Question: what evidence is there for the value of hydroxychloroquine in treating Covid-19?

Title: Reply to Gautret et al: hydroxychloroquine sulfate and azithromycin for COVID-19: what is the evidence and what are the risks? Content: The severity of COVID-19 has resulted in a global rush to find the right antiviral treatment to conquer the pandemic and to treat patients. This requires reliable studies to support treatment. In a recently published study by Gautret et al. the authors concluded that hydroxychloroquine monotherapy and hydroxychloroquine in combination with azithromycin reduced viral load. However, this trial has several major methodological issues, including the design, outcome measure and the statistical analyses. In this paper we discuss the background, clinical evidence, pharmacology and methodological issues related to this clinical trial. We understand the rush to release results, however in case conclusions are far reaching the evidence needs to be robust.

Title: Hydroxychloroquine as prophylaxis or treatment for COVID-19: What does the evidence say? Content: Hydroxychloroquine (HCQ), an antimalarial has been proposed as possible treatment for coronavirus disease-2019 (COVID-19). India has approved the use of HCQ for prophylaxis of asymptomatic health workers treating suspected or confirmed COVID-19 cases, and asymptomatic household contacts of confirmed patients. The U.S. Food and Drug Administration has issued Emergency Use Authorization for the use of HCQ to treat COVID-19 in adolescents and adults. In this review, we go over the available evidence for and against HCQ's use as prophylaxis or treatment for COVID-19, especially in the Indian context.

Title: QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review Content: Chloroquine and hydroxychloroquine are now being widely used for treatment of COVID-19. Both medications prolong the QT interval and accordingly may put patients at increased risk for torsades de pointes and sudden death. Published guidance documents vary in their recommendations for monitoring and managing these potential adverse effects. Accordingly, we set out to conduct a systematic review of the arrhythmogenic effect of short courses of chloroquine or hydroxychloroquine. We searched on MEDLINE and Embase, as well as in the gray literature up to April 17, 2020, for the risk of QT prolongation, torsades, ventricular arrhythmia, and sudden death with short-term chloroquine and hydroxychloroquine usage. This search resulted in 390 unique records, of which 41 were ultimately selected for qualitative synthesis and which included data on 1515 COVID-19 patients. Approximately 10% of COVID-19 patients treated with these drugs developed QT prolongation. We found evidence of ventricular arrhythmia in 2 COVID-19 patients from a group of 28 treated with high-dose chloroquine. Limitations of these results are unclear follow-up and possible publication/reporting bias, but there is compelling evidence that chloroquine and hydroxychloroquine induce significant QT-interval prolongation and potentially increase the risk of arrhythmia. Daily electrocardiographic monitoring and other risk mitigation strategies should be considered in order to prevent possible harms from what is currently an unproven therapy.

Title: QT prolongation, torsades de pointes and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review Content: Chloroquine and hydroxychloroquine are now being widely used as treatments for COVID-19. Both medications prolong the QT interval and accordingly may put patients at increased risk of torsades de pointes and sudden death. Published guidance documents vary in their recommendations for monitoring and managing these potential adverse effects. Accordingly, we set out to conduct a systematic review of the arrhythmogenic effect of short courses of chloroquine or hydroxychloroquine. We searched in MEDLINE and Embase, as well as grey literature up to April 17, 2020, on the risk of QT prolongation, torsades, ventricular arrhythmia, and sudden death with short-term chloroquine and hydroxychloroquine usage. This resulted in 390 unique records, of which fourteen were ultimately selected for qualitative synthesis and which included data on 1515 COVID-19 patients. Approximately 10% of COVID-19 patients treated with these drugs developed QT prolongation. We found evidence of ventricular arrhythmia in two COVID-19 patients out of a group of 28 treated with high-dose chloroquine. A limitation of these results is unclear follow-up and possible publication/reporting bias, but there is compelling evidence that chloroquine and hydroxychloroquine induce significant QT interval prolongation and potentially increase the risk of arrhythmia. Daily ECG monitoring and other risk mitigation strategies should be considered in order to prevent possible harms from what is currently an unproven therapy.

Title: Ethical issues related to the hydroxychloroquine treatment prescription for Covid-19 Content: Abstract The 2019-20 coronavirus pandemic (COVID-19), has led to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, no drugs have demonstrated safety and efficacy in randomized controlled trials for patients with COVID-19. Although the association between Hydroxychloroquine and Azithromycin efficacy lack of solid evidence-base, several governments have adopted it for all virology confirmed Covid-19 cases even for those who are asymptomatic. In the following, we aim to discuss some of the ethical issues associated with the use of this treatment association. We mainly tried to discuss the following controversial questions: Is it ethical not to treat a patient while a treatment exists and is used for other indications than Covid-19 for which it’s not proven yet? If yes, is a randomized controlled trial to prove the hydroxychloroquine for the Covid-19 treatment, necessary, in the context of covid-19 pandemic? If No, is it the government’s right to decide the hydroxychloroquine treatment for all covid-19 patients? and what should be the physicians’ attitudes? Finally, what are the government, physicians, and patient’s rights and responsibilities? The paper conclude that, since health authorities in some countries recommended this off-label use treatment, physicians are challenged by the requirement of veracity while providing care to their patients and the implications of such a requirement; they are facing the challenge of balancing this guideline and their own conviction. Furthermore, the fundamental principles of beneficence and non-maleficence, and respect for persons should underlie any reflection process to address this dilemma. In addition, in a pandemic context, the limits between the government’s, practitioner’s and patient’s rights and obligations are not clear which could significantly endanger the universal ethical principles in clinical practice. It could also undermine any attempt to develop serious clinical trials to prove the considered off-label drug.

Title: Potential therapeutic agents against COVID-19: What we know so far Content: The emerging outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 continues to spread all over the world. Agents or vaccines of proven efficacy to treat or prevent human coronavirus infection are in urgent need and are being investigated vigorously worldwide. This review summarizes the current evidence of potential therapeutic agents, such as lopinavir/ritonavir, remdesivir, favipiravir, chloroquine, hydroxychloroquine, interferon, ribavirin, tocilizumab, and sarilumab. More clinical trials are being conducted for further confirmation of the efficacy and safety of these agents in treating COVID-19.

Title: Former FDA leaders decry emergency authorization of malaria drugs for coronavirus Content: The recent Food and Drug Administration (FDA) emergency use authorization (EUA) for two malaria drugs to treat COVID-19, based on thin evidence of efficacy, has jeopardized research to learn the drugs’ real value against the pandemic coronavirus, say former agency executives under President Donald Trump and former President Barack Obama They also charge that the 28 March EUA for chloroquine phosphate and hydroxychloroquine sulfate undermines FDA’s scientific authority because it appeared to be a response not to scientific evidence, but to fervent advocacy of the drugs by Trump and other political figures FDA has multiple mechanisms to allow the use of unapproved, experimental drugs for small numbers of desperately ill patients outside of clinical trials Because chloroquine and hydroxychloroquine are approved for malaria, doctors could prescribe them “off label” for COVID-19 patients even without the EUA Since Trump first endorsed the drugs on 19 March, however, shortages have been reported, depriving some people with autoimmune disorders such as lupus who also depend on hydroxychloroquine The EUA will immediately add tens of millions of doses of the drugs for distribution to hospitalized COVID-19 patients through health care centers

Title: Should azithromycin be used to treat COVID-19? A rapid review Content: BACKGROUND: There are no established effective treatments for COVID-19. While novel drugs are being developed, azithromycin has been identified as a candidate treatment in the interim. AIM: To review the evidence for the effectiveness and safety of azithromycin in treating COVID-19. DESIGN & SETTING: A rapid review of the literature was conducted. METHOD: Electronic searches were conducted on 16 April 2020 of PubMed, TRIP, EPPI COVID Living Map, MedRxiv, GoogleScholar, and Google. In vivo and in vitro studies were included assessing the safety and effectiveness of azithromycin for treatment of COVID-19, and/or the activity of azithromycin against SARS-CoV-2. In vivo studies needed to include a comparator group. RESULTS: Three studies were identified, two in vitro and one in vivo, which were suitable for inclusion. All three were published as pre-prints. The in vitro studies revealed conflicting results, with one finding anti-SARS-CoV-2 activity for azithromycin alone, while the other found activity against SARS-CoV-2 only when azithromycin was combined with hydroxychloroquine. A small trial of 36 patients, with high risk of bias, found superior viral clearance in patients with COVID-19 treated with azithromycin and hydroxychloroquine combined, compared with hydroxychloroquine alone. CONCLUSION: There is no evidence to support the use of azithromycin for the treatment of COVID-19 outside of the context of clinical trials, unless it is used to treat bacterial super-infection. There is extremely limited evidence of a possible synergy between azithromycin and hydroxychloroquine. The adverse events profile of azithromycin in the context of COVID-19 has not yet been established. Well-conducted clinical trials are urgently needed in this area.

Title: Macrolides and viral infections: focus on azithromycin in COVID-19 pathology Content: The emergence of the new COVID-19 virus is proving to be a challenge in seeking effective therapies. Since the most severe clinical manifestation of COVID-19 appears to be a severe acute respiratory syndrome, azithromycin has been proposed as a potential treatment. Azithromycin is known to have immunomodulating and antiviral properties. In vitro studies have demonstrated the capacity of azithromycin in reducing production of pro-inflammatory cytokines such as IL-8, IL-6, TNF alpha, reduce oxidative stress, and modulate T-helper functions. At the same time there are multiple clinical evidences of the role of azithromycin in acute respiratory distress syndrome and against Middle East Respiratory syndrome (MERS). Some preliminary evidence has demonstrated controversial results regarding efficacy of azithromycin in combination with hydroxychloroquine in COVID-19. First, a French trial demonstrated 100% virological negativizing of six patients treated with azithromycin plus hydroxychloroquine vs. 57.1% of patients treated with only hydroxychloroquine and 12.5% of the control group (P < 0.05). On the other hand, another case series revealed no efficacy at all on 11 patients treated with the same combination and doses. Furthermore, there are some concerns regarding the association of azithromycin and hydroxychloroquine because of potential QT prolongation. In fact, both drugs have this as a potential side effect and evidence regarding the safe use of this combination is controversial. Despite the necessity to quickly find solutions for COVID-19, extreme caution must be used in evaluating the risk-benefit balance. However, based on preclinical and clinical evidence and some preliminary results in COVID-19, azithromycin could have potential in the fight against this new disease.

Title: Macrolides and viral infections: focus on azithromycin in COVID-19 pathology Content: The emergence of the new disease COVID-19, is posing the challenge of seeking effective therapies. Since the most severe clinical manifestation of COVID-19 appeared to be a severe acute respiratory syndrome, azithromycin has been proposed as a potential treatment. Azithromycin is known to have immunomodulating and antiviral properties. In vitro studies have demonstrated the capacity of azithromycin to reduce production of pro-inflammatory cytokines such as IL-8, IL-6, TNF alpha, reduce oxidative stress and modulate T-helper functions. At the same time there are multiple clinical evidences of the role of azithromycin in acute respiratory distress syndrome and against MERS. Some preliminary evidences have demonstrated controversial results regarding efficacy of azithromycin in combination with hydroxychloroquine in COVID-19. Firstly, a French trial demonstrated 100% of virological negativization of six patients treated with azithromycin plus hydroxychloroquine vs 57.1% of patients treated with only hydroxychloroquine and 12.5% of the control group (p<0.05). On the other hand, another case series revealed no efficacy at all on eleven patients treated with same combination and doses. Furthermore, there are some concerns regarding the association of azithromycin and hydroxychloroquine because of the potential Qt prolongation. In fact, both drugs have this as potential side effect and evidences regarding the safety use of this combination are controversial. Despite the necessity to quickly find solutions for COVID-19, extreme caution must be used in evaluating the risk-benefit balance. However, based on preclinical and clinical evidences and some preliminary results in COVID-19, azithromycin could have a potential in the fight against this new disease.

Title: COVID-19 research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine Content: What is new? KEY FINDINGS: Clinical decision-makers must be informed by the best, most trustworthy, highest-quality, robust evidence. This translates into how much confidence we can have in the research findings and thus be optimally informed for decision-making. The estimates of effect in clinical research depends on the underlying research methodology. COVID-19 disease is presenting global health systems, clinicians, and patients grave challenges. No treatment or prophylaxis currently exists for COVID-19. The overall body of COVID-19 research is very flawed methodologically. An examination of hydroxychloroquine-azithromycin research findings due to the recent media focus revealed very low-quality methodology underpins the research. Vast amounts of time and resources are being allocated to COVID-19 research, and being potentially squandered. WHAT THIS ADDS TO WHAT WAS KNOWN: Flawed methodology and sub-optimal reporting of research findings could lead to biased estimates of effect. This could lead to treatment decisions that are not optimal based on biased estimates which could harm the patient. This article provides specific suggestions for improving on the COVID-19 methods and reporting with a focus on the issues that researchers must consider in their methodology and reporting if we are to have confidence in the estimates of effect. Failure to consider harms in research could be detrimental to the patient. This article focuses on the potential harms when therapeutic agents such as hydroxychloroquine, are being considered. WHAT IS THE IMPLICATION AND WHAT SHOULD CHANGE NOW: Research thus far on finding an optimal therapeutic agent (s) for COVID-19 could be hampered by methodologically flawed research. COVID-19 researchers must immediately and acutely focus on improving their methodology and reporting.

