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
Authors: Amir Qaseem, Jennifer Yost, Itziar Etxeandia-Ikobaltzeta, Matthew C. Miller, George M. Abraham, Adam J. Obley, Mary Ann Forciea, Janet A. Jokela, Linda L. Humphrey
Journal: Annals of Internal Medicine (2020)

Letters16 June 2020Update 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 PhysiciansFREEAmir 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, 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.), Jennifer Yost, RN, PhDVillanova University, Villanova, Pennsylvania (J.Y.), Itziar Etxeandia-Ikobaltzeta, PharmD, PhDHospital Santa Margarita Trasera, Irun, Spain (I.E.), Matthew C. Miller, MDPenn Medicine Radnor, Radnor, Pennsylvania (M.C.M.), George M. Abraham, MD, MPHSaint Vincent Hospital-Worcester Medical Center, Worcester, Massachusetts (G.M.A.), Adam J. Obley, MDPortland Veterans Affairs Medical Center, Portland, Oregon (A.J.O.), Mary Ann Forciea, MDUniversity of Pennsylvania, Philadelphia, Pennsylvania (M.A.F.), Janet A. Jokela, MD, MPHUniversity of Illinois College of Medicine, Urbana, Illinois (J.A.J.), and Linda L. Humphrey, MD, MPHOregon Health & Science University, Portland, Oregon (L.L.H.), for the Scientific Medical Policy Committee of the American College of Physicians*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-3862 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail 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.Table. Evidence Summary: What Information Does the Evidence Provide?*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.References1. 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 LinkGoogle Scholar2. 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 LinkGoogle Scholar3. 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 CrossrefMedlineGoogle Scholar4. 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 Scholar5. 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 Google Scholar6. 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 Google Scholar7. 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 Scholar8. 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 Google Scholar9. 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 CrossrefGoogle Scholar10. 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 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 CrossrefMedlineGoogle Scholar12. 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 Scholar13. 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] CrossrefMedlineGoogle Scholar14. 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 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Kevin Sheng-Kai Ma, Shin-Yi TsaiJohns Hopkins University Bloomberg School of Public Health, Department of Health Policy and Management, Baltimore, MD, USA.20 June 2020 Generalizability of clinical trials on prophylactic use of HCQ for COVID-19 pneumonia in a real-world population-based nested case-control study Clinicians and researchers have been advocating for studies evaluating the therapeutic or prophylactic use of chloroquine or hydroxychloroquine (HCQ) for coronavirus disease 2019 (COVID-19) [1]. So far most studies focused on therapeutic potential of HCQ use among patients of mild to moderate symptoms [2], hypoxaemic patients [3], or patients without mechanical ventilation [4]. Although HCQ has been repurposed to treat several infectious or rheumatological diseases [1, 5], and has been considered as a drug candidate for SARS-CoV-2 infection in non-randomized studies [6] as well as in vitro studies [7, 8], no convincing evidence from well-designed clinical studies exists to support the prophylactic use of HCQ for COVID-19. We agree with recent clinical trials that HCQ may not treat COVID-19 pneumonia, and have proposed that other than COVID-19 treatment, HCQ would not protect general population from any suspected viral pneumonia. We determined whether the findings in these therapeutic trials [2, 3, 4] could be generalized to the prophylaxis of viral pneumonia through a real-world setting. In our nested case-control study among Han Chinese population from medical claim data, 31,706 adult patients admitted to hospitals with viral pneumonia specifying International Classification of Diseases, Ninth Revision codes 480, 485, or 486 were retrospectively reviewed, and control group (n=63,412) matched with age-sex were enrolled from general population. The baseline characteristics among pneumonia cases and non-pneumonia controls were comparable after either age-sex matching or propensity score matching on initial severity, pneumonia-associated or HCQ-associated comorbidities, and co-medications involving antiviral or anti-inflammatory agents. Most participants were over 65-year-old (55%) and were males (56%), similar to that of therapeutic trials [2, 3, 4]. Among the two groups, we identified 94,408 trial-eligible participants without prior HCQ exposure for the non-HCQ analysis, and 440 participants with prior HCQ exposure for the HCQ analysis, who were previously prescribed HCQ within one year prior to the primary endpoint, the new onset of viral pneumonia. The odds ratio (OR) of developing viral pneumonia was 0.68 (95% CI = 0.56-0.87) in the non-HCQ analysis, and for the HCQ analysis, it was 0.78 (95% CI = 0.46-1.14) for 200-300mg/day and 1.16 (95% CI = 0.78-1.91) for over 300 mg/day; all of which took the OR for 1-200 mg/day as the reference. These results suggested that prior HCQ use may not alleviate the risk of developing viral pneumonia. We confirmed this finding in a sensitivity analysis with propensity score matching on age, sex, and confounders, which the adjusted OR was 0.82 (95% CI = 0.53-1.42) for 200-300 mg/day and 1.08 (95% CI = 0.71-1.52) for over 300 mg/day in the HCQ group, compared with that of the non-HCQ group (OR = 0.84, 95% CI = 