Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19

TO THE EDITOR: Skipper and colleagues' multicenter trial (1) was conducted in 2 locations (the United States and Canada) with the intention of evaluating the absolute therapeutic efficacy of HCQ in symptomatic, nonhospitalized adults with COVID-19. Patients were randomly assigned to either the HCQ or placebo group. While evaluating the composition of the placebo regimen, we noted that a folic acid tablet, 400 mcg, was used as placebo in the U.S. population and a lactose tablet in the Canadian population.

In in silico studies, folic acid acted as a good binder against severe acute respiratory syndrome coronavirus 2 furin (which is required for viral entry to the host cell) (2). In clinical studies, Itelman and associates (3) reported lower blood folic acid levels among patients with severe disease than in their counterparts with mild disease. Pregnant women seem to be less likely to require hospitalization for COVID-19 (4), and Acosta-Elias and Espinosa-Tanguma (4) postulated that folic acid uptake may be the protective factor. Use of Angiovit (Altayvitaminy), an agent containing folic acid and vitamin B₁₂, has been associated with a shorter duration of “hospital stay” and “fever” compared with mainstay therapy (5). Several trials evaluating folic acid as a therapeutic agent in COVID-19 are currently under way (https://clinicaltrials.gov/ct2/show/NCT04354428 and https://covid-19.cochrane.org/studies/crs-15322074).

Skipper and colleagues concluded that there was no statistically significant difference in “COVID-19–related symptoms,” “incidence of hospitalization,” and “death” between both groups. This comparable efficacy does not indicate the absolute efficacy of HCQ; rather, it indicates the comparative efficacy between HCQ and folic acid, and both performed equally. Again, rather than describing this trial as “placebo controlled,” it would be better classified as a “head-on” comparison between HCQ and folic acid.