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  3. COVID-19 Pandemic, WHO COVID-19 Therapeutics Living Guidelines and uncertainties: Still further imperatives to rekindle‘Multiparameter-Based Medicine (MBM)’ and uphold ‘Non-Pharmaceutical Interventions (NPIs)’

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A living WHO guideline on drugs for covid-19

BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3379 (Published 04 September 2020) Cite this as: BMJ 2020;370:m3379
Visual summary of recommendation Last updated 10 Nov 2023
Interventions Population Disease severity Non-severe Severe Critical Requires life sustaining treatment Acute respiratory distress syndrome Sepsis Septic shock Absence of signs Risk of admissionto hospital: of severe or critical disease This recommendation applies only to people with these characteristics: Patients with confirmed covid-19 Oxygen saturation <90% on room air Signs of pneumonia Strong recommendations in favour Weak or conditional recommendations in favour Weak or conditional recommendations against Strong recommendations against Lopinavir-ritonavir Casirivimab and imdevimab Sotrovimab Hydroxychloroquine Colchicine Ivermectin Convalescentplasma Corticosteroids Ruxolitinib and tofacitinib Should be considered only if neither baricitinib nor IL-6 receptor blockers are available Remdesivir Remdesivir Molnupiravir Mitigation strategies to reduce potential harms should be implemented Remdesivir Molnupiravir Mitigation strategies to reduce potential harms should be implemented Molnupiravir Nirmatrelvirand ritonavir Nirmatrelvirand ritonavir Remdesivir Remdesivir All three may be combined IL-6 receptor blockers Corticosteroids Baricitinib M M M L L L Use the interactive multiple comparison tool to compare and choose treatments for patients at moderate or high risk of hospital admission Fluvoxamine Fluvoxamine Only in research settings The panel inferred that most patients would want to receive fluvoxamine only in the context of a randomised trial, given the uncertainty around potential benefits and the possibility of harms Convalescentplasma Only in research settings The panel inferred that most patients would want to receive convalescent plasma only in the context of a randomised trial, given the uncertainty around potential benefits and the possibility of harms There are also several practical issues related to the use of convalescent plasma, including but not limited to: Collection of plasma Storage and distribution of plasma Infusion of convalescent plasma into recipients Identification and recruitment of potential donors Only in research settings The panel inferred that most patients would want to receive ivermectin only in the context of a randomised trial, given the uncertainty around potential benefits and the possibility of harms Ivermectin Only in research settings The panel inferred that most patients would want to receive VV116 only in the context of a randomised trial, given the uncertainty around potential benefits and the possibility of harms VV116 UPDATE New recommendation UPDATE Ivermectin is no longer recommended for people with non-severe disease, even in research settings Nirmatrelvirand ritonavir H H H UPDATE The following recommendations for people with non-severe disease are now stratified by how likely it is for someone to be admitted to hospital Nirmatrelvir and ritonavir Remdesivir Molnupiravir UPDATE Low L Patients at low risk of hospital admission (0.5%)Includes people who are neither moderate nor high risk. Most patients are at low risk Moderate M Patients at moderate risk of hospital admission (3%)Includes people: over 65 years old with obesity with diabetes with active cancer with disabilities with comorbidities of chronic disease with chronic kidney or liver disease with chronic cardiopulmonary disease High H Patients at high risk of hospital admission (6%)Includes people who have: been diagnosed with immunodeficiency syndromes been diagnosed with immunodeficiency syndromes autoimmune illness, and are receiving immunosuppressants undergone sold organ transplant and are receiving immunosuppressants Signs of severe respiratory distress In adults: Accessory muscle use Inability to complete full sentences Respiratory rate > 30 breaths per minute In children: Very severe chest wall indrawing Grunting Central cyanosis Inability to breastfeed or drink Reduced level of consciousness Lethargy Convulsions

Corticosteroids

Corticosteroids Suggested regimen Acceptable alternative regimens Dexamethasone 6 mg Oral or intravenous Hydrocortisone 50 mg Intravenous Every 8 hours for 7-10 days Daily for7-10 days Every 6 hours for 7-10 days Methylprednisolone 10 mg Intravenous Daily for7-10 days Prednisone 40 mg Oral
Recommendation 1Supportive careCorticosteroidsorPatients withnon-severe covid-19We suggest no corticosteroidsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours corticosteroidsNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality5 fewer2328LowMore

Based on data from 1535 patients in 1 studyCorticosteroids may increase the risk of28-day mortality in patients withnon-severe covid-19LowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilation30 fewer11686ModerateMore

Based on data from 5481 patients in 2 studiesCorticosteroids probably reduce the needfor mechanical ventilationModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Gastrointestinal bleedingNo important difference4851LowMore

Based on data from 5403 patients in 30 studiesCorticosteroids may not increase therisk of gastrointestinal bleedingLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

SuperinfectionsNo important difference186188LowMore

Based on data from 6027 patients in 32 studiesCorticosteroids may not increase therisk of superinfectionsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hyperglycaemia46 fewer286332ModerateMore

Based on data from 8938 patients in 24 studiesCorticosteroids probably increase therisk of hyperglycaemiaModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hypernatremia26 fewer4066ModerateMore

Based on data from 5015 patients in 6 studiesCorticosteroids probably increase therisk of hypernatremiaModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Neuromuscular weaknessNo important difference6975LowMore

Based on data from 6358 patients in 8 studiesCorticosteroids may not increase therisk of neuromuscular weaknessLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Neuropsychiatric effectsNo important difference3528LowMore

Based on data from 1813 patients in 7 studiesCorticosteroids may not increase therisk of neuropsychiatric effectsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Duration of hospital stay1 fewer1312LowMore

Based on data from 6425 patients in 1 studyCorticosteroids may result in animportant reduction in the duration ofhospital stayLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See patient decision aids
See all outcomesNon-severely ill

Individual considerations

Key practical issues The panel inferred that most fully informed individuals with non-severe illness would not want to receive corticosteroids, but many could want to consider this intervention through shared decision-making with their treating physician. When treating patients with non-severe disease, even after 7 days of symptoms, the panel concluded that it was preferable to err on the side of no corticosteroids Values and preferences Corticosteroids Usual supportive care In order to help guarantee access to therapy for severe or critical covid-19 patients, it is reasonable to avoid administering corticosteroids to patients who are less likely to derive benefit No additional practical issues
Recommendation 2Supportive careCorticosteroidsorPatients with severe orcritical covid-19We recommend corticosteroidsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Conditions for use of treatment

IL-6 receptor blockers and baricitinib are also recommended, and may be administered in combination with corticosteroids. The incremental survival benefit afforded by baricitinib exists even among patients also treated with IL-6 receptor blockers and baricitinib Caution is advised when considering combinations in patients with an increased risk of opportunistic infections Consider combining medications in a stepwise fashion in patients who are deteriorating

Evidence profile

Favours supportive careFavours corticosteroidsNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality34 fewer160126ModerateMore

