Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

On March 11, 2020, the World Health Organization (WHO) declared COVID-19 a pandemic.1 From 200 confirmed cases in mid-March, there are now more than 26,000 cases in the Philippines, with a mortality rate of 4.2%.2 At least 800 trials on various treatments for COVID are currently ongoing around the world.3

Among the drugs being investigated as treatment for COVID-19, Chloroquine (CQ) and hydroxychloroquine (HCQ) showed promise, with in-vitro studies demonstrating their anti-viral properties against SARS-COV2,4,5 the virus that causes COVID-19, and early reports from China and France suggesting potential benefit.6,7 Given their established safety profiles and possible effectiveness against COVID, several guidelines suggested the off-label use of HCQ as treatment for COVID.8,9,10,11 On March 28, 2020, the

US FDA issued an emergency use authorization for CQ phosphate and HCQ sulfate for COVID-19 treatment.12

We conducted a rapid review of the evidence on the efficacy and safety of HCQ or CQ for the treatment of COVID-19 in April 2020. Since then, several large observational studies13,14,15 and a randomized controlled trial16 have been published. We aimed to update our rapid review on the current available evidence on efficacy and safety of HCQ and CQ for the treatment of COVID-19.

METHODS

Literature Search

We identified studies on the role of chloroquine or hydroxychloroquine in the treatment of COVID-19 by searching MedLine and PubMed Central for published literature; the Chinese Clinical Trial Registry, Clinicaltrials. gov, and the WHO International Clinical Trials Registry Platform (ICTRP) for completed but unpublished, and ongoing trials; and MedRxiv and BioRxiv fo pre-print/ pre-proof articles between April 14 to June 4, 2020. We last searched the electronic databases on June 16, 2020.

We used the search terms chloroquine, hydroxy- chloroquine, coronavirus, COVID-19, and SARS 2-CoV2 in both free text and MESH. No date or language restrictions were applied. The full search strategy was previously published.17

Selection and quality assessment of included studies

Screening and selection of included studies were done by two reviewers (LPV and EU).

Articles were selected based on the following inclusion criteria:

•Population: Patients with probable or confirmed COVID-19

•Intervention: Hydroxychloroquine or Chloroquine

•Comparator: Placebo, Usual/standard care, or any comparator

•Study designs: randomized controlled trials, observational studies

Two reviewers (LPV and EU) independently assessed the quality of the included studies for effectiveness using the following criteria: randomization, allocation concealment, similarity of baseline characteristics, blinding, intention to treat, adequate follow-up.18 Disagreements were resolved by consensus.

Data Extraction and Analysis

We extracted the following data from the included studies: author, year of publication, study characteristics (population, study interventions, outcomes, study design), and results (e.g. frequency of events, relative risks, mean durations for all reported outcomes).

Rating the quality of evidence

We rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evalua- tion (GRADE) approach.19

RESULTS

We found 3 randomized controlled trials and 5 cohort studies on the efficacy and safety of HCQ or CQ vs standard therapy. Study characteristics are summarized in Appendix 1. The study by Mehra et al. that was published in the Lancet on May 22, 2020 has since been retracted due to concerns regarding the veracity of the study data.20

In the course of scanning for literature relevant to this review, we came across the “COVID-19 Living Data” project.21 The project aims to regularly (every 3 days) monitor, map, and summarize new evidence for treating and preventing COVID-19. The project website includes a summary of studies on the efficacy of hydroxychloroquine and/or chloroquine vs standard therapy. Subsequent to the manuscript retraction by the study’s authors on June 4, 2020, the data from the Mehra et al study were deleted from the website.

Five of the studies identified in our search were included in the project’s evidence summaries (RCTs: Chen J et al22, Chen Z et al23, Tang et al16, quasi-experimental studies: Geleris et al13, Mahevas et al14). Two studies identified in our search were excluded from the project’s evidence summaries: Rosenberg et al15, and Yu et al24.  These 2 studies were excluded as they were not considered “quasi-experimental studies” due to the lack of causal inference analysis (e.g. propensity score, inverse probability weighting).25 Based on our own evaluation, these two studies had a high risk of bias.

