Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial

RECOVERY trial finds no significant benefit for very late stage (9 days after symptom onset) very sick patients. Results may be due to the unusually high dosage used (9.2g total over 10 days) twitter.com, twitter.com (B). The overall dosage used is only 23% less than the high dosage that Borba et al. show greatly increases risk (OR 2.8) Borba.Authors do not report results based on weight, BMI, or related conditions such as diabetes, which may provide additional evidence of toxic dosages. Authors do not adjust dosage based on patient weight, so toxicity may be higher in patients of lower weight.KM curves show a spike in HCQ mortality days 5-8, corresponding to ~85% of the total excess seen at day 28 (a similar spike is seen in the SOLIDARITY trial).Authors note: "we did not observe excess mortality in the first 2 days of treatment ... when early effects of dose-dependent toxicity might be expected", but they are ignoring the very long half-life of HCQ and the dosing regimen - much higher levels of HCQ will be reached later. Increased mortality in Borba et al. occurred after 2 days.Patients were extremely sick (median 9 days post symptoms, 60% requiring oxygen and an additional 17% requiring ventilation/ECMO), with an unusually high mortality rate was seen in both arms. 1,561 HCQ patients, 3,155 SOC.A secondary analysis has found several inconsistencies in the data: francesoir.fr. Hypoxia may inhibit HCQ entering cells twitter.com (C), making it less effective for late stage use. For more on the dosing problems see kristianfranciscomillanielsen.medium.com, also noting that concentrations vary substantially in different tissues and lung concentration may be >30x plasma concentration.