Bai, F

Cozzi-Lepri, A

D'Arminio Monforte, A

Marchetti, G

Tavelli, A

English

UCL Discovery

Journal Pre-proofEffectiveness of Hydroxychloroquine in COVID-19 disease: A done anddusted situation?Antonella d’Arminio Monforte, Alessandro Tavelli, Francesca Bai,Giulia MarchettiPII: S1201-9712(20)30600-7DOI: https://doi.org/10.1016/j.ijid.2020.07.056Reference: IJID 4468To appear in: International Journal of Infectious DiseasesAlessandro Cozzi-LepriPII: S1201-9712(20)30600-7DOI: https://doi.org/10.1016/j.ijid.2020.07.056Reference: IJID 4468To appear in: International Journal of Infectious DiseasesReceived Date: 10 July 2020Please cite this article as: {doi: https://doi.org/This is a PDF file of an article that has undergone enhancements after acceptance, such asthe addition of a cover page and metadata, and formatting for readability, but it is not yet thedefinitive version of record. This version will undergo additional copyediting, typesetting andreview before it is published in its final form, but we are providing this version to give earlyvisibility of the article. Please note that, during the production process, errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journalpertain.© 2020 Published by Elsevier.Effectiveness of Hydroxychloroquine in COVID-19 disease: a done and dusted situation?   Antonella d’Arminio Monforte1, Alessandro Tavelli1, Francesca Bai1, Giulia Marchetti1, Alessandro Cozzi-Lepri2 1 Clinic of Infectious Diseases, Department of Health Science, ASST Santi Paolo e Carlo, University of Milan, Italy 2 Centre for Clinical Research, Epidemiology, Modelling and Evaluation, Institute for Global Health, University College London, London, UK  Correspondence to: Antonella d’Arminio Monforte Institute of Infectious and Tropical Diseases Department of Health Sciences ASST Santi Paolo e Carlo University of Milan, Italy Via A. di Rudinì, 8 20142 Milan Italy Email: antonella.darminio@unimi.it Tel: +39 0281843045     Journal Pre-proofKeywords: COVID-19, SARS-CoV-2, hydroxychloroquine, observational study  Dear Sir, Arshad et al show evidence for a reduced mortality in Covid-19 patients taking hydroxychloroquine alone or with azithromycin in an observational study in USA [1].  Data on effectiveness and toxicity of hydroxychloroquine are controversial  [2-6].   A total of 539 COVID-19 hospitalised patients were included in our cohort in Milan, from February 24 to May 17,2020 of whom 174 died in hospital (day 14 probability of death: 29.5% - 95%CI: 25.5-34.0). We divided a subset of our cohort in three groups who started treatment a median of 1 day after admission: those receiving hydroxycholoroquine alone (N=197), those receiving hydroxycholoroquine+azithromycin (N=94), and those receiving neither (controls) (N=92). Of the latter group, 10 started HIV antivirals (boosted-lopinavir or –darunavir), 1 teicoplanin, 12 immunomodulatory drugs or corticosteroids, 23 heparin and 46 remained untreated. The percent of death in the 3 groups was 27%, 23% and 51%. Mechanical ventilation was used in 4.3% of hydoxychloroquine, 14.2% of hydroxycholoroquine+azithromycin and 26.1% of controls. Unweighted and weighted relative hazards of mortality are shown in Table 1. After adjusting for a number of key confounders (see table), the use of hydroxycholoroquine+azithromycin was associated with a 66% reduction in risk of death as compared to controls; the analysis also suggested a larger effectiveness of hydroxychloroquine in patients with less severe COVID-19 disease (PO2/FiO2>300, interaction p-value<.0001).  Our results are remarkably similar to those shown by Arshad et al.  