Title: Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19 Infection- A Systematic Literature Review Content: Background: Coronavirus pandemic is currently a global public health emergency. At present, no pharmacological treatment is known to treat this condition, and there is a need to review the available treatments. Objective: While there have been studies to describe the role of chloroquine and hydroxychloroquine in various viral conditions, there is limited information about the use of them in COVID-19. This systematic review aims to summarize the available evidence regarding the role of chloroquine in treating coronavirus infection. Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used for this review. A literature search was performed using PUBMED & Google Scholar to find articles about the role of CQ in COVID-19 patients. Results: We included 19 publications (Five published articles, three letters/correspondence, one commentary, five pre-proofs of accepted articles, one abstract of yet to be published article, and four were pre-prints (not yet peer-reviewed) articles) in this systematic review. All the articles mentioned about the role of chloroquine and /or hydroxychloroquine in limiting the infection with SARS-CoV-2 (the virus causing COVID-19). Conclusions: There is theoretical, experimental, preclinical and clinical evidence of the effectiveness of chloroquine in patients affected with COVID-19. There is adequate evidence of drug safety from the long-time clinical use of chloroquine and hydroxychloroquine in other indications. More data from ongoing and future trials will add more insight into the role of chloroquine and hydroxychloroquine in COVID-19 infection.

Title: Update on use of chloroquine/hydroxychloroquine to treat coronavirus disease 2019 (COVID-19) Content: Drugs that are specifically efficacious against SARS-CoV-2 have yet to be established. Chloroquine and hydroxychloroquine have garnered considerable attention for their potential to treat coronavirus disease 2019 (COVID-19). Increasing evidence obtained from completed clinical studies indicates the prospects for chloroquine/hydroxychloroquine to treat COVID-19. More randomized control clinical studies are warranted to determine the feasibility of these two drugs in treating COVID-19.

Title: Update on use of chloroquine/hydroxychloroquine to treat coronavirus disease 2019 (COVID-19). Content: Drugs that are specifically efficacious against SARS-CoV-2 have yet to be established. Chloroquine and hydroxychloroquine have garnered considerable attention for their potential to treat coronavirus disease 2019 (COVID-19). Increasing evidence obtained from completed clinical studies indicates the prospects for chloroquine/hydroxychloroquine to treat COVID-19. More randomized control clinical studies are warranted to determine the feasibility of these two drugs in treating COVID-19.

Title: The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Content: The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.

Title: Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients Content: Background: COVID-19 has rapidly emerged as a pandemic infection that has caused significant mortality and economic losses. Potential therapies and means of prophylaxis against COVID-19 are urgently needed to combat this novel infection. As a result of in vitro evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin. We performed a retrospective observational study to compare hospital outcomes among patients who received hydroxychloroquine and azithromycin plus zinc versus hydroxychloroquine and azithromycin alone. Methods: Data was collected from electronic medical records for all patients being treated with admission dates ranging from March 2, 2020 through April 5, 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. Patients in the study were excluded if they were treated with other investigational medications. Results: The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744). Conclusion: This study provides the first in vivo evidence that zinc sulfate in combination with hydroxychloroquine may play a role in therapeutic management for COVID-19.

Title: [Lack of clinical evidence for the use of hydroxychloroquine to treat SARS-CoV-2 infection]. Content: The severity of COVID-19 disease has led to an urgent need for the discovery of new treatments. Thus, global stocks of hydroxychloroquine (HCQ) have been put under pressure with a study of 26 patients treated with HCQ during their infection with SARS-CoV-2. Despite the study's lack of quality, several countries' medicines agencies subsequently issued guidelines for the use of HCQ for COVID-19. This review aims to elucidate potential mechanisms, which make HCQ treatment interesting in the fight against SARS-CoV-2 infection, as well as the current evidence for clinical use of HCQ to treat COVID-19.

Title: [Lack of clinical evidence for the use of hydroxychloroquine to treat SARS-CoV-2 infection] Content: The severity of COVID-19 disease has led to an urgent need for the discovery of new treatments. Thus, global stocks of hydroxychloroquine (HCQ) have been put under pressure with a study of 26 patients treated with HCQ during their infection with SARS-CoV-2. Despite the study's lack of quality, several countries' medicines agencies subsequently issued guidelines for the use of HCQ for COVID-19. This review aims to elucidate potential mechanisms, which make HCQ treatment interesting in the fight against SARS-CoV-2 infection, as well as the current evidence for clinical use of HCQ to treat COVID-19.

Title: Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine Content: SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus was able to infect millions of people. To date, close to half a million patients succumbed to the viral disease, COVID-19. The high need for treatment options, together with the lack of small animal models of infection has led to clinical trials with repurposed drugs before any preclinical in vivo evidence attesting their efficacy was available. We used Syrian hamsters to establish a model to evaluate antiviral activity of small molecules in both an infection and a transmission setting. Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated animals, which was confirmed by histopathology. In addition, both compounds did not prevent virus transmission through direct contact and thus failed as prophylactic treatments. By modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster infection and transmission model to be a robust model for studying in vivo efficacy of antiviral compounds. The information acquired using hydroxychloroquine and favipiravir in this model is of critical value to those designing (current and) future clinical trials. At this point, the data here presented on hydroxychloroquine either alone or combined with azithromycin (together with previously reported in vivo data in macaques and ferrets) provide no scientific basis for further use of the drug in humans.

Title: Rethinking the role of hydroxychloroquine in the treatment of COVID‐19 Content: There are currently no proven or approved treatments for coronavirus disease 2019 (COVID‐19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID‐19 are treated with these agents and more evidence accumulates, there continues to be no high‐quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto‐immune conditions, and provided a component in the original rationale for their use in patients with COVID‐19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID‐19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID‐19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID‐19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case‐by‐case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Title: Rethinking the role of hydroxychloroquine in the treatment of COVID-19 Content: There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Title: Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study Content: The outbreak of novel coronavirus disease 2019 (COVID-19) has become a pandemic. Drug repurposing may represent a rapid way to fill the urgent need for effective treatment. We evaluated the clinical utility of chloroquine and hydroxychloroquine in treating COVID-19. Forty-eight patients with moderate COVID-19 were randomized to oral treatment with chloroquine (1000 mg QD on Day 1, then 500 mg QD for 9 days; n=18), hydroxychloroquine (200 mg BID for 10 days; n=18), or control treatment (n=12). Adverse events were mild, except for one case of Grade 2 ALT elevation. Adverse events were more commonly observed in the chloroquine group (44.44%) and the hydroxychloroquine group (50.00%) than in the control group (16.67%). The chloroquine group achieved shorter time to clinical recovery (TTCR) than the control group (P=0.019). There was a trend toward reduced TTCR in the hydroxychloroquine group (P=0.049). The time to reach viral RNA negativity was significantly faster in the chloroquine group and the hydroxychloroquine group than in the control group (P=0.006 and P=0.010, respectively). The median numbers of days to reach RNA negativity in the chloroquine, hydroxychloroquine, and control groups was 2.5 (IQR: 2.0-3.8) days, 2.0 (IQR: 2.0-3.5) days, and 7.0 (IQR: 3.0-10.0) days, respectively. The chloroquine and hydroxychloroquine groups also showed trends toward improvement in the duration of hospitalization and findings on lung computerized tomography (CT). This study provides evidence that (hydroxy)chloroquine may be used effectively in treating moderate COVID-19 and supports larger trials.

Title: Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients Content: Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro EC50/EC90 values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.

Title: Efficacy of chloroquine and hydroxychloroquine in the treatment of COVID-19. Content: OBJECTIVE The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also called COVID-19, has caused a pandemic which has swiftly involved the entire world and raised great public health concerns. The scientific community is actively exploring treatments that would potentially be effective in combating COVID-19. Hydroxychloroquine has been demonstrated to limit the replication of SARS-CoV-2 virus in vitro. In malarial pandemic countries, chloroquine is widely used to treat malaria. In malarial non-pandemic nations, chloroquine is not widely used. Chloroquine and hydroxychloroquine share similar chemical structures and mechanisms of action. The aim of this study was to indirectly investigate the efficacy of chloroquine and hydroxychloroquine for the treatment of COVID-19 by determining the prevalence of COVID-19 in malaria pandemic and non-pandemic nations. We sought evidence to support or refute the hypothesis that these drugs could show efficacy in the treatment of COVID-19. MATERIALS AND METHODS We reviewed in vitro studies, in vivo studies, original studies, clinical trials, and consensus reports, that were conducted to evaluate the antiviral activities of chloroquine and hydroxychloroquine. The studies on "COVID-19 and its allied treatment were found from World Health Organization (WHO), ISI-Web of Science, PubMed, EMBASE, Scopus, Google Scholar, and clinical trial registries. The search was based on keywords: antiviral drugs, chloroquine, hydroxychloroquine, COVID-19, COVID-19 treatment modalities, and coronavirus. In addition, we analyzed the prevalence of COVID-19 in malaria pandemic and non-pandemic countries. The review and analyses were performed on March 28, 2020. RESULTS For this study, we identified a total of 09 published articles: 03 clinical trials with sample size 150; 03 in vitro studies and 03 expert consensus reports. These studies were all suggestive that chloroquine and hydroxychloroquine can successfully treat COVID-19 infections. We found that COVID-19 infections are highly pandemic in countries where malaria is least pandemic and are least pandemic in nations where malaria is highly pandemic. CONCLUSIONS Chloroquine and hydroxychloroquine have antiviral characteristics in vitro. The findings support the hypothesis that these drugs have efficacy in the treatment of COVID-19. People are currently using these drugs for malaria. It is reasonable, given the hypothetical benefit of these two drugs, that they are now being tested in clinical trials to assess their effectiveness to combat this global health crisis.

Title: Efficacy of chloroquine and hydroxychloroquine in the treatment of COVID-19 Content: OBJECTIVE: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also called COVID-19, has caused a pandemic which has swiftly involved the entire world and raised great public health concerns. The scientific community is actively exploring treatments that would potentially be effective in combating COVID-19. Hydroxychloroquine has been demonstrated to limit the replication of SARS-CoV-2 virus in vitro. In malarial pandemic countries, chloroquine is widely used to treat malaria. In malarial non-pandemic nations, chloroquine is not widely used. Chloroquine and hydroxychloroquine share similar chemical structures and mechanisms of action. The aim of this study was to indirectly investigate the efficacy of chloroquine and hydroxychloroquine for the treatment of COVID-19 by determining the prevalence of COVID-19 in malaria pandemic and non-pandemic nations. We sought evidence to support or refute the hypothesis that these drugs could show efficacy in the treatment of COVID-19. MATERIALS AND METHODS: We reviewed in vitro studies, in vivo studies, original studies, clinical trials, and consensus reports, that were conducted to evaluate the antiviral activities of chloroquine and hydroxychloroquine. The studies on "COVID-19 and its allied treatment were found from World Health Organization (WHO), ISI-Web of Science, PubMed, EMBASE, Scopus, Google Scholar, and clinical trial registries. The search was based on keywords: antiviral drugs, chloroquine, hydroxychloroquine, COVID-19, COVID-19 treatment modalities, and coronavirus. In addition, we analyzed the prevalence of COVID-19 in malaria pandemic and non-pandemic countries. The review and analyses were performed on March 28, 2020. RESULTS: For this study, we identified a total of 09 published articles: 03 clinical trials with sample size 150; 03 in vitro studies and 03 expert consensus reports. These studies were all suggestive that chloroquine and hydroxychloroquine can successfully treat COVID-19 infections. We found that COVID-19 infections are highly pandemic in countries where malaria is least pandemic and are least pandemic in nations where malaria is highly pandemic. CONCLUSIONS: Chloroquine and hydroxychloroquine have antiviral characteristics in vitro. The findings support the hypothesis that these drugs have efficacy in the treatment of COVID-19. People are currently using these drugs for malaria. It is reasonable, given the hypothetical benefit of these two drugs, that they are now being tested in clinical trials to assess their effectiveness to combat this global health crisis.

Title: Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 Content: BACKGROUND: Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use. METHODS: We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score. RESULTS: Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses. CONCLUSIONS: In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.).

Title: Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin Content: BACKGROUND: Hydroxychloroquine and azithromycin combination therapy is often prescribed for coronavirus disease 2019 (COVID-19). Electrocardiographic (ECG) monitoring is warranted because both medications cause corrected QT-interval (QTc) prolongation. Whether QTc duration significantly varies during the day, potentially requiring multiple ECGs, remains to be established. METHODS: We performed 12‑lead ECGs and 12‑lead 24-h Holter ECG monitoring in all patients aged <80 years admitted to our medical unit for COVID-19, in oral therapy with hydroxychloroquine (200 mg, twice daily) and azithromycin (500 mg, once daily) for at least 3 days. A group of healthy individuals matched for age and sex served as control. RESULTS: Out of 126 patients, 22 (median age 64, 82% men) met the inclusion criteria. ECG after therapy showed longer QTc-interval than before therapy (450 vs 426 ms, p = .02). Four patients had a QTc ≥ 480 ms: they showed higher values of aspartate aminotransferase (52 vs 30 U/L, p = .03) and alanine aminotransferase (108 vs 33 U/L, p < .01) compared with those with QTc < 480 ms. At 24-h Holter ECG monitoring, 1 COVID-19 patient and no control had ≥1 run of non-sustained ventricular tachycardia (p = .4). No patients showed “R on T" premature ventricular beats. Analysis of 24-h QTc dynamics revealed that COVID-19 patients had higher QTc values than controls, with no significant hourly variability. CONCLUSION: Therapy with hydroxychloroquine and azithromycin prolongs QTc interval in patients with COVID-19, particularly in those with high levels of transaminases. Because QTc duration remains stable during the 24 h, multiple daily ECG are not recommendable.

