In new letter to the editor-in-chief of the International Journal of Antimicrobial Agents, Dr Lacout, Lounnas and Professor Perronne explain that the dosage and timing of administration of HCQ (hydroxychloroquine) and AZM (azithromycin) in elderly patients are key elements. The authors return with keen interest to the article by Ly et al.Diagram of SARS-CoV-2 infection in dependent elderly people living in retirement homes in Marseille, France, March-June 2020 »published in the International Journal of Antimicrobial Agents [1] .
They don’t do not dispute the conclusion of the study that, despite certain 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, they think it would have been better if the authors had insisted on that the treatment be administered early, well before the stage when mechanical ventilation is needed, and that they have strictly defined dosage HCQ and AZI.
In the cited study, the investigators could have addressed this problem by making a brief comparison in their discussion with other retrospective studies conducted in a group of patients followed in an institution as in the retrospective study by Magagnoli et al., Conducted on American veterans [2].
Veterans study
- In this particular study, where all patients were hospitalized, the adjusted HCQ + AZI Hazard Ratio (HR measure of risk between the treated group and the placebo group) was 1.31 (with a 95% confidence interval CI, 0.80–2.15 p = 0.28), relative to standard of care (SOC), without distinction whether or not the patient received treatment before ventilation mechanical.
- However, raw data indicated 19.2%, 16.2%, and 23.4% mortality in the HCQ, HCQ + AZI, and HCQ-free groups, respectively, in patients who received HCQ treatment prior to mechanical ventilation. (p = 0.28) indicating a possible benefit of HCQ and HCQ + AZI.
- It should be noted that the HCQ and HCQ + AZI groups had more patients with elevated liver enzymes and inflammatory markers as well as higher percentages of O2 saturation less than 94% indicating aggravated disease which were in principle adjusted for use. the propensity score method; it is not clear how the severity of the disease was adjusted.
- After adjustment, the length of hospital stay (presumably before discharge or death, but not specified) was 33% (p = 0.01) longer in the HCQ group and 38% (p = 0.004) longer in the HCQ + AZI group. However, when interpreting these data, it should be borne in mind that, on the one hand, if fewer patients die, the average stay may increase, while, on the other hand, if fewer patients recover, the average stay may also increase.
- In addition, the differences may also indicate that the most severely affected patients were assigned to the treatments and that the adjustment was not made correctly.
Consequently
- Unlike the study by Magagnoli et al., The nursing home patients of the study by Ly et al. have not been hospitalized and therefore received treatment earlier, at the start of the viral infection phase, which is consistent with better treatment efficiency. 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 possible cardiac side effects.
- The analysis of the study by Magagnoli et al. reveals that the benefit of treatment is statistically masked by the heterogeneity of the initiation of treatment (sometimes initiated after the start of mechanical ventilation) and by an uncontrolled dosage of HCQ and HCQ + AZI left to the discretion of the physician. The median dose of HCQ / day was 400 mg and 25% of treated patients received more than 480 mg / day. The maximum dose is not disclosed, but the text of Magagnoli’s article indirectly suggests HCQ overdose. Ly et al. could have indicated that these problems constitute a marked bias in the adjusted HR calculated in the study by Magagnoli which was unfortunately later included in the meta-analysis by Fiolet et al which highlighted the ineffectiveness and toxicity of HCQ + AZI [3] .
- Further evidence for the need to administer an appropriate dosage comes from the trial of Borba et al. [4] (who delivered the highest dose and reported 16 toxic deaths in 41 patients) and the large multi-center UK Recovery trial [5] , who administered the second highest dose (4 g of HCQ in the first 3 days)) and reported a relative increase in mortality of 9% in the HCQ arm compared to SOC.
Dosage is key
- In vitro studies show that the effect of HCQ is primarily mediated by alkalinization of the phagolysosome where it can concentrate thousands of times more than in plasma. This effect can be achieved 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 obtained using low or moderate (and non-toxic) doses. [6] . High doses of HCQ can be toxic at an early stage (before the cytokine storm) or even deleterious due to the anti-interferon HCQ action (via inhibition of TLR7 / 9 activators of plasmacytoid dendritic cells (pDCs) for produce massive quantities of type I IFN) [7].
- Overproduction of cytokines, however, can lead to more severe forms of the disease. [8] . An interferon deficiency can thus predispose to severe forms, which could also explain the negative results of the Recovery study and conversely the positive results of Ly et al.
And the administration timing too
Indeed, antiviral therapy is only useful during the early and middle viral phase when the virus is present and replicates, and is of no use during the late inflammatory phase (cytokine storm). Most therapeutic trials, unfortunately, have been carried out in hospitalized patients, which is to say probably often too late, because the patients are in the early inflammatory phase.
Assuming that treatment must be given early, reinforces the result of Ly et al. The authors pointed out that it is not always easy to detect the onset of symptoms in elderly patients. Patients diagnosed on a case-by-case basis, and already showing symptoms, had a higher risk of dying (40.6%) compared to those diagnosed “systematically” (16.9%) by PCR.
The study by Ly et al. shows a clear benefit of HCQ plus AZI treatment in particularly vulnerable and fragile patients.
Given the circumstances, this treatment should be urgently proposed as the primary endpoint in a prospective observational study. In addition, given the safety of HCQ when its administration is properly monitored and its likely benefit in moderate doses, the issue of low dose prophylactic therapy under medical supervision could also be considered.
To conclude, Professor Perronne, Dr Lacout and Dr Lounnas do not declare any link or conflict of interest.
–
