key: cord-0969161-e5h4tmy6 authors: Lopez, Alexandre; Duclos, Gary; Pastene, Bruno; Bezulier, Karine; Guilhaumou, Romain; Solas, Caroline; Zieleskiewicz, Laurent; Leone, Marc title: Effects of Hydroxychloroquine on Covid-19 in Intensive Care Unit Patients: Preliminary Results date: 2020-08-08 journal: Int J Antimicrob Agents DOI: 10.1016/j.ijantimicag.2020.106136 sha: feeaae797ea2b74a5c1955b242e8dda9d7b962c0 doc_id: 969161 cord_uid: e5h4tmy6 During the Covid-19 pandemic, a large number of intensive care unit (ICU) patients received hydroxychloroquine. The primary objective of our study was to assess the effects of hydroxychloroquine according to its plasma concentration in ICU patients. To this purpose, a single-center retrospective study was performed from March to April 2020 in an ICU of a university hospital. All patients admitted to our ICU with a confirmed Covid-19 pneumonia and treated by hydroxychloroquine were included. We compared 17 patients in whom the hydroxychloroquine plasma concentration was in the therapeutic target (on-target) and 12 patients in whom the plasma concentration was below the target (off-target). The follow-up of patients was 15 days. No association was found between hydroxychloroquine plasma concentration and viral load evolution (p = 0.77). There was no significant difference between the two groups for the duration of mechanical ventilation, length of ICU stay, in-hospital mortality, and 15-days mortality. This finding suggests that hydroxychloroquine administration for Covid-19 patients hospitalized in ICU is not associated with improved outcomes. These results need confirmation by larger multicenter studies. In March 2020, the World Health Organization announced the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak [1] . A large number of patients was admitted to intensive care units (ICUs) for acute 4 respiratory failure in the context of the Covid-19 [2] . The usefulness of antiviral and other drugs used in these patients does not rely on strong evidence. Hydroxychloroquine, a drug mainly used to prevent and treat malaria [3] , stops the viral entering inside the cells by inhibiting glycosylation of host receptors, proteolytic process and endosomal acidification, and has immunomodulatory effects by decreasing the cytokine storm [4] . In vitro, hydroxychloroquine has an antiviral activity for SARS-CoV-2 [5] . Gautret et al. reported that hydroxychloroquine and azithromycin was associated with viral load reduction in nasopharyngeal samples in patients after six days of treatment [6] . However, ICU patients were not included in this study. The Surviving Sepsis Campaign guidelines on the management of Covid-19 patients concluded there was insufficient evidence to recommend the use of antiviral drugs and hydroxychloroquine in ICU patients [7] . In addition, the use of two different dosing regimens of this drug did not affect the outcomes of critically ill patients [8] . Our study aimed to determine the effects of hydroxychloroquine in ICU patients by measuring plasma concentrations of hydroxychloroquine within the therapeutic target (on-target) and comparing them to patients with concentrations below the therapeutic target (off-target). This single-center, retrospective, observational study was performed in ICU at North Hospital of Marseille from 16 th March 2020 to 19 th April 2020. The study was approved by the Committee for Research Ethics of French Society of Anesthesia & Intensive Care Medicine (CERAR no. IRB 00010254 -2020 -059). Patients were informed regarding the use of their data. Strategies were considered standard care; consent was not required. Confirmed Covid-19 patients with acute respiratory failure were included in the study if they completed the criteria: i) age of 18 or older and; ii) polymerase chain reaction (PCR) documented SARS-CoV-2 in nasopharyngeal samples upon ICU admission. The exclusion criteria were patients with a known allergy to hydroxychloroquine; a contraindication to treatment like retinopathy, glucose-6-phosphate dehydrogenase deficiency or QT prolongation; preexisting treatment that might interact with hydroxychloroquine and patients treated by another drug. We identified two groups: i) the patients with hydroxychloroquine plasma concentration above the target concentration range of 0.1 μg/ml and a full treatment ("on-target group") between [5] ; ii) the patients with hydroxychloroquine plasma concentration below the target or treatment discontinuation ("off-target group"). Upon ICU admission, each patient's demographic, clinical and biological data were collected, and the Simplified Acute Physiology Score II (SAPS II) and the Sepsis-related Organ Failure Assessment (SOFA) score were calculated. The Covid-19 features, the onset of disease, and respiratory and systemic symptoms were reported. The use of catecholamines and the duration of mechanical ventilation were also recorded. All patient underwent an electrocardiogram for the detection of QT prolongation. The virus load was determined from nasopharyngeal swab samples collected every 72 hours. Recovery was defined as two consecutive negative nasopharyngeal swab samples [9] . The follow-up for each patient was 15 days. The treatment consisted of an 800-mg loading dose of hydroxychloroquine and maintenance dose of 400 mg for 9 days. Plasma concentration of hydroxychloroquine was measured every 72 hours; to adjust dose; in the Laboratory of Pharmacokinetics and Toxicology (Timone Hospital -Marseille). Analytical method was previously validated according to European Medicine Agency guidelines and was linear in the 0.015 -2.00 μg/ml range [10] . An additional treatment consisted of a 500-mg loading dose of azithromycin and 250-mg maintenance dose and cefotaxime (6g continuous infusion) for 5 days. Early treatment discontinuation and side effects were recorded. The first endpoint was the reduction/disappearance of SARS-CoV-2 in the