Update Alert 3: 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)

Letters21 October 2020Update Alert 3: 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.)Search for more papers by this author, 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.)Search for more papers by this author, Vinay Pasupuleti, MD, MS, PhDMedErgy HealthGroup, Yardley, Pennsylvania (V.P.)Search for more papers by this author, Joshuan J. Barboza, MScVicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru (J.J.B.)Search for more papers by this author, 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.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1257 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail This report, the third 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 and second updates covered evidence available through 1 July 2020 (2) and 1 August 2020 (3), respectively. This update evaluates evidence published through 21 September 2020.No new evidence about chloroquine was found. One new randomized trial (4) and 5 new cohort studies (5–9) evaluating hydroxychloroquine were found. None of the studies used zinc; all studies (5–8) except for 1 (9) with a hydroxychloroquine group and an azithromycin group evaluated hydroxychloroquine alone. The trial used a “standard care” control group (4) and had high risk of bias, whereas all of the cohort studies had serious risk of bias (5–9). The trial (4) and 3 of the new cohort studies (6, 7, 9) assessed hospital-initiated hydroxychloroquine, whereas 2 of the new cohort studies (5, 8) assessed prehospital initiation.The Supplement Table displays the following for outcomes of all identified trials (4, 10–16, 32, 34) and cohort studies (5–9, 17–31, 33, 35) that addressed treatment with hydroxychloroquine: risk-of-bias assessments, unadjusted estimates of effect, and overall ratings of strength of evidence. In trials, when hydroxychloroquine is initiated in the outpatient setting, there is low strength of evidence that it reduces hospitalizations (11, 12); in cohort studies, there remains insufficient evidence (5, 8, 33). There is now low strength of evidence that hydroxychloroquine has no positive effect on all-cause mortality and need for mechanical ventilation in both trials and cohort studies. Even with 3 new cohort studies assessing intensive care unit admission (5, 6, 8) and 1 trial (4) and 1 cohort study (9) assessing symptom resolution, there is still insufficient evidence for determining hydroxychloroquine's effect on both outcomes. No new trial or studies assessed any other outcome.It is becoming increasingly unlikely that in-hospital use of hydroxychloroquine will yield beneficial effects. The large SOLIDARITY-WHO and ORCHID-NIH trials have been prematurely discontinued, with press releases citing lack of efficacy (36, 37), but preprints or publications of these trials are still not available. However, the outpatient use of hydroxychloroquine is more promising. Trials with some concern of bias (11) and high risk of bias (12) found nonsignificant reductions in hospitalizations, whereas 2 cohort studies with serious risk of bias found significant reductions (5, 8). However, 1 cohort study with critical risk of bias found a significant increase (33). One of these cohort studies (5) found a significant reduction in intensive care unit admission with hydroxychloroquine use, whereas another found a nonsignificant reduction (8), which is in contrast to 2 cohort studies (6, 24) with serious risk of bias assessing inpatient use of hydroxychloroquine where intensive care unit admissions were significantly increased.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. 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-W79. doi:10.7326/L20-0945 LinkGoogle Scholar3. Hernandez AV, Roman YM, Pasupuleti V, et al. Update alert 2: hydroxychloroquine or chloroquine for the treatment or prophylaxis of COVID-19 [Letter]. Ann Intern Med. 2020;173:W128-W129. doi:10.7326/L20-1054 LinkGoogle Scholar4. Abd-Elsalam S, Esmail ES, Khalaf M, et al. Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. Am J Trop Med Hyg. 2020. [PMID: 32828135] doi:10.4269/ajtmh.20-0873 CrossrefMedlineGoogle Scholar5. Sulaiman T, Mohana A, Alawdah L, et al. The effect of early hydroxychloroquine-based therapy in COVID-19 patients in ambulatory care settings: a nationwide prospective cohort study. medRxiv. Preprint posted online 13 September 2020. doi:10.1101/2020.09.09.20184143 Google Scholar6. Catteau L, Dauby N, Montourcy M, et al; Belgian Collaborative Group on COVID-19 Hospital Surveillance. Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants. Int J Antimicrob Agents. 2020;56:106144. [PMID: 32853673] doi:10.1016/j.ijantimicag.2020.106144 CrossrefMedlineGoogle Scholar7. COVID-19 RISK and Treatments (CORIST) Collaboration. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: findings from the observational multicentre Italian CORIST study. Eur J Intern Med. 2020. [PMID: 32859477] doi:10.1016/j.ejim.2020.08.019 CrossrefMedlineGoogle Scholar8. Ip A, Ahn J, Zhou Y, et al. Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: a multi-center observational study. medRxiv. Preprint posted online 25 August 2020. doi:10.1101/2020.08.20.20178772 Google Scholar9. Kalligerosa M, Shehadeha F, Atallaa E, et al. Hydroxychloroquine use in hospitalised patients with COVID-19: an observational matched cohort study. J Global Antimicrob Resist. 2020;22:842-844. [PMID: 32763357] doi:10.1016/j.jgar.2020.07.018 CrossrefMedlineGoogle Scholar10. Cavalcanti AB, Zampieri FG, Rosa RG, et al; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020. [PMID: 32706953] doi:10.1056/NEJMoa2019014 CrossrefMedlineGoogle Scholar11. 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 Scholar12. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19. A randomized trial. Ann Intern Med. 2020;173:623-31. doi:10.7326/M20-4207 LinkGoogle Scholar13. 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 Google Scholar14. Chen C, Lin Y, Chen T, 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 8 July 2020. doi:10.1101/2020.07.08.20148841 Google Scholar15. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. J Zhejiang Univ (Med Sci). 2020;49:215-219. doi:10.3785/j.issn.1008-9292.2020.03.03 CrossrefGoogle Scholar16. Chen L, Zhang Z, Fu J, 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 Scholar17. 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 Scholar18. 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 Scholar19. 