Effectiveness of hydroxychloroquine in COVID-19 disease: A done and dusted deal?

Abstract

Arshad et al. show evidence for reduced mortality in COVID-19 patients taking hydroxychloroquine alone or with azithromycin in an observational study in the USA (Arshad et al., 2020Arshad S. Kigore P. Chaudhry Z.S. Jacobsen G. Wang D.D. Huitsing K. et al.Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalised with COVID-19.Int J Infect Dis. 2020; https://doi.org/10.1016/j.ijid.2020.06.09Crossref PubMed Google Scholar). Data on the effectiveness and toxicity of hydroxychloroquine are controversial (Liu et al., 2020Liu J. Cao R. Xu M. Wang X. Zhang H. Hu H. et al.Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.Cell Discov. 2020; 6: 16Crossref PubMed Scopus (1451) Google Scholar, Devaux et al., 2020Devaux C.A. Rolain J.M. Colson P. Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?.Int J Antimicrob Agents. 2020; (published online March 12)https://doi.org/10.1016/j.antimicag. 2020.105938Crossref Google Scholar, Gautret et al., 2020Gautret F. Lagier J.C. Parola P. Hoang V.T. Meddeb L. Mailhe M. 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)https://doi.org/10.1016/j.antimicag. 2020.105949Crossref PubMed Google Scholar, Tang et al., 2020Tang W. Cao Z. Han M. Wang Z. Chen J. Sun W. et al.Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomised, controlled trial.BMJ. 2020; 369: m1849https://doi.org/10.1136/bmj.m1849Crossref PubMed Scopus (693) Google Scholar, Geleris et al., 2020Geleris J. Sun Y. Platt J. Zucker J. Baldwin M. Hripcsak G. et al.Observational study on hydroxychloroquine in hospitalized patients with COVID-19.N Engl J Med. 2020; 382: 2411-2418https://doi.org/10.1056/NEJMoa2012410Crossref PubMed Scopus (1169) Google Scholar). A total of 539 COVID-19 hospitalized 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 into three groups who started treatment a median of 1 day after admission: those receiving hydroxychloroquine alone (N = 197), those receiving hydroxycholoroquine + azithromycin (N = 94), and those receiving neither (controls) (N = 92). Of the latter group, ten started HIV antivirals (boosted-lopinavir or –darunavir), one teicoplanin, twelve immunomodulatory drugs, or corticosteroids, 23 heparin and 46 remained untreated. The percent of death in the three groups was 27%, 23%, and 51%. Mechanical ventilation was used in 4.3% of hydroxychloroquine, 14.2% of hydroxychloroquine + azithromycin, and 26.1% of controls. Unweighted and weighted relative hazards of mortality are shown in Table 1. After adjusting for several 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 more substantial effectiveness of hydroxychloroquine in patients with less severe COVID-19 disease (PO2/FiO2 > 300, interaction p-value <0.0001). Our results are remarkably similar to those shown by Arshad et al.Table 1Unadjusted and adjusted marginal relative hazards of in-hospital mortalityUnadjusted HR (95% CI)p-ValueAdjusted*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. HR (95% CI)p-ValueAll patientsControl#Heparin, immuno-modulatory drugs, HIV antivirals, combinations of these or no drugs at all. (n = 92)1.001.00Hydroxychloroquine (n = 197)0.43 (0.28, 0.64)<0.0010.66 (0.39, 1.11)0.118Hydroxychloroquine + Azithromycin (n = 94)0.36 (0.21, 0.60)<0.0010.44 (0.24, 0.82)0.009&45 patients missing baseline PO2/FiO2 not included in the stratified analysis.Baseline PO2/FiO2 0-300Control#Heparin, immuno-modulatory drugs, HIV antivirals, combinations of these or no drugs at all. (n = 41)1.001.00Hydroxychloroquine (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<0.001&45 patients missing baseline PO2/FiO2 not included in the stratified analysis.Baseline PO2/FiO2 300+Control#Heparin, immuno-modulatory drugs, HIV antivirals, combinations of these or no drugs at all. (n = 33)1.001.00Hydroxychloroquine (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, combinations of these or no drugs at all.& 45 patients missing baseline PO2/FiO2 not included in the stratified analysis. Open table in a new tab Some important weaknesses in Arshad et al.’s analysis have been pointed out (Lee et al., 2020Lee T.C. MacKenzie L.J. McDonald E.G. Tong S.Y.C. An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (Can’t get no) satisfaction.Int J Infect Dis. 2020; https://doi.org/10.1016/j.ijid.2020.06.095Abstract Full Text Full Text PDF Scopus (18) Google Scholar), 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, cardiovascular 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, which is a conservative bias. These results from two different real-life settings (Italy and USA), conflict with those of two large randomized trials (Horby et al., 2020Horby P. Lim W.S. Emberson J. Mafham M. Bell J.L. Linsell L. et al.Effect of desamethasone in hospitalized patients with CVID-19: preliminary report. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv.2020Google Scholar, World Health Organization, 2020World Health Organization “Solidarity” clinical trial for COVID-19 treatments – update on hydroxychloroquine.2020Google Scholar). Although unmeasured confounding remains the most likely explanation for the discrepancies, a robust meta-analysis is still lacking, and we believe that hydroxychloroquine should be further tested in randomised trials. When best to start treatment is also a question that needs to be addressed in ad-hoc randomized studies. None declared. 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). Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19International Journal of Infectious DiseasesVol. 97PreviewAs of May 27, 2020, there were over 1,678,843 confirmed cases of COVID-19 claiming more than 100,000 lives in the Unites States (CDC, 2020). Currently there is no known effective therapy or vaccine. The urgent need for therapeutic agents has resulted in repurposing and redeployment of experimental agents (McCreary and Pogue, 2020; Sanders et al., 2020). Full-Text PDF Open AccessA sound approach: Hydroxychloroquine reduces mortality in severe COVID-19International Journal of Infectious DiseasesVol. 99PreviewIn response: Full-Text PDF Open Access

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