Hydroxychloroquine treatment does not reduce COVID-19 mortality; underdosing to the wrong patients?

An observational study published in The Lancet Rheumatology by Christopher T Rentsch and colleagues¹ 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,² 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,¹ in which half of the participants are under 70 years old and more than two thirds are women. Rentsch and colleagues¹ 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.3, 4 These studies were all disregarded as methodologically weak, and an opportunity to build upon the interesting aspects of previous research was missed. Rentsch and colleagues¹ 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).3, 4 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,¹ 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.