Based on data from 1703 patients in 7 studiesCorticosteroids probably reduce the riskof 28-day mortality in patients withcritical illness due to covid-19ModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilation30 fewer11686ModerateMore

Based on data from 5481 patients in 2 studiesCorticosteroids probably reduce the needfor mechanical ventilation at 28 daysModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Gastrointestinal bleedingNo important difference4851LowMore

Based on data from 5403 patients in 30 studiesCorticosteroids may not increase therisk of gastrointestinal bleedingLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

SuperinfectionsNo important difference186188LowMore

Based on data from 6027 patients in 32 studiesCorticosteroids may not increase therisk of superinfectionsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hyperglycaemia46 fewer286332ModerateMore

Based on data from 8938 patients in 24 studiesCorticosteroids probably increase therisk of hyperglycaemiaModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Neuromuscular weaknessNo important difference6975LowMore

Based on data from 6358 patients in 8 studiesCorticosteroids may not increase therisk of neuromuscular weaknessLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Neuropsychiatric effectsNo important difference3528LowMore

Based on data from 1813 patients in 7 studiesCorticosteroids may not increase therisk of neuropsychiatric effectsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues The panel inferred that all or almost all fully informed patients with severe or critical covid-19 would choose to take corticosteroids. In considering potential contraindications, clinicians must determine if they warrant depriving a patient from a potentially lifesaving treatment Values and preferences Corticosteroids Usual supportive care Absolute contraindications for 7 to 10 day courses of corticosteroid treatment are rare No clear differences in efficacy or adverse events between different corticosteroids Recommended regimens are available globally, and relatively inexpensive No additional practical issues

Interleukin-6 (IL-6) receptor blockers

Suggested regimen Tocilizumab Max 800 mg 8 mg per kg Intravenous Initial dose over 1 hour or Sarilumab 400 mg Intravenous Initial dose over 1 hour A second dose may be administered after 12 to 48 hours
Recommendation 1Supportive careIL-6 receptor blockersorPatients with severe orcritical covid-19We recommend treatment with IL-6 receptor blockers(tocilizumab or sarilumab)StrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Conditions for use of treatment

Corticosteroids and baricitinib are also recommended, and may be administered in combination with baricitinib. The incremental survival benefit afforded by baricitinib exists even among patients also treated with corticosteroids and baricitinib Caution is advised when considering combinations in patients with an increased risk of opportunistic infections Consider combining medications in a stepwise fashion in patients who are deteriorating

Evidence profile

Favours supportive careFavours IL-6 receptor blockersNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality15 fewer130115HighMore

Based on data from 6526 patients in 17 studiesIL-6 receptor blockers reduce mortalityHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilation23 fewer8663HighMore

Based on data from 5686 patients in 9 studiesIL-6 receptor blockers reduce the needfor mechanical ventilationHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference95Very lowMore

Based on data from 815 patients in 2 studiesThe effect of IL-6 receptor blockers onserious adverse events is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Bacterial infectionsNo important difference10196LowMore

Based on data from 3548 patients in 18 studiesIL-6 receptor blockers may not increasesecondary bacterial infectionsLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Duration of ventilation1.2 fewer14.713.5LowMore

Based on data from 1189 patients in 10 studiesIL-6 receptor blockers may reduceduration of mechanical ventilationLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Length of hospital stay4.5 fewer12.88.3LowMore

Based on data from 6665 patients in 9 studiesIL-6 receptor blockers may reduce lengthof hospital stayLowGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencySeriousPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues The benefit of IL-6 receptor blockers on mortality was deemed of critical importance to patients, despite the small magnitude of effect and the very low certainty around serious adverse events. A majority of the panel inferred that almost all well informed patients would want to receive IL-6 receptor blockers Values and preferences IL-6 receptor blockers Usual supportive care Caution is advised when considering the use of tocilizumab in patients with a history of recurring or chronic infections All patients should be monitored for signs and symptoms of infection No additional practical issues

Janus kinase (JAK) inhibitors

Suggested regimen Baricitinib 4 mg Oral Daily Ruxolitinib 5 mg Oral Twice daily Tofacitinib 10 mg Oral Twice daily For 14 days or until hospital discharge
Recommendation 1Supportive careBaricitiniborPatients with severe orcritical covid-19We recommend treatment with baricitinibStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Conditions for use of treatment

Corticosteroids and IL-6 receptor blockers are also recommended, and may be administered in combination with baricitinib. The incremental survival benefit afforded by baricitinib exists even among patients also treated with corticosteroids and IL-6 receptor blockers Caution is advised when considering combinations in patients with an increased risk of opportunistic infections Consider combining medications in a stepwise fashion in patients who are deteriorating

Evidence profile

Favours supportive careFavours baricitinibNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality20 fewer130110HighMore

Based on data from 10815 patients in 4 studiesBaricitinib reduces mortalityHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilation11 fewer116105ModerateMore

Based on data from 8412 patients in 3 studiesBaricitinib probably reduces mechanicalventilationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference05ModerateMore

Based on data from 1611 patients in 2 studiesBaricitinib probably results in littleor no increase in adverse effectsleading to discontinuationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityDays (median/mean)

Hospital length of stay1.4 fewer12.811.4ModerateMore

Based on data from 2652 patients in 3 studiesBaricitinib probably reduces length ofhospital stayModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Duration of mechanical ventil...3.2 fewer14.711.5ModerateMore

Based on data from 328 patients in 2 studiesBaricitinib probably reduces duration ofmechanical ventilationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Time to clinical stability1 fewer9.98.9LowMore

Based on data from 2558 patients in 2 studiesBaricitinib may reduce time to clinicalstabilityLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues The panel inferred that most patients would want to receive baricitinib. The benefit on mortality was deemed of critical importance to patients and the panel was reassured by the moderate certainty evidence of little or no increase in serious adverse events Values and preferences Baricitinib Usual supportive care Administered as a pill, but can be crushed and administered by a nasogastric or gastrostomy tube Baricitinib must be adjusted for patients who have renal impairment Baricitinib has not been studied in patients with severe hepatic impairment Baricitinib may cause leucopenia, lymphopenia, thrombocytosis, anaemia, clotting abnormalities, hepatic impairment, and secondary infection No additional practical issues
Recommendation 2Supportive careRuxolitiniborPatients with severe orcritical covid-19We suggest not using ruxolitinibStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Conditions for use of treatment

Clinicians should only consider using ruxolitinib if neither baricitinib nor IL-6 receptor blockers (tocilizumab or sarilumab) are available

Evidence profile

Favours supportive careFavours ruxolitinibNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference130115Very lowMore

Based on data from 472 patients in 2 studiesThe effect of ruxolitinib is veryuncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference116108Very lowMore

Based on data from 472 patients in 2 studiesThe effect of ruxolitinib is veryuncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference05LowMore

Based on data from 484 patients in 1 studyRuxolitinib may not result in anincrease in serious adverse eventsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityDays (median/mean)

