Covid-19 – Le feuilleton du printemps… Hydroxychloroquine or not?

Rétrospective (non exhaustive !) -> morceaux choisis ; certains pré-print cités ici ont été depuis publiés et certains articles publiés ont été retirés !

696 publications référencées dans PubMed liées au terme « Hydroxychloroquine » en 2020 !

En résumé …

« Un jour c’est oui, un jour c’est non, un jour c’est d’accord, un jour c’est non pas question… »

09 mars 2020

Yao X, Ye F, Zhang M, et al. 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) [published online ahead of print, 2020 Mar 9]. Clin Infect Dis. 2020;ciaa237.

Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.”

19 mars 2020

Mitjà O, Clotet B. Use of antiviral drugs to reduce COVID-19 transmission. Lancet Glob Health. 2020;8(5):e639‐e640. doi:10.1016/S2214-109X(20)30114-5

“HCQ shows antiviral activity in vitro against coronaviruses, and specifically, SARS-CoV-2. Pharmacological modelling based on observed drug concentrations and in vitro drug testing suggest that prophylaxis with HCQ at approved doses could prevent SARS-CoV-2 infection and ameliorate viral shedding. Clinical trials of hydroxychloroquine treatment for COVID-19 pneumonia are underway in China (NCT04261517 and NCT04307693). We are reviewing the results from China as they emerge. The first study (NCT04261517) has showed positive preliminary outcomes (albeit not conclusive because of the small sample size) in terms of clinical management.”

17 mars 2020

Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID19: results of an openlabel nonrandomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949

20 mars 2020

Hydroxychloroquine, le traitement de toutes les attentes

27 mars 2020

Pre-print Version 1 du 27/03/2020 : “Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study” Philippe Gautret et al.,

30 mars 2020

3 avril 2020

The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine /Azithromycin. Chorin et al., April 3, 2020, MedRxiv

9 avril 2020

10 avril 2020

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study. Lane et al., April 10, 2020. MedRXiV doi:
“Short-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.”

14 avril 2020

>>>> No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. Mahevas et al., MedRxiv, April 14, 2020.

“No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement.”

>>>> Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial.Tang et al., April 14, 2020.
MedRXiV doi:
“The administration of HCQ did not result in a higher negative conversion rate but more alleviation of clinical symptoms than SOC alone in patients hospitalized with COVID-19 without receiving antiviral treatment, possibly through anti-inflammatory effects. Adverse events were significantly increased in HCQ recipients but no apparently increase of serious adverse events.”

21 avril 2020

Le point sur l’hydroxychloroquine dans le traitement du COVID-19. Philippe Casassus, Revue Virologie, 21/04/2020.

“L’étude des 74 articles citant COVID et hydroxychloroquine dans PubMed a fait sélectionner 33 articles pertinents sur la question et suffisamment documentés, parus entre le 20 mars et le 17 avril 2020 pour faire le point des travaux actuellement publiés concernant cette option thérapeutique. […] L’avis général de la quasi-totalité des publications actuelles est qu’il est indispensable et urgent de pouvoir bénéficier des résultats de larges études comparatives méthodologiquement non critiquables pour envisager de recommander un traitement spécifique dans le COVID-19, même s’il est reconnu à l’HCQ un effet antiviral in vitro et quelques effets encourageants, cliniques ou radiologiques, les travaux préliminaires de l’équipe de D. Raoult, notamment, ne remplissant pas ces conditions. […] Au moment où se termine cette synthèse, près de 700 études cliniques concernant le COVID-19 sont enregistrées dans le monde […] : l’espoir est permis…”

25 avril 2020

Andreani J, Le Bideau M, Duflot I, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect [published online ahead of print, 2020 Apr 25]. Microb Pathog. 2020;145:104228. doi:10.1016/j.micpath.2020.104228

“Human coronaviruses SARS-CoV-2 appeared at the end of 2019 and led to a pandemic with high morbidity and mortality. As there are currently no effective drugs targeting this virus, drug repurposing represents a short-term strategy to treat millions of infected patients at low costs. Hydroxychloroquine showed an antiviral effect in vitro. In vivo it showed efficacy, especially when combined with azithromycin in a preliminary clinical trial. Here we demonstrate that the combination of hydroxychloroquine and azithromycin has a synergistic effect in vitro on SARS-CoV-2 at concentrations compatible with that obtained in human lung.”

5 mai 2020

Million M, Lagier JC, Gautret P, et al. Full-length title: Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France [published online ahead of print, 2020 May 5]. Travel Med Infect Dis. 2020;101738.

“A total of 1061 patients were included in this analysis (46.4% male, mean age 43.6 years – range 14-95 years). Good clinical outcome and virological cure were obtained in 973 patients within 10 days (91.7%). Prolonged viral carriage was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis (p < .001) but viral culture was negative at day 10. […] Administration of the HCQ+AZ combination before COVID-19 complications occur is safe and associated with very low fatality rate in patients.”

7 mai 2020

Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 [published online ahead of print, 2020 May 7]. N Engl J Med. 2020;10.1056/NEJMoa2012410. doi:10.1056/NEJMoa2012410

“In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed.”

8 mai 2020

Grassin-Delyle S, Salvator H, Brollo M, et al. Chloroquine inhibits the release of inflammatory cytokines by human lung explants [published online ahead of print, 2020 May 8]. Clin Infect Dis. 2020;ciaa546. doi:10.1093/cid/ciaa546

“On human lung parenchymal explants, chloroquine concentration clinically achievable in the lung (100 μM) inhibited the lipopolysaccharide-induced release of TNF-α (by 76%), IL-6 (by 68%), CCL2 (by 72%) and CCL3 (by 67%). Beside its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses.”

