Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality

Abstract

Background

Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease.

Methods

We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph.

Findings

Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (−0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality.

Interpretation

We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted.

Funding

Medical Research Council.

Plain English Summary

Early in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, it was suggested that hydroxychloroquine - a commonly used treatment for rheumatic diseases - might have benefits for the treatment and prevention of COVID-19. Hydroxychloroquine has since been investigated in several randomised clinical trials and observational studies. Most studies to date have shown no evidence of a benefit of hydroxychloroquine as a treatment for patients admitted to hospital who already have COVID-19.

A separate question remains: does routine ongoing use of hydroxychloroquine in people without coronavirus infection protect against new infections or severe COVID-19 outcomes? We studied a large number of people who were prescribed hydroxychloroquine as part of normal clinical care and followed them up to look for signals of benefit or harm in mortality from COVID-19 and other causes. We found no evidence of benefit or harm after adjusting for important differences between people with the same health conditions prescribed hydroxychloroquine or not.

The scientific community should endeavour to encourage recruitment to trials since, in the absence of a vaccine, there are no current preventative treatments available. This paper adds to evidence of scientific equipoise and can help with recruitment. The use of hydroxychloroquine for prevention of COVID-19 mortality outside trial settings is currently not justified.