Prolongation of repolarisation accumulates with long term
exposure.
A treatment options that is currently being evaluated is the combination
of hydroxychloroquine with azithromycin (44). Studies in small groups of
patients reported significant QTc prolongation in those treated with
this combination, with 11 % of patients showing severe prolongation of
>500 ms (5) – though with no incidence of arrhythmia.
Another retrospective cohort study of 1438 patients demonstrated that
cardiac arrest was significantly more likely in COVID-19 patients
receiving the combination of drugs, but not in patients receiving either
drug alone (6). However, the authors pointed out that there were
potential limitations with this observation. In the absence of
randomized clinical trial data, there therefore exists some degree of
uncertainty about whether there is an additive QT effect of the
combination therapy.
In our study, we first assessed whether the potency of either
hydroxychloroquine or chloroquine against hERG was altered when
administered with 5 µM azithromycin, corresponding to the plasma
Cmax of an IV dosing regime of 500 mg per day (37).
Azithromycin caused only subtle (hydroxychloroquine) or insignificant
changes in the extent of hERG block when compared to each drug in
isolation (Supplementary figure 2), consistent with a purely additive
effect of the drug. This approach however does not take into account the
possibility that azithromycin can i) accumulate in cells and tissue to
much higher concentrations than in plasma (45); and ii) may also act on
other ion channel involved in cardiac repolarisation in addition to
hERG. To address this, we measured the time dependent effect of
hydroxychloroquine, with and without azithromycin, on prolongation of
repolarisation over 48 hours in hiPSC derived cardiomyocytes from three
separate individuals. Our data showed that while there was no
statistically significant difference observed between the effects of the
two drug treatments, there was a significant increase in prolongation
observed over time. This is consistent with previously published
pharmacokinetic studies reporting accumulation of both
hydroxychloroquine (33, 46) and azithromycin (45) in tissue.
Azithromycin has also been shown to potentiate the late sodium current
with longer term exposure (47), which would also prolong repolarisation
and exacerbate the proarrhythmic risk associated with hERG block. The
time dependent effects observed in our experiments therefore likely
result from a combination of each of these effects. We also observed
clear variability in the magnitude of response to the drugs between iPSC
lines derived from different patients. This is consistent with
previously published data from our group (48) and others (49) where we
have measured the transcript levels of cardiac rhythmonome genes and
show that the degree of prolongation measured on multielectrode arrays
is dependent on the genetic background of the individual, specifically
the level of expression of the KCNH2 gene, coding for the hERG
K+ channel. Overall, these data support that longer
term QTc monitoring should be implemented in COVID-19 patients
administered hydroxychloroquine or chloroquine, either alone or in
combination with azithromycin, in addition to baseline ECG screening
recommended in recent guidelines (4).