key: cord-0960285-0u4ar3b5
authors: Suranagi, U. D.; Rehan, H. S.; Goyal, N.
title: Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence
date: 2020-04-22
journal: nan
DOI: 10.1101/2020.04.16.20068205
sha: e7a8fc4ebd9af96e5ab9ef25a406115a4b7c9b7c
doc_id: 960285
cord_uid: 0u4ar3b5

Purpose: The COVID-19 Pandemic has literally left the world breathless in the chase for Pharmacotherapy. With the vaccine approval likely more than a year away and novel drugs in early clinical trials, repurposing of existing drugs takes the center stage. A potential drug discussed both in geopolitical and global scientific community is hydroxychloroquine (HCQ). We intend to systematically weigh and analyze the existing evidence of HCQ in the light of published and pre-print data available so far. Methods: PubMed Ovid MEDLINE, EMBASE, Google scholar databases and official clinical trial Registries of the United States, China, WHO ICTRP were electronically searched for studies for the use of HCQ in patients with COVID-19. Pre-proof article repositories like MedRxiv, BioRxiv, and ChemRxiv were also included in the search. The literature was critically appraised. Results: Total 71 articles were available as of 15 th April of which articles of relevance (three invitro studies, two open label non-randomized trials, two open label randomized control trials, one follow-up study, three reviews, ten short communications) and 88 clinical trials registered in three clinical trial registries were analyzed. HCQ seems to be efficient in inhibiting of SARS CoV-2 in in-vitro cell lines; there is lack of strong evidence from human studies. Conclusions: The in-vitro cell culture based data of viral inhibition does not suffice for the use of hydroxychloroquine in the patients with COVID-19. Currently literature shows inadequate, low level evidence in human studies. Scarcity of safety and efficacy data warrants medical communities, health care agencies and governments across the world against the widespread use of HCQ in COVID-19 prophylaxis and treatment, until robust evidence becomes available. Keywords: Hydroxychloroquine, SARS-CoV-2, COVID-19, Corona virus, nCov2, systematic review

The ongoing Coronavirus disease 2019 (COVID- 19) pandemic has affected most of the countries in the world with unimagined infectious disease morbidity and mortality. Since its first detection in China in late December 2019, COVID-19 has now spread to over 210 countries/territories, with reports of local transmission happening across the world. As per WHO (as of 15th April, 2020), there has been a total of 1,914,916 confirmed cases and 123,010 deaths due to COVID-19 worldwide. 1 However, no specific drug has been approved for the treatment of COVID-19. As most of the affected countries are fighting everyday to flatten the curve by rigorous public health measures and political resolutions, world is eagerly looking for the vaccine or a specific treatment. Recent updates indicate the vaccine quest is at least a year away. Building on experience from past Ebola and MERS pandemics, various human trials on novel pharmacotherapeutics are in progress. 2 Drugs such as remdesivir and favipiravir are in exploratory phases of clinical trials, and need more time to complete phase 3 clinical trials. 3 In these unprecedented times, there is a pursuit for repurposing of existing drugs for treatment of the SARS-coronavirus 2 (SARS-Cov-2) infection on urgent basis. More than 20 drugs such as chloroquine, hydroxychloroquine, lopinavir, ritonavir, human immunoglobulin, arbidol, oseltamivir, methylprednisolone, bevacizumab, interferons and traditional Chinese medicines are aimed to be repositioned for COVID-19 treatment. 4 Forerunners among these are antimalarial drugs chloroquine and hydroxychloroquine which are used extensively in treatment of malaria and elsewhere since many decades. 5,6 These drugs are 4-aminoquinoline derivatives exhibiting wide range of in-vitro activity against viruses. Wide clinical usage experiences, affordability, feasibility of bulk production are the additional advantages. Their antiviral efficacy has been attributed to many different mechanisms. 7 Studies have demonstrated that chloroquine confers its considerable broad-spectrum antiviral effects by interfering with the fusion process of viruses by increasing the local pH. 8 Other mechanisms may include raise in endosomal pH in host cells thereby inhibiting auto-lysosome fusion and disrupting the enzymes needed for the viral replication. 9, 10 Hydroxychloroquine (HCQ) is synthesized by N-hydroxyethyl side chain substitution of chloroquine. This modification renders HCQ more soluble than chloroquine which may confer advantage of relative lesser toxicity. Similar to chloroquine, HCQ increases the pH and confers antiviral activity. Although the antimalarial activity of HCQ is equivalent to that of chloroquine, HCQ is preferred over chloroquine owing to its lower ocular toxicity. 11 It is also used in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus, and systemic lupus erythematosus. In addition to endosomal pH increase mentioned above, HCQ is also said to inhibit terminal glycosylation of ACE2 receptor, which is considered to be the target of SARS-CoV and SARS-CoV-2 cell entry. 12 The non-glycosylated ACE2 receptor might interact inefficiently with the SARS-CoV-2 spike protein, thus inhibiting the viral entry. 13 These myriad mechanisms of HCQ and its relative lesser toxicity profile as compared to chloroquine make it an attractive candidate in the pursuit of drug repositioning. In this highly demanding scenario of huge unmet need and steeply increasing morbidity and mortality of COVID-19, many government bodies and expert panels have recommended the use of chloroquine and HCQ for the prophylaxis and treatment of COVID-19. 14-18 Recent geopolitical and media coverage of the possibility of this drug usage in COVID-19 has caused a huge stir and expectations among laymen and medical fraternity alike. This has lead to countries engaging in mass production, exports and imports of this drug. In this situation of urgency, there is a need to explore the current literature and critically analyze the existing evidence. We intend to conduct a systematic search analysis of current literature and propose our findings.

