key: cord-0744030-yw8eok49
authors: Kashour, Zakariya; Kashour, Tarek; Gerberi, Danielle; Tleyjeh, Imad M.
title: Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID‐19 Patients: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
date: 2021-02-19
journal: Clin Transl Sci
DOI: 10.1111/cts.13001
sha: bfb0926c814f8918bfeb0bed51889626dcd6de88
doc_id: 744030
cord_uid: yw8eok49

Many meta‐analyses have been published about the efficacy of Hydroxychloroquine (HCQ) in COVID‐19. Most of them included observational studies, and few have assessed HCQ as a prophylaxis or evaluated its safety profile. We searched multiple databases and preprint servers for randomized controlled trials (RCTs) that assessed HCQ for the treatment or prevention of COVID‐19. We summarized the effect of HCQ on mortality, viral clearance, and other clinical outcomes. Out of 768 papers screened, 21 RCTs with a total of 14,138 patients were included. A total of 9 inpatient and 3 outpatient RCTs assessed mortality in 8,596 patients with a pooled risk difference of 0.01 [95% CI 0.00, 0.03, I2= 1%, P=0.07]. Six studies assessed viral clearance at 7 days with a pooled risk ratio (RR) of 1.11 [95% CI 0.86, 1.42, I2= 61%, P=0.44] and 5 studies at 14 days with a pooled RR of 0.96 [95% CI 0.89, 1.04, I2= 0%, P=0.34]. Several trials showed no significant effect of HCQ on other clinical outcomes and. Five prevention RCTs with 5012 patients found no effect of HCQ on the risk of acquiring COVID‐19. Thirteen trials showed that HCQ was associated with increased risk of adverse events. We observed, with high level of certainty of evidence, that HCQ is not effective in reducing mortality in COVID‐19 patients. Lower certainty evidence also suggests that HCQ neither improves viral clearance and other clinical outcomes, nor prevents COVID‐19 infection in patients with high‐risk exposure. HCQ is associated with an increased rate of adverse events.

The novel SARS-COV-2 coronavirus that emerged from Wuhan China in December 2019 has resulted in over 27 million cases and close to 900,000 deaths. In addition to the enormous death toll, the economic damage caused by this virus has led to an increase in the demand for the development of effective therapies for managing this disease. In an effort to find a quick solution, many existing drugs have been repurposed as potential treatments in patients with COVID-19, with chloroquine (CQ) and hydroxychloroquine (HCQ) being among one of the first drugs used for this purpose.

This article is protected by copyright. All rights reserved CQ and HCQ received a significant amount of attention for the treatment of COVID-19 patients because of their reported in vitro antiviral activity and the results of early clinical trials. In vitro, HCQ interferes with several cellular processes like endocytosis, exosome release and phagolysosomal fusion. These in turn, can affect several stages of the virus's life cycle from cell entry and replication, to viral particle assembly and release (1) . An early commentary from China on CQ reported improvements in many clinical outcomes such as disease progression, radiologic findings, and disease duration (2) . Later, a non-randomized clinical trial from France, also suggested a significant effect of HCQ in reducing time to viral clearance (3) .

Despite the promising early reports, many subsequent clinical trials and observational studies demonstrated disappointing results. In this meta-analysis, we systematically review the efficacy and safety of hydroxychloroquine (HCQ) for the treatment or prevention of COVID-19 reported by randomized controlled trials (RCTs).

We included double-blinded and open label RCTs that assessed the efficacy and safety of hydroxychloroquine in comparison to either placebo or standard of care (SOC), for the treatment or prevention of COVID-19. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for study design, search protocol, screening, and reporting (4) . 

This article is protected by copyright. All rights reserved Two reviewers independently identified eligible studies (ZK and TK) and extracted the data into a pre-specified data collection form. Discrepancies were resolved with a third reviewer (IT). Data were collected on the following prespecified outcomes:

1-Mortality, viral clearance, disease progression, symptom resolution and clinical recovery, need for mechanical ventilation, and requirement for hospitalization (outpatient trials) for the treatment RCTs.

2-. Risk of acquiring COVID-19 infection in individuals with high-risk exposure for the prevention RCTs.

3-Additionally, we collected data on adverse reactions; these include arrhythmias, elevated liver enzymes, gastrointestinal adverse events (diarrhea, vomiting), neurologic adverse events (dizziness, fatigue, irritability), headaches, visual symptoms and rashes.

