Hydroxychloroquine: Time for Reappraisal of Its Effect in COVID-19 Patients

On January 2020, the WHO named a new human coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as the cause of the novel 2019 coronavirus disease (COVID-19). Chloroquine is an aminoquinolone derivative first developed for the treatment of malaria. Hydroxychloroquine is the other 4-aminoquinoline-derived antimalarial drug. In vitro studies suggested that chloroquine and hydroxychloroquine could interfere with angiotensin-converting enzyme 2 (ACE2) receptor glycosylation of the coronavirus, increase endosomal pH, interfere with post-translational modification of viral proteins, and inhibit the activation of p38 mitogen-activated protein kinase (MAPK), thus inhibiting viral fusion, decreasing viral load, altering virion assembly, and inhibiting virus replication and autophagy. Early in the pandemic, hydroxychloroquine was acclaimed as both a preventive and therapeutic treatment for COVID-19, but subsequent clinical trials have not found any benefit, and some pointed to potential harm. It is important to note that a possible explanation for this failure is based on the pharmacokinetic characteristics of these drugs. Initial clinical studies, reported conflicting results regarding hydroxychloroquine use in COVID-19. However, the majority of the previously identified benefits and positive results from hydroxychloroquine were not reproduced in subsequent and more robust randomized controlled trials (RCTs). The discrepant results between the early studies, showing a positive effect on patient outcomes, and the more recent RCTs, proving a higher mortality rate of COVID-19 patients treated with hydroxychloroquine, endorse the need to rethink and review clinical indications as new evidence emerges, to provide the best care and survival chance to already critically ill patients.