Under the terms o f this licence, you may copy, redistribute and adapt the w ork for non-commercial purposes, provided the w ork is appropriately cited, as indica ted below. In any use o f this w ork, there should be no sugg estion that WHO endorses an y specific organization, products or services. The use o f the WHO log o is no t permitted. If you adapt the w ork, then you must license your work under the same or equiv alent Creative Commons licence. If you create a translation of this w ork, you should add the f ollowing disclaimer along with the sugg ested citation: "This translation was not created by the World Health Organization (WHO). WHO is no t responsible for the content or accuracy of this translation. The original English edition shall be the binding and authen tic edition". Any mediation relating to disputes arising under the lic ence shall be c onducted in ac cordance with the media tion rules of the World Intellectual Property Organization (/.# Summary of the guideline

# Info Box
As of December 2022, there have been o ver 642 million confirmed cases of. The pandemic has thus far claimed approximately 6.62 million lives (10). Vaccination is having a substantial impact on hospitalizations and dea th in a number o f highincome countries, but limitations in global ac cess to COVID-19 vaccines mean that many populations remain vulnerable (10) (11).
Even in v accinated individuals, uncertainties remain about the dur ation of protection and e ffectiveness of current vaccines -and the efficacy of existing treatments for COVID-19 -against emer ging SARS-CoV-2 variants and subvariants.
Taken together, there remains a need f or more effective treatments for COVID-19. The COVID-19 pandemic -and the e xplosion of both research and misinformation -has highligh ted the need f or trustworthy, accessible, and regularly updated living guidance to place emerging findings into context and provide clear recommendations for clinical practice (12).
This living guideline responds to emer ging evidence from RCTs on e xisting and new drug treatments for COVID-19. More than 5000 trials investigating interventions for COVID-19 have been registered and are ongoing or c ompleted (see Section 9 f or emerging evidence) (13). Among these ar e large national and international platform trials (such as A CCT, RECOVERY, WHO SOLIDARITY, REMAP-CAP, and A CTIV), which recruit large numbers of patients in many countries, with a pragmatic and adaptive design (14)(15)( 16) (17). An o verview of ongoing trials is available from the Infectious Diseases Data Observatory, through their living systematic review of COVID-19 clinical trial registrations (13) and the WHO w ebsite.
Several LNMAs associated with this guideline inc orporate emerging trial data and allow for analysis of comparative effectiveness of multiple COVID-19 treatments. To inform the living guidanc e, we also use additional r elevant evidence on sa fety, prognosis, and patient values and preferences related to COVID-19 treatments. A living s ystematic review of 232 risk prediction models in hospitalized patients with COVID-19 identified two promising risk prediction tools that may help in form recommendations; these include the Jehi diagnostic model and the 4C mortality model ( see Section 6.1 f or more details) (18).

# What triggered this update and what is coming next?
This 13th version of the WHO living guideline w as triggered by:
- Availability of data regarding serious adverse reactions with nirmatrelvir-ritonavir in pregnant or breastfeeding women;
- Availability of additional evidence from high quality in vitr o neutralization experiments evaluating monoclonal an tibodies sotrovimab and casirivimab-imdevimab in circulating Omicron variants.
Fig. 1 sho ws other therapeutics in progress for this WHO living guideline, also c ommunicated through the WHO portal (4). Each dot represents a w eek of time. I n deciding which ther apeutics to c over, the WHO c onsiders multiple factors, including the e xtent of available evidence to in form recommendations, and makes a judgmen t on whe ther and when additional e vidence might be an ticipated. The WHO has a standing S teering Committee (see Section 10) to e valuate possibilities for new drug recommendations and upda tes to existing drug recommendations.

# Fig. 1. COVID-19 therapeutics under assessment as of 13 January 2023
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Understanding and applying the WHO severity definitions

# Info Box
This guideline applies to all patients with COVID-19. Recommendations may differ based on the se verity of COVID-19, according to WHO severity definitions (see below) (6). These definitions avoid reliance on ac cess to health care to de fine patient subgroups.

# WHO definitions of disease severity for COVID-19
- Critical COVID-19 -Defined by the criteria for acute respiratory distress syndrome (ARDS), sepsis, sep tic shock, or o ther conditions that would normally require the provision of life-sustaining therapies such as mechanical v entilation (invasive or non-invasive) or vasopressor therapy.
- Severe COVID-19 -Defined by any of:
- oxygen saturation < 90% on r oom air;
- signs of pneumonia;
- signs of severe respiratory distress (in adults, ac cessory muscle use, inability to c omplete full sentences, respiratory rate > 30 breaths per minute; and, in childr en, very severe chest w all in-drawing, grunting, central cyanosis, or presence of any other general danger signs including inability to breastfeed or drink, lethargy, convulsions or reduced level of consciousness).
- Non-severe COVID-19 -Defined as the absenc e of any criteria for severe or critical COVID-19.
The GDG no ted that the oxygen saturation threshold of 90% to de fine severe COVID-19 was arbitrary, and should be interpreted cautiously when de fining disease severity. For example, clinicians must use their judgmen t to de termine whether a low oxygen saturation is a sign o f severity or is normal for a given patient with chronic lung disease. S imilarly, clinicians may interpret a saturation of 90-94% on r oom air as abnormal in the pa tient with normal lungs, and as an early sign o f severe disease in pa tients with a do wnward clinical trajectory. Generally, in cases wher e there is doub t, the GDG sugg ested erring on the side o f considering disease as severe.
The infographic illustrates these three disease se verity groups and key characteristics to apply in pr actice.
Infographic co-produced by the BMJ and MA GIC; designer Will Stahl-Timmins (see BMJ Rapid Recommendations).
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
- Recommendations for therapeutics 6.1 Overview of drugs, recommendations and key issues to c onsider when applying them

# Info Box
The infographic summarizes WHO recommendations, mapped against the WHO se verity criteria. When applying the recommendations, clinicians should also c onsider the following key issues:

# How to choose be tween therapeutics
Several therapeutical options are available for patients with non-se vere COVID-19, and f or those with se vere or critical COVID-19. Choices will depend on a vailability of the drugs, r outes of administration (e.g. parenteral route only f or remdesivir and monoclonal an tibodies), co-administered medication, duration of treatment, and time fr om onset of symptoms to starting treatment. Some can be used in c ombination (i.e. as f or severe or critical  while others are to be used as alterna tives.
Recommended combinations of treatments are based on dir ect comparisons from trials demonstrating additional benefit, such as adding the J AK inhibitor baricitinib to IL-6 receptor blockers and to s ystemic corticosteroids in patients with severe or critical COVID-19.
In the absenc e of direct comparisons of the v arious therapeutics in trials, indirect comparisons from the LNMA ha ve been used (see  to inform use o f one drug o ver another with a related mechanism o f action. To display the bene fits and harms for the alternative therapeutics, we provide an interactive decision support tool that can also be used in shar ed decision-making, for patients with non-se vere COVID-19 at highest risk of hospitalization.

# How to identify patients with non-severe COVID-19 at highest risk of hospitalization
Several recommendations for drugs are only f or those at highest risk for hospitalization because the bene fit would be trivial (in absolute terms) if everyone with non-se vere COVID-19 were to receive treatment. The panel iden tified a risk beyond 10% o f being hospitalized for COVID-19 to represent a threshold at which most pa tients with non-se vere illness would want to be treated (see Section 7).
Reliably identifying those a t highest risk is challenging because o f the changing global c ontext with evolution of the virus and patterns of COVID-19 vaccination, thus raising the importance of validation of models to local c ontext. A living systematic review of 232 risk prediction models f or COVID-19 identified two promising risk prediction tools (18) before Omicron circulation. These tools c oncur that typical characteristics of people a t highest risk include those with older ag e, immunosuppression and/or chr onic diseases, with lack o f COVID-19 vaccination as an additional risk factor to c onsider.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Nirmatrelvir-ritonavir (updated 13 January 2023)
An initial strong recommendation concerning nirmatrelvir-ritonavir for patients with non-se vere COVID-19 at highest risk of hospitalization and a c onditional recommendation against use f or patients at low risk of hospitalization were published on 22 April 2022 as the 10th version of the WHO living guideline and in the BMJ as Rapid Recommendations. This was based on da ta from two RCTs which w ere available at the time (1). Applicability of the recommendations to children, breastfeeding and pregnant women was uncertain, as the included R CTs enrolled only non-pregnant women.
In this 13th iteration, an upda ted recommendation was made c oncerning the use o f nirmatrelvir-ritonavir in breastfeeding and pregnant women with non-se vere illness, based on da ta mainly available through the WHO VigiBase | UMC. While there were no reported serious adverse events linked to nirmatrelvir-ritonavir in pregnant or breastfeeding women -either in mo ther or child -there was residual uncertainty pertaining to the denomina tor to which this estima te of no undesirable effects applied. Therefore, given the likely benefits and residual uncertainty regarding undesirable effects, the recommendation was updated to reflect the GDG's belief that shared, fully in formed decision-making between mother and health care provider should determine the use or non-use o f nirmatrelvir-ritonavir in pregnant or breastfeeding women with non-se vere COVID-19.
For patients with non-severe COVID-19 at highest risk of hospitalization

# Practical Info
Route, dosage and duration: Additional considerations are available in three summaries of practical issues (nirmatrelvir-ritonavir for COVID-19, administration of nirmatrelvir-ritonavir for COVID-19, safety and monitoring f or patients receiving nirmatrelvirritonavir for. Here follows a brief summary of key points:
- The recommended dose f or nirmatrelvir-ritonavir is 300 mg (two 150 mg table ts) of nirmatrelvir and 100 mg o f ritonavir every 12 hours daily for 5 days, as per the r egimen evaluated in large trials informing the recommendation. - In renal insufficiency (GFR 30-59 m L/min) the dose r eduction is 150 mg o f nirmatrelvir and 100 mg o f ritonavir every 12 hours daily for 5 days. - Administration should be as early as possible in the time c ourse of the disease. I n the included studies, nirma trelvir-ritonavir was administered within 5 da ys of disease onse t.
In any patient being c onsidered for nirmatrelvir-ritonavir use, clinicians need to giv e serious consideration to drug in teractions.
The Liverpool COVID-19 drug interaction checker may be use ful in this regard (19).

# Evidence To Decision

# Strong recommendation for
We recommend treatment with nirmatrelvir-ritonavir (strong recommendation f or).
- See Section 6.1 f or help t o identify patients at highest risk.
- Several therapeutic op tions are available: see decision support t ool that displays benefits and harms o f nirmatrelvir-ritonavir, molnupiravir and remdesivir. - The GDG c oncluded that nirmatr elvir-ritonavir represents a superior choic e because it may hav e greater efficacy in preventing hospitalization than the alt ernatives; has f ewer concerns with respect t o harms than does molnupir avir; and is easier t o administer than intravenous remdesivir and the an tibodies. - Clinicians should review all medic ations and no t consider nirmatrelvir-ritonavir in patients with possible dang erous drug interactions (note: many drugs in teract with nirmatr elvir-ritonavir). - Fully informed shared decision-making should det ermine whether nirmatr elvir-ritonavir should be used in pr egnant or breastfeeding women, given possible benefit and r esidual uncertainty regarding potential undesirable effects. - Nirmatrelvir-ritonavir should be administ ered as soon as possible aft er onset o f symptoms, ideally within 5 day s.
In highest risk patients in whom an appr eciable decrease in hospitalization with nirmatrelvir-ritonavir is likely, the bene fits clearly outweigh the harms, thus w arranting the strong recommendation in fa vour of the drug.
In patients with non-se vere COVID-19, nirmatrelvir-ritonavir likely reduces admission to hospital (moder ate certainty evidence). It may have little or no impact on mortality (lo w certainty evidence). There are no da ta reported for time to symptom resolution or mechanical v entilation. Treatment does no t increase the likelihood of adverse effects leading to drug discontinuation (high certainty evidence), though diarrhoea and dy sgeusia (loss of taste) have occurred more frequently with nirmatrelvir-ritonavir as compared with plac ebo.
The GDG ackno wledged that there was a paucity o f information relating to emergence of resistance and much mor e data were needed to in form the recommendation.

# Benefits and harms
The evidence summary on nirmatrelvir-ritonavir was informed by two trials (EPIC-SR and EPIC-HR) with 3100 participan ts included in the LNMA study (1) (20) (21).
Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to c oncerns regarding imprecision and risk o f bias), low for mortality (rated down due to serious impr ecision and indirectness), and high f or adverse effects leading to drug disc ontinuation. We did no t rate the c ertainty of the e vidence for diarrhoea and dysgeusia.

# Certainty of the Evidence
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
Moderate certainty evidence of a substan tial relative risk reduction in hospitalization, and high c ertainty evidence of no adv erse effects requiring drug discontinuation, motivated the strong recommendation in individuals at higher risk of hospitalization. Such individuals are likely to achieve an important reduction in the absolute risk o f hospitalization in c omparison with those no t receiving nirmatrelvir-ritonavir.

# Alternative or combination therapy
The GDG has pr eviously made a c onditional recommendation for molnupiravir (see Section 6.9) and r emdesivir (see Section 6.3) in the highest risk non-severe population. Indirect comparisons in higher and highest risk pa tients found nirmatrelvir-ritonavir may reduce hospitalization when c ompared with molnupiravir (low certainty); however, found little or no difference when compared with remdesivir (low certainty). Without direct data comparisons and low certainty confidence in indirect comparisons, the GDG chose no t to make comparative recommendations between drugs, but r ather remarked that nirmatrelvirritonavir may be superior based on its e fficacy compared with standard of care (moderate certainty), and that ultimately the choice of therapeutic may be made based on pr actical issues, such as ease o f administration and risk profiles.
There is no e vidence for combining antiviral therapies; the GDG ther efore advised against this.
Because pregnancy represents a risk factor f or severe or critical illness in those with non-se vere COVID-19, pregnant women Limitations in available empirically developed risk prediction tools f or establishing patients' risk of hospitalization represent the major source of indirectness for which the GDG r ated down the c ertainty of the e vidence (22).
Applying the agreed upon v alues and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients with a higher risk o f hospitalization would choose to use nirma trelvir-ritonavir.

# Values and preferences

# Acceptability and feasibility
Nirmatrelvir-ritonavir is unlikely to be a vailable for all individuals who, giv en the op tion, would choose to r eceive the treatment. This reinforces that nirmatrelvir-ritonavir should be reserved for those at higher risk.
Obstacles to access in low-and middle-inc ome countries (LMICs) may prove formidable due to c ost and availability. Those with socioeconomic disadvantages tend to ha ve less ac cess to services, including diagnostic testing and tr eatments, in the first 5 days of symptoms, and thus less ac cess to the in terventions. Therefore, if pa tients at higher risk receive the intervention, this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts o f the health s ystem that may provide care for patients with non-se vere COVID-19 (i.e. primary care, community care settings).
The recommendations should provide a stimulus to engag e all possible mechanisms to impr ove global access to the intervention. In promoting access, WHO has pr equalified generic versions of molnupiravir and one g eneric version of nirmatrelvir-ritonavir. In addition, there are additional applications under review for both products. United Nations (UN) partners procure these products and are making them a vailable to LMICs. WHO and UN partners support alloca tion and procurement mechanisms f or countries to ensure that these medicines are available and integrated into national supply chains. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly.
Access to SARS-CoV-2 diagnostics: Since this recommendation involves ideally administering treatment with nirmatrelvirritonavir within 5 days of symptom onset, increasing access and ensuring appropriate use o f diagnostic tests is essen tial for implementation. Thus, availability and use of appropriate SARS-CoV-2 diagnostic tests is needed to impr ove access to drugs, especially those targeting the early phase o f disease. T he appropriate use o f rapid diagnostic tests such as antigen-detection assays can improve early diagnosis in the c ommunity and in primary health care settings. Health care systems must, however, gain e xpertise in choosing and implemen ting rapid tests, choosing those most applicable to their settings.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) might consider using medication that reduces the risk o f disease progression (6). Nirmatrelvir-ritonavir, the drug c ombination the WHO recommends most highly in the c ontext of non-se vere illness for patients at highest risk of hospitalization, represents a possible op tion.
Nevertheless, as with an y medication not formally tested in pregnancy, in c onsidering nirmatrelvir-ritonavir, concerns regarding undesirable effects in bo th mother and fetus immediately arise. Data from the WHO VigiBase, a c omprehensive collection of worldwide unpublished reports of possible adv erse reactions to drugs -in this case, nirma trelvir-ritonavir in pregnant womencan inform the issue o f undesirable effects.
Up to no w, there have been no r eports linking nirmatrelvir-ritonavir to serious adverse reactions in pregnant or breastfeeding women, either in mo ther or child. This is reassuring, but only to an e xtent: we are uncertain of the denomina tor to which this estimate of no undesirable effects applies. If a large number o f women have been e xposed, the absenc e of reported undesirable effects provides considerable reassurance; if only a small number not so. We are uncertain which is the case.
In providing guidance on nirmatrelvir-ritonavir use in pregnancy, the GDG c onsidered the likely benefits (there is no r eason to think the drug will be less e ffective in pregnant women than in o ther people) and the unc ertainty regarding undesirable effects. The GDG believes that shared, fully in formed decision-making between mother and health care provider should determine the use or non-use o f nirmatrelvir-ritonavir in pregnant or breastfeeding women with non-se vere COVID-19.

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19
The LNMA f or nirmatrelvir-ritonavir was informed by two RCTs (EPIC-SR and HR) which en rolled 3100 patients with non-severe illness in outpa tient settings. The two RCTs were registered; and one w as published in a peer -reviewed journal (21). None of the included studies enr olled children or pregnant women. The Table shows the characteristics of the RCTs.
For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of nirmatrelvir-ritonavir compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (3).
The planned subgroup analyses were limited by available data but did no t detect credible subgroup effects for serological status and age (children were not enrolled). As all patients were unvaccinated and w ere randomized within 5 days of symptom onset, and no pa tients received therapeutic co-interventions, these subgroup analyses could not be performed.

# New evidence for pregnant and breastfeeding women
In September 2022, the WHO P harmacovigilance team searched the WHO da tabase called VigiBase | UMC to retrieve ICSRs on nirmatrelvir-ritonavir. The purpose o f this database is to ensure that early signs o f previously unknown medicines-related safety problems are identified as rapidly as possible. VigiBase holds o ver 32 million anonymized reports of suspected adv erse events of medicines and v accines. ICSR retrieved came solely fr om the U nited States and one case o f spontaneous abortion was identified. However, there was not an established causal link to pr ove that nirmatrelvir-ritonavir caused the outc ome and important information was missing. Four ICSRs showed lactation impairment, suggesting a need f or follow up to de termine whether this is a signal or no t.
Alternative sources of information searched consisted of PubMed and E arly Warning System. The latter is a platform used by the WHO Pharmac ovigilance team to le verage machine learning and ar tificial intelligence to support sa fety preparedness and signal de tection functions. Although this s ystem captures a lo t of noise, it allo ws to iden tify adverse events, provided confirmation. The posts identified concerning experiences of pregnant or lactating women using nirmatrelvir-ritonavir were balanced, and do not allow to conclude on any adverse event or signal.

# Outcome Timeframe

# Study results and measurements Comparator

# No nirmatrelvirritonavir

# Certainty of the Evidence
Due to serious imprecision and indirectness 1 Nirmatrelvir-ritonavir may have a small e ffect on mortality

# Mechanical ventilation
The effect of nirmatrelvir-ritonavir is unknown

# Admission to hospital

# Risk in trials
Odds ratio 0.15 (CI 95% 0.06 -0.
Nirmatrelvir-ritonavir has little or no risk of adverse effects leading to drug discontinuation

# Time to symptom resolution

# No data
The effect of nirmatrelvir-ritonavir is unknown 1. Indirectness: serious. Some patients may be a t substantially higher risk of death. Nirmatrelvir-ritonavir probably reduces mortality in these patients. Imprecision: serious. There were only 12 e vents (all in the placebo group); and only one study. 2. Risk of Bias: serious. The study w as stopped early f or benefit. Imprecision: serious. The total sample size does no t meet the optimal information size.
- Risk of Bias: serious. The study w as stopped early f or benefit. Imprecision: serious. The total sample size does no t meet the optimal information size. 4. Risk of Bias: serious. The study w as stopped early f or benefit. Imprecision: serious. The total sample size does no t meet the optimal information size.

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Comparator: Molnupiravir

# Study results and measurements

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary
Odds ratio 0 (CI 95% 0 -0.29) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 f ewer -0 fewer
Due to serious indirectness 1 There is probably little or no difference in mortality

# Mechanical ventilation

# No data
The effect of nirmatrelvir-ritonavir is unknown

# Admission to hospital

# Risk in trials
Odds ratio 0.29 (CI 95% 0.
There is little or no difference in the risk o f adverse effects leading to drug discontinuation.

# Time to symptom resolution

# Very low
Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain

# Study results and measurements

# Intervention Remdesivir
Certainty of the Evidence (Quality of evidence)

# Plain language summary
- Risk of Bias: serious. Indirectness: serious. Some patients may be a t substantially higher risk of death. There may be an important difference in mortality in these pa tients. Imprecision: serious.

# Mechanical ventilation

# No data
The impact on mechanical ventilation is unknown

# Hospital admission

# Risk in trials
Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission

# Hospital admission
Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Adverse events leading to drug discontinuation 0 per 1000

# Very low
Due to v ery serious risk of bias, serious indirectness, and very serious imprecision 5 The impact on adv erse effects leading to drug discontinuation is uncertain

# Time to symptom resolution

# No data
The effect of nirmatrelvir-ritonavir is unknown In any patient being c onsidered for nirmatrelvir-ritonavir use, clinicians need to giv e serious consideration to drug in teractions.
The Liverpool COVID-19 drug interaction checker may be use ful in this regard (19).

# Evidence To Decision

# Conditional recommendation against
We suggest not to use tr eatment with nirmatrelvir-ritonavir (conditional recommendation ag ainst).
- In the GDG' s assessmen t, only a minority o f low-risk patients will choose t o consider using nirmatr elvir-ritonavir.
- Trials on antivirals included patien ts with some risk f actors for hospital admission, resulting in a baseline risk o f 3% that the GDG applied to generate the r ecommendation. T he risk of hospitalization is likely to be lo wer in the g eneral population.
- Clinicians should no t consider nirmatrelvir-ritonavir in patien ts with possible dang erous drug in teractions (note: many drugs interact with nirmatr elvir-ritonavir). - Fully informed shared decision-making should det ermine whether nirmatr elvir-ritonavir should be used in pr egnant or breastfeeding women, c onsidering possible benefits and unc ertainty regarding potential undesirable effects.
In patients with non-se vere COVID-19, nirmatrelvir-ritonavir probably reduces admission to hospital. H owever, in lo w-risk patients, the absolute bene fit is very small and unlikely to be importan t to most pa tients. Nirmatrelvir-ritonavir probably has little or no impact on mortality. Highly relevant to patients at low risk of hospitalization, studies have reported no data for time to s ymptom resolution. EPIC-SR did, ho wever, report a very closely related outcome: time to 4 c onsecutive days of mild or no s ymptoms. For this analysis, the median time w as 13 (95% CI 12 to 15) da ys for nirmatrelvir-ritonavir, and 13 (95% CI 11 to 14) da ys for placebo (p=0.47). Treatment does no t increase the likelihood of adverse effects leading to drug discontinuation, though diarrhoea and dy sgeusia have occurred more frequently with nirmatrelvir-ritonavir, as c ompared with placebo.

# Benefits and harms
The evidence summary on nirmatrelvir-ritonavir was informed by two trials (EPIC-SR and EPIC HR) with 3100 participants included in the LNMA study (1)(20) (21).
Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to c oncerns regarding serious imprecision and risk o f bias), low for mortality (rated down due to serious impr ecision and indirectness), and high f or adverse effects leading to drug disc ontinuation. We did no t rate certainty of evidence for diarrhoea and dysgeusia.

# Certainty of the Evidence
The GDG believes that most low-risk patients would be reluctant to use a medica tion for which the e vidence left high uncertainty regarding effects on outc omes they consider important. This consideration is particularly relevant for shortening of the duration of symptoms, for which w e have no direct evidence supporting a positiv e impact o f nirmatrelvir-ritonavir.

# Values and preferences
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
Most patients who c ontract COVID-19 are at very low risk of hospitalization (under 1%) and a t a vanishingly small risk of mortality. Such patients will experience trivial benefits from the use o f nirmatrelvir-ritonavir. The panel inferred that most such patients would be unin terested in using the drug f or these trivial benefits. Thus, for most patients, sufficient risk -and thus sufficient benefit of nirmatrelvir-ritonavir -to mak e nirmatrelvir-ritonavir use an a ttractive option will require the presence of at least one if no t a c ombination of risk factors. T his is particularly true in low-income settings in which resource constraints and feasibility issues will make nirmatrelvir-ritonavir use less a ttractive.
The GDG, ne vertheless, was cognizant that there are likely to be an appr eciable number of individuals who plac e a high v alue on very small reductions in the risk o f hospitalization and who w ould thus choose use o f nirmatrelvir-ritonavir; therefore, a conditional rather than strong recommendation was made.
Nirmatrelvir-ritonavir is unlikely to be a vailable for all individuals who, giv en the op tion, would choose to r eceive the treatment. This reinforces that nirmatrelvir-ritonavir be reserved for those at highest risk.

# Resources and other considerations
Clinical Question/ PICO
Patients with non-se vere COVID-19
The LNMA f or nirmatrelvir-ritonavir was informed by two RCTs (EPIC-SR and HR) which en rolled 3100 patients with non-severe illness in outpa tient settings. The two RCTs were registered; and one w as published in a peer -reviewed journal (21). None of the included studies enr olled children or pregnant women. The Table shows the characteristics of the RCTs.
For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of nirmatrelvir-ritonavir compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (3).
The planned subgroup analyses were limited by available data but did no t detect credible subgroup effects for serological status and age (children were not enrolled). As all patients were unvaccinated and w ere randomized within 5 days of symptom onset, and no pa tients received therapeutic co-interventions, these subgroup analyses could not be performed.

# New evidence for pregnant and breastfeeding women
In September 2022, the WHO P harmacovigilance team searched the WHO da tabase called VigiBase | UMC to retrieve ICSRs on nirmatrelvir-ritonavir. The purpose o f this database is to ensure that early signs o f previously unknown medicines-related safety problems are identified as rapidly as possible. VigiBase holds o ver 32 million anonymized reports of suspected adv erse events of medicines and v accines. ICSR retrieved came solely fr om the U nited States and one case o f spontaneous abortion was identified. However, there was not an established causal link to pr ove that nirmatrelvir-ritonavir caused the outc ome and important information was missing. Four ICSRs showed lactation impairment, suggesting a need f or follow up to de termine whether this is a signal or no t.
Alternative sources of information searched consisted of PubMed and E arly Warning System. The latter is a platform used by the WHO Pharmac ovigilance team to le verage machine learning and ar tificial intelligence to support sa fety preparedness and signal de tection functions. Although this s ystem captures a lo t of noise, it allo ws to iden tify adverse events, provided confirmation. The posts identified concerning experiences of pregnant or lactating women using nirmatrelvir-ritonavir were balanced, and do not allow to conclude on any adverse event or signal.

# Outcome Timeframe

# Study results and measurements

# No nirmatrelvirritonavir

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary
Due to serious imprecision and indirectness 1
Nirmatrelvir-ritonavir may have a small e ffect on mortality

# Mechanical ventilation
The effect of nirmatrelvir-ritonavir is unknown

# Admission to hospital
Nirmatrelvir-ritonavir has little or no risk of adverse effects leading to drug discontinuation

# Time to symptom resolution

# No data
The effect of nirmatrelvir-ritonavir is unknown 1. Indirectness: serious. Some patients may be a t substantially higher risk of death. Nirmatrelvir-ritonavir probably reduces mortality in these patients. Imprecision: serious. There were only 12 e vents (all in the placebo group); and only one study. 2. Risk of Bias: serious. The study w as stopped early f or benefit. Imprecision: serious. The total sample size does no t meet the optimal information size.
- Risk of Bias: serious. The study w as stopped early f or benefit. Imprecision: serious. The total sample size does no t meet the optimal information size. 4. Risk of Bias: serious. The study w as stopped early f or benefit. Imprecision: serious. The total sample size does no t meet the optimal information size.

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Comparator: Molnupiravir

# Study results and measurements

# Certainty of the Evidence
(Quality of evidence) There is probably little or no difference in mortality

# Plain language summary

# Mechanical ventilation

# No data
The effect of nirmatrelvir-ritonavir is unknown

# Admission to hospital

# Risk in trials
Odds ratio 0.29 (CI 95% 0.

# Study results and measurements

# Comparator Molnupiravir

# Certainty of the Evidence
(Quality of evidence)
Plain language summary 1. Indirectness: serious. Some patients may be a t substantially higher risk of death. There may be an importan t difference in mortality in these pa tients.
There is little or no difference in the risk o f adverse effects leading to drug discontinuation.

# Time to symptom resolution

# Very low
Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain

# Admission to
Odds ratio 0.29

# Outcome Timeframe

# Study results and measurements

# Intervention Remdesivir
Certainty of the Evidence (Quality of evidence)

# Plain language summary
- Risk of Bias: serious. Indirectness: serious. Some patients may be a t substantially higher risk of death. There may be an important difference in mortality in these pa tients. Imprecision: serious.

