Covid-19 living Data

Pharmacologic treatments for covid-19 patients

Lopinavir + Ritonavir vs Standard care

This comparison will not be updated. Last search date 14 Dec, 2022.

Outpatients

Forest plots
(last update: 2022-04-15)

Summary of findings
(last update: 2022-09-27)

Patient or population: COVID-19 patients
Setting: Worldwide
Intervention: Lopinavir + Ritonavir
Comparison: Standard care

Outcome	Relative effect (95% CI)	Absolute effect (95% CI)¹		Certainty of the Evidence (GRADE)
Clinical improvement D28	Outcome not yet measured or reported
Clinical improvement D60	Outcome not yet measured or reported
Hospitalisation or death	RR: 3.00 (0.12 - 72.20)	Absolute effects were not calculated due to zero events in the control group		Very low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Serious despite a multicentre design this is a single study from a single country, therefore results in this population might not be generalizable to other settings. Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
1 trials Lowe DM, 2022 120 participants		Lopinavir + Ritonavir 0 per 1,000 ( - )	Standard care 0 per 1,000
WHO progression score (level 7 or above) D28	Outcome not yet measured or reported
WHO progression score (level 7 or above) D60	Outcome not yet measured or reported
All-cause mortality D28	RR: ( - )	Zero events in both groups		Very low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Serious despite a multicentre design this is a single study from a single country, therefore results in this population might not be generalizable to other settings. Imprecision: Very serious no events in both groups
1 trials Lowe DM, 2022 120 participants		Lopinavir + Ritonavir 0 per 1,000 ( - )	Standard care 0 per 1,000
All-cause mortality D60	RR: 1.86 (0.17 - 20.38)	4 more per 1000 (from 4 fewer to 85 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Serious despite a multicentre design this is a single study from a single country, therefore results in this population might not be generalizable to other settings. Imprecision: Serious due to wide confidence interval consistent with the possibility for no effect/trivial effect and the possibility for harm
1 trials Reis G, 2021 471 participants		Lopinavir + Ritonavir 8 per 1,000 (1 - 90)	Standard care 4 per 1,000
Viral negative conversion D7	RR: 1.03 (0.87 - 1.22)	14 more per 1000 (from 62 fewer to 104 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
2 trials Lowe DM, 2022; Reis G, 2021 591 participants		Lopinavir + Ritonavir 488 per 1,000 (412 - 578)	Standard care 474 per 1,000
Adverse events	RR: 1.62 (1.34 - 1.96)	184 more per 1000 (from 101 more to 284 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
2 trials Lowe DM, 2022; Reis G, 2021 591 participants		Lopinavir + Ritonavir 480 per 1,000 (397 - 580)	Standard care 296 per 1,000
Serious adverse events	RR: 1.60 (0.81 - 3.14)	25 more per 1000 (from 8 fewer to 89 more)		Moderate certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Serious due to wide confidence interval consistent with the possibility for no effect/trivial effect and the possibility for harm
2 trials Lowe DM, 2022; Reis G, 2021 591 participants		Lopinavir + Ritonavir 67 per 1,000 (34 - 131)	Standard care 42 per 1,000

¹The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Hospitalized patients

Forest plots
(last update: 2022-04-29)

Summary of findings
(last update: 2022-09-23)

Patient or population: COVID-19 patients
Setting: Worldwide
Intervention: Lopinavir + Ritonavir
Comparison: Standard care

Outcome	Relative effect (95% CI)	Absolute effect (95% CI)¹		Certainty of the Evidence (GRADE)
Clinical improvement D28	RR: 0.99 (0.90 - 1.09)	7 fewer per 1000 (from 70 fewer to 63 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Despite some concerns with deviations from intended intervention, outcome measurement and selection of reported results, not downgraded for risk of bias because the studies with these concerns contributed only a small proportion of weight to the effect estimate Inconsistency: Serious Inconsistency downgraded by 1 level: I²=60.2% Indirectness: Not serious Imprecision: Serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm. Only downgraded one level because already downgraded for inconsistency.
3 trials Cao B, 2020; Horby P, 2020; Ader F, 2022 5541 participants		Lopinavir + Ritonavir 693 per 1,000 (630 - 763)	Standard care 700 per 1,000
Clinical improvement D60	Outcome not yet measured or reported
WHO progression score (level 7 or above) D28	RR: 1.02 (0.72 - 1.46)	4 more per 1000 (from 50 fewer to 82 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
3 trials Cao B, 2020; Yueping, 2020, Ader F, 2021 552 participants		Lopinavir + Ritonavir 182 per 1,000 (128 - 261)	Standard care 178 per 1,000
WHO progression score (level 7 or above) D60	RR: 1.17 (0.93 - 1.48)	48 more per 1000 (from 20 fewer to 136 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns regarding deviation from intended intervention and missing data Inconsistency: Not serious Indirectness: Not serious Multicentre study conducted across several countries, therefore not downgraded for indirectness Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
1 trials Arabi Y, 2021 645 participants		Lopinavir + Ritonavir 332 per 1,000 (264 - 420)	Standard care 284 per 1,000
All-cause mortality D28	RR: 1.02 (0.92 - 1.12)	4 more per 1000 (from 15 fewer to 23 more)		Moderate certainty Reasons to downgrade Risk of bias: Not serious Despite some concerns with deviations from intervention, not downgraded for risk of bias because the studies with these concerns contributed only a small proportion of the data Inconsistency: Not serious Indirectness: Not serious Imprecision: Serious due to wide confidence interval consistent with the possibility for benefit and the possibility for harm
4 trials Cao B, 2020; Horby P, 2020; Yueping L, 2020, Pan H, 2020 8030 participants		Lopinavir + Ritonavir 195 per 1,000 (176 - 214)	Standard care 191 per 1,000
All-cause mortality D60	RR: 1.33 (0.67 - 2.63)	28 more per 1000 (from 28 fewer to 139 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Multicentre study conducted across several countries, therefore not downgraded for indirectness Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
1 trials Ader F, 2022 302 participants		Lopinavir + Ritonavir 114 per 1,000 (57 - 225)	Standard care 86 per 1,000
Viral negative conversion D7	RR: 1.05 (0.88 - 1.25)	25 more per 1000 (from 60 fewer to 126 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
3 trials Cao B, 2020; Yueping, 2020, Ader F, 2021 345 participants		Lopinavir + Ritonavir 528 per 1,000 (443 - 629)	Standard care 503 per 1,000
Adverse events	RR: 1.10 (0.99 - 1.23)	60 more per 1000 (from 6 fewer to 139 more)		Low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns regarding deviations from intended intervention, outcome measurement and selection of the reported results Inconsistency: Not serious Indirectness: Not serious Imprecision: Serious due to wide confidence interval consistent with the possibility for no effect/trivial effect and the possibility for harm
3 trials Cao B, 2020; Yueping, 2020, Ader F, 2021 552 participants		Lopinavir + Ritonavir 662 per 1,000 (596 - 741)	Standard care 602 per 1,000
Serious adverse events	RR: 1.06 (0.62 - 1.82)	9 more per 1000 (from 60 fewer to 129 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns regarding deviation from intended intervention, outcome measurement and selection of the reported results Inconsistency: Serious Inconsistency downgraded by 1 level: I²=:66.4% Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
4 trials Cao B, 2020; Yueping, 2020, Ader F, 2021; Arabi Y, 2021 1197 participants		Lopinavir + Ritonavir 167 per 1,000 (98 - 287)	Standard care 158 per 1,000

