal University, Brazil
The GDG agreed that the following values and preferences would be
11
representative of those of typical well informed patients:
Mediciti Hospital, Nepal
• Most patients would be reluctant to use a treatment for which the 12
evidence left high uncertainty regarding effects on the outcomes they Antioquia University Medellin, Colombia
consider important. This was particularly so when evidence suggested 13
treatment effects, if they exist, are small and the possibility of Geneva University Hospital, Switzerland
important harm remains. 14
• In an alternative situation with larger benefits and less uncertainty Infection Division, Department of Pulmonology and Respiratory Medicine, Faculty of
Medicine Universitas Indonesia
regarding both benefits and harms, more patients would be inclined
to choose the treatment. 15
University of California, San Francisco, USA

PRACTICE
16 49
Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and St. George’s University Hospital, UK
Research Center 50
17 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Christian Medical College, Vellore, India 51
18 University of Colombo, Sri Lanka
Adult Infectious Disease Centre, University Teaching Hospital, Lusaka, Zambia 52
19 University of Sao Paulo, Brazil
Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam 53
20 Charité - Universitätsmedizin Berlin, Germany
University of Gent, Belgium 54
21 University of North Carolina, USA
Peking Union Medical College Hospital, Beijing, China 55
22 Faculty of Medicine Andres Bello University, Indisa Clinic, Santiago, Chile
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Canada 56
23 Influenza Division, U.S. Centers for Disease Control and Prevention, USA
Division of Emergency Medicine, Faculty of Medicine and Health Sciences, Stellenbosch 57
University, Cape Town, South Africa King’s College, London, UK
24 58
United States University of Stellenbosch, South Africa
25 59
University of Alberta, Canada Ministry of Health, Sri Lanka
26 60
Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia Infectious Diseases Data Observatory (IDDO), Centre for Tropical Medicine and Global
27 Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Ziauddin University, Karachi, Pakistan 61
28 Evidence Based Social Science Research Centre, School of Public Health, Lanzhou
St Thomas’ Hospital, London, UK University, Lanzhou, China and the Department of Social Medicine and Health
29 Management, School of Public Health, Lanzhou University, Lanzhou, China
Aga Khan University, Pakistan 62
30 Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool,
All India Institute of Medical Sciences, New Delhi, India UK
31 63
McMaster University, Canada (alumnus) HCOR Research Institute, Hospital do Coracao, Sao Paulo, Brazil; Pulmonary Division,
32 Heart Institute (InCor), University of Sao Paulo, Sao Paulo, Brazil
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic 64
of Korea Royal Free London NHS Foundation Trust, UK
33 65
Department of Paediatrics and Emergency Medicine, University of British Columbia, Department of Medicine, Lovisenberg Diaconal Hospital Trust, Oslo, Norway
Vancouver, Canada *
34 Not Guideline Development Group member; resource for methodology, systematic
St George’s University of London, UK review, and content support
35 a
Department of Anaesthesia and Critical Care, College of Health Sciences, Makerere co-senior author
University, Kampala, Uganda
Funding: Bill & Melinda Gates Foundation, Norwegian Directorate of Public Health and Germany provided
36
funding for this guideline, with MAGIC providing pro-bono contributions and support to WHO in the
HCOR Hospital do Coracao, Sao Paulo, Brazil
context of the covid-19 pandemic.
37
Department of Paediatrics, All India Institute of Medical Sciences, India Competing interests: All GDG members have completed the WHO interest disclosure form. All authors
38 have completed the BMJ Rapid Recommendations interest of disclosure form. The WHO, MAGIC and
Zimbabwe The BMJ judged that no GDG member or co-chair had any financial conflict of interest. Professional
and academic interests are minimised as much as possible, while maintaining necessary expertise on
39
Emergency Medical Services, Faculty of Medicine, Tunis, Tunisia the GDG to make fully informed decisions. MAGIC and TheBMJ assessed declared interests from other
co-authors of this publication and found no relevant conflicts of interests.
40
Groote Schuur Hospital, University of Cape Town, South Africa Provenance and peer review: This publication was commissioned by The BMJ in partnership with WHO
41 and the MAGIC Evidence Ecosystem Foundation, in the context of the BMJ Rapid Recommendations.
Clinical Scientific Institutes Maugeri, Italy Pre-publication internal and external peer-review managed by WHO, and internal review at The BMJ.
42 Post-publication review through rapid responses on bmj.com and through MAGICapp.
Alcivar Hospital in Guayaquil, Ecuador
We thank all the following collaborators who contributed to this endeavour, as detailed in the WHO
43
Sheikh Shakhbout Medical City, Abu Dhabi guidance (see link in box 1)
44
• World Health Organisation (WHO) Secretariat for Therapeutics and COVID-19
Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
45
• External reviewers for WHO
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, California, USA
We also thank
46
Aga Khan University, Karachi, Pakistan • The living systematic review and network meta-analysis team, led by investigators Reed Siemieniuk
47 and Romina Brignardello-Petersen at McMaster University, Canada
National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
48
Guy’s and St Thomas’ NHS Foundation Trust, London, UK

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