An electronic search of the published literature was done independently by each author to find the role of HCQ in COVID-19 disease. PubMed Ovid MEDLINE, EMBASE, Google scholar databases were searched for existing literature from 2019 to 15 th April 2020. The clinical trial Registries of the United States (Clinicaltrials.gov), Chinese Clinical Trial Registry, WHO International clinical trial registry platform (ICTRP) were searched for ongoing registered studies. For preprint/pre-proof articles, repositories like BioRxiv, MedRxiv and ChemRxiv were searched.

Search words included MeSH Terms (hydroxychloroquine or HCQ) AND (COVID-19 OR Coronavirus or nCov2 or SARS-CoV2). Search terms were used in various combinations as per feasibility in different databases. In the view of possible limited data, Google Scholar search terms were kept flexible to encompass wider literature so as to capture all the potential relevant studies. No language, time, study type and demographic filters were used. The search expansion was done using a snowballing method applied to the authors and references of selected publications. The publications selected in this analysis included the abstracts, original research, in-vitro experimental studies, observational studies, controlled/uncontrolled trials, review articles, editorials, letters to editor, expert opinions, perspectives, and consensus statements-published since the inception till 15th April, 2020. News items, magazine pieces, duplicate papers, articles without the mention of the role of HCQ in COVID-19 infection, or use of HCQ in other conditions were excluded.

We searched databases of clinical trial registries of the United States Clinicaltrials.gov, Chinese Clinical Trial Registry, WHO ICTRP using the search terms 'Hydroxychloroquine', 'HCQ', 'Plaquenil', 'COVID-19', 'SARS-CoV2', 'novel Corona virus' 'nCoV 2'. After identification and elimination of duplicated appearances, 88 clinical trials were found to be registered. Each database was further scanned and analyzed to filter out the non-recruiting, inactive and cancelled trials, finally yielding 27 randomized control trials (RCTs) currently undergoing active recruitment for COVID-19 treatment with HCQ.

Preprint server databases BioRxiv, MedRxiv and ChemRxiv were searched for pre-proof, nonpeer reviewed, unpublished, approval awaited studies and articles. We recognized the authors who have already worked and published articles in the current topic and included the relevant studies in our analysis.

Screening of articles was done independently by investigators according to titles, abstracts, summaries and conclusions. The relevance of each article was decided through independent reading and analysis of the full text of all publications. Any discrepancy about the relevance was solved by mutual consensus after elaborate discussion. The relevant data were extracted from selected articles and pertinent portions of studies were identified, tabulated and were presented in the form of a tables & descriptive summary. Narrative summaries, expert opinions, clinical statements were critically appraised as per the Joanna Briggs Institute (JBI) critical checklist of McArthur, et al., 2015. 19 Inferences and interpretations were discussed as per factual data, and balanced conclusions were drawn accordingly. Randomized clinical trials with active recruitment were analyzed after collecting publically available information on various clinical trial databases. Flow Chart of article selection is shown in Fig 1. 

Total 71 articles were identified on initial search of databases as of 15th April, following screening of titles and abstracts and removal of duplicates, the articles of relevance (three invitro studies, 20, 21, 22 two open label non randomized trials, 23, 24 two open label RCTs, 25,26 one follow-up study, 27 three reviews, 28,29,30 ten short communications [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] were selected for further data extraction and analyses. We identified 88 clinical trials registered in three clinical trial registry databases. Methodical screening and analysis further yielded 27 RCTs currently undergoing active recruitment. Pre-print servers yielded four clinical studies which included a follow up study, a retrospective safety study, and a rapid review of chloroquine and HCQ in COVID-19 patients. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. .