Title: Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin Content: BACKGROUND: Hydroxychloroquine and azithromycin combination therapy is often prescribed for coronavirus disease 2019 (COVID-19). Electrocardiographic (ECG) monitoring is warranted because both medications cause corrected QT-interval (QTc) prolongation. Whether QTc duration significantly varies during the day, potentially requiring multiple ECGs, remains to be established. METHODS: We performed 12lead ECGs and 12lead 24-h Holter ECG monitoring in all patients aged <80 years admitted to our medical unit for COVID-19, in oral therapy with hydroxychloroquine (200 mg, twice daily) and azithromycin (500 mg, once daily) for at least 3 days. A group of healthy individuals matched for age and sex served as control. RESULTS: Out of 126 patients, 22 (median age 64, 82% men) met the inclusion criteria. ECG after therapy showed longer QTc-interval than before therapy (450 vs 426 ms, p = .02). Four patients had a QTc ≥ 480 ms: they showed higher values of aspartate aminotransferase (52 vs 30 U/L, p = .03) and alanine aminotransferase (108 vs 33 U/L, p < .01) compared with those with QTc < 480 ms. At 24-h Holter ECG monitoring, 1 COVID-19 patient and no control had ≥1 run of non-sustained ventricular tachycardia (p = .4). No patients showed "R on T" premature ventricular beats. Analysis of 24-h QTc dynamics revealed that COVID-19 patients had higher QTc values than controls, with no significant hourly variability. CONCLUSION: Therapy with hydroxychloroquine and azithromycin prolongs QTc interval in patients with COVID-19, particularly in those with high levels of transaminases. Because QTc duration remains stable during the 24 h, multiple daily ECG are not recommendable.

Title: Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review. Content: BACKGROUND Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). PURPOSE To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19). DATA SOURCES PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020. STUDY SELECTION Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection. DATA EXTRACTION Independent, dually performed data extraction and quality assessments. DATA SYNTHESIS Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate 500 mg once or twice daily with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine. LIMITATION There were few controlled studies, and control for confounding was inadequate in observational studies. CONCLUSION Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Title: Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review Content: BACKGROUND: Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). PURPOSE: To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19). DATA SOURCES: PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020. STUDY SELECTION: Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection. DATA EXTRACTION: Independent, dually performed data extraction and quality assessments. DATA SYNTHESIS: Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate 500 mg once or twice daily with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine. LIMITATION: There were few controlled studies, and control for confounding was inadequate in observational studies. CONCLUSION: Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Title: Hydroxychloroquine for COVID-19: What is our Current State of Knowledge? Content: Chloroquine and Hydroxychloroquine are drugs which have been widely used in malaria and rheumatoid arthritis respectively for over 50 years. There was anecdotal evidence of their efficacy in the earlier SARS outbreak in 2003. This prompted physicians from across the world to use them in the present SARS-CoV- 2 pandemic that is currently sweeping the globe, with 5 million people already infected to date. These drugs are already in widespread use for the treatment of COVID-19 in India, mainly because they are cheap and easily available, and because of the absence of any readily available alternative therapy. This timely review discusses the pre-clinical evidence, and data from the eight available clinical trials. We emphasise that careful monitoring for cardiac toxicity is required when these drugs are used. Finally, we conclude that current data does not allow us to recommend for or against the use of these drugs. Results of two large RCTs, one from the NIH and the other from WHO (Solidarity) are eagerly awaited before the role of these drugs in COVID-19 can be definitively established.

Title: Quantifying treatment effects of hydroxychloroquine and azithromycin for COVID-19: a secondary analysis of an open label non-randomized clinical trial (Gautret et al, 2020) Content: Human infections with a novel coronavirus (SARS-CoV-2) were first identified via syndromic surveillance in December of 2019 in Wuhan China. Since identification, infections (coronavirus disease-2019; COVID-19) caused by this novel pathogen have spread globally, with more than 250,000 confirmed cases as of March 21, 2020. An open-label clinical trial has just concluded, suggesting improved resolution of viremia with use of two existing therapies: hydroxychloroquine (HCQ) as monotherapy, and in combination with azithromycin (HCQ-AZ). The results of this important trial have major implications for global policy in the rapid scale-up and response to this pandemic. The authors present results with p-values for differences in proportions between the study arms, but their analysis is not able to provide effect size estimates. To address this gap, more modern analytical methods including survival models, have been applied to these data, and show modest to no impact of HCQ treatment, with more significant effects from the HCQ-AZ combination, potentially suggesting a role for co-infections in COVID-19 pathogenesis. The trial of Gautret and colleagues, with consideration of the effect sizes, and p-values from multiple models, does not provide sufficient evidence to support wide-scale rollout of HCQ monotherapy for the treatment of COVID-19; larger randomized studies should be considered. The trial of Gautret and colleagues, with consideration of the effect sizes, and p-values from multiple models, does not provide sufficient evidence to support wide-scale rollout of HCQ monotherapy for the treatment of COVID-19; larger randomized studies should be considered. These data also suggest further randomized-controlled studies of HCQ-AZ combination therapy should be undertaken.

Title: Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review Content: BACKGROUND: On the 11 March 2020, the World Health Organization (WHO) declared that COVID-19 was a pandemic. To date, there are no medical treatments for COVID-19 with proven effectiveness. Novel treatments and/or vaccines will take time to be developed and distributed to patients. In light of this, there has been growing interest in the use of existing medications, such as chloroquine (CQ) and hydroxychloroquine (HCQ), as potential treatments of this disease. AIM: To establish the current evidence for the effectiveness of CQ and HCQ in treating COVID-19. DESIGN & SETTING: A rapid review of the literature was conducted. METHOD: Electronic searches in PubMed and Google Scholar were conducted on 21 March 2020. A further search was conducted in Google for relevant literature on 28 March 2020. RESULTS: There is limited evidence of in vitro activity of CQ/HCQ against SARS-CoV-2. A number of in vivo clinical trials are underway. The empirical data available from two of these trials reveal conflicting results. Both trials are characterised by small numbers of participants (n = 30 and n = 36) and suffer methodological limitations. No medium or long-term follow-up data is available. CONCLUSION: At present, there is insufficient evidence to determine whether CQ/HCQ are safe and effective treatments for COVID-19. High quality, adequately powered randomised clinical trials in primary and secondary care settings are urgently required to guide policymakers and clinicians. These studies should report medium- and long-term follow-up results, and safety data.

Title: Emerging Treatment and Prevention Strategies against COVID-19: A Brief Update Content: Patients with novel coronavirus disease 2019 (COVID-19) are at significantly increased risk for mortality and morbidity. Current management remains supportive care, ranging from symptomatic outpatient management to full–intensive care support, including intravenous fluids, invasive, and non-invasive oxygen supplementation. In patients with septic shock, treatment with antibiotics and vasopressors are recommended to keep mean arterial pressure (MAP) ≥ 65 mm Hg and lactate < 2 mmol/L. Because of the lack of effectiveness and possible adverse effects, routine corticosteroids should be avoided unless they are indicated for another reason (exacerbation of asthma or chronic obstructive pulmonary disease [COPD], and septic shock in whom fluids and vasopressors do not restore hemodynamic stability). There is currently no sufficient evidence of efficacy of hydroxychloroquine/chloroquine, remdesivir, and other antivirals in the treatment or prevention of COVID-19. Limited evidence shows that COVID-19 convalescent plasma can be used as a treatment of COVID-19 without the occurrence of severe adverse events. Drug regulatory agencies granted an emergency-use authorization of chloroquine/hydroxychloroquine and remdesivir to treat patients when a clinical trial is not available or participation is not feasible. Chloroquine and hydroxychloroquine are associated with QT interval prolongation and life-threatening cardiac arrhythmia in patients with pre-existing cardiovascular disease. Guidelines are issued for use of convalescent plasma in patients with serious or immediately life-threatening COVID-19. Data from several ongoing randomized controlled trials will provide further evidence regarding the safety and efficacy of these drugs for the treatment of COVID-19.

Title: Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety Content: Background: The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the repurposing of existing drugs. Several drugs are now being repurposed with the aim of identifying if these drugs provide some level of disease resolution. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ), first developed as an antimalarial therapy. There is increasing concern with regards to the efficacy and safety of these agents. The aims of this review are to systematically identify and collate studies describing the use of CQ and HCQ in human clinical trials and provide a detailed synthesis of evidence of its efficacy and safety. Methods and Findings: Searches for (COVID AND chloroquine [title/abstract] AND outcomes[full text]) and two (COVID AND hydroxychloroquine[title/abstract] AND outcomes[full text]) yielded 272 unique articles. Unique articles were manually checked for inclusion and exclusion criteria and also subjected to a quality appraisal assessment. A total of 19 articles were included in the systematic review. Seventy-five percent of observational studies employing an endpoint specific to efficacy recorded no significant difference in the attainment of outcomes, between COVID-19 patients given a range of CQ and/or HCQ doses, and the control groups. All clinical trials and 82% of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Seventy-five percent of the total papers focusing on cardiac side-effects found a greater incidence among patients administered a wide range of CQ and/or HCQ doses, with QTc prolongation the most common finding, in addition to its consequences of VT and cardiac arrest. Of the total studies using mortality rate as an end-point, 60% reported no significant change in the risk of death, while 30% showed an elevation, and 10% a depression, in treated relative to control patients. Conclusion: The strongest available evidence suggests that, relative to standard in-hospital management of symptoms, the use of CQ and HCQ to treat hospitalised COVID-19 patients has likely been unsafe. At the very least, the poor quality of data failing to find any significant changes in the risk of VT should preclude definitive judgment on drug safety until the completion of high-quality randomised clinical trials.

Title: Commentary on “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial” by Gautret et al Content: The results of a clinical trial comparing hydroxychloroquine with or without azithromycin to the standard of care for the treatment of COVID-19 were recently published by Philippe Gautret et al. This study provides outstanding results for the combination of hydroxychloroquine and azithromycin over the standard of care, but the evidence was deemed insufficiently robust to warrant a public health decision to widen the use of hydroxychloroquine for the treatment of COVID-19. We provide a scientific critical review of the Gautret et al. publication, put the results in the context of the current knowledge, provide an evaluation of the validity of the results (from a methodologic perspective), and discuss public health implications. The study has a number of limitations, including small sample size, lack of comparability between patients in active treatment and control arms, lack of blinding, use of interim analyses without controlling for the risk of type 1 error, use of analysis in the per-protocol population instead of the intention-to-treat population, and inconsistencies between the study protocol and article. However, none of these observations is of a nature to reverse the conclusions. The study brings useful knowledge consistent with available evidence and clinical practice from China and South Korea, which could have prompted quicker policy decision-making.

Title: Chloroquine and hydroxychloroquine effectiveness in human subjects during coronavirus: a systematic review Content: In a search to find effective treatments for COVID-19, chloroquine and hydroxychloroquine have gained attention. We aim to provide evidence to support clinical decision-making regarding medication for the treatment of COVID-19 by carrying out a systematic review of the literature. The electronic databases MEDLINE, EMBASE, Global Health, and HMIC were searched up to April 2020. Eligible study outcomes included: extubation or patient recovery. Relevant data were extracted and analysed by narrative synthesis. Our results included six studies in the review of which four studies were of good or fair quality. All eligible studies included were for coronavirus involving the use of either chloroquine or hydroxychloroquine to treat common symptoms such as fever, cough, shortness of breath and fatigue. Outcomes most commonly reported were improved lung function, viral clearance, and hospital discharge. Strong evidence to support the use of chloroquine and hydroxychloroquine in the treatment of COVID-19 is lacking. Fast track trials are riddled with bias and may not conform to rigorous guidelines which may lead to inadequate data being reported. The use of these drugs in combination with other medications may be useful but without knowing which groups they are suited for and when they may cause more harm than good.

Title: Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019 Content: Background/Aims: The efficacies of lopinavir-ritonavir or hydroxychloroquine remain to be determined in patients with coronavirus disease 2019 (COVID-19). To compare the virological and clinical responses to lopinavir-ritonavir and hydroxychloroquine treatment in COVID-19 patients. Methods: This retrospective cohort study included patients with COVID-19 treated with lopinavir-ritonavir or hydroxychloroquine at a single center in Korea from February 17 to March 31, 2020. Patients treated with lopinavir-ritonavir and hydroxychloroquine concurrently and those treated with lopinavir-ritonavir or hydroxychloroquine for less than 7 days were excluded. Time to negative conversion of viral RNA, time to clinical improvement, and safety outcomes were assessed after 6 weeks of follow-up. Results: Of 65 patients (mean age, 64.3 years; 25 men [38.5%]), 31 were treated with lopinavir-ritonavir and 34 were treated with hydroxychloroquine. The median duration of symptoms before treatment was 7 days and 26 patients (40%) required oxygen support at baseline. Patients treated with lopinavir-ritonavir had a significantly shorter time to negative conversion of viral RNA than those treated with hydroxychloroquine (median, 21 days vs. 28 days). Treatment with lopinavir-ritonavir (adjusted hazard ratio [aHR], 2.28; 95% confidence interval [CI], 1.24 to 4.21) and younger age (aHR, 2.64; 95% CI 1.43 to 4.87) was associated with negative conversion of viral RNA. There was no significant difference in time to clinical improvement between lopinavir-ritonavir- and hydroxychloroquine-treated patients (median, 18 days vs. 21 days). Lymphopenia and hyperbilirubinemia were more frequent in lopinavir-ritonavir-treated patients compared with hydroxychloroquine-treated patients. Conclusions: Lopinavir-ritonavir was associated with more rapid viral clearance than hydroxychloroquine in mild to moderate COVID-19, despite comparable clinical responses. These findings should be confirmed in randomized, controlled trials.

Title: Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019. Content: Background/Aims The efficacies of lopinavir-ritonavir or hydroxychloroquine remain to be determined in patients with coronavirus disease 2019 (COVID-19). To compare the virological and clinical responses to lopinavir-ritonavir and hydroxychloroquine treatment in COVID-19 patients. Methods This retrospective cohort study included patients with COVID-19 treated with lopinavir-ritonavir or hydroxychloroquine at a single center in Korea from February 17 to March 31, 2020. Patients treated with lopinavir-ritonavir and hydroxychloroquine concurrently and those treated with lopinavir-ritonavir or hydroxychloroquine for less than 7 days were excluded. Time to negative conversion of viral RNA, time to clinical improvement, and safety outcomes were assessed after 6 weeks of follow-up. Results Of 65 patients (mean age, 64.3 years; 25 men [38.5%]), 31 were treated with lopinavir-ritonavir and 34 were treated with hydroxychloroquine. The median duration of symptoms before treatment was 7 days and 26 patients (40%) required oxygen support at baseline. Patients treated with lopinavir-ritonavir had a significantly shorter time to negative conversion of viral RNA than those treated with hydroxychloroquine (median, 21 days vs. 28 days). Treatment with lopinavir-ritonavir (adjusted hazard ratio [aHR], 2.28; 95% confidence interval [CI], 1.24 to 4.21) and younger age (aHR, 2.64; 95% CI 1.43 to 4.87) was associated with negative conversion of viral RNA. There was no significant difference in time to clinical improvement between lopinavir-ritonavir- and hydroxychloroquine-treated patients (median, 18 days vs. 21 days). Lymphopenia and hyperbilirubinemia were more frequent in lopinavir-ritonavir-treated patients compared with hydroxychloroquine-treated patients. Conclusions Lopinavir-ritonavir was associated with more rapid viral clearance than hydroxychloroquine in mild to moderate COVID-19, despite comparable clinical responses. These findings should be confirmed in randomized, controlled trials.