# Mechanical ventilation

# No data
The impact on mechanical ventilation is unknown

# Hospital admission

# Risk in trials
Odds ratio 1.64 (CI 95% 0.33 -7.57)
Due to serious risk of bias and imprecision 2
There may be little or no difference in hospital admission

# Hospital admission

# Higher risk
Odds ratio 1.64 (CI 95% 0.33 -7.57)
per 1000 Difference:
per 1000 6 more per 1000 ( CI 95% 6 f ewer -55 more
Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission

# Hospital admission

# Highest risk
Odds ratio 1.64 (CI 95% 0.33 -7.57)
per 1000 Difference:
per 1000 10 more per 1000 ( CI 95% 11 f ewer -94 more
Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Adverse events leading to drug discontinuation 0 per 1000

# Very low
Due to v ery serious risk of bias, serious indirectness, and very serious imprecision 5 The impact on adv erse effects leading to drug discontinuation is uncertain

# Time to symptom resolution

# No data
The effect of nirmatrelvir-ritonavir is unknown
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Mechanism of action
Nirmatrelvir inhibits the SARS-CoV-2 protease (3CLpro), thereby preventing cleavage of the viral polyprotein which is needed f or viral proteins to bec ome functional (23). Inhibition of the protease renders the virus unable to r eplicate. Nirmatrelvir is coadministered with ritonavir, an HIV pr otease inhibitor, used in this c ontext to boost the pharmac okinetics of nirmatrelvir but without exerting any direct antiviral activity itself (24). Therefore, the c ombination should be c onsidered as an tiviral monotherapy. Nirmatrelvir was developed as an or ally deliverable analogue of an in travenous prodrug (lufotrelvir; PF-07304814). The drug w as originally developed for SARS-CoV, and has been subsequen tly repurposed for SARS-CoV-2.
Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 in differentiated normal human bronchial epithelial cells with an EC50 of 0.06 micr omolar and an E C90 of 0.18 micromolar (24). In healthy volunteers, plasma maximum c oncentrations of nirmatrelvir were 2210 ng/m L with a half -life of 6 hours f ollowing a 300/100 mg dose o f nimatrelvir-ritonavir, and steady-sta te pharmacokinetics were achieved on da y 2 (25) (an EC90 of 0.18 micromolar equates to approximately 90 ng/m L). High doses (300 mg/kg) o f unboosted nima trelvir was active against murine-adapted SARS-CoV-2 in mic e but with maximum concentrations higher than those achie ved at 300/100 mg doses in health y human v olunteers (24). High doses (250 mg/kg) o f unboosted nimatrelvir also had efficacy in SARS-CoV-2-infected Syrian golden hamsters but no pharmac okinetic data are available in this species (26). Based upon the g enome sequence of Omicron, there appears to be no molecular basis f or a loss o f activity. Nimatrelvir retains activity against all SARS-CoV-2 lineages studied in vitro to date (27)(28) but in vivo data are currently unavailable.
Much more data are required to asc ertain the rate at which resistance will emerge for nirmatrelvir. Single amino acid chang es introduced into the protease sequence can reduce activity of nirmatrelvir by between 23. 6-and 39-f old (25). Mouse hepatitis virus (used as a be tacoronavirus surrogate) acquired several mutations under a selectiv e pressure in vitro, and these r educed nirmatrelvir activity by between 4-and 91-f old (25). Two amino substitutions w ere described in clinical trials, one o f which did not impact nirmatrelvir activity.
Through its impact on me tabolism and clearance, ritonavir is a perpetrator of many drug-drug interactions that will require careful consideration. Short durations of therapy needed in C OVID-19 may make drug interactions easier to manag e than they are for HIV, but twic e daily administration means that the ritonavir dose is double tha t used in most modern an tiretroviral regimens. The impact o f ritonavir on metabolism may also outlast dosing b y several days. The Liverpool COVID-19 drug interaction checker may constitute a valuable tool for management of drug interactions with nirmatrelvir-ritonavir (19).

# Remdesivir (updated 16 September 2022)
An initial conditional recommendation was made on 20 N ovember 2020, sugg esting not to use r emdesivir for patients with COVID-19, regardless of illness severity. This was based on da ta from four RCTs which w ere available at the time, with 7333 participants hospitalized for COVID-19. In the 10th iteration of the guideline, a ne w recommendation was made f or the use o f remdesivir for patients with non-se vere illness. In the 12th iteration of the guideline, upda ted recommendations for patients with severe or critical COVID-19 were provided, given new trial data providing sufficiently trustworthy evidence for a subgroup effect demonstrating modest bene fit in patients with severe, but no t critical COVID-19.
For patients with non-severe COVID-19 at highest risk of hospitalization

# Practical Info
Route, dosage and duration: Additional considerations are available in three summaries of practical issues (remdesivir for COVID-19, administration of remdesivir for COVID-19, safety and monitoring in pa tients receiving remdesivir for COVID-19).
Here follows a brief summary of the key points:
- The recommended dose f or remdesivir is one dose daily f or 3 consecutive days as intravenous infusion, as per the r egimen evaluated in large trials informing the recommendation. Remdesivir is given as 200 mg in travenously on da y 1, f ollowed by 100 mg in travenously on da ys 2 and 3. - Administration should be as early as possible in the time c ourse of the disease. I n the included studies, r emdesivir was administered within 7 da ys of disease onse t. - It may be reasonable to monitor pa tients for a brief period f ollowing infusion. Any health care workers administering the infusions should f ollow recommended infection prevention and c ontrol recommendations in the outpa tient setting. - One should use caution when administering r emdesivir to patients with significant liver or kidney disease.
- The GDG no ted that there is insufficient evidence to make a recommendation around the use o f remdesivir in children and further studies are needed. - Additionally, the trials did no t enrol pregnant or breastfeeding women. The decision regarding use o f this therapeutic should be made be tween the pregnant person and their health car e provider while discussing whe ther the potential benefit justifies the potential risk to the mo ther and fetus (see Research evidence and WHO in formation sheet).

# Evidence To Decision

# Conditional recommendation for
We suggest treatment with remdesivir (conditional recommendation f or).
- See Section 6.1 regarding approach to identify patients at highest risk f or hospitalization.
- Several therapeutic op tions are available: see decision support t ool that displays benefits and harms o f nirmatrelvir-ritonavir, molnupiravir and remdesivir. - The GDG c oncluded that nirmatr elvir-ritonavir represents a superior choic e because it may hav e greater efficacy in preventing hospitalization than alt ernatives, has f ewer concerns with respect t o harms than does molnupir avir; and is easier t o administer than a 3-day c ourse of intravenous remdesivir. - Remdesivir should be administ ered as soon as possible aft er onset o f symptoms, ideally within 7 day s.
In patients with non-se vere COVID-19, remdesivir probably reduces admission to hospital and and ma y have little or no impact on mortality. The effect of remdesivir on mechanical v entilation and time to s ymptom resolution is very uncertain. Treatment probably does no t increase the likelihood of adverse effects leading to drug disc ontinuation.
The balance between benefits and potential harms favours treatment, but only in the highest risk gr oup. This is because absolute benefit of remdesivir on hospital admission depends on a giv en patient's prognosis. The GDG de fined a threshold of a 6% absolute r eduction in hospital admission to r epresent what most pa tients would value as an important benefit. Remdesivir would exert such a bene fit in patients at highest risk of hospitalization (above 10% baseline risk), such as older people, or those with immunode ficiencies and/or chr onic diseases, further enhanc ed by lacking vaccination. The conditional recommendation for the use o f remdesivir in those a t highest risk (above 10% baseline risk) reflects this threshold: 73 f ewer hospitalizations per 1000 pa tients.
The planned subgroup analyses for remdesivir versus standard care including age, time o f symptom onset and disease severity could not be performed in the absenc e of subgroup data reported publicly or provided by investigators. There were eight children (12 years or more of age) enrolled in the PINETREE trial (29); however, none died or w ere hospitalized.

# Benefits and harms
The evidence summary w as informed by five trials with 2709 participants included in the LNMA, with one trial in forming the outcome of hospital admission (1) (29).

# Certainty of the Evidence
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
When moving from evidence to the c onditional recommendation to use r emdesivir in patients with non-se vere COVID-19, the GDG emphasized the bene fits of decreased need f or hospitalization, along with little or no serious adv erse effects attributable to the drug. F easibility and complexity of administration were also carefully considered, and led to the r ecommendation for use only in the highest risk pa tients. Typical characteristics of people a t highest risk include older people, or those with immunodeficiencies and/or chr onic diseases with being un vaccinated further contributing to risk.
Costs and ac cess were important considerations, and the GDG r ecognizes that this recommendation could exacerbate health inequities. The GDG did no t anticipate important variability in patient values and preferences (see Evidence to D ecision).
Certainty of evidence was rated as: moderate for decreased admission to hospital ( due to serious imprecision); low for mortality (due to serious imprecision and indirectness); very low for mechanical ventilation (due to v ery serious imprecision and serious indirectness); and moderate for adverse effects leading to drug disc ontinuation.
Limitations in available empirically developed risk prediction tools f or establishing patients' risk of hospitalization represent the major source of indirectness for which the GDG r ated down the c ertainty of the e vidence (18) (22). See Section 6.1 f or more details.
Applying the agreed values and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients with a low risk of hospitalization would decline remdesivir, and only those a t highest risk w ould choose to r eceive treatment.

# Values and preferences

# Acceptability and feasibility
Remdesivir is administered as one in travenous infusion daily over 3 consecutive days, representing a f easibility challenge in outpatients aiming to a void hospital admission. F urthermore, remdesivir is unlikely to be a vailable for all individuals who, given the op tion, would choose to r eceive the treatment. This reinforces that remdesivir should be reserved for those at highest risk.
Obstacles to access in LMICs due to c ost, feasibility and availability are of concern (30). Challenges in shared decisionmaking and in c ommunicating the harms v ersus benefits of remdesivir may also be incr eased in LMICs. F or example, those with socioeconomic disadvantages tend to ha ve less ac cess to services, including diagnostic testing and tr eatments in the first 7 days of symptoms, and thus less ac cess to the in terventions. Therefore, if pa tients at highest risk receive the intervention, this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts o f the health s ystem that may provide care for patients with non-se vere COVID-19 (i.e. primary care, community care settings).
The recommendations should provide a stimulus to engag e all possible mechanisms to impr ove global access to the intervention. As an e xample of this, on 17 D ecember 2021, WHO published the 8th invitation to M anufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO P requalification Unit. If this e valuation demonstrates that a product and its c orresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list o f medicinal products that are considered to be acceptable for procurement by UN or ganizations and o thers. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly.
Access to SARS-CoV-2 diagnostics: Since this recommendation emphasizes the need to administer tr eatment with remdesivir within 7 days of symptom onset, increasing access and ensuring appropriate use o f diagnostic tests is essen tial. Thus, availability and use of reliable and timely S ARS-CoV-2 diagnostic tests (including the use o f nucleic acid amplifica tion tests (NAAT) and antigen-based rapid detection tests (Ag-RDTs)) are needed to impr ove access to drugs, especially those targeting the early phase o f disease. T he appropriate use o f Ag-RDTs by individuals and trained professionals can improve early diagnosis and earlier access to clinical care, particularly in the c ommunity and in primary health care settings. National programmes should op timize their testing s ystems to reflect local epidemiology, response objectives, available resources and needs o f their populations.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Alternative or combination therapy
The GDG has pr eviously made a c onditional recommendation for molnupiravir in the highest risk non-severe population (see Section 6.9), a strong recommendation for nirmatrelvir-ritonavir and a c onditional recommendation against nirmatrelvirritonavir in the lower risk non-severe population (see Section 6.2). I ndirect comparisons in higher and highest risk pa tients found remdesivir may reduce hospitalization when c ompared with molnupiravir (low certainty); and found little or no difference when compared with nirmatrelvir-ritonavir (low certainty). Without direct data and low certainty confidence in indirect comparisons the GDG chose no t to make comparative recommendations between drugs, but r ather remark that nirmatrelvir-ritonavir may be superior based on its e fficacy compared with standard of care and that ultimately, choice of therapeutic may be based on practical issues such as administr ation and po tential drug-drug interactions.
There is no e vidence for combining antiviral therapies; the GDG ther efore advised against this.
Only one o f the included trials included childr en (12 years of age and older), and the numbers w ere extremely small; therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of remdesivir to pregnant or lactating women. The decision regarding use o f this therapeutic should be made be tween the pregnant individual and their health care provider while discussing whe ther the potential benefit justifies the po tential risk to the mother and fetus (see Research evidence and P ractical info tabs).
The GDG also had c oncerns about whe ther the drug w ould retain efficacy against emerging variants of concern such as O micron BA.1 or B A.2. S urveillance is needed f or SARS-CoV-2 strains with reduced susceptibility to remdesivir and further research examining the role of combination therapy in se verely immunocompromised patients. Until further data are available, we have no reason to believe that activity against known variants will be diminished.

# Very low
Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain

# Mechanical ventilation

# No data
The impact on mechanical ventilation is unknown

# Hospital admission

# Risk in trials

# Very low
Due to v ery serious risk of bias, serious indirectness, and very serious imprecision 5 The impact on adv erse effects leading to drug discontinuation is uncertain For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of remdesivir compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (3).

# Hospital admission
The PINETREE trial was the only study to r eport subgroups within the non-se vere subgroup (29). The planned subgroup analyses were limited by available data but did no t detect credible subgroup effects for serological status and age. As all patients were unvaccinated, randomized within 7 da ys of symptom onset, and did no t receive therapeutic cointerventions; these subgroup analyses could not be performed. Of note, for age, 1.4% (n=8) w ere between 12 and 18 years old in the PINETREE trial, and none died or w ere hospitalized; no subgr oup effect was noted for > 60 v s  60 years old patients (p=0.78).

# Very low
Due to v ery serious imprecision and serious indirectness 2 The impact o f remdesivir on mechanical ventilation is unc ertain 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Does not meet optimal information size; few events (50 total events).

# Admission to hospital
- Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. There may be an important difference in mechanical ventilation in these patients. Imprecision: very serious. Credible interval includes important benefit and important harm. Does not meet optimal information size; few events (11 total).
- Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 4. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 5. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 6. Imprecision: serious. 7. Imprecision: extremely serious.

# Adverse effects leading to drug discontinuation

# Very low
Due to e xtremely serious imprecision 7 The impact o f remdesivir on time to s ymptom resolution is unc ertain 1. Indirectness: serious. Some patients may be a t substantially higher risk of death. There may be an importan t difference in mortality in these pa tients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 e vents for molnupiravir vs. control. 2. Risk of Bias: serious. The evidence for molnupiravir was at high risk of bias. Inconsistency: no serious. Indirectness: serious. Some patients may be a t substantially higher risk of mechanical v entilation. There may be an importan t difference in mechanical ventilation in these pa tients. Imprecision: no serious. Publication bias: no serious.

# Mechanical ventilation
Odds ratio 1.08 (CI 95% 0.12 -9) 8 per 1000 Difference:
per 1000 1 more per 1000 ( CI 95% 13 f ewer -16 more
Due serious risk of bias and indirectness 2 The there may be little or no difference in mechanical ventilation

# Admission to hospital
Due to v ery serious imprecision 4 Remdesivir may reduce hospital admission more than molnupiravir

# Admission to hospital

# Very low
Due to serious risk of bias, imprecision and indirectness 6 The impact on adv erse events leading to drug discontinuation is uncertain Time to symptom resolution

# Very low
Due to e xtremely serious imprecision 7 The impact on time to symptom resolution is very uncertain
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
For patients with severe COVID-19

# Practical Info
Route, dosage and duration: Additional considerations are available in three summaries of practical issues (remdesivir for COVID-19, administration of remdesivir for COVID-19, safety and monitoring in pa tients receiving remdesivir for COVID-19).
Here follows a brief summary of the key points:
- The recommended dose f or remdesivir is one dose daily as in travenous infusion. Remdesivir is given as 200 mg intravenously on da y 1, f ollowed by 100 mg in travenously on da ys 2-10. S horter regimens of 5 da ys are described in the smaller trials and local practice may be f ollowed. - Administration should be as early as possible in the time c ourse of the disease.
- One should use caution when administering r emdesivir to patients with significant liver or kidney disease.
- The GDG no ted that there is insufficient evidence to make a recommendation around use in childr en and further studies are needed. - Additionally, the trials did no t enrol pregnant or breastfeeding women. The decision regarding use o f this therapeutic should be made be tween the pregnant person and their health car e provider while discussing whe ther the potential benefit justifies the potential risk to the mo ther and fetus (see Research evidence and WHO in formation sheet).
Evidence To Decision

# Conditional recommendation for
We suggest treatment with remdesivir (conditional recommendation f or).
In patients with severe COVID-19, remdesivir possibly reduces mortality and probably reduces the need f or mechanical ventilation and probably has little or no impact on time to s ymptom improvement. The drug w as well tolerated and adverse events were rare.
The GDG critically evaluated the credibility of the da ta for severe and critical subgroups and the need to mak e separate recommendations (see Justification). It was felt that remdesivir would have an important effect in the se vere subgroup and a conditional recommendation could be made f or this group.
Subgroup analysis based on ag e was not possible due to lack o f trial level data. The GDG no ted with c oncern the dearth of pediatric data and a strong call f or research in this area was made. T he lack of data regarding the e ffect in immunocompromised patients was also highlighted. While there is limited e vidence in v accinated populations, the GDG f elt that the data were sufficient to c onditionally recommend the use o f remdesivir.
The timing o f initiation of therapy was not well reported across the studies and ther e was no clear subgroup effect based on time.

# Benefits and harms
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
When moving from evidence to the c onditional recommendation to use r emdesivir in patients with severe COVID-19, the GDG emphasized the bene fits on survival and reduction in need f or invasive mechanical ventilation and the likelihood of little or no serious adverse events attributable to the drug. The GDG ackno wledged that some serious adv erse events, may not have been accurately captured during the relatively short follow-up period in the included trials. O f note, although the GDG has recommended for other antiviral drugs in non-se vere patients, remdesivir is the only one with a r ecommendation for use in severe patients.
The GDG did no t anticipate important variability in patient values and preferences although the lo w certainty of evidence and ongoing uncertainty in effect contributed to the c onditional recommendation (see Evidence to D ecision). There were insufficient trial level data to examine subgroups based on ag e, or to c onsider patients requiring non-invasive ventilation (those on bilevel ventilation or high flo w nasal cannula) as a separate subgroup of interest.

# Credibility of subgroup effect based on se verity of disease
When making the recommendation for treatment with remdesivir, the GDG car efully considered the credibility of subgroup findings based on se verity of disease. W hen patients with severe and critical COVID-19 were considered together, pooled analysis demonstrated that remdesivir probably had little or no impact on mortality ( OR 0.95, 95% CI 0.84 to 1.07). W hen considered separately, remdesivir possibly has an important reduction on mortality (OR 0.89, 95% CI 0.78 to 1.02) in those with severe COVID-19, while possibly ha ving no impact on mortality in those with critical C OVID-19 (OR 1.15, 95% CI 0.89 to 1.51).
The GDG used the ICEMAN tool to assess the cr edibility of this subgroup finding as this w as crucial to informing the direction of the recommendation. The probability of an OR f or subgroup interaction < 1 in the B ayesian model demonstrated a p-v alue of 0.03, this is one-sided and can be c onsidered equivalent to a p-v alue of 0.06 f or subgroup interaction. Based on this, the GDG considered chance a po tential explanation of the apparent effect modification. This lowered the credibility of the subgroup finding as opposed to if the p-v alue for interaction had been smaller. That being said, the GDG c onsidered a number o f factors Certainty of evidence was rated as: low for decreased mortality (rated down from high f or imprecision and inc onsistency given the ong oing uncertainty regarding credibility of the se verity of illness subgroup effect modification); moderate for reduction in need f or invasive mechanical ventilation; and moderate for little or no impact on time to s ymptom improvement.

# Certainty of the Evidence
Applying the agreed upon v alues and preferences (see Section 7), the GDG in ferred that the majority of well-informed patients with severe COVID-19 would want to receive remdesivir due to the possible r eduction in mortality and need f or invasive mechanical ventilation. The benefit of remdesivir on mortality was deemed o f critical importance to pa tients and the GDG w as reassured by the sa fety of the drug. T he GDG an ticipated little variation in v alues and preferences between patients for this intervention.

# Values and preferences

# Acceptability and feasibility
Remdesivir is administered as one in travenous infusion daily over 10 consecutive days, and rather than in an outpa tient setting, this is more easily operationalized in hospitalized patients with severe disease.
Obstacles to access in LMICs due to c ost, feasibility and availability are of concern (30). Challenges in shared decisionmaking and in c ommunicating the harms v ersus benefits of remdesivir may also be incr eased in LMICs. T he recommendations should provide a stimulus to engag e all possible mechanisms to impr ove global access to the in tervention.
As an e xample of this, on 17 D ecember 2021, WHO published the 8th invitation to M anufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO P re-qualification Unit. If this evaluation demonstrates that a product and its c orresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list o f medicinal products that are considered to be ac ceptable for procurement by UN organizations and o thers. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
which increased the credibility of this subgroup finding. T his subgroup analysis was based en tirely on within-trial comparisons rather than between-trial comparisons which increased the credibility. The effect modification was mostly similar between included trials although predominantly driven by the largest SOLIDARITY study. There was uncertainty regarding whether the direction of effect modification was correctly hypothesized a priori -earlier in the pandemic one ma y have hypothesized that sicker patients (critical) may benefit more from intervention than those tha t are less sick ( severe). However, now that our understanding of COVID-19 disease c ourse has improved, it fits tha t those earlier in their disease trajectory (severe, but no t yet critical) may have more viral replication and therefore benefit more from an an ti-viral therapy. Ultimately, the GDG decided tha t the direction of effect modification was probably correctly hypothesized, which incr eased the credibility of the subgroup finding.
Only a small number o f effect modifiers were considered and a r andom effect model w as used, bo th factors which incr eased the credibility of the subgroup finding. A fter accounting for all of these individual factors, the GDG ultimately decided the cr edibility for this subgroup finding based on se verity of illness w as moderate and therefore to c onsider separate recommendations for each, while still recognizing remaining uncertainty.
None of the included R CTs enrolled children, and therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of remdesivir to pregnant or lactating women. The decision regarding use o f this therapeutic should be made be tween the pregnant individual and their health care provider while discussing whether the potential benefit justifies the po tential risk to the mo ther and fetus (see Research evidence and P ractical info tabs).
As the pandemic e volves, and similar to o ther COVID-19 interventions, there is ong oing uncertainty related to the e ffect of remdesivir based on v ariants and individual immune sta tus.

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19

# Intervention: Remdesivir
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of remdesivir in patients with severe and critical COVID-19 compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA that included five RCTs which enrolled 7643 participants (3). The planned subgroup analyses were limited by available data but did demonstrate sufficient credibility of a subgroup effect to in form specific recommendations for severe versus critical disease. Therefore these S ummary of Findings tables are presented separately.

# Adverse events leading to drug discontinuation
Odds ratio 1.35 (CI 95% 0. 31 -9.27
Due to serious imprecision 3 Remdesivir probably does not increase risk of adverse events leading to drug discontinuation.

# Length of hospital stay
The LNMA f or remdesivir in severe COVID-19 was informed by five RCTs which enrolled 6631 patients. All RCTs were published in peer-reviewed journals. None of the included studies enr olled children or pregnant women. T he Table shows characteristics of the R CTs.
For patients with severe COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of remdesivir compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (3).
The planned subgroup analyses were limited by available data but demonstrated low to moder ate credibility of a For patients with critical COVID-19

# Practical Info
Given the c onditional recommendation against using remdesivir for patients with critical COVID-19, practical considerations subgroup effect based on se vere versus critical disease and therefore these are presented separately and with separ ate recommendations. We were unable to perf orm subgroup analysis by age given the sparsity o f data.

# Outcome Timeframe

# Study results and measurements

# No remdesivir

# Intervention Remdesivir
Certainty of the Evidence (Quality of evidence)
Plain language summary 1. Inconsistency: serious. There is only lo w-to-moderate credibility of a subgroup effect between severe and critical disease. If there is no e ffect modification, then it is mor e likely that there is no diff erence in. Indirectness: no serious. Imprecision: serious. Does not meet optimal information size.
Due to serious imprecision 3 Remdesivir probably has little or no impact on time to s ymptom improvement

# Conditional recommendation against
We suggest not to use r emdesivir (conditional recommendation ag ainst).
were felt to be less r elevant here. See practical info for use o f remdevisir in patients with non-se vere or severe COVID-19 if needed.

# Evidence To Decision Justification
When moving from evidence to the c onditional recommendation against remdesivir in patients with critical COVID-19, the GDG emphasized the lack o f benefit on survival or other patient important outcomes. The GDG recognized there is ong oing uncertainty, and there may still be a subse t of patients that would benefit (e.g. immunoc ompromised, persistent viraemia) but there is insufficient evidence to make recommendations specific to these subse ts of critical patients.
The GDG did no t anticipate important variability in patient values and preferences although the lo w certainty of evidence and ongoing uncertainty in effect contributed to the c onditional recommendation (see Evidence to D ecision). There were insufficient trial level data to examine subgroups based on ag e, or to c onsider patients requiring non-invasive ventilation (those on bilevel ventilation or high flo w nasal cannula) as a separate subgroup of interest.

# Credibility of subgroup effect based on se verity of disease
When making the recommendation for treatment with remdesivir, the GDG car efully considered the credibility of subgroup findings based on se verity of disease. W hen patients with severe and critical COVID-19 were considered together, pooled analysis demonstrated that remdesivir probably had little or no impact on mortality ( OR 0.95, 95% CI 0.84-1.07). W hen considered separately, remdesivir possibly has an important reduction on mortality (OR 0.89, 95% CI 0.78-1.02) in those with severe COVID-19, while possibly ha ving no impact on mortality in those with critical C OVID-19 (OR 1.15, 95% CI 0.89-1.51).
The GDG used the ICEMAN tool to assess the cr edibility of this subgroup finding as this w as crucial to informing the direction of the recommendation. The probability of an OR f or subgroup interaction < 1 in the B ayesian model demonstrated a p-v alue of
In patients with critical COVID-19, remdesivir possibly has little or no e ffect on mortality, need f or mechanical ventilation and has an unc ertain effect on time to s ymptom improvement. The drug w as well tolerated and adverse events were rare. Subgroup analysis based on ag e was not possible due to lack o f trial level data. The GDG c onsidered the po tential of small subgroup effects in immunoc ompromised patients and critically ill patients with prolonged detection of SARS-CoV-2 RNA in blood specimens; ho wever, given the paucity o f data and concerns for harm, it w as felt that a c onditional recommendation against the use o f remdesivir was appropriate.

# Benefits and harms
Certainty of evidence was rated as: low for no impact on mortality or in vasive mechanical ventilation (rated down from high for imprecision and inc onsistency given the ong oing uncertainty regarding credibility of the se verity of illness subgroup effect modification); and very low for no impact on time to s ymptom improvement.

# Certainty of the Evidence
Applying the agreed upon v alues and preferences (see Section 7), the GDG in ferred that the majority of well-informed patients with critical COVID-19 would not want to receive remdesivir due to little or no impact on pa tient important outcomes including mortality and need f or invasive mechanical ventilation. The GDG an ticipated little variation in v alues and preferences between patients for this intervention.

# Values and preferences

# Acceptability and feasibility
Remdesivir is administered as one in travenous infusion daily over 10 consecutive days, and rather than in an outpa tient setting, this is more easily operationalized in hospitalized patients with critical disease.
Obstacles to access in LMICs due to c ost, feasibility and availability are of concern (30). Challenges in shared decisionmaking and in c ommunicating the harms v ersus benefits of remdesivir may also be incr eased in LMICs.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) 0.03, this is one-sided and can be c onsidered equivalent to a p-v alue of 0.06 f or subgroup interaction. Based on this, the GDG considered chance a po tential explanation of the apparent effect modification. This lowered the credibility of the subgroup finding as opposed to if the p-v alue for interaction had been smaller. That being said, the GDG c onsidered a number o f factors which increased the credibility of this subgroup finding. T his subgroup analysis was based en tirely on within-trial comparisons rather than between-trial comparisons which increased the credibility. The effect modification was mostly similar between included trials although predominantly driven by the largest SOLIDARITY study. There was uncertainty regarding whether the direction of effect modification was correctly hypothesized a priori -earlier in the pandemic one ma y have hypothesized that sicker patients (critical) may benefit more from intervention than those tha t are less sick ( severe). However, now that our understanding of COVID-19 disease c ourse has improved, it fits tha t those earlier in their disease trajectory (severe, but no t yet critical) may have more viral replication and therefore benefit more from an an tiviral therapy. Ultimately, the GDG decided tha t the direction of effect modification was probably correctly hypothesized, which incr eased the credibility of subgroup finding. The probability of an OR f or subgroup interaction < 1 in the B ayesian model demonstrated a p-v alue of 0.03, this is one-sided and can be c onsidered equivalent to a p-v alue of 0.06 f or subgroup interaction. Based on this, the GDG c onsidered chance a likely or unclear explanation of the apparent effect modification. This lowered the credibility of the subgroup finding as opposed to if the p-v alue for interaction had been smaller. Only a small number o f effect modifiers were considered and a r andom effect model was used, bo th factors which incr eased the credibility of the subgroup finding. A fter accounting for all of these individual factors, the GDG ultima tely decided the cr edibility for this subgroup finding based on se verity of illness w as moderate and therefore to c onsider separate recommendations for each, while still r ecognizing remaining uncertainty.
None of the included R CTs enrolled children or pregnant woman, and therefore the applicability of this recommendation to children remains uncertain. As the pandemic e volves, and similar to o ther COVID-19 interventions, there is ong oing uncertainty related to the e ffect of remdesivir based on v ariants and individual immune sta tus.

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19

# Intervention: Remdesivir
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of remdesivir in patients with severe and critical COVID-19 compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA that included five RCTs which enrolled 7643 participants (3). The planned subgroup analyses were limited by available data but did demonstrate sufficient credibility of a subgroup effect to in form specific recommendations for severe versus critical disease. Therefore these S ummary of Findings tables are presented separately.

# Adverse events leading to drug discontinuation
Odds ratio 1.35 (CI 95% 0. 31 -9.27
Due to serious imprecision 3 Remdesivir probably does not increase risk of adverse events leading to drug discontinuation.

# Length of hospital stay
The LNMA f or remdesivir in critical COVID-19 was informed by three RCTs which enrolled 1012 patients. All RCTs were published in peer-reviewed journals. None of the included studies enr olled children or pregnant women. T he Table shows characteristics of the R CTs.
For patients with critical COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of

# Mechanism of action
Remdesivir was developed for treatment of hepatitis C virus infection, and w as also studied in Ebola and M arburg virus infections before being repurposed for SARS-CoV-2. Remdesivir is a nucleoside drug. I ts mechanism o f action in volves chain termination, which is diff erent to lethal mutagenesis: the drug is inc orporated preferentially to the endog enous adenosine nucleoside by the S ARS-CoV-2 polymerase during replication of the RNA g enome. Unlike many other chain-terminating nucleoside drugs used f or other viruses, remdesivir elicits delayed chain termination because RNA s ynthesis is terminated after remdesivir compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (3).
The planned subgroup analyses were limited by available data but demonstrated low to moder ate credibility of a subgroup effect based on se vere versus critical disease and therefore these are presented separately and with separ ate recommendations. We were unable to perf orm subgroup analysis by age given the sparsity o f data.

# Very low
Due to e xtremely serious imprecision 3 The impact o f remdesivir is very uncertain Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) the addition of three more nucleotides, rather than at the poin t of remdesivir incorporation (33).
Emergence of antiviral resistance: Under a selective pressure in vitro, SAR-CoV-2 resistance to remdesivir emerged and w as associated with mutations (e.g. E802D and V792I) within the sequenc e coding for the polymerase (34) (35). The E802D muta tion was reported in a case study describing an immunoc ompromised patient receiving remdesivir who experienced recrudescence of high-grade viral shedding following a transient virological response to the drug (36). Moreover, the V792I muta tion has also been documented in tw o transplant recipients with persistant SARS-CoV-2 infection (37). The clinical significance of these observations if remdesivir were widely used in an outpa tient setting is unclear.

# Janus kinase inhibitors (updated 16 September 2022)
Baricitinib, for patients with severe or critical COVID-19

# Practical Info
Additional considerations are available in a summary of practical issues. Useful information can also be f ound in the U nited States Food and D rug Administration (FDA) fact sheet for health care providers, based on the emer gency use authorization (EUA) of baricitinib (38). Here follows a brief summary of key points:
Route, dosage and duration:
- The recommended dose is 4 mg daily or ally in adults with e GFR  60 m L/min/1.73 m 2.
- A duration of 14 da ys of total treatment or until hospital discharge, whichever is first. The optimal duration of treatment is unknown, and the pr oposed duration reflects what was used in the trials pr oviding evidence on treatment effects of baricitinib.

