key: cord-0903060-8406ejvs
authors: Singh, Harmanjit; Chauhan, Prerna; Kakkar, Ashish Kumar
title: Hydroxychloroquine for the treatment and prophylaxis of COVID-19: The journey so far and the road ahead
date: 2020-11-03
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173717
sha: 45c08a9b399e78d8f3559975fc8d2f5147500dd7
doc_id: 903060
cord_uid: 8406ejvs

As mortality and morbidity from novel coronavirus disease (COVID-19) continue to mount worldwide, the scientific community as well as public health systems are under immense pressure to contain the pandemic as well as to develop effective medical countermeasures. Meanwhile, desperation has driven prescribers, researchers as well as administrators to recommend and try therapies supported by little or no reliable evidence. Recently, hydroxychloroquine-sulfate (HCQS) has got significant media and political attention for the treatment as well as prophylaxis of COVID-19 despite the lack of convincing and unequivocal data supporting its efficacy and safety in these patients. This has unfortunately, yet foreseeably led to several controversies and confusion among the medical fraternity, the patient community as well as the general public. Based on the available studies, many with high risk of bias, relatively small sample sizes, and abbreviated follow-ups, HCQS is unlikely to be of dramatic benefit in COVID-19 patients and yet has the potential to cause harm, particularly when used in combination with azithromycin or other medications in high risk individuals with comorbidities. Although definitive data from larger well-controlled randomized trials will be forthcoming in the future, and we may be able to identify specific patient subpopulations likely to benefit from hydroxychloroquine, till that time it will be prudent to prescribe it within investigational trial settings with close safety monitoring. Here we review the current evidence and developments related to the use of HCQS in COVID-19 patients and highlight the importance of risk-benefit assessment and rational use of HCQS during this devastating pandemic.

other investigational agents available through compassionate use and expanded access programs (Management of COVID-19, 2020) .

Use of broad-spectrum antiviral drugs like neuraminidase inhibitors, ribonucleic acid (RNA) synthesis inhibitors, nucleoside analogues, and human immunodeficiency virus (HIV)-protease inhibitors could possibly play a key role in the management of affected patients, although the current evidence base supporting their use is rather weak (Lu, 2020) . Furthermore, a number of drugs have received emergency use authorization or are in pipeline such as -remdesivir, galidesivir, lopinavir/ritonavir combination, favipiravir, and several vaccines in both preclinical as well as early and late phase clinical trials (Pang et al., 2020) . Recently, experimental use of hydroxychloroquine sulphate (HCQS) for treatment as well as prophylaxis of COVID-19 has led to several controversies and confusion among the medical fraternity as well as the lay public, often fuelled by political statements (Lowe, 2020; President's Tweet, 2020) . In this review, we critically examine the current evidence and developments related to the usage of HCQS in COVID-19, controversies surrounding its use for prevention and treatment, and highlight the importance of rational use of HCQS to ensure its benefits outweigh the associated risks. A global timeline of significant developments related to the deployment of HCQS for the management of COVID-19 is outlined in Table 1 .

For this study, an open search for pertinent publications was conducted through google search and MEDLINE using keywords like "hydroxychloroquine sulphate", "hydroxychloroquine", "chloroquine", "COVID-19", "SARS-CoV-2", "coronavirus", "2019-nCoV", "acute respiratory distress syndrome", and with their corresponding MeSH terms, if any, connected by OR, AND Boolean operators, wherever applicable.

No search filters were applied. In addition, we used the snowball technique to gather further relevant papers from the reference lists of the initial search result articles.

J o u r n a l P r e -p r o o f 7 investigation. The study raised the hopes of various stakeholders, however, few weeks later, it led to significant controversies related to its methodology and concerns regarding inclusion criteria amongst others (Molina et al., 2020; Retraction Watch., 2020) . Consequently the journal instituted an additional independent peer review to clarify these concerns as per publisher policies and standards of the Committee on Publication Ethics (COPE) (Joint ISAC and Elsevier Statement on Gautret et al., 2020;  Statement on IJAA Paper. Joint ISAC and Elsevier Statement on Gautret et al., 2020) .

