key: cord-0917645-xro082go
authors: Kumar, Jogender; Jain, Siddharth; Meena, Jitendra; Yadav, Arushi
title: Efficacy and Safety of Hydroxychloroquine/chloroquine against SARS-CoV-2 Infection: A Systematic Review and Meta-analysis
date: 2021-02-22
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.02.021
sha: 95cef73faa26e05a9adb007337320b0019ab4cf4
doc_id: 917645
cord_uid: xro082go

Introduction Hydroxychloroquine (HCQ) has been evaluated for treatment and prophylaxis against SARS-CoV-2 infection in various studies with conflicting results. We performed a systematic review to synthesize the currently available evidence over the efficacy and safety of HCQ/CQ therapy alone against SARS-CoV-2 infection. Methods We searched Embase, PubMed, Web of Science, and Cochrane central for randomized controlled trials (RCTs) and prospective cohort studies published until October 15, 2020 and assessing the efficacy of HCQ alone against SARS-CoV-2 infection. We included studies evaluating HCQ/CQ alone as intervention and placebo/standard care as a control group. Retrospective studies and studies using other drugs (namely azithromycin, corticosteroids, immunomodulators, etc.) we excluded. Thirteen RCTs and three prospective cohort studies were included in this review. We pooled data using a random-effect model. Results Pooled data from nine RCTs (9171 participants) showed that HCQs increase mortality as compared to placebo/standard of care (RR 1.10; 95% CI:1.00-1.21). Hydroxychloroquine did not reduce the need for hospitalization in out-patients (RR 0.57; 95% CI 0.31-1.02). HCQ group has a significantly higher rate of any adverse event (RR 2.68; 95% CI 1.55-4.64), as compared to the control group. Also, using HCQ for prophylaxis against SARS-CoV-2 infection did not reduce the risk of acquiring SARS-CoV-2 infection (RR 1.04; 95% CI 0.58-1.88). Conclusions HCQ therapy for COVID-19 is associated with an increase in mortality and other adverse events. The negative effects are more pronounced in hospitalized patients. Therefore, with the available evidence, HCQ should not be used in prophylaxis or treatment of patients with COVID-19.

With close to 53 million cases and 1.3 million deaths globally, the coronavirus disease 2019 pandemic has caused unprecedented damage and continues to wreak havoc, plaguing healthcare systems globally [1] . Despite being almost a year since the pandemic commenced, a conclusively efficacious and safe therapy for COVID-19 still evades us.

Numerous antiviral and immunomodulatory drugs have been tried, but none has shown unequivocal evidence of efficacy and safety across the studies in COVID-19 [2] . Chloroquine (CQ) and Hydroxychloroquine (HCQ) are one such group of immunomodulatory agents that were considered to have antiviral property against SARS-CoV-2 and were used extensively without any strong evidence [3] . Several mechanisms have been proposed for their role in COVID-19. These mechanisms include: (i) Direct antiviral action (by inhibiting viral attachment/biosynthesis of sialic acid/inhibition of replication and transcription); (ii)

Interleukins, and Th17 differentiation); and (iii) Anti-thrombotic effect (by decreased platelet aggregation, inhibiting the membrane binding of clotting proteins, and improvement of endothelial relaxation) [4, 5] .

Hydroxychloroquine formed a part of the national guidelines for prophylaxis in some countries like India, based on preliminary evidence [6] . Recently, HCQ/CQ has been evaluated as prophylactic and therapeutic agents using rigorous study designs with varying results [7] [8] [9] [10] [11] [12] . Serious concerns were raised over the adverse cardiovascular effects associated with HCQ use [13, 14] . However, the long multidecadal experience of its safety (comparable doses) as an immunomodulator in rheumatic diseases arose the possibility of confounding by the underlying disease and the effect of concomitant therapy such as macrolides [15] . Recently few reviews summarized the available evidence, however, they J o u r n a l P r e -p r o o f included studies with heterogeneous intervention and control groups [16] [17] [18] . Therefore, the evidence of safety and efficacy of HCQ/CQ alone against COVID-19 is unclear.