# Dose regimen adjustment:
- Patients with leukopenia, renal impairment or hepatic impairment (note: these parameters should be monitored during treatment); - Patients taking strong organic anion transporter 3 (OAT3) inhibitors (e.g. probenecid), there are drug interactions which warrant dose reductions.
Timing: Baricitinib (like IL-6 receptor blockers) should be initiated at the same time as s ystemic corticosteroids; specific timing during hospitalization or the c ourse of illness is no t specified.

# Info Box
The initial strong recommendation concerning baricitinib for patients with severe or critical COVID-19, was updated in the 12th version of the guideline. I t followed the availability of new evidence demonstrating that the incremental survival benefit afforded by baricitinib exists even among pa tients also treated with c orticosteroids and IL-6 receptor blockers.

# Strong recommendation for
We recommend treatment with baricitinib (strong recommendation f or).
- Corticosteroids and IL-6 receptor blockers (tocilizumab and sarilumab) are also recommended, and may be administered in combination with baricitinib to patients with se vere or critic al. - The panel ackno wledged that giv en that the clinic al trials were not representative of the global population and that the riskbenefit may be less adv antageous, particularly in ar eas where certain infectious diseases such as HIV in fections, tuber culosis and certain fungal infections are endemic or in patien ts with an incr eased risk o f opportunistic in fections. - The panel an ticipated that ther e would be situations wher e clinicians may op t for less aggr essive immunosuppressive therapy and/ or to combine medic ations in a st epwise fashion in patien ts who ar e deteriorating. - None of the included R CTs enrolled children, and ther efore the applic ability of this recommendation t o children remains uncertain.

# Evidence To Decision
In patients with severe or critical illness, baricitinib reduces mortality and probably reduces duration of mechanical ventilation and hospital length o f stay. It probably results in little or no increase in serious adv erse events. Subgroup analyses were undertaken for JAK inhibitors as a class (rather than on individual drugs) and revealed no e vidence of a subgroup effect on relative risk in younger (< 70 y ears) versus older patients; those with critical v ersus severe COVID-19; those receiving and no t receiving corticosteroids at baseline; and those r eceiving and no t receiving remdesivir or IL-6 blockers at baseline.

# Benefits and harms
Certainty of evidence was rated as: high f or decreased mortality (although the panel ackno wledged that the relatively short follow-up period close to 28 da ys is possibly insufficient to cap ture all relevant events); moderate for reduction in hospital length of stay, mechanical v entilation and serious adv erse events, all rated down for serious imprecision; and lo w for time to clinical stability, rated down for very serious imprecision.
The GDG no ted in particular that the risk of serious infections (bacterial and fungal) may vary considerably in different parts of the w orld according to the backgr ound prevalence of infections (such as tuberculosis). This may not be so importan t given the short course of baricitinib used f or treatment of COVID-19, but e vidence is limited given the limited g eographic spread of the included trials and short f ollow-up periods.

# Certainty of the Evidence
Applying the agreed upon v alues and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients with severe or critical COVID-19 would want to receive baricitinib due to the lik ely reduction in mortality, and moder ate certainty evidence of little or no increase in serious adv erse events. The benefit of baricitinib on mortality was deemed o f critical importance to pa tients and the GDG w as reassured by the moderate certainty evidence of little or no increase in serious adverse events. The GDG an ticipated little variation in v alues and preferences between patients for this intervention.

# Values and preferences

# Resource implications, equity and human rights
Compared with some o ther candidate treatments for COVID-19, baricitinib is expensive. The recommendation does no t take account of cost-effectiveness. Access to these drugs is challenging in man y parts of the w orld and, without c oncerted effort, is likely to remain so, especially in r esource-poor areas. It is therefore possible that this strong recommendation could exacerbate health inequity. The GDG w as also sensitive to the fact tha t allowing the c ombined use o f the JAK inhibitor baricitinib and IL-6 receptor blockers would likely further reduce the a vailability of these medica tions. The GDG strongly reinforces the need to impr ove drug availability, particularly in resource-constrained areas.
On the o ther hand, given the demonstrated benefits for patients, it should also pr ovide a stimulus to engag e all possible mechanisms to improve global access to these tr eatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. On 17 D ecember 2021, WHO published the 7th I nvitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which includes baricitinib.
At a time o f drug shortage, it may be nec essary to prioritize use o f baricitinib through clinical triage (6) such as prioritizing patients with the highest baseline risk f or mortality (e.g. those with critical disease o ver those with se vere disease), in whom the absolute benefit of treatment is therefore greatest. Other suggestions for prioritization, which lack dir ect evidence, include focusing on pa tients with an activ ely deteriorating clinical course, and avoiding baricitinib in those with established multiorgan failure (in whom the bene fit is likely to be smaller).

# Acceptability and feasibility

# Resources and other considerations Justification
In the 12th iteration of the guideline, the GDG c onfirmed the existing strong recommendation to use baricitinib in pa tients with severe or critical COVID-19. The update was based on additional da ta from 8156 pa tients enrolled in the RE COVERY trial, which confirmed the survival (now high c ertainty evidence) and other benefits, with little or no serious adverse events, of a drug that may be administered easily (39). The GDG ackno wledged that some serious adv erse events, such as fungal in fections, may not have been ac curately captured during the relatively short follow-up period in the included trials. B ecause of different mechanisms of action, the GDG c onsidered baricitinib separately from other JAK inhibitors (as outlined below).
Costs and ac cess remain important considerations and the GDG r ecognizes that this recommendation could exacerbate health inequities. This strong recommendation further strengthens the impe tus to address these c oncerns and maximize access across regions and c ountries. The GDG did no t anticipate important variability in patient values and preferences, and judg ed that other contextual factors would not alter the recommendation (see Evidence to D ecision).

# The role of IL-6 receptor blockers and baricitinib
The GDG had pr eviously made a strong recommendation for the use o f IL-6 receptor blockers (tocilizumab and sarilumab) or baricitinib as alternative agents administered in addition to c orticosteroids for patients with severe or critical COVID-19. The GDG had elected to r efrain from recommending combining these three immunosuppressive drugs until clear evidence of incremental benefit emerged. The RECOVERY trial has now provided evidence that combining corticosteroids, IL-6 receptor blockers and baricitinib provides incremental survival benefit (39). Specifically, in RECOVERY, 2659 pa tients received baricitinib along with c orticosteroids and IL-6 receptor blockers. The effect of baricitinib in this subgroup was consistent with the bene ficial effect of baricitinib in patients who w ere not treated with IL-6 receptor blockers (39). Although these thr ee immunosuppressIve drugs are recommended and ma y be administered jointly, the panel an ticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy and/or to c ombine medications in a step wise fashion in pa tients who are deteriorating. However, since the drugs ha ve not undergone direct comparisons, if this situation arises, the GDG f elt that clinicians should choose be tween baricitinib and IL-6 receptor blockers on the basis o f experience and c omfort using the drugs; local institutional policies; route of administration (baricitinib is oral; IL-6 receptor blockers are intravenous); and cost.
None of the included R CTs enrolled children, and therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of baricitinib to pregnant or lactating women. The decision regarding use o f this therapeutic should be made be tween the pregnant individual and their health care provider while discussing whether the potential benefit justifies the po tential risk to the mo ther and fetus (see Research evidence and P ractical info tabs).
As baricitinib is administered orally once daily, hospitalized patients should find it eas y to ac cept this treatment. In patients who canno t swallow tablets, baricitinib can be crushed, dispersed in w ater, and giv en via a nasogastric tube (see Practical info).

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19

# Intervention: Baricitinib

# Summary Evidence summary
The LNMA f or baricitinib was informed by four RCTs which enrolled 10 815 pa tients across disease severities (40)( 41) (42)(39). All RCTs were registered, and three were published in peer -reviewed journals (41)(42)( 39); one study w as a pre-print (40). All RCTs enrolled patients in in-patient settings. None of the included studies enr olled children or pregnant women. The Table shows characteristics of the R CTs.
For patients with severe or critical COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute effects of baricitinib compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (1).

# Baseline risk estimates
For severe and critical illness, f or the critical outcome of mortality, the applied baseline risk estima te was 13% (130 in 1000). As f or other related recommendations in this guideline, the estima te is derived from the SOLID ARITY trial for severe and critical pa tients adjusted for treatment effects of corticosteroids. For other outcomes, w e used the median o f the control arm of the R CTs that contributed to the evidence (see Section 7).

# Subgroup analysis
Four pre-specified subgroup analyses were undertaken for JAK inhibitors as a class r ather than for individual drugs: 1. Age: younger adults (< 70 y ears) versus older adults ( 70 years). No evidence of subgroup effects was identified on the r elative risk of critical outcomes across all pre-specified effect modifiers.
Baricitinib reduces mortality.

# Mechanical ventilation

# Adverse effects leading to drug discontinuation
Due to serious imprecision 3 Baricitinib probably reduces duration of hospitalization.

# Duration of mechanical ventilation
Lower better Based on da ta from 328
Due to serious imprecision 4 Baricitinib probably reduces duration of mechanical ventilation.

# Ruxolitinib and tofacitinib, for patients with severe or critical COVID-19

# Practical Info
Route, dosage and duration: We refer to the table o f trial characteristics (ruxolitinib and tofacitinib) to guide the administr ation of these ag ents, in the absenc e of other available information.
Timing: Ruxolitinib or tofacitinib (like IL-6 receptor blockers) should be initiated with systemic corticosteroids; specific timing during hospitalization or the c ourse of illness is no t specified.

# Conditional recommendation against
We suggest not to use rux olitinib or tofacitinib (conditional recommendation ag ainst).
- Clinicians should c onsider using these drugs only if neither baricitinib nor IL -6 receptor blockers (tocilizumab or sarilumab) are available. - The GDG emphasiz ed the need f or more trial evidence to better inform the recommendations.
The effects of ruxolitinib or tofacitinib on mortality, need f or mechanical ventilation and hospital length o f stay remain uncertain. Tofacinib may increase adverse events leading to drug disc ontinuation. Subgroup analyses were undertaken for JAK inhibitors as a class (rather than on individual drugs) and revealed no e vidence of a subgroup effect on relative risk in younger (< 70 y ears) versus older patients; those receiving and no t receiving corticosteroids; those with se vere versus critical COVID-19; and those r eceiving and no t receiving remdesivir.

# Benefits and harms
Due to serious imprecision due to small c ohorts (ruxolitinib: two RCTs, 475 pa tients; tofacitinib: one RCT, 289 pa tients) with few events and serious indirectness (pertaining to RCTs for ruxolitinib, most patients did no t receive corticosteroids), certainty of evidence was rated as low or v ery low for all prioritized outcomes for both drugs.

# Certainty of the Evidence Justification
When moving from evidence to the c onditional recommendation not to use rux olitinib or tofacitinib in patients with severe or critical COVID-19, the GDG emphasiz ed the lo w to v ery low certainty evidence for mortality, duration of mechanical v entilation and possible increase in serious adv erse events (particularly for tofacitinib).
The GDG emphasiz ed the need f or more trial evidence to be tter inform the recommendations; this is an ticipated through ongoing trials for these JAK inhibitors.
None of the included R CTs enrolled children; therefore, the applicability o f this recommendation to children remains uncertain. Uncertainty also remains with regard to the administration of ruxolitinib or toficitinib to pregnant or lactating women.
Applying the agreed values and preferences (see Section 7), the GDG in ferred that, given the lo w or v ery low certainty evidence on mortality and the o ther prioritized benefit outcomes and the r emaining possibility of serious adverse effects, the majority of well-informed patients would not want to receive ruxolitinib or tofacitinib. The GDG an ticipated, however, that because bene fit has not been e xcluded, and because a class e ffect of JAK inhibitors might exist (such that baricitinib provides indirect evidence of benefit for the other JAK inhibitors), a minority of well-informed patients would choose to receive one or o ther drug in circumstances in which neither baricitinib nor IL -6 receptor blockers (tocilizumab or sarilumab) were available.

# Values and preferences

# Resource implications, equity and human rights
The GDG no ted that, given the recommendation against use o f ruxolitinib or tofacitinib, efforts to ensure access to drugs should focus on those tha t are currently recommended.

# Acceptability and feasibility
As ruxolitinib and tofacitinib are administered orally twice daily, this treatment should be eas y to ac cept for hospitalized patients with severe and critical COVID-19. In patients unable to sw allow whole table ts, they can be dispersed in w ater to take orally or via nasogastric tube ( see Practical info).

# Resources and other considerations

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19

# Intervention: Ruxolitinib

# Summary Evidence summary
The LNMA on rux olitinib was informed by two RCTs that enrolled 475 patients across non-se vere, severe and critical illness subgroups (43)(44). Both RCTs were registered, one w as published in a peer -reviewed journal, and one w as a trial registration only. Both RCTs enrolled patients in in-patient settings. None of the included studies enr olled children or pregnant women. The Table shows the characteristics of the R CTs.
For patients with severe and critical COVID-19, the GRADE S ummary of Findings table f or ruxolitinib shows the relative and absolute effects compared with usual care for the outcomes of interest, with c ertainty ratings. See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
The GDG pre-specified several subgroup analyses of interest across all JAK inhibitors of interest; of these, no significan t relative subgroup effects were found. Please see the S ummary accompanying the recommendation for baricitinib for more details.

# Outcome Timeframe

# Study results and measurements

# Standard care

# Certainty of the Evidence
(Quality of evidence)
Plain language summary 1. Indirectness: serious. Most patients probably did no t receive corticosteroids at baseline. Concomitant use o f corticosteroids potentiates the bene ficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the J anus kinase pathway. Therefore, the e ffect of ruxolitinib may have been larger had most pa tients received steroids. Further, the ruxolitinib trial probably included many patients with non-se vere disease. A bene ficial effect of Janus kinase inhibitors may be limited to pa tients with severe or critical disease. Imprecision: very serious. The credible interval includes important harm and important benefit.

# Very low
Due to serious indirectness and very serious imprecision 1 The effect of ruxolitinib is very uncertain.

# Mechanical ventilation

# Very low
Due to serious indirectness and very serious imprecision 2 The effect of ruxolitinib is very uncertain.

# Adverse effects leading to drug discontinuation
Due to v ery serious imprecision 3 Ruxolitinib may not cause an important increase in adverse effects leading to drug discontinuation.

# Hospital length of stay

# Very low
Due to serious indirectness and very serious imprecision 4 The impact o f ruxolitinib on hospital length o f stay is v ery uncertain.

# Duration of mechanical ventilation
Based on data from 3 participants in 1 study. (Randomized controlled)

# days (Median)

# Very low
Insufficient data 5 The effect of ruxolitinib on mechanical ventilation is unkno wn.

# Time to clinical stability
Lower better Based on da ta from 472 participants in 2 studies. (Randomized controlled)

# Very low
Due to serious indirectness and very serious imprecision 6 The impact o f ruxolitinib on time to clinical stability is very uncertain.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) 2. Indirectness: serious. Most patients probably did no t receive corticosteroids at baseline. Concomitant use o f corticosteroids potentiates the bene ficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the J anus kinase pathway. Therefore, the e ffect of ruxolitinib may have been larger had most pa tients received steroids. Further, the ruxolitinib trial probably included many patients with non-se vere disease. A bene ficial effect of Janus kinase inhibitors may be limited to pa tients with severe or critical disease. Imprecision: very serious. The credible interval includes important harm and important benefit. 3. Imprecision: very serious. There was only one e vent in the single trial tha t reported this outcome, of 424 pa tients enrolled in the study. 4. Indirectness: serious. Most patients probably did no t receive corticosteroids at baseline. Concomitant use o f corticosteroids potentiates the bene ficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the J anus kinase pathway. Therefore, the e ffect of ruxolitinib may have been larger had most pa tients received steroids. Further, the ruxolitinib trial probably included many patients with non-se vere disease. A bene ficial effect of Janus kinase inhibitors may be limited to pa tients with severe or critical disease. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of Bias: serious. Indirectness: serious. Imprecision: very serious. 6. Indirectness: serious. Most patients probably did no t receive corticosteroids at baseline. Concomitant use o f corticosteroids potentiates the bene ficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the J anus kinase pathway. Therefore, the e ffect of ruxolitinib may have been larger had most pa tients received steroids. Further, the ruxolitinib trial probably included many patients with non-se vere disease. A bene ficial effect of Janus kinase inhibitors may be limited to pa tients with severe or critical disease. Imprecision: very serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 da y).

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19

# Intervention: Tofacitinib

# Summary Evidence summary
The LNMA f or tofacitinib was informed by one R CT that enrolled 289 patients across non-se vere, severe and critical illness subgroups (45). The trial was registered and published in a peer -reviewed journal; it e xcluded children and pregnant women. The Table shows the characteristics of the R CT.
For patients with severe or critical COVID-19, the GRADE S ummary of Findings table f or tofacitinib shows the relative and absolute effects compared with standard care for the outcomes of interest, with c ertainty ratings. See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
The GDG pre-specified several subgroup analyses of interest across all JAK inhibitors of interest; of these, no significan t relative subgroup effects were found. Please see the S ummary accompanying the recommendation for baricitinib for more details.

# Outcome Timeframe

# Study results and measurements

# Standard care

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary Mortality
Odds ratio 0.47 (CI 95% 0.11 -1.63) 13078

# Very low
Due to e xtremely
The effect of tofacitinib is uncertain.

# Very low
Due to e xtremely serious imprecision 2 The effect of tofacitinib is uncertain.

# Adverse effects leading to drug discontinuation
Due to v ery serious imprecision 3 Tofacitinib may increase adverse effects leading to drug discontinuation.

# Hospital length of stay
Due to v ery serious imprecision 4 Tofacitinib may reduce duration of hospitalization.

# Duration of mechanical ventilation

# days (Median)

# Very low

# No data
The impact o f tofacitinib on duration of mechanical ventilation is unknown.

# Time to clinical stability

# days (Median)

# Very low
The effect of tofacitinib on time to clinical stability is unknown.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Mechanism of action
Type I and type II cytokine r eceptors are a family o f receptors employed by over 50 interleukins, interferons, colony stimulating factors, and hormones (46). The intracellular signalling triggered by these receptors is mediated by Janus kinases (JAKs), a small family of kinases including J AK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Type I cytokines include IL -2, IFN-, IL-12, and TNFb, and type II cytokines include IL -4, IL-5, IL-6, IL-10, and IL-13.
JAK inhibitors are a class o f drugs which inhibit in tracellular signalling through multifactorial effects on cytokine signalling. As a consequence, they interfere with man y cellular responses, including an tiviral responses, angiotensin-converting enzyme 2 (ACE2) expression, T c ell function and diff erentiation, and macrophage activation (46). Baricitinib, ruxolitinib, and tofacitinib are three of at least nine JAK inhibitors. These three drugs are all generally considered to be non-specific J AK inhibitors, but differences in the specificity and po tency for different JAKs are evident. Baricitinib has been described as a J AK1/JAK2 inhibitor, ruxolitinib as JAK1/JAK2 > TYK2, and to facitinib as JAK3/JAK1 > JAK2/TYK2; o ther differences have also been pr eviously described (46)( 47) (48).
Studies evaluating JAK inhibitors for the treatment of COVID-19 have been c onducted at doses that are as high or higher than those approved for other indications, such as rheuma toid arthritis, myelofibrosis, and ulc erative colitis. Therefore, plausibility is contingent upon the r ole of cytokine signalling in C OVID-19, and no t on whe ther the pharmacokinetics at the studied dose is sufficient to inhibit the target proteins. There are notable differences in the appr oved doses, schedules, pharmac okinetics, contraindications, and indications of these drugs f or other indications. Collectively, these differences limit the c onfidence to consider a class-wide recommendation with currently available data.

# Sotrovimab (updated 13 January 2023)
For patients with non-severe COVID-19

# Practical Info
Given the strong recommendation against using so trovimab for patients with non-se vere COVID-19, practical considerations were felt to be less r elevant here.

# Info Box
Updated evidence supporting the initial strong recommendation against use o f sotrovimab for patients with non-se vere COVID-19 was published in this 13th iter ation of the guideline, f ollowing the a vailability of data showing in vitro neutralization activity is diminished with so trovimab with currently circulating SARS-CoV-2 variants and subvariants (e.g. O micron).

# Strong recommendation against
We recommend against treatment with so trovimab (strong recommendation ag ainst).

# - Several other therapeutic op tions for patients with non-se vere COVID-19 at highest risk o f hospitalization are available: see decision support t ool that displays benefits and harms o f nirmatrelvir-ritonavir, molnupiravir, and remdesivir. - The GDG c onsidered in vitro data demonstrating that neutr alization of currently circulating variants of SARS-CoV-2 and their
subvariants with so trovimab is diminished. - There was consensus among the panel that the meaningful r eduction o f in vitro neutralization activity str ongly sugg ests absenc e of clinical effectiveness o f monoclonal an tibodies such as so trovimab. - There was also c onsensus regarding the need f or clinical trial evidence in order to confirm clinical effectiveness o f new monoclonal antibodies that r eliably neutralize circulating strains in vitro.

# Updated evidence, no chang e in recommendation

# Evidence To Decision Justification
Although previous clinical trial evidence available via the LNMA (2) remains accurate, the panel c oncluded that it is no long er applicable to COVID-19 caused b y the S ARS-CoV-2 variants that are currently circulating globally. The panel surmised tha t the likelihood of COVID-19 caused b y former variants was extremely low and tha t accordingly, evidence of sotrovimab's clinical effectiveness for COVID-19 was nonexistent.
Of note, the panel applied the same r ationale to the recommendation for casirivimab-imdevimab.

# Reliance on in vitro evidence
The GDG agreed that large high-quality clinical trials generally provide the best e vidence of clinical effectiveness for therapeutic
On the basis o f clinical trial evidence that remains available via the LNMA (2), in the 8th v ersion of this guideline, GDG had previously made a c onditional recommendation for use o f sotrovimab to patients with non-se vere COVID-19 at highest risk of hospitalization. At the time, the panel ackno wledged that the emergence of future variants could reduce the clinical effectiveness of sotrovimab.
In the 12th v ersion of this guideline, r ather than new clinical trial evidence, the chang e in recommendation was triggered by new in vitro evidence demonstrating that sotrovimab has very diminished in vitro neutralization activity to currently circulating subvariants of SARS-CoV-2. T here was consensus among the panel tha t it is highly unlikely that the clinical effectiveness of sotrovimab would persist in the absenc e of adequate in vitro neutralization of the circulating variants. Accordingly, the panel c oncluded that the evidence upon which the pr evious recommendation hinged was no long er applicable.
For this 13th v ersion of the guideline, the GDG r eviewed additional in vitro neutralization data that emerged after the change in the guideline f or sotrovimab and casirivimab-imdevimab, and that included information on ne w variants. This incremental evidence supports the chang e in recommendation and strengthens the GDG' s confidence that the strong recommendation not to use so trovimab (and casirivimab-imdevimab) is applicable to the curr ent SARS-CoV2 ecology. More information on the in terpretation of the results of in vitro neutralization data can be f ound in Section 6.6.1 (mechanism o f action) and in c orrespondence published in The Lancet (49).

# Benefits and harms
In light of the recent in vitro evidence, the GDG c oncluded that the clinical e ffects of sotrovimab for COVID-19 caused b y the currently circulating variants and subvariants of SARS-CoV-2 are highly unc ertain.
The existing trial evidence identified in the LNMA (2) was judged to be a t moderate certainty for reduced hospitalization and high c ertainty for absence of infusion reactions, with no or small diff erences in mortality or mechanical v entilation. With the new circulating SARS-CoV-2 variants, this trial evidence would be rated as very low, meaning tha t the bene fits of sotrovimab cannot be de termined by trials performed before the ne w variants occurred.

# Certainty of the Evidence
Applying the agreed upon v alues and preferences (see Section 7), the GDG in ferred that, in the absenc e of compelling evidence of clinical effectiveness for the currently circulating SARS-CoV-2 variants, almost all w ell-informed patients would choose no t to receive sotrovimab.

# Values and preferences

# Acceptability and feasibility
The strong recommendation against the use o f sotrovimab is further supported b y the challenges with availability and feasibility, such as limited pr oduction, intravenous administration and requirement for expertise to offer such treatment while oral antiviral therapies are also available.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
interventions. The GDG also c ontinues to base its r ecommendations strictly on critically important outcomes. From the perspective of clinical guidelines, mechanistic studies and surr ogate outcomes are useful to iden tify candidate therapies for clinical trials, but are of no use in c onfirming clinical effectiveness. The panel c oncluded that the emerging evidence demonstrating the reduced neutralization of current variants by sotrovimab in vitro would likely have justified not launching clinical trials and now renders the results of previous trials inapplicable. In vitro assays were deemed sufficient to rule out a clinical effect. Notwithstanding, proof of potent in vitro neutralization would not be sufficient to c onfirm clinical effectiveness. Therefore, the GDG will only c onsider making recommendations for new monoclonal an tibodies once they have been rigorously evaluated in clinical trials.

# Mechanism of action
- Sotrovimab (VIR-7831; GSK4182136) is a single human monoclonal an tibody that binds to a c onserved epitope o f the SARS-CoV-2 spike protein, preventing the virus from entering cells. - Antiviral activity in a S yrian golden hamster model o f SARS-CoV-2 infection was demonstrated at 5 mg/kg IP but with a version of the an tibody that was not Fc-engineered (50). Neutralization of SARS-CoV-2 (USA WA1/2020) w as achieved in Vero E6 c ells with an E C90 value of 0.19 g/m L (51). Sotrovimab serum concentrations in COMET-ICE (single 500 mg IV infusion) provided geometric mean Cmax (at the end o f a 1 hr IV in fusion) of 117.6 g/m L (N=129, CV% 40) and a geometric mean Day 29 serum c oncentration of 24.5 g/m L (51). Population mean serum c oncentrations are therefore expected to be 129-f old higher after 29 days than the c oncentrations needed in vitr o to neutralize the original strain of SARS-CoV-2. - Information in the FDA Emergency Use Authorization states "no chang e" in activity o f sotrovimab against Alpha, B eta, Gamma, Epsilon, Iota, Kappa, Delta (including with K417N), Lambda and M u in pseudo-typed virus-lik e particle neutralization assays (51). Sotrovimab has been r eported to retain activity against BA.1 Omicron in pseudo virus assays but with higher concentrations being required for neutralization compared with the wild-type virus (52). - The FDA summarized the reported in vitro neutralization data (EC90) available for BA.2 Omicron and its in terpretation in the context of the pharmacokinetics of sotrovimab in humans (53). The presented data show the E C90 to be be tween 25.3and 48.1-f old higher for BA.2 Omicron than f or pre-Omicron variants. In the associated analysis, assuming a 6.5% or 12% penetration of antibody from serum into the lung ( as described for other monoclonal antibodies), it was shown that concentrations required for robust neutralization were unlikely to be achie ved in the lung. F urthermore, the independen t safety monitoring committee for the COMET-TAIL trial recommended early termination of the 250 mg in tramuscular (IM) sotrovimab arm due to a higher r ate of hospitalization than either 500 mg IM or 500 mg in travenous (IV) arms. Since the serum neutralization of 500 mg IV so trovimab against the O micron BA.  60)). Therefore, the presented analysis is relevant to many of the currently dominant Omicron sub-lineages. - An E340A amino acid substitution in the c onserved epitope o f the spike protein emerged rapidly under a selective pressure with sotrovimab in cell culture, and subsequen t characterization using a pseudo virus assay resulted in a > 100-f old reduction in susc eptibility to sotrovimab (51). Sixteen other substitutions introduced into the epitope w ere also described as reducing neutralization by sotrovimab by between 5.4 and > 297-f old (51). - The GDG members surmise tha t monoclonal antibodies most likely need to pene trate the respiratory tract to achieve clinical effectiveness. On the basis o f available empirical and quantitative pharmacology evidence for other monoclonal antibodies, the GDG estima tes that the likely lung-to-serum ratio is 65-120% (61)(62)(63)( 64) (65). Considering all available in vitro neutralization experiments, when serum c oncentrations are corrected for penetration into the lung, the tar get concentrations (defined by the e ffective concentration required for 90% neutralization  of viral particles) are unlikely to be achie ved. - The GDG has c onsidered but rejected the sugg estion that target concentrations neutralizing 50% of viral particles in serum can reliably predict clinical effectiveness (57) (49). EC90 is at least nine times higher than E C50. Not fully neutralizing the virus population not only carries the risk o f inefficacy but also increases the likelihood of emergence of selected resistance. Emergence of selected resistance has already been widely documen ted with so trovimab use against susc eptible variants, particularly in the context of immunocompromised patients (66)(67)(68)(69)( 70) (71).
For all patients with COVID-19

# Practical Info
Given the strong recommendation against using casirivimab-imdevimab for all patients with COVID-19, practical considerations were felt to be less r elevant here.

# Evidence To Decision

# Info Box
Updated evidence supporting the initial strong recommendation against the use o f the neutralizing antibodies casirivimabimdevimab for patients with COVID-19 was published in this 13th v ersion of the WHO living guideline. P reviously, a c onditional recommendation was provided for patients with non-se vere COVID-19 at highest risk of hospitalization and f or patients with severe and critical illness with ser onegative status. Following the emergence of the currently circulating SARS-CoV-2 variants and subvariants (such as O micron) now dominating worldwide, and availability of in vitro data showing lack o f or diminished neutralization activity, the GDG made a str ong recommendation against the use o f casirivimab-imdevimab for all patients with COVID-19; new evidence further affirms this recommendation.

# Strong recommendation against
We recommend against treatment with casirivimab-imdevimab (strong recommendation ag ainst).
- Several other therapeutic op tions exist f or patients with C OVID-19 across the se verity spectrum: see decision support t ool that displays benefits and harms o f nirmatrelvir-ritonavir, molnupiravir and remdesivir. - The GDG c onsidered in vitro data demonstrating that c asirivimab-imdevimab does no t neutralize the curr ently circulating variants of SARS-CoV-2 and their sub variants. - There was consensus among the panel that the meaningful r eduction o f in vitro neutralization activity str ongly sugg ests absenc e of clinical effectiveness o f monoclonal an tibodies such as so trovimab and c asirivimab-imdevimab. - There was also c onsensus regarding the need f or clinical trial evidence in order to confirm clinical effectiveness o f new monoclonal antibodies that r eliably neutralize circulating strains in vitro.