Title: Does Adding of Hydroxychloroquine to the Standard Care Provide any Benefit in Reducing the Mortality among COVID-19 Patients?: a Systematic Review Content: Hydroxychloroquine has been promoted for its use in treatment of COVID-19 patients based on in-vitro evidences. We searched the databases to include randomized and observational studies evaluating the effect of Hydroxychloroquine on mortality in COVID-19 patients. The outcome was summarized as odds ratios (OR) with a 95% confidence interval (CI).We used the inverse-variance method with a random effect model and assessed the heterogeneity using I2 test. We used ROBINS-I tool to assess methodological quality of the included studies. We performed the meta-analysis using 'Review manager software version 5.3'. We identified 6 observationalstudies satisfying the selection criteria. In all studies, Hydroxychloroquine was given as add on to the standard care and effect was compared with the standard care alone. A pooled analysis observed 251 deaths in 1331 participants of the Hydroxychloroquine arm and 363 deaths in 1577 participants of the control arm. There was no difference in odds of mortality events amongst Hydroxychloroquine and supportive care arm [1.25 (95% CI: 0.65, 2.38); I2 = 80%]. A similar trend was observed with moderate risk of bias studies [0.95 (95% CI: 0.44, 2.06); I2 = 85%]. The odds of mortality were significantly higher in patients treated with Hydroxychloroquine + Azithromycin than supportive care alone [2.34 (95% CI: 1.63, 3.34); I2 = 0%]. A pooled analysis of recently published studies suggests no additional benefit for reducing mortality in COVID-19 patients when Hydroxychloroquine is given as add-on to the standard care. Graphical Abstract.

Title: Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring. Content: Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected COVID-19. Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We performed a case series of COVID-19 positive/suspected patients admitted between 2/1/2020 and 4/4/2020 who were treated with azithromycin, hydroxychloroquine, or a combination. We evaluated baseline and post-medication QT interval (QTc, Bazett's) using 12-lead ECGs. Critical QTc prolongation was defined as: a) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and b) increased QTc of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID-19 positive/suspected patients, 314 (64%) received either/both drugs, and 98 (73 COVID-19 positive, 25 suspected) met study criteria (age 62±17 yrs, 61% male). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36 ms (p=0.005) with medications. Significant prolongation was observed only in men (18±43 ms vs -0.2±28 ms in women, p=0.02). 12% of patients reached critical QTc prolongation. Changes in QTc were highest with the combination compared to either drug, with much greater prolongation with combination vs. azithromycin (17±39 vs. 0.5±40 ms, p=0.07). No patients manifested torsades de pointes. Conclusions Overall 12% of patients manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients should be carefully assessed.

Title: Serious Adverse Events Associated With Hydroxychloroquine Amidst COVID-19 Pandemic: Case Series and Literature Review Content: COVID-19 represents a global health crisis. Several studies are evaluating potential therapies including hydroxychloroquine (HCQ) which is given to patients based on limited observational evidence. However, it can cause serious adverse events. Moreover, recent studies showed no benefits due to HCQ. We present two COVID-19 patients treated with HCQ and had adverse events.

Title: Does Adding of Hydroxychloroquine to the Standard Care Provide any Benefit in Reducing the Mortality among COVID-19 Patients?: a Systematic Review Content: Hydroxychloroquine has been promoted for its use in treatment of COVID-19 patients based on in-vitro evidences. We searched the databases to include randomized and observational studies evaluating the effect of Hydroxychloroquine on mortality in COVID-19 patients. The outcome was summarized as odds ratios (OR) with a 95% confidence interval (CI).We used the inverse-variance method with a random effect model and assessed the heterogeneity using I(2) test. We used ROBINS-I tool to assess methodological quality of the included studies. We performed the meta-analysis using ‘Review manager software version 5.3’. We identified 6 observationalstudies satisfying the selection criteria. In all studies, Hydroxychloroquine was given as add on to the standard care and effect was compared with the standard care alone. A pooled analysis observed 251 deaths in 1331 participants of the Hydroxychloroquine arm and 363 deaths in 1577 participants of the control arm. There was no difference in odds of mortality events amongst Hydroxychloroquine and supportive care arm [1.25 (95% CI: 0.65, 2.38); I(2) = 80%]. A similar trend was observed with moderate risk of bias studies [0.95 (95% CI: 0.44, 2.06); I(2) = 85%]. The odds of mortality were significantly higher in patients treated with Hydroxychloroquine + Azithromycin than supportive care alone [2.34 (95% CI: 1.63, 3.34); I(2) = 0%]. A pooled analysis of recently published studies suggests no additional benefit for reducing mortality in COVID-19 patients when Hydroxychloroquine is given as add-on to the standard care. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11481-020-09930-x) contains supplementary material, which is available to authorized users.

Title: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 Content: BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

Title: Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for QT Interval Monitoring Content: Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected coronavirus disease 2019 (COVID-19). Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We analyzed a case series of COVID-19-positive/suspected patients admitted between February 1, 2020, and April 4, 2020, who were treated with azithromycin, hydroxychloroquine, or a combination of both drugs. We evaluated baseline and postmedication QT interval (corrected QT interval [QTc]; Bazett) using 12-lead ECGs. Critical QTc prolongation was defined as follows: (1) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and (2) QTc increase of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID-19-positive/suspected patients, 314 (64%) received either/both drugs and 98 (73 COVID-19 positive and 25 suspected) met study criteria (age, 62±17 years; 61% men). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36 ms (P=0.005) with medications. Significant prolongation was observed only in men (18±43 ms versus -0.2±28 ms in women; P=0.02). A total of 12% of patients reached critical QTc prolongation. Changes in QTc were highest with the combination compared with either drug, with much greater prolongation with combination versus azithromycin (17±39 ms versus 0.5±40 ms; P=0.07). No patients manifested torsades de pointes. Conclusions Overall, 12% of patients manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients should be carefully assessed.

Title: Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring Content: Background: Despite a paucity of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected COVID-19. Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods: We performed a case series of COVID-19 positive/suspected patients admitted between 2/1/2020 and 4/4/2020 who were treated with azithromycin, hydroxychloroquine or a combination. We evaluated baseline and post-medication QT interval (QTc, Bazett) using 12-lead ECGs. Critical QTc prolongation was defined as: a) maximum QTc [≥]500 ms (if QRS <120 ms) or QTc [≥]550 (if QRS [≥]120 ms) and b) increased QTc of [≥]60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Results: Of 490 COVID-19 positive/suspected patients, 314 (64%) received either/both drugs, and 98 (73 COVID-19 positive, 25 suspected) met study criteria (age 62{+/-}17 yrs, 61% male). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448{+/-}29 ms and increased to 459{+/-}36ms (p=0.005) with medications. Significant prolongation was observed only in men (18{+/-}43 ms vs -0.2{+/-}28 ms in women, p=0.02). 12% of patients reached critical QTc prolongation. In a multivariable logistic regression, age, sex, Tisdale score, Elixhauser score, and baseline QTc were not associated with critical QTc prolongation (p>0.14). Changes in QTc were highest with the combination compared to either drug, with many-fold greater prolongation with the combination vs. azithromycin alone (17{+/-}39 vs. 0.5{+/-}40 ms, p=0.07). No patients manifested torsades de pointes. Conclusions: Overall, 12% of patients manifested critical QTc interval prolongation, and traditional risk indices failed to flag these patients. With the drug combination, QTc prolongation was several-fold higher compared to azithromycin alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients with these drugs should be carefully assessed prior to use.

Title: Intentional Hydroxychloroquine Overdose Treated with High-Dose Diazepam: an Increasing Concern in the COVID-19 Pandemic Content: INTRODUCTION: Recent attention on the possible use of hydroxychloroquine and chloroquine to treat COVID-19 disease has potentially triggered a number of overdoses from hydroxychloroquine. Toxicity from hydroxychloroquine manifests with cardiac conduction abnormalities, seizure activity, and muscle weakness. Recognizing this toxidrome and unique management of this toxicity is important in the COVID-19 pandemic. CASE REPORT: A 27-year-old man with a history of rheumatoid arthritis presented to the emergency department 7 hours after an intentional overdose of hydroxychloroquine. Initial presentation demonstrated proximal muscle weakness. The patient was found to have a QRS complex of 134 ms and QTc of 710 ms. He was treated with early orotracheal intubation and intravenous diazepam boluses. Due to difficulties formulating continuous diazepam infusions, we opted to utilize an intermitted intravenous bolus strategy that achieved similar effects that a continuous infusion would. The patient recovered without residual side effects. DISCUSSION: Hydroxychloroquine toxicity is rare but projected to increase in frequency given its selection as a potential modality to treat COVID-19 disease. It is important for clinicians to recognize the unique effects of hydroxychloroquine poisoning and initiate appropriate emergency maneuvers to improve the outcomes in these patients.

Title: Model informed dosing of Hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and Gaps Content: AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic considerations, the dose and treatment duration for hydroxychloroquine (HCQ) COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800mg day on D1 followed by 600mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best the benefit/risk balance.

Title: Model informed dosing of Hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and Gaps. Content: AIMS In the absence of a commonly agreed dosing protocol based on pharmacokinetic considerations, the dose and treatment duration for hydroxychloroquine (HCQ) COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800mg day on D1 followed by 600mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION Our results were clear indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best the benefit/risk balance.

Title: Hydroxychloroquine against COVID-19: A critical appraisal of the existing evidence Content: Hydroxychloroquine (HCQ) has sparked much interest in the therapeutics of the Coronavirus Disease 2019 (COVID-19) pandemic. Its antiviral properties have been studied for years; regarding the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2), it has been shown that HCQ may act at multiple levels. These extend from the initial attachment of the virus to the respiratory epithelium to the inhibition of its replication by the alkalinisation of the phagolysosome's microenvironment and the post-translational modification of certain viral proteins. Preliminary clinical evidence from China and France showed significant virological and clinical benefit in HCQ-treated patients, while other studies, mostly including critically ill patients, did not show favorable results. In this review, we critically appraise the existing evidence on HCQ against SARS-CoV-2 with particular emphasis on its protective and therapeutic role. Safety concerns that are relevant to the short-term HCQ use are also discussed. In the context of the rapid evolution of the COVID-19 pandemic that strains the health care systems worldwide and considering limited population-wide testing rates in most of the vulnerable countries, early empiric short-term administration of HCQ in symptomatic individuals, may be a promising, safe and low-cost strategy.

Title: Hydroxychloroquine against COVID-19: A critical appraisal of the existing evidence. Content: Hydroxychloroquine (HCQ) has sparked much interest in the therapeutics of the Coronavirus Disease 2019 (COVID-19) pandemic. Its antiviral properties have been studied for years; regarding the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2), it has been shown that HCQ may act at multiple levels. These extend from the initial attachment of the virus to the respiratory epithelium to the inhibition of its replication by the alkalinisation of the phagolysosome's microenvironment and the post-translational modification of certain viral proteins. Preliminary clinical evidence from China and France showed significant virological and clinical benefit in HCQ-treated patients, while other studies, mostly including critically ill patients, did not show favorable results. In this review, we critically appraise the existing evidence on HCQ against SARS-CoV-2 with particular emphasis on its protective and therapeutic role. Safety concerns that are relevant to the short-term HCQ use are also discussed. In the context of the rapid evolution of the COVID-19 pandemic that strains the health care systems worldwide and considering limited population-wide testing rates in most of the vulnerable countries, early empiric short-term administration of HCQ in symptomatic individuals, may be a promising, safe and low-cost strategy.

Title: Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis of confounder-adjusted 20212 hospitalized patients Content: Objective: To evaluate the comparative efficacy and safety of pharmacological interventions used in treating COVID-19 and form a basis for an evidence-based guideline of COVID-19 management by evaluating the level of evidence behind each treatment regimen in different clinical settings. Design: Systematic review and network meta-analysis Data Sources: PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov up to June 9th, 2020. Study Selection: Published and unpublished randomized controlled trials (RCTs) and baseline-adjusted observational studies which met our predefined eligibility criteria. Main Outcome Measures: The outcomes of interest were mortality, progression to severe disease (severe pneumonia or admission to intensive care unit (ICU)), time to viral clearance, QT prolongation, fatal cardiac complications, and non-cardiac serious adverse events. The level of evidence behind each outcome was also measured using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results: 49 studies with a total of 20212 confounder-adjusted patients were included for analysis. The risk of progression to severe pneumonia or ICU admission was significantly reduced with tocilizumab (GRADE low), anakinra (GRADE very low), and remdesivir (GRADE high) compared to standard care. Tocilizumab was shown to reduce mortality rate for both moderate-severe patients in the non-ICU setting at admission (Odds ratio (OR) 0.31, 95% confidence interval (CI) 0.18 to 0.54, GRADE low) and critically ill patients in the ICU setting (OR 0.67, 95% CI 0.50 to 0.91, GRADE low). High dose IVIG reduced death rate (GRADE low) while corticosteroids increased mortality for critically ill patients (GRADE moderate). Convalescent plasma and hydroxychloroquine were shown to promote viral clearance (OR 11.39, 95% CI 3.91 to 33.18, GRADE low and OR 6.08, 95% CI 2.74 to 13.48, GRADE moderate, respectively) while not altering mortality or progression to the severe courses. The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 1,85, 95% CI 1.05 to 3.26, GRADE low) and fatal cardiac complications in cardiac-impaired populations (OR 2.26, 95% CI 1.26 to 4.05, GRADE low). High-dose (>600mg/day) hydroxychloroquine monotherapy was significantly associated with increased non-cardiac serious adverse events (GRADE moderate). Conclusion: Anti-inflammatory agents (tocilizumab, anakinra, and IVIG) and remdesivir may safely and effectively improve outcomes of hospitalized COVID-19 patients. Widely used hydroxychloroquine provides marginal clinical benefit in improving viral clearance rates whilst posing both cardiac and non-cardiac safety risks, especially in the vulnerable population. Only 20% of current evidence on pharmacological management of COVID-19 is on moderate and high evidence certainty; remaining 80% are of low or very low certainty and warrant further studies to establish firm conclusions. Systematic Review Registration: PROSPERO 2020: CRD42020186527.