patient samples at Day 15. The secondary endpoints were the number of days before obtaining a negative PCR, the length of ICU and hospital stays, the length of mechanical ventilation, the use of vasopressor and 15-days mortality. No statistical samples were performed a priori, and sample size was equal to the number of treated patients during the period. The X², Fisher's exact test, t test and Mann Whitney test were used to compare variables between ontarget and off-target groups, as appropriate. For the viral load, the data were analyzed in order to confirm whether or not our first endpoint was reached at Day 15. Statistical significance was defined as p < .05. Analyses were performed using Prism 7 (GraphPad Software, San Diego, CA, USA). From 16 th March to 19 th April 2020, 35 Covid-19 confirmed cases were referred to our ICU, of whom 6 patients were excluded (5 patients received other antiviral drugs and 1 patient had missing data). Finally, 29 patients (17 in the ontarget group and 12 in the off-target group) received hydroxychloroquine and azithromycin according to our protocol ( Figure 1A) . Upon ICU admission, no significant differences in demographic characteristics, severity scores and clinical symptoms were observed between the 2 groups ( Table 1 ). The plasma concentrations of hydroxychloroquine in the 2 groups are shown in Figure 1B . Hydroxychloroquine was discontinued in 75% in the off-target group and 6% of cases in the on-target group (p < 0.001). Side effects, notably cardiac conduction disorders, were reported in 1 (6%) patients in the on-target group and 6 (50%) patients in the offtarget group (p = 0.01). On Day 15 after ICU admission, the nasopharyngeal swab PCR results were negative in 8 (67 %) patients in the off- Table 1 ). The duration of mechanical ventilation and the use of vasopressors were also similar (p = 0.92 and p = 0.95, respectively). No statistical difference was found in the 15-day mortality rate (0 (0%) patient in the ontarget group and 2 (17%) patients in the off-target group, p = 0.16) ( Table 1 ). Our study compared patients in whom the hydroxychloroquine plasma concentration reached the therapeutic target to those in whom it did not. We showed that the viral load at Day 15, viral clearance and the clinical endpoints did not differ significantly between the 2 groups. The benefits of hydroxychloroquine for Covid-19 patients are still debated. Due to potential side effects, its indication should be carefully balanced. In ICU patients, the use of antiviral drugs is also discussed. Oseltamivir, used 7 to treat or prevent influenza, appears to have no benefits for critically ill patients [11] . In our study, the mean duration between symptom onset and treatment initiation was seven days, which probably made this treatment ineffective [12] . In fact, antiviral drugs seem to be effective at the onset of the infection, and their beneficial effects diminish as the disease progresses [11] . In this study, patients in whom hydroxychloroquine did not reach the therapeutic concentration were used as controls. The pharmacokinetics of hydroxychloroquine has been previously described [5] . The clinical and viral courses of the disease were similar regardless of the plasma concentration of hydroxychloroquine, suggesting a low probability of efficacy in these patients [13] . Moreover, an 800-mg bolus dose followed by daily 400-mg dose did not reach a plasma therapeutic concentration in 14 (82 %) patients between Days 4 and 6. Furthermore, we noted a significant number of side effects. These side effects may have been related to the patients' medical histories and comorbidities and to interactions with other drugs [14] . They resulted in a treatment discontinuation in 7 cases and were not associated with plasma concentrations. Our study has several limitations. It is a retrospective series with a small sample without a placebo group. We did not clearly consider the effects of azithromycin, which also prolongs QT interval, as an accompanying factor. Moreover, although the 2 groups were similar in most demographic and clinical variables, undetermined variables may have resulted in differences between them. The negative results of PCR were meaningful, but the comparison of viral load is controversial because of the limitation of the technical problem to collect samples. Finally, we arbitrarily determined that the plasma concentration should reach the therapeutic value between Days 4 and 6, which seems reasonable if an effect is to be expected by Day 15. The choice was based on in vitro data and is debatable [5] . In conclusion, our results showed that there was no association between the plasma concentration of hydroxychloroquine and the viral and clinical evolution of ICU patients admitted for Covid-19. This finding suggests that the use of this drug at this stage of the disease could be not useful. Randomized controlled trials are required to show whether this drug may be useful in ICU patients admitted for Covid-19 [15] . We did not represent patients which were a treatment discontinuation. The viral load (in cycle threshold (Ct) of PCR assay) between on-target group and off-target groups (p = 0.98). WHO Director-General's opening remarks at the media briefing on COVID-19 -11 Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19) 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 Novel coronavirus (SARS-CoV-2) -Discharge criteria for confirmed COVID-19 cases. European Centre for Disease Prevention and Control Bioanalytical method validation Early Oseltamivir After Hospital Admission Is Associated With Shortened Hospitalization: A 5-Year Analysis of Oseltamivir Timing and Clinical Outcomes Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis The authors thank Emmanuelle Hammad, MD; Chatelon Jeanne; MD and Piclet Jules, MD (Department of Anesthesiology and Intensive Care, APHM, Marseille) for participating to patient management.