Hydroxychloroquine use prior to coronavirus infection may not reduce COVID-19 deaths…but clinical trials required

Dr Christopher T Rentsch
Early in the COVID-19 pandemic, it was suggested a commonly used treatment for rheumatic diseases might have benefits for the treatment and prevention of COVID-19.
Hydroxychloroquine tablets

Hydroxychloroquine was quickly thrown into a global spotlight after it garnered simultaneous praise and criticism from a number of high-profile sources.  

The drug 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.  

But a separate question remains: does routine ongoing use of hydroxychloroquine in people without coronavirus infection protect against new infections or severe COVID-19 outcomes?  

This possibility is currently being addressed in clinical trials. However, unjustified extrapolation and exaggerated safety concerns, together with intense politicisation and negative publicity, may stop COPCOV, the only large, global clinical trial testing hydroxychloroquine in COVID-19 prevention, from ever finding out. 

As we await the results of these ongoing clinical trials, real-world evidence of the drug’s effectiveness can be obtained from observational data.  

Early in the pandemic on behalf of NHS England, a team of researchers and software developers from LSHTM, Oxford, and TPP created OpenSAFELY. This new data analytics platform allows near real-time analysis of pseudonymised primary care records at scale, covering approximately 40% of the population in England and operating within the electronic health record vendor’s highly secure data centre.  

In a new study, published in Lancet Rheumatology, The OpenSAFELY team 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. They found no evidence of benefit or harm after adjusting for important differences between people with the same health conditions prescribed hydroxychloroquine or not.  

In this and other published and forthcoming studies, the OpenSAFELY team has demonstrated that it is possible to study the effects of prescribed medicines in relation to COVID-19 in a transparent manner that protects patients' privacy.  

This evidence can be used to help prioritise clinical trials and to inform regulatory bodies’ decision making in the absence of high quality, randomised trial data. All code to extract, clean, and analyse the data has been shared as open source for review and re-use, to support open and efficient science. 

 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. 

However, due to the observational nature of the study, a degree of uncertainty persists that can only be addressed through large-scale randomised trials.  

With no vaccine or possible preventative treatments for COVID-19, recruitment to these trials should continue so a definitive answer on whether hydroxychloroquine can COVID-19. 


C. T. Rentsch et al. Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platformThe Lancet Rheumatology. DOI: 10.1016/S2665-9913(20)30378-7

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