Title: Practice considerations on the use of investigational anti‐COVID‐19 medications: Dosage, administration and monitoring Content: WHAT IS KNOWN AND OBJECTIVE: Understanding investigational medications is important. Many older drugs are being investigated for repurposing against COVID‐19. We comment on various drugs currently undergoing such trials to optimize their safe use. COMMENT: We describe medications used during early COVID‐19 outbreaks in South Korea, focusing on practice aspects including the method of drug administration, drug formulation, patient‐monitoring for adverse reactions and drug interactions informed by our experience during the 2015 outbreak of Middle East respiratory syndrome (MERS). We comment on hydroxychloroquine, chloroquine, lopinavir/ritonavir with zinc supplement, remdesivir, tocilizumab, ciclesonide, niclosamide and high‐dose intravenous immunoglobulin (IVIG). WHAT IS NEW AND CONCLUSION: Effective therapies are urgently needed to manage COVID‐19, and existing drugs such as antivirals and antimalarials are under investigation for repurposing to meet this need. This process requires up‐to‐date drug information to ensure optimum use, particularly safety and efficacy profiles of the medications, until convincing evidence is reported.

Title: Practice considerations on the use of investigational anti-COVID-19 medications: Dosage, administration and monitoring Content: WHAT IS KNOWN AND OBJECTIVE: Understanding investigational medications is important. Many older drugs are being investigated for repurposing against COVID-19. We comment on various drugs currently undergoing such trials to optimize their safe use. COMMENT: We describe medications used during early COVID-19 outbreaks in South Korea, focusing on practice aspects including the method of drug administration, drug formulation, patient-monitoring for adverse reactions and drug interactions informed by our experience during the 2015 outbreak of Middle East respiratory syndrome (MERS). We comment on hydroxychloroquine, chloroquine, lopinavir/ritonavir with zinc supplement, remdesivir, tocilizumab, ciclesonide, niclosamide and high-dose intravenous immunoglobulin (IVIG). WHAT IS NEW AND CONCLUSION: Effective therapies are urgently needed to manage COVID-19, and existing drugs such as antivirals and antimalarials are under investigation for repurposing to meet this need. This process requires up-to-date drug information to ensure optimum use, particularly safety and efficacy profiles of the medications, until convincing evidence is reported.

Title: The ICMR bulletin on targeted hydroxychloroquine prophylaxis for Covid-19: Need to interpret with caution Content: The National Task Force for Covid-19 of the Indian Council of Medical Research (ICMR) in a bulletin dated March 21, 2020 recommended the use of hydroxychloroquine for prophylaxis in asymptomatic health care workers caring for suspected or confirmed patients and household contacts of confirmed patients. This is cause for concern with regard to bioethics and good clinical practice. The evidence for the efficacy of chloroquine and hydroxychloroquine is currently derived from open label trials and cell culture studies with no conclusive evidence available from randomised clinical trials. Hydroxychloroquine also carries contraindications in the case of conditions such as maculopathy, retinopathy and QTc prolongation and should be used with caution in vulnerable populations such as children, pregnancy, lactation and the elderly. Despite this, there has been a rush to procure and self-medicate with hydroxychloroquine, which has been addressed by the National Task Force. The WHO and the FDA have not found adequate evidence to recommend any specific medication for the treatment of Covid-19. While further evidence is awaited, including from trials registered with the FDA and the ICMR, it is recommended that the administration of hydroxychloroquine for chemo-prophylaxis be considered on a case by case basis with monitoring by a registered medical practitioner including electrocardiography (ECG). The potential for retinal and cardiac toxicity must also be borne in mind. It is further recommended that a public advisory regarding the need for caution in chemo-prophylaxis be made available in the public domain. Keywords: Coronavirus, Covid-19, SARS-CoV-2, hydroxychloroquine, chloroquine, chemoprophylaxis, bioethics, evidence- based medicine.

Title: The ICMR bulletin on targeted hydroxychloroquine prophylaxis for Covid-19: Need to interpret with caution. Content: The National Task Force for Covid-19 of the Indian Council of Medical Research (ICMR) in a bulletin dated March 21, 2020 recommended the use of hydroxychloroquine for prophylaxis in asymptomatic health care workers caring for suspected or confirmed patients and household contacts of confirmed patients. This is cause for concern with regard to bioethics and good clinical practice. The evidence for the efficacy of chloroquine and hydroxychloroquine is currently derived from open label trials and cell culture studies with no conclusive evidence available from randomised clinical trials. Hydroxychloroquine also carries contraindications in the case of conditions such as maculopathy, retinopathy and QTc prolongation and should be used with caution in vulnerable populations such as children, pregnancy, lactation and the elderly. Despite this, there has been a rush to procure and self-medicate with hydroxychloroquine, which has been addressed by the National Task Force. The WHO and the FDA have not found adequate evidence to recommend any specific medication for the treatment of Covid-19. While further evidence is awaited, including from trials registered with the FDA and the ICMR, it is recommended that the administration of hydroxychloroquine for chemo-prophylaxis be considered on a case by case basis with monitoring by a registered medical practitioner including electrocardiography (ECG). The potential for retinal and cardiac toxicity must also be borne in mind. It is further recommended that a public advisory regarding the need for caution in chemo-prophylaxis be made available in the public domain. Keywords: Coronavirus, Covid-19, SARS-CoV-2, hydroxychloroquine, chloroquine, chemoprophylaxis, bioethics, evidence- based medicine.

Title: Efficacy and Safety of Hydroxychloroquine and Chloroquine for COVID-19: A systematic review Content: BACKGROUND: Hydroxychloroquine and chloroquine are widely used to treat hospitalized COVID-19 patients primarily based on antiviral activity in in vitro studies. Our objective was to systematically evaluate their efficacy and safety in hospitalized patients with COVID-19. METHODS: We systematically reviewed PubMed, ClinicalTrials.gov, and Medrxviv for studies of hydroxychloroquine and chloroquine in COVID-19 hospitalized patients on April 26, 2020. We evaluated the quality of trials and observational studies using the Jadad criteria and Newcastle Ottawa Scale, respectively. RESULTS: After a review of 175 citations, we included 5 clinical trials (total of 345 patients), 9 observational studies (n = 2529), and 6 additional studies (n = 775) reporting on the QT interval. Three studies reported treatment benefits including two studies reporting benefit on virologic outcomes, which was statistically significant in one study, and another reported significant improvement on cough symptoms. Three studies reported that treatment was potentially harmful, including an significantly increased risk of mortality in two studies and increased need for respiratory support in another. Eight studies were unable to detect improvements on virologic outcomes (n = 3) or pneumonia or transfer to ICU/death (n = 5). The proportion of participants with critical QTc intervals of [≥] 500 ms or an increase of [≥] 60 ms from baseline ranged from 8.3% to 36% (n = 8). One clinical trial and six observational studies were of good quality. The remaining studies were of poor quality. CONCLUSIONS: Our systematic review of reported clinical studies did not identify substantial evidence to support the efficacy of hydroxychloroquine or chloroquine in hospitalized COVID-19 patients and raises questions about potential harm from QT prolongation and increased mortality.

Title: Hydroxychloroquine and mortality risk of patients with COVID-19: a systematic review and meta-analysis of human comparative studies Content: Background: Global COVID-19 deaths reached at least 400,000 fatalities. Hydroxychloroquine is an antimalarial drug that elicit immunomodulatory effects and had shown in vitro antiviral effects against SRAS-CoV-2. This drug divided opinion worldwide in the medical community but also in the press, the general public and in public health policies. The aim of this systematic review and this meta-analysis was to bring a new overview on this controversial drug and to assess whether hydroxychloroquine could reduce COVID-19 mortality risk in hospitalized patients. Methods and Findings: Pubmed, Web of Science, Cochrane Library, MedRxiv and grey literature were searched until 10 June 2020. Only studies of COVID-19 patients treated with hydroxychloroquine (with or without azithromycin) compared with a comparative standard care group and with full-text articles in English were included. Studies reporting effect sizes as Odds Ratios, Hazard Ratio and Relative Risk for mortality risk and the number of deaths per groups were included. This meta-analysis was conducted following PRISMA guidelines and registered on PROSPERO (Registration number: CRD42020190801). Independent extraction has been performed by two independent reviewers. Effect sizes were pooled using a random-effects model. The initial search leaded to 112 articles, from which 16 articles met our inclusion criteria. 15 studies were retained for association between hydroxychloroquine and COVID-19 survival including 15,081 patients (8,072 patients in the hydroxychloroquine arm and 7,009 patients in the standard care arm with respectively, 1,578 deaths and 1,423 deaths). 6 studies were retained for hydroxychloroquine with azithromycin. Hydroxychloroquine was not significantly associated with mortality risk (pooled Relative Risk RR=0.82 (95% Confidence Interval: 0.62-1.07, I2=82, Pheterogeneity<0.01, n=15)) within hospitalized patients, nor in association with azithromycin (pooled Relative Risk RR=1.33 (95% CI: 0.92-1.92, I2=75%, Pheterogeneity<0.01, n=6)), nor in the numerous subgroup analysis by study design, median age population, published studies (vs unpublished articles), level of bias risk. However, stratified analysis by continents, we found a significant decreased risk of mortality associated with hydroxychlroquine alone but not with azithromycin among European (RR= 0.62 (95%CI: 0.41-0.93, n=7)) and Asian studies (RR=0.36 (95%CI:0.18-0.73, n=1)), with heterogeneity detected across continent (Pheterogeneity between=0.003). These finding should be interpreted with caution since several included studies had a low quality of evidence with a small sample size, a lack of adjustment on potential confounders or selection and intervention biases. Conclusion: Our meta-analysis does not support the use of hydroxychloroquine with or without azithromycin to reduce COVID-19 mortality in hospitalized patients. It raises the question of the hydroxychloroquine use outside of clinical trial. Additional results from larger randomised controlled trials are needed

Title: Chloroquine, hydroxychloroquine and COVID-19 Content: The media have featured the antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) to treat coronavirus (COVID-19). Political leaders have touted their use and recommended availability to the public. These anti-inflammatory agents have substantial human toxicity with a narrow therapeutic window. CQ and HCQ poisoning cause myocardial depression and profound hypotension due to vasodilation. Bradycardia and ventricular escape rhythms arise from impaired myocardial automaticity and conductivity due to sodium and potassium channel blockade. With cardiotoxicity, ECGs may show widened QRS, atrioventricular heart block and QT interval prolongation. CQ may also cause seizures, often refractory to standard treatment. Of concern is pediatric poisoning, where 1–2 pills of CQ or HCQ can cause serious and potentially fatal toxicity in a toddler. The treatment of CQ/HCQ poisoning includes high-dose intravenous diazepam postulated to have positive ionotropic and antidysrhythmic properties that may antagonize the cardiotoxic effects of CQ. Infusions of epinephrine titrated to treat unstable hypotension, as well as potassium for severe hypokalemia may be required. Current scientific evidence does not support treatment or prophylactic use of these agents for COVID-19 disease. Regulatory and public health authorities recognize that CQ/HCQ may offer little clinical benefit and only add risk requiring further investigation before wider public distribution.

Title: Outcomes of Hydroxychloroquine Treatment Among Hospitalized COVID-19 Patients in the United States- Real-World Evidence From a Federated Electronic Medical Record Network Content: On March 28, 2020, in response to the rapidly accelerating COVID-19 pandemic, U.S FDA issued emergency use authorization for hydroxychloroquine (HCQ) in hospitalized COVID-19 patients based on limited in-vitro and anecdotal clinical data. Analysis of the accumulated real-world data utilizing electronic medical records (EMR) could indicate HCQ therapy benefits as we await the results of clinical trials. However, any such analysis of retrospective observational data should account for variables such as demographics and comorbidities that could affect treatment strategies or outcomes. Therefore, we report the outcomes of HCQ treatment in a propensity-matched cohort of COVID-19 hospitalized patients. Our analysis of a large retrospective cohort of hospitalized COVID-19 patients treated with HCQ did not show benefits in mortality or the need for mechanical ventilation when compared to a matched cohort of patients who did not receive HCQ.

Title: Hydroxychloroquine treatment in COVID‐19: a descriptive observational analysis of 30 cases from a single center in Wuhan, China Content: Hydroxychloroquine (HCQ) garnered scientific attention in early February following publication of reports showing in vitro activity of chloroquine (CQ) against COVID‐19. While studies are mixed on this topic, the therapeutic effect of HCQ or CQ still need more valid clinical evidence. In this descriptive observational study, we aimed to discuss the treatment response of HCQ in COVID‐19 infected patients and 30 cases were included. The demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and interleukin‐6 (IL‐6) before and after HCQ therapy and clinical outcome in the 30 COVID‐19 patients were assessed. In order to evaluate the effect of mediation time point, we also divided these cases into two groups, patients began administrated with HCQ within 7 days hospital (defined as early delivery group) and 7 days after hospital (defined as later delivery group). We found that, the elevated IL‐6, a risk factor in severe patients were reduced to normal level after HCQ treatment. More importantly, patients treated with HCQ at the time of early hospital recovered faster than those who treated later or taken as second line choose for their obvious shorter hospitalization time. In summary, early use of HCQ was better than later use and the effect of IL‐6 and CRP level can not be ruled out. This article is protected by copyright. All rights reserved.