In a randomized prospective pilot study reported by Chen J et al., 30 patients diagnosed with COVID-19 were included, and the efficacy and safety of HCQS were evaluated.

Patients were randomized to either HCQS 400 mg once daily for five days in addition to conventional treatment or conventional treatment alone. On day 7, no significant difference was found in throat swabs negative patients in HCQS (86.7%) vs. control group (93.3%). In addition, no statistical difference was observed in the median time taken from hospitalization to virus nucleic acid negativity between the two study groups (HCQS group -4 days; Control group -2 days). Even temperature normalization and radiological progression were comparable. No significant benefit of using HCQS in COVID-19 was demonstrated in this study and the authors concluded that adequately powered studies are required to conclusively determine the efficacy of HCQS in the management of COVID-19 patients .

In another randomized trial conducted by Chen Z et al. among 62 patients suffering from COVID-19, 31 were randomized to receive an additional five days therapy with HCQS 400 mg per day. All the study participants received the standard therapy consisting of oxygen, antimicrobial agents, and immunoglobulins, with or without glucocorticoids. The authors found that time to clinical recovery, temperature recovery, and remission of cough were significantly improved in patients receiving HCQS and J o u r n a l P r e -p r o o f also a greater number of these patients demonstrated improvement in pneumonia (81%) as compared to controls (55%). They concluded that HCQS could significantly shorten clinical recovery times and improve pneumonia in COVID-19 patients . Evidently, this randomized study had a better sample size as compared to the above two studies and a well-defined control group and inclusion criteria. However, the data are yet to be published after having undergone a rigorous peer review and the manuscript is currently available as a preprint version. Since this article is reporting a yet to be evaluated, new medical research, the results cannot be conclusively applied to clinical practice as yet.

In an another observational study done in France by Gautret et al. , the efficacy of HCQS and azithromycin combination was evaluated in eighty patients diagnosed with COVID-19. The authors reported a substantial reduction in the viral load -83% of the patients showed negative results on quantitative polymerase chain reaction (qPCR) on day 7 and 93% on day 8. They also reported that respiratory sample viral cultures were negative in nearly 98% of the patients on the fifth day, which helped patients to be discharged earlier (Gautret et al., 2020b) . This data may be encouraging, but this study suffered from lack of a control group. Also, the early discharge and negative test status of the patients would depend on their individual baseline immune status, which has not been accounted for or adjusted for in the study results. The observational nature of the study, small sample size, and loosely defined inclusion and exclusion criteria are some of the major limitations of this study.

In a study by Million et al., data pertaining to 1061 patients diagnosed with COVID-19, who were treated with HCQS plus azithromycin for at least 3 days at IHU Méditerranée Infection, Marseille, France, were reported. The authors found improved clinical J o u r n a l P r e -p r o o f outcomes and virologic cure in 92% of the patients within ten days of hospitalization. A poor outcome was reported only in 4.3% of the patients, and mortality was reported in less than 1% of the patients. They did not report any cardiotoxicity among these patients, and poor clinical outcome was related to older age, disease severity and low hydroxychloroquine concentrations. Limitations of the study were the lack of control group as well as incomplete data for some patients, including computed tomography scans and serum HCQS levels (Million et al., 2020) .

In a multicentric network cohort and self-controlled case series reported by Lane et al., nearly 310,000 users of HCQS and sulfasalazine, 323,000 users of HCQS and azithromycin, and 352,000 users of HCQS and amoxicillin were included. The authors did not find any increased risk of serious adverse events with 30-day HCQS versus sulfasalazine use. On the other hand, HCQS-azithromycin was associated with an excess risk of 30-day cardiovascular mortality, congestive cardiac failure and angina when compared to users of HCQS and amoxicillin. The authors concluded that while short-term therapy with HCQS is safe, azithromycin addition may lead to significant cardiovascular morbidity and mortality, possibly due to synergistic effects on QT interval, and hence a cautious approach is warranted (Lane et al., 2020) . This multinational study, although has a large sample size and is based on claims data and electronic medical records from 14 sources, it is still available as a preprint and hence cannot be translated into clinical practice recommendations as of now. These data discourage the concomitant use of HCQS and azithromycin and are contrary to those of studies reported by Gautret et al (Gautret et al., 2020a; Gautret et al., 2020b) .