The reviewers independently assessed the risk of bias for each study using the Cochrane risk-of-bias tool for randomized trials (5) and resolved differences among themselves. RoB 2 is structured into 6 domains of bias: 1) Randomization process: 2) Deviations from intended interventions; 3) Missing outcome data: 4) Measurement of the outcome: 5) Selection of the reported result: and 6) Overall bias. Within each domain, a series of questions aim to elicit information about features of the trial that are relevant to risk of bias. A proposed judgement about the risk of bias arising from each domain is generated by an algorithm, based on answers to the signaling questions. Judgement can be 'Low' or 'High' risk of bias or can express 'Some concerns'. Certainty of evidence for each outcomes was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach (6, 7) . This method evaluates the certainty of evidence by assessing the following domains: Limitations, indirectness, inconsistency, imprecision, and publication bias.

The efficacy outcomes of interest in this review are mortality and viral clearance as well hospitalization requirement (outpatient trials) in the treatment RCTs and the incidence of infection in patients with high risk exposure in the prevention RCTs. The safety outcomes were the occurrence of adverse events. The meta-analysis was performed using the Mantel-Haenszel method for dichotomous

This article is protected by copyright. All rights reserved data. Outcomes were reported as Risk Ratios (RR) or Risk Differences (RD) whenever appropriate with 95% Confident Interval (CI). We reported pooled RD and 95% CI when studies had zero events and we used RD to calculate number needed to harm (NNH) and 95% CI for each adverse event. We evaluated statistical heterogeneity using the I 2 statistic which estimates the variability percentage in effect estimates that is due to heterogeneity rather than to chance (8) .

Fixed and random-effects models were used depending on statistical heterogeneity. We constructed funnel plots to assess for asymmetry and publication bias. All statistical analyses were performed using Review Manager 5.4.

Out of 768 papers screened for eligibility, 21 RCT (9-29) with a total of 14,138 patients were included ( Figure 1 ). Sixteen RCTs assessed the efficacy and safety of HCQ in patients with confirmed COVID-19 disease, among which, 10 studies were multicentre (9,10,14, [16] [17] [18] 22, 24, 25, 29) and 6 studies were single center (11) (12) (13) 15, 19, 28) , 2 were double-blind (17, 25) and 14 were open-label (9) (10) (11) (12) (13) (14) (15) (16) 18, 19, 22, 24, 28, 29) . Thirteen studies (9) (10) (11) (12) (13) (14) (15) 18, 22, 24, (27) (28) (29) were conducted in the in-patient setting, while 3 studies (17, 20, 21) were conducted in the outpatient setting. Five RCTs studied the role of HCQ in the prevention of COVID-19 disease (20, 21, 23, 26, 27) . The study design of all these trials is described in Table S1 . The quality of the RCTs was assessed using the Cochrane ROB tool; the results of which are shown in Figure S1 .

Seventeen studies are at low risk of bias (9) (10) (11) 13, 14, 16, 17, (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) , 1 study was at a moderate (15) , and 3 studies at high risk of bias (12, 18, 19) .The study with moderate risk of bias used patients who refused treatment as controls, but this had no effect on the baseline characteristics of the patients. All studies with high risk of bias had deviations from treatment protocol or baseline differences that were likely to affect the study outcomes.

Sixteen RCTs studied the effect of HCQ on several outcomes that include, mortality, viral clearance, disease progression, disease severity scores, symptom resolution or clinical recovery, need for

This article is protected by copyright. All rights reserved mechanical ventilation, hospital length of stay, need for hospitalization and resolution of CT changes.

A summary of the findings, and strength of evidence for each outcome is shown in Table 1 .

A total of 9 inpatient (9,10, [12] [13] [14] 18, 24, 28, 29) and 3 outpatient RCTs (17, 19, 21) assessed mortality in 8,596

patients. In hospitalized patients, there was a trend towards increased mortality in the HCQ group compared with the control risk difference of 0.02 [95% CI 0.00, 0.03 I 2 = 0%, P=0.07]. There was no significant difference between treatment groups in non-hospitalized patients, risk difference -0.00 [95% CI -0.01, 0.01 I 2 = 0%, P=1.0]. The total pooled effect estimate of risk difference in combined hospitalized and non-hospitalized patients was 0.01 [95% CI 0.00, 0.03, I 2 = 1%, P=0.07] (Figure 2 ).

