Hydroxychloroquine treatment does not reduce COVID-19 mortality; underdosing to the wrong patients?
Authors: Luis Ayerbe, Carlos Risco-Risco, Iván Núñez-Gil, Maria Perez-Piñar, Salma Ayis
Journal: The Lancet Rheumatology (2021)

An observational study published in The Lancet Rheumatology by Christopher T Rentsch and colleagues1Rentsch CT DeVito NJ MacKenna B 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 platform.Lancet Rheumatol. 2021; 3: e19-e27Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar showed no association between pre-exposure use of hydroxychloroquine and reduced mortality in patients with COVID-19 who also have systemic lupus erythematosus or rheumatoid arthritis. 138 440 (71·1%) participants were women, and the study population was relatively young, with 50% of the participants younger than 66 years. In a previous study,2Williamson EJ Walker AJ Bhaskaran K et al.Factors associated with COVID-19-related death using OpenSAFELY.Nature. 2020; 584: 430-436Crossref PubMed Scopus (3957) Google Scholar the death rate in patients younger than 70 years was low, and it was lower for women than men; therefore, the differences in mortality might be very difficult to appreciate in the study by Rentsch and colleagues,1Rentsch CT DeVito NJ MacKenna B 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 platform.Lancet Rheumatol. 2021; 3: e19-e27Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar in which half of the participants are under 70 years old and more than two thirds are women. Rentsch and colleagues1Rentsch CT DeVito NJ MacKenna B 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 platform.Lancet Rheumatol. 2021; 3: e19-e27Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar did not reference any of the several large peer reviewed studies showing an association between hydroxychloroquine and lower mortality in patients with COVID-19, or the systematic reviews that have critically appraised and summarised these studies.3Fiolet T Guihur A Rebeaud M Mulot M Peiffer-Smadja N Mahamat-Saleh Y Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis.Clin Microbiol Infect. 2021; 27: 19-27Summary Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 4Di Castelnuovo A Costanzo S Cassone A Cauda R de Gaetano G Iacoviello L Low dose hydroxychloroquine is associated with lower mortality in COVID-19: a meta-analysis of 26 studies and 44,521 patients.medRxiv. 2020; (published online Nov 4.) (preprint)https://doi.org/10.1101/2020.11.01.20223958Google Scholar These studies were all disregarded as methodologically weak, and an opportunity to build upon the interesting aspects of previous research was missed. Rentsch and colleagues1Rentsch CT DeVito NJ MacKenna B 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 platform.Lancet Rheumatol. 2021; 3: e19-e27Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar mentioned that the dose at which hydroxychloroquine is given for systemic lupus erythematosus (SLE) and rheumatoid arthritis is similar to the one used in an ongoing clinical trial (NCT04303507) for prevention of COVID-19 (200–400 mg per day). However, even when hydroxychloroquine is used at maximum dose, patients with SLE or rheumatoid arthritis do not receive doses as high as those used in patients with COVID-19 in studies that showed an association between hydroxychloroquine and reduced mortality (800 mg on day 1 followed by 400 mg a day for four days).3Fiolet T Guihur A Rebeaud M Mulot M Peiffer-Smadja N Mahamat-Saleh Y Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis.Clin Microbiol Infect. 2021; 27: 19-27Summary Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 4Di Castelnuovo A Costanzo S Cassone A Cauda R de Gaetano G Iacoviello L Low dose hydroxychloroquine is associated with lower mortality in COVID-19: a meta-analysis of 26 studies and 44,521 patients.medRxiv. 2020; (published online Nov 4.) (preprint)https://doi.org/10.1101/2020.11.01.20223958Google Scholar The large number of studies on hydroxychloroquine that show contradictory results on different outcomes of COVID-19 might reflect the methodological limitations of each study on both sides of the debate. It could mean that hydroxychloroquine might only be beneficial at a certain dose, in specific phase of the disease, or in patients with a particular sociodemographic or clinical profile. Like Rentsch and colleagues,1Rentsch CT DeVito NJ MacKenna B 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 platform.Lancet Rheumatol. 2021; 3: e19-e27Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar we think that additional studies are required on the potential benefit of hydroxychloroquine, which is economical, has not proven to be harmful at the dose used for COVID-19, and could be prescribed to ambulatory patients right after the diagnosis before they develop respiratory distress. We declare no competing interests. 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 platformWe 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. Full-Text PDF Open AccessHydroxychloroquine treatment does not reduce COVID-19 mortality; underdosing to the wrong patients? – Authors' replyWe thank Luis Ayerbe and colleagues for the opportunity to further discuss our Article.1 The choice of our study population—individuals with rheumatoid arthritis or systemic lupus erythematosus—was made to minimise the potential for confounding by indication when estimating the effectiveness of hydroxychloroquine use rather than investigating how to prevent severe COVID-19 in this population. The key question is whether our study had sufficient statistical power to detect a real difference in mortality, if one existed? As stated in the Article, the CIs around our key estimate (hazard ratio 1·03 [95% CI 0·80–1·33]) suggested that we could exclude substantial benefit, although a modest benefit or harm on a relative scale could not be ruled out; therefore, trials were warranted. Full-Text PDF