Title: Experiences of Patients With Rheumatic Diseases in the United States During Early Days of the COVID-19 Pandemic Content: OBJECTIVE: Patients with rheumatic diseases such as rheumatoid arthritis (RA) and lupus have increased risk of infection and are treated with medications that may increase this risk yet are also hypothesized to help treat COVID-19. We set out to understand how the COVID-19 pandemic has impacted the lives of these patients in the United States. METHODS: Participants in a US-wide longitudinal observational registry responded to a supplemental COVID-19 questionnaire by e-mail on March 25, 2020, about their symptoms, COVID-19 testing, health care changes, and related experiences during the prior 2 weeks. Analysis compared responses by diagnosis, disease activity, and new onset of symptoms. Qualitative analysis was conducted on optional free-text comment fields. RESULTS: Of the 7061 participants invited to participate, 530 responded, with RA as the most frequent diagnosis (61%). Eleven participants met COVID-19 screening criteria, of whom two sought testing unsuccessfully. Six others sought testing, three of whom were successful, and all test results were negative. Not quite half of participants (42%) reported a change to their care in the prior 2 weeks. Qualitative analysis revealed four key themes: emotions in response to the pandemic, perceptions of risks from immunosuppressive medications, protective measures to reduce risk of COVID-19 infection, and disruptions in accessing rheumatic disease medications, including hydroxychloroquine. CONCLUSION: After 2 weeks, many participants with rheumatic diseases already had important changes to their health care, with many altering medications without professional consultation or because of hydroxychloroquine shortage. As evidence accumulates on the effectiveness of potential COVID-19 treatments, effort is needed to safeguard access to established treatments for rheumatic diseases.

Title: Experiences of Patients With Rheumatic Diseases in the United States During Early Days of the COVID‐19 Pandemic Content: OBJECTIVE: Patients with rheumatic diseases such as rheumatoid arthritis (RA) and lupus have increased risk of infection and are treated with medications that may increase this risk yet are also hypothesized to help treat COVID‐19. We set out to understand how the COVID‐19 pandemic has impacted the lives of these patients in the United States. METHODS: Participants in a US‐wide longitudinal observational registry responded to a supplemental COVID‐19 questionnaire by e‐mail on March 25, 2020, about their symptoms, COVID‐19 testing, health care changes, and related experiences during the prior 2 weeks. Analysis compared responses by diagnosis, disease activity, and new onset of symptoms. Qualitative analysis was conducted on optional free‐text comment fields. RESULTS: Of the 7061 participants invited to participate, 530 responded, with RA as the most frequent diagnosis (61%). Eleven participants met COVID‐19 screening criteria, of whom two sought testing unsuccessfully. Six others sought testing, three of whom were successful, and all test results were negative. Not quite half of participants (42%) reported a change to their care in the prior 2 weeks. Qualitative analysis revealed four key themes: emotions in response to the pandemic, perceptions of risks from immunosuppressive medications, protective measures to reduce risk of COVID‐19 infection, and disruptions in accessing rheumatic disease medications, including hydroxychloroquine. CONCLUSION: After 2 weeks, many participants with rheumatic diseases already had important changes to their health care, with many altering medications without professional consultation or because of hydroxychloroquine shortage. As evidence accumulates on the effectiveness of potential COVID‐19 treatments, effort is needed to safeguard access to established treatments for rheumatic diseases.

Title: Antiretroviral HIV drugs in COVID-19 research: promises and risks. An opinion piece Content: The unprecedented global scale of COVID-19 globally has triggered a race to discover interventions to reduce associated morbidity and mortality and rapid release of research findings prior to any degree of critical review. As with previous novel infection outbreaks, antiretrovirals are just one drug class that has been held up as a potential strategy for prophylaxis and treatment with scant evidence and risk of harm. Here we summarise the evidence for antiretrovirals to treat COVID-19 and, as a drug that has also been studied in HIV, hydroxychloroquine, and flag some of the pitfalls of using therapies that have not been evaluated robustly.

Title: Antiretroviral HIV drugs in COVID‐19 research: promises and risks. An opinion piece Content: The unprecedented global scale of COVID‐19 globally has triggered a race to discover interventions to reduce associated morbidity and mortality and rapid release of research findings prior to any degree of critical review. As with previous novel infection outbreaks, antiretrovirals are just one drug class that has been held up as a potential strategy for prophylaxis and treatment with scant evidence and risk of harm. Here we summarise the evidence for antiretrovirals to treat COVID‐19 and, as a drug that has also been studied in HIV, hydroxychloroquine, and flag some of the pitfalls of using therapies that have not been evaluated robustly.

Title: Psychiatric Aspects of Chloroquine and Hydroxychloroquine Treatment in the Wake of COVID-19: Psychopharmacological Interactions and Neuropsychiatric Sequelae Content: BACKGROUND: Chloroquine and hydroxychloroquine are among several experimental treatments being investigated in the urgent response to the COVID-19. With increased use of these medications, physicians need to become knowledgeable of these drugs’ neuropsychiatric side effects and interactions with psychiatric medications. METHODS: Literature review was performed in PubMed from 1950-2020 regarding psychiatric topics and targeted pharmacological properties of chloroquine and hydroxychloroquine. REVIEW: First, chloroquine and hydroxychloroquine may mildly inhibit CYP2D6 metabolism of psychiatric medications, and psychiatric medications that interfere with CYP2D6 or CYP3A4 activity could alter chloroquine and hydroxychloroquine levels. Second, they may prolong the QT interval, warranting caution with concomitant prescription of other QT prolonging agents. Finally, neuropsychiatric side effects are very uncommon but possible, and include a potentially prolonged phenomenon of “psychosis following chloroquine.” Hydroxychloroquine has less information available about its neuropsychiatric side effects than chloroquine, with psychosis literature limited to several case reports. It is not clear whether patients with psychiatric illness are more vulnerable to neuropsychiatric sequela of these medications, however, overdose on these medications by suicidal patients has high risk of mortality. CONCLUSION: The risk of neuropsychiatric side effects of chloroquine and hydroxychloroquine when used for COVID-19 treatment is not known. Best practice may include suicide risk assessment for patients treated with hydroxychloroquine. However, delirium is expected to be a more likely etiology of neuropsychiatric symptoms in critically ill patients treated for COVID-19, and adjustment disorder is a much more likely etiology of anxiety and depression symptoms than the side effects of chloroquine or hydroxychloroquine.

Title: Targeting the SARS-CoV-2 Main Protease to Repurpose Drugs for COVID-19 Content: Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (M(Pro)). Of these tested small molecule medicines, six displayed an IC(50) value in inhibiting M(Pro) below 100 μM. Three medicines pimozide, ebastine, and bepridil are basic small molecules that are expected to exert a similar effect as hydroxychloroquine in raising endosomal pH for slowing down the SARS-CoV-2 entry into human cell hosts. Bepridil has been previously explored in a high dose as 100 mg/kg for treating diseases. Its high dose use will likely achieve dual functions in treating COVID-19 by both raising the endosomal pH to slow viral entry and inhibiting M(Pro) in infected cells. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

Title: Chloroquine and hydroxychloroquine for the treatment of COVID-19: A living systematic review protocol Content: OBJECTIVE: To determine the relative impact of the use of chloroquine and hydroxychloroquine on outcomes important to patients with COVID 19. DESIGN: This is the protocol of a living systematic review. DATA SOURCES: We will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries, grey literature and in a centralised repository in L-OVE (Living OVerview of Evidence). L-OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L-OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation). We will include randomised controlled trials evaluating the effect of chloroquine and hydroxychloroquine - as monotherapy or in combination with other drugs - versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating chloroquine and hydroxychloroquine in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low- or very low-certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates. ETHICS AND DISSEMINATION: No ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.

Title: Similar incidence of Coronavirus Disease 2019 (COVID-19) in patients with rheumatic diseases with and without hydroxychloroquine therapy Content: Background: Hydroxychloroquine is currently being tested as post-exposure prophylaxis against coronavirus disease 2019 (COVID-19) in several ongoing clinical trials. Objective: To compare the incidence of COVID-19 in Spanish patients with autoimmune rheumatic diseases treated with and without hydroxychloroquine. Methods: Retrospective electronic record review, from February 27th to April 16th, of patients with autoimmune inflammatory diseases followed at two academic tertiary care hospitals in Seville, Spain. The cumulative incidence of COVID-19, confirmed or suspected, was compared between patients with and without hydroxychloroquine as part of their treatment of autoimmune inflammatory diseases. Results: Among 722 included subjects, 290 (40%) were receiving hydroxychloroquine. During the seven-week study period, five (1.7% [95% CI: 0.5%-4.0%] cases of COVID-19 were registered among patients with hydroxychloroquine and five (1.2% [0.4%-2.7%]) (p=0.523) in without hydroxychloroquine. COVID-19 was confirmed by PCR in one (0.3%, 95% CI 0.008-1.9%) patient with hydroxychloroquine and two (0.5%, 95% CI 0.05%-1.6%) without hydroxychloroquine (p=1.0). One patient on hydroxychloroquine and two subjects without hydroxychloroquine were admitted to the hospital, none of them required to be transferred to the intensive care unit and no patient died during the episode. Conclusions: The incidence and severity of COVID-19 among patients with autoimmune rheumatic diseases with and without hydroxychloroquine was not significantly different. Hydroxychloroquine does not seem to be an appropriate therapy for post-exposure prophylaxis against COVID-19.

Title: Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19 Content: PURPOSE: To assess efficacy and safety of chloroquine (CQ)/hydroxychloroquine (HCQ) for treatment or prophylaxis of COVID-19 in adult humans. MATERIALS AND METHODS: MEDLINE, PubMed, EMBASE and two pre-print repositories (bioRxiv, medRxiv) were searched from inception to 8th June 2020 for RCTs and nonrandomized studies (retrospective and prospective, including single-arm, studies) addressing the use of CQ/HCQ in any dose or combination for COVID-19. RESULTS: Thirty-two studies were included (6 RCTs, 26 nonrandomized, 29,192 participants). Two RCTs had high risk, two ‘some concerns’ and two low risk of bias (Rob2). Among nonrandomized studies with comparators, nine had high risk and five moderate risk of bias (ROBINS-I). Data synthesis was not possible. Low and moderate risk of bias studies suggest that treatment of hospitalized COVID-19 with CQ/HCQ may not reduce risk of death, compared to standard care. High dose regimens or combination with macrolides may be associated with harm. Postexposure prophylaxis may not reduce the rate of infection but the quality of the evidence is low. CONCLUSIONS: Patients with COVID-19 should be treated with CQ/HCQ only if monitored and within the context of high quality RCTs. High quality data about efficacy/safety are urgently needed.

Title: Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial Content: OBJECTIVE: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). DESIGN: Multicentre, open label, randomised controlled trial. SETTING: 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. PARTICIPANTS: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). INTERVENTIONS: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). MAIN OUTCOME MEASURE: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. RESULTS: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. CONCLUSIONS: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. TRIAL REGISTRATION: ChiCTR2000029868.

Title: Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial Content: OBJECTIVE: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). DESIGN: Multicentre, open label, randomised controlled trial. SETTING: 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. PARTICIPANTS: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). INTERVENTIONS: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). MAIN OUTCOME MEASURE: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. RESULTS: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval -10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. CONCLUSIONS: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. TRIAL REGISTRATION: ChiCTR2000029868.

Title: Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe Covid-19 in a French university hospital Content: BACKGROUND: Data from non-randomized studies have suggested that hydroxychloroquine could be an effective therapeutic agent against Covid-19. METHODS: We conducted an observational, retrospective cohort study involving hospitalized adult patients with confirmed, mild to severe Covid-19 in a French university hospital. Patients who received hydroxychloroquine (200mg tid dosage for 10 days) on a compassionate basis in addition to SOCwere compared to patients without contraindications to hydroxychloroquine who received SOCalone. A propensity score-weighted analysis was performed to control for confounders: age, sex, time between symptom onset and admission ≤ 7 days, Charlson comorbidity index, medical history of arterial hypertension, and obesity, NEWS2 score at admission, and pneumonia severity. The primary endpoint was time to unfavorable outcome, defined as: death, admission to an intensive care unit, or decision to withdraw or withhold life-sustaining treatments, whichever came first. RESULTS: Data from 89 patients with laboratory-confirmed Covid-19 were analyzed, 84 of whom were considered in the primary analysis; 38 patients treated with hydroxychloroquine and 46 patients treated with SOCalone. At admission, the mean age of patients was 66 years, the median Charlson comorbidity index was 3, and the median NEWS2 severity score was 3. After propensity score weighting, treatment with hydroxycholoroquine was not associated with a significantly reduced risk of unfavorable outcome (HR 0.90 [0.38; 2.1], p = 0.81). Overall survival was not significantly different between the two groups (HR 0.89 [0.23; 3.47], p = 1). CONCLUSION: In hospitalized adults with Covid-19, no significant reduction of the risk of unfavorable outcomes was observed with hydroxychloroquine in comparison to standard of care. Unmeasured confounders may however have persisted despite careful propensity-weighted analysis and the study might be underpowered. Ongoing controlled trials in patients with varying degrees of initial severity on a larger scale will help determine whether there is a place for hydroxychloroquine in the treatment of Covid-19.

