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Practice Rapid Recommendations

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 13 Jan 2023
Interventions Population Disease severity Non-severe Severe Critical Requires life sustaining treatment Acute respiratory distress syndrome Sepsis Septic shock Absence of signs 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 Convalescentplasma Corticosteroids Ruxolitinib and tofacitinib Should be considered only if neither baricitinib nor IL-6 receptor blockers are available Remdesivir Molnupiravir Mitigation strategies to reduce potential harms should be implemented Nirmatrelvirand ritonavir Use the interactive multiple comparison tool to compare and choose treatments Remdesivir Remdesivir All three may be combined IL-6 receptor blockers Corticosteroids Baricitinib UPDATE Pregnant or lactating women can now be offered nirmatrelvir and ritonavir in shared decision making UPDATE New evidence has demonstrated that in vitro neutralisation of currently circulating SARS-CoV-2 variants and subvariants is diminished. For those with highest risk of hospital admission The panel recommended that the intervention should be reserved for those at a risk above 10% of being admitted to hospotal with covid-19.Typical characteristics of people at high risk include: Lack of vaccination Older people Immunodeficiency Chronic diseases 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 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

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 with severeor critical 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
Recommendation 2Supportive 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

Mortality with non-severe illness5 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
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

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 severeor critical 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 severeor critical 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 duration ofhospitalizationModerateGRADE 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 ventilation3.2 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 severeor critical 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 severeor critical 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
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 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,highest admission riskWe recommend nirmatrelvir and ritonavir, for those athighest 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,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

Mortality6 fewer6.00LowMore

Based on data from 3100 patients in 2 studiesNirmatrelvir and ritonavir may have asmall effect on mortalityLowGRADE 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 trials)30 fewer355ModerateMore

Based on data from 3078 patients in 2 studiesNirmatrelvir and ritonavir probablyreduces hospital admission, for patientswith a baseline risk of 35 per 1000 (theaverage baseline risk of patientsincluded in the trials)ModerateGRADE 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

Admission to hospital (higher risk)51 fewer609ModerateMore

Based on data from 3078 patients in 2 studiesNirmatrelvir and ritonavir probablyreduces hospital admission, for patientswith a baseline risk of 60 per 1000(higher baseline risk than the averagerisk of patients included in the trials)ModerateGRADE 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

Admission to hospital (highest risk)84 fewer10016ModerateMore

Based on data from 3078 patients in 2 studiesNirmatrelvir and ritonavir probablyreduces hospital admission, for patientswith a baseline risk of 100 per 1000 (anarbitrary example of highest baselinerisk)ModerateGRADE 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

Serious adverse eventsNo important difference00HighMore

Based on data from 2246 patients in 1 studyNirmatrelvir and ritonavir has little orno risk of adverse effects leading todrug 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
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Individual considerations

Key practical issues The panel inferred that almost all well informed patients at at highest risk of hospital admission (such as unvaccinated, older, or immunosuppressed) would choose to receive nirmatrelvir and ritonavir, whereas the majority of well informed patients with a low risk of hospital admission would decline this treatment Values and preferences Nirmatrelvir and ritonavir Usual supportive care Administration should be as early as possible in the time course of the disease. In the included studies, nirmatrelvir and ritonavir was administered within five days of disease onset Use among pregnant or lactating women can be offered in shared decision making, weighing the likely benefits with the remaining uncertainty regarding undesirable effects Nirmatrelvir and ritonavir should not be offered to children 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 careMolnupiravirorPatients withnon-severe covid-19We suggest treatment with molnupiravir, for those athighest 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

Conditions for use of treatment

The panel recommended that molnupiravir should be reserved for those at a risk above 10% of being admitted to hospital with covid-19. Typical characteristics of people at high risk include: Lack of vaccination Chronic diseases Older people Immunodeficiency

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

Mortality6 fewer60LowMore

Based on data from 4796 patients in 6 studiesMolnupiravir may have a small effect onmortalityLowGRADE 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

Mechanical ventilationNo important difference88Very lowMore

Based on data from 1220 patients in 1 studyThe effect of molnupiravir on mechanicalventilation is very uncertainVery lowGRADE rating,because of:Risk of biasSeriousImprecisionExtremely 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 (risk in trials)16 fewer3519ModerateMore

Based on data from 4688 patients in 5 studiesMolnupiravir probably reduces hospitaladmission, for patients with a baselinerisk of 35 per 1000 (the averagebaseline risk of patients included inthe trials)ModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concerns