However, this study was not been done on actual COVID-19 patients; rather the safety data have been extrapolated given the potential use of HCQS and azithromycin in these patients. HCQS has also been utilized for post-exposure prophylaxis against COVID-19 in a Korean study. This study conducted in a long term care hospital involved 211 participants, including 189 patients and 22 hospital workers. Post-exposure prophylaxis with HCQS 400 mg/day for 14 days was completed by more than 95% of the participants. Interestingly both the baseline as well as 14-day follow-up PCR tests for COVID-19 were negative in all individuals and none of the patients reported any serious adverse event during the study. The study did not have a control group, while 92 other hospital workers including clinicians and nurses who did not receive HCQS also tested negative at the end of the 14-day period. The choice of the dose also seems to be arbitrary and high, especially when compared to the approved dosage for malaria prophylaxis that is 400 mg per week (Lee et al., 2020) .

Tang et al. conducted a randomized controlled trial to evaluate the effects of adding HCQS to standard care in 150 mild to moderate laboratory confirmed COVID-19 patients at 16 treatment centres across China. HCQS was administered as a loading dose of 1.2 g mg per day for 3 days, followed by 0.8 g per day for 2-3 weeks depending upon disease severity. The authors did not find a significant difference in the J o u r n a l P r e -p r o o f probability of SARS-CoV-2 negative conversion in HCQS group vs. standard care alone at 4 weeks (85.4% vs 81.3%). Thirty percent of the patients in the HCQS group reported adverse events, mostly gastrointestinal, versus 9% in the control group. The main limitations of this study were open label design and failure to achieve the predetermined sample size of 360 patients due to a rapid decline in the number of eligible participants following the control of outbreak .

In a retrospective analysis of 807 COVID-19 patients admitted to US Veterans Health Administration (VA) medical centres, comparisons were drawn between patients not receiving HCQS (n=395), receiving HCQS alone (n=198) or in combination with azithromycin (HCQS+AZ, n=214). The mortality rates found were 19%, 23%, and 9% (P<0.001) among patients who received HCQS alone, HCQS plus AZ, and no HCQS respectively. In contrast, the mechanical ventilation rates in the three study groups were 19%, 21%, and 20% respectively (P=0.94). After propensity score adjustments, the authors found a significantly higher risk of mortality from any cause in the HCQS group as compared to non-users (adjusted hazard ratio (aHR) 1.8, 95%confidence interval(CI): 1.2-2.9, P=0.009) but not in the combination therapy group (aHR 1.3, 95% CI 0.8-2.15, P=0.28). The risk of ventilation as well as death after mechanical ventilation was comparable in the three study groups. Thus there was no significant reduction in the deaths or in the requirement for mechanical ventilation with HCQS +/azithromycin treatment. Besides methodologic limitations such as retrospective analyses and non-randomized treatment allocations, the study results may have been biased by residual confounding and the use of codes for identification of patient characteristics and outcomes. Moreover, being a veteran study, there was a considerably high proportion of males (>95%) among the participants (Magagnoli et al., 2020) . Mahevas et al. collected data from routine care of 181 COVID-19 patients J o u r n a l P r e -p r o o f requiring oxygen across four French hospitals. While eighty-four of them received HCQS 600 mg daily within 48 hours of admission, 97 did not receive HCQS, and the patients were assessed for primary outcome of survival without intensive care unit transfer at 21 days of inclusion. A weighted analysis was done, and no significant difference was found for the primary outcome (76% in HCQS vs. 75% in non-HCQS group, weighted HR-0.9,95% CI-0.4-2.1). The two groups were comparable in terms of overall survival as well as survival without acute respiratory distress syndrome at 21 days. Eight patients in the HCQS group were found to have electrocardiogram (ECG) changes requiring treatment discontinuation. Thus, their study results failed to support the use of HCQS for improving outcomes in COVID-19 patients who require oxygen support. Although authors reported the use of robust statistical methods for adjustment, residual confounding could have biased the study results and four crucial prognostic variables-confusion at admission, liver cirrhosis, heart failure, and chronic kidney disease, could not be balanced in their propensity score model. The study did not include a power analysis and centre effect was not taken in the propensity score model (Mahévas et al., 2020) .

