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

Open AccessPublished:July 29, 2020DOI:https://doi.org/10.1016/j.ijid.2020.07.056
      Dear Sir,
      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 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.
      ). Data on the effectiveness and toxicity of hydroxychloroquine are controversial (
      • Liu 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.
      ,
      • Devaux 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?.
      ,
      • Gautret 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.
      ,
      • Tang 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.
      ,
      • Geleris J.
      • Sun Y.
      • Platt J.
      • Zucker J.
      • Baldwin M.
      • Hripcsak G.
      • et al.
      Observational study on hydroxychloroquine in hospitalized patients with COVID-19.
      ).
      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 mortality
      Unadjusted 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-Value
      All patients
      Control
      Heparin, immuno-modulatory drugs, HIV antivirals, combinations of these or no drugs at all.
      (n = 92)
      1.001.00
      Hydroxychloroquine (n = 197)0.43 (0.28, 0.64)<0.0010.66 (0.39, 1.11)0.118
      Hydroxychloroquine + 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 0-300
      Control
      Heparin, immuno-modulatory drugs, HIV antivirals, combinations of these or no drugs at all.
      (n = 41)
      1.001.00
      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
      <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)
      1.001.00
      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, combinations of these or no drugs at all.
      & 45 patients missing baseline PO2/FiO2 not included in the stratified analysis.
      Some important weaknesses in Arshad et al.’s analysis have been pointed out (
      • Lee 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.
      ), 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 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.
      ,
      • World Health Organization
      “Solidarity” clinical trial for COVID-19 treatments – update on hydroxychloroquine.
      ). 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.

      Declarations of interest

      None declared.

      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).

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