We reported the risk difference because many studies reported no mortality in either group. However, the mortality risk ratio from 6 inpatient studies also showed a trend of increased mortality with HCQ with pooled RR of 1.09 [95% CI 0.99, 1.20, I 2 = 0%, P= 0.07] ( Figure S2 ). Funnel plot analysis indicates that there was no evidence of publication bias among HCQ treatment RCTs ( Figure S3 ).

Because Cavalcanti et al (9) had an extra arm of a combination of HCQ and azithromycin, we performed a sensitivity analysis by including the patients from this arm in the mortality analysis and found no change in the pooled effect estimates ( Figure S4 A) . Similarly, the pooled effect estimates did not change when we excluded three studies at high risk of bias (12, 18, 19) ( Figure S4 B) . Since, one of the included trials (14) was very large with a calculated weight of 51.9%, a sensitivity analysis after removing this trial did not affect the overall pooled estimates.

Six studies (10) (11) (12) 15, 18, 25) assessed viral clearance and 2 studies assessed viral load (16, 28) at different points in time in response to HCQ or its comparators. The pooled RR of viral clearance of 6 studies (11, 12, 15, 18, 24, 25) (16) assessed viral load at 3, 7 and 14 days and observed no significant effects of HCQ on viral load in comparison with the control group. Additionally Lyngbakken et al. (28) found no difference in the rate of decline in viral load at 96 hours between the HCQ and control group. These findings suggest that HCQ has no effect on the rate of viral clearance in COVID-19

This article is protected by copyright. All rights reserved patients. The pooled effect estimate did not change when we excluded the two studies at high risk of bias (12, 18) (Figure S5 A and B) .

Eight inpatient (9) (10) (11) (12) (13) (14) (15) 18) and two outpatient (17, 19) RCTs with a total of 6,410 patients assessed the effect of HCQ on COVID-19 disease progression. HCQ demonstrated a trend towards a higher risk of disease progression among the inpatient studies with an RR of 1.07 [95% CI 0.99, 1.15, I 2 = 0%, P=0.07]. The RR for the outpatient trials was 0.85 [95% CI 0.58, 1.26, I 2 = 0%, P=0.42] with the pooled RR for the 10 trial of 1.06 [95% CI 0.99, 1.14, I 2 = 0%, P=0.12] ( Figure 4A ). These findings indicate that HCQ might be associated with a trend of worse disease progression in COVID-19

disease.

Seven inpatient (9,10, 14, 18, 22, 25, 29) and 3 outpatient (16, 17, 19) RCTs Figure 4B ). Therefore, HCQ therapy did not result into better symptom resolution or clinical recovery among COVID-19 patients. We performed a sensitivity analysis by excluding the two studies at high risk of bias (18, 19) and did not find any change in the pooled effect estimates ( Figure S6 ). 

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Eight RCTs, 3 treating outpatients with mild COVID-19 disease (16, 17, 19) and 5 prevention trials using HCQ as a prophylaxis (20, 21, 23, 26, 27) assessed the effect of HCQ on the need for hospitalization in these patient populations. The pooled RR was 0.80 [95% CI 0.54, 1.20, I 2 = 0%, P=0.28] (Figure 4D ), which indicates that HCQ failed to reduce the need for hospitalization among non-hospitalized COVID-19 patients with mild to moderate disease and among individuals with high risk exposure.

Five studies (20, 21, 23, 26, 27) with 5012 patients assessed the efficacy of HCQ as a prophylactic treatment for patients with a high-risk exposure to COVID-19. There was no significant difference in the incidence of infection between HCQ and control groups, RR 0.85 [95% CI 0.69, 1.04, I 2 = 0%, Furthermore, we also analysed several types of HCQ induced adverse events individually. We found that HCQ therapy was associated with a higher rate of gastrointestinal symptoms (defined as vomiting or diarrhea) RR 3.32 [95% CI 1.66, 6.67]. HCQ was associated with a trend towards higher incidence of non-lethal cardiovascular arrhythmias 1. 37 (14) reported one case of Torsades de Pointes (TdP) in the HCQ group. Also, Dabbous et al (14) reported one case of lethal myocarditis with HCQ and Pan et al (14) reported death due to any cardiac cause in 4 patients from HCQ and 2 from control groups.

Our systematic review and meta-analysis included 21 RCTs with a total of 14,138 patients. We found with high certainty that HCQ is not effective in reducing short term mortality of COVID-19 patients with different disease severities. Additionally, lower quality evidence suggests that HCQ had no impact on viral clearance rate at 7 and 14 days and did not improve other important clinical outcomes such as disease progression, symptom relief or clinical recovery, need for mechanical ventilation or need for hospitalization. Further, in post-exposure prophylaxis RCTs, we found, with moderate certainty, that HCQ failed in preventing COVID-19 infection.