In a retrospective cohort study including 1438 patients admitted across twenty-five hospitals, Rosenberg et al. found the adjusted HR for mortality to be 1.08 for HCQS alone, 0.56 for azithromycin alone, and 1.35 for HCQS plus azithromycin group as compared to treatment with neither agent, none of the values being statistically significant. Cardiac arrest, however, was more likely to occur in individuals who received the combination therapy (adjusted odds ratio (OR) 2.13, 95% CI 1.12-4.05).

The authors concluded that treatment with any of three experimental regimens failed to improve mortality in COVID-19 patients. The main limitations of this observational study were mortality data limited only to in-hospital deaths, possible lack of temporal association of adverse events with drug intake, unmeasured residual confounders, and lack of power for some of the study analyses (Rosenberg et al., 2020) .

In an observational study done by Geleris et al., more than 1400 COVID-19 patients were enrolled, and the effect of HCQS administration on the risk of intubation or mortality was examined. The outcomes were compared among patients who were given HCQS (n=811) at a dose of 600 mg twice on day 1 followed by 400 mg per day for a median period of 5 days vs. those who were not administered HCQS (n=565). Out of 1376 patients (rest died or excluded), 811 received HCQS. The study authors did not find any significant relationship between HCQS use and intubation or mortality (HR-1.04, 95% CI-0.8, 1.3), and they concluded that HCQS administration did not lead to either a significantly higher or lower risk of death or intubation. The authors confirmed these results in multiple sensitivity analyses, although some degree of unmeasured confounding cannot be ruled out. Other limitations of this study include the involvement of single study centre, some missing data, as well as reliance on electronic health records (Geleris et al., 2020) .

A double-blind, placebo-controlled randomized trial by Boulware et al., evaluated the role of HCQS in post-exposure prophylaxis (PEP) of COVID-19 with the primary outcome as the occurrence of COVID-19 within two weeks -either confirmed by laboratory testing or as a new compatible illness. Adult participants who were either household or occupational close contacts of diagnosed Covid-19 patients were enrolled in this trial. Individuals were randomized to receive either placebo (n=407) or HCQS (n=414) in a dose of 800 mg, followed by 600 mg within 6 -8 hours, followed by 600 mg per day for four more doses. Eleven subjects in the HCQS arm (2.7%) and 9 in the placebo arm (2.2%) developed lab-confirmed COVID-19 (P=0.82) The study groups J o u r n a l P r e -p r o o f independent reviewers were unable to verify the primary data sources due to potential violation of confidentiality agreements with the clients (Editors, 2020; Mehra,, et al., 2020a; Mehra et al., 2020b) .

