SYSTEMATIC REVIEW - PRELIMINARY REPORT - Lopinavir/ritonavir for the treatment of COVID-19

SYSTEMATIC REVIEW – PRELIMINARY REPORT – Lopinavir/ritonavir for the treatment of COVID-19

Last update: 23 March 2020

This report does not constitute or replace a recommendation. It is an input for decision-makers to inform their processes with the best available evidence.

A full systematic review will be submitted as soon as possible for publication in a peer-reviewed journal.

The information about the Working Group conducting the evidence synthesis about this and other questions about COVID-19 can be found in this link.

The methods used in this systematic review can be found in this link.

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Lopinavir/ritonavir is a fixed dose combination antiviral widely used for HIV infection. It has been suggested as a possible treatment in the context of the COVID-19 pandemic in 2019/2020.

Key messages:

Lopinavir/ritonavir may slightly decrease mortality in patients at low or moderate risk (low certainty evidence) and it may decrease mortality in patients at high risk (low certainty evidence)
The effects on some outcomes are difficult to interpret. The observed effect might be a consequence of the limitations of the available evidence. For example, the studies show lopinavir/ritonavir may reduce the risk of developing respiratory failure or acute respiratory distress syndrome, lead to a small clinical improvement at 14 days, and make no difference in the length of hospitalization (low certainty evidence)
Lopinavir/ritonavir may not lead to a substantial increase in the risk of serious adverse effects (low certainty of evidence) although it may produce non-serious adverse effects (moderate certainty of evidence)
It is not possible to establish clearly if there is an effect on the risk of requiring mechanical ventilation or extracorporeal membrane oxygenation, because the certainty of the evidence has been evaluated as very low.

Interactive Summary of Findings (iSoF) table:

https://isof.epistemonikos.org/#/finding/5e728d80e3089d04c36eb79b

To access the evidence supporting this summary or activate email notifications about new evidence evaluating this question, click here to L·OVE (Living OVerview of Evidence) platform

Appendix 1. References

Cao, Bin, Wang, Yeming, Wen, Danning, Liu, Wen, Wang, Jingli, Fan, Guohui, Ruan, Lianguo, Song, Bin, Cai, Yanping, Wei, Ming, Li, Xingwang, Xia, Jiaan et al.. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine; 2020-03-18.
Diamond Princess COVID-19 Cases. https://www.niid.go.jp/niid/en/2019-ncov-e/9417-covid-dp-fe-02.html
Coronavirus disease 2019 (COVID-19). Situation Report – 57. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200317-sitrep-57-covid-19.pdf?sfvrsn=a26922f2_4

Appendix 2. Search strategy

Epistemonikos strategy:

((coronavir* OR coronovirus* OR “corona virus” OR “virus corona” OR “corono virus” OR “virus corono” OR hcov* OR “covid-19” OR covid19* OR “covid 19” OR “2019-nCoV” OR cv19* OR “cv-19” OR “cv 19” OR “n-cov” OR ncov* OR “sars-cov-2” OR (wuhan* AND (virus OR viruses OR viral) OR coronav*) OR (covid* AND (virus OR viruses OR viral)) OR “sars-cov” OR “sars cov” OR “sars-coronavirus” OR “severe acute respiratory syndrome” OR “mers-cov” OR “mers cov” OR “middle east respiratory syndrome” OR “middle-east respiratory syndrome”)) AND ((lopinavir* OR “ABT-378” OR “ABT 378” OR ABT378)) AND ((ritonavir* OR Norvir)).

Minor modifications were conducted to the epistemonikos strategy in order to adapt it to other databases.

Appendix 3. Forest plots

Forest plots

Appendix 4. Downloadable files

Revman

GRADEpro files

Appendix 5. Summary of Findings table (GRADE), static version.