Title: Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe Covid-19 in a French university hospital Content: BACKGROUND: Data from non-randomized studies have suggested that hydroxychloroquine could be an effective therapeutic agent against Covid-19. METHODS: We conducted an observational, retrospective cohort study involving hospitalized adult patients with confirmed, mild to severe Covid-19 in a French university hospital. Patients who received hydroxychloroquine (200mg tid dosage for 10 days) on a compassionate basis in addition to SOCwere compared to patients without contraindications to hydroxychloroquine who received SOCalone. A propensity score-weighted analysis was performed to control for confounders: age, sex, time between symptom onset and admission ≤ 7 days, Charlson comorbidity index, medical history of arterial hypertension, and obesity, NEWS2 score at admission, and pneumonia severity. The primary endpoint was time to unfavorable outcome, defined as: death, admission to an intensive care unit, or decision to withdraw or withhold life-sustaining treatments, whichever came first. RESULTS: Data from 89 patients with laboratory-confirmed Covid-19 were analyzed, 84 of whom were considered in the primary analysis; 38 patients treated with hydroxychloroquine and 46 patients treated with SOCalone. At admission, the mean age of patients was 66 years, the median Charlson comorbidity index was 3, and the median NEWS2 severity score was 3. After propensity score weighting, treatment with hydroxycholoroquine was not associated with a significantly reduced risk of unfavorable outcome (HR 0.90 [0.38; 2.1], p = 0.81). Overall survival was not significantly different between the two groups (HR 0.89 [0.23; 3.47], p = 1) CONCLUSION: In hospitalized adults with Covid-19, no significant reduction of the risk of unfavorable outcomes was observed with hydroxychloroquine in comparison to standard of care. Unmeasured confounders may however have persisted despite careful propensity-weighted analysis and the study might be underpowered. Ongoing controlled trials in patients with varying degrees of initial severity on a larger scale will help determine whether there is a place for hydroxychloroquine in the treatment of Covid-19.

Title: A New Drug-Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study Content: INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.

Title: A New Drug–Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study Content: INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug–drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase(®), the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as ‘fatal outcomes’. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9–139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6–13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.

Title: Efficacy of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-Analysis Content: Background The antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) show promising SARS-CoV-2 anti-viral activity in vitro; however, clinical studies have reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin (AZ) on outcomes of COVID-19 patients. Methods We performed a systematic review and meta-analysis of studies published through July 7, 2020. We searched Medline, Embase, EBM Reviews, Scopus, Web of Science, preprints and grey literature. We included studies that assessed COVID-19 patients treated with CQ or HCQ, with or without AZ. We pooled only adjusted effect estimates of mortality using a random effect model and estimated between studies heterogeneity using I2 statistic. We summarized the effect of CQ or HCQ on viral clearance and ICU admission/ mechanical ventilation. Results Out of 1463 citations screened for eligibility, five RCTs and 14 cohort studies were included (20,263 patients, all hospitalized but with a variable disease severity spectrum). Thirteen studies (1 RCT and 12 cohorts) with 19,573 patients examined the effect of HCQ on short term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96-1.15, I2=0 %, p=0.647). Six cohort studies examined the effect of HCQ and AZ combination among 3430 patients. After excluding a study that examined only patients with cancers, the pooled adjusted OR was (1.15, 95% CI 0.99-1.34, I2=0.0%). Two cohort studies and three RCTs found no significant effect of HCQ on viral clearance. One RCT with 48 patients demonstrated improved viral clearance in patients treated with CQ and HCQ. Three cohort studies found that HCQ with or without AZ had no significant effect on mechanical ventilation/ ICU admission. Conclusion Moderate certainty evidence suggests that HCQ, with or without AZ, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19. Our findings are consistent with the recommendations from medical societies that HCQ should only be used to treat COVID-19 patients in the context of clinical trials. Trials of HCQ as pre-exposure prophylaxis are ongoing.

Title: The immunology of COVID-19: is immune modulation an option for treatment? Content: In December, 2019, an outbreak of COVID-19 emerged in Wuhan, China and quickly spread globally. As of May 7, 2020, there were 3 672 238 confirmed infections and 254 045 deaths attributed to COVID-19. Evidence has shown that there are asymptomatic carriers of COVID-19 who can transmit the disease to others. The virus incubation time shows a wide range (0–24 days) and the virus displays a high infectivity. It is therefore urgent to develop an effective therapy to treat patients with COVID-19 and to control the spread of the causative agent, severe respiratory syndrome coronavirus 2. Repurposing of approved drugs is widely adopted to fight newly emerged diseases such as COVID-19, as these drugs have known pharmacokinetic and safety profiles. As pathological examination has confirmed the involvement of immune hyperactivation and acute respiratory distress syndrome in fatal cases of COVID-19, several disease-modifying anti-rheumatic drugs (DMARDS), such as hydroxychloroquine and tocilizumab, have been proposed as potential therapies for the treatment of COVID-19. In this Review, we discuss the immunological aspects of COVID-19 and the potential implication of DMARDs in treating this disease.

Title: Hydroxychloroquine in COVID-19 patients: what still needs to be known about the kinetics Content: Different dosage regimens of hydroxychloroquine are used to manage COVID-19 patients, without information on the pharmacokinetics in this population.Blood samples (n=101) were collected from 57 COVID-19 patients for 7 days and concentrations were compared with simulated kinetic profiles.Hydroxychloroquine exposure is low and cannot be predicted by other populations.

Title: Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence Content: 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

Title: Chloroquine paradox may cause more damage than help fight COVID-19 Content: Novel coronavirus disease 2019 (COVID-19) pandemic is the most recent health care crisis without specific prophylactic or therapeutic drugs. Antimalarial drug chloroquine (CHL) and its safer derivative hydroxychloroquine (HCHL) have been proposed to be repurposed to treat SARS coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. CHL/HCHL have anti-inflammatory activity and are used to treat rheumatoid arthritis, osteoarthritis and lupus. Although, CHL/HCHL have an anti-viral activity against several viruses in cell-cultures, the anti-viral activity in-vivo is questionable. Repurposing of CHL/HCHL to treat SARS-CoV-2 infection is appealing. However, there is empirical evidence from animal studies with other viruses suggesting that CHL/HCHL may have an untoward paradoxical effect. One thus cannot exclude the possibility that CHL may increase the severity of the disease and prove deleterious both for the patients and public health efforts to contain the highly contagious and explosive spread of SARS-CoV-2.

Title: Chloroquine paradox may cause more damage than help fight COVID-19 Content: Abstract Novel coronavirus disease 2019 (COVID-19) pandemic is the most recent health care crisis without specific prophylactic or therapeutic drugs. Antimalarial drug chloroquine (CHL) and its safer derivative hydroxychloroquine (HCHL) have been proposed to be repurposed to treat SARS coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. CHL/HCHL have anti-inflammatory activity and are used to treat rheumatoid arthritis, osteoarthritis and lupus. Although, CHL/HCHL have an anti-viral activity against several viruses in cell-cultures, the anti-viral activity in-vivo is questionable. Repurposing of CHL/HCHL to treat SARS-CoV-2 infection is appealing. However, there is empirical evidence from animal studies with other viruses suggesting that CHL/HCHL may have an untoward paradoxical effect. One thus cannot exclude the possibility that CHL may increase the severity of the disease and prove deleterious both for the patients and public health efforts to contain the highly contagious and explosive spread of SARS-CoV-2.

Title: When there is a pandemic there is no time to waste: should we have hydroxychloroquine in our armoury against COVID-19 infected patients? Content: The current use of chloroquine and/or hydroxychloroquine, a drug currently used to treat autoimmune rheumatic diseases, in treating severe acute respiratory syndrome caused by coronavirus 2 (SARSCoV-2) or COVID-19-infected patients with pneumonia is a matter of intense consideration. We wish to enter the ongoing debate as to whether this well-known drug must be given to Greek COVID-19-infected patients, especially those with pneumonia. Our arguments are based on the existing data and the capacity of the Greek health system to afford potent anti-viral treatments, which are under immense investigation. We propose several suggestions related to treatment of COVID-19 pneumonia with chloroquine/hydroxychloroquine that we think must be taken into consideration to fit the evolving situation of the pandemic in Greece.

Title: Doubtful precipitation of hemolysis by hydroxychloroquine in glucose‐6‐phosphate dehydrogenase deficient patient with COVID‐19 infection Content: We read with great interest the recent article by Beauverd et al.(1) on an interesting case of severe hemolysis in a patient with COVID‐19 treated with hydroxychloroquine. The authors concluded that COVID‐19 infection was possibly the initial trigger for hemolysis. However, the article also suggested that hydroxychloroquine possibly worsened the hemolysis, and further cautioned the use of hydroxychloroquine in glucose‐6‐phosphate dehydrogenase (G6PD)‐deficient patients. We would like to comment on the authors’ attribution of accentuated hemolysis to the use of hydroxychloroquine.

Title: Doubtful precipitation of hemolysis by hydroxychloroquine in glucose-6-phosphate dehydrogenase deficient patient with COVID-19 infection Content: We read with great interest the recent article by Beauverd et al.1 on an interesting case of severe hemolysis in a patient with COVID-19 treated with hydroxychloroquine. The authors concluded that COVID-19 infection was possibly the initial trigger for hemolysis. However, the article also suggested that hydroxychloroquine possibly worsened the hemolysis, and further cautioned the use of hydroxychloroquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient patients. We would like to comment on the authors' attribution of accentuated hemolysis to the use of hydroxychloroquine.

Title: National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study Content: COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group. This univariate analysis is of course only one additional piece of evidence in the debate regarding the efficiency of anti-malaria drugs, and it is also limited as the two groups certainly have other systemic differences in the way they responded to the pandemic, in the way they report death or in their population that better explain differences in dynamics (systematic differences that may also explain their choice to rely on anti-malaria drugs in the first place). Nevertheless, the difference in dynamics is so striking that we believe that the urgency context commands presenting the univariate analysis before delving into further analysis. In the end, this data might ultimately be either a piece of evidence in favor or anti-malaria drugs or a stepping stone in understanding further what other ecological aspects place a role in the dynamics of COVID-19 deaths.

Title: Electrocardiographic safety of daily Hydroxychloroquine 400mg plus Azithromycin 250mg as an ambulatory treatment for COVID-19 patients in Cameroon. Content: Objective : To determine the early electrocardiographic changes in a cohort of ambulatory cameroonian COVID-19 patients treated with hydroxychloroquine and Azithromycin. Design : Prospective study. Setting : Treatment centres of the city of Yaounde, Cameroon, from May 7th to 24th 2020. Participants : We enrolled 51 consecutive confirmed COVID-19 on RT-PCR who having mild forms of COVID-19 and treated by hydroxychloroquine 200mg twice daily during seven days plus Azithromycin 500 mg the first day and 250 mg the remaining 4 days as per national standard. Main outcomes measures : The primary end-point was the change in QTc interval between day 0 (D0), day 3 (D3) and day 7 (D7). Secondary endpoints were changes in all other cardiac electrical conductivity patterns and the occurrence of clinical arrhythmic events during the course of treatment. Results: The population (29 men and 22 women) was aged 39 +/- 11 years (range 17 to 61 years). Mean Tisdale score was 3.35 +/- 0.48. No significant change from baseline (D0) of QTc was observed at D7 (429 +/- 27 ms at D0 versus 396 +/- 26 ms at D7; p = 0.27). A reduction of heart rate was observed between the D0 and D7 (75 +/- 13 bpm versus 70 +/- 13 bpm, p = 0.02) with increased QRS duration between D0 and D7 (95 +/- 10 ms versus 102 +/- 17 ms, p = 0.004). No symptomatic arrhythmic events occurred during the treatment course. Conclusions: No life-threatening modifications of the QT interval was observed in non-severe COVID-19 patients treated ambulatory with hydroxychloroquine and azithromycin. Studies are needed in critical-ill and older patients.