Length of hospital stayNo important difference12.811.4Very lowMore

Based on data from 472 patients in 2 studiesThe impact of ruxolitinib on length ofhospital stay is very uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Time to clinical stabilityNo important difference9.99.8Very lowMore

Based on data from 472 patients in 2 studiesThe impact of ruxolitinib on time toclinical stability is very uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

The panel inferred that, given the uncertain benefits and the possibility of serious adverse events, the majority of patients would not want ruxolitinib. However, a minority of patients might choose to receive it if neither baricitinib nor IL-6 receptor blockers were available. Values and preferences
Recommendation 3Supportive careTofacitiniborPatients with severe orcritical covid-19We suggest not using tofacitinibStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Conditions for use of treatment

Clinicians should only consider using tofacitinib if neither baricitinib nor IL-6 receptor blockers (tocilizumab or sarilumab) are available

Evidence profile

Favours supportive careFavours tofacitinibNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference13078Very lowMore

Based on data from 289 patients in 1 studyThe effect of tofacitinib is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference11668Very lowMore

Based on data from 289 patients in 1 studyThe effect of tofacitinib is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse events77 fewer077LowMore

Based on data from 284 patients in 1 studyTofacitinib may increase serious adverseeventsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityDays (median/mean)

Length of hospital stay1.1 fewer12.811.7LowMore

Based on data from 289 patients in 1 studyTofacitinib may reduce length ofhospital stayLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
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Individual considerations

The panel inferred that, given the uncertain benefits and the possibility of serious adverse events, the majority of patients would not want tofacitinib. However, a minority of patients might choose to receive them if neither baricitinib nor IL-6 receptor blockers were available Values and preferences

Nirmatrelvir and ritonavir

Suggestedregimen Nirmatrelvir and ritonavir Nirmatrelvir 300 mg Ritonavir 100 mg Oral Every 12 hoursfor 5 days Nirmatrelvir and ritonavir Nirmatrelvir 150 mg Ritonavir 100 mg Oral Every 12 hoursfor 5 days With renalinsufficiencyGFR 30-59 ml/min
Recommendation 1Supportive careNirmatrelvir and ritonavirorNon-severe covid-19,high admission riskWe recommend nirmatrelvir and ritonavir, for those athigh risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Recommendation 2Supportive careNirmatrelvir and ritonavirorNon-severe covid-19,moderate admission riskWe suggest nirmatrelvir and ritonavir, for those atmoderate risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Recommendation 3Supportive careNirmatrelvir and ritonavirorNon-severe covid-19,low admission riskWe suggest no nirmatrelvir and ritonavir, for thoseat low risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours nirmatrelvir and ritonavirNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality (low risk)No important difference0.50.02HighMore

Based on data from 2224 patients in 1 studyNirmatrelvir/ritonavir does not resultin an important reduction on mortalityfor those at low risk of hospitaladmissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (low risk)No important difference50.7HighMore

Based on data from 3078 patients in 2 studiesNirmatrelvir/ritonavir does not resultin an important reduction in hospitaladmission for those at low risk ofhospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (moderate risk)No important difference30.1HighMore

Based on data from 2224 patients in 1 studyNirmatrelvir/ritonavir does not resultin an important reduction on mortalityfor those at moderate risk of hospitaladmissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (moderate...25 fewer305HighMore

Based on data from 3078 patients in 2 studiesNirmatrelvir/ritonavir reduces hospitaladmission for those at moderate risk ofhospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (high risk)6 fewer60ModerateMore

Based on data from 2224 patients in 1 studyNirmatrelvir/ritonavir probably reducesmortality for those at high risk ofhospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (high risk)51 fewer609HighMore

Based on data from 3078 patients in 2 studiesNirmatrelvir/ritonavir reduces hospitaladmission for those at high risk ofhospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo data--NoneMore

Based on data from 0 patients in 0 studiesThe effect of nirmatrelvir/ritonavir onmechanical ventilation is unknownNoneGRADE rating,because of:Risk of biasNAImprecisionNAIndirectnessNAInconsistencyNAPublication biasNAGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference00HighMore

Based on data from 2224 patients in 1 studyNirmatrelvir/ritonavir does not resultin an important increase in adverseeffects leading to drug discontinuationHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom resolutionNo important difference99LowMore

Based on data from 662 patients in 1 studyNirmatrelvir/ritonavir may not reducetime to symptom resolutionLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
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Individual considerations

Key practical issues The panel inferred that:• Almost all well informed patients at high risk of hospital admission would choose to receive nirmatrelvir and ritonavir. • Among patients at moderate risk, many patients would choose the same, but a minority would not.• Among patients at low risk, many patients would choose not to receive nirmatrelvir and ritonavir, though an appreciable minority may choose to do so. Values and preferences Nirmatrelvir and ritonavir Usual supportive care Nirmatrelvir and ritonavir in general represents a superior choice to remdesivir and molnupiravir, the former involving intravenous administration and the latter because of concerns about potential harms and a smaller reduction in risk of hospital admission Clinicians should engage pregnant or breastfeeding women in fully informed shared decision making Patients should receive nirmatrelvir and ritonavir as soon as possible after onset of symptoms, ideally within 5 days of symptom onset Clinicians need to give serious consideration to drug interactions No additional practical issues

Molnupiravir

Suggested regimen Molnupiravir 800 mg Oral Every 12 hoursfor 5 days
Recommendation 1Supportive careMolnupiravirorNon-severe covid-19,high admission riskWe suggest treatment with molnupiravir, for those athigh risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Recommendation 2Supportive careMolnupiravirorNon-severe covid-19,moderate admission riskWe suggest no treatment with molnupiravir, for thoseat moderate risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Recommendation 3Supportive careMolnupiravirorNon-severe covid-19,low admission riskWe recommend no treatment with molnupiravir, forthose at low risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours molnupiravirNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality (low risk)No important difference0.50.1HighMore

Based on data from 30332 patients in 9 studiesMolnupiravir does not have an importantimpact on mortality for those at lowrisk of hospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (low risk)No important difference53HighMore

Based on data from 30221 patients in 8 studiesMolnupiravir does not result in animportant reduction in hospitaladmission for those at low risk ofhospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (moderate risk)No important difference30.6HighMore

Based on data from 30332 patients in 9 studiesMolnupiravir does not have an importantimpact on mortality for those atmoderate risk of hospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (moderate...No important difference3019ModerateMore

Based on data from 30221 patients in 8 studiesMolnupiravir probably does not result inhospital admission for those at moderaterisk of hospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (high risk)5 fewer61ModerateMore

Based on data from 30332 patients in 9 studiesMolnupiravir probably has a marginaleffect on mortality for those at highrisk of hospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (high risk)21 fewer6039ModerateMore

Based on data from 30221 patients in 8 studiesMolnupiravir probably reduces hospitaladmission for those at high risk ofhospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference2914LowMore

