Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19? Living Practice Points From the American College of Physicians (Version 1)
Authors: Amir Qaseem, Jennifer Yost, Itziar Etxeandia-Ikobaltzeta, Matthew C. Miller, George M. Abraham, Adam Jacob Obley, Mary Ann Forciea, Janet A. Jokela, Linda L. Humphrey
Journal: Annals of Internal Medicine (2020)

Special Articles13 May 2020Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19? Living Practice Points From the American College of Physicians (Version 1)FREECorrection(s) for this article:CorrectionsJul 2020Correction: Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19?FREEAmir Qaseem, MD, PhD, MHA, Jennifer Yost, RN, PhD, Itziar Etxeandia-Ikobaltzeta, PharmD, PhD, Matthew C. Miller, MD, George M. Abraham, MD, MPH, Adam Jacob Obley, MD, Mary Ann Forciea, MD, Janet A. Jokela, MD, MPH, and Linda L. Humphrey, MD, MPH, for the Scientific Medical Policy Committee of the American College of Physicians*Amir Qaseem, MD, PhD, MHAAmerican College of Physicians, Philadelphia, Pennsylvania (A.Q., I.E.), Jennifer Yost, RN, PhDAmerican College of Physicians, Philadelphia, and Villanova University, Villanova, Pennsylvania (J.Y.), Itziar Etxeandia-Ikobaltzeta, PharmD, PhDAmerican College of Physicians, Philadelphia, Pennsylvania (A.Q., I.E.), Matthew C. Miller, MDPenn Medicine, Philadelphia, Pennsylvania (M.C.M.), George M. Abraham, MD, MPHUniversity of Massachusetts Medical School/Saint Vincent Hospital, Worcester, Massachusetts (G.M.A.), Adam Jacob Obley, MDPortland Veterans Affairs Medical Center and Oregon Health & Science University, Portland, Oregon (A.J.O., L.L.H.), Mary Ann Forciea, MDUniversity of Pennsylvania Health System, Philadelphia, Pennsylvania (M.A.F.), Janet A. Jokela, MD, MPHUniversity of Illinois at Urbana-Champaign, Champaign, Illinois (J.A.J.), and Linda L. Humphrey, MD, MPHPortland Veterans Affairs Medical Center and Oregon Health & Science University, Portland, Oregon (A.J.O., L.L.H.), for the Scientific Medical Policy Committee of the American College of Physicians*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-1998 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail An update is available for this article.Key Question 1Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for Prophylaxis Against COVID-19?Key Question 2Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for Treatment of COVID-19?BackgroundUsing chloroquine or hydroxychloroquine, with or without azithromycin, to prevent coronavirus disease (COVID-19) after infection with novel coronavirus (SARS-CoV-2) or to treat COVID-19 began to receive attention following preliminary reports from in vitro (1) and human (2) studies. While multiple studies are planned or under way (3, 4), it is imperative to continually synthesize the results from the best available evidence to inform point-of-care decisions about the use of chloroquine or hydroxychloroquine. These practice points are based on a rapid and living systematic evidence review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and will be updated as new evidence becomes available. The practice points development and update methods are included in the Appendix, available at Annals.org. This version of the practice points, based on an evidence review conducted on 17 April 2020, was approved by the American College of Physicians Board of Regents on 4 May 2020 and submitted to Annals of Internal Medicine on 6 May 2020. Practice PointsThe efficacy of chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with SARS-CoV-2 or to treat patients with COVID-19 is not established and future clinical trials are needed to answer these questions. There are known harms of these medications when used to treat other diseases (5, 6). Current evidence about efficacy and harms for use in the context of COVID-19 is sparse, conflicting, and from low quality studies, increasing the uncertainty and lowering our confidence in the conclusions of these studies when assessing the benefits or understanding the balance when compared with harms. These interim practice points are based on best available evidence. We will maintain these practice points as a living guidance document, updated as new evidence becomes available.• Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis against COVID-19 due to known harms and no available evidence of benefits in the general population.• Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as a treatment of patients with COVID-19 due to known harms and no available evidence of benefits in patients with COVID-19.• In light of known harms and very uncertain evidence of benefit in patients with COVID-19, using shared and informed decision making with patients (and their families), clinicians may treat hospitalized COVID-19–positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial. Should chloroquine or hydroxychloroquine alone or in combination with azithromycin be used as prophylaxis against COVID-19 in the general population? Should chloroquine or hydroxychloroquine alone or in combination with azithromycin be used for treatment of patients with COVID-19? Figure. Evidence Description for COVID-19 Studies*.COVID-19 = coronavirus disease 2019; RCT = randomized controlled trial.