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).