Background The 2020 COVID-19 pandemic has stunned the world, financial markets, and healthcare systems. Researchers are rushing to identify effective treatments while maintaining rigorous adherence to the scientific method. Clinicians are doing their best to provide evidence-based care in a setting of very little good evidence. To date, no effective treatments exist for COVID-19 management. Unfortunately, traditional and social media coupled with world leader commentary have led some to believe hydroxychloroquine offers a bona fide cure and even prevention. The purpose of this commentary is to review the medical literature related to hydroxychloroquine building on knowledge over the past 17 years since the 2003 SARS-CoV epidemic

Benson, B.

Boulware, D.

Charles, A.

Chipman, J.G.

Connett, J.

Ingraham, N.E.

Murray, T.

Schacker, T.

Sparks, J.A.

Sparks, M.A.

Tignanelli, C.J.

The 2020 COVID-19 pandemic has stunned the world, financial markets, and healthcare systems. Researchers are rushing to identify effective treatments while maintaining rigorous adherence to the scientific method. Clinicians are doing their best to provide evidence-based care in a setting of very little good evidence. To date, no effective treatments exist for COVID-19 management. Unfortunately, traditional and social media coupled with world leader commentary have led some to believe hydroxychloroquine offers a bona fide cure and even prevention. The purpose of this commentary is to review the medical literature related to hydroxychloroquine building on knowledge over the past 17 years since the 2003 SARS-CoV epidemic

Ingraham, Nicholas E.

Boulware, David

Sparks, Matthew A.

Schacker, Timothy

Benson, Bradley

Sparks, Jeffrey A.

Murray, Thomas

Connett, John

Chipman, Jeffrey G.

Charles, Anthony

Tignanelli, Christopher J.

Hochschulbibliothekszentrum des Landes Nordrhein-Westfalen (hbz)