More recent studies have demonstrated similar trends with observational studies reporting positive results while randomized controlled trials failing to replicate those significant benefits in COVID-19 patients. Arshad et al. conducted a multicentric retrospective observational study enrolling more than 2500 patients. These individuals were treated with HCQS alone, HCQS plus azithromycin, azithromycin alone, or neither of these agents. The overall mortality in these four study groups was found to be 13.5%, 20%, 22%, and 26%, respectively (P<0.001). In the multivariable Cox regression model, the authors reported a 66% (P<0.001) mortality hazard ratio reduction in the HCQS alone group and a 71% reduction in HCQS plus azithromycin group (P<0.001). No episodes of torsades de pointes were recorded in the study participants (Arshad et al., 2020) placebo-controlled study across US and Canada and included nearly 420 symptomatic, non-hospitalized adults who received either oral hydroxychloroquine or placebo. The primary end point was change in the overall severity of symptoms over two weeks using a ten point visual analogue scale. The study failed to detect a significant improvement in symptom severity (P=0.12). Importantly, the number of patients reporting drug related adverse events were nearly double in the HCQS group (43%) as compared to placebo (22%) (P<0.001). The number of patients undergoing hospitalizations did not differ between the two study groups .

Mitja et al. conducted a multicentric, open label study in Catalonia to assess whether early intervention with HCQS was effective in reducing the viral RNA load or shortening the time to symptom resolution in patients with mild COVID-19. Their study enrolled 293 patients who were randomized to either of the two study groups: HCQS for one week or no antiviral treatment. They found no statistical differences in the mean reduction in viral loads at day 3 or 7 in the two study groups. HCQS also did not reduce the risk for hospitalization or lead to early resolution of symptoms. No major HCQS related adverse events were recorded in their study (Mitjà et al., 2020) .

Current clinical evidence does not seem to be definitive enough to support or refute the use of HCQS for COVID-19 management. Several preprint studies are yet to be peer reviewed and the global investigative efforts are probably not well coordinated. Given the equivocal data on safety as well as efficacy for HCQS especially in combination therapy, the prevailing benefit-risk dilemma can only be resolved by data derived from further well designed, adequately powered, randomized, and controlled clinical trials. However, no guidance on the prophylactic use was given and it only recommended the use of HCQS among serious COVID-19 patients. The healthcare professionals were also expected to report serious adverse events and patient outcomes associated with the use of HCQS and chloroquine in COVID-19 patients (HHS Accepts Donations, 2020; Hinton DM, 2020; Lenzer, 2020).

In April 2020, the FDA issued a safety warning against the use of these medicines outside the ambit of clinical trials or hospitals due to the possible risk of arrhythmias, including prolongation of QT interval and ventricular tachycardias. The agency particularly highlighted a heightened risk in patients using concomitant azithromycin or those with cardiac or renal comorbidity (FDA, 2020b) . In an alert issued on June 15, the FDA rescinded the EUA for both the drugs based on the ongoing review of available evidence. The agency determined that HCQS and chloroquine are not likely to be efficacious in treating COVID-19 patients, and the potential benefits of treatment no longer outweigh the attending risks from serious cardiac and other adverse events (Coronavirus (COVID-19) Update , 2020).

World Health Organization (WHO) has also taken the initiative to test the effectiveness and safety of potentially useful therapeutic agents against COVID-19, including HCQS.

The international study known as "Solidarity" trial, has been launched by WHO and partners and is a large adaptive clinical study that allows dropping of ineffective therapy arms and including other potentially useful drugs. In this trial, the study subjects are allocated to either standard of care alone group or standard of care plus one out of HCQS, chloroquine, remdesivir, lopinavir/ritonavir or lopinavir/ritonavir plus interferon beta-1a. This multicentric trial aims to identify therapies that can slow down the disease progression or improve survival among affected patients. Given the lack of sufficient evidence presently, WHO has warned physicians, medical authorities as well as the common public likely to be engaged in self-medication, about the risk of using unproven treatments for COVID-19 as this can lead to more harm rather than benefit (WHO, 2020a) . In response to the large observational study published by Mehra et al. (Mehra, et al., 2020a) , WHO suspended the HCQS arm of the Solidarity trial (WHO Suspends Hydroxychloroquine Study, 2020). However, following the review of the trial They failed to detect any significant effect of HCQS treatment on the primary end point of 28-day mortality (26% vs. 24% in usual care group; HR 1.1, 95% C.I, 0.9-1.3; P=0.10). HCQS was also not able to demonstrate any beneficial effect on the duration of hospital stay or associated outcomes. The trialists were convinced of the lack of mortality benefit of HCQS in COVID-19 patients (Statement from the Chief Investigators, 2020).