# Updated evidence, no chang e in recommendation
On the basis o f clinical trial evidence that remains available via the LNMA (2), the GDG had pr eviously made a c onditional recommendation to administer casirivimab-imdevimab to patients with non-se vere COVID-19 driven by benefits in reduction of hospital admission) as well as seronegative patients with severe and critical illness (driven by reductions in mortality and mechanical ventilation) as shown in previous GRADE S ummary of Findings tables. A t the time, the panel acknowledged that the emergence of future variants could reduce the clinical e ffectiveness of casirivimab-imdevimab.
Rather than new clinical trial evidence, the chang e in recommendation was triggered by new in vitro evidence demonstrating that casirivimab-imdevimab has very diminished in vitro neutralization activity to currently circulating subvariants of SARS-CoV-2. T here was consensus among the panel tha t it is highly unlikely that the clinical e ffectiveness of casirivimab-imdevimab would persist in the absenc e of adequate in vitro neutralization of the circulating variants. Accordingly, the panel c oncluded that the evidence upon which the pr evious recommendations hinged was no long er applicable.
The GDG reviewed additional in vitro neutralization data that emerged after the change in the guideline f or sotrovimab and casirivimab-imdevimab and that included information on ne w variants. This incremental evidence supports the chang e in recommendation and strengthens the GDG' s confidence that the strong recommendation not to use casirivimab-imdevimab (and sotrovimab) is applicable to the curr ent SARS-CoV2 ecology. More information on the in terpretation of the results of in vitro neutralization data can be f ound in S ection 6.6.1 (mechanism o f action) and in c orrespondence published in The Lancet (49).
Benefits and harms 6.6 Casirivimab-imdevimab (updated 13 January 2023)
Although previous clinical trial evidence available via the LNMA (2) remains accurate, the panel c oncluded that it is no long er applicable to COVID-19 caused b y the S ARS-CoV-2 variants that are currently circulating globally. The panel surmised tha t the likelihood of COVID-19 caused b y former variants was extremely low and tha t, accordingly, evidence of casirivimab-imdevimab clinical effectiveness for COVID-19 was nonexistent.
Of note, the panel applied the same r ationale to the recommendation for sotrovimab.

# Reliance on in vitro evidence
The GDG agreed that large high-quality clinical trials generally provide the best e vidence of clinical effectiveness for therapeutic interventions. The GDG also c ontinues to base its r ecommendations strictly on predefined patient-important outcomes. From the perspective of clinical practice guidelines, mechanistic studies and surr ogate outcomes are useful to iden tify candidate therapies for clinical trials, but are of no use in c onfirming clinical effectiveness. The panel c oncluded that the emerging evidence demonstrating that casirivimab-imdevimab did not comparatively neutralize current variants in vitro would have justified not launching clinical trials and now renders the results of previous trials inapplicable. In vitro assays were deemed sufficient to rule out a clinical e ffect. Notwithstanding, proof of potent in vitro neutralization would not be sufficient to c onfirm clinical effectiveness. Therefore, the GDG will only c onsider making recommendations for new monoclonal an tibodies once they have been rigorously evaluated in clinical trials.

# Mechanism of action
Casirivimab and imdevimab are two fully human an tibodies (REGN10933 and REGN10987). Their mechanism of action is v ery plausible: they bind to the S ARS-CoV-2 spike protein (74) and have demonstrated antiviral activity in rhesus macaques and Syrian golden hamsters (72). Pharmacokinetic data in patients with non-se vere COVID-19 show that antiviral concentrations of both antibodies against pre-Omicron variants are achieved and maintained for at least 28 da ys after intravenous administration of the c ombination at a total dose of 1200 mg (600 mg each antibody) or above (73). Pre-Omicron antiviral concentrations are also achieved and maintained using a subcutaneous to tal dose of 1200 mg (600 mg o f each an tibody) in uninfected individuals for prophylaxis (75). Half-lives range from 25 to 37 da ys for both antibodies.
It was postulated that administration might have differential effects in pa tients who ha ve produced their own anti-SARS-CoV-2 spike protein antibodies (hereafter seropositive) compared with those who ha ve not (hereafter seronegative). It was hypothesized that effects might be larger, or restricted to, seronegative individuals who ha ve not yet mounted an e ffective antibody response.
In light of the recent in vitro evidence, the GDG c oncluded that the clinical e ffects of casirivimab-imdevimab for COVID-19 caused by the currently circulating variants and subvariants of SARS-CoV-2 are highly unc ertain. Trials performed before these variants occurred provided overall moderate certainty evidence for modest bene fits and negligible harms, as demonstrated in GRADE S ummary of Findings tables a vailable in previous versions of this living guideline.

# Certainty of the Evidence
Applying the agreed upon v alues and preferences (see Section 7), the GDG in ferred that, in the absenc e of compelling evidence of clinical effectiveness for the currently circulating SARS-CoV-2 variants, almost all well-informed patients would choose to no t receive casirivimab-imdevimab.

# Values and preferences

# Acceptability and feasibilty
The strong recommendation against the use o f casirivimab-imdevimab is further supported b y the challenges with availability and feasibility, such as limited pr oduction, intravenous administration and requirement for expertise to offer such treatment while oral options are also available.  78). Furthermore, neither casirivimab nor imdevimab neutralize BQ.1 or BQ.1.1 sublineages (59)( 60)). Therefore, currently available preclinical data do no t support activity of the casirivimab and imde vimab combination against currently circulating Omicron sub-lineages.

# Resources and other considerations

# Fluvoxamine (published 14 July 2022)
For patients with non-severe COVID-19

# Practical Info
The GDG made a r ecommendation against using fluv oxamine for treatment of patients with COVID-19 outside the se tting of a clinical trial and therefore practical considerations are less relevant for this drug.

# Evidence To Decision

# Info Box
The recommendation concerning fluvoxamine for patients with non-se vere COVID-19 was published on 14 J uly 2022, in the eleventh version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the a vailability of three RCTs, as per the LNMA on drug ther apies (1). No changes were made f or the recommendation in this 13th v ersion of the guideline.

# Only in research settings
We recommend not to use fluv oxamine, except in the c ontext of a clinical trial (recommended only in r esearch settings).
- Several therapeutic op tions are recommended f or patients with non-se vere COVID-19 including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. - For choosing betw een the ther apeutic op tions, see S ection 6.1 and the decision support t ool, which display s benefits and harms o f the options.
In patients with non-se vere COVID-19, fluvoxamine probably has little or no e ffect on mortality and ma y have little or no effect on mechanical v entilation and hospitalization, with no da ta reported for time to s ymptom resolution and adverse effects leading to drug disc ontinuation. The GDG c oncluded that the balance between benefits and potential harms does not favour treatment.
The planned subgroup analyses for fluvoxamine versus standard care for age and time o f symptom onset did no t support any differences in relative effects, whereas disease severity could not be performed since trials only enrolled patients with non-severe COVID-19.

# Benefits and harms
The evidence summary w as informed by 3 trials with 2225 participants included in the LNMA. T he largest trial (n=1480)

# Certainty of the Evidence Justification
When moving from evidence to the r ecommendation not to use fluv oxamine in patients with non-se vere COVID-19 except in the context of a clinical trial, the GDG emphasiz ed the lack o f a clear mechanism o f action and the lo w certainty evidence suggesting little to no e ffect on hospitalization and mechanical v entilation, moderate certainty evidence of little or no e ffect on mortality, as w ell as the absenc e of reliable data on serious adv erse effects attributable to the drug known for significant pharmacological interactions. The panel no ted that in the largest trial more patients discontinued the investigational product in the fluvoxamine group than in the plac ebo group. N oting that effective therapeutic alternatives exist for non-severe COVID-19, the GDG did no t anticipate important variability in patient values and preferences. The panel also did no t believe that other considerations, such as r esource considerations, accessibility, feasibility, and equity ( see summary of these factors under Evidence to D ecision) impacted this specific recommendation.
Special populations: None of the included studies enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel did no t see a r eason to assume tha t children with COVID-19 would respond any differently to treatment with fluvoxamine.
exclusively enrolled patients in Brazil (79).
Certainty of evidence was rated as: moderate for mortality (due to serious indirectness), and low for mechanical ventilation (due to serious indirectness, imprecision, and some c oncerns regarding risk of bias) and hospitalization (due to serious imprecision and risk o f bias). Acknowledging that its evaluation of the c ertainty of the e vidence may differ from other published meta-analyses (80), panel members poin ted out that early stopping due to appar ent benefit may have biased the results of the largest trial. They argued that, although the stopping rules w ere pre-specified, the decision w as based on the effect estimate on a c omposite outcome of questionable importance, meanwhile the number o f important events was lower.
The panel also r aised concerns regarding the unc ertain applicability of this trial conducted in a single c ountry.
Given the agreed upon v alues and preferences statement (see Section 7), the GDG in ferred that almost all w ell-informed patients would choose no t to receive fluvoxamine therapy for COVID-19 based on the a vailable evidence. The GDG did no t believe that other considerations, such as f easibility, acceptability, equity and c ost, would impact this specific recommendation. Specifically, the GDG did no t consider the potential role of fluvoxamine as an an tidepressant for this guideline of medications for COVID-19.

# Values and preferences
The panel ackno wledged that effective therapeutic alternatives for non-severe COVID-19 were expensive, which c ould limit their availability in resource-constrained areas. However, although fluv oxamine is relatively inexpensive, compared with other drugs used f or COVID-19, and widely a vailable, including in low-income settings, the evidence does no t justify the use of fluvoxamine for non-severe COVID-19 anywhere. Although the c ost of fluvoxamine may be lo w, the GDG panel r aised concerns regarding the risk o f diverting attention and resources away from interventions that are more likely to provide a benefit. To avoid the risk o f writing recommendations that would risk perpetuating and legitimizing unequal ac cess to more effective drugs, the panel belie ved that it would be preferable to emphasize the need f or more equitable access to e ffective therapeutic options.

# Resources and other considerations
Clinical Question/ PICO
Patients with non-se vere COVID-19

# Intervention: Fluvoxamine
The LNMA f or fluvoxamine was informed by three RCTs which enrolled 2225 patients with non-se vere illness in outpatient settings. All three RCTs were registered, and tw o were published in a peer -reviewed journal. All three studies were conducted in outpa tients. None of the included studies enr olled children. The Table shows characteristics of the RCTs.
For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of fluvoxamine compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (1).
Based on da ta from the TOGETHER trial (79), no cr edible subgroup effects were observed on the primary outc ome by age (children vs adults vs older adults) and time from symptom onset (0-3 days vs 4-7 da ys). Planned subgroup analyses for disease severity, age and chronic conditions (absolute effects), serological status and vaccination status were precluded by lack of available data.

# Outcome Timeframe

# Study results and measurements

# No fluvoxamine

# Intervention Fluvoxamine

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary Mortality
Odds ratio 0.68 (CI 95% 0.

# Study results and measurements

# No fluvoxamine

# Intervention Fluvoxamine

# Certainty of the Evidence
(Quality of evidence)
Plain language summary 1. Indirectness: serious. The baseline risk across the en tire population is very low, meaning tha t any impact on mortality will be very small. There are some people with much higher baseline risk, which ar e not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. 2. Indirectness: serious. Some patients may be a t substantially higher risk of mechanical v entilation. Imprecision: serious.
- Imprecision: very serious. The credible interval includes both important harm and important benefit. 4. Imprecision: very serious. The credible interval includes both important harm and important benefit. 5. Imprecision: very serious. The credible interval includes both important harm and important benefit.

# Adverse effects leading to drug discontinuation
No data The effect of fluvoxamine is unknown

# Time to symptom resolution

# No data
The effect of fluvoxamine is unknown

# Very low
Due to serious indirectness, imprecision, and serious risk of bias 1The impact on mortality is very uncertain

# Mechanical ventilation
No data 2 The effect on mechanical ventilation is unkno wn 1. Risk of Bias: serious. The EPIC-HR study w as stopped early f or benefit. Indirectness: serious. The baseline risk across the entire population is very low, meaning tha t any impact on mortality will be v ery small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible tha t fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events.
- Inconsistency: no serious. Indirectness: serious. Some patients may be a t substantially higher risk of mechanical ventilation. Imprecision: serious. Publication bias: no serious.
- Risk of Bias: serious. The nirmatrelvir-ritonavir study (EPIC-HR) was stopped early f or benefit. Imprecision: serious. 1. Indirectness: serious. The baseline risk across the en tire population is very low, meaning tha t any impact on mortality will be very small. There are some people with much higher baseline risk, which ar e not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events.

# Hospital admission
- Indirectness: serious. Some patients may be a t substantially higher risk of mechanical v entilation. Imprecision: very serious.
- Imprecision: very serious. The credible interval includes both important harm and important benefit.

# Very low
Due to serious indirectness and very serious imprecision 2
The effect on mechanical ventilation is unc ertain

# Hospital admission
Due to v ery serious imprecision 3 There may be little or no difference in hospital admission

# Adverse effects leading to drug discontinuation

# No data
The effect on adv erse effects is unkno wn

# Time to symptom resolution

# No data
The effect on time to symptom resolution is unknown

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Intervention: Fluvoxamine

# Mechanism of action
Fluvoxamine is a selectiv e serotonin reuptake inhibitor (SSRI) approved as an an tidepressant. The antidepressant effects of fluvoxamine are related to inhibition o f the serotonin transporter in the brain, which serves to increase the c oncentrations of Outcome Timeframe

# Study results and measurements

# Intervention Fluvoxamine
Certainty of the Evidence (Quality of evidence)
Plain language summary 1. Indirectness: serious. The baseline risk across the en tire population is very low, meaning tha t any impact on mortality will be very small. There are some people with much higher baseline risk, which ar e not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events.
- Indirectness: serious. Some patients may be a t substantially higher risk of mechanical v entilation. Imprecision: very serious.
- Imprecision: very serious.
Odds ratio 0.87 (CI 95% 0.27 -2.85) (Randomized controlled)
Due to serious indirectness and serious imprecision 1 There may be little or no difference in mortality

# Mechanical ventilation

# Very low
Due to serious indirectness and very serious imprecision 2
The effect on mechanical ventilation is unc ertain

# Hospital admission
Due to v ery serious imprecision 3 Remdesivir may reduce hospitalization more than fluvoxamine

# Adverse effects leading to drug discontinuation

# No data
The effect on adv erse effects is unkno wn

# Time to symptom resolution

# No data
The effect on time to symptom resolution is unknown
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) serotonin in the s ynaptic cleft. In COVID-19, several putative anti-inflammatory or antiviral mechanisms of action ha ve been proposed (81) (82). First, anti-inflammatory properties have been postula ted as a result of serotonin transporter inhibition in platelets and/or lungs, but this is based upon indir ect evidence from non-COVID-19 disease models. S econdly, host-directed antiviral properties have been proposed via ag onism of the sigma-1 r eceptor, for which some e vidence exists from other viruses for an involvement in RNA replication, but there are currently no published pr eclinical studies that directly demonstrate or refute a mechanism in C OVID-19. Therefore, plausibility requires interpretation of indirect evidence for anti-inflammatory or antiviral mechanisms, which ar e currently unproven preclinically and not directly related to the mechanism and site o f action in depression.

# Colchicine (published 14 July 2022)
For patients with non-severe COVID-19

# Practical Info
The GDG made a str ong recommendation against using c olchicine for treatment of patients with non-se vere COVID-19 and therefore practical considerations are less relevant.

# Evidence To Decision

# Info Box
The recommendation concerning colchicine for patients with non-se vere COVID-19 was published on 14 J uly 2022, in the eleventh version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the a vailability of 13 RCTs that enrolled 18 172 pa tients, as per the LNMA on drug ther apies (1). No changes were made f or the recommendation in this 13th version of the guideline.

# Strong recommendation against
We recommend against treatment with c olchicine (strong recommendation ag ainst).
- Several therapeutic op tions are recommended f or patients with non-se vere COVID-19 including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. - For choosing betw een the ther apeutic op tions, see S ection 6.1 and the decision support t ool, which display s benefits and harms o f the options.
In patients with non-se vere COVID-19, colchicine probably has little or no impact on mortality and mechanical v entilation, may have little or no impact on hospitaliza tions, and ma y increase the likelihood of adverse effects leading to drug discontinuation. The panel discussed the risk o f drug interactions and c olchicine's narrow therapeutic window, particularly in patients with or a t risk of hepatic and renal failure. Colchicine toxicity can be se vere, and some times fatal. The planned subgroup analyses for colchicine versus standard care did no t show different relative effects for disease severity, and ag e (children, adults, older) with no da ta reported from illness onset.

# Benefits and harms
The evidence summary on c olchicine was informed by a s ystematic review including 13 trials with 18 172 participan ts. The evidence was most abundant for mortality with incomplete reporting for other outcomes (e.g. five trials with 598 participants for adverse effects). A single trial o f 4488 participants (83), which c ontributed almost all of the e vidence on hospitalizations, was stopped prematurely.

# Certainty of the Evidence
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
When moving from evidence to the str ong recommendation against the use o f colchicine for patients with non-se vere COVID-19, the GDG emphasiz ed the moderate certainty evidence of no e ffect on mortality and mechanical v entilation, and the low certainty evidence of no e ffect on hospitalizations, but possible harm associa ted with treatment. Specifically, the panel recognized the risks o f diarrhoea, cytopenia, and o ther toxicities, particularly among patients with, or a t risk of, renal failure, as potentially important to pa tients with non-se vere COVID-19. Noting that effective therapeutic alternatives exist for non-severe COVID-19, the GDG did no t anticipate important variability in patient values and preferences. The panel also did no t believe that other considerations, such as r esource considerations, accessibility, feasibility, and equity ( see summary of these factors under Evidence to D ecision) impacted this specific r ecommendation.
Special populations: None of the included studies enr olled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel did no t see a r eason to assume tha t children with COVID-19 would respond any differently to treatment with c olchicine.
Certainty of evidence was rated as: moderate for mortality and mechanical ventilation (rated down for indirectness); low for admission to hospital (rated down for imprecision and risk o f bias); and low for adverse effects leading to drug discontinuation (rated down for imprecision and risk o f bias).
Given the agreed upon v alues and preferences statement (see Section 7), the GDG in ferred that almost all w ell-informed patients would choose no t to receive colchicine based on a vailable evidence regarding relative benefits and harms. T he GDG did no t believe that other considerations, such as f easibility, acceptability, equity, and c ost, impacted this specific recommendation.

# Values and preferences
The panel ackno wledged that effective therapeutic alternatives for non-severe COVID-19 were expensive, which c ould limit their availability in resource-constrained areas. However, although c olchicine is relatively inexpensive, compared with o ther drugs used f or COVID-19, and widely a vailable, including in low-income settings, the evidence does no t justify the use o f colchicine for non-severe COVID-19 anywhere. Although the c ost of colchicine may be lo w, the GDG r aised concerns regarding the risk o f diverting attention and resources away from interventions that are more likely to provide a bene fit. To avoid writing recommendations that would risk perpetuating and legitimizing unequal ac cess to more effective drugs, the panel believed that it would be preferable to emphasize the need f or more equitable access to e ffective therapeutic options.

# Resources and other considerations
Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Intervention: Colchicine
Comparator: Standard care
The systematic review for colchicine included 13 trials that enrolled 18 172 pa tients. All but three trials were registered. None of the studies enr olled children. The Table shows characteristics of the R CTs.
For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of colchicine compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (1).
Based on da ta from the COLCORONA trial (83), no cr edible subgroup effects were observed on the primary outc ome by
Due to serious risk of bias and serious imprecision 6 Colchicine may increase the risk of adverse effects leading to drug discontinuation Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Mechanism of action
Colchicine is an an ti-inflammatory drug used to tr eat gout, recurrent pericarditis, familial Mediterranean fever, and o ther inflammatory indications. There are several proposed mechanisms o f action tha t are theorized to ob viate inflammationassociated pathology seen in C OVID-19 (84)( 85), which include a r eduction in chemo taxis of neutrophils, inhibition of inflammasome signalling, and decreased production of cytokines such as in terleukin-1b (IL-1b). There are no published da ta at the time o f publication from animal models o f SARS-CoV-2 infection to support or r efute pre-clinical efficacy or harm of colchicine in associated disease pathology. The mechanism o f action is postula ted to be similar to tha t for the indications for which colchicine is already approved, but plausibility of effect in COVID-19 requires assumptions around similarities between COVID-19 and o ther diseases to be ac cepted. There are marked differences between trials in terms of the doses and schedules that have been in vestigated in COVID-19. Within the studies included in the NMA, doses r anged between 0.5 and 2 mg per da y, course durations ranged between 6 and 30 da ys, some studies used onc e daily dosing, some used twic e daily dosing, and o thers used three times daily dosing. I n addition, some studies used dosing schedules which chang ed throughout the c ourse, starting with one dose or schedule and then changing to a diff erent dose or schedule a fter a predetermined interval. The pharmacokinetics of colchicine are dose linear be tween 0.5 mg and 1.5 mg (86)( 87) but the substantive variation between studies included in the NMA pr ecludes a robust interpretation of differences in outc ome associated with dose and schedule.

# Molnupiravir (published 3 March 2022)
For patients with non-severe COVID-19 at highest risk of hospitalization (excluding pregnant and breastfeeding women, and children)
- Imprecision: very serious. 6. Risk of Bias: serious. Imprecision: serious.

# Info Box
Recommendations concerning molnupiravir for patients with non-se vere COVID-19 were published on 3 M arch 2022 as the ninth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the a vailability of six RCTs, as per the LNMA on drug ther apies (1). No changes were made to the molnupir avir recommendation in this 13th v ersion of the guideline.

# Conditional recommendation for
We suggest treatment with molnupiravir (conditional recommendation f or).
- See Section 6.1 f or help t o identify patients at highest risk f or hospitalization.
- Several therapeutic op tions are available: see decision support t ool that displays benefits and harms o f nirmatrelvir-ritonavir, molnupiravir and remdesivir. - The longer-term harms o f molnupiravir remain unknown in the absenc e of clinical evidence, both for individual patients and at the population level. These include g enotoxicity, emergence of resistance, and emer gence of new v ariants (see M echanism of action). - The conditional recommendation reflects the c oncern for widespread treatment with molnupiravir before more safety data become available. - Use of molnupiravir should be ac companied by mitigation strategies such as av oiding the drug in younger adults, activ e pharmacovigilance programmes, and monit oring viral polymerase and spik e sequenc es (see J ustification).

# Practical Info
Route, dosage and duration: Additional considerations are available in three summaries of practical issues (molnupiravir for COVID-19, administration of molnupiravir for COVID-19, safety and monitoring f or patients receiving molnupiravir for COVID-19). Here follows a brief summary of the key points:
- The recommended dose f or molnupiravir is 800 mg table t every 12 hours daily f or 5 days, as per the r egimen evaluated in large trials informing the recommendation. - Administration should be as early as possible in the time c ourse of the disease. I n the included studies, molnupir avir was administered within 5 da ys of disease onse t.

# Evidence To Decision
In patients with non-se vere COVID-19, molnupiravir probably reduces admission to hospital and time to s ymptom resolution, and ma y reduce mortality. The effect of molnupiravir on mechanical v entilation is very uncertain. Treatment does not increase the likelihood of adverse effects leading to drug disc ontinuation.
However, potential long-term harms of molnupiravir remain uncertain and a matter of concern, in the absenc e of clinical data. Potential harms include emergence of resistance, and the po tential harm coming from the risk o f molnupiravir-induced mutagenesis. These deliberations (see Justification section) were based on molnupir avir's mechanism o f action and a vailable pre-clinical data (see Mechanism of action section.
The balance between benefits and potential harms was close, but fa voured treatment in the highest risk gr oup, if implemented with o ther mitigation strategies to avoid harm at individual and population level (see Mitigation strategies section). There is a risk tha t monotherapy with molnupiravir (as for other antiviral monotherapies) may be associa ted with emergence of drug resistance, as has been seen with o ther antivirals (see Mechanism of action section.
The absolute bene fits of molnupiravir on hospital admission depend on the pr ognosis. The GDG de fined a threshold of a 6% absolute reduction in hospital admission to r epresent what most pa tients would value as an important benefit. Molnupiravir would exert such a bene fit in patients at highest risk of hospitalization (above 10% baseline risk), such as those tha t lack COVID-19 vaccination, older people, or those with immunode ficiencies and/or chr onic diseases. T he conditional recommendation for the use o f molnupiravir in those a t highest risk reflects this threshold: 60 f ewer hospitalizations per 1000 patients, and a greater anticipated absolute survival benefit, although this w as not possible to quan tify in the absenc e of data.
The planned subgroup analyses could not be performed in the absenc e of subgroup data reported publicly or provided by investigators.

# Benefits and harms
The evidence summary w as informed by six trials with 4796 participan ts included in the LNMA, including the MO Ve-OUT study (88).
Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to serious impr ecision); low for mortality (rated down due to serious impr ecision and indirectness); moderate for time to s ymptom resolution (rated down due to serious risk o f bias); very low for mechanical ventilation (rated down due to e xtremely serious imprecision and serious risk of bias); and high f or adverse effects leading to drug disc ontinuation.
Limitations in available empirically developed risk prediction tools f or establishing patients' risk of hospitalization represent the major source of indirectness for which the GDG r ated down the c ertainty of the e vidence (22). In addition, the GDG f elt that there was some indirectness because o f the possible emer gence of variants (including Omicron) for which the effectiveness of currently available monoclonal antibodies may be reduced.
The GDG decided against r ating certainty down for imprecision for outcomes where low event rates reflected very low baseline risks (e.g. mortality).

# Certainty of the Evidence Justification
A combination of the e vidence, safety concerns based on pr eclinical data, values and preferences, and f easibility contributed to the conditional recommendation for the use o f molnupiravir only in pa tients with non-se vere COVID-19 at highest risk of hospitalization. Typical characteristics of people a t highest risk include those who ar e unvaccinated, older people, or those with immunodeficiencies and/or chr onic diseases (e.g. diabetes).
Only a minority of patients who are at highest risk are likely to achieve sufficient benefit to compensate for the risks, and o ther limitations and disadvantages of therapy. These include a lack o f reliable tools to identify high-risk patients, limited availability of the drug, and the sa fety concerns summarized below.
- The GDG had c oncerns about the risk o f emergent resistance with a ne w antiviral deployed as mono therapy (see Mechanism of action section. Significant uncertainty exists regarding how quickly resistance will emerge; in the absenc e of sufficient clinical data, the GDG c oncluded large uncertainties remain. - Concerning the risk of the drug pr omoting the emergence of new variants, the GDG no ted that there was a low likelihood that the drug w ould result in a selectiv e pressure for a new variant; large uncertainty remains in the absenc e of sufficient clinical data.
Applying the agreed values and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients with a low risk of hospitalization would decline molnupiravir, and only those a t highest risk (e.g. un vaccinated, older, or immunosuppressed) would choose to r eceive treatment.
In the absenc e of research evidence, in a pr evious survey (see recommendation for casirivimab-imdevimab), the GDG expressed the vie w that most pa tients with a risk o f hospitalization above 10%, and thus an absolute risk r eduction of approximately 6%, w ould choose to r eceive treatment, whereas most o f those belo w that risk level would decline treatment.
A similar survey was completed by the GDG f or this recommendation; the GDG e xpressed the vie w that most pa tients would consider a reduction in the absolute risk o f death of 3 per 1000 (incr ease in survivors from 995 to 998 per 1000 patients) to be important.

# Values and preferences

# Acceptability and feasibility
Molnupiravir is unlikely to be a vailable for all individuals who, giv en the op tion, would choose to r eceive the treatment. This reinforces that molnupiravir should be reserved for those at highest risk.
Obstacles to access in LMICs due to c ost and availability are of concern (30). Challenges in shared decision-making and in communicating the harms v ersus benefits of molnupiravir may also be incr eased in LMICs. F or example, those with socioeconomic disadvantages tend to ha ve less ac cess to services, including diagnostic testing and tr eatments, in the first 5 days of symptoms, and thus less ac cess to the in terventions. Therefore, if pa tients at highest risk receive the in tervention this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health s ystem that may provide care for patients with non-se vere COVID-19 (i.e. primary care, community care settings).
The recommendations should provide a stimulus to engag e all possible mechanisms to impr ove global access to the intervention. In promoting access, WHO has pr equalified generic versions of Molnupiravir and one g eneric version of Nirmatrelvir-ritonavir. In addition, there are additional applications under review for both products. UN partners procure these products and are making them a vailable to low-and middle-inc ome countries. WHO and UN partners support allocation and procurement mechanisms f or countries to ensure that these medicines are available and integrated into national supply chains. Individual countries may formulate their guidelines considering available resources and prioritize treatment options according.
Access to SARS-CoV-2 diagnostics: Since this recommendation emphasizes the need to administer tr eatment with molnupiravir within 5 days of symptom onset; increasing access and ensuring appropriate use o f diagnostic tests is essen tial. Thus, availability and use of reliable and timely COVID-19 diagnostic tests (including the use o f NAAT and Ag-RD Ts) is needed to improve access to drugs, especially those tar geting the early phase o f disease. T he appropriate use o f Ag-RDTs by individuals and trained professionals can improve early diagnosis and earlier ac cess to clinical care, particularly in the community and in primary health care settings. National programs should op timize their testing s ystems to reflect local epidemiology, response objectives, available resources and needs o f their populations.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
- Molnupiravir is mutagenic in mammalian c ells in vitro, but there is no e vidence of mutagenicity in animal models or humans. The GDG therefore acknowledged uncertainty regarding longer term genetic toxicity and potential for malignancy associated with molnupiravir. - Given evidence from rat pups o f an impact on gr owth plate thickness, molnupiravir should not be used in childr en. Similarly, since molnupiravir elicited embryo-fetal lethality and teratogenicity in offspring when given to pregnant animals, it should not be used in pr egnant or breastfeeding women. - The GDG ackno wledged that spermatogenesis may also be especially pr one to the mutag enic effects of molnupiravir, but that there was uncertainty regarding the c onsequences to children conceived by fathers receiving or having recently received molnupiravir.
The applicability of this recommendation to children, breastfeeding and pregnant women, is currently uncertain, as the included RCTs enrolled only non-pregnant adults. However, the GDG c oncluded that molnupiravir should not be o ffered to children, breastfeeding or pregnant women with C OVID-19. In addition, men planning to c onceive should be orien ted on the po tential for temporary genotoxic effect on sperm c ell production (see Mitigation strategies section). The unknown long-term risk o f genotoxicity is likely to be higher in y ounger patients as c ompared with older pa tients, thus its use in y ounger adults not a high risk should be avoided.
The GDG also had c oncerns about whe ther the drug w ould retain efficacy against emerging variants of concern such as Omicron. W hile there is no molecular basis f or a loss o f efficacy, the GDG no ted that the higher viral loads and associa ted disease severity may impact the e ffectiveness of molnupiravir. This represents another area of uncertainty, given currently available data did not include patients with ne wer variants, including Omicron (see Section 9).

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Intervention: Molnupiravir

# Summary Evidence summary
The LNMA f or molnupiravir was informed by six RCTs which enrolled 4827 patients with non-se vere illness in outpatient settings; the LNMA team had ac cess to da ta for 4796 patients. All RCTs were registered; none w ere published in peer-reviewed journals. None of the included studies enr olled children or pregnant women. The appendix summarizes study characteristics and risk of bias ratings, effect estimates by outcome and associa ted forest plots for molnupiravir versus standard care.
For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of molnupiravir compared with standard care for the outcomes of interest, with c ertainty ratings, informed by the LNMA (3).