We aimed to systematically synthesize the evidence over the efficacy and safety of HCQ or CQ alone as compared to placebo or no active intervention in adults with COVID-19.

We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines during the conduct of this systematic review [19] . A predefined specific search strategy was developed for each electronic database October 15, 2020 . We used keywords related to the study population (exposed to patients with SARS-CoV-2 infection or having RT-PCR confirmed SARS-CoV-2 Infection), and intervention (Hydroxychloroquine or Chloroquine) for literature search. The electronic search was also supplemented by a hand search of the bibliography of the included studies and relevant review articles. We did not use any language restriction. The studies in non-English language were converted to English using google translator and relevant data was extracted.

The protocol for this systematic review was registered at the PROSPERO database (CRD42020201750). Criteria mentioned in the above protocol were used for the assessment of the eligibility of the studies. Studies investigating the role of Hydroxychloroquine or Chloroquine as a therapeutic or prophylactic agent for SARS-CoV-2 infection were considered eligible for the review. Initially, two researchers (JK, JM) independently screened the titles and abstracts for eligibility. Later three authors (AY, JM, JK) examined the full-text J o u r n a l P r e -p r o o f articles for inclusion and exclusion criteria. Studies were included if they met all the following criteria: (i) Population-studies enrolling patients with clinically suspected or RT-PCR-confirmed SARS CoV-2 infection (therapeutic studies) or their contacts (prophylaxis studies), (ii) Intervention-HCQ or chloroquine (CQ) along with standard care for prophylaxis or treatment. (iii) Comparison-control group should receive standard care alone (that does not include antivirals or immunomodulators) or placebo. We included prospective cohort studies or randomized/non-randomized controlled trials. Considering the rapidly evolving evidence and the long-time taken to get a study published after peer-review, we also included pre-print studies after rigorous methodology checks. The methodology check comprised of inclusion of the latest version of the manuscript uploaded on pre-print server, ensuring that the trial protocol was registered with one of the registries and is accessible to public, and the authors followed standard reporting guidelines for presenting the results. We also checked the comments associated with the pre-print version (which act like a peer-review) to ensure that there are no serious concerns associated with data-quality or results.

We excluded: (i) studies comparing HCQ or CQ with active control or comparator group However, if no such data was provided and the majority were confirmed COVID-19, data of all the patients were included.

A well-structured, standardized proforma was used for data extraction. Two investigators [JM, JK] independently extracted data from the full text of the eligible studies. Data extraction included information about: Author's name, year of publication, journal, study design, study setting, study methodology, study population, inclusion and exclusion criteria, baseline demographic characteristics, details of intervention and control group, case definition of SARS-CoV-2 infection, and contacts, intervention (dosage, duration, frequency, and co-administration of other therapy if any),and outcomes (mortality, the proportion of patients recovered, time to clinical recovery, time to viral clearance, the proportion of participants requiring hospitalization, the proportion of patients developing severe disease, duration of hospital stay, duration of ICU stay, the proportion of acquiring infection among exposed ones, adverse effects, etc.). Any disagreement between the two investigators was resolved through discussion with the third investigator (SJ). A researcher (AY) independently rechecked the extracted data for its accuracy and completeness. The quality of the RCTs was assessed using the Cochrane risk of bias tool [20] , while for observational studies, the Newcastle Ottawa scale [21] was used. Two investigators (JM, JK) independently assigned an overall risk of bias to each eligible study, and if they disagreed, another researcher (SJ) was called to resolve the discrepancy.