Title: Effect of hydroxychloroquine on COVID-19 prevention in cancer patients undergoing treatment: a structured summary of a study protocol for a randomised controlled trial Content: OBJECTIVES: In this study, we investigate the effect of hydroxychloroquine on the prevention of Novel Coronavirus Disease (COVID-19) in cancer patients being treated. TRIAL DESIGN: This is a multi-centre, two-arm, parallel-group, triple-blind, phase 2-3 randomised controlled trial. PARTICIPANTS: All patients over the age of 15 from 5 types of cancer are included in the study. Patients with acute lymphoid and myeloid leukemias in the first line treated with curative intent, patients with high-grade non-Hodgkin's lymphoma treated with leukemia protocols and patients with non-metastatic breast and colon cancer in the first line of treatment will enter the study. The exclusion criteria will include known sensitivity to Hydroxychloroquine, weight below 35 kilograms, history of retinopathy, history of any cardiac disease, acute respiratory tract infection in the last 2 months, having COVID-19 in the first two weeks of entering the trial, having Diabetes Mellitus, having an immuno-suppressive disease other than cancer, having chronic pulmonary disease and taking immuno-suppressant drug other than chemotherapeutic agents for current cancer. This study is performed in five academic centres affiliated to Mashhad University of Medical Sciences, Mashhad, Iran. INTERVENTION AND COMPARATOR: Patients are randomly assigned to two groups; one being given hydroxychloroquine and the other is given placebo. During two months of treatment, the two groups are treated with either hydroxychloroquine (Amin® Pharmaceutical Company, Isfahan, Iran) or placebo (identical in terms of shape, colour, smell) as a single 200 mg tablet every other day. Patients will be monitored for COVID-19 symptoms during the follow-up period. If signs or symptoms occur (fever, cough, shortness of breath), they will be examined and investigated with a high-resolution computed tomography (CT) scan of the lungs, COVID-19 specific IgM, IgG antibody assay and a nucleic acid amplification test (NAT) for the SARS-CoV-2 virus. MAIN OUTCOMES: The primary end point of this study is to investigate the incidence of COVID-19 in patients being treated for their cancer over a 2-month period. RANDOMISATION: Randomisation will be performed using randomly permuted blocks. By using an online website (www.randomization.com) the randomization sequence will be produced by quadruple blocks. The allocation ratio in intervention and control groups is 1:1. BLINDING (MASKING): Participants and caregivers do not know whether the patient is in the intervention or the control group. The outcome assessor and the data analyst are also blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 60 patients, with 30 patients in each group. TRIAL STATUS: The trial began on April 14, 2020 and recruitment is ongoing. Recruitment is anticipated to be completed by June 14, 2020 There has been no change in study protocol since approval, protocol version 1 was approved April 12, 2020. TRIAL REGISTRATION: This trial has been registered by the title of "Effect of Hydroxychloroquine on Novel Coronavirus Disease (COVID-19) prevention in cancer patients under treatment" in Iranian Registry of Clinical Trials (IRCT) with code "IRCT20200405046958N1", https://www.irct.ir/trial/46946. Registration date is April 14, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Title: Effect of hydroxychloroquine on COVID-19 prevention in cancer patients undergoing treatment: a structured summary of a study protocol for a randomised controlled trial Content: OBJECTIVES: In this study, we investigate the effect of hydroxychloroquine on the prevention of Novel Coronavirus Disease (COVID-19) in cancer patients being treated. TRIAL DESIGN: This is a multi-centre, two-arm, parallel-group, triple-blind, phase 2-3 randomised controlled trial. PARTICIPANTS: All patients over the age of 15 from 5 types of cancer are included in the study. Patients with acute lymphoid and myeloid leukemias in the first line treated with curative intent, patients with high-grade non-Hodgkin's lymphoma treated with leukemia protocols and patients with non-metastatic breast and colon cancer in the first line of treatment will enter the study. The exclusion criteria will include known sensitivity to Hydroxychloroquine, weight below 35 kilograms, history of retinopathy, history of any cardiac disease, acute respiratory tract infection in the last 2 months, having COVID-19 in the first two weeks of entering the trial, having Diabetes Mellitus, having an immuno-suppressive disease other than cancer, having chronic pulmonary disease and taking immuno-suppressant drug other than chemotherapeutic agents for current cancer. This study is performed in five academic centres affiliated to Mashhad University of Medical Sciences, Mashhad, Iran. INTERVENTION AND COMPARATOR: Patients are randomly assigned to two groups; one being given hydroxychloroquine and the other is given placebo. During two months of treatment, the two groups are treated with either hydroxychloroquine (Amin® Pharmaceutical Company, Isfahan, Iran) or placebo (identical in terms of shape, colour, smell) as a single 200 mg tablet every other day. Patients will be monitored for COVID-19 symptoms during the follow-up period. If signs or symptoms occur (fever, cough, shortness of breath), they will be examined and investigated with a high-resolution computed tomography (CT) scan of the lungs, COVID-19 specific IgM, IgG antibody assay and a nucleic acid amplification test (NAT) for the SARS-CoV-2 virus. MAIN OUTCOMES: The primary end point of this study is to investigate the incidence of COVID-19 in patients being treated for their cancer over a 2-month period. RANDOMISATION: Randomisation will be performed using randomly permuted blocks. By using an online website (www.randomization.com) the randomization sequence will be produced by quadruple blocks. The allocation ratio in intervention and control groups is 1:1. BLINDING (MASKING): Participants and caregivers do not know whether the patient is in the intervention or the control group. The outcome assessor and the data analyst are also blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 60 patients, with 30 patients in each group. TRIAL STATUS: The trial began on April 14, 2020 and recruitment is ongoing. Recruitment is anticipated to be completed by June 14, 2020 There has been no change in study protocol since approval, protocol version 1 was approved April 12, 2020. TRIAL REGISTRATION: This trial has been registered by the title of “Effect of Hydroxychloroquine on Novel Coronavirus Disease (COVID-19) prevention in cancer patients under treatment” in Iranian Registry of Clinical Trials (IRCT) with code “IRCT20200405046958N1”, https://www.irct.ir/trial/46946. Registration date is April 14, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Title: Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19 Content: Importance: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high mortality. The most urgent thing is to find effective treatments. Objective: To determine whether hydroxychloroquine application may be associated with a decreased risk of death in critically ill COVID-19 patients and what is potential mechanism. Design, Setting and Patients: This retrospective study included all 568 critically ill COVID-19 patients who were confirmed by pathogen laboratory tests despite antiviral treatment and had severe acute respiratory distress syndrome, PAO2/FIO2 <300 with need of mechanical ventilation in Tongji Hospital, Wuhan, between February 1 of 2020 to April 8 of 2020. All 568 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them additionally received oral hydroxychloroquine (HCQ) treatment (200 mg twice a day for 7-10 days). Primary endpoint is mortality of patients, and inflammatory cytokines levels were compared between hydroxychloroquine and non-hydroxychloroquine (NHCQ) treatments. MAIN OUTCOMES AND MEASURES: In-hospital death and hospital stay time (day) were obtained, level of inflammatory cytokine (IL-6) was measured and compared between HCQ and NHCQ treatments. RESULTS: The median age of 568 critically ill patients is 68 (57, 76) years old with 37.0% being female. Mortalities are 18.8% (9/48) in HCQ group and 45.8% (238/520) in NHCQ group (p<0.001). The time of hospital stay before patient death is 15 (10-21) days and 8 (4 - 14) days for the HCQ and NHCQ groups, respectively (p<0.05). The level of inflammatory cytokine IL-6 was significantly lowered from 22.2 (8.3-118.9) pg/mL at the beginning of the treatment to 5.2 (3.0-23.4) pg/ml (p<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. CONCLUSIONS AND RELEVANCE: Hydroxychloroquine treatment is significantly associated with a decreased mortality in critically ill patients with COVID-19 through attenuation of inflammatory cytokine storm. Therefore, hydroxychloroquine should be prescribed for treatment of critically ill COVID-19 patients to save lives.

Title: Coronavirus disease-2019 in cancer patients. A report of the first 25 cancer patients in a western country (Italy) Content: Background: We describe cancer patients with coronavirus disease-2019 (COVID-19) infection treated at the Piacenza’s general hospital (north Italy). Materials & methods: Twenty-five cancer patients infected by COVID-19 admitted at the Piacenza’s general hospital from 21 February to 18 March 2020. Outcome from the infection were compared with infected noncancer patients. Results: Twenty patients (80%) were treated with antiviral therapy and hydroxychloroquine and five (20%) received hydroxychloroquine alone. Nine (36%) patients died, while 16 (64%) overcome the infection. In the control group the mortality was 16.13% and the overcome from infection was 83.87%. Conclusion: Mortality for COVID-19 was greater in cancer patients when compared with noncancer patients, worse prognosis for older age, women and patients treated with hydroxychloroquine alone. However, the comparisons did not reach statistical significance in most cases. This could be due to the small sample size that is the main limitation of the study.

Title: Coronavirus disease-2019 in cancer patients. A report of the first 25 cancer patients in a western country (Italy) Content: Background: We describe cancer patients with coronavirus disease-2019 (COVID-19) infection treated at the Piacenza's general hospital (north Italy). Materials & methods: 25 cancer patients infected by COVID-19 admitted at the Piacenza's general hospital from 21 February to 18 March 2020. Outcome from the infection were compared with infected noncancer patients. Results: 20 patients (80%) were treated with antiviral therapy and hydroxychloroquine and five (20%) received hydroxychloroquine alone. Nine (36%) patients died, while 16 (64%) overcome the infection. In the control group the mortality was 16.13% and the overcome from infection was 83.87%. Conclusion: Mortality for COVID-19 was greater in cancer patients when compared with noncancer patients, worse prognosis for older age, women and patients treated with hydroxychloroquine alone. However, the comparisons did not reach statistical significance in most cases. This could be due to the small sample size that is the main limitation of the study.

Title: Systematic Review and Meta-analysis of the Effectiveness and Safety of Hydroxychloroquine in COVID-19. Content: Backgrounds. Since COVID-19 outbreak, various agents have been tested but no proven effective therapies have been identified. This has led to a lot of controversies among associated researches. Hence, in order to address the issue of using hydroxychloroquine in treating COVID-19 patients, we conducted a systematic review and meta-analysis. Methods. A thorough search was carried out to find relevant studies in MEDLINE, medRxiv, PubMed, Cochrane Database, China Academic Journals Full-text Database and Web of Science. Two investigators independently reviewed 274 abstracts and 23 articles. The trials which evaluated hydroxychloroquine for treatment of COVID-19 were included for this systematic review. Two investigators assessed quality of the studies and data extraction was done by one reviewer and cross checked by the other. Results. Five trials involving 677 patients were included while conducting the meta-analysis. Compared with the control group, hydroxychloroquine with or without azithromycin showed benefits in positive-to-negative conversion of SARS-CoV-2 (odds ratio [OR], 1.95 [95% CI,0.19 to 19.73] and a reduction in progression rate (OR, 0.89 [95% CI, 0.58 to 1.37]), but without demonstrating any statistical significance. This systematic review has also suggested a possible synergistic effect of the combination therapy which included hydroxychloroquine and azithromycin. However, the use of hydroxychloroquine alone was associated with increased mortality in COVID-19 patients. Conclusion. The use of hydroxychloroquine with or without azithromycin for treatment of COVID-19 patients, seems to be effective. The combination of hydroxychloroquine and azithromycin has shown synergic effects. However, mortality rate was increased when the treatment was conducted with hydroxychloroquine.

Title: COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine Content: OBJECTIVES/BACKGROUND AND OBJECTIVES: Prior epidemics of high-mortality human coronaviruses, such as the acute respiratory syndrome coronavirus (SARS-CoV or SARS-1) in 2003, have driven the characterization of compounds that could be possibly active against the currently emerging novel coronavirus SARS-CoV-2 (COVID-19). Presently, no approved treatment or prophylaxis is available for COVID-19. We comment on the existing COVID-19 research methodologies in general and the published reporting. Given the media attention and claims of effectiveness, we chose chloroquine and hydroxychloroquine, in combination with azithromycin, as an area of COVID-19 research to examine. METHODS/STUDY DESIGN AND SETTING: MEDLINE and EMBASE electronic databases were searched from 2019 to present (April 3rd, 2020) using a mix of keywords such as COVID-19 and chloroquine and hydroxychloroquine. We also searched the largest clinical medicine preprint repository, medRxiv.org. RESULTS: We found 6 studies, 3 randomized control trials and 3 observational studies, focusing on chloroquine and hydroxychloroquine (with azithromycin). We critically appraised the evidence. CONCLUSION: We found that the COVID-19 research methodology is very poor in the area of chloroquine/hydroxychloroquine research. In screening the literature, we observed the same across COVID-19 research in relation to potential treatments. The reporting is very poor and sparse, and patient-important outcomes needed to discern decision-making priorities are not reported. We do understand the barriers to perform rigorous research in health care settings overwhelmed by a novel deadly disease. However, this emergency pandemic situation does not transform flawed methods and data into credible results. The adequately powered, comparative, and robust clinical research that is needed for optimal evidence-informed decision-making remains absent in COVID-19.

Title: Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence Content: Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Title: Chloroquine and hydroxychloroquine in the management of COVID-19: much kerfuffle but little evidence Content: Summary Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Title: Safety considerations of chloroquine and hydroxychloroquine in treatment of COVID-19 Content: Chloroquine and hydroxychloroquine are both used to treat COVID-19. Safety data in this specific population is largely unknown. In particular, cardiologic, gastro-intestinal and neuropsychiatric side-effects of (hydroxychloroquine) needs special attention in COVID-19 patients.

Title: Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks Content: Detailed data on clinical presentations and outcomes of children with COVID-19 in Europe are still lacking. In this descriptive study, we report on 130 children with confirmed COVID-19 diagnosed by 28 centers (mostly hospitals), in 10 regions in Italy, during the first months of the pandemic. Among these, 67 (51.5%) had a relative with COVID-19 while 34 (26.2%) had comorbidities, with the most frequent being respiratory, cardiac, or neuromuscular chronic diseases. Overall, 98 (75.4%) had an asymptomatic or mild disease, 11 (8.5%) had moderate disease, 11 (8.5%) had a severe disease, and 9 (6.9%) had a critical presentation with infants below 6 months having significantly increased risk of critical disease severity (OR 5.6, 95% CI 1.3 to 29.1). Seventy-five (57.7%) children were hospitalized, 15 (11.5%) needed some respiratory support, and nine (6.9%) were treated in an intensive care unit. All recovered.Conclusion:This descriptive case series of children with COVID-19, mostly encompassing of cases enrolled at hospital level, suggest that COVID-19 may have a non-negligible rate of severe presentations in selected pediatric populations with a relatively high rates of comorbidities. More studies are needed to further understand the presentation and outcomes of children with COVID-19 in children with special needs. What is Known: â¢ There is limited evidence on the clinical presentation and outcomes of children with COVID-19 in Europe, and almost no evidence on characteristics and risk factors of severe cases. What is New: â¢ Among a case series of 130 children, mostly diagnosed at hospital level, and with a relatively high rate (26.2%) of comorbidities, about three-quarter had an asymptomatic or mild disease. â¢ However, 57.7% were hospitalized, 11.5% needed some respiratory support, and 6.9% were treated in an intensive care unit.

Title: Plasma IL-6 Levels following Corticosteroid Therapy as an Indicator of ICU Length of Stay in Critically ill COVID-19 Patients Content: Intensive Care Unit (ICU) admissions and mortality in severe COVID-19 patients are driven by cytokine storms and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays superior 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. Among 16 patients with plasma IL-6 measurement post-corticosteroid administration, a higher proportion of patients with an IL-6 value over 10 pg/mL have worse outcomes (i.e. ICU Length of Stay > 15 days or death) when compared to 41 patients treated with non-corticosteroid drugs including antivirals, tocilizumab, azithromycin, and hydroxychloroquine (p-value = 0.0024). Given this unexpected clinical association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the Glucocorticoid Receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single cell RNA-seq data from bronchoalveolar lavage fluid of severe COVID-19 patients and nearly 2 million human cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express both NR3C1 and IL-6. The mechanism of Glucocorticoid Receptor (GR) agonists mitigating pulmonary and multi-organ inflammation in some COVID-19 patients with respiratory failure, may be in part due to their successful antagonism of IL-6 production within lung macrophages and vasculature.