# Subgroup analysis
Five pre-specified subgroup analyses were requested by the GDG:
Due to serious imprecision and indirectness 1 Molnupiravir may have a small effect on mortality

# Mechanical ventilation
Odds ratio 1 (CI 95% 0.

# Very low
Due to serious risk of bias and extremely serious imprecision 2 The effect of molnupiravir on mechanical ventilation is very uncertain

# Admission to hospital

# Molnupiravir probably reduces hospital admission

# Adverse effects leading to drug discontinuation
There is little or no difference in adverse effects leading to drug discontinuation

# Time to symptom resolution
Lower better Based on da ta from 3,078 participants in 3 studies. (Randomized controlled)
(Median) Difference: 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, who are not easily identifiable. For these patients, molnupiravir may have an important impact on mortality. Imprecision: serious. There were only 11 events total (10 in the control arms and 1 in the molnupiravir arms).
- Risk of Bias: serious. The single trial reporting mechanical ventilation was not blinded. Imprecision: extremely serious. Very few events, resulted in very large credible intervals that include important and unimportant effects.
- Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 4. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 5. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 6. Risk of Bias: serious. All three trials were at high risk of bias for deviations from intended intervention (lack of blinding).
One trial was at high risk of bias for possible inadequate randomization concealment.
In vitro and animal studies sugg est the possibility of carcinogenesis

# Very low
No human da ta with long-term follow-up
The effect of molnupiravir on cancer is uncertain Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
Mitigation strategies to address safety concerns

# Mechanism of action
Molnupiravir an orally available antiviral, which w as originally designed as an in fluenza treatment, although no t approved. The drug inhibits replication of SARS-CoV-2 with an in vitr o potency broadly, similar to remdesivir, and w as re-purposed early in development as an an tiviral for SARS-CoV-2 (90) (91).
Molnupiravir is an orally available prodrug of -D-N4-h ydroxycytidine (NHC). It is a nucleoside drug, but the mechanism o f action involves lethal mutagensis of the virus. T his contrasts with chain-termination seen with o ther antiviral nucleoside analogues (e.g. remdesivir and those used in HIV or HCV (92). NHC is inc orporated by the S ARS-CoV-2 RdRp, instead o f either C or U nucleosides, in to the g enomic or subg enomic RNA during c opying of the RNA templa te genome. T he resultant NHCcontaining RNAs are then themselves used as a templa te for production of subsequent RNAs which ar e predicted to be muta ted and therefore not believed to f orm functional viruses (92) (93).
Molnupiravir is given orally twice daily unlike remdesivir, which is giv en by intravenous infusion once daily. In healthy volunteers, molnupiravir (800mg) achieves maximum plasma c oncentrations of its active metabolite at 3600 ng/m L (94). This is higher than that of remdesivir (2200 ng/m L) (95). However, the in tracellular half-life of molnupiravir active metabolite is shorter in human cell lines (3h) compared with that of remdesivir's active metabolite (35h) (94).
High doses o f molnupiravir (250 mg/kg twic e daily) have been sho wn to be e ffective in S ARS-CoV-2-infected Syrian golden hamsters; however, the animal plasma pharmac okinetics were not reported to benchmark against those seen in humans (96).
Evidence of antiviral activity is also a vailable from a study in S ARS-CoV-2-infected ferrets at lower doses (97). When molnupiravir was combined with fa vipiravir in infected Syrian golden hamsters, the e fficacy was greater than when either drug was given alone (98).
Molnupiravir retains activity against Alpha and B eta variants in vivo (99), and the D elta and Omicron variants in vitro (100) (101).
No data are currently available demonstrating activity against the D elta or Omicron variants in vivo, and while ther e appears to be no molecular basis f or a loss o f activity, there is residual uncertainty around whether a higher replication or transmission rate may impact e fficacy of the drug.

# Info Box
With the safety concerns related to molnupiravir (see Mechanism of action section, the WHO r ecognizes the need to mitiga te risks, both for individual patients and at the population level.
The conditional recommendation takes into account one such str ategy: limiting the in tervention to pa tients that are at higher risk of hospitalization or death. Typical characteristics of people a t highest risk include those with older age, immunodeficiencies and/or chronic diseases (e.g. diabetes) and lack o f COVID-19 vaccination. See WHO r ecommendations for further information on COVID-19 vaccination Strategic Advisory Group of Experts on I mmunization for more details.
Other mitigation strategies include:
- Decisions around treatment with molnupiravir must be done using a shar ed decision-making model, ensuring the clinician is well educated on the po tential benefits and harms of therapy and able to e xplain these to the pa tient in order to make well-informed decisions. S ee Practical information section.
- Molnupiravir should not be given to pregnant or breastfeeding women or to children. In case o f doubt about pregnancy, a pregnancy test should be perf ormed prior to treatment initiation. If a w oman of child bearing ag e is c onsidered for treatment, counselling regarding birth control during treatment and f or 4 days after the last dose o f molnupiravir should be facilitated. - Men planning to c onceive should be orien ted on the po tential for temporary genotoxic effect on sperm c ell production, and those who ar e sexually active with f emales should be c ounselled to use birth c ontrol during treatment and f or at least 3 months after the last dose o f molnupiravir (89). - The unknown long-term risk o f genotoxicity is likely to be higher in y ounger patients as c ompared with older pa tients; thus use in y ounger adults who are not at high risk should be limited.
- Active sequence monitoring of SARS-CoV-2 detected in clinical respiratory samples (i.e. ma y include polymerase and spike) should be arranged for patients receiving therapy, including higher risk individuals (immunocompromised). - Pharmacovigilance: use o f molnupiravir should be ac companied by a robust, active pharmacovigilance programme.

# Emergence of resistance:
The emergence of resistance to drugs used f or other viruses is varied; with some resistance emerges readily, and with o thers emerging more slowly. The barrier to resistance for a given drug with a giv en virus is g enerally considered to increase with the number o f mutations that are required to emerge. Insufficient data are currently available to ascertain how high the barrier o f resistance is with S ARS-CoV-2 for molnupiravir. Based on e xperiences with o ther nucleoside antiviral drugs (some have a high barrier to r esistance and some ha ve a lo w barrier to resistance), molnupiravir will place a selective pressure for viral resistance mutations within an individual, with the po tential to spread at a population level. Nonclinical and/or clinical data are therefore needed, but ar e not currently available for molnupiravir.
Resistance occurs through inherent variability in viral sequences that happen spon taneously as the virus replicates. Chance variations become selected, kno wn as selectiv e pressure, when the y confer a survival advantage in the pr esence of the drug. Sometimes, there is a fitness c ost to the virus and sec ondary mutations can subsequen tly be selected to r estore fitness. T he major uncertainty relates to ho w quickly resistance will emerge rather than whether it will emerge. There may be a higher risk o f resistance in immunoc ompromised patients because o f a long er tail of replication in this group. There may also be a higher risk of resistance in pa tients with poor adherence where the virus is e xposed to subop timal drug concentrations. The rate at which resistance emerges will be slo wer if drugs are given in c ombination because more mutations will be required to c onfer resistance to multiple drugs than will be r equired for one drug. O f note, animal studies have also demonstrated drug combinations to be more effective. The risk of resistance to individual pa tients is drug failure due to c ompromised efficacy. If resistance is transmitted, there is a risk o f efficacy failure at a population level and subsequen t attempts to c ombine the drug ma y be futile because of "functional mono therapy" with the partner ag ent. The genetic barrier to resistance cannot be estimated without data.
Emergence of new variants: It has been pr oposed that random mutagenesis arising from the molnupiravir mechanism of action might increase diversity in the viral sequences that may result in more rapid emergence of new variants (102). Unlike in the considerations for resistance, there is no c onceptual basis for molnupiravir placing a selective pressure on emergence of new variants. Sequence variation is lower given molnupiravir is only inc orporated in place of two of the f our nucleotide bases in the genome than it w ould be if inc orporated in place of any nucleotide. There is no dir ect evidence to support or r efute the v ariants hypothesis and as such the risk is curr ently unquantifiable.
The rate of resistance emergence and the risk o f additional diversity in the viral genome leading to ne w variants, were acknowledged to be higher with a higher number o f patients receiving the intervention.

# Non-clinical safety:
The GDG reviewed the publically a vailable data on non-clinical sa fety of molnupiravir from the FD A meeting documents for molnupiravir Emergence Use Authorization (30 November 2021) (103). The following safety concerns were highlighted:
- Genetic toxicology data demonstrated that molnupiravir is mutagenic in vitro, but there was no e vidence of mutagenicity in animal models. The GDG ackno wledged uncertainties in the a vailable data and concluded that based upon the a vailable information molnupiravir may or may not be carcinogenic in humans. - An increase in thickness o f growth plate associated with decreased bone f ormation was observed in rapidly growing rats but not in mice, rats or dogs. T he GDG de termined that molnupiravir should not therefore be administered to paediatric patients. - Importantly, low concentrations of NHC (0.09% ma ternal exposures) were detectable in 10-day old rat pups sugg esting that NHC is present in breast milk. The GDG de termined molnupiravir should not be administered to breastfeeding women. - In developmental and reproductive toxicology assessments, reduced foetal body w eights were observed in rats and rabbits, with higher exposures also being associa ted with embryo-foetal lethality and teratogenicity in rats. Accordingly, molnupiravir should not be administered during pregnancy. - There was an absenc e of available data relating to spermatogenesis, which ma y be particularly prone to the e ffect of a mutagen in adult males. N o data are available to quantify the c onsequences of this f or embryo/foetus conceived by fathers who w ere receiving or had recently received molnupiravir.
For patients with non-severe COVID-19

# Practical Info
The GDG made a str ong recommendation against using c onvalescent plasma for the treatment of patients with non-se vere COVID-19 and a r ecommendation against using c onvalescent plasma in those with se vere or critical COVID-19 outside the context of a clinical trial. Given this, w e will not go into detail regarding the many practical issues related to c onvalescent plasma including but not limited to: identification and recruitment of potential donors, collection of plasma, storage and distribution o f plasma, and infusion of convalescent plasma into recipients.

# Evidence To Decision

# Info Box
Recommendations concerning convalescent plasma for patients with non-se vere, severe and critical COVID-19 were published on 7 D ecember 2021 as the seventh version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the a vailability of 16 R CTs across disease se verities, as per the LNMA on an tibody and c ellular therapies (2). No changes were made to the c onvalescent plasma recommendations in this 13th v ersion of the guideline.

# Strong recommendation against
We recommend against treatment with c onvalescent plasma (strong recommendation ag ainst).
In non-severe patients, convalescent plasma does no t result in an important impact on mortality. Convalescent plasma probably does no t impact mechanical v entilation. There were no da ta evaluating the risk o f hospitalization with convalescent plasma and therefore the impact is v ery uncertain.
Convalescent plasma probably does no t result in important increases in risks of transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), or allergic reactions.

# Benefits and harms
The certainty in mortality was high, whereas mechanical ventilation was moderate due to serious risk o f bias. C ertainty was rated as moderate for TRALI and TACO due to serious risk o f bias, and f or allergic reactions due to c oncerns regarding risk of bias and impr ecision.

# Certainty of the Evidence
The GDG in ferred that, in addition to the agr eed upon v alues and preferences (see Section 7), almost all w ell-informed patients would choose against r eceiving convalescent plasma based on a vailable evidence regarding relative benefits and harms. From a popula tion perspective, feasibility, acceptability, equity and c ost are other important elements to take into account (see Section 7).
For patients with non-se vere illness, the GDG c onsidered that resource and f easibility issues may be amplified in the outpatient setting, and mobilizing the use o f convalescent plasma on a lar ge scale w ould likely be o f questionable f easibility.

# Values and preferences

# Acceptability and feasibility
The GDG no ted that convalescent plasma use is associa ted with significant resource requirements including identification of potential donors, testing o f donors to ensur e adequate titres of anti-SARS-CoV-2 antibodies, collection of donor plasma,
Resources and other considerations 6.10 Convalescent plasma (published 7 December 2021)
A combination of the e vidence, values and preferences, and f easibility contributed to the strong recommendation against convalescent plasma in pa tients with non-se vere COVID-19. Most importantly, given there was no bene fit demonstrated in any of the critical or important outcomes for either non-severe or severe or critical COVID-19, the GDG did no t see any justification for the resources (including time and c ost) that would be associa ted with administration of convalescent plasma. The recommendation also took in to account possible associated harms (although not demonstrated in the e vidence summary, there is always a po tential for harms with blood pr oduct transfusion), the low baseline risk o f mortality, mechanical v entilation, and hospitalization in non-se vere illness, and f easibility challenges with the administration of convalescent plasma.
Titres of neutralizing antibodies varied substantially between included trials, with o ver half of the trials not reporting or considering recipient titres at all. In fact, the lar gest trial (RECOVERY) did not report on donor an tibody titres at all. Even when titres were reported, the me thod for testing and the v olume of plasma infused varied. This made it impossible to pr ovide any analysis based on donor titr e levels or assess f or credible subgroup effects.
The applicability of this recommendation to children or pregnant women is currently uncertain, as the included R CTs enrolled non-pregnant adults. The GDG had no r eason to think tha t children with COVID-19 would respond any differently to treatment with convalescent plasma. However, the risk o f hospitalization in children is g enerally extremely low and the GDG in ferred that in the absenc e of immunosuppression or another significant risk factor children should no t receive the in tervention.
storage of plasma, transportation of plasma to r ecipient location, and administration of plasma. T hese resources and feasibility issues are compounded f or those with non-se vere disease who ar e most o ften outpatients. Also, this pr ocess is costly and time-c onsuming. Given the number o f patients with non-se vere disease and the lo w event rate in this subgroup of patients, mobilizing the use o f convalescent plasma on a lar ge scale w ould be o f questionable f easibility.
Although blood transfusion is ac ceptable to most, there is a subse t of the popula tion that will not accept allogenic blood transfusion. There are also regulatory challenges in most jurisdictions r elated to blood pr oduct transfusion.

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Summary Evidence summary
The LNMA on c onvalescent plasma included 16 R CTs that enrolled 16 236 pa tients across non-se vere, severe, and critical illness subgroups. All R CTs were registered, and 80% w ere published in peer -reviewed journals; 20% w ere preprints. 99% o f participants were enrolled from in-patient settings; of them, 15% w ere admitted to the in tensive care unit (ICU). 1% of patients were enrolled from outpatient settings. None of the included studies enr olled children or pregnant women. The Table shows characteristics of the R CTs, of which tw o trials used c omparisons to plasma as plac ebo and were not included in the e vidence summaries. We are aware of two additional published R CTs comparing convalescent plasma to standard care or placebo (104) (105). These trials were not incorporated in the la test analysis presented to the GDG, based on which r ecommendations were made.
For patients with non-se vere COVID-19, the GRADE S ummary of Findings table sho ws the relative and absolute e ffects of convalescent plasma compared with usual care for the outcomes of interest,with certainty ratings. This evidence summary was informed by the LNMA (2) pooling data from 1602 pa tients in 4 R CTs for the outcome of mortality and less data available for other outcomes, except for allergic reactions (8 RCTs,243 patients). See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
We pre-specified the f ollowing subgroup analyses of interest:
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
- Age: younger adults ( 70 y ears). 2. Severity of illness (at time o f treatment initiation): non-severe versus severe and critical. 3. Treatment dose: higher titre versus lower titre plasma.
The subgroup analyses were performed on pa tients across all disease se verities. The majority of subgroups did no t have sufficient data across outcomes of interest to pursue subgr oup analyses.
Of those tha t did, w e found no significan t subgroup effects for severity of illness (p=0.80) and ag e (p=0.84) on mortality, and of severity of illness (p=0.17) on mechanical v entilation.
Due to c oncerns with risk of bias and imprecision 10 Convalescent plasma probably does no t result in an important increase in allergic reactions.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
For patients with severe or critical COVID-19

# Practical Info
The GDG made a r ecommendation against using c onvalescent plasma in those with se vere or critical COVID-19 outside the context of a clinical trial and a str ong recommendation against using c onvalescent plasma for treatment of patients with nonsevere COVID-19. Given this, w e will not go into detail regarding the many practical issues related to c onvalescent plasma including but not limited to: identification and recruitment of potential donors, collection of plasma, storage and distribution o f plasma, and infusion of convalescent plasma into recipients.
Evidence To Decision 2. Risk of Bias: no serious. The GDG did no t rate down for risk of bias due to lack o f blinding.. 3. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 4. Risk of Bias: serious. Imprecision: no serious. The GDG did no t rate down for imprecision, because the cr edible interval excludes an important benefit and important harm. 5. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 6. Risk of Bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided no t to rate down for imprecision, because credible interval excludes an important effect and baseline risk is v ery low. 7. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 8. Risk of Bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided no t to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is v ery low. 9. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 10. Risk of Bias: serious. 2 trials (491 patients; 3% o f total) were at low risk of bias v s. 6 trials (14 910 pa tients) at high risk of bias. Imprecision: serious. GDG agreed the credible interval includes some c oncern regarding allergic reactions, though acknowledges that the baseline risk is lo w.

# Only in research settings
We recommend not to use c onvalescent plasma for treatment of COVID-19, except in the c ontext of a clinical trial (recommended only in r esearch settings).
In severe or critical patients, convalescent plasma may not result in an important impact on mortality, mechanical ventilation, time to s ymptom improvement, length o f hospital stay or ventilator-free days.
Convalescent plasma probably does no t result in important increases in risks of TRALI, TACO or allergic reactions. However, there is always potential for harms with blood pr oduct transfusion although no t demonstrated in the e vidence summary.

# Benefits and harms
The certainty in mortality was low due to c oncerns with indirectness, risk of bias and impr ecision. The GDG rated down certainty to low for mechanical ventilation, length o f hospital stay and v entilator-free days for serious risk of bias and serious imprecision, and to lo w for time to s ymptom improvement due to v ery serious imprecision.

# Certainty of the Evidence
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
After substantial discussion, the GDG decided to mak e a recommendation against convalescent plasma in pa tients with severe or critical COVID-19, except in the c ontext of clinical trials. Given the lo w certainty evidence suggesting a small or no e ffect on mortality, mechanical v entilation, and time to s ymptom improvement, with possible associa te harms (although not demonstrated in the evidence summary, there is always a po tential for harms with blood pr oduct transfusion) the panel agreed further research addressing these pa tient-important outcomes would be v aluable. This research focus on se vere or critical COVID-19 was also informed by the f easibility (patients are already hospitalized) and baseline risk o f mortality and requiring life support interventions (higher in severe or critical. The panel iden tified high titre products as the highest priority f or future research as w ell as the need o f reporting on donor titre and v olume infused which can giv e an idea o f dilution o f titres in the recipient. Similarly, the panel iden tified seronegative COVID-19 patients as the highest priority f or future convalescent plasma research.
A recommendation to only use a drug in the se tting of clinical trials is appropriate when there is low certainty evidence, and future research has a po tential for reducing uncertainty about the e ffects of the in tervention and f or doing so a t a reasonable cost.
Certainty was rated as moderate for TRALI and TACO due to serious risk o f bias, and f or allergic reactions due to c oncerns regarding risk of bias and impr ecision.
The GDG in ferred that, in addition to the agr eed upon v alues and preferences (see Section 7), almost all w ell-informed patients would choose against r eceiving convalescent plasma based on a vailable evidence regarding relative benefits and harms. From a popula tion perspective, feasibility, acceptability, equity and c ost are other important elements to take into account (see Section 7).

# Values and preferences

# Acceptability and feasibility
The GDG no ted that convalescent plasma use is associa ted with significant resource requirements including identification of potential donors, testing o f donors to ensur e adequate titres of anti-SARS-CoV-2 antibodies, collection of donor plasma, storage of plasma, transportation of plasma to r ecipient location, and administration of plasma. Also, this process is c ostly and time-consuming.
Although blood transfusion is ac ceptable to most, there is a subse t of the popula tion that will not accept allogenic blood transfusion. There are also regulatory challenges in most jurisdictions r elated to blood pr oduct transfusion.

# Resources and other considerations
Clinical Question/ PICO Population:
Patients with severe or critical COVID-19

# Summary Evidence summary for convalescent plasma
Please see summary f or patients with non-se vere COVID-19 above. It provides details about the LNMA and 16 included trials across disease se verities, as well as subgroup analyses that did no t detect credible effects based on ag e, severity of illness, or dosage of convalescent plasma.
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of convalescent plasma compared with usual care for the outcomes of interest for patients with severe and critical COVID-19, with c ertainty ratings. This evidence summary w as informed by the LNMA (2), pooling da ta from from 14 366 pa tients in 10 studies f or the outcome of mortality, with less da ta available for other outcomes.

# Baseline risk estimates
For severe and critical illness, f or the critical outcome of mortality, the applied baseline risk estima te was 13% (130 in 1000). As f or other related recommendations in this guideline, the estima te is derived from the SOLID ARITY trial for severe and critical pa tients adjusted for treatment effects of corticosteroids. For other outcomes, w e used the median o f the control arm of the R CTs that contributed to the evidence (see Section 7).

# Subgroup analysis
We pre-specified the f ollowing subgroup analyses of interest:
- Age: younger adults ( 70 y ears).
- Severity of illness (at time o f treatment initiation): non-severe versus severe and critical. 3. Treatment dose: higher titre versus lower titre plasma.
The majority of subgroups did no t have sufficient data across outcomes of interest to pursue subgr oup analyses.
Of those tha t did, w e found no significan t subgroup effects for severity of illness (p=0.80) and ag e (p=0.84) on mortality, and of severity of illness (p=0.17) on mechanical v entilation. 1. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 2. Risk of Bias: serious. Indirectness: serious. Imprecision: serious. Credible intervals include both important benefit and important harm.
- Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 4. Risk of Bias: serious. Imprecision: serious. The GDG decided the cr edible intervals warranted downgrading only onc e for imprecision. 5. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 6. Risk of Bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided no t to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is lo w. 7. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 8. Risk of Bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided no t to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is lo w. 9. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references:
Due to c oncerns with risk of bias and imprecision 10 Convalescent plasma probably does no t result in an important increase in allergic reactions.

# Time to symptom improvement

# Lower better
Based on da ta from 472 participants in 3 studies. 11 (Randomized controlled)
MD 0 f ewer ( CI 95% 10.4 fewer -33.6 more
Due to v ery serious imprecision 12 Convalescent plasma may not impact time to symptom improvement.

# Length of hospital stay

# Measured by: days
Lower better Based on da ta from 1,015 participants in 7 studies. 13
Due to serious risk of bias and serious imprecision 16 Convalescent plasma may not impact the number of ventilatorfree days.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Mechanism of action
The proposed primary mechanism o f action f or convalescent plasma involves the transfer of endogenously produced neutralizing antibodies present within the plasma fr om previously infected and recovered patients into patients with active infection (120). Therefore, the underlying plausibility f or this mechanism o f action depends upon whe ther sufficient antibody concentrations remain following the dilution fr om donor to r ecipient. As such, the neutr alizing antibody titre within the donor plasma as well as the v olume administered are likely to be importan t. Data generated in Syrian golden hamsters have demonstrated efficacy of convalescent plasma against S ARS-CoV-2 at a titre of 1:2560, but no t at a titre of 1:320, when giv en at a volume of 1 mL, which e xtrapolates based on a verage blood v olume to a human dosing v olume of 300 m L (121).
At the e xtremes of the studies which ha ve investigated convalescent plasma clinically and reported the dose in terms o f neutralizing antibody titre and v olume administered, administration of 200 m L would be e xpected to result in an a verage dilution of 25-fold whereas administration of 1000 m L would be e xpected to result in an a verage dilution of 5-fold from those titres present in the circulation of the donor themselv es (assuming an average human blood v olume of 5 L ( 122)). It should be further recognized that the c oncentrations (titre) of neutralizing antibodies present within convalescent plasma are highly variable between donors and tha t there are different methodologies available to measure it (123).
Antibody titre, methodology employed, and the v olume of convalescent plasma administered all vary widely across the studies that have investigated this approach in COVID-19. It should be further no ted that in some trials, the an tibody titre reported for eligibility was higher than the r eported antibody titre in the donor plasma tha t was used because o f the differences in methodology used f or the two assessments (e.g. to tal IgG for donor eligibility with subsequen t assessment of the specific neutralizing antibody titre (124)). There is clear unc ertainty surrounding the dose o f neutralizing antibodies given in different trials and this uncertainty is summarised as f ollows:
For trials in severe/critical patients:
- No cut-off in neutralizing antibody titre of the donor w as applied in 9/16 studies.
- Antibody titre of the donor plasma w as not recorded in 12/16 trials, meaning the titr e may have been high or ma y have been low. However, in 3 o f the trials in which donor titr e was not recorded, a lo wer cut-off was applied at a titre of either 1:160 (for 2 trials) or 1:400. - The largest trial (RECOVERY) did not report donor antibody titres although only donors with a titr e above 1:100 w ere eligible - One (1/16) trial did no t provide information on wha t volume of plasma w as administered meaning v olume could have been high or could have been lo w. - Both volume and donor titre were only kno wn for 6/16 trials. D onor titres were 1:80, 1:87, 1:300, 1:320, 1:526, and 1:640 with volumes of 300, 500, 400-600, appr ox. 480, 750-975, and 300 m L, respectively (estimated dose range of 6-fold).
- Risk of Bias: serious. 2 trials (491 patients; 3% o f total) were at low risk of bias v s. 6 trials (14 910 pa tients) at high risk of bias. Imprecision: serious. GDG agreed the credible interval includes some c oncern regarding allergic reactions, though acknowledges the baseline risk is lo w. 11. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 12. Imprecision: very serious.
- Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 14. Risk of Bias: serious. All studies except one w ere not adequately blinded. Imprecision: serious. Credible interval does not exclude small but important benefit. 15. Systematic review. Baseline/comparator: Control arm of reference used f or intervention. Supporting references: 16. Risk of Bias: serious. Almost all patients were randomized to trials that were not blinded. Imprecision: serious. Credible interval does no t exclude important benefit.
- Only three trials were conducted in non-se vere patients using antibody titres of 1:40, 1:292, and 1:3200 with v olumes administered of 250-300 m L, 400 m L and 250 m L, respectively (estimated dose range of 100-fold). - Two trials studied both non-severe and se vere/critical patients, one o f which didn 't record antibody titre, and the o ther which used 200-250 +/-75 m L of plasma with a titr e of 1:160.

# Interleukin-6 receptor blockers (published 6 July 2021)
For patients with severe or critical COVID-19

# Practical Info
Route: IL-6 receptor blockers are administered intravenously for the treatment of patients with severe or critical COVID-19; subcutaneous administration is no t used in this case. IL -6 receptor blocker therapy should be administered in c ombination with systemic corticosteroids, which ma y be administered both orally and intravenously, with due c onsideration to their high bioavailability but possible malabsorption in the case o f intestinal dysfunction with critical illness.
Duration: Tocilizumab and sarilumab are administered as single in travenous doses, typically o ver 1 hour. A sec ond dose ma y be administered 12 to 48 hours a fter the first dose; this w as offered variably in major clinical trials at the discretion of treating clinicians if a clinical response w as felt to be inadequa te. Duration of concurrent systemic corticosteroids is typically up to 10 days, though ma y vary between 5 and 14 da ys.
Tocilizumab is dosed a t 8 mg per kilogr am of actual body w eight, up to a maximum o f 800 mg. S arilumab is most commonly dosed a t 400 mg, c onsistent with wha t was used in REMAP -CAP. Renal dose adjustment is not currently warranted for either drug.
Monitoring: Routine bloodwork including neutrophil count, platelets, transaminases, and total bilirubin should be checked prior to initiation of therapy. All patients should be monitor ed for signs and s ymptoms of infection, given the increased risk with immunosuppression in addition to s ystemic corticosteroids. Patients on long er term IL-6 receptor blocker therapy are at risk of active tuberculosis, invasive fungal in fections and opportunistic pathogens. Risks and benefits of therapy should be c onsidered carefully in patients with any active, severe infection other than COVID-19; caution is advised when c onsidering the use o f tocilizumab in patients with a history o f recurring or chronic infections or with underlying c onditions which ma y predispose them to infections.
Timing: IL-6 receptor blockers should be initiated with systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. That being said, IL-6 receptor blockers have been administered early in the course of hospitalization in the included trials and clinicians may consider this approach if possible. See section on resource implications, equity and human rights.

# Info Box
The recommendation concerning IL-6 receptor blockers (tocilizumab or sarilumab) was published on 6 J uly 2021 as the fifth version of the WHO living guideline. It followed the publication of RECOVERY and REMAP-CAP trial publications in February 2021, and ne w trial data from 1020 pa tients randomized head-to-head to either tocilizumab or sarilumab in REMAP -CAP being made available to the WHO on 1 J une 2021. I n the 12th o f the guideline (S eptember 15 2022), WHO upda ted the strong recommendation for baricitinib in patients with severe and critical COVID-19, reflecting that IL-6 receptor blockers and baricitinib may be giv en together. No changes were made to the recommendations in this 13th v ersion of the guideline.

# Strong recommendation for
We recommend treatment with IL-6 receptor blockers (tocilizumab or sarilumab) (strong recommendation f or).
- Corticosteroids have previously been str ongly recommended in patien ts with se vere and critic al COVID-19 (see Section 6.15), and we recommend patien ts meeting these se verity criteria should receive both corticosteroids and IL-6 receptor blockers. - The JAK inhibitor baricitinib is no w recommended f or the tr eatment of patients with se vere and critic al. IL-6 receptor blockers and baricitinib may be giv en together.
For trials in non-severe patients:

# Evidence To Decision
IL-6 receptor blockers reduce mortality and need f or mechanical ventilation based on high c ertainty evidence. Low certainty evidence suggests they may also reduce duration of mechanical v entilation and hospitalization (3)( 126) (127). The RECOVERY trial demonstrated reduced risk of death also in pa tients already receiving corticosteroids and IL-6 receptor blockers., resulting in an upda ted recommendation to allow the c ombination of IL-6 receptor blockers and baricitinib in the 12th iteration of this WHO guideline.
The evidence regarding the risk o f serious adverse events (SAEs) is uncertain. Low certainty evidence suggested that the risk of bacterial infections in the c ontext of immunosuppression treatment with IL-6 receptor blockers may be similar to usual care (1). However the GDG had some c oncerns that, given the short-term f ollow-up o f most trials and the challeng es associated with accurately capturing adverse events such as bacterial or fungal in fection, the e vidence summary may underrepresent the risks of treatment with IL-6 receptor blockers. Furthermore, the trials of IL-6 receptor blockers that inform this recommendation were mostly performed in high-income countries where the risk o f certain infectious complications may be less than in some o ther parts of the w orld, and so the g eneralizability of the da ta on adverse events is unclear. We did no t have any data examining differential risk of harm based on whe ther patients received one or tw o doses o f IL-6 receptor blocker.
Subgroup analyses indicated no e ffect modification based on IL-6 receptor blocker drug (sarilumab or tocilizumab) or disease severity (critical vs severe) and therefore this recommendation applies to all adult pa tients with either severe or critical. We were unable to e xamine subgroups based on ele vation of inflammatory markers or age due to insufficient trial data (see Research evidence). Subgroup analyses evaluating baseline steroid use f ound greater benefit of IL-6 receptor blockers in patients receiving steroids compared with those who w ere not (p=0.026), demonstrating that steroid use does no t abolish and migh t enhance the bene ficial effect of IL-6 receptor blockers. Since steroids are already strongly recommended in pa tients with severe and critical COVID-19, we did no t formally evaluate the credibility of this subgroup analysis as there would be no r ationale for a subgroup recommendation for patients not receiving corticosteroids.

