A Rapid Guidance Summary from the
Penn Medicine Center for Evidence-based Practice
Last updated July 1, 2020. All links rechecked June 30 unless otherwise noted.
This Rapid Guidance Summary is a description of existing guidance and evidence reviews from a variety of sources that was in effect at the time of publication. It should not be used or interpreted as a clinical practice guideline, but instead can be used in development of local recommendations and policies.
Key Questions Answered in This Summary
- Is hydroxychloroquine effective for prevention of clinical disease in patients who have been exposed to SARS-CoV-2?
Use of hydroxychloroquine for treatment of confirmed COVID-19 disease is outside the scope of this report.
Summary of Major Recommendations
- Use of hydroxychloroquine or chloroquine for prevention of COVID-19 disease is not recommended outside of approved clinical trials.
- A systematic review of clinical evidence found only one trial evaluating HCQ for preventing COVID-19 disease in persons with history of exposure to infected patients. Results of that single trial did not demonstrate reduced COVID-19 disease with hydroxychloroquine, and the risk of adverse events is possibly increased. The risk of bias in that study was high.
- There are no medical centers using hydroxychloroquine or chloroquine for prevention of COVID-19 disease outside of approved clinical trials.
Recent Public Health Agency and Professional Society Guidelines on Prophylactic Use of Hydroxychloroquine
Public health agencies
The Emergency Use Authorization for hydroxychloroquine (now withdrawn) applied only to patients hospitalized with COVID-19 disease; prophylactic use was never authorized.
We recommend that chloroquine and hydroxychloroquine (± azithromycin) not be administered as treatment or prophylaxis for COVID-19, outside of the context of clinical trials.
The American College of Physicians specifically does not recommend use of chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis against COVID-19.
For people exposed to individuals with COVID-19, only administer hydroxychloroquine for post-exposure prophylaxis in the context of randomized trials with appropriate ethical approval.
Hydroxychloroquine and chloroquine are not recommended for use for widespread prophylaxis against COVID-19. Strength of evidence: not recommended, insufficient evidence. Level of confidence: low.
CEP NOTE: NIH guidelines do not apply to prophylaxis in persons with SARS-CoV-2 exposure
Systematic Reviews With Quantitative Data Synthesis
For outcome of positive COVID-19 disease within 14 days of exposure to infected person: Summary risk ratio 0.83, 95% CI 0.58-1.18, p = 0.30, I2 not applicable, 1 trial, 821 patients, moderate risk of bias.
For outcome of adverse events: Summary risk ratio 2.39, 95% CI 1.83-3.11, p < 0.001, I2 not applicable, 1 trial, 701 patients, high risk of bias.
CEP NOTE: Please see linked page for current review results including forest plots of results.
CEP NOTE: The protocol for a Cochrane Review on this topic has been published, but the review is not yet completed.
Other Recent Evidence Reviews on Prophylactic Use of Hydroxychloroquine
A randomized trial of hydroxychloroquine for postexposure prophylaxis within 4 days after high-risk or moderate- risk exposure to Covid-19 showed no prevention of Covid-19 or compatible illness, although most patients did not start therapy for at least 3 days after SARS-CoV-2 exposure
A recent randomized, double-blind, placebo-controlled trial of hydroxychloroquine as post-exposure prophylaxis after a high risk exposure to COVID-19 did not show any clinical benefit. The majority of subjects enrolled (87.6%) had a high risk exposure defined as being less than 6 feet from someone with confirmed COVID-19 without a face mask or eye shield for greater than 10 minutes. Subjects were randomized to HCQ 800 mg orally once followed by 600 mg daily x 4 days vs placebo. There was no significant difference in the development of confirmed or probable COVID-19 in the HCQ group vs placebo (11.8% vs 14.3%, p = 0.35). There were more side effects, predominantly gastrointestinal in nature, in the hydroxychloroquine group.