Shining a light on the evidence for hydroxychloroquine in SARS-CoV-2

Carolina Digital Repository

COMMENTARY Open AccessShining a light on the evidence forhydroxychloroquine in SARS-CoV-2Nicholas E. Ingraham1*, David Boulware2, Matthew A. Sparks3, Timothy Schacker4, Bradley Benson5,Jeffrey A. Sparks6, Thomas Murray7, John Connett7, Jeffrey G. Chipman8, Anthony Charles9,10 andChristopher J. Tignanelli10,11Keywords: Evidence-based medicine, COVID-19, Hydroxychloroquine, Pandemic, RCT, SARSBackgroundThe 2020 COVID-19 pandemic has stunned the world,financial markets, and healthcare systems. Researchers arerushing to identify effective treatments while maintainingrigorous adherence to the scientific method. Clinicians aredoing their best to provide evidence-based care in a settingof very little good evidence. To date, no effective treat-ments exist for COVID-19 management. Unfortunately,traditional and social media coupled with world leadercommentary have led some to believe hydroxychloroquineoffers a bona fide cure and even prevention. The purposeof this commentary is to review the medical literaturerelated to hydroxychloroquine building on knowledge overthe past 17 years since the 2003 SARS-CoV epidemic.Main textPre-clinical evidenceHydroxychloroquine has been used for the treatment of mal-aria since 1955 and is approved for the treatment of rheuma-toid arthritis and lupus. Currently, the potential mechanismof action for hydroxychloroquine’s effect on SARS-CoV1and SARS-CoV2 is not fully known. It is hypothesized thatincreases in endosomal pH may inhibit viral fusion and repli-cation with interference in ACE2 receptor glycosylation orSigma-1 receptor [1, 2]. Chloroquine and hydroxychloro-quine seem effective in killing SARS-CoV in vitro [1, 3]. Re-cent reports show it also may be effective at killing SARS-CoV-2-infected cells in vitro [4]. Unfortunately, effectivetreatments in vitro frequently do not translate in vivo andthe efficacy of hydroxychloroquine is yet to be determined.Pre-clinical animal (in vivo) models more accuratelymodel human safety and efficacy and enable better pre-diction of translational failure into humans. Chloroquinewas not found to be efficacious in mouse models in-fected with SARS-CoV despite multiple dosing schedulesand treatment routes [5]. To date, no pre-clinical studieshave evaluated the efficacy of hydroxychloroquine in thecurrent SARS-CoV-2 pandemic.Current evidenceA recent article published in Chinese found no benefit withchloroquine in a 1:1 randomized trial with 30 patients [6].As yet there are no published randomized controlled trialsof hydroxycholoroquine in SARS-CoV-1 or 2. Recently, apublication by Gautret et al. has been touted by non-medical public figures as proof of a cure for COVID-19 [7].This has led to significant interest in news outlets, socialmedia, and the general public. This study was a non-randomized, non-blinded, open label, and underpoweredtrial. Given these limitations, it does not meet the rigor forevaluation of scientific efficacy. To illustrate, Gautret et al.treated 26 patients with hydroxychloroquine (six receivedconcomitant azithromycin) that met study inclusion cri-teria. The control group was subsequently made up of 16patients who did not meet the study inclusion criteria. Theprimary outcome was viral load, defined by a cycle time(CT) threshold of 35. CT is the number of reverse tran-scription PCR cycles necessary to detect the presence of© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: ingra107@umn.edu1Division of Pulmonary and Critical Care, Department of Medicine, Universityof Minnesota, MMC 195, 420 Delaware St SE, Minneapolis, MN 55455, USAFull list of author information is available at the end of the articleIngraham et al. Critical Care          (2020) 24:182 https://doi.org/10.1186/s13054-020-02894-7viral RNA. A lower CT is associated with increased viralload. A CT greater than or equal to 35 was deemed as anegative viral titer. It was unclear whether this thresholdwas set a priori or post hoc. After enrollment of 42 patients,an interim analysis was conducted and published. A criticalresult was the exclusion of six patients from the treatmentarm. One died, three decompensated requiring transfer tothe ICU, one withdrew from the study due to drug-relatedcomplications, and one was lost to follow-up. These pa-tients were excluded by the authors from final analysis. Theauthors then compared viral titers from 20 patients that re-ceived hydroxychloroquine (or combination with azithro-mycin) with the 16 control patients that were ineligible toreceive hydroxychloroquine. In unadjusted analyses, the au-thors identified significantly reduced viral titers in thehydroxychloroquine arm. No comment was made regard-ing the higher mortality, complication, and adverse eventrate in the hydroxychloroquine group.Excluding those who did poorly with hydroxychloro-quine is a biased analysis that impacts the potential val-idity of the study. Reincorporation of the 6 patients intothe statistical analysis would have significantly changedthe results of this study. In the hydroxychloroquinegroup, 5 