Relatively lesser toxicity profile and fewer drug-drug interactions make HCQ an attractive candidate for testing for the antiviral properties. Various broad spectrum antiviral mechanisms of HCQ are proposed viz. change in the pH at the surface of the cell membrane, inhibition of nucleic acid replication, glycosylation of viral proteins, disruption of virus assembly, interruption of viral transport, inhibition of the viral release etc. 41 Previously during the SARS outbreak, HCQ was shown to exhibit anti-SARS CoV effect in an in-vitro study. 20 In this background, Yao et al, assessed the pharmacological activity of chloroquine and hydroxychloroquine using SARS-CoV-2 infected Vero cells. Further as continued part of the study, they simulated physiologically-based pharmacokinetic models (PBPK) on the in vitro data obtained. The researchers found HCQ to be more potent than chloroquine to inhibit SARS -CoV-2 in vitro. Based on PBPK extrapolation, they recommended a loading dose of 400 mg twice daily of HCQ sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days. 21 In another correspondence report letter of an in-vitro study by Liu et al, the investigators used VeroE6 cells and compared the antiviral activity of Chloroquine versus HCQ against SARS-CoV-2 to determine different multiplicities of infection (MOIs) by quantification of viral RNA copy numbers. They found out that 50% maximal effective concentration (EC50) for HCQ was significantly higher than chloroquine and HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. 22 Previously in 2006, French researchers demonstrated that Chloroquine and HCQ effectively inhibit both human and feline SARS COV in the infected Vero cells. EC50 for HCQ was significantly higher than chloroquine. 20 The in-vitro studies using cell culture models demonstrate considerable anti-corona viral activity of HCQ, particularly against SARS CoV2. (Table 1) 

In the positive background of successful in-vitro data and in the situation of an emerging epidemic, the Chinese authorities issued a consensus statement for the use of chloroquine in COVID-19 patients. 14 The earliest data of chloroquine administration in humans came from various parts of China in February 2020. These collective reports were published in the form of exploratory report letter by Gao et al. The authors reported clinical experience data of treating more than 100 patients with chloroquine in various locations. They mentioned that chloroquine reduced the duration of illness and improved the pneumonia and pulmonary image changes in COVID-19 positive patients. The authors also recommended the drug to be included in the COVID-19 Guidelines issued by the National Health Commission of China for the use of drug in larger populations. 42 It is pertinent to note that this data was a brief report from the ongoing studies from multiple settings. 43 The first empirical evidence of use of HCQ in humans was obtained by a small RCT conducted by Chen J et al, in 30 adult COVID-19 patients. The treatment group received 400mg HCQ for 5 days, while the standard care was given to control group. The primary outcome was nasopharyngeal swab test results on Day 7. Investigators found out that there is no difference between treatment and control group in the number of patients testing negative for COVID-19 on Day 7 (13 v/s 14 ), the duration of illness did not differ significantly (all p= >0.05). There was one drop out and seven (three in treatment group and four in control) adverse events. The authors concluded that COVID-19 has good prognosis and larger sample size with better endpoints is needed to investigate the effects further. 25 An open-label, non-randomized clinical trial was conducted by Gautret et al in France with 36 patients diagnosed with COVID-19. HCQ in dose of 200mg three times daily was given to 20 patients for 10 days, additionally six patients in this group received azithromycin (500 mg on day 1, 250mg on days 2-5) to prevent bacterial superinfection. The control group received standard care. The primary outcome was detection of SARS-CoV-2 RNA in nasopharyngeal All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . samples. The authors reported that patients in the treatment group significantly differed for SARS-CoV-2 detection than controls. On Day 6 of post initiation, 70% of HCQ treated patients were virologically cured compared to 12.5% in the control group (p= 0.001). They concluded that HCQ treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin. 23 (Table 2) 

