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)



# Background
Using 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 [bib_ref] Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated..., Gao [/bib_ref] studies. While multiple studies are planned or under way, 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 points
The 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. 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. (9).

## Insufficient

## Obs
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on the conversion to negative on day 3 (50% vs. 6%), day 4 (60% vs. 25%), day 5 (65% vs. 19%), and day 6 (70% vs. 13%) via nasopharyngeal PCR in 1 cohort study [bib_ref] Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label..., Gautret [/bib_ref]. Pulmonary radiologic assessment

## Rcts
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on the progression or exacerbation of pulmonary lesions on CT scan in 2 RCTs (33.3% vs. 46.7% [bib_ref] A pilot study of hydroxychloroquine in treatment of patients with common coronavirus..., Chen [/bib_ref] and 6.5% vs. 29%and radiologic improvement of pneumonia (80.6% vs. 54.8%) in 1 RCT (8).

## Insufficient
Resolution of fever, respiratory symptoms, and oxygenation

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone (50%) compared with standard treatment (43.6%) in 1 RCT (9).

## Insufficient

## Resolution of fever 2 rcts
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 RCTs; median, 1 day vs. 1 day in 1 RCT (7), and mean, 2.2 days vs. 3.2 days in another RCT.

## Insufficient

## Resolution of cough

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (mean 2.0 days vs. 3.1 days) in 1 RCT.

## Insufficient
Progression to severe disease

## Rcts
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 RCTs; 6.7% vs. 0% (7) and 0% vs. 12.9% (8).

## Insufficient
All-cause mortality 1 RCT The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (0% vs. 0%) in 1 RCT (7).

## Insufficient

## Obs
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 cohort studies; 12.9% vs. 3.13% (10) and 2.8% vs. 4.6%.
Continued on the following page

## Insufficient

## Any adverse event 3 rcts
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on adverse effects in 3 RCTs; 26.7% vs. 20% (7), 6.5% vs. 0% (8), and 30% vs. 8.8%. Prolonged QTc interval

## Obs
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (8.3% vs. 0%) in 1 cohort study.

## Insufficient

## Diarrhea 2 rcts
The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment; 13.3% vs. 0% (7) and 10% vs. 0% (9).

## Insufficient
Abnormal liver function

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone (6.7%) compared with standard treatment (6.7%) in 1 RCT (7).

## Insufficient

## Rash

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone (3.2%) compared with standard treatment (0%) in 1 RCT (8).

## Insufficient

## Headache

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone (3.2%) compared with standard treatment (0%) in 1 RCT (8).

## Insufficient

## Anemia

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone (0%) compared with standard treatment (6.7%) in 1 RCT (7).

## Insufficient
Elevated serum creatinine

## Rct
The evidence is very uncertain about the effect of hydroxychloroquine alone (0%) compared with standard treatment (6.7%) in 1 RCT (7).

## Insufficient
Hydroxychloroquine in combination with azithromycin for treatment of COVID-19 Diarrhea 1 OBS The evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin in 1 case series study [bib_ref] Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in..., Gautret [/bib_ref] ; 5.0% patients experienced diarrhea.

## Insufficient
Any adverse event series study; 8.7% of patients treated with hydroxychloroquine alone experienced adverse effects [bib_ref] Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in..., Gautret [/bib_ref].

## Prolonged qtc interval

## Obs
The evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin. In 2 case series studies, 9% (15) and 11% (13) of patients showed a prolonged QTc. The QTc interval significantly increased (435 6 24 ms at baseline to a maximal value of 463 6 32 ms) in 1 case series study; however, a prolonged QTc interval was not reported for any patients in another case series study [bib_ref] The latest hydroxychloroquine data, Lowe [/bib_ref].

## Insufficient
Evidence Gaps for COVID-19 Clinical Considerations - The use and extent of parallel treatment interventions, in addition to hydroxychloroquine alone or in combination with azithromycin, is difficult to determine. - Known harms of chloroquine in patients without COVID-19 include (but not limited to): cardiovascular (cardiomyopathy, ECG changes), hematologic (aplastic anemia, thrombocytopenia), nervous system (seizures, psychosis, extrapyramidal disorders), ophthalmic macular degeneration) (5). - Known harms of hydroxychloroquine in patients without COVID-19 include (but not limited to): cardiovascular (cardiomyopathy, cardiac failure, ventricular arrhythmias, torsade de pointes), endocrine (hypoglycemia), hematologic (aplastic anemia, thrombocytopenia), nervous system (seizures, psychosis, extrapyramidal disorders), ophthalmic macular degeneration) (6). - Shared and informed decision making with a patient (and/or families) should include a discussion of potential harms of chloroquine and hydroxychloroquine and lack of known benefits in patients with COVID-19. - In the evidence reviewed, hydroxychloroquine doses did not exceed 600 mg daily for 5 to 10 days. - Chloroquine and hydroxychloroquine are used to manage other major ailments, such as rheumatic diseases, with a known benefit and are in short supply in the United States. - Inappropriate and overuse of antibiotics (e.g., azithromycin) is an important contributor to the antibiotic resistance, an immediate public health threat [bib_ref] High Value Care Task Force of the American College of Physicians and..., Harris [/bib_ref]. CT = computed tomography; ECG = electrocardiography; ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; OBS = observational study; PCR = polmerase chain reaction; RCT = randomized controlled trial. Evidence search conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group. * Efficacy cannot be evaluated in case-series studies [bib_ref] The latest hydroxychloroquine data, Lowe [/bib_ref] [bib_ref] The hierarchy of evidence: levels and grades of recommendation, Petrisor [/bib_ref].  Certainty: insufficient, when confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its impact on a health outcome; low, confidence in the effect is limited as the true effect may be substantially different from the estimated effect; moderate, confidence in the effect is moderate as the true effect is likely close to the estimated effect, but there is a sizable possibility that it is substantially different; high, confident that the true effect is close to the estimated effect. Financial Support: Financial support for the development of the Practice Points comes exclusively from the ACP operating budget.
Disclosures: 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 of 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-managementsummary-for-scientific-medical-policy. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=M20-1998.
[fig] Figure: Evidence [/fig]
[fig] From 1: OBS The evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin in 1 American College of Physicians, Philadelphia, Pennsylvania (A.Q., I.E.-I.); American College of Physicians, Philadelphia, and Villanova University, Villanova, Pennsylvania (J.Y.); Penn Medicine, Philadelphia, Pennsylvania (M.C.M.); University of Massachusetts Medical School/Saint Vincent Hospital, Worcester, Massachusetts (G.M.A.); Portland Veterans Affairs Medical Center and Oregon Health & Science University, Portland, Oregon (A.J.O, L.L.H.); University of Pennsylvania Health System, Philadelphia, Pennsylvania (M.A.F.); and University of Illinois at Urbana-Champaign, Champaign, Illinois (J.A.J.). [/fig]
[fig] : Efficacy and safety of chloroquine used alone or in combination with azithromycin for prophylaxis or treatment of COVID-19 [no evidence]. Efficacy and safety of hydroxychloroquine used alone or in combination with azithromycin for prophylaxis of COVID-19 infection [no evidence]. Efficacy and safety of hydroxychloroquine used alone or in combination with azithromycin for treatment of patients with COVID-19 with varying severity of disease [insufficient evidence]. Evaluation of important clinical outcomes including survival, respiratory failure, duration of mechanical ventilation, and use of ECMO [no evidence]. [/fig]