There was a higher rate of adverse events among patients taking HCQ compared to controls. In terms of clinical recovery or symptom resolution, only one small trial by Abd-Esalam et al. showed benefit of HCQ in terms of improving clinical recovery (22) . In contrary, the large SOLIDARITY trial showed that standard of care was better than HCQ (29) . This is likely due to differences in the studied patient populations and variation of the standard therapies in these two studies, sample size and the time of ascertainment of the outcome. The other 5 studies showed no benefit of HCQ on clinical recovery or symptom resolution with their effect estimates crossing the unity line.

Although several meta-analyses addressing the role of HCQ in COVID-19 disease have been published (30-36) among others, in all of these meta-analyses, the bulk of their data were derived from observational studies, with the exception of 3 studies. Many of these observational studies suffer from serious methodological weaknesses, including treatment selection bias, immortal time bias, competing risk bias and residual confounding. Moreover, some meta-analyses pooled unadjusted effect estimates of the included studies, which result in a very biased results (31) . Only three authors (35) (36) (37) included only RCTs in their meta-analyses similar to us; however, in contrast to ours, these meta-analyses were

This article is protected by copyright. All rights reserved small (included 4-7 RCTs). One meta-analysis by Hussain et al. (36) had a total of 381 patient with only two trials (111 patients) had data on mortality. The second meta-analysis by Pathak et al (35) pooled different clinical outcomes together as a composite endpoint. Recently Lewis et al published a metaanalysis that included only four trials that addressed only the efficacy and safety of HCQ for COVID-19 prophylaxis (37) . Chowdhury et al (38) performed a systematic review of 7 RCTs without metaanalysis and concluded that there was not sufficient data to support the routine use of HCQ in the treatment of COVID-19.

These small systematic reviews/ metanalyses of the HCQ RCTs had conflicting results ranging from being efficacious (38) to not effective (35) or harmful (35) . To date, our meta-analysis is the largest metaanalysis of RCTs (21 trials) that addressed the efficacy and safety of HCQ in the prevention and treatment of COVID-19 disease, which gives it the power to better answer these questions.

Despite the promising results from in-vitro studies and early in vivo studies, the majority of subsequent studies failed to demonstrate any significant benefits for HCQ in COVID-19. There are many possible reasons for this observation. The most important are: First, many in-vitro studies introduced the virus after pre-treating the cells with HCQ or CQ. For instance, Vincent et al. (39) demonstrated that cells treated 5 hours after viral adsorption required up to 5 times the dose given to cells pretreated with CQ to achieve a similar level of viral inhibition. However, the 5 trials included in this review failed to demonstrate any effectiveness of HCQ as a prophylaxis in patients with a highrisk exposure. Additionally, a study conducted on 14,250 patients found that chronic use of HCQ was not associated with decreased SARS-CoV-2 infection (40) .

Second, a wide range of 50% effective concentration (EC 50 ) values for HCQ were reported ranging from 0.72 to 17.31 µM. The lowest reported EC 50 was from a study by Yao et al. ( 

This article is protected by copyright. All rights reserved mg/L. In a prevention trial, Rajasingham et al. (26) measured HCQ concentrations in the dried whole blood samples from 180 patients receiving prophylaxis doses of HCQ of either 400 mg per week or 400 mg twice a week. The blood levels of HCQ were ranging from 0.098 mg/L in the once/week to 0.2 mg/L in the twice a week regimens (26) . Yao et al. proposed a dosing regimen for HCQ consisting of 400 mg twice daily for one day followed by 200 mg twice daily for 4 days based on their physiologically-based pharmacokinetic models and simulation (41) . It is noteworthy to mention that this proposed regimen was based on the estimated free lung trough concentration to in vitro EC 50 ratio because HCQ achieves high tissue concentrations. However, HCQ is known to accumulate in the acidic compartments of the cells like lysosomes and gets sequestered by these organelles reaching up to 80 M when the extracellular concentrations are in the 0.5 M range (43) . Based on these properties,

of the appropriate dosing regimen should be based on the free HCQ plasma concentrations, which are similar to the extracellular concentrations rather than the lung tissue concentrations (44) . They concluded from their repeated calculations that were based on Yao et al.'s EC 50 measurements that current dosing regimens of HCQ may not have adequate in vivo antiviral activity against SARS-Cov-2 (44) . Similarly, Garcia-Cremades et al. used a complex model that integrated in vivo and in vitro data and population pharmacokinetic model of HCQ and found out that the extrapolated patient EC 50 is 4.7 M (1.58 mg/L). They predicted that HCQ dose of 400 mg or higher twice daily for 5 days will be necessary to achieve adequate antiviral concentration but with a higher risk QT prolongation (45) .

