Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has to date
infected ~110 million people worldwide (December 2020),
resulting in ~2.5 million deaths ( COVID-19
Dashboard, Johns Hopkins University). There are currently no small
molecule medications approved to prevent or treat COVID-19. Throughout
2020, there was considerable interest in the use of hydroxychloroquine
and chloroquine, two drugs used for treatment of lupus erythematosus,
other inflammatory disorders and malaria, which are also effective in
inhibiting replication of SARS-CoV-2 in vitro (1). Open-label
observational studies purported to show therapeutic benefit for these
drugs either when used as a monotherapy, or in combination with the
macrolide antibiotic azithromycin (2). Consequently, the Food and Drug
Administration (FDA) gave limited authorisation for emergency use of
hydroxychloroquine in COVID-19 patients. However, this was subsequently
been withdrawn with interim results from major clinical trials reporting
negative results for efficacy against COVID-19 (3). Despite this, more
than 150 clinical trials testing hydroxychloroquine and chloroquine,
alone or in combination with azithromycin, for treatment of COVID-19 are
still recruiting
(www.clinicaltrials.gov), with
many using doses several times higher than those recommended for their
approved indications.
Significant concern exists around the cardiac safety profiles of
hydroxychloroquine, chloroquine and azithromycin (4-6) as they are all
known to prolong the QT interval on the electrocardiogram (ECG),
primarily via block of the hERG/Kv11.1 potassium channel, and thus
increase the risk of arrhythmias and sudden cardiac death (7). There are
hundreds of cases of drug-induced arrhythmias, and cardiac arrest,
associated with these drugs in the FDA’s adverse events reporting system
(FAERS; www.fda.gov). In the context of COVID-19 patients, this concern
was most recently highlighted in a multinational registry analysis that
showed increased risk of arrhythmias in patients treated with
hydroxychloroquine and chloroquine, either with or without azithromycin
(8). However, this study was subsequently retracted due to concerns over
the veracity of the data (9). Consequently, there is scant and
inconsistent data regarding the cardiac safety of these drugs at doses
relevant to COVID-19.
In addition to the intrinsic risk associated with these drugs, many
factors associated with the pathophysiology of COVID-19 may increase the
risk of proarrhythmic activity. For example, fever, electrolyte changes
including hypokalaemia and hypermagnesaemia, and systemic acidosis
associated with respiratory failure, are common in COVID-19 patients (8,
10, 11) and can all modify potency of hERG block and by extension
proarrhythmic risk (12-15). Indeed, emerging evidence suggests that the
QT prolongation observed for these drugs appears more profound in
COVID-19 patients than in healthy individuals (5) suggesting a role for
patient attributes in modifying proarrhythmic risk. Thus, there is a
need for a thorough assessment of the cardiac safety profile of
chloroquine, hydroxychloroquine and azithromycin in the context of
changes in pathophysiological state associated with COVID-19, to guide
clinical decision making and management of these patients.
Here, we have undertaken a multiplatform, preclinical cardiac safety
evaluation combining high-throughput screening of hERG potency, in
silico prediction of population risk, and analysis of repolarization
changes in human induced pluripotent stem cell derived cardiomyocytes
(hiPSC-CM) from multiple individuals to assess both acute and long term
effects. Our data demonstrate a significant proarrhythmic risk for
hydroxychloroquine and chloroquine at doses being proposed to treat
COVID-19 and suggest that clinicians should implement long term QT
interval monitoring in trials, particularly in patients with electrolyte
imbalances (Graphical Abstract). Aside from specific relevance of our
results to use of these drugs in treatment of COVID-19, this study also
acts as a blueprint for how high-throughput in vitro screening,
combined with in silico simulations, can be used to build
reference datasets for how proarrhythmic risk of QT prolonging drugs can
be modified by metabolic changes associated with disease in order to
help guide clinicians in management of patients.