* Evidence search was conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group. Current search for evidence, completed on 17 April 2020, aimed to identify all studies about the use of chloroquine or hydroxychloroquine alone or in combination for prophylaxis or treatment of patients with COVID-19. (See Supplement, available at Annals.org.)† The use and extent of parallel treatment interventions was difficult to determine. For example, in some studies, it was documented that patients received parallel interventions, whereas in other studies there was insufficient information to determine if patients did or did not receive parallel interventions.‡ In 2 cohort studies (11, 12), the administration of azithromycin was not randomized, precluding judgment of efficacy Download figure Download PowerPoint Evidence Summary: What Information Does the Evidence Provide? Appendix: Practice Points Development ProcessThe Scientific Medical Policy Committee (SMPC), in collaboration with staff from ACP's Department of Clinical Policy, developed these Practice Points based on a rapid systematic evidence review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group. The SMPC comprises 11 internal medicine physicians representing various clinical areas of expertise and 1 public (nonclinician) member and includes members with expertise in epidemiology, healthy policy, and evidence synthesis. In addition to contributing clinical, scientific, and methodological expertise, Clinical Policy staff provided administrative support and liaised among the SMPC, evidence review funding entity and evidence team, and the journal. Clinical Policy staff and the SMPC reviewed and prioritized potential topic suggestions from ACP members, SMPC members, and ACP governance. A committee subgroup, including the chair of SMPC, worked with staff to draft the key questions and lead the development of the Practice Points. Clinical Policy staff worked with the subgroup and the evidence review team to refine the key question(s) and determine appropriate evidence synthesis methods for each key question. Via conference calls and e-mail, Clinical Policy staff worked with the committee subgroup to draft the Practice Points based on the results of the rapid systematic evidence review. The full SMPC reviewed and approved the final Practice Points. Before publication, ACP's Executive Committee of the Board of Regents also reviewed and approved the Practice Points on behalf of the ACP Board of Regents. The evidence review will be continually updated by the evidence review team. ACP will update the Practice Points based on the evidence review using the same process as for Version 1 (described above).References1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019- nCoV) in vitro [Letter]. Cell Res. 2020;30:269-271. [PMID: 32020029] doi:10.1038/s41422-020-0282-0 Google Scholar2. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14:72-73. [PMID: 32074550] doi:10.5582/bst.2020.01047 Google Scholar3. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed at https://clinicaltrials.gov/ct2/home on 3 April 2020. Google Scholar4. Belhadi D, Peiffer-Smadja N, Lescure F-X, et al. A brief review of antiviral drugs evaluated in registered clinical trials for COVID- 19. Preprint. Posted 28 March 2020. medRxiv. doi:10.1101/ 2020.03.18.20038190 Google Scholar5. Aralen Chloroquine Prescribing Information. Sanofi-Aventis; March 2013. Accessed at www.accessdata.fda.gov/drugsatfda_docs/label/2013/006002s043lbl.pdf on 3 April 2020. Google Scholar6. Plaquenil Hydroxychloroquine Prescribing Information. Concordia Pharmaceuticals; January 2017. Accessed at www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf on 3 April 2020. Google Scholar7. Chen J, Ping L, Li L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Journal of Zhejiang University (Medical Science). 2020;49. doi:10.3785/j.issn.1008-9292.2020.03.03 Google Scholar8. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Preprint. Posted 10 April 2020. medRxiv. doi:10.1101/ 2020.03.22.20040758 Google Scholar9. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. Preprint. Posted online 14 April 2020. medRxiv. doi:2020.04. 10.20060558 Google Scholar10. Barbosa J, Kaitis D, Freedman R, et al. Clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19: a quasi-randomized comparative study. NEJM submission ID 20- 08882. 4 April 2020. Google Scholar11. 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. 2020:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949 Google Scholar12. Mahevas M, Tran VT, Roumier M, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized forCOVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. Preprint. Posted online 14 April 2020. medRxiv. doi:10.1101/2020.04.10.20060699 Google Scholar13. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/ azithromycin. Preprint. Posted 3 April 2020. medRxiv. doi:10.1101/ 2020.04.02.20047050 Google Scholar14. Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med Infect Dis. 2020:101663. [PMID: 32289548] doi:10.1016/j.tmaid.2020.101663 Google Scholar15. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection [Letter]. Med Mal Infect. 2020. [PMID: 32240719] doi:10.1016/j.medmal.2020.03.006 Google Scholar16. Lowe D. The latest hydroxychloroquine data, as of April 11. In the Pipeline blog. 11 April 2020. Accessed at https:// blogs.sciencemag.org/pipeline/archives/2020/04/11/the-latesthydroxychloroquine- data-as-of-april-11 on 12 April 2020. Google Scholar17. Harris AM, Hicks LA, Qaseem A; High Value Care Task Force of the American College of Physicians and for the Centers for Disease Control and Prevention. Appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016;164:425- 434. [PMID: 26785402] doi:10.7326/M15-1840 Google Scholar18. Petrisor B, Bhandari M. The hierarchy of evidence: levels and grades of recommendation. Indian J Orthop. 2007;41:11-15. [PMID: 21124676] doi:10.4103/0019-5413.30519 Google Scholar Comments0 CommentsSign In to Submit A Comment Mahmood Pazirandehrheumatology practice at SDAMC IN SAN DIEGO14 May 2020 hydroxycloroquine safety and risks It is believed that Lupus erythematosus patients who are taking Hydroxychloroquin have not had Covid 19 infection. Taking HCQ in the light of no data and base on clinical observation is not dangerous. HCQ retinopathy is rare and only after taking it for several years or high doses at 600 mg my cause retinal damage, even this side effect is detectable by many ophthalmologist before vision loss. HCQ has been used since 1940's and 50' for all kind of rheumatic disease and visual loss has been extremely. It might help Covid 19 and trying it for 14 days is not dangerous Fernando Lopez, MD, FACPPrivate Physician Services of San Antonio15 May 2020 Primum non nocere Excellent review. Unfortunately, many clinicians continue to ignore the evidence (or lack thereof) and persist in promoting unproven and potentially harmful therapeutics for COVID-19. Would be good to use this opportunity to revive the old EBM series that JAMA used to publish. Or something like it. During the early days of the pandemic I saw many clinicians in the community and in large academic medical centers eschew EBM. We should also take this opportunity to establish an on-call national team of clinicians to improve the ACP's ability to quickly issue guidance to general practitioners on acute national emergencies especially where there is controversy about therapeutics in the absence of data. The ACP course guide has been exemplary and timely but it could have more forcefully discouraged the widespread use of hydroxychloroquine and azithromycin. There was a void of data but there was also a void of clinical leadership that was filled by well meaning but poorly informed practitioners. I wonder how many died as a result? Now is the time to analyze and plan for the next pandemic. Amir Qaseem, MD, PhD, MHA, Jennifer Yost, RN, PhD, Itziar Etxeandia-Ikobaltzeta, PharmD, PhD, Matthew C. Miller, MD, George M. Abraham, MD, MPH, Adam J. Obley, MD, Mary Ann Forciea, MD, Janet A. Jokela, MD, MPH, Linda L. Humphrey, MD, MPH*24 June 2020 Update Alert: Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19? Living Practice Points From the American College of Physicians In this letter, we update the American College of Physicians' previous practice points about chloroquine or hydroxychloroquine alone or in combination with azithromycin for prophylaxis or treatment of coronavirus disease 2019 (COVID-19) (1), using an updated evidence review conducted on 8 May 2020 (2). The evidence update identified 6 new studies: 4 observational studies (3–6) addressed use of hydroxychloroquine alone, 1 observational study (7) focused on hydroxychloroquine alone and in combination with azithromycin, and 1 observational study (8) assessed use of chloroquine alone (previously, no studies were available on the use of chloroquine alone). All new studies evaluated use of the pharmacologic interventions for treatment of COVID-19. The new evidence added support to previous conclusions but resulted in no conceptual changes to the practice points (see the next section and the Table). The Supplement summarizes the evidence, evidence gaps, and clinical considerations. Practice Points: These interim practice points are based on the best available evidence. We will maintain these practice points as a living guidance document that will be updated as new evidence becomes available.• Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis against COVID-19. • Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as a treatment of patients with COVID-19. • Clinicians may choose to treat hospitalized COVID-19–positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial, using shared and informed decision making with patients (and their families). Rationale for Prophylaxis: There continues to be no available evidence about the benefits and harms of use of chloroquine or hydroxychloroquine alone or in combination with azithromycin for prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, both chloroquine and hydroxychloroquine are associated with harms in patients without COVID-19. In the absence of evidence in patients with COVID-19, the risk for known harms in patients without COVID-19 outweighs the potential of any unknown benefit to prevent SARS-CoV-2 infection. Rationale for Treatment: The evidence remains very uncertain about the benefits and harms of use of chloroquine or hydroxychloroquine alone or in combination with azithromycin for treatment of COVID-19, even with the new studies about the benefits and harms of chloroquine alone or hydroxychloroquine alone or in combination with azithromycin. There is still no available evidence about the benefits and harms of use of chloroquine in combination with azithromycin. Both chloroquine and hydroxychloroquine are associated with harms in patients without COVID-19. In light of very uncertain evidence on the benefit for the treatment of COVID-19, the risk for known harms outweighs the potential for unknown benefit. However, clinicians may choose to treat hospitalized COVID-19–positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial using shared and informed decision making with patients and their families. These hospitalized patients will need to be carefully and closely monitored for any potential harms. This article was published at Annals.org on 17 June 2020. * Individuals who served on the Scientific Medical Policy Committee from initiation of the project until its approval were Linda L. Humphrey, MD, MPH (Chair); Robert M. Centor, MD (Vice Chair); Elie A. Akl, MD, MPH, PhD; Rebecca Andrews, MS, MD; Thomas A. Bledsoe, MD; Mary Ann Forciea, MD; Ray Haeme (nonphysician public representative); Janet A. Jokela, MD, MPH; Devan L. Kansagara, MD, MCR; Maura Marcucci, MD, MSc; Matthew C. Miller, MD; and Adam Jacob Obley, MD. 1. Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? Ann Intern Med. 2020. [PMID: 32422063] doi:10.7326/M20-1998 2. 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. [PMID: 32459529] doi:10.7326/M20-2496 3. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with covid-19. N Engl J Med. 2020. [PMID: 32379955] doi:10.1056/NEJMoa2012410 4. 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 5. 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 5 May 2020. doi:10.20944/preprints202005.0057.v1 6. Yu B, Wang DW, Li C. Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19. medRxiv. Preprint posted online 1 May 2020. doi:10.1101/2020.04.27.20073379 7. 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 8. Huang M, Li M, Xiao F, et al. Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19. medRxiv. Preprint posted online 4 May 2020. doi:10.1101/2020.04.26.20081059 9. Chen J, Liu D, Liu L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Journal of Zhejiang University (Medical Science). 2020. doi:10.3785/j.issn.1008-9292.2020.03.03 10. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial. medRxiv. Preprint posted online 7 May 2020. doi:10.1101/2020.04.10.20060558 11. 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. 2020:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949 12. 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 13. MacIntyre CR, Cauchemez S, Dwyer DE, et al. Face mask use and control of respiratory virus transmission in households. Emerg Infect Dis. 2009;15:233-41. [PMID: 19193267] 14. MacIntyre CR, Zhang Y, Chughtai AA, et al. Cluster randomised controlled trial to examine medical mask use as source control for people with respiratory illness. BMJ Open. 2016;6:e012330. [PMID: 28039289] doi:10.1136/bmjopen-2016-012330 Disclosures: For disclosures, please go to https://www.acpjournals.org/doi/10.7326/M20-3862 H. Robert Silverstein, MD, FACCPreventive Medicine Center (Hartford, CT)3 August 2020 Not So Sure You Have It Right This is an earlier email I sent today: "You said: 'However, several pragmatic RCTs were conducted, and definitive findings of no benefit for hydroxychloroquine in hospitalized patients with COVID-19 have been announced.7,8. You seem to have skipped over the deficiencies of those studies (7,8): dose too high, treatment too short, not all patients even proven to have CoV2-19, treatment started too late for the (early on) benefit of HCQ,... And of course you are aware, even as mentioned in your article, of the multiple errors in design (as originally noted in the 1965 A B Hill Proceedings of the Royal Society of Medicine article) of just how many things can and do go wrong in many, if not most, studies that are published including those that you give as references 7 and 8. Just a passing thought: It is not a case of 'Don't confuse me with the facts', but the best clinical insights actually DO exceed