Background Haemodialysis patients are at risk of developing severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: coronavirus disease 2019 (COVID-19). In March 2020, hydroxychloroquine (HCQ) and azithromycin (AZI) were proposed as potential treatments of COVID-19, but with warnings concerning their possible toxicity. No data are available regarding the toxicity of this treatment in haemodialysis patients.
Methods We report the use of HCQ and AZI in a cohort of COVID-19 haemodialysis patients with focus on safety concerns.
Results Twenty-one patients received 200 mg HCQ thrice daily during 10 days, and AZI 500 mg on Day 1, and 250 mg on the four following days. HCQ plasma concentrations were within the recommended range (0.1–1.0 µg/mL) in all patients except one, in which maximum concentration was 1.1 µg/mL. HCQ concentration raised until the third day and remained stable thereafter. No cardiac event occurred in spite of progressive lengthening of corrected QT interval (QTc) during the treatment. One patient experienced a long QTc syndrome (QTc >500 ms) without any arrhythmia episode, although HCQ concentration was in the target range. Five (23.8%) patients experienced hypoglycaemia, a well-known HCQ side-effect. SARS-CoV-2 RNA remained detectable in nasopharyngeal swabs for a long time in haemodialysis patients (mean time 21 days).
Conclusions HCQ and AZI are safe in haemodialysis patients at these doses but can lead to long QTc syndrome and hypoglycaemia. HCQ concentrations were not correlated with side effects. We recommend monitoring of the QTc length throughout treatment, as well as glycaemia. SARS-CoV-2 could persist for longer in haemodialysis patients than in the general population.
The study was not designed to estimate the efficacy of the treatment. Considering the 24 COVID-19 patients of our centre, 4 (16.7%) died, 1 (4.2%) needed mechanical ventilation in ICU and then recovered, and the 19 (79.2%) others had favourable outcome without mechanical ventilation.
All deceased patients were old (mean age 84.6 ± 2.8 years), had severe respiratory symptoms of COVID-19, and, according to age and comorbidities, were not transferred in our ICU. Mean delay between diagnosis and death was short. One patient had received no HCQ treatment, while the others had received, respectively, 2, 4 and 5 days of treatment before death.
The patient who was transferred in the ICU was aged 51 years old. He had received 48 h of HCQ before he was put on mechanical ventilation, but treatment was continued in ICU and he recovered.
Among the 18 patients for whom the regular follow-up of RT-PCR was available, 3 still had positive nasopharyngeal swabs at the end of the study (respectively, on Days 21, 37 and 39). Fifteen patients became RT-PCR negative at a mean delay of 21.1 ± 8.5 days. Within them, one was negative at Day 7 but was positive again at Day 20, and finally negative on Day 23.
Our study is the first reporting tolerance of treatment with AZI and HCQ prescribed for COVID-19 treatment in haemodialysis patients.
Haemodialysis patients are at high risk of COVID-19: patients meet each other three times a week during several hours, need a medicated shuttle each time and often caregivers nursing at home . Scarpioni et al. described that 16% of their centre had COVID-19 . At the time of this study, 24 (8.8%) out of 270 haemodialysis patients had COVID-19, but the epidemic is still ongoing.
As haemodialysis patients are often aged and comorbid individuals, the COVID-19-associated rate of mortality is high: some units reported a mortality rate up to 41% . In France, on 20 April 2020, the REIN registry described 209 (19.2%) deaths in 1089 patients (https://www.agence-biomedecine.fr/IMG/pdf/bulletin_no4_version1.pdf). Treatments with HCQ and AZI were provided to our patients to try to reduce these very high mortality rates, as these molecules were proposed as a treatment for COVID-19 by experts .
Our main objective was to describe the safety of this treatment, especially the cardiac tolerance in haemodialysis patients with potassium homoeostasis disturbances and cardiac abnormalities. AZI and HCQ are known to elongate QTc. Chorin et al. have reported recently an 11% rate of QTc >500 ms (long QTc syndrome) after treatment with HCQ 200 mg twice daily and AZI In their cohort of 84 non-CKD patients, the maximal average QTc occurred at 3.6 days of treatment, which is the time at which the HCQ concentrations became relatively stable in our cohort. In our population, QTc increased during the whole duration of treatment. Although it is not possible to differentiate the respective role of each of the drugs, this may be more in favour of HCQ being the culprit, as AZI was only prescribed for 5 days.
As in the study from Chorin et al., we performed a daily ECG monitoring, and had no cardiac arrhythmia event. Although HCQ dose was higher in our patients (200 mg TID), we only noticed one long QTc syndrome, which occurred at the seventh day of treatment, raising concerns about tissue accumulation. This effect was not associated with an elevated HCQ concentration and the patient had no hypokalaemia.
The lack of correlation between plasma HCQ concentrations and QTc in our population could be explained by an accumulation of the drug in the whole blood or tissue compartments, which might explain the increase in QTc length observed during the treatment, but we did not determine HCQ concentration in these compartments. A role for AZI in QTc elongation could also be hypothesized.
HCQ plasma concentrations were determined in only 13 out of 21 patients, which is a limit of our study. Since almost no patient had high HCQ plasma concentration and these concentrations were not correlated with QTc length, we believe that HCQ plasma concentration monitoring is not necessary to prevent cardiac toxicity in this population. We rather recommend ECG and potassium monitoring, throughout treatment.
Five patients experienced hypoglycaemia during the treatment. Because of COVID-19, many patients had mild anorexia, ate less and lost weight, which led to lessening of their dry weight during haemodialysis. Poor intakes might have favoured hypoglycaemia, but the occurrence of hypoglycaemia in a patient with no antidiabetic treatment favours a side effect of HCQ. This has already been reported in the diabetic population and even in peritoneal dialysis [25, 26]. HCQ improves insulin sensitivity and reduces insulin degradation . Thus, blood glucose level should be monitored during treatment and anti-diabetic treatment dosing might need to be reduced during the treatment. No patients had a visual complaint, which was not surprising given the very short course of treatment: visual impairment has been described after treatment of several months.
We did not determine HCQ metabolites concentrations, which might accumulate in haemodialysis patients; so far, no HCQ metabolites have been clearly identified and considered as more accurate in order to evaluate the efficacy or toxicity of the drug
Our study was not designed to analyse the efficiency of HCQ and AZI in COVID-19 and we did not have any control group. The effect of HCQ-AZI is based on its ability to avoid membrane–cell fusion, therefore avoiding the entry of the virus into the cell . One can hypothesize that the best effect of the treatment would be obtained if given early after diagnosis. We cannot conclude on the efficacy of HCQ-AZI in this situation, but given these crude data, the treatment could be more efficient if started early. Interestingly, the long delay between diagnosis and COVID-19 cure is in contrast to the substantially shorter delay of 6 days previously described  . This could be related to the different type of population (haemodialysis versus general population) and the immunocompromised status of haemodialysis patients. Haemodialysis patients should thus remain in quarantine longer than the general population.
In conclusion, HCQ 200 mg TID during 10 days associated with AZI during 5 days for COVID-19 treatment in haemodialysis patients was safe. We recommend electrocardiography monitoring because QTc increases during the treatment. Blood glucose should also be monitored because of the risk of hypoglycaemia. HCQ plasma monitoring seems not to be useful since side effects were not associated with HCQ plasma concentrations and HCQ remained within the recommended range.
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