Based on data from 2746 patients in 3 studiesThere may be no important effect ofmolnupiravir on mechanical ventilationLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference00HighMore

Based on data from 5383 patients in 9 studiesThere is no important difference inadverse effects leading to drugdiscontinuationHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

MalignancyNo data--NoneMore

Based on data from 0 patients in 0 studiesThe effect of molnupiravir on cancer isuncertainNoneGRADE rating,because of:Risk of biasNAImprecisionNAIndirectnessNAInconsistencyNAPublication biasNAGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityDays (median/mean)

Time to symptom resolution2.7 fewer96.3ModerateMore

Based on data from 22245 patients in 5 studiesMolnupiravir probably reduces durationof symptomsModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
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Individual considerations

Key practical issues The panel inferred that:• The panel inferred that most well informed patients at high risk of hospital admission would choose molnupiravir over standard care.• Most well informed patients at moderate risk of hospital admission, and almost all or all patients at low risk of the same, would decline use of molnupiravir. Values and preferences Molnupiravir Usual supportive care Patients should receive molnupiravir as soon as possible after onset of symptoms, ideally within 5 days from symptom onset Use of molnupiravir should be accompanied by mitigation strategies such as avoiding the drug in younger adults, children and pregnant patients, active pharmacovigilance programmes, and monitoring viral polymerase and spike sequences Nirmatrelvir/ritonavir and remdesivir both generally represent superior choices to molnupiravir. This is because of a greater reduction in risk of hospital admission in patients at high risk of admission with both drugs, and because of safety concerns with molnupiravir Longer term harms of molnupiravir remain unknown in the absence of clinical evidence, both for individual patients and at the population level No additional practical issues

Remdesivir

Suggested regimen Remdesivir 200 mg Intravenous Remdesivir 100 mg Intravenous Daily on days 2 and 3 then Patients with non-severe covid-19 Remdesivir 100 mg Intravenous Daily from day 2 up to 5-10 days Patients with severe or critical covid-19 On thefirst day
Recommendation 1Supportive careRemdesivirorNon-severe covid-19,high admission riskWe suggest treatment with remdesivir, for those athigh risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Recommendation 2Supportive careRemdesivirorNon-severe covid-19,moderate admission riskWe suggest no treatment with remdesivir, for those atmoderate risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Recommendation 3Supportive careRemdesivirorNon-severe covid-19,low admission riskWe recommend no treatment with remdesivir, for thoseat low risk of hospital admissionStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours remdesivirNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality (low risk)No important difference0.50.33HighMore

Based on data from 2946 patients in 6 studiesRemdesivir has little or no impact onmortality for those at low risk ofhospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (low risk)No important difference51HighMore

Based on data from 562 patients in 1 studyRemdesivir has little or no impact onadmission to hospital for those at lowrisk of hospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (moderate risk)No important difference32ModerateMore

Based on data from 2946 patients in 6 studiesRemdesivir may have little or no impacton mortality for those at moderate riskof hospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (moderate...22 fewer308ModerateMore

Based on data from 562 patients in 1 studyRemdesivir probably reduces admission tohospital for those at moderate risk ofhospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (high risk)No important difference64ModerateMore

Based on data from 2946 patients in 6 studiesRemdesivir may have little or no impacton mortality for those at high risk ofhospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (high risk)44 fewer6016ModerateMore

Based on data from 562 patients in 1 studyRemdesivir probably reduces admission tohospital for those at high risk ofhospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference2920LowMore

Based on data from 2952 patients in 5 studiesRemdesivir may have little or no impacton mechanical ventilationLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference04Very lowMore

Based on data from 1846 patients in 4 studiesThe impact on adverse events leading todiscontinuation is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom resolutionNo important difference98.6LowMore

Based on data from 1200 patients in 3 studiesRemdesivir may have little or no impacton time to symptom resolutionLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencySeriousPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
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Individual considerations

Key practical issues The panel inferred that:• Most well informed patients at high risk of hospital admission would choose to receive remdesivir rather than standard care, but an appreciable minority would decline. • Among patients at moderate risk of hospital admission, most patients would choose not to receive remdesivir, though a minority would choose to do so. • Among patients at low risk of hospital admission, all or almost all patients would decline remdesivir. Values and preferences Remdesivir Usual supportive care Administration via intravenous infusion Remdesivir should be administered as soon as possible after onset of symptoms, ideally within 7 days May be relatively costly, and there may be limited availability Not a significant inducer or inhibitor of CYP enzymes but should be monitored when co-administrated with strong inducers or inhibitors Caution with significant liver or renal disease It may be reasonable to monitor patients for a brief period following infusion Any health care workers administering the infusions should follow recommended infection prevention and control recommendations in the outpatient setting Insufficient evidence to make a recommendation around the use of remdesivir in children; further studies are needed Remdesivir is likely to be the desirable option in patients for whom nirmatrelvir and ritonavir or molnupiravir are not options Clinicians should engage pregnant or breastfeeding women in fully informed shared decision making, including discussing whether the potential benefit justifies the potential risk to the mother and fetus Nirmatrelvir and ritonavir may represent a superior choice to remdesivir because of the practical difficulty that arises from the intravenous administration of remdesivir No additional practical issues
Recommendation 4Supportive careRemdesivirorPatients with severecovid-19We suggest treatment with remdesivirStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours remdesivirNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality13 fewer130117LowMore

Based on data from 6631 patients in 5 studiesRemdesivir may reduce mortalityLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencySeriousPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilation14 fewer116102ModerateMore

Based on data from 6620 patients in 5 studiesRemdesivir probably reduces mechanicalventilationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom improvementNo important difference9.99.2ModerateMore

Based on data from 2599 patients in 2 studiesRemdesivir probably has little or noimpact on time to symptom improvementModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
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Individual considerations

Key practical issues The panel inferred that the majority of well informed patients with severe covid-19 would want to receive remdesivir owing to the possible reduction in mortality and need for invasive mechanical ventilation Values and preferences Remdesivir Usual supportive care Administration via intravenous infusion Optimal timing, duration and dosing remain unclear May be relatively costly, and there may be limited availability Caution with significant liver or renal disease Not a significant inducer or inhibitor of CYP enzymes but should be monitored when co-administrated with strong inducers or inhibitors No additional practical issues
Recommendation 5Supportive careRemdesivirorPatients with criticalcovid-19We suggest not using remdesivirStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours remdesivirNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference386420LowMore

Based on data from 1012 patients in 3 studiesRemdesivir may have little or no impacton mortalityLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencySeriousPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Invasive mechanical ventilationNo important difference316309LowMore

Based on data from 285 patients in 1 studyRemdesivir may have little or no impacton invasive mechanical ventilationLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom improvementNo important difference9.910.3Very lowMore

