Early Alterations of QTc in Patients with COVID-19 Treated with Hydroxychloroquine or Chloroquine in Libreville, Gabon

Round 1

Reviewer 1 Report

In present study, authors have presented the results of an observational trial where, they studied the change in QT values of COVID 19 patients in Gabon, who have been treated by hydroxy-chloroquine and chloroquine in combination with Azithromycin for 48 hours. They showed that the increase in QT values is linked with the treatments however the study design of the trial is not very convincing. Different studies have shown that hydroxy-chloroquine, chloroquine treatments and Covid itself is able to increase the QT values. I would like to see what happen to the cases who are covid 19 negative and have been administered HQC or CQ with AZT. The number of sample size is small to clearly confirm the effect of drugs on QT values of COVID patients. I agree with authors that the such data from Sub Sahara African country is not available and I appreciate their efforts for conducting this study in crucial time but I would like to see more focused discussion about how in spite of low sample size, the study suggest that the HCQ and CQ with AZT are the main cause of increased QT values in covid patients and their is no effect of COVID disease itself. Is there any COVID patient population who have not been treated with these drugs? What happened to those who have been treated with these drugs but don't have COVID? Please update the legends in the figure 1. Its hard to read indicators in figure 1. 

Author Response

In present study, authors have presented the results of an observational trial where, they studied the change in QT values of COVID 19 patients in Gabon, who have been treated by hydroxy-chloroquine and chloroquine in combination with Azithromycin for 48 hours. They showed that the increase in QT values is linked with the treatments however the study design of the trial is not very convincing. Different studies have shown that hydroxy-chloroquine, chloroquine treatments and Covid itself is able to increase the QT values.

 I would like to see what happen to the cases who are covid 19 negative and have been administered HQC or CQ with AZT.

Unfortunately, CQ is not widely used in Gabon since more than 20 years. It received an exceptional import licence for its use for COVID-19 treatment. Thus, the group of COVID-19 negative patients treated with CQ could not be constituted. This limit was added into the discussion section. Moreover, HCQ and CQ were the only molecules available during the study time (see line 269).

The number of sample size is small to clearly confirm the effect of drugs on QT values of COVID patients. I agree with authors that the such data from Sub Sahara African country is not available and I appreciate their efforts for conducting this study in crucial time but I would like to see more focused discussion about how in spite of low sample size, the study suggest that the HCQ and CQ with AZT are the main cause of increased QT values in covid patients and their is no effect of COVID disease itself.

We thank the reviewer for this remark. Indeed, some authors showed that cardiac arrythmias in COVID-19 patients with severe or critical disease or with myocardial impact also involve QTc prolongation (Duckheim M, Schreieck J. COVID-19 and Cardiac Arrhythmias. Hamostaseologie. 2021 Oct;41(5):372-378. doi: 10.1055/a-1581-6881); while other found that QTc prolongation is rare during COVID-19 but drugs like HCQ and azithromycin are associated with a significant risk of QTc prolongation in SARS-COv2 infected persons; this risk increases when azithromycin is associated with HCQ (Gumilang RA, Siswanto, Anggraeni VY, Trisnawati I, Budiono E, Hartopo AB. QT interval and repolarization dispersion changes during the administration of hydroxychloroquine/chloroquine with/without azithromycin in early COVID 19 pandemic: A prospective observational study from two academic hospitals in Indonesia. J Arrhythm. 2021 Aug 28;37(5):1184-1195. doi: 10.1002/joa3.12623; Farmakis IT, Minopoulou I, Giannakoulas G, Boutou A. Cardiotoxicity of azithromycin in COVID-19: an overall proportion meta-analysis. Adv Respir Med. 2022 Feb 1. doi: 10.5603/ARM.a2022.0022). And COVID-19 patients were shown to be more susceptible to drug-induced QTc prolongation.

However, the difference observed between HCQ and CQ treated individuals who received azithromycin, suggest a potential effect of both drug, as observed by others. Thus, these drugs would contribute to the QTc modification in treated COVID-19 patients.

Is there any COVID patient population who have not been treated with these drugs? What happened to those who have been treated with these drugs but don't have COVID? Please update the legends in the figure 1. Its hard to read indicators in figure 1. 

Figure 1 has been changed.

Reviewer 2 Report

Dear Authors

The abstract and introduction are well structured, presenting the goal ann main results in a clear manner. In the same way, the limitations of the study are frankly presented,  and assumable, at the end of the discussion.

The Figure 1 is not clear; The chosen graphic style does not help to the interpretation of the results. It not contributing to the undestanding of the reading.

The QT interval was measured upon admission and compared to 48 h of treatment; It would be helpful some paragraph explaining how much time, in general, took between admission and the beginning of the treatment, and if during this time, others treatments (ventilation or not) of viral diseases could interfere withre results.

Author Response

The Figure 1 is not clear; The chosen graphic style does not help to the interpretation of the results. It not contributing to the undestanding of the reading.

Figure 1 has been changed.

The QT interval was measured upon admission and compared to 48 h of treatment; It would be helpful some paragraph explaining how much time, in general, took between admission and the beginning of the treatment, and if during this time, others treatments (ventilation or not) of viral diseases could interfere withre results.