so-called knowledge by at least 1 step. We are in that era where what is called science is no more correct than good clinical judgment. Just FYI, Yale, NYU, NYC's MSH, Hartford Hospital, the Henry Ford system, 30% of polled practitioners, are actually using hydroxychloroquine, and in my belief, correctly for the treatment of CoV2-19. My apologies for the blue print and underlining created by my using the tail of your references. Finally, you may find of some interest my own opinions on the corona virus as published (link) on the home page of www.thepmc.org. Disclosures: This author has nothing to disclose. Amir Qaseem, MD, PhD, MHA, Jennifer Yost, RN, PhD, Itziar Etxeandia-Ikobaltzeta, PharmD, PhD, Linda L. Humphrey, MD, MPHAmerican College of Physicians5 August 2020 Update Alert 2: Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19? Living Practice Points From the American College of Physicians This letter serves to retire the American College of Physicians' (ACP) rapid, living practice points on the use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of coronavirus disease 2019 (COVID-19) (1, 2) from the living status. This decision was made in light of recent information on the topic. Three large, in-progress randomized controlled trials (RCTs) with strong study designs ceased enrollment for the hydroxychloroquine-only versus control comparison early due to lack of efficacy in preliminary analyses (3–5). In addition, the 2 literature updates produced no evidence to alter these conclusions. The U.S. Food and Drug Administration also recently revoked its emergency use authorization for chloroquine and hydroxychloroquine for the treatment of COVID-19 due to potential significant harms and lack of benefits (6). The ACP's Scientific Medical Policy Committee (SMPC) has determined that the emergence of new evidence is unlikely to change the existing practice points; therefore, regularly scheduled updates are no longer warranted. The SMPC will continue to review the planned ongoing surveillance through November 2020 (7). The updated evidence review (8) identified 1 new RCT (9), 5 new cohort studies (10–14), and published reports of studies previously available as preprints, which resulted in changes in rating of the risk of bias (15, 16). A sixth newly published large cohort study was identified but not considered further because it was retracted due to concerns about the veracity of the data (17, 18). The newly available evidence has high risk of bias and showed conflicting direction and magnitude of results, leading to unchanged conclusions from the initial review with insufficient evidence to support the effectiveness or safety of chloroquine or hydroxychloroquine alone or in combination with azithromycin for the treatment of COVID-19 in hospitalized patients. Furthermore, 3 RCTs were stopped early (3–5) and no data were available to assess from those RCTs. Practice Points Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis against COVID-19. Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as a treatment of patients with COVID-19. Clinicians may choose to treat hospitalized COVID-19–positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial, using shared and informed decision making with patients (and their families). This article was published at Annals.org on 30 July 2020. References 1. Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? living practice points from the American College of Physicians (Version 1). Ann Intern Med. 2020;173:137-142. [PMID: 32422063] doi:10.7326/M20-1998 2. Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Update alert: should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? living practice points from the American College of Physicians [Letter]. Ann Intern Med. 2020;173:W48-W51. [PMID: 32551892] doi:10.7326/M20-3862 3. RECOVERY trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19: statement from the chief investigators of the randomised evaluation of covid-19 therapy (RECOVERY) trial on hydroxychloroquine. 5 June 2020. Accessed at www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19 on 6 July 2020. 4. World Health Organization. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19 [news release]. 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. 5. National Institutes of Health. NIH halts clinical trial of hydroxychloroquine: study shows treatment does no harm, but provides no benefit [news release]. 20 June 2020. Accessed at www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine on 6 July 2020. 6. U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for chloroquine and hydroxychloroquine [news release]. 15 June 2020. Accessed at www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and on 16 July 2020. 7. 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. [PMID: 32459529] doi:10.7326/M20-2496 8. 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. [PMID: 32667853] doi:10.7326/L20-0945 9. 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 controll