We provided a quantitative synthesis of primary and secondary outcomes. The dichotomous outcomes are reported as risk ratio (RR) with 95% CI and continuous data as mean difference (MD) with 95% CI. We pooled the data using the random-effects model. Heterogeneity J o u r n a l P r e -p r o o f among studies was assessed by inspection of the forest plot as well as using the Chi-square test on Cochrane's Q statistics and I² statistics. The publication bias was assessed by Funnel plot asymmetry. We used RevMan 5.3 for statistical analysis. We also graded the level of evidence using GRADEpro software. For GRADE evidence, only randomized controlled trials were used.

We screened a total of 3560 records and identified 16 studies [8] [9] [10] [11] [12] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] Table   1 . The quality of the studies was assessed using the Cochrane risk of bias tool for RCTs ( Figure 2 ) and the Newcastle-Ottawa scale for observational studies (Supplementary Table   S2 ). We intend to assess publication bias using funnel plot; however, the number of studies was insufficient for the same (only 6 RCT and 2 non-RCT reported mortality). The Cochrane handbook recommends using tests for funnel plot asymmetry only when there are J o u r n a l P r e -p r o o f at least 10 studies included in the meta-analysis, as with fewer studies, the power of test becomes too low to detect real asymmetry.

Nine RCTs (9171 patients) reported data on all-cause mortality. The overall mortality rate was 14.7% and 16.5% in the HCQ and control group, respectively. Treatment with HCQs as compared to the control group increases the risk of mortality (RR 1.10; 95% CI 1.00-1.21) (Table 2) . Among the patients who were not on mechanical ventilation at the time of randomization, HCQ does not reduce the need for mechanical ventilation (RR 1.12; 95% CI 0.95-1.33) (Fig.4) . Two RCTs reported the proportion of patients requiring admission to the intensive care unit and did not find any significant difference between the HCQ and control group ( J o u r n a l P r e -p r o o f CI 0.72-1.95). Though in a single prospective cohort, HCQ has a significantly higher viral recovery rate, the same was not seen in randomized controlled trials (Table 2) .

HCQ group has a significantly higher rate of any adverse event (41.3 % vs. 16 

Use of HCQ for prophylaxis (pre-or post-exposure) against SARS-CoV-2 infection neither reduces the risk of acquiring SARS-CoV-2 infection (RR 1.04; 95% CI 0.58-1.88) nor the need for hospitalization (RR 0.64; 95% CI 0.28-1.47). On the other hand, it increases the risk for any adverse event (RR 1.87; 95% CI 1.39-2.51). None of the trials reported any serious adverse event associated with HCQ use as prophylaxis.

In this meta-analysis, we have pooled key efficacy and safety outcomes of the use of HCQ or CQ alone for the treatment and prophylaxis of COVID-19. All except one used HCQ in the intervention arm. The use of HCQ alone for the treatment of COVID-19 was found to increase the risk of all-cause mortality (moderate-quality evidence). On subgroup analysis, this increase in mortality was predominantly seen in hospitalized patients (high-quality evidence) but not in non-hospitalized patients (low-quality evidence). Also, HCQ use led to a significantly higher adverse event rate (low-quality evidence), but the serious adverse event rate was similar to the control group (very-low quality evidence). There was no significant difference in other secondary efficacy outcomes (low to very low-quality evidence).

A subgroup analysis of the primary outcome as per the disease severity found the effect on mortality to be limited to trials involving patients of all types of disease severity. Separate subgroup analysis for mild, moderate, and severe disease severity was not feasible due to a lack of reporting of separate data for different disease categories. In the trials including patients with mild-to-moderate disease, there was a trend towards increased mortality, though it did not reach statistical significance [9, 10, 23] . This difference could be due to the low event rate in the later population.