So far, HCQS has not been conclusively shown to be safe and effective for the treatment or prophylaxis of COVID-19. However, amidst the speculation regarding its beneficial role based mainly on in vitro and patchy clinical data, its use amongst diagnosed or suspected patients is expected to cause potential safety concerns, some of which are already well known from the previous experience with this drug.

Use of HCQS in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency is linked to an increased risk of haemolytic anaemia. Therefore, screening of G6PD deficiency is crucial before administering HCQS (Mohammad et al., 2018) . It is possible that in this pandemic situation, it will be difficult to obtain a detailed history of all patients and there is a significant concern of misuse of HCQS as self-medication among lay public, especially in developing countries where the drug sales and availability are loosely regulated. Such scenarios can lead to increased incidence of haemolysis in individuals at risk, thus causing harm rather than any significant benefit.

National Institute for the Infectious Diseases -Italy has recommended the evaluation of G6PD deficiency in patients before administering HCQS in its guidelines for the management of patients with COVID-19 (Nicastri et al., 2020) .

Cardiac toxicity is a serious concern with HCQS. It can result in cardiomyopathy leading to heart failure, which could be fatal in some cases and the drug should be discontinued if such symptoms develop. It can also lead to conduction defects like bundle branch block or atrioventricular heart block and biventricular hypertrophy (Chatre et al., 2018; Hydroxychloroquine: Drug Information, n.d.; Plaquenil®. Hydroxychloroquine Sulfate, n.d.). Its use has been associated with QT prolongation, raising concerns of fatal ventricular arrhythmias. The risk of cardiotoxicity increases J o u r n a l P r e -p r o o f significantly when HCQS is used in combination with other cardiotoxic drugs.

Concurrent use of HCQS and azithromycin can lead to QT prolongation and ventricular arrythmias, and therefore, these drugs should be cautiously used, and close clinical monitoring is required (Drug Interactions Checker, n.d.) . In such situations, ECG assessments should be done at baseline and regularly during treatment with HCQS.

When consumed in unsupervised situations, for example. self-medication for prophylaxis of COVID-19, the possibility of widespread harm cannot be ruled out. Maximum prolongation of QTc interval was observed at a mean of 3.6 days post initiation of therapy with a maximal average value of 463+/-32 millisec. Notably, 11% of their patients had severe QTc interval prolongation of more than 500 millisec (Chorin et al., 2020) . Routine examination of ECG has been recommended to rule out the incidence of QT interval prolongation or bradycardia. Along with this, it has also been recommended to avoid the concurrent use of drugs that cause QT interval prolongation such as -macrolides, quinolones, anti-psychotic, anti-arrhythmic and antidepressants (Multicenter Collaboration Group, 2020) . Notably, a parallel group, randomized, double-blind Brazilian study where 81 hospitalized COVID-19 were receiving either low dose (total dose 2.7g) or high dose (total dose 12 g) chloroquine in addition to oseltamivir and azithromycin, was recently stopped due to safety concerns in the higher dose group. Greater incidence of corrected QT interval by Fridericia's method (QTcF) >500ms (19%) and deaths (39%) were reported in high dose chloroquine group as compared to lower dosage arm (11% and 15% respectively), leading to immediate termination of recruitment in the high dose arm (Borba et al., 2020) . In a cohort of 90 COVID-19 patients, over a 4-week study period, nearly 25% J o u r n a l P r e -p r o o f patients treated with HCQS alone or with azithromycin had either significant QTc prolongation or delta QTc of 60 milliseconds or more (Mercuro et al., 2020) .