of 26 (19.2%) of COVID-19 patients suffereddeath, medical deterioration, or adverse event comparedwith 0 (0%) in the control arm (Barnard’s test: p = 0.07)with a number needed to harm (NNH) of 5.2.ConclusionUntil data from randomized controlled trials are available,we suggest caution utilizing hydroxychloroquine off labelfor patients with COVID-19. Reports of overdoses arenow occurring. There are currently no evidence support-ing hydroxychloroquine as prophylaxis, but unfortunatelythese data are being extrapolated to the indication poten-tially resulting in drug shortages for patients with rheum-atic diseases who require this medication. Furthermore,we caution medical and world leaders against prematurecomments of treatment efficacy during the COVID-19pandemic. Such comments may exacerbate shortages forpatients reliant on these medications or cause harm dueto medication side effects and overdose [8].AcknowledgementsNot applicable.Authors’ contributionsAll authors significantly contributed to developing, writing, and revising thismanuscript. All authors read and approved the final manuscript.FundingNicholas E. Ingraham is supported by the NIH NHLBI T32HL07741 grant.Availability of data and materialsNot applicable.Ethics approval and consent to participateThis manuscript did not require ethics approval or consent.Consent for publicationNot applicable.Competing interests1. CJT: PI for 2 RCTs investigating ARBs in the treatment of COVID-19 amonginpatient and outpatients. CoIs for these trials include NEI, TS, and JGC.2. DB is the PI for an RCT investigating HCQ as prophylaxis for high-riskindividuals with recent exposure to COVID-19.3. JAS: Site PI of a phase 2 RCT investigating HCQ for the prevention ofrheumatoid arthritis (funded by NIH/NIAID/Autoimmune Centers ofExcellence) and has performed consultancy for Bristol-Myers Squibb,Gilead, Inova, Janssen, and Optum unrelated to this work.Author details1Division of Pulmonary and Critical Care, Department of Medicine, Universityof Minnesota, MMC 195, 420 Delaware St SE, Minneapolis, MN 55455, USA.2Division of Infectious Diseases and International Medicine, Department ofMedicine, University of Minnesota, Minneapolis, USA. 3Division ofNephrology, Department of Medicine, Duke University, Durham, NC, USA.4Division of Medicine and Infectious Disease, Department of Medicine,University of Minnesota, Minneapolis, MN, USA. 5Division of General InternalMedicine, Department of Medicine, University of Minnesota, Minneapolis,MN, USA. 6Department of Medicine, Brigham and Women’s Hospital; HarvardMedical School, Division of Rheumatology, Inflammation, and Immunity,Boston, MA, USA. 7Division of Biostatistics, School of Public Health, Universityof Minnesota, Minneapolis, USA. 8Division of Acute Care Surgery, Departmentof Surgery, University of Minnesota, Minneapolis, MN, USA. 9Department ofSurgery, University of North Carolina School of Medicine, Chapel Hill, NC,USA. 10School of Public Health, University of North Carolina School ofMedicine, Chapel Hill, NC, USA. 11Institute for Health Informatics, University ofMinnesota, Minneapolis, MN, USA.Received: 31 March 2020 Accepted: 14 April 2020References1. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG,Seidah NG, Nichol ST. Chloroquine is a potent inhibitor of SARS coronavirusinfection and spread. Virol J. 2005;2(1):69.2. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O'Meara MJ, Guo JZ,Swaney DL, Tummino TA, Hüttenhain R et al: A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing. bioRxiv 2020:2020.2003.2022.002386, Pre-Print. https://doi.org/10.1101/2020.03.22.002386.3. Biot C, Daher W, Chavain N, Fandeur T, Khalife J, Dive D, De Clercq E.Design and synthesis of hydroxyferroquine derivatives with antimalarial andantiviral activities. J Med Chem. 2006;49(9):2845–9.4. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G.Remdesivir and chloroquine effectively inhibit the recently emerged novelcoronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71.5. Barnard DL, Day CW, Bailey K, Heiner M, Montgomery R, Lauridsen L, ChanPK, Sidwell RW. Evaluation of immunomodulators, interferons and knownin vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/cmice. Antivir Chem Chemother. 2006;17(5):275–84.6. Chen Jun LIUDLIULLIUPXUQXIALLYH: Preliminary study ofhydroxychloroquine sulfate in treating common coronavirus disease(COVID-19) patients in 2019. J Zhejiang Univ (Med Sci) 2020, 49(1).7. Gautret P LJ, Parola P, et al.: Hydroxychloroquine and azithromycin asa treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020, Pre-Print.https://doi.org/10.1101/2020.03.16.20037135.8. Nigeria reports chloroquine poisonings after Trump praised drug. https://www.bloomberg.com/news/articles/2020-03-21/nigeria-reports-chloroquine-poisonings-after-trump-praised-drug. Accessed 22 Mar 2020.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Ingraham et al. Critical Care          (2020) 24:182 Page 2 of 2

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Shining a light on the evidence for hydroxychloroquine in SARS-CoV-2

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