Based on data from 2599 patients in 1 studyThe impact of remdesivir is veryuncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues The panel inferred that the majority of well-informed patients with critical covid-19 would not want to receive remdesivir owing to little or no impact on important outcomes including mortality and need for invasive mechanical ventilation Values and preferences Remdesivir Usual supportive care Administration via intravenous infusion Optimal timing, duration and dosing remain unclear May be relatively costly, and there may be limited availability Not a significant inducer or inhibitor of CYP enzymes but should be monitored when co-administrated with strong inducers or inhibitors No additional practical issues Caution with significant liver or renal disease

VV116

No suggested regimen
Recommendation 1Supportive careVV116orPatients with covid-19at any severityWe recommend not using VV116, except inthe context of a clinical trialStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Rationale

When formulating this recommendation, the panel emphasised the high degree ofuncertainty in critical outcomes including mortality and hospital admission. Thepanel was informed by only a single randomised controlled trial comparing VV116to nirmatrelvir and ritonavir, as opposed to standard of care or placebo

Evidence profile

Favours supportive careFavours vv116No important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality (low risk)No important difference0.50Very lowMore

Based on data from 771 patients in 1 studyThe effect of VV116 on mortality is veryuncertain for people at low risk ofadmission to hospitalVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (low risk)No data5-NoneMore

Based on data from 0 patients in 0 studiesThe effect of VV116 on admission tohospital is unknown for people at lowrisk of admission to hospitalNoneGRADE rating,because of:Risk of biasNAImprecisionNAIndirectnessNAInconsistencyNAPublication biasNAGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (moderate risk)No important difference30Very lowMore

Based on data from 771 patients in 1 studyThe effect of VV116 on mortality is veryuncertain for people at moderate risk ofadmission to hospitalVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (moderate...No data30-NoneMore

Based on data from 0 patients in 0 studiesThe effect of VV116 on admission tohospital is unknown for people atmoderate risk of admission to hospitalNoneGRADE rating,because of:Risk of biasNAImprecisionNAIndirectnessNAInconsistencyNAPublication biasNAGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (high risk)No important difference60Very lowMore

Based on data from 771 patients in 1 studyThe effect of VV116 on mortality is veryuncertain for people at high risk ofadmission to hospitalVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (high risk)No data60-NoneMore

Based on data from 0 patients in 0 studiesThe effect of VV116 on admission tohospital is unknown for people at highrisk of admission to hospitalNoneGRADE rating,because of:Risk of biasNAImprecisionNAIndirectnessNAInconsistencyNAPublication biasNAGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo data--NoneMore

Based on data from 0 patients in 0 studiesThe effect of VV116 on mechanicalventilation is unknownNoneGRADE rating,because of:Risk of biasNAImprecisionNAIndirectnessNAInconsistencyNAPublication biasNAGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse effectsNo important difference00HighMore

Based on data from 771 patients in 1 studyThere is little or no difference inadverse effects leading to drugdiscontinuationHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom resolutionNo important difference99Very lowMore

Based on data from 771 patients in 1 studyThe effect of VV116 on time to symptomresolution is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

The panel anticipated little variation in values and preferences between patients when it came to this intervention Values and preferences

Ivermectin

No suggested regimen
Recommendation 1Supportive careIvermectinorPatients withnon-severe covid-19We recommend not using ivermectinStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Rationale

The panel emphasised the very low likelihood of benefit given both evidence fromrandomised trials and the lack of biological basis for any effect of ivermectinon the virus, combined with probable (although modest) harm associated withtreatment.

Evidence profile

Favours supportive careFavours ivermectinNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality (low risk)No important difference0.50.37HighMore

Based on data from 3050 patients in 9 studiesIvermectin does not result in animportant reduction in mortality forthose at low risk of hospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (low risk)No important difference64HighMore

Based on data from 2316 patients in 4 studiesIvermectin does not result in animportant reduction in hospitaladmission for those at low risk ofhospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (moderate risk)No important difference32.19HighMore

Based on data from 3050 patients in 9 studiesIvermectin does not result in animportant reduction in mortality forthose at moderate risk of hospitaladmissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (moderate...No important difference3020ModerateMore

Based on data from 2316 patients in 4 studiesIvermectin probably does not result inan important reduction in hospitaladmission for those at moderate risk ofhospital admissionModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mortality (high risk)No important difference64.39HighMore

Based on data from 3050 patients in 9 studiesIvermectin does not result in animportant reduction in mortality forthose at high risk of hospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission (high risk)19 fewer6041LowMore

Based on data from 2316 patients in 4 studiesIvermectin may reduce hospital admissionfor those at high risk of hospitaladmissionLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference2922ModerateMore

Based on data from 2806 patients in 9 studiesIvermectin probably does not result inan important reduction in mechanicalventilationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse events10 fewer010ModerateMore

Based on data from 1332 patients in 6 studiesIvermectin probably results in anincrease in adverse events leading todiscontinuationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom resolutionNo important difference10.79.73ModerateMore

Based on data from 2816 patients in 5 studiesIvermectin probably does not reduceduration of symptomsModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Length of hospital stayNo important difference10.8810.03ModerateMore

Based on data from 383 patients in 3 studiesIvermectin probably does not reducelength of hospital stayModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes
Recommendation 2Supportive careIvermectinorPatients with severe orcritical covid-19We recommend not using ivermectin,except in research settingsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Rationale

The panel emphasised the high degree of uncertainty in the most criticaloutcomes such as mortality and mechanical ventilation. It also noted theevidence suggesting possible harm associated with treatment, with increasedadverse events

Evidence profile

Favours supportive careFavours ivermectinNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality56 fewer7014Very lowMore

Based on data from 1419 patients in 7 studiesThe effect of ivermectin on mortality isuncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilation10 fewer2010Very lowMore

Based on data from 687 patients in 5 studiesThe effect of ivermectin on mechanicalventilation is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasSeriousGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Viral clearanceNo important difference500618LowMore

Based on data from 625 patients in 6 studiesIvermectin may increase or have noeffect on viral clearanceLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencySeriousPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Hospital admission32 fewer5018Very lowMore

Based on data from 398 patients in 1 studyThe effect of ivermectin on hospitaladmission is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionEXTREME_SERIOUSIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse events18 fewer927LowMore

Based on data from 584 patients in 3 studiesIvermectin may increase the risk ofserious adverse events leading to drugdiscontinuationLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to clinical improvementNo important difference1110.5LowMore

Based on data from 633 patients in 2 studiesIvermectin may have little or nodifference on time to clinicalimprovementLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Length of hospital stay1.1 fewer12.811.7Very lowMore

Based on data from 252 patients in 3 studiesThe effect of ivermectin on hospitallength of stay is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencySeriousPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Time to viral clearanceNo important difference7.35.7Very lowMore

Based on data from 559 patients in 4 studiesWe are uncertain whether ivermectinimproves or worsens time to viralclearanceVery lowGRADE rating,because of:Risk of biasSeriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Fluvoxamine

No suggested regimen
Recommendation 1Supportive careFluvoxamineorPatients withnon-severe covid-19We recommend not to use fluvoxamine,except in research settingsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours fluvoxamineNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference43ModerateMore