Apart from cardiac side effects, HCQS can also lead to retinal toxicity and sometimes irreversible retinal damage can occur in patients who receive high doses of HCQS, especially for prolonged periods. A thorough discussion regarding possible ocular toxicity of HCQS with prospective recipients is must before commencing treatment within this agent (Hydroxychloroquine: Drug Information., n.d.; Plaquenil®. Hydroxychloroquine Sulfate, n.d.) .

HCQS is also known to cause hypoglycaemia that can lead to loss of consciousness and can be dangerous in diabetic individuals treated with or without antidiabetic drugs (Hydroxychloroquine: Drug Information., n.d.; Plaquenil®. Hydroxychloroquine Sulfate, n.d.) . Treating clinicians must take a thorough history of COVID-19 patients and discuss the risks of hypoglycaemia and ways to avoid such situations. Many geriatric patients with COVID-19 may have diabetes as comorbidity, which itself is a risk factor for severe disease and increased mortality among COVID-19 patients (Jordan et al., 2020) . Thus, the uninformed use of HCQS can further complicate the clinical situation in these patients.

Other adverse reactions include hematologic effects like neutropenia, hypersensitivity reactions, dermatologic adverse effects, and hepatotoxicity, amongst others (Makin et al., 1994; Murphy & Carmichael, 2001) . Possible immune suppression effects, along with neutropenia can be dangerous in those who are likely to take HCQS for prophylaxis against COVID-19 (FDA, 2020b) . Since healthcare providers and close contacts of COVID-19 patients are at an increased risk of contracting the infection, use of HCQS at this time can potentially suppress their immunity and increase their J o u r n a l P r e -p r o o f susceptibility to COVID-19 infection. Unsupervised use of HCQS for COVID-19 may also lead to an increased incidence of allergic reactions including anaphylaxis in vulnerable subjects (Hydroxychloroquine: Drug Information, n.d.; Plaquenil®. Hydroxychloroquine Sulfate, n.d.) . Recently FDA has also warned against a possible drug interaction between HCQS and remdesivir -the antiviral drug that has received emergency use authorization for the treatment of adult as well as paediatric COVID-19

patients. In vitro studies have shown that HCQS might interfere with the metabolic activation and hence the antiviral activity of remdesivir leading to reduction of its efficacy (FDA, 2020a).

Hydroxychloroquine use for its labelled indications -malaria, SLE, and RA is well known and for SLE it is one of the most effective therapies. The drug offers several advantages including effective management of joint pains and rashes, reducing flare ups, organ damage, osteoporosis and thrombotic events, sparing glucocorticoids use, and prolonging life expectancy in these patients. Given the current hype around HCQS being one of the promising therapies against COVID-19, acute shortages are already being experienced by both prescribers as well as patients who are prescribed HCQS for its labelled indications. This is a rather unfortunate and unprecedented situation where off label drug use is depriving such users of a low cost, efficacious and well tolerated therapy (Jakhar & Kaur, 2020; Yazdany & Kim, 2020) . Widespread use of HCQS for COVID-19 prophylaxis, could also lead to a false sense of security among users who, in turn might neglect proven effective measures including social distancing and hand and respiratory hygiene. This might lead to more harm than benefit for the individuals as well as for the society at large.

In an editorial by Ferner and Aronson, it was highlighted that it is premature and potentially harmful to use HCQS and chloroquine in COVID-19 patients. They stressed J o u r n a l P r e -p r o o f more on the need for treatments or vaccines targeting specific structures in the virus rather than relying solely on older repurposed medicines. Despite the promise shown in laboratory studies, these drugs lack supporting data for their clinical use, and thus eventually may lead to more harm than good (Ferner & Aronson, 2020) .