The narrow therapeutic window for HCQ, the increased rate of adverse events associated with its use and the difficulty of achieving adequate therapeutic concentration make HCQ not a good option for the treatment of COVID-19 disease (46) .

The occurrence of life-threatening adverse events was very uncommon among the included studies.

Horby et al. (14) reported ventricular arrhythmias (6 in HCQ vs 9 in SOC) and one case of TdP in the HCQ group. However, Cavalcanti et al (9) reported significant increase in QTc prolongation of > 480 ms among patients on HCQ or HCQ, azithromycin combination in comparison to SOC patients

This article is protected by copyright. All rights reserved (14.3%, 16.5% and 1.7% respectively). Similarly, Ulrich et al (25) reported significant increase in the mean QTc duration among HCQ patients (16 ms +/-30.0 vs. 2.1 ms +/-25.3, p= 0.029) with three patients in the HCQ developing QTc>500 ms compared to one patient in the control arm. In the SOLIDARITY trial (29) death due to any cardiac cause occurred in four patients compared to two in the control arm. Other reported cardiac adverse events in association with HCQ treatment include one case of syncope associated with new supraventricular tachycardia (26) and one fatal myocarditis (24) but a cause and effect relationship between HCQ and these events cannot be made. Nonetheless, these observations indicate that HCQ use among COVID-19 patients is potentially associated with nontrivial serious cardiac adverse events despite the short duration of the therapy and the exclusion of patients with underlying QT prolongation, history of arrhythmias and cardiac risk factors and the inclusion of trials that enrolled non-hospitalized and asymptomatic patients.

On the other hand, the incidence of non-cardiac side effects was very common among HCQ treated COVID-19 patients with overall incidence of 45.1% in comparison to 15.0% for placebo or SOC.

Several types of adverse events have reported among COVID-19 patients treated with HCQ with GI side effects being the most significant.

This review has several strengths. We included published and unpublished studies thereby limiting publication bias. Our review is, to our knowledge, the first large meta-analysis that analyzed data only from RCTs, thereby minimizing the risk of treatment selection bias, immortal time bias, competing risk bias and residual confounding that would otherwise undermine the results of observational studies. Our meta-analysis has also certain limitations. First, the results of our meta-analysis are affected by inherent limitations of the individual trials included in this study such as the significant variations in the use of other medical therapies, which might affect patient outcomes, variations in HCQ dosing regimens and reported patient outcomes. Second, we could not analyze viral clearance at different time points due the discrepancy in outcomes reported in individual RCTs. Finally, we could

This article is protected by copyright. All rights reserved not quantitatively analyze other outcomes of interest such as hospital length of stay and radiological improvement of COVID-19 pneumonia, because RCTs did not report on these outcomes consistently.

In this systematic review, we observed, with high level of certainty of evidence, that HCQ is not effective in reducing mortality in COVID-19 patients. Lower certainty evidence also suggests that HCQ neither improve other clinical outcomes in COVID-19, nor prevent COVID-19 infection in patients with high-risk exposure. HCQ is associated with an increased rate of adverse events.

What is the current knowledge on the topic?

• Anti-malarial agents have been shown to exert in-vitro anti SARS-CoV-2 activity, with conflicting clinical results. The data of the published meta-analyses came mainly from observational studies, hence limiting the reliability of their findings.

What question did this study address?

• This study explores the efficacy and safety of hydroxychloroquine in COVID-19 disease, using data from a large number of randomized clinical trials.

What does this study add to our knowledge?

• Our study provides conclusive evidence that hydroxychloroquine has no benefit in the treatment or prevention of COVID-19 disease. Hydroxychloroquine therapy was also associated with higher incidence of adverse events.

How might this change clinical pharmacology or translational science?

• Our findings will stimulate further mechanistic studies to resolve the contradictory findings of clinical and in-vitro findings.

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This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

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Z.K., I.T., and T.K. wrote the manuscript. I.T. and D.G. designed the research. I.T. and Z.K. performed the research. Z.K., I.T. and T.K.analyzed the data.