Update Alert 2: Hydroxychloroquine or Chloroquine for the Treatment or Prophylaxis of COVID-19
Authors: Adrian V. Hernandez, Yuani M. Roman, Vinay Pasupuleti, Joshuan J. Barboza, C. Michael White
Journal: Annals of Internal Medicine (2020)

Letters27 August 2020Update Alert 2: Hydroxychloroquine or Chloroquine for the Treatment or Prophylaxis of COVID-19FREEAdrian V. Hernandez, MD, PhD, Yuani M. Roman, MD, MPH, Vinay Pasupuleti, MD, MS, PhD, Joshuan J. Barboza, MSc, and C. Michael White, PharmDAdrian V. Hernandez, MD, PhDUniversity of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and Hartford Hospital Department of Research Administration, Hartford, Connecticut, School of Pharmacy, Storrs, Connecticut, and Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru (A.V.H.), Yuani M. Roman, MD, MPHUniversity of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and Hartford Hospital Department of Research Administration, Hartford, Connecticut (Y.M.R.), Vinay Pasupuleti, MD, MS, PhDMedErgy HealthGroup, Yardley, Pennsylvania (V.P.), Joshuan J. Barboza, MScVicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru (J.J.B.), and C. Michael White, PharmDUniversity of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and Hartford Hospital Department of Research Administration, Hartford, Connecticut, and School of Pharmacy, Storrs, Connecticut (C.M.W.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1054 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail This report, the second update of a previously published living systematic review (1), focuses on treatment (not prophylaxis) of coronavirus disease 2019 (COVID-19) with hydroxychloroquine or chloroquine. The first update covered evidence available through 1 July 2020 (2); this update evaluates evidence published through 1 August 2020.No new evidence regarding chloroquine was found. Five new randomized trials (3–7) and 4 new cohort studies (7–10) evaluating hydroxychloroquine were found. None of the studies used zinc; all studies (4–10) except for 1 trial (3) with a hydroxychloroquine group and an azithromycin group evaluated hydroxychloroquine alone. One trial was placebo controlled (5); other studies used "standard care" control groups (3, 4, 6–10). Two (3, 5) of the trials had high risk of bias, whereas 3 trials (4, 6, 7) had some concerns of bias. Three (7, 9, 10) of the cohort studies had critical risks of bias, whereas 1 cohort study (8) had serious risk of bias.The Supplement Table displays the following for outcomes of all identified trials (3–7, 11, 12, 26, 27) and cohort studies (7–10, 13–25, 28) that addressed treatment with hydroxychloroquine: risk-of-bias assessments, unadjusted estimates of effect, and overall ratings of strength of evidence. Although the strength of evidence was previously rated insufficient regarding effects on mortality, there is now low strength of evidence from trials and cohort studies that hydroxychloroquine has no positive effect on all-cause mortality and need for mechanical ventilation. Trials show low strength of evidence for no positive effect on intubation or death and discharge from the hospital, whereas evidence from cohort studies about these outcomes remains insufficient. Newer trials and cohort studies did not alter the findings for other outcomes that the data are insufficiently strong to support a treatment benefit of hydroxychloroquine.Of note, 2 of the new trials and 1 cohort study assessed the early prehospitalization administration of hydroxychloroquine in patients with COVID-19; none demonstrated benefits or reductions in hospitalizations (4, 5, 10). The largest trial—the RECOVERY trial (6)—used a much larger dose of hydroxychloroquine (loading dose of 800 mg at 0 and 6 hours, 400 mg at 12 hours; maintenance dose of 400 mg every 12 hours for 9 days or until discharge) than other trials and found no benefits from therapy. Finally, the large SOLIDARITY-WHO and ORCHID-NIH trials have been prematurely discontinued, with press releases citing lack of efficacy (29, 30), but preprints or publications of these trials are still not available.References1. Hernandez AV, Roman YM, Pasupuleti V, et al. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19. A living systematic review. Ann Intern Med. 2020;173:287-296. [PMID: 32459529]. doi:10.7326/M20-2496 LinkGoogle Scholar2. Hernandez AV, Roman YM, Pasupuleti V, et al. Update alert: hydroxychloroquine or chloroquine for the treatment or prophylaxis of COVID-19 [Letter]. Ann Intern Med. 2020;173:W78-9. [PMID: 32667853]. doi:10.7326/L20-0945 LinkGoogle Scholar3. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020. doi:10.1056/NEJMoa2019014 CrossrefMedlineGoogle Scholar4. Mitjà O, Corbacho-Monné M, Ubals M, et al; BCN PEP-CoV-2 RESEARCH GROUP.. Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clin Infect Dis. 2020. [PMID: 32674126] doi:10.1093/cid/ciaa1009 CrossrefMedlineGoogle Scholar5. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19. A randomized trial. Ann Intern Med. 2020. [PMID: 32673060]. doi:10.7326/M20-4207 LinkGoogle Scholar6. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. Preprint posted online 15 July 2020. . doi:10.1101/2020.07.15.20151852 CrossrefGoogle Scholar7. Chen CP, Lin YC, Chen TC, et al. A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19). medRxiv. Preprint posted online 10 July 2020. doi:10.1101/2020.07.08.20148841 Google Scholar8. Paccoud O, Tubach F, Baptiste A, et al. Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe Covid-19 in a French university hospital. Clin Infect Dis. 2020. [PMID: 32556143] doi:10.1093/cid/ciaa791 CrossrefMedlineGoogle Scholar9. Lecronier M, Beurton A, Burrel S, et al. Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis. Crit Care. 2020;24:418. [PMID: 32653015] doi:10.1186/s13054-020-03117-9 CrossrefMedlineGoogle Scholar10. Komissarov A, Molodtsov I, Ivanova O, et al. Hydroxychloroquine has no effect on SARS-CoV-2 load in nasopharynx of patients with mild form of COVID-19. medRxiv. Preprint posted online 3 July 2020. doi:10.1101/2020.06.30.20143289 Google Scholar11. Chen J, Ping L, Li L, et al. Preliminary study of hydroxychloroquine sulfate in treating common coronavirus disease (COVID-19) patients in 2019. Journal of Zhejiang University (Medical Science). 2020. doi:10.3785/j.issn.1008-9292.2020.03.03 CrossrefGoogle Scholar12. Chen L, Zhang ZY, Fu JG, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. medRxiv. Preprint posted online 22 June 2020. doi:10.1101/2020.06.19.20136093 Google Scholar13. Barbosa J, Kaitis D, Freedman R, et al. Clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19: a quasi-randomized comparative study. Accessed at www.dropbox.com/s/urzapkyij542qx5/NEJM_Clinical%20Outcomes%20of%20Hydroxychlorquine%20in%20Patients%20with%20COVID19.pdf on 10 July 2020. Google Scholar14. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv. Preprint posted online 23 April 2020. doi:10.1101/2020.04.16.20065920 Google Scholar15. Mallat J, Hamed F, Balkis M, et al. Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to moderate disease: a retrospective study. medRxiv. Preprint posted online 2 May 2020. doi:10.1101/2020.04.27.20082180 Google Scholar16. Membrillo de Novales FJ, Ramírez-Olivencia G, Estébanez M, et al. Early hydroxychloroquine is associated with an increase of survival in COVID-19 patients: an observational study. Preprints. Preprint posted online 6 May 2020. doi:10.20944/preprints202005.0057.v1 Google Scholar17. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382:2411-2418. [PMID: 32379955] doi:10.1056/NEJMoa2012410 CrossrefMedlineGoogle Scholar18. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020. [PMID: 32392282] doi:10.1001/jama.2020.8630 CrossrefMedlineGoogle Scholar19. Mahévas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with Covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844. [PMID: 32409486] doi:10.1136/bmj.m1844 CrossrefMedlineGoogle Scholar20. Ip A, Berry DA, Hansen E, et al. Hydroxychloroquine and tocilizumab therapy for COVID-19 patients—an observational study. medRxiv. Preprint posted online 21 May 2020. doi:10.1101/2020.05.21.20109207 Google Scholar21. Sbidian E, Josse J, Lemaitre G, et al. Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 inpatients in France. medRxiv. Preprint posted online 16 June 2020. doi:10.1101/2020.06.16.20132597 Google Scholar22. Singh S, Khan A, Chowdhry M, et al. Outcomes of hydroxychloroquine treatment among hospitalized COVID-19 patients in the United States—real-world evidence from a federated electronic medical record network. medRxiv. Preprint posted online 12 May 2020. doi:10.1101/2020.05.12.20099028 Google Scholar23. Yu B, Li C, Chen P, et al. Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19. Sci China Life Sci. 2020. [PMID: 32418114] doi:10.1007/s11427-020-1732-2 CrossrefMedlineGoogle Scholar24. Arshad S, Kilgore P, Chaudhry ZS, et al; Henry Ford COVID-19 Task Force.. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. 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Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949 CrossrefMedlineGoogle Scholar29. World Health Organization. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. 4 July 2020. Accessed at www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19 on 6 July 2020. Google Scholar30. National Institutes of Health. NIH halts clinical trial of hydroxychloroquine: study shows treatment does no harm, but provides no benefit. 20 June 2020. Accessed at www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine on 6 July 2020. Google Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Adrian V. Hernandez, MD, PhD; Yuani M. Roman, MD, MPH; Vinay Pasupuleti, MD, MS, PhD; Joshuan J. Barboza, MSc; C. Michael White, PharmDAffiliations: University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and Hartford Hospital Department of Research Administration, Hartford, Connecticut, School of Pharmacy, Storrs, Connecticut, and Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru (A.V.H.)University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and Hartford Hospital Department of Research Administration, Hartford, Connecticut (Y.M.R.)MedErgy HealthGroup, Yardley, Pennsylvania (V.P.)Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru (J.J.B.)University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and Hartford Hospital Department of Research Administration, Hartford, Connecticut, and School of Pharmacy, Storrs, Connecticut (C.M.W.)Disclaimer: The findings and conclusions in this document are those of the authors, who are responsible for its contents. The findings and conclusions do not necessarily represent the views of the Agency for Healthcare Research and Quality (AHRQ). No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.Financial Support: By AHRQ (contract HHSA290-2015-00012I).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1054.Corresponding Author: C. Michael White, PharmD, University of Connecticut School of Pharmacy, 69 North Eagleville Road, U-3092, Storrs, CT 06269; e-mail, charles.white@uconn.edu.This article was published at Annals.org on 27 August 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19 Adrian V. Hernandez , Yuani M. Roman , Vinay Pasupuleti , Joshuan J. Barboza , and C. 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Hernandez, MD, PhD, Yuani M. Roman, MD, MPH, Vinay Pasupuleti, MD, MS, PhD, Joshuan J. Barboza, MSc, and C. Michael White, PharmDIs Machine Learning a Better Way to Identify COVID-19 Patients Who Might Benefit from Hydroxychloroquine Treatment?—The IDENTIFY Trial 6 October 2020Volume 173, Issue 7 Page: W128-W129 Keywords Chloroquine Cohort studies COVID-19 Disclosure Hydroxychloroquine Mortality Prophylaxis Systematic reviews Ventilators Zinc ePublished: 27 August 2020 Issue Published: 6 October 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...