We explored the possible reasons for increased mortality in the HCQ group and did not find any difference in baseline characteristics like age, disease severity, the timing of initiation of therapy after symptom onset, care given other than the intervention, etc. among the two groups. Furthermore, we excluded studies employing combination therapy of HCQ/CQ with antivirals, macrolides, and other active agents in either control or intervention group, therefore, the confounding effect of the other drugs (macrolides, corticosteroids, immunomodulators, etc.) or any other therapy is unlikely. Also, there was a trend towards the increased need for mechanical ventilation (low-quality evidence) in patients treated with HCQ, for reasons not clearly understood. Besides, treatment with HCQ did not reduce the need for ICU admission (very-low quality evidence), progression to severe disease, or duration of hospital stay in patients with COVID-19. Taken together, these data highlight that the use of HCQ may preferably be avoided in patients hospitalized with COVID-19.

Interestingly, there was no increase in mortality in non-hospitalized patients of COVID-19 treated with HCQ (low-quality evidence). Also, there was a trend towards a reduction in the need for hospitalization in outpatients treated with HCQ (low-quality evidence). Taken together, this may point to a possible benefit of HCQ in this cohort of patients, which needs to be addressed separately in dedicated randomized controlled trials.

Although one small study reported better radiological recovery with HCQ (very-low quality evidence),the impact over clinical recovery was not observed (very-low quality evidence) [28] . The pooling of data on virological recovery with HCQ yielded conflicting results. The data from relatively large prospective cohort studies reported higher (low-quality evidence) and faster (very-low quality) virological clearance with HCQ, but the same was not consistently seen in RCTs. The virological clearance may have significant public health importance, with a faster clearance potentially helping in curbing transmission and achieving disease control. However, with the current evidence, we are unsure about its effect over virological clearance, a fundamental basis on which it was widely used even before the clinical evidence emerged.

Furthermore, a higher rate of adverse events in the HCQ group (low-quality evidence) is worrisome, even though the pooled risk of serious adverse events (including cardiac arrhythmias) was not different (very-low quality evidence). Dose-adverse effect correlation could not be attempted due to the wide variability in the dosing regimens used in different studies. This data suggest that the high rates of cardiac toxicity noted in a few observational studies of HCQ may, at least in part, be because of concomitant therapies like azithromycin, and frequently observed cardiac involvement by SARS-CoV-2 [33].

Although case-control and unpublished studies from India reported positive results with HCQ prophylaxis in healthcare workers, none of the three RCTs to this end found any reduction in the incidence of COVID-19 with HCQ prophylaxis (moderate-quality evidence) [6] [7] [8] 29, 30] .

Besides, adverse events were also found to be increased (moderate-quality evidence), though serious adverse events (including cardiac arrhythmias) were not seen. Taken together, HCQ should not be used in prophylaxis against COVID-19.

We have registered protocol for this systematic review in PROSPERO and followed it rigorously during the conduct of this systematic review. We have included only randomized clinical trials and prospective cohort studies with controlled groups comparing HCQ/CQ alone with placebo/control to avoid selection bias and confounding effects of other interventions. This systematic review also has a few limitations. First, included trials enrolled patients with mild to severe disease and did not report separate data for individual disease severity hence, we could not assess the effect of HCQ separately on patients with severe COVID-19 for which the evidence is most needed. Although, we did attempt a separate analysis comparing mild-moderate disease patients with all types of disease severity (including severe ones). Second, we could find only limited data for most of the secondary outcomes hence, the overall quality for these outcomes was low to very-low. Third, with the available data, we could not assess the dose-response relationship of HCQ. However, the findings were consistent across all trials, and it is unlikely that any given dosage has a protective effect against COVID-19.

Moderate quality evidence suggests that the use of hydroxychloroquine as a treatment for COVID-19 is associated with a considerable increase in mortality and other adverse events.

The negative effects are more pronounced in hospitalized patients. Therefore, based on current evidence the HCQ should be avoided for prophylaxis or treatment of COVID-19 in hospitalized patients. However, the positive effects of HCQ over the need for hospitalization without any increase in mortality in out-patients (mild disease) warrants further exploration. Data Availability Statement: Data will be made available on request. 

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