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      Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

      , M.D., , Ph.D., , Ph.D., , M.D., , M.D., , M.D., , M.D., , M.D., , Pharm.D., , M.D., Dr.P.H., , M.D., M.P.H., , M.D.

      The New England Journal of Medicine

      Massachusetts Medical Society

      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_9Keyword part (keyword): Global Health , 18, Infectious Disease, Keyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_9Keyword part (keyword): Global Health , 18_1, Infectious Disease General, 18_6, Viral Infections, 18_9, Global Health

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          Abstract

          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.)

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          Most cited references 12

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          Multiple Imputation for Nonresponse in Surveys

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            Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

            Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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              In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

              Abstract Background The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile. Results Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
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                Author and article information

                Journal
                N Engl J Med
                N. Engl. J. Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                07 May 2020
                07 May 2020
                Affiliations
                From the Divisions of General Medicine, Infectious Diseases, and Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine (J.G., J.Z., M.B., A.L., D.K.M., C.K., R.G.B., M.E.S., N.W.S.), the Departments of Biostatistics (Y.S.) and Epidemiology (J.P., R.G.B., N.W.S.), Mailman School of Public Health, and the Department of Biomedical Informatics (G.H.), Vagelos College of Physicians and Surgeons, Columbia University, and New York–Presbyterian Hospital–Columbia University Irving Medical Center (J.G., J.Z., M.B., A.L., D.K.M., C.K.,R.G.B., M.E.S., N.W.S.) — all in New York.
                Author notes
                Address reprint requests to Dr. Schluger at the Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, PH-8 E., Rm. 101, 622 W. 168th St., New York, NY 10032, or at ns311@ 123456cumc.columbia.edu .
                Article
                NJ202005073830101
                10.1056/NEJMoa2012410
                7224609
                32379955
                Copyright © 2020 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                Product
                Funding
                Funded by: National Institutes of Health, FundRef http://dx.doi.org/10.13039/100000002;
                Award ID: RO1-HL077612
                Award ID: RO1-HL093081
                Award ID: RO1-HL121270
                Award ID: RO1-LM006910
                Funded by: National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, FundRef http://dx.doi.org/10.13039/100005258;
                Award ID: 200-2009-32593
                Categories
                Original Article
                Custom metadata
                2020-05-07T17:00:00-04:00
                2020
                05
                07
                17
                00
                00
                -04:00

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