It is time to drop hydroxychloroquine from our COVID-19 armamentarium

Abstract

Chloroquine (CQ) and hydroxychloroquine (HCQ) were among the first drugs repurposed for the treatment of SARS-CoV-2 infection. A few in vitro studies confirmed that both drugs exhibited dose dependent anti-SARS-CoV-2 activities. These observations and the encouraging results from early poorly conducted observational studies created a major hype about the therapeutic potential of these drugs in the treatment of COVID-19 disease. This was further catalyzed by media and political influences leading to a widespread use of these agents. Subsequent randomized trials revealed lack of efficacy of these agents in improving the outcomes of COVID-19 or in preventing infection in post-exposure prophylaxis studies. Nevertheless, many ongoing trials continue to actively recruit tens of thousands of patients to receive HCQ worldwide. In this perspective, we address the possible mechanisms behind the lack of efficacy and the increased risk of cardiac toxicity of HCQ in COVID-19 disease. For the lack of efficacy, we discuss the fundamental differences of treatment initiation between in vitro and in vivo studies, the pitfalls of the pharmacological calculations of effective blood drug concentrations and related dosing regimens, and the possible negative effect of HCQ on the antiviral type-I interferon response. Although it has been repeatedly claimed that HCQ has a longstanding safety track record for many decades in use, we present counterarguments for this contention due to disease-drug and drug-drug interactions. We discuss the molecular mechanisms and the cumulative epidemiological evidence of HCQ cardiac toxicity.

Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID‐19 patients: A systematic review and meta‐analysis of randomized controlled trials

“…The narrow therapeutic window for HCQ, the increased rate of adverse events associated with its use and the difficulty of achieving adequate therapeutic concentration make HCQ not a good option for the treatment of COVID-19 disease (46) .…”

Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review

“…Initially, based on physiological pharmacokinetic models, Yao et al recommended for SARS-CoV-2 infection a loading oral HCQ dose of 400 mg twice daily, followed by a maintenance dose of 200 mg administered twice daily for four days [ 50 ]. However, this recommended HCQ dosage regimen was based only on the ratio of free lung trough concentration to in vitro EC 50 values (the EC 50 of HCQ for SARS-CoV-2 ranged between 0.72 and 17.31µM) and did not consider the tendency of HCQ to accumulate within acidic cellular organelles like endosomes, lysosomes, and Golgi apparatus [ 69 ]. In fact, it has been demonstrated that HCQ concentration in lysosomes is higher than the extracellular concentration (80 µM vs .…”

Hypotheses and Ethics in the Time of the Covid-19 Pandemic

“…Numerous hypotheses have been published urging to repurpose available bacterial and viral vaccines and anti-inflammatory drugs to curb the COVID-19 pandemic. While vaccine hypotheses were mainly based on observations of cross-reactivity and low COVID-19 cases in regularly vaccinated pediatric populations [6,7], drug repurposing suggestions were relying on a limited experience of previously controlled coronavirus epidemics [8].…”