# Benefits and harms
Certainty of evidence was rated as high f or mortality and need f or mechanical ventilation. Certainty in duration of mechanical ventilation was rated as low due to serious risk o f bias due to c oncerns regarding lack of blinding in included trials, and for imprecision as the lo wer limit of the c onfidence interval suggested no e ffect. Certainty in duration of hospitalization was rated as low due to serious risk o f bias from lack o f blinding in included trials, and f or inconsistency related to differences in poin t estimates and lack o f overlap in confidence intervals.
Certainty in serious adv erse events was rated as very low due to risk o f bias related to lack o f blinding and asc ertainment bias, and very serious imprecision due to v ery wide c onfidence intervals which did no t rule out important benefit or harm; certainty in risk of bacterial or fungal in fections was rated as low due to similar c oncerns regarding serious risk of bias and serious imprecision.
Certainty in evidence was rated as moderate when c omparing the effect on mortality be tween tocilizumab and sarilumab due to issues with impr ecision.

# Certainty of the Evidence
Applying the agreed values and preferences (see Section 7), the majority o f the GDG in ferred that almost all w ell-informed patients would want to receive IL-6 receptor blockers. The benefit of IL-6 receptor blockers on mortality was deemed o f critical importance to pa tients, despite the v ery low certainty around serious adverse events. The GDG an ticipated little variation in v alues and preferences between patients for this intervention.

# Values and preferences
When moving from evidence to the str ong recommendation to use IL-6 receptor blockers (tocilizumab or sarilumab) in patients with severe or critical COVID-19, the GDG emphasiz ed the high c ertainty evidence of improved survival and reduction in need for mechanical ventilation. Additional trial data from REMAP-CAP (see Research Evidence section) provided more conclusive evidence regarding the equivalence of tocilizumab and sarilumab.
The GDG ackno wledged the unc ertain data regarding SAEs and bacterial infections, but f elt that the evidence of benefit for the two most important patient outcomes warranted a strong recommendation. Costs and ac cess were important considerations and it w as recognized that this recommendation could exacerbate health inequities. H opefully this strong recommendation will provide impetus to address these c oncerns and ensure access across regions and c ountries. The GDG did no t anticipate important variability in patient values and preferences, and judg ed that other contextual factors would not alter the recommendation (see Evidence to D ecision).

# Subgroup analyses
The GDG did no t find any evidence of a subgroup effect across patients with different levels of disease se verity (severe vs critical), or by IL-6 receptor blocker drug (tocilizumab vs sarilumab).
There were insufficient data to assess subgr oup effect by elevation of inflammatory markers or age. Although the GDG considered a subgroup analysis of patients receiving corticosteroids at baseline as c ompared with those tha t were not, the panel did not see a need to c onsider subgroup recommendations for IL-6 receptor blockers in those no t receiving corticosteroids as all severe and critical COVID-19 patients should be r eceiving corticosteroids (see previous strong recommendation below). Taken together, the GDG f elt that the recommendation applies to bo th tocilizumab and sarilumab and all adult pa tients with severe or critical COVID-19.

# The role of IL-6 receptor blockers and baricitinib
The GDG had pr eviously made a strong recommendation for use o f baricitinib or IL-6 receptor blockers (tocilizumab and sarilumab) or baricitinib as alternative agents administered in addition to c orticosteroids for patients with severe or critical COVID-19. The GDG had elected to r efrain from recommending combining these three immunosuppressive drugs until clear evidence of incremental benefit emerged. The RECOVERY trial has now provided this evidence that combining corticosteroids, IL-6 receptor blockers and baricitinib provides incremental survival benefit (39). Specifically, in RECOVERY 2659 pa tients

# Resource implications, equity and human rights
The GDG no ted that, compared with some o ther candidate treatments for COVID-19, IL-6 receptor blockers are more expensive and the r ecommendation does no t take account of cost-effectiveness. Currently, access to these drugs is challenging in many parts of the w orld, and without c oncerted effort is likely to remain so, especially in r esource-poor areas.
It is therefore possible that this strong recommendation for IL-6 receptor blockers could exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, it should also pr ovide a stimulus to engag e all possible mechanisms to improve global access to these tr eatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly.
At a time o f drug shortage, it may be nec essary to prioritize use o f IL-6 receptor blockade through clinical triage (6). Many jurisdictions have suggested mechanisms f or triaging use of these treatments. These include prioritizing patients with the highest baseline risk for mortality (e.g. those with critical disease o ver those with se vere disease), in whom the absolute benefit of treatment is therefore greatest. For example, despite c onsistent relative effects (OR 0.86 f or mortality) with IL-6 receptor blockers, the absolute risk reduction for mortality in the critically ill would be 31 f ewer deaths per 1000 (95% CI 11 to 47 f ewer deaths) and in the se verely ill would be 13 f ewer deaths per 1000 (95% CI 5 to 19 f ewer deaths).
Other suggestions for prioritization, which lack dir ect evidence, include f ocusing on pa tients with an activ ely deteriorating clinical course and avoiding IL-6 receptor blocker therapy in those with established multi-or gan failure (in whom the bene fit is likely to be smaller).

# Acceptability and feasibility
As IL-6 receptor blockers require intravenous administration, this treatment would be primarily indicated for patients with severe and critical COVID-19 who r equire hospitalization. IL-6 receptor blockers are relatively easy to administer, and only require one, or a t most, tw o doses.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) received baricitinib along with c orticosteroids and IL-6 receptor blockers. The effect of baricitinib in this subgroup was consistent with the bene ficial effect of baricitinib in patients who w ere not treated with IL-6 receptor blockers (39). Although these three immunosuppressIve drugs are recommended and ma y be administered jointly, the panel an ticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy and/or to c ombine medications in a stepwise fashion in pa tients who are deteriorating. However, since the drugs ha ve not undergone direct comparisons, if this situation arises, the GDG f elt that clinicians should choose be tween baricitinib and IL-6 receptor blockers on the basis o f experience and c omfort using the drugs; local institutional policies; r oute of administration (baricitinib is oral; IL-6 receptor blockers are intravenous); and cost.
None of the included R CTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the GDG had no r eason to think tha t children with COVID-19 would respond any differently to treatment with IL-6 receptor blockers. This is especially true giv en tocilizumab is used in childr en safely for other indications including polyarticular juvenile rheumatoid arthritis, systemic onset of juvenile chronic arthritis, and chimeric antigen receptor T-cell induced cytokine release syndrome. S arilumab is not approved in children, so if an IL -6 receptor blocker is used in this population, tocilizumab is preferred. The GDG also r ecognized that in many settings children are commonly admitted to hospital with acute respiratory illnesses caused by other pathogens; as a r esult, it may be challenging to de termine who is ill with se vere COVID-19, even with a positiv e test, and ther efore likely to bene fit from IL-6 receptor blockade. There were similar considerations in regard to pregnant women, with no da ta directly examining this population, but no r ationale to sugg est they would respond differently than other adults. The drug may, however, cross the plac ental membrane, although it is unc ertain what effect transient immunosuppression in the f etus may have and this should be w eighed against the po tential benefit for the mother.

# Clinical Question/ PICO Population:
Patients with severe and critical COVID-19

# Intervention: Baricitinib
Interleukin-6 receptor blockers
Due to serious imprecision and ongoing recruitment in a large RCT 1 Baricitinib may reduce mortality.

# Mechanical ventilation
Due to v ery serious imprecision 2 There may be little or no difference on mechanical ventilation.

# Adverse effects leading to drug discontinuation
Due to serious imprecision 3 There is probably little to no difference in adverse effects leading to discontinuation.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Outcome Timeframe

# Study results and measurements

# IL-6 receptor blockers

# Certainty of the Evidence
(Quality of evidence)
Plain language summary 1. Imprecision: serious. The credible interval includes no important difference. 2. Risk of Bias: no serious. Most of the da ta on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: very serious. The credible interval includes important benefit and important harm.
- Imprecision: serious. The credible interval includes small but important harm. 4. Risk of Bias: serious. Most of the da ta on interleukin-6 receptor blockers comes from trials that were unblinded. Inconsistency: serious. The trials that studied interleukin-6 receptor blockers had discrepant results: some increased length of stay, others reduced length o f stay. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of Bias: serious. Most of the da ta on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. The credible interval includes no important difference. 6. Risk of Bias: serious. Most of the da ta on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 da y).

# Hospital length of stay

# Very low
Due to serious risk of bias, serious inconsistency, and very serious imprecision 4 The impact on hospital length of stay is v ery uncertain.

# Duration of mechanical ventilation
Lower better Based on da ta from 328 participants in 2 studies. (Randomized controlled)
Due to serious risk of bias and imprecision 5 Baricitinib may reduce duration of mechanical ventilation.

# Time to clinical stability
Due to serious risk of bias and imprecision 6 There may not be an important impact on time to clinical stability.

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19
Intervention: IL-6 receptor blockers

# Summary Evidence summary
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
The LNMA (8) on IL-6 receptor blockers was informed by 30 RCTs with 10 618 participants and provided relative estimates of effect for all patient-important outcomes except mortality, which came fr om the prospective meta-analysis (PMA) (127). Of the trials included in the LNMA, all w ere registered and e xamined patients with severe or critical illness related to COVID-19 (trial characteristics table available upon request). Of the trials, 37% w ere published in peerreviewed journals, 3% w ere available as preprints and 60% w ere completed but unpublished.
The evidence summary for mortality was based on 27 R CTs and 10 930 participan ts from the PMA (127). We used the PMA for mortality as it included some additional unpublished da ta that reported on this outc ome. The GDG recognized that usual care is likely variable between centres and regions, and has e volved over time. However, given all of the da ta come from RCTs, use o f these c o-interventions that comprise usual care would be e xpected to be balanc ed between study patients randomized to either the in tervention or usual care arms.
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of IL-6 receptor blockers compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with c ertainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
All included RCTs evaluated IL-6 receptor blockers exclusively in severely or critically ill adults with C OVID-19 requiring hospitalization. The GDG requested subgroup analyses based on ag e (< 70 y ears versus older), disease severity (severe versus critical), levels of inflammatory markers and baseline c orticosteroid use f or the following outcomes: mortality, need for and duration of mechanical v entilation, duration of hospitalization, and risks o f SAEs and bacterial infections.
Based on subgroup analyses, the GDG de termined that there was no subgroup effect across any pre-specified outcomes of interest based on disease se verity. The GDG c onsidered the results of a subgroup analysis of all included R CTs based on systemic corticosteroid use f or the outcome of mortality. The analysis suggested that the relative effects of IL-6 receptor blockers varied as a function o f the use o f systemic corticosteroids at baseline. Crucially, steroids did no t abolish and may even enhance the bene ficial effect of IL-6 receptor blockers on mortality. For reasons described below, the GDG did no t formally evaluate the credibility of this subgroup analysis.
When comparing tocilizumab and sarilumab, based on the PMA, ther e was no e vidence of a subgroup effect (127). However, there were more data, and therefore greater precision, for tocilizumab+steroids versus steroids alone (OR 0.77, 95% CI 0.68 -0.87) as c ompared with sarilumab+steroids versus steroids alone (OR 0.92, 95% CI 0.61 -1.38). In addition to these subgr oup data, the GDG r eviewed head-to-head da ta from REMAP-CAP investigators which demonstrated no difference between tocilizumab as c ompared with sarilumab in a popula tion of patients all receiving corticosteroids (36.5% mortality with tocilizumab, 33.9% mortality with sarilumab. The NMA estima te of tocilizumab+steroids versus sarilumab+steroids, incorporating both direct and indirect data, provided moderate certainty data of no diff erence between the drugs ( OR 1.07, 95% CI 0.86 -1.

# Mechanical ventilation
Odds ratio 0.72 (CI 95% 0.57 -0.9) Based on da ta from 5,686 participants in 9 studies. 2  1.. Baseline/comparator: Primary study. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19, adjusted f or corticosteroids as part o f standard of care (16% baseline risk x RR 0.79 f or corticosteroids = 13%). T he control arm of the WHO SOLID ARITY trial, performed across a wide v ariety of countries and geographical regions, w as identified by the GDG panel as g enerally representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation for severely and critically ill patients with COVID-19.
- Systematic review . Baseline/comparator: Primary study. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLID ARITY trial for patients with severe and critical COVID-19, adjusted f or corticosteroids as part of standard of care (16% baseline risk x RR 0.79 f or corticosteroids = 13%). T he control arm of the WHO SOLID ARITY trial, performed across a wide v ariety of countries and geographical regions, w as identified by the GDG panel as g enerally representing the most r elevant source of evidence for baseline risk estimates for mortality and mechanical ventilation for severely and critically ill patients with COVID-19.
- Systematic review. Baseline/comparator: Control arm of reference used f or intervention. We used the median e vent rate for all patients randomized to usual car e across included studies. Supporting references: 4. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding and asc ertainment bias. Imprecision: very serious. We downgraded due to v ery wide c onfidence intervals crossing the null. 5. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding and asc ertainment bias. Imprecision: serious. Downgraded due to wide c onfidence intervals crossing the null. 6. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding. Imprecision: serious. We downgraded as the lo wer limit of the c onfidence interval was close to the null. 7. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding. Inconsistency: serious. Downgraded due to diff erences in poin t estimates and lack o f overlap in confidence intervals.

# Adverse events leading to drug discontinuation
Odds ratio 0.5 (CI 95% 0.03 -9.08) Based on da ta from 815 participants in 2 studies. 3 (Randomized controlled)
per 1000 Difference:
per 1000 4 fewer per 1000 ( CI 95% 0 mor e -67 more

# Very low
Due to serious risk of bias and very serious imprecision 4 The effect of IL-6 receptor blockers on adverse events leading to discontinuation is uncertain.

# Bacterial infections
Due to serious risk of bias and serious imprecision 5 IL-6 receptor blockers may not increase secondary bacterial infections.

# Duration of mechanical ventilation
Lower better Based on da ta from 1,189 participants in 10 studies. (Randomized controlled)
Due to serious risk of bias and serious imprecision 6 IL-6 receptor blockers may reduce duration of mechanical ventilation.

# Duration of hospitalization

# Mechanical ventilation

# Adverse events leading to drug discontinuation

# Very low
Due to serious risk of bias and very serious imprecision 3 The effect of IL-6 inhibitors on adverse events leading to discontinuation is uncertain.

# Bacterial infections
Due to serious risk of bias and serious imprecision 4 IL-6 inhibitors may not increase secondary bacterial infections.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Mechanism of action
IL-6 is a pleio tropic cytokine which activ ates and regulates the immune response to in fections. Elevated IL-6 concentrations are associated with severe outcomes in COVID-19, including respiratory failure and dea th, although the r ole of IL-6 in disease pathogenesis is unclear.
Tocilizumab and sarilumab are monoclonal an tibodies approved for use in rheuma toid arthritis. They antagonize the membrane bound and soluble f orms of the IL-6 receptor (IL-6R/sIL-6R). Tocilizumab is approved for intravenous use in rheuma toid arthritis and sarilumab for subcutaneous use, although in C OVID-19 both have been studied in travenously. At the studied doses in COVID-19, both medicines are expected to achie ve very high levels of receptor occupancy based upon studies in rheuma toid arthritis (29). IL-6 receptor blockers are being repurposed in terms o f indication but no t in terms o f the primary pharmacological mechanism of action. E fficacy in COVID-19 depends upon the importanc e of IL-6 signalling in the pa thophysiology of the disease, rather than upon whe ther the doses used achie ve target concentrations. 1. Source: pairwise meta-analysis 2. Source: pairwise meta-analysis 3. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding and asc ertainment bias. Imprecision: very serious. We downgraded due to v ery wide c onfidence intervals crossing the null. 4. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding and asc ertainment bias. Imprecision: serious. Downgraded due to wide c onfidence intervals crossing the null. 5. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding. Inconsistency: no serious. Indirectness: no serious. Imprecision: serious. We downgraded as the lo wer limit of the c onfidence interval was close to the null. Publication bias: no serious. 6. Risk of Bias: serious. We downgraded for some c oncerns regarding risk of bias due to lack o f blinding. Inconsistency: serious. Downgraded due to diff erences in poin t estimates and lack o f overlap in confidence intervals. For patients with COVID-19, regardless of disease severity

# Duration of hospitalization

# Practical Info
The GDG made a r ecommendation against using iv ermectin for treatment of patients with COVID-19 outside the se tting of a clinical trial and therefore practical considerations are less relevant for this drug.

# Evidence To Decision

# Info Box
The recommendation concerning ivermectin was published on 31 M arch 2021 as the fourth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the increased international attention on iv ermectin as a potential therapeutic option. No changes were made to the iv ermectin recommendation in this 13th v ersion of the guideline.
We are aware of a f ew relatively small trials published since our recommendation was made and tha t one key trial has since been retracted given concerns about research fraud (128) (129). However, the upda ted evidence summary from the LNMA is consistent with our previously made recommendation.

# Only in research settings
We recommend not to use iv ermectin, except in the c ontext of a clinical trial (recommended only in r esearch settings).
Remark: This recommendation applies t o patients with an y disease se verity and an y duration of symptoms.
A recommendation t o only use a drug in the setting o f clinical trials is appr opriate when ther e is very low certainty evidence and futur e research has a lar ge potential for reducing unc ertainty about the eff ects o f the in tervention and f or doing so at r easonable c ost.
The effects of ivermectin on mortality, mechanical v entilation, hospital admission, dur ation of hospitalization and viral clearance remain uncertain because of very low certainty of evidence addressing each o f these outc omes. Ivermectin may have little or no e ffect on time to clinical impr ovement (low certainty evidence). Ivermectin may increase the risk o f SAEs leading to drug disc ontinuation (low certainty evidence).
Subgroup analyses indicated no e ffect modification based on dose. W e were unable to e xamine subgroups based on pa tient age or severity of illness due to insufficien t trial data (see Research evidence). Therefore, we assumed similar effects in all subgroups. This recommendation applies to pa tients with any disease se verity and any duration of symptoms.

# Benefits and harms
For most key outcomes, including mortality, mechanical v entilation, hospital admission, dur ation of hospitalization and viral clearance, the GDG c onsidered the e vidence of very low certainty. Evidence was rated as very low certainty primarily because of very serious imprecision for most outcomes: the aggregate data had wide c onfidence intervals and/or v ery few events. There were also serious c oncerns related to risk o f bias f or some outc omes, specifically lack o f blinding, lack o f trial pre-registration, and lack o f outcome reporting for one trial that did no t report mechanical ventilation despite pre-specifying it in their protocol (publication bias).
For more details, see the J ustification section f or this recommendation. For other outcomes, including S AEs and time to clinical improvement, the c ertainty of the e vidence was low.

# Certainty of the Evidence Justification
When moving from evidence to a r ecommendation on the use o f ivermectin in patients with COVID-19 only in the c ontext of a clinical trial, the GDG emphasized the high degr ee of uncertainty in the most critical outc omes such as mortality and need f or mechanical ventilation. It also noted the e vidence suggesting possible harm associa ted with treatment, with increased adverse events. The GDG did no t anticipate important variability in patient values and preferences. Other c ontextual factors, such as resource considerations, accessibility, feasibility and impact on health equity did no t alter the recommendation.
Compared with previous drugs evaluated as part o f the WHO Therapeutics and C OVID-19: living guideline currently there are far fewer RCT data available for ivermectin. The existing data on ivermectin also have a substantially higher degree of uncertainty, with included trials having enrolled substantially fewer patients with far f ewer events.

# High degree of uncertainty
The certainty in effect estimates for ivermectin on the main outc omes of interest, including mortality, is v ery low and therefore the effect of ivermectin on these outc omes remains uncertain. There are two domains that contribute to this uncertainty: serious risk of bias; and serious impr ecision. Although 16 R CTs contributed to the evidence summary informing this drug, only five directly compared ivermectin with standard of care and reported mortality (130)( 131) (132)(133)(134)( 135) (136). Of note, and in keeping with our me thodology, the LNMA team e xcluded quasi-randomized trials, or any RCT that did no t use e xplicit randomization techniques. O f these fiv e RCTs, two (130)(131) were at high risk of bias, due to inadequa te blinding. One of these two trials (130) also started enrolling and randomizing patients prior to the protocol being publicly posted, ano ther factor that contributes to an increased risk of bias. T he potential impact of risk of bias is e xemplified by subgroup analyses for mortality based on trial risk of bias. As demonstr ated in the f orest plot (Fig. 2), the pooled estima te across all five RCTs that directly compare ivermectin with standard care suggests a reduction in mortality with iv ermectin, but this e ffect is no t apparent if w e only consider the trials at low risk of bias (which together contribute nearly two-thirds of the e vidence). This finding increases the degree of uncertainty regarding the true e ffect of ivermectin on mortality. Consistent with the direct evidence, a similar phenomenon is observ ed with the indirect evidence comparing ivermectin to standard of care (via comparisons against hydroxychloroquine and lopinavir/ritonavir). The indirect evidence suggesting a reduction in mortality with iv ermectin is driven almost entirely by one study which is a t high risk of bias (128) due to a lack o f detailed description of blinding or randomization and the lack o f a publicly a vailable study protocol (figure not shown).
Applying the agreed values and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients would want to receive ivermectin only in the c ontext of a randomized trial, given that the evidence left a very high degree of uncertainty in effect on mortality, need f or mechanical ventilation, need f or hospitalization and o ther critical outcomes of interest and there was a possibility o f harms, such as tr eatment-associated SAEs. The panel an ticipated little variation in values and preferences between patients when it came to this in tervention.

# Values and preferences
Ivermectin is a relatively inexpensive drug and is widely a vailable, including in low-income settings. The low cost and wide availability do not, in the GDG' s view, mandate the use o f a drug in which an y benefit remains very uncertain and ongoing concerns regarding harms remain. Although the c ost may be lo w per pa tient, the GDG r aised concerns about diverting attention and resources away from care likely to provide a bene fit such as c orticosteroids in patients with severe COVID-19 and other supportive care interventions. Also, use o f ivermectin for COVID-19 would divert drug supply aw ay from pathologies for which it is clearly indica ted, potentially contributing to drug shortages, especially f or helminth control and elimination programmes. Other endemic infections that may worsen with corticosteroids should be c onsidered. If steroids are used in the tr eatment of COVID-19, empiric treatment with ivermectin may still be c onsidered in S trongyloidiasis endemic areas, at the discretion of clinicians overseeing treatment, albeit not for treatment of COVID-19 itself.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
IV: inverse variance.
In addition to c oncerns related to risk o f bias, f or the outcome of mortality, there are very serious concerns related to imprecision. According to GRADE, impr ecision is evaluated based on bo th a c onfidence interval approach and an e valuation of information size (event number), ensuring there is adequate information on which to mak e informed judgments (137). In this case, despite c onfidence intervals that suggest benefit with ivermectin, the information size is v ery low. For mortality (and ignoring the concerns related to risk o f bias discussed abo ve), there were nine dea ths across all 511 pa tients randomized to ivermectin (1.76%) and 22 dea ths across all 404 pa tients randomized to standard of care (5.45%). T his is an e xtremely small number of events on which to base c onclusions, and far belo w the op timal information size. In fact, perf orming a theoretical exercise in which a chang e of three events (deaths) is made from those randomized to standard of care to those randomized to iv ermectin eliminates any statistical significance, a finding tha t suggests that results could reasonably be due to chance alone. F urthermore, the e vidence informing this comparison is from multiple small trials, adding to the risk o f unrecognized imbalances in study arms. G iven the strong likelihood that chance may be pla ying a role in the observ ed findings, the panel believed there was very serious imprecision further lowering the overall certainty in findings.
This combination of serious risk of bias and v ery serious imprecision contributed to very low certainty of evidence for mortality despite a poin t estimate and c onfidence interval that appear to sugg est benefit with ivermectin. As a r esult, the panel c oncluded that the e ffect of ivermectin on mortality is unc ertain. Similar considerations were applied to the o ther critical outcomes including mechanical ventilation, hospital admission, and dur ation of hospitalization and resulted in very low certainty for these outcomes as w ell.

# Subgroup analyses
We conducted subgroup analysis only f or effect by ivermectin dose and the panel did no t find any evidence of a subgroup effect (see Research evidence). A lack o f within-trial comparisons prevented subgroup analyses by age or disease se verity. Therefore, the panel did no t make any subgroup recommendation for this drug. In other words, the recommendation against ivermectin except in the c ontext of clinical trials is applicable across disease se verity, age groups, and all dose r egimens of ivermectin.
None of the included R CTs enrolled children under 15, and ther efore the applicability of this recommendation to children is currently uncertain. However, the panel had no r eason to think tha t children with COVID-19 would respond any differently to treatment with ivermectin. There were similar considerations for pregnant women, with no da ta directly examining this population, but no r ationale to sugg est they would respond differently to other adults.

# Clinical Question/ PICO Population:
Patients with COVID-19 (all disease severities)

# Intervention: Ivermectin
Comparator: Standard care Fig. 2. Forest plot demonstrating direct comparison of ivermectin versus standard of care for mortality with subgroup analysis by risk of bias

# Summary Evidence summary
The LNMA on iv ermectin was based on 16 R CTs and 2407 participan ts. Of the included studies, 75% e xamined patients with non-severe disease and 25% included bo th severe and non-se vere patients. A number o f the included studies did not report on our outc omes of interest. Of the studies, 25% w ere published in peer -reviewed journals, 44% w ere available as preprints and 31% w ere completed but unpublished ( see Table on trial characteristics). We excluded a number of quasi-RCTs (138)( 139)( 140) (141).
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of ivermectin compared to usual car e for the outcomes of interest in patients with COVID-19, with c ertainty ratings. See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
The NMA team perf ormed subgroup analyses which c ould result in distinct recommendations by subgroups. From the available data, subgroup analyses were only possible b y dose o f ivermectin and considering the outcomes of mortality, mechanical ventilation, admission to hospital, and adv erse events leading to drug disc ontinuation. The ivermectin dose subgroup analyses were performed from the direct comparison of ivermectin versus usual care. For these analyses, meta-regression was used to e valuate the e ffect of cumulative dose as a c ontinuous variable, and further adding a c ovariate for single vs multiple dosing regimens. This approach was based on input fr om the pharmacology experts (led by Professor Andrew Owen) who performed pharmacokinetic simulations across trial doses, and f ound that cumulative ivermectin dose w as expected to c orrelate with key pharmacokinetic parameters when single-and multiple-dose studies were segregated. It should be no ted that the included trials did no t directly assess the pharmac okinetics of ivermectin, and our approach was based upon simula tions validated where possible against published pharmac okinetics in humans.
The panel used a pr e-specified framework incorporating the ICEMAN tool to assess the cr edibility of subgroup findings (125).
The GDG panel r equested subgroup analyses based on: ag e (considering children vs younger adults vs older adults; illness severity (non-severe vs severe vs critical COVID-19); time from onset of symptoms; and use o f concomitant medications. However, there was insufficient within-trial data to perform any of these subgroup analyses, based on our pr e-specified protocol. The panel recognized that usual care is likely variable between centres and regions, and has e volved over time. However, given all of the da ta come from RCTs, use o f these c o-interventions that comprise usual care should be balanc ed between study pa tients randomized to either the in tervention or usual care arms.

# Very low
Due to serious risk of bias and very serious imprecision 2 The effect of ivermectin on mortality is uncertain.

# Mechanical ventilation
Odds ratio 0.51 (CI 95% 0.12 -1.

# Very low
Due to v ery serious imprecision and publication bias 3 The effect of ivermectin on mechanical ventilation is unc ertain. 1. Systematic review . Baseline/comparator: Control arm of reference used f or intervention. We elected to use the control arm of the WHO SOLID ARITY trial, reflecting usual care across countries participating in the trial. 2. Risk of Bias: serious. The large trial contributing most of the e ffect estimate was driven by studies that were not blinded. Imprecision: very serious. The number o f total events was very small. 3. Imprecision: very serious. Very few events and credible intervals that include both important benefit and harm.

# Viral clearance

# Very low
Due to e xtremely serious imprecision 5 The effect of ivermectin on hospital admission is uncertain.

# Serious adverse events leading to discontinuation
Due to v ery serious imprecision 6 Ivermectin may increase the risk of serious adverse events leading to drug discontinuation.

# Time to clinical improvement
Due to v ery serious imprecision 7 Ivermectin may have little or no difference on time to clinical improvement.

# Duration of hospitalization

# Very low
Due to serious imprecision, inconsistency and serious risk of bias 8The effect of ivermectin on hospital length o f stay is unc ertain.

# Time to viral clearance

# Very low
Due to v ery serious imprecision and serious risk of bias 9 We are uncertain whether ivermectin improves or w orsens time to viral clearance.

# Mechanism of action
Ivermectin is an an tiparasitic agent that interferes with nerve and muscle function o f helminths through binding glutamate-gated chloride channels (142). Based on in vitro experiments, some ha ve postulated that ivermectin may have a direct antiviral effect against SARS-CoV-2. However, in humans the c oncentrations needed f or in vitro inhibition are unlikely to be achie ved by the doses proposed for COVID-19 (143) (144)(145). Ivermectin had no impact on S ARS-CoV-2 viral RNA in the S yrian golden hamster model of SARS-CoV-2 infection (146). The proposed mechanism remains unclear: multiple targets have been proposed based upon either analogy to o ther viruses with very different life cycles, or, like several hundred other candidates, simulations indicating molecular docking with multiple vir al targets including spike, RdRp and 3CLpro (147)(148)( 149)( 150) (151). No direct evidence for any mechanism o f antiviral action against S ARS-CoV-2 currently exists. Some have proposed, based pr edominantly upon research in o ther indications, that ivermectin has an immunomodula tory effect, but again the mechanism r emains unclear. Historical data showed that ivermectin improved survival in mice given a le thal dose of lipopolysaccharide (152), and has bene fits in murine models o f atopic dermatitis and allergic asthma (153) (154). For SARS-CoV-2, one h ypothesis suggests immunomodulation mediated by allosteric modulation of the alpha-7 nic otinic acetylcholine receptor (indirectly by modulating the activity o f ligands o f the receptor). Although investigators have demonstrated this action in vitro, concentrations used in these e xperiments have been e ven higher than those r equired for an antiviral effect (155), and therefore very unlikely to be achie ved in humans. I n the S yrian golden hamster model o f SARS-CoV-2 infection, ivermectin resulted in some chang es in pulmonary immune pheno type consistent with allosteric modulation of the alpha-7 nic otinic acetylcholine receptor (146). However, ivermectin did not appear to rescue body w eight loss which is a hallmark o f disease in this model, and drug c oncentrations were not measured to e xtrapolate to those achie ved in humans. Taken together, there remains great uncertainty regarding the relevance of any immunomodulatory or anti-inflammatory action of ivermectin.

# Hydroxychloroquine (published 17 December 2020)
- Imprecision: extremely serious. Credible interval includes important benefit and harm. 6. Imprecision: very serious. Credible interval includes little to no difference. 7. Imprecision: very serious. 8. Risk of Bias: serious. Result driven by one study that was not blinded. Inconsistency: serious. Despite overlapping confidence intervals, point estimates discrepant. Imprecision: serious. Credible intervals include no difference. 9. Risk of Bias: serious. Concerns around risk of bias. Imprecision: very serious. Credible interval includes important benefit and important harm.