¹The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CI: Confidence interval; RR: Risk ratio

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Permanent URL for this comparison: https://covid-nma.com/living_data/index.php?comparison=1

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Trial	Funding	Comparisons		Design	Participants	Sample size	Overall risk of bias Highest assessment	Full description
		Treatment 1	Treatment 2
NCT04499677 FLARE Lowe DM, PLoS Med, 2022 Full text Full text Commentary Commentary Commentary	Mixed	Favipiravir Lopinavir + Ritonavir Lopinavir + Ritonavir + Favipiravir Favipiravir	Placebo Placebo Placebo Lopinavir + Ritonavir	RCT	Outpatients with confirmed COVID-19 (mild) treated by 2 centers in the UK	N=240	Some concerns Details	Full description
NCT02735707 Arabi Y, Intensive Care Med, 2021 Full text Commentary	Mixed	Lopinavir + Ritonavir Hydroxychloroquine Hydroxychloroquine+Lopinavir+Ritonavir Lopinavir + Ritonavir Lopinavir + Ritonavir Hydroxychloroquine	Standard care Standard care Standard care Hydroxychloroquine Hydroxychloroquine+Lopinavir+Ritonavir Hydroxychloroquine+Lopinavir+Ritonavir	RCT	Patients with suspected or confirmed COVID-19 (critical) admitted to a multiple centers in Australia, Canada, France, Germany, Ireland, Netherlands, New Zealand, Portugal, Saudi Arabia, UK, and USA	N=726	Some concerns Details	Full description
NCT04403100 TOGETHER Reis G, JAMA, 2021 Full text Commentary Commentary	Public/non profit	Lopinavir-Ritonavir Hydroxychloroquine Lopinavir-Ritonavir	Placebo Placebo Hydroxychloroquine	RCT	Outpatients with confirmed COVID-19 (mild) treated at local public health facilities in 10 cities in Brazil	N=685	Some concerns Details	Full description
NCT04315948 DisCoVeRy Ader F, medRxiv, 2022 Full text Full text Commentary Commentary Commentary	Mixed	Lopinavir-Ritonavir Lopinavir-Ritonavir+Interferon beta-1a Hydroxychloroquine Lopinavir-Ritonavir Lopinavir-Ritonavir Lopinavir-Ritonavir+Interferon beta-1a	Standard care Standard care Standard care Lopinavir-Ritonavir+Interferon beta-1a Hydroxychloroquine Hydroxychloroquine	RCT	Patients with confirmed COVID-19 (mild-critical) admitted to 32 centers in France and Luxembourg.	N=603	Some concerns Details	Full description
ISRCTN83971151; NCT04315948 SOLIDARITY (LPV/r) Pan H, N Engl J Med, 2020 Full text Full text Commentary	Mixed	Lopinavir-Ritonavir	Standard care	RCT	Patients with COVID-19 (mild-critical) admitted to 405 centers in 30 countries.	N=2791	Low Details	Full description
NCT04381936 RECOVERY (LPV/r) Horby P, Lancet, 2020 Full text Commentary	Mixed	Lopinavir-Ritonavir	Standard care	RCT	Patients with suspected or confirmed COVID-19 (mild-critical) admitted to 163 centers in the UK	N=5040	Some concerns Details	Full description
ChiCTR2000029308 Cao B, N Engl J Med, 2020 Full text Commentary Commentary	Mixed	Lopinavir-Ritonavir	Standard care	RCT	Patients with confirmed COVID-19 (severe) admitted to a single center in China.	N=199	Some concerns Details	Full description
NCT04252885 Yueping L, CellPress, 2020 Full text Commentary	Public/non profit	Lopinavir-Ritonavir Umifenovir Lopinavir-Ritonavir	Standard care Standard care Umifenovir	RCT	Patients with confirmed COVID-19 (mild-moderate) admitted to a single center in China.	N=86	Some concerns Details	Full description