On 26 June the UK Medicines and Healthcare products Regulatory Agency announced that it had “given the [COPCOV] clinical trial the green light to recruit more participants at the request of the COPCOV trialists, who are studying the use of hydroxychloroquine in preventing COVID-19. At the same time, MHRA reminded prescribers that “Chloroquine and hydroxychloroquine are not licensed to treat COVID-19 related symptoms or prevent infection” and that “until we have clear, definitive evidence that these treatments are safe and effective for the treatment of COVID-19, they should only be used for this purpose within a clinical trial.”
Major media outlets have reported hydroxychloroquine does not prevent COVID-19. This is based on a randomized, double-blind placebo controlled trial of 821 asymptomatic participants in which the investigators concluded there was no difference in the incidence of new illness between placebo and hydroxychloroquine. Some have argued, however, the study may not be definitive, because the participants self-reported symptoms and there was no testing, raising the question of the trial design.
Efficacy and safety of hydroxychloroquine for treatment or prevention of COVID-19 is not established.
No data to date indicating that in vitro activity against SARS-CoV-2 corresponds with clinical efficacy for treatment or prevention of COVID-19
Only limited clinical trial data available to date to evaluate use of hydroxychloroquine for prevention of COVID- 19.
Brigham June 23
The first randomized control trial for COVID-19 post-exposure prophylaxis was published on June 3, 2020. Asymptomatic patients who had household or occupational exposures to others with COVID-19 for more than 10 minutes within 4 days of exposure were randomized to receive either placebo (n=407) or hydroxychloro- quine 800 mg once, 600 mg in 6-8 hours, then 600 mg daily for 4 additional days (n=414). The incidence of new illness compatible with COVID-19 was 11.8% in the hydroxychloroquine arm and 14.3% in the placebo arm (absolute difference -2.4%, 95% CI -7 to 2.2%, p=0.35). Side effects were more common in the hydroxychloroquine arm (40.1% vs. 16.8%), but no serious adverse reactions were reported.
Role for post-exposure prophylaxis is not compelling, at least among clinical/healthcare worker exposures
Washington June 9
A double-blind placebo-controlled RCT found that prophylactic hydroxychloroquine fails to prevent symptomatic infection after SARS-CoV-2 exposure.
Medical Center Guidance on Prophylactic Use of Hydroxychloroquine
There is currently no proven role for post exposure prophylaxis for healthcare workers with a known COVID-19 exposure. No benefit of hydroxychloroquine was seen in a double-blinded placebo randomized controlled trial.
Hydroxychloroquine is not recommended outside of the context of a clinical trial.
We do not recommend routine post-exposure prophylaxis.
ACOEM- American College of Occupational and Environmental Medicine ACP–American College of Physicians
ASHP–American Society of Health System Pharmacists CEBM–University of Oxford Centre for Evidence-based Medicine EM-RAP–Emergency Medicine Reviews and Perspectives
Living Evidence–an ad hoc collaboration of Cochrane Collaboration members and hospital health technology assessment specialists
SIDP–Society of Infectious Disease Pharmacists
July 1: Updated ACP and medical center guidance. Outdated guidance removed. New section for systematic reviews, other evidence reviews updated. Conclusions strengthened.
April 21: Updated evidence reviews and medical center guidance. April 11: Initial report.
About this report
A Rapid Guidance Summary is a focused synopsis of recommendations from selected guideline issuers and health care systems, intended to provide guidance to Penn Medicine providers and administrators during times when latest guidance is urgently needed. It is not based on a complete systematic review of the evidence. Please see the CEP web site for further details on the methods for developing these reports.
Lead analyst: Matthew D. Mitchell, PhD (CEP) Evidence team leader: Emilia J. Flores, PhD, RN (CEP)
Reviewers: George L. Anesi, MD, MSCE, MBE (Crit. Care); Kathleen O. Degnan, MD (Medicine); Keith W. Hamilton, MD (Medicine); Nikhil K. Mull, MD (CEP)
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