Some important weaknesses of the analysis by Arshad have been pointed out [7] but not all of these apply to our study. Our propensity scores include some of the potential confounders that were missing in the analysis by Arshad (e.g. calendar day of admission, disease severity, cardio-vascular disease (CVD), baseline plasma CRP); second, we have excluded people receiving other drugs which could have biased the effect of hydroxychloroquine when used in combination. Third, although residual confounding is a possibility (e.g. people with CVD were more frequent in control), people in the control group were more likely to undergo mechanical ventilation that is a conservative bias. These results from two different real-life settings (Italy and USA), are conflicting with those of two large randomised trials [8, 9]. Although unmeasured confounding remains the most likely explanation for the discrepancies, a robust meta-analysis is still lacking and we question whether hydroxychloroquine should be further tested.  When best to start treatment is also a question that needs to be addressed in ad-hoc randomised studies.    Jonal Pre-profTable 1- Unadjusted and adjusted marginal relative hazards of in-hospital mortality    Unadjusted HR (95% CI) p-value Adjusted*£ HR (95% CI) p-value   All Patients Control# (n=92) 1.00   1.00   Hydroxychloroquine (n=197) 0.43 (0.28, 0.64) <.001 0.66 (0.39, 1.11) 0.118 Hydroxychloroquine +Azithromycin (n=94) 0.36 (0.21, 0.60) <.001 0.44 (0.24, 0.82) 0.009   &Baseline PO2/FiO2 0-300 Control# (n=41) 1.00   1.00   Hydroxychloroquine (n=83) 0.52 (0.31, 0.87)   0.71 (0.37, 1.35)   Hydroxychloroquine +Azithromycin (n=28) 0.46 (0.23, 0.93)   0.59 (0.26, 1.35)           p-value for interaction         <.001   &Baseline PO2/FiO2 300+ Control# (n=33) 1.00   1.00   Hydroxychloroquine (n=100) 0.39 (0.15, 0.97)   0.49 (0.15, 1.63)   Hydroxychloroquine +Azithromycin (n=60) 0.56 (0.21, 1.52)   0.62 (0.19, 1.97)   *adjusted for age, gender, number of comorbidities,CVD (yes/no), duration of symptoms, date of admission, CRP and censoring using IPW £the overall estimate was also adjusted for baseline COVID-19 disease severity #Heparin, immuno-modulatory drugs, HIV antivirals, a combinations of these or no drugs at all & 45 patients missing baseline PO2/FiO2 not included in the stratified analysis    Declarations of interest: none Funding: none   Ethical Approval:  This analysis is part of the study approved by Ethic Committee Area 1, Milan Italy (2020/ST/049 and 2020/ST/049_BIS, 11/03/2020).   Journal Pre-proofReferences  1- Arshad S, Kigore P, Chaudhry ZS et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalised with COVID-19. Int J Infect Dis 2020; http://doi.org/10.1016/j.ijid.2020.06.09 2- Liu J, Cao R, Xu M et al. Hydroxycholoroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6:16. 3- Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what tp expect for COVID-19? Int J Antimicrob Agents 2020; published online March 12, DOI 10.1016/j.antimicag. 2020.105938. 4-  Gautret F, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomised clinical trial. Int J Antimicrob Agents 2020; published online March 12, DOI 10.1016/j.antimicag. 2020.105949. 5- Tang W, Cao Z, Han M et al. Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomised, controlled trial. BMJ 2020; 369:m1849. DOI: 10.1136/bmj.m1849. 6- Geleris J, Sun Y, Playy J et al. Observational study on hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020; 2020;382:2411-8. DOI: 10.1056/NEJMoa2012410 7- Lee TC, MacKenzie LJ, McDonald EG, Tong SYC: An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (Can’t get no) satisfaction. Int J Infect Dis 2020; http://doi.org/10.1016/j.ijid.2020.06.095 8- Horby P, Lim WS, Emberson J et al: Effect of desamethasone in hospitalized patients with CVID-19: preliminary report. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv 9- World Health Organization. "Solidarity” clinical trial for COVID-19 treatments - Update on Hydroxychloroquine; 2020. Available from: https://www.who.int/emergencies/diseases/novelcoronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-forcovid-19-treatments [Accessed June 21 2020].   Journal Pr-proof

Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?

https://discovery.ucl.ac.uk/10107180/3/Cozzi-Lepri_1-s2.0-S1201971220306007-main.pdf

Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?

Abstract

Similar works

Full text

Available Versions

UCL Discovery