Except for reservations in the assessment of quality of evidence (see footnote in Table 1), we agree with the approach taken by the “COVID-19 Living Data” project and, with due attribution, use the evidence summaries (forest plots, evidence profiles, and summary of findings) published on their website as of June 16, 2020 as a basis for the current update of our rapid review.

Randomized Controlled Trials (RCTs)

Overall quality of evidence from 3 RCTs was very low due to concerns regarding risk of bias, and imprecision (Table 1). Chen J et al22 and Chen Z et al23 recruited patients with mild to moderate disease. Tang et al16 recruited patients with moderate disease.

Results were equivocal for the outcomes of viral nega- tive conversion (Day(D)7), all-cause mortality (D7, D14 to D28), adverse events (D7), and serious adverse events (D7, D14 to D28). A meta-analysis (Figure 1) from two RCTs suggests that the use of HCQ may increase the incidence of adverse events at D14 to D28 (RR 2.49, 95% confidence interval: 1.04 to 5.98, low quality of evidence); the most common adverse event across the two trials is diarrhea (n=8).

Quasi-experimental studies

Two cohort studies were classified as quasi-RCTs by the “COVID-19 Living Data” project. These studies provide additional evidence on the efficacy and safety of HCQ or CQ vs standard care. We caution that although these studies used statistical means to correct for confounding (i.e. propensity score matching, inverse probability weighting), these methods can only correct for known and measured confounders.

Our own assessment showed that each of these studies had at least a moderate risk of bias. Well-designed observational studies start as low quality evidence in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.19 Based on a moderate risk of bias, the quality of evidence from these studies is further rated down to very low.

Geleris et al13 and Mahevas et al14 primarily included patients with moderate to severe COVID-19. Both studies showed equivocal results for the outcome of intubation or death. Mahevas et al showed equivocal results for the outcomes of death, and ARDS. (Table 2).

Table 2. Summary of results from quasi-RCTs

Study	n	Outcome Effect Estimate (95% CI)
Geleris et al	1376	Time to intubation or death
		• HR 1.04 (0.82 to 1.32)*
Mahevas et al	181	ICU + Death
		• RR 0.93 (0.48 to 1.81)
		Death
		• RR 0.61, (0.13 to 2.90)

ARDS

• RR 1.15, (0.66 to 2.01)

ECG abnormalities (reported only for HCQ arm, n=84):

• QTc >60ms: 7

• First degree AV block: 1

ARDS: Acute Respiratory Distress Syndrome, CI: Confidence Interval,

CQ: Chloroquine, ECG: Electrocardiogram, HCQ: Hydroxychloroquine,

HR: Hazards Ratio, ICU: Intensive Care Unit, RR: Relative Risk

*Primary adjusted analysis (Inverse probability weighting)

On June 5, 2020, the investigators of the Recovery trial, a randomized controlled trial investigating various treatments for COVID-19 including HCQ, released a

statement about the interim results for the HCQ arm. Based on data from 4,674 patients hospitalized with COVID-19 (1,542 randomized to HCQ, 3,132 randomized to usual care alone), no significant clinical benefit was found for HCQ in terms of 28-day mortality (25.7% HCQ vs. 23.5% usual care, HR 1.11 [95% CI 0.98 to 1.26]), length of hospital stay, or other outcomes.26 Full results have yet to be published.

On June 15, 2020, the US FDA revoked the emergency use authorization for Chloroquine and Hydroxychloroquine that it issued on March 28, 2020 in light of recent evidence from a large randomised trial that did not demonstrate benefit for mortality or other important clinical outcomes such as length of hospital stay or need for mechanical ventilation among patients hospitalized for COVID-19.27 As a result, the US National Institutes of Health, in the June 16, 2020 update of its treatment guidelines for COVID-19, recommended against the use of HCQ or CQ for the treatment of COVID-19, except in a clinical trial.28

On June 17, 2020, the WHO Solidarity trial, which is investigating the relative effectiveness of 4 treatment options for COVID-19 (remdesivir, HCQ, Lopinavir/ritonavir, interferon beta-1a) on top of standard care vs. standard care alone, announced that it has stopped further recruitment to the HCQ arm.29 This decision was based on a review of current evidence, the results of the Recovery trial, and results from the Solidarity trial.