A study group from Wuhan University, China conducted an RCT to demonstrate the efficacy of HCQ in COVID-19 patients. 62 patients were randomized 1:1 with HCQ 400mg for 5 days including standard care as compared with standard care alone. Time taken to clinical recovery All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment with HCQ. Researchers reported that TTCR, body temperature recovery time and cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia were in the HCQ treatment group (80.6%) as compared with the control group (54.8%). Four patients in the control group progressed to severe illness. The researchers concluded that HCQ significantly shortens TTCR and promotes the resolution of pneumonia in COVID-19 patients. 26 A six-day pilot, uncontrolled, non-comparative observational follow-up study was conducted by French investigators to assess the Clinical and microbiological effect of a combination of HCQ and azithromycin in 80 COVID-19 patients. The investigators reported that all patients but two (an 86 yr old succumbed to illness, a 74 yr old needed ICU) showed clinical improvement with the combination therapy. qPCR testing showed a rapid fall of nasopharyngeal viral load-83% and 93% patients were negative at Day 7, and Day 8 respectively. 97.5% of respiratory samples were negative for virus cultures at Day 5. The researchers urged to evaluate the combination strategy to treat patients in early course and avoid the spread of the disease. 27 Imitating the previous non-randomized open label study by Gautret et al 23 another group of French investigators intended to evaluate the rapid antiviral clearance or clinical benefit with the Combination of HCQ and azithromycin in patients with severe COVID-19. The researchers prospectively assessed the virological clearance and clinical outcome in 11 patients. They used similar dosage regimen of HCQ (600 mg/d for 10 days) and azithromycin (500 mg Day 1 and 250 mg days 2 to 5) as used by Gautret et al 23 , they noted that in contrast to the previous findings, the current study had 8 out of 10 patients (except one death) remaining positive for SARS-CoV2 RNA at days 5 to 6 after treatment initiation, one patient died within 5 days, two were transferred to ICU, and one patient dropped out due to prolongation of QT interval. Investigators concluded that there is no evidence of a strong antiviral activity or clinical benefit of the combination of HCQ and azithromycin for the treatment of hospitalized patients with severe COVID-19. 24 In a retrospective study, group of American researchers reported increased QT interval in 84 COVID-19 patients treated with Hydroxychloroquine/azithromycin combination. The authors noted that in 30% of patients, increase in QTc was greater than 40ms and 11% patients showed QTc increase to greater than 500ms, they commented that development of acute renal failure during the therapy could be a strong predictor of extreme QTc prolongation. 44 (Table 3)   Table 3 Summary of preprint articles reporting the use of HCQ in treatment of COVID-19 patients All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . Many of the ongoing RCTs conducted are studying the effect of HCQ compared to placebo (NCT04342221, NCT04333654, NCT04332991, NCT04331834), few of the RCTs have parallel design arms of HCQ and Azithromycin (NCT04341727, NCT04341207, NCT04334382). Some RCTs have robust trial designs with quadruple masking and strong endpoints (NCT04333654, NCT04332991, NCT04331834). Few RCTs are in advance phases of clinical trials (NCT04316377, NCT04341493) and some studies have large sample size to measure the effect with higher strength of confidence (NCT04328012, NCT04328467). There are studies which are considering the safety endpoints in the main outcome measures (ChiCTR2000029868). Some RCTs are also testing antiretroviral drugs like lopinavir/ritonavir, emtricitabine/tenofovir along with HCQ arm ( 

