SYSTEMATIC REVIEW - PRELIMINARY REPORT Antimalarials for the treatment of COVID-19

SYSTEMATIC REVIEW – PRELIMINARY REPORT Antimalarials for the treatment of COVID-19

Last update: 31 March 2020

What is new in this update to our report

This update adds the appraisal of a second randomized trial, published after we posted our last report. It is a study with very serious limitations and does not report outcomes which are critical for decision-making. In any case, the incorporation of its results did not lead to substantive changes in the certainty of the totality of the available evidence.

We also made some changes to the way in which we present outcomes. They now follow available Core Outcome Sets for COVID-19.

Finally, the study by Gautret et al is no longer considered an included study, for it does not add any relevant information to the one presented by the included randomized trials.

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This report does not offer a recommendation, but a critical summary of the best available evidence, intended to facilitate decision-making.

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

The information about the Working Group conducting the evidence synthesis for this and other questions about COVID-19 is available in this link.

The methods used in this systematic review are described in this link.

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Hydroxychloroquine and chloroquine were widely used for the treatment of malaria. Currently, they are still used in rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders. Because of its effects on inhibiting pH-dependent steps of the replication of several viruses, they have been suggested as a possible treatment in the context of the COVID-19 pandemic in 2019/2020.

Key messages:

We are uncertain whether the use of antimalarials as part of the treatment of COVID-19 has any effect on outcomes critical for decision-making (e.g. mortality or need of mechanical ventilation) as the certainty of the evidence has been assessed as very low.
The addition of antimalarials may not even increase the number of patients achieving SARS-CoV-2 clearance, but the certainty of the available evidence is low.
Adding antimalarials to standard treatment may increase the risk of serious adverse effects.

Interactive Summary of Findings (iSoF) table:

https://isof.epistemonikos.org/#/finding/5e78f4e1e3089d04c5c04f48

The evidence supporting this summary is publicly available through the L·OVE (Living OVerview of Evidence) platform. Use this link to access L·OVE and activate email notifications of new articles addressing this question.

Appendix 1. References

1. Gautret et al

Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents [Internet] 2020 March 20 [Accessed March 26] Available from:.
Epistemonikos | DOI

2. Chen, Hongzhou et al (NCT04261517)
Chen Jun, Liu Danping. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Journal of Zhejiang University (Medical Science) [Internet] 2020 [Accessed March 26] ;49(1):0-0.:

Epistemonikos | DOI

3. Hongzhou Lu, Shanghai Public Health Clinical Center. Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV ( HC-nCoV ). ClinicalTrials.gov [Internet] registration number: NCT04261517 [Accessed March 26].

Epistemonikos | DOI

Appendix 2. Search strategy

Epistemonikos strategy:

((coronavir* OR coronovirus* OR “corona virus” OR “virus corona” OR “corono virus” OR “virus corono” OR “sars-coronavirus” OR hcov* OR (wuhan* AND (virus OR viruses OR viral) OR coronav*) OR (covid* AND (virus OR viruses OR viral)) OR cv19 OR “cv-19” OR “cv 19” OR “n-cov” OR ncov* OR “sars-cov-2” OR “mers-cov” OR “mers cov” OR “sars-cov” OR “sars cov”)) AND ((antimalari* OR “anti-malarial” OR “anti-malarials” OR “anti-malaria”) OR (chloroquine* OR CQ OR Aralen) OR (hydroxychloroquine* OR HCQ OR Plaquenil))

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

Appendix 3. Forest plots

Appendix 4. Downloadable files

Revman

GRADEpro files

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

Antimalarials for the treatment of SARS-CoV-2 infection
Patients	SARS-CoV-2 infection
Intervention	Addition of antimalarials (hydroxychloroquine or chloroquine) to standard treatment (as defined by the studies)
Comparison	Placebo or no treatment (added to standard treatment as defined by the studies)
Outcomes	Relative effect (95% CI) — Participants/ studies	Absolute effect*			Certainty of evidence (GRADE)	Key messages
		WITHOUT antimalarials	WITH antimalarials	Difference (95% CI)
Mortality	— 30 patients/ 1 trial [2]	On trial reported that all participants were still alive at 2 weeks of follow-up.			⨁○○○1,2 Very low	We are uncertain whether the addition of antimalarials to standard treatment decreases mortality as the certainty of the evidence has been assessed as very low.
Mechanical ventilation	The outcome mechanical ventilation or extracorporeal membrane oxygenation has not been reported by the analyzed evidence.				—	—
Extracorporeal membrane oxygenation	The outcome extracorporeal membrane oxygenation has not been reported by the analyzed evidence.				—	—
Length of hospital stay	The outcome length of hospital stay has not been reported in the evidence analyzed.				—	—
Respiratory failure	— 92 patients/ 2 trials [2,3]	No studies were found evaluating respiratory failure or acute respiratory distress syndrome, however, indirect evidence was found: The trials reported that the group receiving antimalarials had less progression of lung disease*** compared to the control group (RR 0.46, 95% CI 0.15 to 1.39).			⨁○○○1,3,4 Very low	We are uncertain whether the addition of antimalarials to standard treatment decreases respiratory failure as the certainty of the evidence has been assessed as very low.
Serious adverse effects	— 92 patients/ 2 trials [2,3]	No studies were found evaluating serious adverse effects, however indirect evidence was found: The trials reported that the group receiving antimalarials presented more total adverse effects**** compared to the control group (RR 1.65, 95% CI 0.50 to 5.50).			⨁⨁○○1,3,4 Low	The addition of antimalarials to standard treatment may increase the incidence of serious adverse effects (low certainty of evidence)
SARS-CoV-2 clearance*****	RR 0.93 (0.73 a 1.18) —30 patients/ 1 trial [2]	933 per 1000	868 per 1000	65 less (252 less to 168 more)	⨁⨁○○1,3 Low	The addition of antimalarials to standard treatment may not increase SARS-CoV-2 clearance (low certainty of evidence)
95 CI%: 95% confidence interval RR: Relative risk. GRADE: Evidence grades Grading of Recommendations Assessment, Development and Evaluation. The risk WITHOUT antimalarials* is based on the risk in the control group of the trials. The risk WITH antimalarials (and its confidence interval) is calculated from relative effect (and its confidence interval). 2 weeks of follow-up. * Evaluated with CT scan at day 3 [2] and 6 [3]. ** Total adverse effects evaluated at 2 weeks [2] and 6 days [3] of follow-up, including diarrhea, anemia, elevated creatinine, transient AST elevation, rash and headache. *** Defined as the proportion of patients with negative nasopharyngeal PCR at day 7. 1 The certainty of the evidence was downgraded in one level for risk of bias, since there are limitations regarding the randomization process, administration of co-interventions and outcomes measurements. For the outcome serious adverse effects, we decided not to decrease the certainty of the evidence for this reason, since the absence of bias would reinforce the conclusion. 2 The certainty of the evidence was downgraded in two levels for imprecision, since it cannot be ruled out that the observed effect is a product of chance, given the low number of events and sample size (n = 30). 3 The certainty of the evidence was downgraded in one level for imprecision since different decisions would be taken at each end of the confidence interval. 4 The certainty of the evidence was downgraded in one level for indirectness since the reported outcomes correspond to surrogates of respiratory failure and serious adverse effects. There is also controversy about indirectness regarding hydroxychloroquine therapeutic dose (400 mg qd). However, we did not downgrade for this factor because we did not find convincing evidence or consensus regarding the optimal dose.