3.2 Chloroquine and hydroxychloroquine
Chloroquine and its derivative, hydroxychloroquine, are widely used as
inexpensive and safe anti-malarial drugs. In particular, the established
good tolerability of chloroquine/hydroxychloroquine has made them safe
to use even in pregnancy (Villegas et al., 2007). In addition to
anti-malarial activity, both drugs have immunomodulating effects and are
used for the treatment of autoimmune diseases including systemic and
discoid lupus erythematosus, psoriatic arthritis, and rheumatoid
arthritis. Chloroquine/hydroxychloroquine concentrate extensively in
acidic vesicles including the endosomes, Golgi vesicles, and the
lysosomes (Ohkuma & Poole, 1981). This leads to lysosomal membrane
permeabilisation or dysfunction of several enzymes including acid
hydrolases and palmitoyl-protein thioesterase 1 (Rebecca et al., 2019;
Savarino, Boelaert, Cassone, Majori, & Cauda, 2003; Schrezenmeier &
Dorner, 2020). Although the precise mechanisms of the anti-viral effects
are not fully understood, it has been proposed that
chloroquine/hydroxychloroquine can prevent virus infection
(pre-infection) by interfering with the glycosylation of cellular
receptors and impair viral replication by increasing endosomal pH
(post-infection) (Savarino et al., 2003; Savarino et al., 2004; Vincent
et al., 2005).
Owing to their efficacy against viruses (mostly demonstrated in
vitro ) including influenza, HIV, coronavirus OC43, and SARS-CoV, a
large number of clinical trials (>160) have been registered
worldwide using chloroquine/hydroxychloroquine alone, or in combination
with other drugs (e.g. azithromycin) for the treatment of COVID-19.
Despite promising in vitro antiviral results for
hydroxychloroquine/chloroquine, there is no convincing evidence of
efficacy at present (Gao, Tian, & Yang, 2020; Gautret, Lagier, Parola,
Hoang, Meddeb, Mailhe, et al., 2020; Gautret, Lagier, Parola, Hoang,
Meddeb, Sevestre, et al., 2020; J. Liu et al., 2020; Magagnoli, 2020;
Mathian et al., 2020; Million et al., 2020; Tang, 2020; Yao et al.,
2020). A post-exposure prophylaxis randomised controlled trial of 821
participants failed to show any benefit of hydroxychloroquine (n=414)
compared with placebo (n=407) (Boulware et al., 2020). At the time of
writing, the RECOVERY trial (clinical trial identifier NCT04381936)
which is the largest randomised control trial so far conducted for the
treatment of COVID, has stopped recruiting to the hydroxychloroquine arm
(1542 patients compared with 3132 on standard care) because of no
beneficial effect either in terms of mortality or hospital stay (Horby
& Landray, 2020). There are still many other trials on-going testing
the efficacy of hydroxychloroquine for either prophylaxis or treatment.
Both chloroquine and hydroxychloroquine have been in clinical use for
many years for rheumatoid diseases, and thus their safety profile is
well established. Dose-dependent retinal toxicity has long been
recognized as the major AE with long-term use of
chloroquine/hydroxychloroquine (Marmor et al., 2011). Besides retinal
toxicity, gastrointestinal, liver and renal toxicity have also been
reported (Giner Galvan, Oltra, Rueda, Esteban, & Redon, 2007;
Michaelides, Stover, Francis, & Weleber, 2011; Mittal, Zhang, Feng, &
Werth, 2018). As both drugs are mainly metabolised in the liver and
excreted by renal clearance, their use in patients with liver or renal
impairment may worsen the function of these organs. For chloroquine
treatment, prescribing information recommends the full dose at all
degrees of renal impairment but suggests that monitoring of renal
function may be useful (Sanofi-Aventis, 2017 ). For hydroxychloroquine,
reductions in dosage are advised for patients with impaired renal
function, as well as those taking concomitant medications with known
risks of kidney damage (Concordia Pharmaceuticals Inc, 2017).
A serious AE associated with chloroquine/hydroxychloroquine is
cardiotoxicity, which can take many forms including cardiomyopathy in
rare instances. Prolonged treatment or high dosage of
chloroquine/hydroxychloroquine has been shown to increase of the risk of
QT interval prolongation, polymorphic ventricular tachycardia, and
sudden cardiac death (Chatre, Roubille, Vernhet, Jorgensen, & Pers,
2018). A large epidemiological analysis in patients with rheumatoid
arthritis has recently shown that 30-day cardiovascular mortality was
increased by more than 2-fold when hydroxychloroquine was combined with
azithromycin. The lethal ventricular arrhythmias are primarily due to
inhibition of a potassium channel (the inward rectifier Kir2.1 channel)
and may occur at low µM concentrations (IC50=8.7 µM)
(Rodriguez-Menchaca et al., 2008). While therapeutic doses of
chloroquine typically result in plasma concentrations of 2-5 µM, much
higher concentrations in the heart are expected based on a 400-fold
increase observed in rat PK studies (McChesney, Banks, & Fabian, 1967;
Walker, Dawodu, Adeyokunnu, Salako, & Alvan, 1983). The binding of
chloroquine to the inward rectifier Kir2.1 channel can be stabilized by
negatively charged and aromatic amino acids (Rodriguez-Menchaca et al.,
2008). The binding of chloroquine/hydroxychloroquine to proteins is also
stereoselective, but whether one of the chloroquine/hydroxychloroquine
enantiomers has a stronger interaction with the Kir2.1 channel is not
known. Caution is needed when hydroxychloroquine is used in combination
with other drugs (including azithromycin), which increase the QT
interval because of a pharmacodynamic synergistic interaction.
Given the comorbidities in many patients with COVID-19, especially those
with underlying cardiovascular disease, and the fact that COVID-19
itself is associated with cardiac manifestations, this may increase the
risk of cardiotoxicity associated with the use of
chloroquine/hydroxychloroquine. Indeed, excessive QTc prolongation was
observed in 36 % of patients as reported by Bessiere at al. and greater
QTc prolongation was also seen in patients taking the combination of
hydroxychloroquine and azithromycin than those taking hydroxychloroquine
alone, highlighting the importance of pharmacodynamic interactions
(Bessiere et al., 2020; Mercuro et al., 2020). Furthermore, a phase IIb
trial in Brazil showed that a higher dose of chloroquine (600 mg twice
daily) in patients hospitalised with COVID-19 had a higher fatality rate
(30 %) compared with 15 % in the lower dose (450 mg twice daily) group
(Borba et al., 2020). QTc interval prolongation >500 msec
was observed in 19 % of the high dose group compared with 11 % of the
low dose group. The US prophylaxis randomised control trial however did
not show any increase in cardiovascular AEs (Boulware et al., 2020). We
await the publication of the RECOVERY trial to determine whether there
was an excess of cardiovascular events. However, it is important to note
that despite the size of the RECOVERY trial (n = 1542 patients), it may
still be under-powered to identify an excess number of cardiovascular
events when compared with standard of care.