key: cord-0836245-j7car9pp
authors: LACOUT, Dr Alexis; LOUNNAS, Dr VALERE; PERRONNE, Pr Christian
title: Timing and dosage may be the key in the realization of hydroxychloroquine + azithromycin treatment benefit in Covid-19 elderly patients
date: 2021-03-17
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2021.106314
sha: 43ec5c3f8720e1a03e9e4bafecc7512bcb88b945
doc_id: 836245
cord_uid: j7car9pp

nan

We do not dispute the conclusion of the study that, despite some limitations, it shows a 50% reduction in mortality in COVID-19 patients treated with hydroxychloroquine (HCQ) + azithromycin (AZI) for at least 3 days as part of a well-defined treatment strategy.

However, we believe that it would have been preferable that the authors had insisted on treatment being delivered early, long before the stage when mechanical ventilation is needed, and that they had strictly defined the HCQ and AZI dosage. We believe that they could have addressed this by conducting a short comparison in their discussion with other retrospective studies conducted in an institutionally followed group of patients such as in the retrospective study by Magagnoli et al., conducted on US veterans (2) . In that particular study, where all patients were hospitalized, the HCQ+AZI adjusted Hazard Ratio (HR) was 1.31; 95% CI, 0.80-2.15; p = 0.28, compared with standard of care (SOC), with no distinction on whether or not patient had received treatment before mechanical ventilation. However, raw data indicated a mortality of 19.2%, 16.2%, and 23.4% in the HCQ, HCQ+AZI, and no HCQ groups, respectively, in patients who received HCQ treatment before mechanical ventilation (p = 0.28) indicating a possible benefit of HCQ and HCQ + AZI. Of note, the HCQ and HCQ+AZI groups had more patients with elevated hepatic enzymes and inflammatory markers as well as higher percentages of O2 saturation below 94% indicating an aggravated disease condition that were in principle adjusted for using the propensity score method; it is not clearly indicated how disease severity was adjusted for. After adjustment, the length of hospital stay (presumably before discharge or death, but this is not specified) was 33% (p = 0.01) longer in the HCQ group and 38% (p = 0.004) longer in the HCQ+AZI group. However, in interpreting these data it needs to be borne in mind that on one handif fewer patients die the mean stay may increase, whereas on the other hand if fewer patients recover the mean stay may increase as well. Moreover, the differences may also indicate that more severely affected patients were allocated to treatments and that adjustment was not properly carried out.

Contrary to the study of Magagnoli et al., the retirement-home patients in the study of Ly et al. were not hospitalized and, therefore received treatment earlier, at the beginning of the viral infection phase, which is consistent with a better treatment efficacy. The treatment was well established (HCQ 200 mg three times daily for ten days and AZI 500 mg on day 1 followed by 250 mg daily for the next four days for at least three days) and patients were monitored for potential cardiac sideeffects. In vitro studies show that the effect of HCQ is mainly mediated by alkalinization of the phagolysosome where it can concentrate thousands times more than in plasma. This effect can be obtained with low doses of HCQ due to its long elimination half-life (30-50 days). Small doses may be more adequate to achieve antiviral action. Indeed, due to the high concentration of HCQ in the endosomes, the antiviral effect could be achieved using small or moderate (and non-toxic) doses (6) . High doses of HCQ may be toxic at an early stage (before the cytokine storm) or even deleterious due to HCQ anti-interferon action (via inhibition of TLR7/9 activators of the plasmacytoid dendritic cells (pDCs) to produce massive quantities of type I IFN) (7) .

Overproduction of cytokines may be however that may result in more severe forms of the disease (8) . Interferon deficiency may thus predispose to severe forms, which could also explain the probably often too late, as the patients are in the early inflammatory phase.

Assuming that treatment has to be given early, strengthens the result of Ly et al. The authors pointed out that it is not always easy to detect the appearance of symptoms in elderly patients. Patients diagnosed on a case-by-case basis, and already presenting with symptoms, had a higher chance of dying (40.6%) compared to those diagnosed "systematically" (16.9%) by PCR.

The study of Ly et al. shows a clear benefit of the HCQ plus AZI treatment in particularly vulnerable and frail patients. Given the circumstances, this treatment should be urgently proposed as the primary endpoint in a prospective observational study. Furthermore, given the safety of HCQ when its administration is properly monitored and its likely benefit at moderate doses, the question of medically supervised prophylactic low dose treatment might also be considered.

Pattern of SARS-CoV-2 infection among dependant elderly residents living in long-term care facilities

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19

Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and metaanalysis

Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection: a randomized clinical trial

Effect of hydroxychloroquine in hospitalized patients with Covid-19

The pharmacokinetic and pharmacodynamic properties of hydroxychloroquine and dose selection for COVID-19: putting the cart before the horse

Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine. Front Immunol

Hydroxychloroquine in Hospitalized Patients with Covid-19

Ethical Approval: Not required