Based on data from 1649 patients in 2 studiesThere is probably little or nodifference in mortalityModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference1813LowMore

Based on data from 1649 patients in 2 studiesThere may be little or no difference inmechanical ventilationLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital (risk in t...10 fewer3525LowMore

Based on data from 2196 patients in 3 studiesFluvoxamine may reduce hospitaladmission, for patients with a baselinerisk of 35 per 1000 (the averagebaseline risk of patients included inthe trials)LowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital (higher ...17 fewer6043LowMore

Based on data from 2196 patients in 3 studiesFluvoxamine may reduce hospitaladmission, for patients with a baselinerisk of 60 per 1000 (higher baselinerisk than the average risk of patientsincluded in the trials)LowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital (highes...28 fewer10072LowMore

Based on data from 2196 patients in 3 studiesFluvoxamine may reduce hospitaladmission, for patients with a baselinerisk of 100 per 1000 (an arbitraryexample of highest baseline risk)LowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

The panel inferred that almost all well informed patients would choose not to receive fluvoxamine based on available evidence Values and preferences

Convalescent plasma

No suggested regimen
Recommendation 1Supportive careConvalescent plasmaorPatients withnon-severe covid-19We recommend against administering convalescentplasma for treatment of covid-19StrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours convalescent plasmaNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference22HighMore

Based on data from 1672 patients in 6 studiesConvalescent plasma does not result inan important impact on mortalityHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference43ModerateMore

Based on data from 715 patients in 4 studiesConvalescent plasma probably does notimpact mechanical ventilationModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Viral clearance168 more500668LowMore

Based on data from 431 patients in 2 studiesConvalescent plasma may increase viralclearance at 7 daysLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Circulatory overload6 fewer06ModerateMore

Based on data from 1665 patients in 5 studiesConvalescent plasma probably results ina small increase intransfusion-associated circulatoryoverload (TACO) within 28 daysModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Acute lung injuryNo important difference01ModerateMore

Based on data from 1365 patients in 4 studiesConvalescent plasma probably does notresult in an important increase intransfusion-related acute lung injury(TRALI) within 28 daysModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Allergic reactionsNo important difference24ModerateMore

Based on data from 15 243 patients in 8 studiesConvalescent plasma probably does notresult in an important increase inallergic reactions within 28 daysModerateGRADE rating,because of:Risk of biasBorderlineImprecisionBorderlineIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues Most patients would decline convalescent plasma given the lack of benefit in any important outcomes Values and preferences Convalescent plasma Usual supportive care Identification and recruitment of potential donors Collection of plasma Storage and distribution of plasma Infusion of convalescent plasma into recipients No additional practical issues
Recommendation 2Supportive careConvalescent plasmaorPatients with severe orcritical covid-19We recommend against using convalescentplasma, except in research settingsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Conditions for use of treatment

The panel inferred that most patients would want to receive convalescent plasma only in research settings, given the uncertainty around potential benefits and the possibility of harms.

Evidence profile

Favours supportive careFavours convalescent plasmaNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference130120LowMore

Based on data from 14 809 patients in 14 studiesConvalescent plasma may have a small orno effect on mortalityLowGRADE rating,because of:Risk of biasBorderlineImprecisionBorderlineIndirectnessBorderlineInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference8682LowMore

Based on data from 862 patients in 7 studiesConvalescent plasma may not impactmechanical ventilationLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Circulatory overload6 fewer06ModerateMore

Based on data from 1665 patients in 5 studiesConvalescent plasma probably results ina small increase intransfusion-associated circulatoryoverload (TACO) within 28 daysModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Acute lung injuryNo important difference01ModerateMore

Based on data from 1365 patients in 4 studiesConvalescent plasma probably does notresult in an important increase intransfusion-related acute lung injury(TRALI) within 28 daysModerateGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Allergic reactionsNo important difference24ModerateMore

Based on data from 15 243 patients in 8 studiesConvalescent plasma probably does notresult in an important increase inallergic reactions within 28 daysModerateGRADE rating,because of:Risk of biasBorderlineImprecisionBorderlineIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to symptom improvementNo important difference15.015.0LowMore

Based on data from 472 patients in 3 studiesConvalescent plasma may not affect timeto symptom improvementLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Length of hospital stayNo important difference11.711.0LowMore

Based on data from 1769 patients in 10 studiesConvalescent plasma may not affectlength of hospital stayLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Ventilator-free daysNo important difference13.713.0LowMore

Based on data from 1873 patients in 4 studiesConvalescent plasma may not affect thenumber of ventilator-free daysLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues Most patients would decline convalescent plasma given the lack of benefit in any important outcomes. Use could be considered as part of a clinical trial Values and preferences Convalescent plasma Usual supportive care Identification and recruitment of potential donors Collection of plasma Storage and distribution of plasma Infusion of convalescent plasma into recipients No additional practical issues

Colchicine

No suggested regimen
Recommendation 1Supportive careColchicineorPatients withnon-severe covid-19We recommend against treatment withcolchicineStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours colchicineNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference43ModerateMore

Based on data from 17914 patients in 10 studiesColchicine probably has little or noimpact on mortalityModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference97ModerateMore

Based on data from 12746 patients in 5 studiesColchicine probably has little or noimpact on mechanical ventilationModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital (risk in t...No important difference3524ModerateMore

Based on data from 4949 patients in 3 studiesColchicine probably has little or noimpact on hospital admission, forpatients with a baseline risk of 35 per1000 (the average baseline risk ofpatients included in the trials)ModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital (higher ...No important difference6042ModerateMore

Based on data from 4949 patients in 3 studiesColchicine probably has little or noimpact on hospital admission, forpatients with a baseline risk of 60 per1000 (higher baseline risk than theaverage risk of patients included in thetrials)ModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital (highes...No important difference10070LowMore

Based on data from 4949 patients in 3 studiesColchicine may have little or no impacton hospital admission, for patients witha baseline risk of 100 per 1000 (anarbitrary example of highest baselinerisk)LowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse events34 fewer034LowMore

Based on data from 598 patients in 5 studiesColchicine may increase the risk ofadverse effects leading to drugdiscontinuationLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

The panel inferred that almost all well informed patients would choose not to receive colchicine based on available evidence Values and preferences

Hydroxychloroquine

No suggested regimen
Recommendation 1Supportive careHydroxychloroquineorPatients with covid-19at any severityWe recommend against administeringhydroxychloroquine or chloroquineStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours hydroxychloroquineNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference106116ModerateMore

Based on data from 10 859 patients in 29 studiesHydroxychloroquine probably does notreduce mortalityModerateGRADE rating,because of:Risk of biasBorderlineImprecisionBorderlineIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference105123ModerateMore

Based on data from 6379 patients in 5 studiesHydroxychloroquine probably does notreduce mechanical ventilationModerateGRADE rating,because of:Risk of biasBorderlineImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Viral clearance at 7 daysNo important difference483502Very lowMore