# Info Box
The recommendation concerning hydroxychloroquine was published 17 D ecember 2020 as the third version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the pre-print publication of the WHO SOLID ARITY trial on 15 October 2020, reporting results on treatment with hydroxychloroquine, remdesivir and lopinavir/ritonavir in hospitalized patients with COVID-19. No changes were made to the h ydroxychloroquine recommendation in this 13th v ersion of the guideline.
For patients with COVID-19, regardless of disease severity

# Practical Info
The GDG made a str ong recommendation against using h ydroxychloroquine or chloroquine for treatment of patients with COVID-19. The use o f hydroxychloroquine may preclude the use o f other important drugs that also prolong the Q T interval, such as azithromycin and fluoroquinolones. Concomitant use o f drugs that prolong the Q T interval should be done with e xtreme caution.

# Evidence To Decision

# Strong recommendation against
We recommend not to use h ydroxychloroquine or chloroquine (strong recommendation ag ainst).
Remark: This recommendation applies t o patients with an y disease se verity and an y duration of symptoms.
Hydroxychloroquine and chloroquine probably do no t reduce mortality or mechanical ventilation and may not reduce duration of hospitalization. The evidence does no t exclude the po tential for a small increased risk of death and mechanical ventilation with h ydroxychloroquine. The effect on o ther less important outcomes, including time to s ymptom resolution, admission to hospital, and dur ation of mechanical v entilation, remains uncertain.
Hydroxychloroquine may increase the risk o f diarrhoea and nausea/v omiting; a finding c onsistent with evidence from its use in other conditions. Diarrhoea and vomiting may increase the risk o f hypovolaemia, hypotension and acute kidne y injury, especially in settings where health care resources are limited. W hether or not and to wha t degree hydroxychloroquine increases the risk o f cardiac toxicity, including life-threatening arrhythmias, is uncertain.
Subgroup analyses indicated no e ffect modification based on se verity of illness (comparing either critical vs severe/nonsevere or non-se vere vs critical/severe) or age (comparing those aged < 70 y ears vs older). Further, the cumula tive dose and predicted Day 3 serum trough concentrations did no t modify the e ffect for any outcome. Therefore, we assumed similar effects in all subgroups.
We also reviewed evidence comparing the use o f hydroxychloroquine plus azithromycin vs hydroxychloroquine alone. T here was no e vidence that the addition o f azithromycin modified the e ffect of hydroxychloroquine for any outcome (very low certainty).

# Benefits and harms
For the key outcomes of mortality and mechanical v entilation, the panel c onsidered the e vidence to be o f moderate certainty. There were residual concerns about lack o f blinding in the lar gest trials and the imprecision. For example, the credible interval around the pooled e ffect leaves open the possibility o f a v ery small reduction in mortality. The quality of evidence was low for diarrhoea and nausea/v omiting because o f lack o f blinding in man y of the trials and because the to tal number of patients enrolled in trials reporting these outc omes was smaller than the op timal information size (although the credible interval laid entirely on the side o f harm for both outcomes).
For all other outcomes, the c ertainty of the e vidence was low or v ery low. The primary concerns with the da ta were imprecision (credible intervals included both important benefit and important harm) as well as risk of bias (lack o f blinding).

# Certainty of the Evidence
Applying the agreed values and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients would not want to receive hydroxychloroquine given the e vidence suggesting there was probably no e ffect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea and v omiting. The panel did not expect there would be much v ariation in v alues and preferences between patients when it came to this in tervention.

# Values and preferences
When moving from evidence to the str ong recommendation against the use o f hydroxychloroquine or chloroquine for patients with COVID-19, the panel emphasiz ed the moderate certainty evidence of probably no reduction in mortality or need f or mechanical ventilation. It also noted the e vidence suggesting possible harm associa ted with treatment, with increased nausea and diarrhoea. The GDG did no t anticipate important variability in patient values and preferences, and o ther contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity ( see summary of these factors under Evidence to decision.

# Subgroup analyses
The panel did no t find any evidence of a subgroup effect across patients with different levels of disease se verity, between adults and older adults, and b y different doses, and ther efore did no t make any subgroup recommendation for this drug. In other words, the strong recommendation is applicable across disease se verity, age groups, and all doses and dose schedules o f hydroxychloroquine.
The trials included patients from around the w orld, with all disease se verities, and treated in different settings (outpatient and inpatient). Although the trials did no t report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease c ourse. The GDG panel ther efore felt that the evidence applies to all pa tients with COVID-19.

# Special populations
None of the included R CTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no r eason to think tha t children with COVID-19 would respond any differently to treatment with hydroxychloroquine. There were similar considerations in regards to pregnant women, with no da ta directly examining this population, but no r ationale to sugg est they would respond differently than other adults. Hydroxychloroquine crosses the placental barrier and there are concerns that it may lead to r etinal damage in neona tes. Although h ydroxychloroquine has been used in pregnant women with s ystemic autoimmune diseases, such as s ystemic lupus erythematosus, pregnant women may have even more reasons than o ther patients to be r eluctant to use h ydroxychloroquine for COVID-19.

# In combination with azithromycin
There was no e vidence from the NMA tha t the addition o f azithromycin modified the e ffect of hydroxychloroquine for any outcome. As there were no trial data suggesting that azithromycin favourably modifies the e ffect of hydroxychloroquine, the recommendation against hydroxychloroquine and chloroquine applies to pa tients whether or not they are concomitantly receiving azithromycin.
Please see end o f documen t for residual uncertainties (Section 9). T he GDG panel f elt that it was unlikely future studies w ould identify a subgroup of patients that are likely to bene fit from hydroxychloroquine or chloroquine.
Hydroxychloroquine and chloroquine are relatively inexpensive compared with o ther drugs used f or COVID-19 and are already widely available, including in low-income settings. Despite this, the panel f elt that almost all patients would choose not to use h ydroxychloroquine or chloroquine because the harms outw eigh the bene fits. Although the c ost may be lo w per patient, the GDG panel r aised concerns about diverting attention and resources away from care likely to provide a bene fit such as c orticosteroids in patients with severe COVID-19 and o ther supportive care interventions.

# Resources and other considerations

# Clinical Question/ PICO Population:
Patients with COVID-19 (all disease severities)

# Intervention: Hydroxychloroquine

# Summary Evidence summary
The LNMA on h ydroxychloroquine was based on 30 R CTs with 10 921 participan ts, providing relative estimates of effect for patient-important outcomes (see Table. Five of the trials (414 to tal participants) randomized some pa tients to chloroquine.
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of hydroxychloroquine compared with usual care for the outcomes of interest in patients with COVID-19, with c ertainty ratings. See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
For hydroxychloroquine, the GDG panel r equested subgroup analyses based on ag e (considering children vs younger adults  vs older adults, illness severity (non-severe vs severe vs critical COVID-19) and based on whe ther or not it was co-administered with azithromycin.
The panel also r equested a subgroup analysis based on high dose v s low dose h ydroxychloroquine. A ca tegorical approach to h ydroxychloroquine dosing proved impossible because the trials used v arying loading doses, c ontinuation doses and durations. Therefore, in c ollaboration with a pharmac ology expert (Professor Andrew Owen), we modelled the expected serum c oncentrations over time. We hypothesized that higher trough concentrations early in the treatment course (e.g. trough concentration on D ay 3) might be more effective than lower early trough concentrations. We also hypothesized that higher maximum serum c oncentrations (e.g. peak c oncentration on the last da y) might result in higher risk of adverse effects than lower maximum serum concentrations. In our pharmacokinetic model, the cumula tive dose was highly correlated with all measures of serum c oncentrations on D ay 3 and the final da y of treatment, and therefore we decided to use cumula tive dose as the primary analy sis. Day 3 trough concentration was least strongly correlated with total cumulative dose (R2 = 0.376) and ther efore we performed a sensitivity subgroup analysis with predicted Day 3 trough concentrations for efficacy outcomes.

# Mechanical ventilation

# Very low
Due to v ery serious imprecision 5 The effect of hydroxychloroquine on viral clearance is v ery uncertain.

# Admission to hospital
Odds ratio 0.39 (CI 95% 0.12 -1.

# Very low
Due to v ery serious imprecision and serious indirectness 6 The effect of hydroxychloroquine on admission to hospital is uncertain.
( CI 95% 41 f ewer -12 more

# Study results and measurements

# Standard care

# Hydroxychloro quine

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary

# Cardiac toxicity
Based on da ta from 3,287 participants in 7 studies. (Randomized controlled)
per 1000 Difference:
per 1000 10 more per 1000 ( CI 95% 0 mor e -30 more

# Very low
Due to serious imprecision, risk of bias, and indirectness 7 The effect of hydroxychloroquine on cardiac toxicity is uncertain.
Due to serious imprecision and risk of bias 8 Hydroxychloroquine may increase the risk o f diarrhoea.

# Nausea/ vomiting

# Very low
Due to v ery serious imprecision and serious indirectness 10 The effect of hydroxychloroquine on delirium is uncertain.

# Time to clinical improvement

# Very low
Due to serious risk of bias, imprecision, and indirectness 11 The effect of hydroxychloroquine on time to clinical improvement is uncertain.

# Duration of hospitalization

# Time to viral clearance

# Very low
Due to serious risk of bias and very serious imprecision 13 The effect of hydroxychloroquine on time to viral clearance is uncertain.
For patients with COVID-19, regardless of disease severity

# Evidence To Decision Justification
When moving from evidence to the str ong recommendation against the use o f lopinavir-ritonavir for patients with COVID-19, the panel emphasized the moderate certainty evidence of probably no reduction in mortality or need f or mechanical ventilation. It also noted the e vidence suggesting possible harm associa ted with treatment, with increased nausea and diarrhoea. T he GDG did not anticipate important variability in patient values and preferences, and o ther contextual factors, such as r esource considerations, accessibility, feasibility and impact on health equity w ould not alter the recommendation (see summary of these factors under Evidence to D ecision).

# Strong recommendation against
We recommend not to use lopina vir-ritonavir (strong recommendation ag ainst).
Remark: This recommendation applies t o patients with an y disease se verity and an y duration of symptoms.
The GDG panel f ound a lack o f evidence that lopinavir-ritonavir improved outcomes that matter to patients such as r educed mortality, need f or mechanical ventilation, time to clinical impr ovement and o thers. For mortality and need f or mechanical ventilation this w as based on moder ate certainty evidence, for the other outcomes low or v ery low certainty evidence.
There was low certainty evidence that lopinavir-ritonavir may increase the risk o f diarrhoea and nausea and v omiting, a finding consistent with the indirect evidence evaluating its use in pa tients with HIV. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension and acute kidne y injury, especially in se ttings where health care resources are limited.
There was an unc ertain effect on viral clearance and acute kidne y injury.
Subgroup analysis indicated no e ffect modification based on se verity of illness (comparing either critical vs severe/nonsevere or non-se vere vs critical/severe) or age (comparing those aged < 70 y ears versus those 70 y ears and older). As there was no e vidence of a statistical subgroup effect, we did no t formally evaluate using the ICEMAN tool.

# Benefits and harms
The evidence is based on a link ed systematic review and NMA o f seven RCTs; pooling da ta from 7429 pa tients hospitalized with various severities of COVID-19 and v ariably reporting the outcomes of interest to the guideline panel (1). The panel agreed that there was moderate certainty for mortality and need f or mechanical ventilation, low certainty for diarrhoea, nausea and duration of hospitalization and v ery low certainty in the estima tes of effect for viral clearance, acute kidney injury and time to clinical impr ovement. Most outcomes were lowered for risk of bias and impr ecision (wide confidence intervals which do no t exclude important benefit or harm).

# Certainty of the Evidence
Applying the agreed values and preferences (see Section 7), the GDG in ferred that almost all w ell-informed patients would not want to receive lopinavir-ritonavir given the e vidence suggested there was probably no e ffect on mortality or need f or mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea and v omiting. The panel did not expect there would be much v ariation in v alues and preferences between patients when it came to this in tervention.

# Values and preferences
Although the c ost of lopinavir-ritonavir is not as high as some o ther investigational drugs for COVID-19, and the drug is generally available in most health care settings, the GDG raised concerns about opportunity c osts and the importanc e of not drawing attention and resources away from best supportive care or the use o f corticosteroids in severe COVID-19.

# Resources and other considerations
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Outcome Timeframe

# Study results and measurements

# Standard care

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary

# Mechanical ventilation
Due to v ery serious imprecision 5 The effects of lopinavirritonavir on viral clearance is v ery uncertain.

# Acute kidney injury

# Very low
Due to serious risk of bias and very serious imprecision 6 The effect of lopinavirritonavir on acute kidne y injury is uncertain. Lopinavir-ritonavir may increase the risk o f diarrhoea.

# Nausea/ vomiting

# Very low
Due to serious risk of bias and very serious imprecision 9 The effect of lopinavirritonavir improves on time to clinical improvement is very uncertain.

# Duration of hospitalization
Due to serious risk of bias and imprecision 10 Lopinavir-ritonavir may have no e ffect on duration of hospitalization.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) dexamethasone is very high (that is, similar concentrations are achieved in plasma a fter oral and intravenous intake), critically ill patients may be unable to absorb an y nutrients or medications due to in testinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected.
Duration: While more patients received corticosteroids in the f orm of dexamethasone 6 mg daily f or up to 10 da ys, the to tal duration of regimens evaluated in the se ven trials varied between 5 and 14 da ys, and treatment was generally discontinued at hospital discharge (that is, the dur ation of treatment could be less than the dur ation stipulated in the pr otocols).
The once daily dexamethasone formulation may increase adherence. A dose o f 6 mg o f dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg o f hydrocortisone (that is, 50 mg e very 8 hours), 40 mg o f prednisone, or 32 mg o f methylprednisolone (8 mg e very 6 hours or 16 mg e very 12 hours).
Monitoring: It would be prudent to monitor gluc ose levels in patients with severe and critical COVID-19, regardless of whether the patient is known to ha ve diabetes.
The timing o f therapy from onset of symptoms was discussed b y the panel. T he RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy 7 da ys or more after symptom onset may be more beneficial than treatment initiated within 7 da ys of symptom onset. A post hoc subgr oup analysis within the PMA did no t support this hypothesis. While some panel members belie ved that postponing s ystemic corticosteroids until after viral replication is contained by the immune s ystem may be reasonable, many noted that, in practice, it is o ften impossible to asc ertain symptom onset and that signs o f severity often appear late (that is, deno te a c o-linearity between severity and timing). The panel concluded that, given the e vidence, it w as preferable to err on the side o f administering corticosteroids when treating patients with severe or critical COVID-19 (even if within 7 da ys of symptoms onset) and to err on the side o f not giving c orticosteroids when treating patients with non-se vere disease (even if a fter 7 days of symptoms onset).

# Evidence To Decision
Panel members who v oted for a conditional recommendation argued that the trials evaluating systemic corticosteroids for COVID-19 reported limited information regarding potential harm. Between the tw o panel mee tings, indirect evidence regarding the po tential harmful effects of systemic corticosteroids from studies in sepsis, ARDS and c ommunity-acquired pneumonia (CAP) was added to the summary o f findings table (157) (158). While generally of low certainty, these da ta were reassuring and suggested that corticosteroids are not associated with an increased risk of adverse events, beyond likely increasing the incidence of hyperglycaemia (moderate certainty evidence; absolute e ffect estimate 46 more per 1000 patients, 95% CI: 23 mor e to 72 mor e) and hypernatraemia (moderate certainty evidence; 26 more per 1000 pa tients, 95% CI: 13 more to 41 mor e). Panel members also no ted that, given the e xpected effect of systemic corticosteroids on mortality, most patients would not refuse this intervention to a void adverse events believed to be mark edly less important to most patients than death.
In contrast with new agents proposed for COVID-19, clinicians have a v ast experience of systemic corticosteroids and the panel was reassured by their overall safety profile. Moreover, the panel w as confident that clinicians using these guidelines would be aw are of additional potential side-effects and c ontraindications to s ystemic corticosteroid therapy, which ma y vary geographically in function o f endemic microbiological flora. Notwithstanding, clinicians should exercise caution in use of corticosteroids in patients with diabetes or underlying immunoc ompromise.
Ultimately, the panel made its r ecommendation on the basis o f the moder ate certainty evidence of a 28-da y mortality reduction of 8.7% in the critically ill and 6.7% in pa tients with severe COVID-19 who w ere not critically ill, respectively. In the fifth iteration of this living guideline, mortality baseline risk estima tes were updated based on the WHO SOLID ARITY trial, considered to represent the best sour ce of prognosis across countries facing the COVID-19 pandemic. T his resulted in an overall 3.3% reduction in 28-da y mortality for patients with severe or critical COVID-19, still with moder ate certainty evidence and c onsidered by the panel to r epresent a clear bene fit to patients, with no impact on the established recommendations.

# Benefits and harms
The panel took an individual pa tient perspective to v alues and preferences but, giv en the burden of the pandemic f or health

# Values and preferences
This recommendation was achieved after a vote, which c oncerned the strength of the recommendation in fa vour of systemic corticosteroids. Of the 23 v oting panel members, 19 (83%) v oted in favour of a strong recommendation, and 4 (17%) v oted in favour of a c onditional recommendation. The reasons for the four cautionary votes, which w ere shared by some panel members who voted in favour of a strong recommendation, are summarized below.
Panel members who v oted for a conditional recommendation argued that many patients who w ere potentially eligible for the RECOVERY trial were excluded from participating in the e valuation of corticosteroids by their treating clinicians and that without detailed information on the char acteristics of excluded patients, this precluded, in their opinion, a str ong recommendation. Other panel members f elt that such a pr oportion of excluded patients was the norm rather than the e xception in pragmatic trials and that, while de tailed information on the r easons for excluding patients were not collected, the main reasons for refusing to o ffer participation in the trial w ere likely related to safety concerns of stopping c orticosteroids in patients with a clear indication for corticosteroids (confirmed as per personal c ommunication from the RECOVERY Principal Investigator). Panel members noted that there are few absolute c ontraindications to a 7-10 da y course of corticosteroid therapy, that recommendations are intended for the average patient population, and tha t it is understood tha t even strong recommendations should not be applied to pa tients in whom the in tervention is c ontraindicated as de termined by the treating clinician.
Eventually, the panel c oncluded that this recommendation applies to pa tients with severe and critical COVID-19 regardless of hospitalization status. The underlying assumption is that these patients would be treated in hospitals and r eceive respiratory support in the f orm of oxygen; non-invasive or invasive ventilation if these op tions were available. Following GRADE guidanc e, in making a strong recommendation, the panel has in ferred that all or almost all fully in formed patients with severe COVID-19 would choose to tak e systemic corticosteroids. It is understood tha t even in the c ontext of a strong recommendation, the intervention may be c ontraindicated for certain patients. Absolute c ontraindications for 7-10 da y courses of systemic corticosteroid therapy are rare. In considering potential contraindications, clinicians must de termine if they warrant depriving a patient of a po tentially life-saving therapy.
The applicability of the recommendation is less clear f or populations that were under-represented in the c onsidered trials, such as children, patients with tuberculosis, and those who ar e immunocompromised. Notwithstanding, clinicians will also c onsider the risk of depriving these pa tients of potentially life-saving therapy. In contrast, the panel c oncluded that the recommendation should definitely be applied to c ertain patients who w ere not included in the trials, such as pa tients with severe and critical care systems globally, also plac ed a high v alue on resource allocation and equity. The benefits of corticosteroids on mortality was deemed o f critical importance to pa tients, with little or no an ticipated variability in their preference to be o ffered treatment if se verely ill from COVID-19.

# Resource implications, feasibility, equity and human rights
In this guideline, the panel took an individual pa tient perspective, but also plac ed a high v alue on resource allocation. In such a perspective, attention is paid to the opportunity c ost associated with the widespr ead provision of therapies for COVID-19. In contrast to other candidate treatments for COVID-19 that, generally, are expensive, often unlicensed, difficult to ob tain and require advanced medical infrastructure, systemic corticosteroids are low cost, easy to administer, and readily available globally (159). Dexamethasone and prednisolone are among the most c ommonly listed medicines in na tional essential medicines lists; listed by 95% o f countries. Dexamethasone was first listed by WHO as an essen tial medicine in 1977, while prednisolone was listed 2 y ears later (160). Accordingly, systemic corticosteroids are among a r elatively small number of interventions for COVID-19 that have the potential to reduce inequities and improve equity in health. T hose considerations influenced the strength of this recommendation.
The ease o f administration, the relatively short duration of a c ourse of systemic corticosteroid therapy, and the g enerally benign safety profile of systemic corticosteroids for up to 7-10 da ys led the panel to c onclude that the acceptability of this intervention was high.

# Resources and other considerations
COVID-19 who c ould not be hospitalized or receive oxygen because o f resource limitations.
The recommendation does no t apply to the f ollowing uses o f corticosteroids: transdermal or inhaled administration, high-dose or long-term regimens, or prophylaxis.

# Clinical Question/ PICO Population:
Patients with severe or critical COVID-19 (updated baseline mortality risk)

# Summary Evidence summary
This guideline was triggered on 22 J une 2020 b y the publication of the preliminary report of the RECOVERY trial, later published as a peer -reviewed paper (14). Corticosteroids are listed in the WHO M odel List of Essential Medicines, readily available globally at a low cost, and o f considerable interest to all stakeholder groups. The guideline panel w as informed by combining two meta-analyses which pooled da ta from eight randomized trials (7184 participants) of systemic corticosteroids for COVID-19 (1)(161). The panel discussions w ere also informed by two other meta-analyses, which were already published and pooled da ta about the sa fety of systemic corticosteroids in distinct but r elevant patient populations.
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of systemic corticosteroids compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with c ertainty ratings. Below we provide more details about the trials and me ta-analysis as w ell as a subgroup analysis that informed the recommendation. See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.
On 17 July 2020, the panel r eviewed evidence from eight RCTs (7184 patients) evaluating systemic corticosteroids versus usual care in COVID-19. RECOVERY, the largest of the se ven trials, from which mortality da ta were available by subgroup (severe and non-se vere), evaluated the e ffects of dexamethasone 6 mg giv en once daily (oral or intravenous) for up to 10 da ys in 6425 hospitalized patients in the U nited Kingdom (2104 w ere randomized to de xamethasone and 4321 were randomized to usual car e) (14). At the time o f randomization, 16% w ere receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; 60% w ere receiving oxygen only (with or without non-in vasive ventilation); and 24% w ere receiving neither.
The data from seven other smaller trials included 63 non-critically ill patients and approximately 700 critically ill patients (definitions of critical illness varied across studies). For the latter, patients were enrolled up to 9 J une 2020, and approximately four-fifths were invasively mechanically ventilated; approximately half were randomized to receive corticosteroid therapy, and half r andomized to no c orticosteroid therapy. Corticosteroid regimens included: methylprednisolone 40 mg e very 12 hours f or 3 days and then 20 mg e very 12 hours f or 3 days (GLUCOCOVID) (162); dexamethasone 20 mg daily f or 5 days followed by 10 mg daily f or 5 days (two trials, DEXA-COVID19, CoDEX) (163) (164); hydrocortisone 200 mg daily f or 4 to 7 da ys followed by 100 mg daily f or 2 to 4 da ys and then 50 mg daily for 2 to 3 da ys (one trial, CAPE-COVID) (165); hydrocortisone 200 mg daily f or 7 days (one trial, REMAP-CAP) (16); methylprednisolone 40 mg e very 12 hours f or 5 days (one trial, Steroids-SARI) (166).
Seven of the trials w ere conducted in individual c ountries (Brazil, China, Denmark, France, Spain) whilst REMAP-CAP was an international study (recruiting in 14 E uropean countries, Australia, Canada, New Zealand, Saudi Arabia and the United Kingdom). All trials reported mortality 28 days after randomization, except for one trial at 21 days and ano ther at 30 days. Because the mortality data from one trial (GLUCOCOVID, n=63) w ere not reported by subgroup, the panel reviewed only the da ta pertaining to the outc ome of mechanical v entilation from this trial (162). An additional trial, which randomized hospitalized patients with suspected S ARS-CoV-2 infection, published on 12 A ugust 2020 (MetCOVID) (167), was included as a supplemen t in the PMA publica tion, as it w as registered after the searches of trial registries were performed. The supplement showed that inclusion would not change results other than reduce inconsistency.

# Subgroup analyses
While all other trials evaluated systemic corticosteroids exclusively in critically ill patients, the RECOVERY trial enrolled hospitalized patients with COVID-19. The panel c onsidered the results of a subgroup analysis of the RECOVERY trial suggesting that the relative effects of systemic corticosteroids varied as a function o f the le vel of respiratory support received at randomization. On the basis o f the peer-reviewed criteria for credible subgroup effects (125), the panel determined that the subgroup effect was sufficiently credible to w arrant separate recommendations for severe and nonsevere COVID-19.
However, acknowledging that during a pandemic, ac cess to health care may vary considerably over time as w ell as between different countries, the panel decided against de fining patient populations concerned by the recommendations on the basis o f access to health in terventions (i.e. hospitalization and respiratory support). Thus, the panel a ttributed the effect modification in the RE COVERY trial to illness severity.
The panel also ackno wledged the e xistence of variable definitions for severity and use o f respiratory support interventions. The WHO clinical guidanc e for COVID-19 published on 27 M ay 2020 (version 3) defined severity of COVID-19 by clinical indicators, but modified the o xygen saturation threshold from 94% to 90%, in or der to align with previous WHO guidanc e (6). See Section 5 f or the WHO se verity criteria and Infographic for three disease se verity groups for which the r ecommendations apply in pr actice.
Due to serious risk of bias 3 Systemic corticosteroids probably reduce the need of mechanical ventilation.

# Gastrointestinal bleeding
Relative risk 1.06 (CI 95% 0.85 -1.33) Based on da ta from 5,403 participants in 30 studies.

# per 1000
3 more per 1000 ( CI 95% 7 f ewer -16 more
Due to serious indirectness, Due to serious imprecision 4 Corticosteroids may not increase the risk o f gastrointestinal bleeding.
Relative risk 1.01 (CI 95% 0.9 -1.13) Based on da ta from 6,027 participants in 32 studies.

# per 1000
per 1000 2 more per 1000 ( CI 95% 19 f ewer -24 more
Due to serious indirectness, Due to serious imprecision 5 Corticosteroids may not increase the risk o f super-infections.
Due to serious indirectness 6 Corticosteroids probably increase the risk o f hyperglycaemia.
Due to serious indirectness, Due to serious imprecision 9 Corticosteroids may not increase the risk o f neuropsychiatric effects.

# Duration of hospitalization
Due to serious risk of bias and serious imprecision 10 Steroids may result in an important reduction in the duration of hospitalizations.

# Conditional recommendation against
We suggest not to use s ystemic corticosteroids (conditional recommendation ag ainst).
Due to serious risk of bias 3 Systemic corticosteroids probably reduce the need for mechanical ventilation.

# Gastrointestinal bleeding
Relative risk 1.06 (CI 95% 0.85 -1.33) Based on da ta from 5,403 participants in 30 studies. 4

# per 1000
3 more per 1000 ( CI 95% 7 f ewer -16 more
Due to serious indirectness and serious imprecision 5 Corticosteroids may not increase the risk o f gastrointestinal bleeding.
Relative risk 1.01 (CI 95% 0.9 -1.13) Based on da ta from 6,027 participants in 32 studies.

# per 1000
per 1000 2 more per 1000 ( CI 95% 19 f ewer -24 more
Due to serious indirectness, Due to serious imprecision 6 Corticosteroids may not increase the risk o f super-infections.
Due to serious indirectness 7 Corticosteroids probably increase the risk o f hyperglycaemia.
Due to serious indirectness 8 Corticosteroids probably increase the risk o f hypernatremia.

# Neuromuscular weakness
Due to serious indirectness and serious imprecision 9 Corticosteroids may not increase the risk o f neuromuscular weakness.

# Neuropsychiatri c effects
Due to serious indirectness and serious imprecision 10 Corticosteroids may not increase the risk o f neuropsychiatric effects.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Methods: how this guideline was created
This living WHO guideline w as developed according to standards and me thods for trustworthy guidelines, making use o f an inno vative process to achie ve efficiency in dynamic upda ting of recommendations. The methods are aligned with the WHO Handbook for guideline development and according to a pr e-approved protocol (planning proposal) by the G uideline Review Committee (GRC) (168).

# Related guidelines
This living WHO guideline f or COVID-19 treatments is related to the larger, more comprehensive guidance for COVID-19 Clinical management: living guideline which has a wider sc ope of content and has been r egularly updated (6). The first 11 v ersions of this WHO Therapeutics and C OVID-19: living guideline addressing corticosteroids, remdesivir, hydroxychloroquine, lopinavir/ritonavir, ivermectin, IL-6 receptor blockers, casirivimab-imdevimab (neutralizing monoclonal antibodies), convalescent plasma, JAK inhibitors, sotrovimab, molnupiravir, remdesivir, nirmatrelvir-ritonavir, colchicine and fluvoxamine can be ac cessed via the WHO w ebsite (4).
Guidelines regarding the use o f drugs to pr event (rather than treat) COVID-19 are included in a separ ate document, WHO Living guideline: D rugs to prevent COVID-19, that can be ac cessed via the WHO w ebsite and the BMJ (8).
This guideline is living -dynamically upda ted and globally disseminated once new evidence warrants a chang e in recommendations (169). The aim is f or a 6-w eek timeframe from the public a vailability of trial data that trigger the guideline development process to WHO publica tion, while main taining standards for trustworthy guidelines (WHO Handbook for guideline development) (168) (170).
Stepwise approach Here we outline the appr oach, involving simultaneous processes, taken to improve efficiency and timeliness o f development and dissemination of living, trustworthy guidance.
Step 1: E vidence monitoring and mapping and trigg ering of evidence synthesis Comprehensive daily monitoring o f all emerging RCTs occurs on a c ontinuous basis, within the c ontext of the living s ystematic review and network meta-analysis (NMA), using e xperienced information specialists, who r eview all relevant information sources for new RCTs addressing interventions for COVID-19. Incorporating pre-print data, which ha ve not yet undergone peer review, promote rapid data sharing in a public health emer gency and its inclusion can ac celerate the assessment and clinical use o f COVID-19 therapeutic interventions. Guidelines are periodically updated to assess da ta that have undergone peer review in the in tervening period and ne w data. Once practice-changing evidence, or increasing international interest, are identified, the WHO T herapeutics Steering Committee triggers the guideline de velopment process. The trigger for producing or upda ting specific recommendations is based on the f ollowing (any of the three may initiate a recommendation):
- likelihood to chang e practice; - sufficient RCT data on therapeutics to in form the high-quality e vidence synthesis living systematic review; - relevance to a global audienc e.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
Step 2: C onvening the GDG WHO selected GDG members to ensur e global g eographical representation, gender balance, and appropriate technical and clinical expertise, and pa tient representatives. For each intervention, the technical unit c ollected and managed declarations of interests (DOIs) and found no GDG member and c o-chairs to have a c onflict of interest. In addition to the distribution of a DOI f orm, during the meeting, the WHO S ecretariat described the DOI pr ocess and an opportunity w as given to GDG members to declar e any interests not provided in written form. No verbal conflicts were declared. Web searches did no t identify any additional interests that could be perceived to a ffect an individual's objectivity and independenc e during the de velopment of the recommendations.
The pre-selected expert GDG (see Section 10) convened most recently in two subsequent online meetings; in 2 J une 2022 to addr ess baricitinib and sotrovimab and on 15 J uly 2022 to addr ess remdesivir. These meetings involved a review of the basics o f GRADE methodology including f ormulating population, intervention, comparator, outcome (PICO) questions and subgroups of interests, and prioritization of patient-important outcomes (see step 4 belo w). The GDG subsequen tly reviewed analyses, including pre-specified subgroup analyses presented in summary o f findings tables, considered an individual pa tient perspective and f easibility issues specific to this intervention, and f ormulated recommendations. The GDG also r eviewed the mechanism o f actions and non-clinical e vidence around safety.
For the 13th iteration of this guideline, no ne w evidence was identified that warranted a chang e in the strength or direction of recommendations for drugs currently covered in the living guideline. H owever, new evidence was identified for the use o f nirmatrelvirritonavir and its use in pr egnant and breastfeeding women (WHO Vigi Base, see justification under sec tion 6.2) as w ell as more supportive evidence for the strong recommendations against the use of monoclonal antibodies. As this evidence did not warrant a change in the existing recommendations, the GDG reviewed the new guideline content and provided feedback accordingly by email (15 December 2022). The GDG has not been convened for this iteration.

