Hydroxychloroquine for COVID-19: more harm than good?

EDITOR'S NOTE: The study discussed in this post was retracted by the Lancet on June 5 at the request of three of the study authors because they could no longer vouch for the accuracy of the primary data sources. For further details, see Dr. Middleton's June 8 AFP Community Blog post.

Hydroxychloroquine and chloroquine, with or without a second-generation macrolide antibiotic, have been touted as possible treatments for COVID-19 since the early days of the pandemic. A few small, open-label studies showed promise, but much of the medical community, including the American College of Physicians, continued to advise caution. A much larger registry study, published last week, casts further doubt on that early optimism.

The study authors reviewed data from over 96,000 patients across 671 hospitals worldwide of patients who were admitted with a positive SARS-CoV-2 test and divided them into cohorts of those who received hydroxychloroquine or chloroquine, with or without a macrolide (most commonly azithromycin), and those who did not receive any of those medications (the control group). Included patients received one or more of these medications within 48 hours of admission, were not on mechanical ventilation when the regimen was started, and did not receive antiviral treatment with remdesivir:

These specific exclusion criteria were established to avoid enrolment [sic] of patients in whom the treatment might have started at non-uniform times during the course of their COVID-19 illness and to exclude individuals for whom the drug regimen might have been used during a critical phase of illness, which could skew the interpretation of the results. Thus, we defined four distinct treatment groups, in which all patients started therapy within 48 h of an established COVID-19 diagnosis: chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide. All other included patients served as the control population.

All four of the medication groups had a higher in-hospital mortality than the control group (hydroxychloroquine hazard ratio [HR] 1.335 [95% confidence interval 1.223, 1.457],  hydroxychloroquine with a macrolide HR 1.447 [95% CI 1.36, 1.531], chloroquine HR 1.365 [95% CI 1.218, 1.531], and chloroquine with a macrolide HR 1.368 [95% CI 1.273, 1.469]). Additionally, all 4 medication groups had a higher risk of new onset ventricular arrhythmia (hydroxychloroquine HR 2.369 [95% CI 1.935, 2.900], hydroxychloroquine with a macrolide HR 5.106 [95% CI 4.106, 5.983], chloroquine HR 3.561 [95% CI 2.760, 4.596), and chloroquine with a macrolide HR 4.011 [95% CI 3.344, 4.812]). 

The study authors employed multiple techniques to control for potentially confounding variables, including baseline comorbid conditions, age, sex, ethnicity, and smoking status. The authors note that "[d]ue to the observational study design...a cause-and-effect relationship between drug therapy and survival should not be inferred" and that "[r]andomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients."

We will have to wait for randomized controlled trials to definitively answer the question of causation, but for now, the best evidence to date suggests that they are unlikely to be helpful and may even worsen outcomes. Stockpiling them and/or taking them as a preventive measure (despite certain high-profile persons touting as such) is not recommended by the National Institutes for Health and may limit their access to the patients who truly can benefit from them (especially patients with lupus and other connective tissue diseases who rely on hydroxychloroquine).

AFP's comprehensive list of COVID-19 resources is being regularly updated if you'd like to read more about the latest findings related to the pandemic.