After three months of its detection in China in late December 2019, novel SARS Cov-2 infection has spread to almost all countries in the world and by far threatening to be the biggest pandemic of modern times. With nearly two million infections and more than 123,000 deaths growing up in alarming rate, specific treatment is the most important requirement of the world. Hydroxycholoroquine with the relatively better safety profile than choloroquine 45 and possible better antiviral efficacy 21 offers to be a compelling hope of choice in times of desperation, in the midst of pandemic. We systematically searched various databases and Clinical trial registries to evaluate the evidence. During the previous outbreak of SARS, an in-vitro study demonstrated the anti-corona viral effect of HCQ and choloroquine. 20 More recently Chinese researchers conducted in-vitro studies in cell lines and demonstrated the potential antiviral activity of HCQ against SARS-CoV2 as compared to chloroquine. 21, 22 It is relevant to note that these studies were the basis of initial opinions and general consensus statements given by various panels across the world during the early stages of the current pandemic. We found out that there is scarcity of well conducted and adequately reported human studies of HCQ use in COVID-19. This is in agreement with the other authors with similar findings of lack of literature in this regard. 28, 29, 30, 46 The earliest nonempirical evidence came from China in form of report letter in which more than 100 patients with COVID pneumonia showed clinical improvement and changes in image findings on chloroquine administration. 43 It is pertinent to note that this letter was the brief report of ongoing many trials in various locations in China, neither it mentioned any specific data regarding interventions, study design, study population and outcome measures, nor any adverse events were discussed. We encountered and translated another Chinese RCT of HCQ compared to standard care in 30 COVID-19 patients. The investigators did not find any significant difference between treatment and control group in both nasopharyngeal swab negativity and duration of illness. 25 This study was an open label trial with small sample size and had high risk of confounding and selection bias, the authors agreed that primary end point was weak and more robust end points with larger sample size is required to establish the effects. Gautret et al, 23 in a non randomized clinical trial in 36 COVID-19 patients, reported viral load reduction by HCQ and its reinforcement by azithromycin. This study had major limitations in the form of small sample size, absence of randomization and masking, lack of intention to treat analysis and long term follow up, there was no clinical endpoint as outcome measure. Among pre-print, non-peer reviewed studies, an RCT by Chen Z et al. exploring HCQ and azithromycin in 62 patients reported significant improvement in time to clinical recovery and radiological findings. However, sample size in this study is small and risk of selection bias (omission of severely ill patients, and patients with organ dysfunctions) and confounding bias is high. Authors did not involve patients with prolonged QT intervals and comments on safety profile of the treatment were brief. Endpoints did not include viral RNA clearance and lab investigations; follow-up is not reported in the study. 26 A non-comparative observational French follow-up study in 80 COVID-19 patients reported 97.5% of respiratory samples were negative for virus cultures at Day 5. This study too involved only mild illness patients and did not report adverse effect profile and being an uncontrolled observational study, the strength of evidence tends to be low. 27 In contrast, a similar study from France, which imitated the dosage regimen of the previous French non randomized open label study, 23 observed that there is no evidence of rapid viral reduction and clinical benefit from the combination therapy of HCQ and azithromycin. It is pertinent to note that this study was conducted only in 11 patients with severe COVID-19. 24 We also searched, identified and analyzed clinical trial databases to explore the ongoing active clinical trials (Supplementary table 1) and found out relevant 27 clinical trials. Many trials among these are in advanced phases and few trials are expecting completion in near future. Earlier registered Chinese clinical trials are expected to come out with definitive results in next few weeks and also robust designed RCTs elsewhere in the world are expected to produce their interim results shortly henceforth. (Supplementary table 1) All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . It is appropriate to note that none of the published studies of HCQ in COVID-19 have emphasized on the adverse effects and toxicity profile of the drugs in treated patients. Chen Z et al 26 reported two adverse events, however due to very small sample size it is difficult to attribute these to HCQ. Even though HCQ has relatively better safety profile than chloroquine, owing to its prolonged pharmacokinetics (537 hours half life) and gradual elimination, it has potential to cause various adverse events ranging from commonly seen gastrointestinal upset, 47 and chronic retinal toxicity, 48 to serious adverse effects like fulminant hepatic failure, 49 severe cutaneous adverse reactions. 50 An important adverse effect of HCQ is cardiac conduction defects and ventricular arrhythmias. QT prolongation and arrhythmias can be precipitated by concomitant use of azithromycin. 44 Small but absolute risk of cardiovascular death is seen to be associated significantly with azithromycin as compared to fluoroquinolones. 51 It is important to note that overdose or poisoning of HCQ is difficult to treat. Caution is warranted in patients with hepatic and renal dysfunction, and regular ECG monitoring is advised in patients with cardiovascular diseases. Irrational use in general population without credible evidence may pose greater risk than benefit. To best of our knowledge, this systematic review is the most comprehensive exploration and analysis of existing literature in this topic till date. Our review has limitations in its rigor due to the scarce existing data and diverse study types available. The rapidly emerging knowledge base of COVID-19 poses the possibility that few studies (particularly unpublished/under peerreview) remain un-captured. However, we have tried our best to mitigate this by allowing broadest search terms and by including many databases and repositories. We have also tried to comprehensively analyze and assess the existing data under the critical lens of factual judgment. In this background, we believe that expert opinions and clinical consensus statements given by various international authorities for the use of HCQ either as prophylaxis to high risk individuals 15 and healthcare professionals 16 or as emergency treatment of COVID-19 patients. 17,18 lacks strong evidence base.

The in-vitro cell culture based data of viral inhibition does not suffice for the use of hydroxychloroquine in the patients with COVID-19. Current literature shows scant and low level evidence in human studies. Understandably due to the urgency and unmet need of the pandemic, various expert guidance and consensus statements recommend the empirical use of HCQ. However, at this stage due to insufficient evidence on efficacy and safety, it is reasonable to suggest against the use HCQ as prophylaxis both in general population as well as health care workers. Considering the toxicity profile, chances of overdoses and poisoning can pose serious health threats if HCQ is used widely. Ongoing well designed clinical trials are expected to provide explicit answer in near future. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. End-Oct 2020

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In the view of inadequacy of existing evidence, it is advisable that medical communities, health care agencies and governments across the world should be warranted against the widespread use of HCQ in COVID-19 prophylaxis and treatment, until robust evidence becomes available.