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.