Based on data from 280 patients in 2 studiesThe effect of hydroxychloroquine onviral clearance is very uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospitalNo important difference4719Very lowMore

Based on data from 465 patients in 1 studyThe effect of hydroxychloroquine onadmission to hospital is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Cardiac toxicityNo important difference4656Very lowMore

Based on data from 3287 patients in 7 studiesThe effect of hydroxychloroquine oncardiac toxicity is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Diarrhoea106 fewer149255LowMore

Based on data from 979 patients in 6 studiesHydroxychloroquine may increase the riskof diarrhoeaLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Nausea or vomiting62 fewer99161LowMore

Based on data from 1429 patients in 7 studiesHydroxychloroquine may increase the riskof nausea or vomitingLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

DeliriumNo important difference6295Very lowMore

Based on data from 423 patients in 1 studyThe effect of hydroxychloroquine ondelirium is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to clinical improvementNo important difference11.09.0Very lowMore

Based on data from 479 patients in 5 studiesThe effect of hydroxychloroquine on timeto clinical improvement is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Length of hospital stayNo important difference12.812.9LowMore

Based on data from 5534 patients in 5 studiesHydroxychloroquine may have no effect onlength of hospital stayLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Time to viral clearanceNo important difference9.710.6Very lowMore

Based on data from 440 patients in 5 studiesThe effect of hydroxychloroquine on timeto viral clearance is uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityTotal number per arm

Serious adverse eventsNo important difference20Very lowMore

Based on data from 210 patients in 3 studiesThe effect of hydroxychloroquine onadverse events leading to drugdiscontinuation is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionExtremely seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues The panel inferred that almost all well informed patients would not want to receive hydroxychloroquine given there are probably no positive effects and there was a risk of adverse events. The panel did not expect there would be much variation in values and preferences between patients for this intervention Values and preferences Hydroxychloroquine Usual supportive care Should be used with caution in patients with a history of tachyarrhythmias or ventricular tachycardia/fibrillation, prolonged QT interval, or who are prescribed other medications that prolong the QT interval Most patients should have renal and hepatic monitoring No additional practical issues

Lopinavir-ritonavir

No suggested regimen
Recommendation 1Supportive careLopinavir-ritonavirorPatients with covid-19at any severityWe recommend against administeringlopinavir-ritonavirStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours supportive careFavours lopinavir-ritonavirNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

MortalityNo important difference106106ModerateMore

Based on data from 8061 patients in 4 studiesLopinavir-ritonavir probably does notreduce mortalityModerateGRADE rating,because of:Risk of biasBorderlineImprecisionBorderlineIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Mechanical ventilationNo important difference105120ModerateMore

Based on data from 7579 patients in 3 studiesLopinavir-ritonavir probably does notreduce mechanical ventilationModerateGRADE rating,because of:Risk of biasBorderlineImprecisionBorderlineIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Viral clearance at 7 daysNo important difference483246Very lowMore

Based on data from 171 patients in 1 studyThe effect of lopinavir-ritonavir onviral clearance is uncertainVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Acute kidney injuryNo important difference4525Very lowMore

Based on data from 259 patients in 2 studiesThe effect of lopinavir-ritonavir onacute kidney injury is uncertainVery lowGRADE rating,because of:Risk of biasVery seriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Diarrhoea168 fewer67235LowMore

Based on data from 370 patients in 4 studiesLopinavir-ritonavir may increase therisk of diarrhoeaLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Nausea or vomiting160 fewer17177LowMore

Based on data from 370 patients in 4 studiesLopinavir-ritonavir may increase therisk of nausea or vomitingLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
Evidence qualityMean days

Time to clinical improvementNo important difference11.010.0Very lowMore

Based on data from 199 patients in 1 studyThe effect of lopinavir-ritonavir ontime to clinical improvement is veryuncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionVery seriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Length of hospital stayNo important difference12.812.5LowMore

Based on data from 5239 patients in 2 studiesLopinavir-ritonavir may have no effecton length of hospital stayLowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

Key practical issues The panel inferred that almost all well informed patients would not want to receive lopinavir-ritonavir given there are probably no positive effects and there was a risk of adverse events. The panel did not expect there would be much variation in values and preferences between patients for this intervention Values and preferences lopinavir-ritonavir Usual supportive care Should be used with caution in those with severe hepatic impairment Contraindicated in breastfeeding mothers Risk of drug-drug interactions with potent CYP3A inducers No additional practical issues

Casirivimab and imdevimab

No suggested regimen
Recommendation 1Supportive careCasirivimab and imdevimaborPatients with covid-19at any severityWe recommend against treatment withcasirivimab-imdevimabStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Individual considerations

Justification The panel concluded that, in the absence of compelling evidence of clinical effectiveness for the currently circulating SARS-CoV-2 variants, almost all well-informed patients would choose to not receive casirivimab-imdevimab Values and preferences The panel reviewed additional in vitro neutralisation data that included information on new variants. This incremental evidence strengthened the panel’s confidence that the strong recommendation not to use casirivimab-imdevimab is applicable to the current SARS-CoV2 ecology

Sotrovimab

No suggested regimen
Recommendation 1Supportive careSotrovimaborPatients withnon-severe covid-19We recommend against treatment withsotrovimabStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Individual considerations

The panel inferred that, in the absence of compelling evidence of clinical effectiveness for the currently circulating SARS-CoV-2 variants, almost all well-informed patients would not choose to receive sotrovimab Values and preferences Justification The panel reviewed additional in vitro neutralisation data that included information on new variants. This incremental evidence strengthened the panel’s confidence that the strong recommendation not to use sotrovimabis applicable to the current SARS-CoV2 ecology

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Rapid Response:

COVID-19 Pandemic, WHO COVID-19 Therapeutics Living Guidelines and uncertainties: Still further imperatives to rekindle‘Multiparameter-Based Medicine (MBM)’ and uphold ‘Non-Pharmaceutical Interventions (NPIs)’

Dear Editor

The ‘Global Strategies’ for ‘COVID-19 Pandemic Control’ involve ‘Global Solidarity’ integrating ‘COVID-19 Pharmaceuticals’-‘Non-Pharmaceutical Interventions (NPIs)’. The ‘COVID-19 Pharmaceuticals’ include: Drugs-Antivirals, Monoclonal Antibodies, Convalescent Plasma-Serum and Vaccines. This ‘Communication’ concerns ‘WHO Living Guidelines on COVID-19 Therapeutics’; the ‘12th Version’-‘11th Update’ with the ‘Clinical Question’: ‘The Role of Drugs in the Treatment of COVID-19 Patients’[1]. ‘Living Guidelines’ are developed by continuously dynamically incorporating emerging ‘New-Best Available Research Evidence (BARE)’[2,3] from the over 5000 ‘Registered On-going Clinical Trials’[4] to formulate the ‘Guidelines-Recommendations’. The ‘BARE’ accrues from ‘Systematic Reviews and Meta-Analyses (SRMA)’. The BARE and SRMA have been critically disposed in previous ‘Communications’; not a ‘Sine Qua Non’ to undergird ‘Guidelines-Recommendations Development’[5-16]. Some of the Clinical Trials reportedly did not have ‘Satisfactory Population Diversity’ with under-representation of some ‘Vulnerable Groups’: Immunocompromised Patients at risk for Opportunistic Infections especially where HIV and Tuberculosis are prevalent; ‘SARS-CoV-2 Variants-Subvariants Issues’ too. Also, better evidence is reportedly needed on ‘Patient Values and Preferences’ for ‘COVID-19’. It is, therefore, not surprising that several ‘WHO Living Guidelines’ have ‘Recommendations’ tagged with ‘Uncertainties’[1].