Hydroxychloroquine has received significant attention from clinical experts, politicians, media as well as the lay public ever since the pandemic flared up in most parts of the world and reports of its efficacy in in vitro experiments and early observational studies were published. Although the initial findings were mostly positive, these studies had several methodological flaws and were subject to numerous biases and confounders. They employed diverse dosing regimens, outcomes assessed were variable, and many of them lacked comparative control groups. In contrast, the accumulating evidence from randomized controlled trials has failed to maintain this hype. Given the lack of clinical meaningful reduction in mortality based on evaluation of interim data, several large multicentric clinical trials have been either terminated or have stopped further recruitment of participants in the HCQS arms of the study. In addition, emergency use authorization for HCQS has been withdrawn, highlighting the lack of unequivocal benefit and risk of toxicity especially in unsupervised settings. A survey of clinicaltrials.gov registry reveals several ongoing studies that continue to investigate the role of HCQS in the treatment as well as prophylaxis of COVID-19. The emerging data from high quality clinical studies are expected to further shape our understanding, and these may identify relevant subgroup(s) that might benefit from the use of HCQS. Till that time, it will be prudent to administer HCQS to COVID-19 patients as per national, regional, or local treatment guidelines; however, strictly under investigational settings followed by close monitoring of patients.

J o u r n a l P r e -p r o o f 

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Department of Health and Family Welfare. Gazette notification, 2020. New Delhi, the 26th

… BCN PEP-CoV-2 RESEARCH GROUP

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Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-patients with severe COVID-19 infection

Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for thetreatment of novel coronavirus pneumonia

Fatal toxic epidermal necrolysis associated with hydroxychloroquine

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Hydroxychloroquine sulfate tablets

Hydroxychloroquine-COVID-19 study did not meet publishing society's "expected standard

Revised advisory on the use of Hydroxychloroquine (HCQ) as prophylaxis for SARS-CoV-2 infection

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

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Observational study design, mortality data limited only to inhospital deaths, lack of definitive temporal association between adverse events and drug intake, residual confounders, and some underpowered study analyses.Rosenberg et al.

Observational study. Primary endpoint was a composite of intubation or death in a time to event analysis. (N=1446) N=811 received HCQS in a dose of 600 mg twice on day 1 and then 400 mg daily for a median of 5 days and rest of the participants did not receive it.No significant association was detected between HCQS use and intubation or death (HR, 1.04, 95% CI, 0.82 to 1.32). HCQS administration did not lead to either a greatly lowered or an increased risk of the intubation or death.Observational study design, residual confounding, some missing data and potential for inaccuracies in the electronic health records.

Double-blind, placebo-controlled RCT. The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days. Adult individuals who were either household or occupational close contacts of confirmed Covid-19 patients HCQS dose was 800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days.HCQS, n=414, Placebo, n=407 11 subjects in HCQS arm (2.7%) and 9 in placebo arm (2.2%) had laboratory confirmed COVID-19 (P=0.82) . No significant difference was found in the occurrence of COVID-19 compatible new illness; HCQS (11.8%) vs. placebo (14.3%), (P=0.35). HCQS led to more adverse effects (40.1% vs. 16.8%), with no serious adverse effects as compared to placebo.Use of a priori symptomatic case definition instead of universal laboratory confirmation; data were obtained by means of participant reports, and greater proportion of younger populations. The primary outcome for this study was in mortality among hospitalized COVID-19 patients (N=2541) HCQS: 400 mg twice daily on day 1, followed by 200 mg twice daily from days 2-5. Azithromycin: 500 mg once daily on day 1 followed by 250 mg once daily for the next 4 days.

HCQS+AZ, n=783,The overall mortality in this study was 18%; Mortality in the four study groups was found to be 13.5% (HCQS), 20% (HCQS+AZ), 22% (AZ) and 26% (Neither) (P<0.001). There was a 66% (P<0.001) mortality hazard ratio reduction in the HCQS group and 71% reduction in HCQS plus AZ group (P<0.001 No antiviral therapy, n=157 No significant differences in the mean reduction in viral loads was found between the two study groups at day 3 or 7. HCQS did not reduce the risk for hospitalization or lead to early resolution of symptoms.Open label design, fewer patients were analysed at day 7 for viral positivity; concomitant use of cobicistat-boosted darunavir in some patients; more than 4/5 th of participants were healthcare