22 mai 2020

>>>> Funck-Brentano C, Salem JE. Chloroquine or hydroxychloroquine for COVID-19: why might they be hazardous? [published online ahead of print, 2020May 22]. Lancet. 2020;S0140-6736(20)31174-0. doi:10.1016/S0140-6736(20)31174-0“The findings from Mehra and colleagues’ study add to preliminary reports suggesting that regimens of chloroquine or hydroxychloroquine, alone or with azithromycin, are not useful and could be harmful in hospitalised patients with COVID-19.”
“Despite limitations inherent to the observational nature of this study, Mehra and colleagues should be commended for providing results from a well designed and controlled study of the effects of chloroquine or hydroxychloroquine, with or without a macrolide, in a very large sample of hospitalised patients with COVID-19.”

>>>> Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis [published online ahead of print, 2020 May 22]. Lancet. 2020;S0140-6736(20)31180-6. doi:10.1016/S0140-6736(20)31180-6

– Multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19.
– The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2.
“96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. »
“We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.”

23 mai 2020

25 mai 2020

26 mai 2020

28 mai 2020

Chatterjee P, Anand T, Singh KJ, Rasaily R, Singh R, Das S, Singh H, Praharaj I, Gangakhedkar RR, Bhargava B, Panda S. Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19. Indian J Med Res [Epub ahead of print] [cited 2020 Jun 5].

“Until results of clinical trials for HCQ prophylaxis become available, this study provides actionable information for policymakers to protect HCWs at the forefront of COVID-19 response. The public health message of sustained intake of HCQ prophylaxis as well as appropriate personal protective equipment use need to be considered in conjunction with risk homoeostasis operating at individual levels.”

29 mai 2020

3 juin 2020

>>>> EDITORIAL: Hydroxychloroquine for the Prevention of Covid-19 — Searching for Evidence. Myron S. Cohen, NEJM, June 3, 2020 DOI: 10.1056/NEJMe2020388

>>>> A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. David R. Boulware et al., NEJM, June 3, 2020, DOI: 10.1056/NEJMoa2016638

“This randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for Covid-19. Whether preexposure prophylaxis would be effective in high-risk populations is a separate question, with trials ongoing. In order to end the pandemic, a reduction in community transmission is needed.”

4 juin 2020

5 juin 2020

Arrêt de l’essai clinique RECOVERY avec HCQ

« On Thursday 4 June, in response to a request from the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the independent Data Monitoring Committee conducted a further review of the data. Last night, the Committee recommended the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial.
We have concluded that there is no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19. We have therefore decided to stop enrolling participants to the hydroxychloroquine arm of the RECOVERY Trial with immediate effect. We are now releasing the preliminary results as they have important implications for patient care and public health.
A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes.
These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19. Full results will be made available as soon as possible.

19 juin 2020

Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France. Sbidian et al., MedRXiV, preprint. Posted June 19, 2020.doi:

“Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials.”

24 juin 2020

Nimgampalle M, Devanathan V, Saxena A. Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets [published online ahead of print, 2020 Jun 24]. J Biomol Struct Dyn. 2020;1-13.

“We have conducted molecular docking and related studies between Chloroquine and its derivatives and SARS-CoV-2 viral proteins, and the findings show that both Chloroquine and Hydroxychloroquine can bind to specific structural and non-structural proteins implicated in the pathogenesis of SARS-CoV-2 infection with different efficiencies. Our current study also shows that some of the chemically synthesized Chloroquine derivatives can also potentially inhibit various SARS-CoV-2 viral proteins by binding to them and concomitantly effectively disrupting the active site of these proteins. These findings bring into light another possible mechanism of action of Chloroquine and Hydroxychloroquine and also pave the way for further drug repurposing and remodeling.”

25 juin 2020

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Lagier et al., Travel Medicine and Infectious Disease.Available online 25 June 2020.

“We retrospectively report the clinical management of 3,737 screened patients, including 3,119 (83.5%) treated with HCQ-AZ (200 mg of oral HCQ, three times daily for ten days and 500 mg of oral AZ on day 1 followed by 250 mg daily for the next four days, respectively) for at least three days and 618 (16.5%) patients treated with other regimen (“others”). Outcomes were death, transfer to the intensive care unit (ICU), ≥10 days of hospitalization and viral shedding. […] Although this is a retrospective analysis, results suggest that early diagnosis, early isolation and early treatment of COVID-19 patients, with at least 3 days of HCQ-AZ lead to a significantly better clinical outcome and a faster viral load reduction than other treatments.”

29 juin 2020

Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection. Ferreira et al. MedRxiV, preprint (not peer-reviewed). Posted June 29, 2020.

“We have detected all laboratory confirmed cases of SARS-CoV-2 infection and all laboratory confirmed negative cases in the Portuguese population (mandatorily registered in a centrally managed database). Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases of SARS-CoV-2 infection with laboratory confirmed negative cases. Results: Out of 26,815 SARS-CoV-2 positive patients, 77 (0.29%) were chronically treated with HCQ, while 1,215 (0.36%) out of 333,489 negative patients were receiving it chronically (P=0.04). After adjustment for age, sex, and chronic treatment with corticosteroids and/or immunosuppressants, the odds ratio of SARS-CoV-2 infection for chronic treatment with HCQ has been 0.51 (0.37-0.70). Conclusions: Our data suggest that chronic treatment with HCQ confer protection against SARS-CoV-2 infection.”

A suivre …