The ‘Guidelines’ dispose the ‘COVID-19 Classification’ (Non-Severe, Severe and Critical Disease) with the ‘Indicated Criteria’ and the ‘Guidelines-Recommendations’ are: ‘Strong, Weak and Conditional’ and they are disposed ‘For or Against’ named/ listed ‘Drugs/ Antivirals’ in defined ‘COVID-19 Severity’[1]. The ‘Recommendations Quality’ reflect considerations of ‘Relative Benefits and Harms’-‘Values and Preferences’-‘Feasibility Issues’-‘Key Outcomes’-‘Equity and Human Rights’-‘Mortality’-‘Mechanical Ventilation’-‘Cost-Benefit Analyses’ etc. For instance, Remdesivir, and in combination with Corticosteroids, Interleukin-6 (IL-6) Receptor Blockers (Tocilizumab and Sarilumab), Janus Kinase (JAK) Inhibitors (Baricitinib), reportedly has ‘Strong Recommendation’ for ‘Severe and Critical Covid-19’ and Remdesivir has ‘Conditional Recommendation’ for ‘Severe COVID-19’ while it has ‘Conditional Recommendation’ against use in ‘Critical COVID-19’[1].The combination of IL-6 Receptor Blockers and JAK Inhibitors with Corticosteroids has ‘Recommendation’ for ‘Severe and Critical COVID-19’ BUT Neutralizing Monoclonal Antibodies (Sotrovimab and Casirivimab-Indevimab) have ‘Strong Recommendations’ against use in ‘COVID-19’ replacing the previous ‘Conditional Recommendation’ for use[1]. There is reportedly ‘Recommendation’ against the following in ‘COVID-19’: Lopinavir-Ritonavir, Convalescent Plasma, Colchicine, Ivermectin, Hydroxychloroquine, Sotrovimab, Casirivimab-Indevimab; some used only in ‘Research Trials’[1].

It is reported that if ‘Neutralizing Monoclonal Antibodies’ have ‘No In-Vitro Activity’, they are not likely to have ‘Clinical Efficacy’ BUT for those with ‘In-Vitro Activity’, RCTs are recommended to confirm ‘Clinical Value’[1]. Also, ‘anti-Coagulation Therapy’ in’COVID-19’ is scheduled for further evaluation in ‘Future Guidelines Update’[1].

Concerning ‘Uncertainties’, the ‘Living Guidelines’ counsel the ‘Treating Clinician’s Perception’ to become ‘Determinant’ for ‘Patient Care Decision-making’. Here lies the imperative to ‘Rekindle’ the ‘Multiparameter-based Medicine (MBM)’ as it recognizes ‘Expert Opinion/ Clinical Experience’ in addition to ‘Other Spheres of Influence’[6, 10-16].The MBM is a ‘Welcome Locus’ on the ‘Evidence-based Medicine (EBM) Improvement Movement’ towards achieving the envisioned ‘Optimal Patient Care’ and in this circumstance: ‘Optimal Treatment of COVID-19 Patients’.

Also, with the ‘Uncertainties’, which are the resultant of the ‘BARE and SRMA Difficulties’, the ‘Attending Treating Clinician’ is cautiously, constantly and carefully ‘Counselled to Take Responsibility’ for the ‘Ultimate Care of the Patient’ and the ‘Responsible Guidelines Development Group (GDG), WHO, BMJ Publishing Group Ltd, MAGICapp, MATCH-IT etc’ depose ‘Not Accepting Any Responsibility’ for ‘Patient Outcomes’ from the ‘Guidelines Use’; WHO encourages ‘Recommendations’-Adaptation’-‘Contextualization’ for ‘Maximized-Impact’. This is tantamount to ‘Corporate Indemnifying Disclaimer’ and is a ‘Clarion Call’ for ‘Measured and Guided Use’ of ‘Published and Disseminated Guidelines’ for the desired ‘Optimal Patient Care’.

In the circumstance that even the ‘12th Updated WHO COVID-19 Therapeutics Living Guidelines’ are replete with ‘Recommendations’ with some tagged with ‘Uncertainties’, the dictum ‘Prevention is Better than Cure’ holds sway and, therefore, the imperative to ‘Prevent COVID-19’ by upholding the ‘Non-Pharmaceutical Interventions (NPIs)’ MUST be urgently rekindled[17-19].

REFERENCES
1. Agarwal A, Rochwerg B, Lamontagne F et al. A living WHO guidelines on drugs for covid-19. BMJ 2020; 370:m3379
2. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ2020;370:m2980. doi:10.1136/bmj.m2980 pmid:32732190
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18. Eregie C.O. COVID-19 Pandemic, COVID-19 Vaccines and Rapidly Transmuting SARS-CoV-2 Variants/ Sub-variants: The Quest for Pan-Sarbecoviruses Vaccine Variants; A Further Imperative to Guard Against Global Interventional Precocity in Downing Guards. https://www.bmj.com/content/377/bmj.o1257/rr-0 of 17th June 2022
19. Eregie C.O. ‘COVID-19 pandemic, Immunity and Infectivity: evolving facts support the imperative for sustained compliance with non-pharmaceutical interventions’. https://www.bmj.com/content/378/bmj-2020-061402/rr-1 of 23rd July 2022

Professor Charles Osayande Eregie,
MBBS, FWACP, FMCPaed, FRCPCH (UK), Cert. ORT (Oxford), MSc (Religious Education),
Professor of Child Health and Neonatology, University of Benin, Benin City, Nigeria.
Consultant Paediatrician and Neonatologist, University of Benin Teaching Hospital, Benin City, Nigeria.
UNICEF-Trained BFHI Master Trainer,
ICDC-Trained in Code Implementation,
*Technical Expert/ Consultant on the FMOH-UNICEF-NAFDAC Code Implementation Project in Nigeria,
*No Competing Interests.

Competing interests: No competing interests

17 October 2022
CHARLES OSAYANDE EREGIE
MEDICAL DOCTOR
Professor of Child Health and Neonatology, University of Benin, Benin City, Nigeria and Consultant Paediatrician and Neonatologist, University of Benin Teaching Hospital, Benin City, Nigeria
Institute of Child Health, University of Benin, PMB 1154, Benin City, Nigeria.