At admission, there were no other antiviral drugs prescribed. The patients were admitted with a positive RT-PCR test and they were put on treatment upon admission (the same day). The QTc was measured before the beginning of the treatment and 48 hours after the first administration of HCQ or CQ.

Reviewer 3 Report

Dear Authors:

I commend your courage to take on this important study.

I have some major comments/suggestions:

Line 39: we are dealing with access (not necessarily availability). Consider changing the word "availability" to "accessibility."

Line 65: Following your inclusion criteria, what were your exclusion criteria?

Line 68: If what you mean as "molecules" are CQ or HCQ, I would suggest you consider changing the word "molecules" to "medications."

Lines 76 - 80: please consider splitting this sentence into two at least. 

Line 84: why were the ECG parameters checked twice? Is it an internal policy/recommendation for quality control? If checked twice, was it by the same personnel or a different person? Please clarify.

Line 98: provide your source please.

Line 110: How come your study participants was 224, when you had mentioned that 72 were excluded from 296 in Lines 106-107? You may want to tell us the final number you analyzed.

Line 180: Do you mean Table 2? If that's it, then consider changing "II" to "2."

Table 2 is not clear. Please re-work this to make it easy to follow by a diverse audience of readers.

Line 225: the names of authors listed here are unnecessary.

Line 229: Can you provide a reference for this statement of fact?

Line 245 - 247: You may want to move these findings to the result section.

Line 259: consider changing the word "dangerous" to "fatal" and please state how the prolonged QTc can pose a threat with due reference/citation.

Line 268: Maybe another limitation could be that it was a single site study limiting its generalizability.

Line 275: what you mean here is that this combination of drugs will lead to QTc prolongation. This negates your findings as not all your patient has this presentation. You may want to rephrase your conclusion to mirror your results.

Author Response

REVIEWER 3 Open Review

Line 39: we are dealing with access (not necessarily availability). Consider changing the word "availability" to "accessibilité.": corrected

Line 65: Following your inclusion criteria, what were your exclusion criteria? : the exclusion criteria were allergy to quinine, known long QT syndrom, history of drug-induced QT prolongation, the presence of an acute phase of another disease, an uninterpretable ECG, refusal to participate

Line 68: If what you mean as "molecules" are CQ or HCQ, I would suggest you consider changing the word "molecules" to "medications." : corrected

Lines 76 - 80: please consider splitting this sentence into two at least: corrected

Line 84: why were the ECG parameters checked twice? Is it an internal policy/recommendation for quality control? If checked twice, was it by the same personnel or a different person? Please clarify. : As a internal procedure, ECG were read by two independent specialist. In case of discrepancy between both, a third reader interpret the ECG and the two closest results were considered.

Line 98: provide your source please: added, reference 14

Line 110: How come your study participants was 224, when you had mentioned that 72 were excluded from 296 in Lines 106-107? You may want to tell us the final number you analysed: added in text; see lines

Line 180: Do you mean Table 2? If that's it, then consider changing "II" to "2." : corrected

Table 2 is not clear. Please re-work this to make it easy to follow by a diverse audience of readers: The table has been corrected

Line 225: the names of authors listed here are unnecessary: the names have been removed

Line 229: Can you provide a reference for this statement of fact?: the reference is  added (Tikkanen JT, Kentta T, Porthan K, Anttonen O, Eranti A, Aro AL, Kerola T, Rissanen HA, Knekt P, Heliövaara M, Holkeri A, Haukilahti A, Niiranen T, Hernesniemi J, Jula A, Nieminen MS, Myerburg RJ, Albert CM, Salomaa V, Huikuri HV, Junttila MJ. The Risk of Sudden Cardiac Death Associated with QRS, QTc and JTc intervals in the General Population Revision #4. Heart Rhythm. 2022 Apr 23:S1547-5271(22)01940-3. doi: 10.1016/j.hrthm.2022.04.016).

Line 245 - 247: You may want to move these findings to the result section: These findings have been moved to result section

Line 259: consider changing the word "dangerous" to "fatal" and please state how the prolonged QTc can pose a threat with due reference/citation.: “dangerous” was changed and a reference on the threat of prolonged QTc was added.

Line 268: Maybe another limitation could be that it was a single site study limiting its generalizability.: included this limitation in text

Line 275: what you mean here is that this combination of drugs will lead to QTc prolongation. This negates your findings as not all your patient has this presentation. You may want to rephrase your conclusion to mirror your results: the conclusion has been reworded

Round 2

Reviewer 3 Report

Line 24: consider adding the word "patients" after "COVID-19"

Line 66-67: spelling of "syndrome", and transition with an "and" between the last two criteria.

Line 74: since you are referring to multiple patients, you may want to change "was" to "were"

Line 235: You mean "others"? Please add an "s" to "other". "some others" may be appropriate here.

Author Response

Dear Reviewer

Thank you for your comments. The corrections on lines 24, 66-67, 74, 235 are performed according to your suggestions. 

Kind regards

Marielle Bouyou