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 Scholar20. 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 Scholar21. 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 Scholar22. 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 Scholar23. 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 Scholar24. 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;323:2493-2502. [PMID: 32392282] doi:10.1001/jama.2020.8630 CrossrefMedlineGoogle Scholar25. Mahévas M, Tran V-T, 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 Scholar26. Ip A, Berry DA, Hansen E, et al. Hydroxychloroquine and tocilizumab therapy in COVID-19 patients—an observational study. medRxiv. Preprint posted online 25 May 2020. doi:10.1101/2020.05.21.20109207 Google Scholar27. 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 in-patients in France. medRxiv. Preprint posted online 19 June 2020. doi:10.1101/2020.06.16.20132597 Google Scholar28. 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 19 May 2020. doi:10.1101/2020.05.12.20099028 Google Scholar29. 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;63:1515-1521. [PMID: 32418114] doi:10.1007/s11427-020-1732-2 CrossrefMedlineGoogle Scholar30. 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. Int J Infect Dis. 2020;97:396-403. [PMID: 32623082] doi:10.1016/j.ijid.2020.06.099 CrossrefMedlineGoogle Scholar31. Mahévas M, Tran VT, Roumier M, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. medRxiv. Preprint posted online 14 April 2020. doi:10.1101/2020.04.10.20060699 Google Scholar32. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. Preprint posted online 10 April 2020. doi:10.1101/2020.03.22.20040758 Google Scholar33. 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 Scholar34. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. [PMID: 32409561] doi:10.1136/bmj.m1849 CrossrefMedlineGoogle Scholar35. Gautret P, Lagier JC, Parola P, et al. 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 Scholar36. 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 Scholar37. 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 Vinu ArumughamIndependent21 October 2020 How many will die because the medical community failed to get HCQ dosage and timing right? The authors write: "However, the outpatient use of hydroxychloroquine is more promising." Tells you the importance of timing, as many have been pointing out forever. Ignore all the cited studies that used HCQ >400 mg/day as those are unacceptable overdoses. Looking at the rest of the studies, the benefit of HCQ is obvious. But 9 months later, the medical community has utterly failed to use this cheap, safe and effective drug correctly to save lives. Robert Stine, MDRetired from private practice of Allergy and Immunology.24 October 2020 When will physicians help patients early in the covid19 viremia? Why is Covid19 allowed to go on unabated until the patient needs admission to the hospital? Treating the patient should begin with prophylaxsis with vitamin D, vitamin C and Zinc since these are low or insufficient in many of the population , especially the upper age group. When the patient begins with symptoms the study for Covid19 should be done and as soon as possible get the report and start the patient on antivirals such as hydroxychloraquine, azythromymycin and aspirin to slow the viral replication as soon as possible and the aspirin to reduce the potential for clotting, rather than waitng for the cytokine storm and all the devastation. CDC says it is up to the care taker and the patient, also the CDC reports it does not endorse any medication for the treatment of Covi19. Therefore the physician has an obligation to go with the best information that he has and for the patients sake, I would hope that slowing the replication of the virus with what is available would rule the day unless the patient is allergic to those medications or due to cardiac problems they are contraindicated. Also if there are chest symptoms bronchdilators and steroids should be started and pulse oximetry should be started even at home with levels under 94% or so indicating the need for admission to the hospital for more intensive treatments. Sincerely, Robert H Stine, MD Disclosures: None 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.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1257.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 21 October 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. Michael White Update Alert: Hydroxychloroquine or Chloroquine for the Treatment or Prophylaxis of COVID-19 Adrian V. Hernandez , Yuani M. Roman , Vinay Pasupuleti , Joshuan J. Barboza , and C. Michael White Update Alert 2: Hydroxychloroquine or Chloroquine for the Treatment or Prophylaxis of COVID-19 Adrian V. Hernandez , Yuani M. Roman , Vinay Pasupuleti , Joshuan J. Barboza , and C. Michael White Metrics Cited byEvidence in decision-making in the context of COVID-19 in Latin AmericaDrug-induced diabetes and hepatoxicity in COVID-19 patientsCharacteristics, quality and volume of the first 5 months of the COVID-19 evidence synthesis infodemic: a meta-research studyAssessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA conceptUse of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysisImmunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to considerEfficacy and Safety of Hydroxychloroquine for Hospitalized COVID-19 Patients: A Systematic Review and Meta-AnalysisImpact of Prophylactic Hydroxychloroquine on People at High Risk of COVID-19: A Systematic Review and Meta-AnalysisWillingness to participate in COVID-19 vaccine trials; a survey among a population of healthcare workers in UgandaResponse to: ‘The role of antimalarials in COVID-19: observational data from a cohort of rheumatic patients’ by Favalli et alHydroxychloroquine use and progression or prognosis of COVID-19: a systematic review and meta-analysisCOVID‐19: Current knowledge in clinical features, immunological responses, and vaccine developmentChanges in the Scientific Information Environment During the COVID-19 Pandemic: The Importance of Scientific Situational Awareness in Responding to the InfodemicReal-World Inpatient Use of Medications Repurposed for Coronavirus Disease 2019 in United States Hospitals, March–May 2020Epidemiology of COVID-19 in Latin AmericaPerceptions of Romanian Physicians on Lockdowns for COVID-19 Prevention 1 December 2020Volume 173, Issue 11 Page: W156-W157 ePublished: 21 October 2020 Issue Published: 1 December 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...