Shunt due to Hydroxychloroquine Sub-lethal Dosage Resulted in Excess Transfer to Mechanical Ventilation and Death in Hospitalized Patients with Covid-19

Abstract

We have recently published, on February 11, 2021, a letter of concern in the NEJM, regarding hydroxychloroquine overdosing in Recovery, the British mutli-center randomized clinical trial [1,2]. Our letter indicates also that at lower dose (around 400 mg/day) HCQ may be active due to its extremely high concentration in phagolysosomes, the organelles mediating SARS-Cov2 entry in the cell. We mention as well that too a high dose of HCQ may suppress anti-inflammatory cytokines production. In their reply to our letter the principal investigators of Recovery have argued that their HCQ maintenance dosage was well below (half) that of the trial of Borba et al. that was prematurely stopped due to toxic deaths [1]. They persist that they have established proper dosage, based on their own pharmacokinetics (PK) investigations, with a loading dose of 2.4 g on day 1, whereas PK of HCQ in the context of Covid-19 was already published online (March 09, 2020) in a peer reviewed international journal. This study indicated, for European patients, a loading dose of 800 mg (400 mg twice daily) on day 1, followed by a maintenance dose of 400 mg (200 mg twice daily) the next 4 days [3]. These published PK data show that after 5 days this dosage reaches 3 times the potency (ratio concentration in the lungs/EC50; EC50 being in vitro measurement of anti-viral activity) of chloroquine phosphate when given 500 mg twice daily. Hydroxychloroquine (EC50 = 0.72 μM) was found to be more potent than chloroquine (EC50 = 5.47 μM) in vitro.