CONCLUSION

There is insufficient evidence to support the routine use of HCQ or CQ for the treatment of COVID-19. Results from the interim analyses of 2 large RCTs, the Recovery and the Solidarity trials, reportedly showed no clinical benefit from HCQ for hospitalized patients with COVID-19; the detailed results of these 2 studies are still not publicly available at the time of this review.

Conflicts of Interest

LPV is participating in the ACT Trial, which will investigate various therapies for COVID-19. It originally included HCQ as one of the study treatments, but has since removed HCQ as a treatment after the release of the Recovery trial results. EU was previously employed with Abbvie. The company holds marketing authorization for Kaletra (Lopinovir/Ritonavir) which is currently being investigated as a treatment for COVID-19.

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12.Hinton DM (U. SF and DA Maryland, US A). Letter to: Dr. Rick Bright, PhD. (Biomedical Advanced Research and Development Authority, Office of Assistant Secretary for Preapredness and Response, U.S. Department of Health and Human Services, Washington D.C.). 2020.

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14.Mahevas M, Tran V-T, Roumier M, Chabrol A, Paule R, Guillaud C, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial [Internet]. Infectious Diseases (except HIV/AIDS); 2020 Apr [cited 2020 May 24]. Available from: http://medrxiv.org/ lookup/doi/10.1101/2020.04.10.20060699

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20.Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloro- quine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May; S0140-6736(20)31180-6. doi: 10.1016/S0140-6736(20)31180-6.

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22.Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 May; 49(2):215-9. doi: 10.3785/j.issn.1008-9292.2020.03.03.

23.Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020 Apr 10. doi: https://doi.org/ 10.1101/2020.03.22.20040758.

24.Yu B, Li C, Chen P, Zhou N, Wang L, Li J, et al. Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19. Sci China Life Sci. 2020 Oct; 63(10):1515-1521. doi: 10.1007/s11427-020-1732-2.

25.Boutron I, Chaimani A, Devane D, Meerpohl JJ,Tovey D, Hróbjartsson A, et al. Interventions for preventing and treating COVID-19: protocol for a living mapping of research and a living systematic review. doi:10.5281/zenodo.3903347

26.RECOVERY Trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19 [Internet]. [cited 2020 Jun 17]. Available from: https://www.recoverytrial.net/news/statement- from-the-chief-investigators-of-the-randomised-evaluation-of- covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june- 2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in- hospitalised-patients-with-covid-19

27.Commissioner O of the. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine [Internet]. FDA. FDA; 2020 [cited 2020 Jun 17]. Available from: https://www.fda.gov/news-events/ press-announcements/coronavirus-covid-19-update-fda-revokes- emergency-use-authorization-chloroquine-and

28.National Institutes of. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines [Internet]. [cited 2020 Jun 17]. Available from: https://www. covid19treatmentguidelines.nih.gov/.

29.“Solidarity” clinical trial for COVID-19 treatments [Internet]. [cited 2020 Jun 18]. Available from: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/global-research-on-novel- coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19- treatments

Author Study Design

Chen J RCT

n=30

Population	Intervention	Comparator	Outcome	Estimate of Effect
- Adult, clinically	HCQ 400 mg	Standard care	- Virologic clearance	- Computed RRs
diagnosed COVID-19	OD for 5 days		(pharyngeal swabs.	- Negative conversion (D7): 0.93
patients (n=30)			Sputum or LRT	- No deaths
- Mild to moderate			secretions) on D7	- Adverse events: 1.33
illness			- Death within 2 weeks
			- ADEs within 2 weeks