0.59-1.02) (Table 1). Moreover, the subgroup analysis among propensity score-matched HCQ users revealed the dose-response relationship between HCQ uptake and the risk of developing viral pneumonia, which prior HCQ exposure were stratified according to their prescription coverage days (Table 2). When setting the ORs of developing viral pneumonia among those taking 1-200 mg/day as the reference, for those taking HCQ less than 1 month before primary endpoint, the ORs were 1.04 (95% CI = 0.48-2.04) for 200-300 mg/day and 1.28 (95% CI = 0.76-2.10) for over 300 mg/day; for those with HCQ uptake less than 3 months before primary endpoint, the ORs were 0.59 (95% CI = 0.31-1.04) for 200-300 mg/day and 1.24 (95% CI = 0.72-1.98) for over 300 mg/day; for those with HCQ prescription within 12 months before primary endpoint, the ORs were 0.78 (95% CI = 0.46-1.14) for 200-300 mg/day and 1.18 (95% CI = 0.78-1.91) for over 300 mg/day. Overall, the ORs of developing viral pneumonia were lower in non-HCQ users compared to those with prior HCQ exposure for a wide range of dosages. Thus, real-world precedent use of HCQ for curtailing viral pneumonia was suboptimal, due to not only the neutral to negative findings but also the proven adverse effect [2, 3, 4]. In conjunction with recent studies [2, 3, 4], our real-world evidence provides further perspective on the repurposing of HCQ: apart from COVID-19 treatment, prophylactic use of HCQ is not recommended for patients at risk of all viral pneumonia, regardless of uptake dosages, initial severity, comorbidities, or co-medications. Those viral pneumonia involved not only COVID-19, but a considerate proportion of hard-to-diagnose viral infections, such as cytomegalovirus (CMV) pneumonia [9]. As real-world evidence allows for external validity and generalizability that couldn't be provided by randomized trials [10], we call for clinical studies that are pragmatically designed to facilitate the translation of therapeutic trials into routine clinical practice. References: 1. Principi N, Esposito S. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis 2020; published online April 17. https://doi.org/10.1016/S1473-3099(20)30296-6. 2. 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. 3. Mahévas Matthieu, Tran Viet-Thi, Roumier Mathilde, Chabrol Amélie, Paule Romain, Guillaud Constance 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 4. Mehra MR, Desai SS, Ruschitzka F, Patel AN, Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet, published:May 22, 2020 DOI: https://doi.org/10.1016/S0140-6736(20)31180-6 5. Perricone C, Triggianese P, Bartoloni E, et al. The anti-viral facet of anti-rheumatic drugs: lessons from COVID-19. J Autoimmun 2020; published online April 17. DOI:10.1016/j.jaut.2020.102468. 6. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949. 7. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. 8. Yao X, Ye F, Zhang M, et al. 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). Clin Infect Dis 2020. doi:10.1093/cid/ciaa237. 9. Fonseca Brito L, Brune W, Stahl FR. Cytomegalovirus (CMV) Pneumonitis: Cell Tropism, Inflammation, and Immunity. Int J Mol Sci. 2019;20(16):3865. 10. Berger ML, Sox H, Willke RJ, et al. Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making. Pharmacoepidemiol Drug Saf. 2017;26(9):1033‐1039. Disclosures: NA Author, Article, and Disclosure InformationAuthors: 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, MPHAffiliations: American College of Physicians, Philadelphia, Pennsylvania (A.Q.)Villanova University, Villanova, Pennsylvania (J.Y.)Hospital Santa Margarita Trasera, Irun, Spain (I.E.)Penn Medicine Radnor, Radnor, Pennsylvania (M.C.M.)Saint Vincent Hospital-Worcester Medical Center, Worcester, Massachusetts (G.M.A.)Portland Veterans Affairs Medical Center, Portland, Oregon (A.J.O.)University of Pennsylvania, Philadelphia, Pennsylvania (M.A.F.)University of Illinois College of Medicine, Urbana, Illinois (J.A.J.)Oregon Health & Science University, Portland, Oregon (L.L.H.)Note: The Practice Points are developed by the Scientific Medical Policy Committee of the American College of Physicians. The Practice Points are "guides" only and may not apply to all patients and all clinical situations. All Practice Points are considered automatically withdrawn or invalid 5 years after publication or once an update has been issued.Financial Support: Financial support for the development of the Practice Points comes exclusively from the ACP operating budget.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-3862. All financial and intellectual disclosures of interest were declared, and potential conflicts were discussed and managed. A record of disclosures of interest and management of conflicts is kept for each Scientific Medical Policy Committee meeting and conference call and can be viewed at https://www.acponline.org/about-acp/who-we-are/leadership/boards-committees-councils/scientific-medical-policy-committee/disclosure-of-interests-and-conflict-of-interest-management-summary-for-scientific-medical-policy.Corresponding Author: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, aqaseem@acponline.org.This article was published at Annals.org on 16 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. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoUpdate 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 Amir Qaseem , Jennifer Yost , Itziar Etxeandia-Ikobaltzeta , and Linda L. 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Humphrey, MD, MPH 21 July 2020Volume 173, Issue 2Page: W48-W51KeywordsChloroquineClinical trialsCOVID-19Decision makingDisclosureHydroxychloroquineObservational studiesProphylaxisPublic policyUpper respiratory tract infections ePublished: 16 June 2020 Issue Published: 21 July 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...