Lopinavir/ritonavir for the treatment of COVID-19
Patients	COVID-19 infection
Intervention	Addition of lopinavir/ ritonavir to standard treatment (as defined by studies)
Comparison	Placebo or no treatment (added to standard treatment as defined by studies)
Outcomes	Relative effect (95% CI) — Patients/ studies	Absolute effect*			Certainty of evidence (GRADE)	Key messages
		WITHOUT lopinavir/ ritonavir	WITH lopinavir/ ritonavir	Difference (CI 95%)
Mortality**	RR 0.77(0.45 to 1.30) — 199 patients/ 1 randomized trial [1]	Low risk patients**			⨁⨁○○1,2 LOW	Addition of lopinavir/ritonavir to standard treatment may slightly reduce mortality (low certainty evidence) Addition of lopinavir/ritonavir to standard treatment may slightly reduce mortality (low certainty evidence) Addition of lopinavir/ritonavir to standard treatment may reduce mortality (low certainty evidence)
		20 per 1000	15 per 1000	5 less per 1000 (11 less to 6 more )
		Moderate risk patients***
		41 per 1000	32 per 1000	9 less per 1000 (23 less to 12 more)
		High risk patients****
		250 per 1000	193 per 1000	57 less per 1000 (138 less to 75 more)
Development of respiratory failure or acute respiratory distress syndrome (ARDS)**	RR 0.56 (0.32 to 0.99)—197 patients/ 1 randomized trial [1]	273 per 1000	153 per 1000	120 less per 1000 (185 to 3 less)	⨁⨁○○1,2 LOW	Addition of lopinavir/ritonavir to standard treatment may reduce the risk of developing respiratory failure or ARDS (low certainty evidence).
Mechanical ventilation or Extracorporeal membrane oxygenation (ECMO) at day 7	RR 1.48(0.43 to 5.09) — 199 patients/ 1 randomized trial [1]	43 per 1000	64 per 1000	21 more per 1000 (25 less to 176 more)	⨁○○○1,2 VERY LOW	We are uncertain whether addition of lopinavir/ritonavir to standard treatment increases the risk of mechanical ventilation or ECMO as the certainty of the evidence has been assessed as very low.
Clinical improvement at day 14	HR 1.31 (0.95 to 1.85)— 199 patients/ 1 randomized trial [1]	300 per 1000	373 per 1000	73 more per 1000 (13 less to 183 more)	⨁⨁○○LOW	Addition of lopinavir/ritonavir to standard treatment may slightly increases clinical improvement at day 14 (low certainty evidence)
Duration of hospitalization**	199 patients/ 1 randomized trial [1]	16 days	15 days	MD: 1 day less (0 to 3 less)	⨁⨁○○1,2 LOW	Addition of lopinavir/ritonavir to standard treatment may make little or no difference to duration of hospitalization (low certainty evidence)
Serious adverse effects**	RR 0.62(0.38 to 1.01) — 194 patients/ 1 randomized trial [1]	High risk patients****			⨁⨁○○1,2LOW	Addition of lopinavir/ritonavir to standard treatment may not be associated with a substantial increase in the risk of serious adverse effects (low certainty evidence)
		323 per 1000	200 per 1000	123 less per 1000 (200 less to 3 more)
Total adverse effects		Low and moderate risk patients**			⨁⨁⨁○3 MODERATE	Addition of lopinavir/ritonavir to standard treatment probably produce adverse effects (moderate certainty evidence)
		A systematic review [6] reports the most common adverse effects were diarrhea and nausea. Adverse events possible relationship to lopinavir/ritonavir therapy were diarrhea, nausea, asthenia , abdominal pain, vomiting, headache, and rash.
Margin of error: 95% confidence interval (CI). RR: Risk ratio. HR: Hazard ratio. MD: Mean difference. GRADE: Grados de evidencia Grading of Recommendations Assessment, Development and Evaluation. The risk WITHOUT* lopinavir/ ritonavir is based on the risk in the control group of the trials. The risk WITH lopinavir/ ritonavir (and its margin of error) is calculated from relative effect (and its margin of error). 28-day follow-up The low risk population estimate is based on data from patients with symptomatic COVID-19 infection on the Diamond Princess cruise ship [2]. *The moderate risk population estimate is based on the mortality reported by the World Health Organization of confirmed cases as of 03-17-20 [3]. ***The high risk population estimate is based on a randomized trial of patients with severe COVID-19 infection [1]. 1 The certainty of the evidence was downgraded in one level for risk of bias since the trial was not blinded and selective reporting of outcomes was identified. 2 The certainty of the evidence was downgraded in one level for imprecision, since each end of the confidence interval would lead to different conclusions. In the case of “Respiratory failure or ARDS”, it was decided to decrease an additional level due to for this outcome few events were observed (n = 10) and it has a greater width of the confidence interval compared to the rest of the outcomes. 3 The certainty of evidence was downgraded in one level for indirectness, since the evidence comes from studies of lopinavir/ritonavir in HIV-Infected adults.