# Step 3: E vidence synthesis
The living systematic review/NMA team, as r equested by the WHO T herapeutics Steering Committee, performed an independen t systematic review to e xamine the benefits and harms of the in terventions (1). The systematic review team includes s ystematic review experts, clinical experts, clinical epidemiologists and biostatisticians. Team members have expertise in GRADE me thodology and rating certainty of evidence specifically in NMAs, including dir ect and indirect comparisons of treatment alternatives. The NMA team considered deliberations from the initial GDG mee ting, specifically focusing on the outc omes and subgroups prioritized by the GDG and produced GRADE e vidence summaries to in form development of recommendations. In situations where no head-to-head c omparisons of therapeutics were available from RCTs, the LNMA team perf ormed indirect comparisons and produced additional GRADE e vidence summaries that the GDG used to in form recommendations. The methods team rated credibility of subgroups using the ICEMAN tool (125). The technical unit collected and managed declarations of interests (DOIs) and found no s ystematic review team member to have a c onflict of interest.

# Step 4: F inal recommendations
The GRADE approach provided the framework for establishing evidence certainty and g enerating both the direction and strength of recommendations ( 171) (172). Methods and clinical c o-chairs facilitated deliberations to reach final recommendations. A priori voting rules informed procedures if the GDG failed to r each consensus by discussion; c o-chairs were not eligible to v ote in this se tting. For recommendations revised or added in the curr ent iteration, there was no need f or voting.
The following key factors informed transparent and trustworthy recommendations:
- absolute benefits and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE summary o f findings tables) ( 173); - quality/certainty of the e vidence (171)( 174); - values and preferences of patients (175); - resources and o ther considerations (including considerations of feasibility, applicability, equity) (175); - effect estimates and c onfidence intervals for each outc ome, with an associa ted rating of certainty in the e vidence, as presented in summary of findings tables. I f such da ta are not available, the GDG reviews narrative summaries (173); - recommendations are rated as either c onditional or strong, as de fined by GRADE. If the GDG members disagr ee regarding the evidence assessment or strength of recommendations, WHO will apply v oting according to established rules (172) (175).
When possible, w e used research evidence to in form discussion around these key factors. If not available, discussion of these factors was informed by expert opinion, supported b y surveys of the GDG members as outlined belo w.

# Benefits and harms
The GDG members prioritized outcomes (rating from 9  to 1  in pa tients with non-se vere COVID-19 and in patients with severe and critical COVID-19, taking a pa tient perspective (Tables 1 and 2 belo w). The GDG's questions w ere structured using the PICO format (see evidence profile under the recommendations). The prioritization was performed through a survey, most lately in May 2021, f ollowed by a GDG discussion. T hese prioritized outcomes were used to upda te the LNMA (2).
Selecting and rating the importance of outcomes GDG members prioritized outcomes from the perspectiv e of patients with non-se vere illness (Table 1) and se vere and critical illness (Table 2).  SD: standard deviation. Note: 7 to 9 -critical; 4 to 6 -importan t; 1 to 3 -o f limited importance.

# Derivation of absolute effects for drug treatments
For patients with non-se vere illness, we used the median o f the c ontrol arm of the R CTs that contributed to the evidence, identified in the LNMA (1) (2). For admission to hospital, the GDG de fined a 10% (100 admissions per 1000 pa tients) threshold for a baseline risk that would reflect an important absolute benefit for the therapeutics under consideration (i.e. 60 f ewer admissions per 1000 pa tients).
For patients with severe and critical illness, the GDG iden tified the control arm of the WHO SOLID ARITY trial, performed across a wide variety of countries and geographical regions, as representing the most r elevant source of evidence for baseline risk estimates for mortality and mechanical ventilation. Systemic corticosteroids now represent standard of care in pa tients with severe and critical COVID-19 (see strong recommendation issued b y WHO S eptember 2020). Therefore, the baseline risk estima tes in the e vidence summaries for JAK inhibitors, convalescent plasma and IL-6 receptor blockers were adjusted for treatment effects of corticosteroids for the outcome of mortality and mechanical v entilation. The applied baseline risk estima te for mortality was 13% (130 dea ths per 1000 patients). For other outcomes, w e used the median o f the c ontrol arm of the R CTs that contributed to the evidence.
Specific deliberations on baseline risk are presented for each recommendation.
The GDG ackno wledged that baseline risks, and thus absolute e ffects, may vary significantly geographically and over time. Thus, users of this guideline ma y prefer estimating absolute effects by using local e vent rates.

# Values and preferences
We had insufficient information to provide the GDG with an e vidence-based description of patient experiences or values and preferences regarding treatment decisions f or COVID-19 drug treatments. The GDG, therefore, relied on their o wn judgments of what well-informed patients would value after carefully balancing the bene fits, harms, and burdens of treatment. Judgments on v alues and preferences were crucially informed through the e xperiences of former COVID-19 patients, represented in the GDG.
The GDG agreed that the f ollowing values and preferences would be typical o f well-informed patients:
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
- Most patients would be reluctant to use a medica tion for which the e vidence left high unc ertainty regarding effects on outc omes they consider important. This was particularly so when e vidence suggested treatment effects, if the y do e xist, are small, and the possibility of important harm remains. - In an alternative situation with larger benefits and less unc ertainty regarding both benefits and harms, more patients would be inclined to choose the in tervention.
In addition to taking an individual pa tient perspective, the GDG also c onsidered a popula tion perspective in which f easibility, acceptability, equity and c ost were important considerations.
Specific deliberations on v alues and preferences and associated feasibility and resource related considerations are presented for each recommendation.
Step 5: Ext ernal and internal review An external review group reviewed the final guideline documen t to identify factual errors, and to c omment on clarity o f language, contextual issues and implications for implementation. The technical unit c ollected and managed declarations of interests (DOIs) of the external reviewers and found no e xternal reviewer to have a c onflict of interest. However, for certain therapeutics, pharmaceutical company technical representative may be asked to c omment on a ne w drug from the industry perspectiv es, in line with the WHO Handbook for guideline de velopment (page 70), as c omments from such individuals or or ganizations on a dr aft guideline may be help ful in anticipating and dealing with c ontroversy, identifying factual errors, and promoting engagement with all stakeholders. Comments on contextual issues were considered taking into account their interests. The conflict of interest of such individuals will be tr ansparent, as their affiliation will appear in the ackno wledgement section.
The guideline w as then reviewed and approved by the WHO GR C and the P ublication Review Committee.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# How to access and use this guideline
This is a living guideline fr om WHO. The recommendations included here will be upda ted, and ne w recommendations will be added f or other drugs for COVID-19.
How to access the guideline:
- WHO w ebsite in PDF f ormat (4): This is a full r ead out o f the MA GICapp content for those without reliable web access. It can also be downloaded directly from MAGICapp (see cogwheel on top righ t). - MAGICapp in online, multilayered formats: This is the fullest v ersion of the guideline, as de tailed below.
- BMJ Rapid Recommendations ( 5

# How to navigate this guideline
The guideline is written, disseminated, and upda ted in MAGICapp, with a f ormat and structure that ensures user-friendliness and ease of navigation (170). It accommodates dynamic upda ting of evidence and recommendations that can f ocus on wha t is new while keeping existing recommendations, as appropriate, within the guideline.
The purpose o f the online f ormats and additional tools, such as the in fographics, is to mak e it easier to na vigate and make use o f the guideline in busy clinical practice. The online multilayered formats are designed to allo w end-users to find r ecommendations first and then drill down to find supporting e vidence and o ther information pertinent to applying the r ecommendations in practice, including tools for shared decision-making (clinical encounter decision aids) (170).
Fig. 4 sho ws how the online multila yered formats are designed to allo w end-users to find r ecommendations first and then drill do wn to find supporting information pertinent to applying the r ecommendations in practice. End-users will also need to understand wha t is meant by strong and c onditional recommendations (displayed immediately below) and certainty of evidence (the extent to which the estimates of effect from research represent true effects from treatment).
For each recommendation additional information is available through the f ollowing tabs:
- Research evidence: Readers can find de tails about the research evidence underpinning the recommendations as GRADE S ummary of Findings tables and narr ative evidence summaries (shown in Fig. 3). - Evidence to decision: The absolute bene fits and harms are summarized, along with o ther factors such as the v alues and preferences of patients, practical issues around delivering the treatment as w ell as considerations concerning resources, applicability, feasibility, equity and human righ ts. These latter factors are particularly important for those in need o f adapting the guidelines f or the national or local context. - Justification: Explanation of how the GDG c onsidered and in tegrated evidence to decision factors when cr eating the recommendations, focussing on c ontroversial and challenging issues. - Practical information: For example, dosing, duration and administration of drugs, or ho w to apply tests to iden tify patients in practice. - Decision aids: Tools for shared decision-making in clinical enc ounters.

# Fig. 3. E xample of how research evidence is available one click away, with narrative evidence summary giving additional details to GRADE Summary of Findings table
This living guideline from WHO is also used to in form the activities o f the WHO Prequalification of Medicinal Products.
We would like to thank H etero, Dr Reddy's Laboratories and MSD (known as Merck in the United States and Canada) and Ridgeback Biotherapeutics for sharing pre-published data that were used to c onduct the me ta-analysis which in forms the ninth version of the WHO living guideline upda te.

# Lopinavir-ritonavir (published 17 December 2020) Outcome Timeframe

# Study results and measurements

# Standard care

# Hydroxychloro quine
Certainty of the Evidence (Quality of evidence)

# Plain language summary

# Adverse events leading to drug discontinuation
Based on da ta from 210 participants in 3 studies. (Randomized controlled)
Two of 108 pa tients randomized to hydroxychloroquine discontinued treatment because o f adverse effects. None of 102 pa tients did so in the placebo/standard care group.

# Very low
Due to e xtremely serious imprecision 14 The effect of hydroxychloroquine on adverse events leading to drug discontinuation is uncertain.

# Info Box
The recommendation concerning lopinavir-ritonavir was published 17 D ecember 2020 as the third version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the pre-print publication of the WHO SOLID ARITY trial on 15 October 2020, reporting results on treatment with lopinavir-ritonavir, remdesivir and hydroxychloroquine in hospitalized patients with. No changes were made to the lopina vir-ritonavir recommendation in this 13th v ersion of the guideline.

# Subgroup analysis
The panel did no t find any evidence of a subgroup effect across patients with different levels of disease se verity, or be tween adults and older adults and ther efore did no t make any subgroup recommendation for this drug. Although the trials did no t report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease c ourse. The strong recommendation is applicable across disease se verity and age groups.
None of the included R CTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no r eason to think tha t children with COVID-19 would respond any differently to treatment with lopinavir-ritonavir. There were similar considerations in regards to pregnant women, with no da ta directly examining this population, but no r ationale to sugg est they would respond differently than other adults. In patients using lopinavir-ritonavir for HIV infection, it should g enerally be continued while receiving care for COVID-19.
Please see end o f documen t for residual uncertainties (Section 9). T he GDG panel f elt that it was unlikely future studies w ould identify a subgroup of patients that are likely to bene fit from lopinavir-ritonavir.

# Additional considerations
In patients who ha ve undiagnosed or un treated HIV, use o f lopinavir-ritonavir alone may promote HIV resistance to important antiretrovirals. Widespread use o f lopinavir-ritonavir for COVID-19 may cause drug shortag es for people living with HIV.

# Clinical Question/ PICO Population:
Patients with COVID-19 (all disease severities)

# Summary Evidence summary
The LNMA on lopina vir-ritonavir was based on 7 R CTs with 7429 participan ts. Of note, none o f the included studies enrolled children or adolescents under the ag e of 19 y ears old (see Table. The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of lopinavir-ritonavir compared with usual care for the outcomes of interest in patients with COVID-19 across all disease se verities, with certainty ratings. See Section 7 f or sources of baseline risk estimates informing absolute estimates of effect.

# Subgroup analysis
For lopinavir-ritonavir, the GDG panel r equested subgroup analyses based on ag e (considering children vs younger adults  vs older adults, and illness se verity (non-severe vs severe vs critical COVID-19). The GDG discussed o ther potential subgroups of interest including time from onset of symptoms until initiation of therapy and c oncomitant medications, but recognized that these analyses would not be possible without access to individual participant data and/or more detailed reporting from the individual trials.

# Outcome Timeframe

# Study results and measurements

# Standard care

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary
Odds ratio 1 (CI 95% 0.82 -1.2) Based on da ta from 8,061 participants in 4 studies. 1

# Study results and measurements

# Standard care

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary
Difference: MD 0.3 lo wer ( CI 95% 3 lo wer -2.5 higher

# Info Box
The recommendations for corticosteroids were first published as WHO living guidelines on 2 S eptember 2020, and as BMJ Rapid Recommendations on 5 S eptember 2020. It followed the publication of the preliminary report of the RECOVERY trial, later published as a peer -reviewed paper. No changes were made to the c orticosteroids recommendations in this 13th v ersion of the guideline.
Whereas the recommendations remain unchanged, the e vidence summary for corticosteroids in patients with COVID-19 was updated before the 6th iteration of this living guideline. T he baseline risk estimates for mortality are now based on the WHO SOLIDARITY trial (as for other drugs in this guideline) (15) rather than the initial ISARIC cohort study (156) that likely overestimates current mortality risks at the global le vel. The update was also needed to in form the baseline risk f or mortality in the evidence summary informing the strong recommendation for IL-6 receptor blockers, in addition to standard of care for patients with severe or critical COVID-19, where corticosteroids provide a relative reduction in mortality by 21%.

# Strong recommendation for
We recommend treatment with systemic corticosteroids (strong recommendation f or).
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)

# Practical Info
With the c onditional recommendation against the use o f corticosteroids in patients with non-se vere COVID-19 the f ollowing practical information apply in situa tions where such treatment is to be c onsidered: Route: Systemic corticosteroids may be administered both orally and intravenously. Of note, while the bioa vailability of dexamethasone is very high (i.e. similar c oncentrations are achieved in plasma a fter oral and intravenous intake), critically ill patients may be unable to absorb an y nutrients or medications due to in testinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected.
Duration: While more patients received corticosteroids in the f orm of dexamethasone 6 mg daily f or up to 10 da ys, the to tal duration of regimens evaluated in the se ven trials varied between 5 and 14 da ys, and treatment was generally discontinued at hospital discharge (i.e. the dur ation of treatment could be less than the dur ation stipulated in the pr otocols).
The once daily dexamethasone formulation may increase adherence. A dose o f 6 mg o f dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg o f hydrocortisone (e.g. 50 mg e very 8 hours), or 40 mg o f prednisone, or 32 mg o f methylprednisolone (e.g. 8 mg e very 6 hours or 16 mg e very 12 hours). It would be prudent to monitor gluc ose levels in patients with severe and critical COVID-19, regardless of whether the patient is known to ha ve diabetes.
The timing o f therapy from onset of symptoms was discussed b y the panel. T he RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy 7 da ys or more after symptom onset may be more beneficial than treatment initiated within 7 da ys of treatment onset. A post hoc subgr oup analysis within the PMA did no t support this hypothesis. While some panel members belie ved that postponing s ystemic corticosteroids until after viral replication is contained by the immune s ystem may be reasonable, many noted that, in practice, it is o ften impossible to asc ertain symptom onset and that signs o f severity frequently appear late (i.e. deno te a c o-linearity between severity and timing). The panel concluded that, given the e vidence, it w as preferable to err on the side o f administering corticosteroids when treating patients with severe or critical COVID-19 (even if within 7 da ys of symptoms onset) and to err on the side o f not giving c orticosteroids when treating patients with non-se vere disease (even if a fter 7 days of symptoms onset).
Other endemic infections that may worsen with corticosteroids should be c onsidered. For example, for Strongyloides st ercoralis hyperinfection associated with c orticosteroid therapy, diagnosis or empiric treatment may be c onsidered in endemic ar eas if steroids are used.

# Evidence To Decision
The panel made its r ecommendation on the basis o f low certainty evidence suggesting a po tential increase of 3.9% in 28-day mortality among pa tients with COVID-19 who are not severely ill. The certainty of the e vidence for this specific subgroup was downgraded due to serious impr ecision (i.e. the e vidence does no t allow to rule out a mortality r eduction) and risk of bias due to lack o f blinding. In making a c onditional recommendation against the indiscriminate use o f systemic corticosteroids, the panel in ferred that most fully in formed individuals with non-se vere illness would not want to receive systemic corticosteroids, but man y could want to c onsider this intervention through shared decision-making with their treating physician (6) (169).
Note: WHO recommends antenatal corticosteroid therapy for pregnant women at risk of preterm birth from 24 to 34 weeks' gestation when there is no clinical e vidence of maternal infection, and adequa te childbirth and newborn care is available. However, in cases wher e the w oman presents with mild or moder ate COVID-19, the clinical bene fits of antenatal corticosteroid might outweigh the risks o f potential harm to the mo ther. In this situation, the balance of benefits and harms for the w oman and the pr eterm newborn should be discussed with the w oman to ensure an informed decision, as this assessment may vary depending on the w oman's clinical condition, her wishes and tha t of her family, and a vailable health care resources.

# Benefits and harms
See Benefits and Harms section.

# Certainty of the Evidence
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
This recommendation was achieved by consensus.
This recommendation applies to pa tients with non-se vere disease regardless of their hospitalization status. The panel no ted that patients with non-se vere COVID-19 would not normally require acute care in hospital or r espiratory support, but that in some jurisdictions, these patients may be hospitalized for isolation purposes only, in which case the y should no t be treated with systemic corticosteroids. The panel c oncluded that systemic corticosteroids should no t be stopped f or patients with non-se vere COVID-19 who are already treated with systemic corticosteroids for other reasons (e.g. pa tients with chronic obstructive pulmonary disease or o ther chronic autoimmune diseases need no t discontinue a c ourse of systemic oral corticosteroid). If the clinical condition of patients with non-se vere COVID-19 worsens (i.e. increase in respiratory rate, signs o f respiratory distress or hypoxaemia) they should receive systemic corticosteroids (see recommendation for severe and critical COVID-19).
The weak or conditional recommendation was driven by likely variation in pa tient values and preferences. The panel judg ed that most individuals with non-se vere illness would decline systemic corticosteroids. However, many may want them after shared decision-making with their tr eating physician.

# Values and preferences

# Resource implications, feasibility, equity and human rights
The panel also c onsidered that in order to help guarantee access to s ystemic corticosteroids for patients with severe and critical COVID-19, it is reasonable to avoid administering this intervention to pa tients who, giv en the current evidence, would not appear to derive any benefit from this intervention.

# Resources and other considerations

# Clinical Question/ PICO Population:
Patients with non-se vere COVID-19

# Summary Evidence summary
Please see e vidence summary above (placed under recommendation for patients with severe and critical COVID-19 to find more information about the eigh t RCTs pooled in to two systematic reviews with me ta-analysis. It also provides information about additional s ystematic reviews used to in form safety outcomes and results of subgroup analyses resulting in separate recommendations for patients with non-se vere COVID-19 and those with se vere and critical illness.
The GRADE S ummary of Findings table sho ws the relative and absolute e ffects of systemic corticosteroids compared with usual care for the outcomes of interest in patients with non-se vere COVID-19, with c ertainty ratings.

# Outcome Timeframe

# Study results and measurements

# Standard care

# Systemic corticosteroids

# Certainty of the Evidence
(Quality of evidence)

# Plain language summary

# Duration of hospitalization
Due to serious risk of bias and serious imprecision 11 Steroids may result in an important reduction in the duration of hospitalizations.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
Additional educational modules and implementation tools for health workers:
- WHO COVID-19 essential supplies forecasting tool (COVID-ESFT) assists governments, partners, and o ther stakeholders to forecast the nec essary volume of personal protective equipment, diagnostic test equipmen t, consumable medical supplies, biomedical equipment for case management, and essen tial drugs for supportive care and treatment of COVID-19. - WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation provides algorithms and practical tools for clinicians working in acute care hospitals managing adult and paedia tric patients with acute respiratory infection, including se vere pneumonia, acute respiratory distress syndrome, sepsis and sep tic shock. T his includes information on screening, testing, monitoring and treatments. - WHO Openwho.org clinical management course series hosts a full course series on COVID-19 which c overs a holistic pa thway of care for a patient, from screening and triage to rehabilitation, testing and tr eatments and palliative care. - Safety monitoring of molnupiravir for treatment of mild to moder ate COVID-19 infection in lo w and middle-inc ome countries using cohort event monitoring: a WHO study.

# Uncertainties, emerging evidence and future research
The guideline recommendations for COVID-19 therapeutics demonstrate remaining uncertainties concerning treatment effects for all outcomes of importance to pa tients. There is also a need f or better evidence on prognosis and on v alues and preferences of patients with COVID-19.
Here we outline an upda te of the key uncertainties for remdesivir, sotrovimab and casirivimab-imdevimab identified by the GDG, adding to those f or remdesivir, sotrovimab and casirivimab-imdevimab and nirmatrelvir-ritonavir, molnupiravir, JAK inhibitors, convalescent plasma, ivermectin, corticosteroids, hydroxychloroquine, lopinavir-ritonavir, and IL-6 receptor blockers identified when recommendations were initially formulated in previous versions of the living guideline. T hese uncertainties may inform future research, i.e. the pr oduction of higher c ertainty and more relevant evidence to in form policy and pr actice. We also outline emerging evidence in the rapidly changing landscape o f trials for COVID-19.

# Ongoing uncertainties and opportunities for future research
- accurate clinical prediction guides to establish the individual pa tient risk of hospitalization in pa tients presenting with non-se vere COVID-19 in order to best iden tify patients that would most bene fit from this intervention; - resistance and e fficacy against newer variants of interest; - efficacy in immunocompromised, vaccinated, children, pregnant patients, and o ther specific subgroups of patients; - optimal duration of therapy; - combination therapy with o ther COVID-19 drugs, and head-to-head c omparison against other antiviral agents;
- longer term outcomes.

# JAK inhibitors
- safety and e fficacy of combination therapy of baricitinib with corticosteroids and IL-6 receptor blockers on longer term outcomes; - safety and e fficacy in areas where certain infections such as HIV in fections, tuberculosis, and c ertain fungal infections are endemic; - relative benefits of tofacitinib and ruxolitinib to baricitinib; - safety and e fficacy in children, and pregnant and lactating women.

# Sotrovimab and c asirivimab-imdevimab
- clinical effectiveness with emerging variants; - if in vitro evidence of effectiveness with emerging variants, then dosing and administr ation routes in non-se vere and se vere/critical COVID-19 patients; - safety and e fficacy in children and pregnant women; - accurate clinical prediction guides to establish the individual pa tient risk of hospitalization in pa tients presenting with non-se vere COVID-19 in order to best iden tify patients that would most bene fit from this intervention.
The panel's recommendation reflects the panel's perception that the current evidence does no t justify using fluv oxamine to treat COVID-19. However, the panel has no t implied that fluvoxamine was proven to be ine ffective. Decisions to further investigate the effects of fluvoxamine for COVID-19 will likely hinge on ho w stakeholders perceive the opportunity c ost of investigating the e ffects of fluvoxamine over other candidate therapies. The panel discussions illuminated the f ollowing knowledge gaps:
- What are the e ffects of fluvoxamine in patients who suff er from a c ombination of non-se vere COVID-19 at risk of deteriorating and significant symptoms of anxiety? - What are the side-e ffects of fluvoxamine therapy in pa tients with non-se vere COVID-19 at risk of deteriorating? - What proportion of patients with non-se vere COVID-19 at risk of deteriorating would be ineligible due to risk o f pharmacological interactions?
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
The panel surmised tha t, in the futur e, investigators would have to carefully consider whether fluvoxamine could still be c ompared with placebo or no tr eatment given that effective treatments are available. If the rationale to further investigate fluvoxamine is its advantageous cost and availability, non-inferiority designs may be considered.
- accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention;
- resistance and efficacy against newer variants of interest;
- efficacy in immunocompromised, vaccinated, children, pregnant patients, and other specific subgroups of patients;
- optimal duration of therapy;
- combination therapy with other COVID-19 drugs, and head-to-head comparison against other antiviral agents;
- longer term outcomes.
The GDG panel belie ved that it was unlikely future studies w ould identify subgroups of patients who ma y benefit from colchicine.
- need for clinical data to investigate safety and applicability concerns (including in children, lactating or pregnant women, and men; and long-term impact on mutag enesis and canc er risk); - accurate clinical prediction guides to establish the individual pa tient risk of hospitalization in pa tients presenting with non-se vere COVID-19 in order to best iden tify patients that would most bene fit from this intervention; - data to inform individual and population-level concerns, such as the emer gence of resistance and e fficacy against new variants; - comparative effectiveness of molnupiravir compared with o ther treatment options (e.g. monoclonal an tibodies or other antivirals) in the non-se vere population, including c ombination therapy; - the relative intracellular nucleotide ratios of endogenous: molnupiravir cell lines and animal models to assess g enetic toxicity;
- how readily mutations arise under a selective pressure with NHC in vitro and molnupiravir in animal models and patients with SARS-CoV-2 infection; - if mutations arising under selective pressure in vitro, in viv o or in humans:
- confer a decreased antiviral activity for NHC;
- arise in the spike protein and/or do the y confer an increase in replicative potential/transmission;
- longer term outcomes.

# Convalescent plasma
- effects in se vere and critical illness (low to moder ate certainty evidence for most patient-important outcomes);
- long-term mortality and functional outc omes in COVID-19 survivors;
- safety and e fficacy in children, pregnant, and lactating women;
- effects of high-titre convalescent plasma on mortality and o ther patient-important outcomes;
- effects in pa tients with seronegative antibody status.

# IL-6 receptor blockers
- long-term mortality and functional outc omes in COVID-19 survivors;
- safety data in terms o f nosoc omial infections;
- data in children, pregnant patients and those tha t are already immunocompromised;
- patients with non-se vere COVID-19;
- immunity and the risk o f a subsequen t infection, which ma y impact the risk o f death after 28 days;
- outcomes by different IL-6 receptor blocker dosing and op timal timing of drug initiation.
Given the v ery low certainty in estimates for most critical outcomes of interest, the GDG f elt that further high-quality clinical trials examining this drug w ould be essen tial before any recommendation for use as part o f clinical care. This includes further RCTs examining both inpatients and outpatients and those with v arying disease severities and using different ivermectin dosing regimens. The focus of these studies should be on outc omes important to pa tients such as mortality, quality of life, need f or hospitalization, need f or invasive mechanical ventilation and time to clinical or s ymptom improvement. Also, a be tter characterization of potential harms with ivermectin in patients with COVID-19 would be important.
Although some unc ertainty remains, the GDG panel f elt that further research was unlikely to unc over a subgroup of patients that would benefit from hydroxychloroquine on the most importan t outcomes (mortality, mechanical v entilation) given the c onsistent results in trials across disease se verity and location.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO)
Although some unc ertainty remains, the GDG panel f elt that further research was unlikely to unc over a subgroup of patients that would benefit from lopinavir-ritonavir on the most importan t outcomes (mortality, mechanical v entilation) given the c onsistent results in trials across disease se verity and location.
- long-term mortality and functional outc omes in COVID-19 survivors;
- patients with non-se vere COVID-19 (i.e. pneumonia without h ypoxaemia);
- outcomes, when used in c ombination with additional therapies for COVID-19, such as no vel immunomodulators. It will become increasingly important to ascertain how these in teract with systemic corticosteroids. All investigational therapies for severe and critical COVID-19 (including remdesivir) should be c ompared with s ystemic corticosteroids or evaluated in c ombination with systemic corticosteroids vs systemic corticosteroids alone; - immunity and the risk o f a subsequen t infection, which ma y impact the risk o f death after 28 days; - outcomes, by different steroid preparation, dosing, and op timal timing of drug initiation.

# Emerging evidence
The unprecedented volume of planned and ong oing studies f or COVID-19 interventions -o ver 5000 RCTs -implies that more reliable and relevant evidence will emerge to in form policy and pr actice (13) (see appendix). An o verview of registered and ong oing trials for COVID-19 therapeutics and prophylaxis is available from the Infectious Diseases Data Observatory, through their living s ystematic review of COVID-19 clinical trial registrations (13), the WHO w ebsite and other repositories, such as the COVID-NMA initiative.
Whereas most o f these studies ar e small and o f variable methodological quality, a number o f large, international platform trials (e.g. RECOVERY, SOLIDARITY, and DISCOVERY) are better equipped to provide robust evidence for a number o f potential treatment options (14)(15)( 16) (17). Such trials can also adap t their design, recruitment strategies, and selection o f interventions based on ne w insights, exemplified by the unc ertainties outlined above.
Therapeutics and COVID-19: living guideline -W orld Health Organization (WHO) 10. Authorship, contributions, acknowledgements WHO w ould like to thank the c ollaborative efforts of all those in volved to make this process rapid, efficient, trustworthy and transparent.

# WHO Therapeutics Steering Committee (updated for baricitinib, sotrovimab and remdesivir updates)
The committee includes representatives from various WHO departments at headquarters and the regions and has been appr oved by the WHO Director of the C ountry Readiness Department, and the WHO Chie f Scientist. The WHO S ecretariat meets on a r egular basis to discuss when to trigg er guideline updates based on e vidence updates from the WHO r apid review team, and o ther sources of evidence and selects the members o f the Guideline Development Group (GDG) for the living guideline. Francois Lamontagne (corticosteroids, sotrovimab, sotrovimab updates, colchicine, fluvoxamine, casirivimab-imdevimab update, baricitinib updates, hydroxychloroquine prophylaxis).

# Clinical chairs
Heike Geduld (remdesivir update); Michael Jacobs (casirivimab-imdevimab, IL-6 receptor blockers, ivermectin, remdesivir, hydroxychloroquine, lopinavir-ritonavir, JAK inhibitors, remdesivir updates); Leticia Kawano-Dourado (convalescent plasma, sotrovimab, molnupiravir); Yee-Sin Leo (corticosteroids); Miriam Stegemann (fluvoxamine, colchicine, baricitinib updates, sotrovimab updates, nirmatrelvir-ritonavir update, casirivimab-imdevimab update).

# Methods resource persons