Re: effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: author's response

  • Thibault Fiolet
    Correspondence
    Corresponding author. Thibault Fiolet, Center for Research in Epidemiology and Population Health Inserm U1018 “Health across Generations” Team and Paris-Sud 11 University/Paris-Saclay University, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
    Affiliations
    CESP (Center for Research in Epidemiology and Population Health), Fac. de Médecine - Univ. Paris-Sud, Fac. de Médecine - UVSQ, INSERM, Université Paris Saclay, Villejuif, France

    Gustave Roussy, Villejuif, France
    Search for articles by this author
  • Anthony Guihur
    Affiliations
    Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, Switzerland
    Search for articles by this author
  • Mathieu Edouard Rebeaud
    Affiliations
    Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, Switzerland
    Search for articles by this author
  • Matthieu Mulot
    Affiliations
    Laboratory of Soil Biodiversity, Faculty of Science, University of Neuchâtel, Switzerland
    Search for articles by this author
  • Nathan Peiffer-Smadja
    Affiliations
    Université de Paris, IAME, INSERM, Paris, France

    National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, London, UK

    Infectious and Tropical Diseases Department, Bichat-Claude Bernard Hospital, AP-HP, Paris, France
    Search for articles by this author
  • Yahya Mahamat-Saleh
    Affiliations
    CESP (Center for Research in Epidemiology and Population Health), Fac. de Médecine - Univ. Paris-Sud, Fac. de Médecine - UVSQ, INSERM, Université Paris Saclay, Villejuif, France

    Gustave Roussy, Villejuif, France
    Search for articles by this author
Published:November 06, 2020DOI:https://doi.org/10.1016/j.cmi.2020.10.031
      To the editor,
      We would like to explain several points raised by Védrines et al.
      • 1.
        We agree that Geleris et al. used a composite endpoint [
        • Geleris J.
        • Sun Y.
        • Platt J.
        • Zucker J.
        • Baldwin M.
        • Hripcsak G.
        • et al.
        Observational study of hydroxychloroquine in hospitalized patients with covid-19.
        ]. However, (a) intubation is a main prognostic factor for death, (b) exclusion of this study from the pooled RR estimation did not change our conclusion (see Table S4) and (c) Geleris et al. did not report adjusted hazard ratio (HRa) for death only.
      In our main analysis, we used this adjusted HR which takes into account indication bias (following the Cochrane recommendation [
      ]). Crude relative risk (RR) for death only may be estimated from the data reported in Geleris et al.: with 157 deaths among the hydroxychloroquine group (n = 811) and 75 deaths among the control group (n = 565), the new estimated RR is even higher: 1.45 (95% CI 1.13–1.87).
      • 2.
        Magagnoli et al. used a specific Cox model adapted for length-biased data on the overall population (n = 807) [
        • Magagnoli J.
        • Narendran S.
        • Pereira F.
        • Cummings T.H.
        • Hardin J.W.
        • Sutton S.S.
        • et al.
        Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19.
        ,
        • Qin J.
        • Shen Y.
        Statistical methods for analyzing right-censored length-biased data under cox model.
        ]. The subanalysis among patients who were admitted during the first 4 weeks of study, discussed by Védrines et al. represents half of the initial cohort: that is why we used the HR reported in their main analysis.
      Using the HR from the subgroup cohort and the new HR for Geleris et al. leads to similar results with the pooled RR = 0.82 (95% CI 0.64–1.04) for hydroxychloroquine (HCQ) (Fig. S1) and RR = 1.23 (95% CI 1–1.53) for HCQ + azithromycin (AZI) (Fig. S2), indicating no benefit from HCQ with or without AZI. We thank Védrines et al. for leaving us the opportunity to illustrate again the robustness of our conclusion.
      • 3.
        The point concerning Rivera et al. was already answered [
        • Fiolet T.
        • Guihur A.
        • Rebeaud M.E.
        • Mulot M.
        • Peiffer-Smadja N.
        • Mahamat-Saleh Y.
        “Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients” – author’s reply.
        ]. We note that this is the second letter from Dr Lacout, which is quite uncommon for the same study.
      • 4.
        The Arshad et al. study was excluded from our main analysis because of numerous critical biases described in our supplementary materials and in two letters and one editorial [
        • Arshad S.
        • Kilgore P.
        • Chaudhry Z.S.
        • Jacobsen G.
        • Wang D.D.
        • Huitsing K.
        • et al.
        Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
        ,
        • Malviya A.
        The continued dilemma about the usage of hydroxychloroquine: respite is in randomized control trials.
        ,
        • 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.
        ,
        • Varisco T.J.
        • Johnson M.L.
        • Thornton D.
        Comment on Arshad et al.: treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
        ].
      Briefly, this study suffers from immortal time bias and residual confounding, and it is not possible to know if the observed risk reduction is due to hydroxychloroquine or corticosteroids use. Finally, Védrines et al. may be interested by the sensitivity analysis including studies at risk of critical bias, which was provided in our Table S6 [
      • Fiolet T.
      • Guihur A.
      • Rebeaud M.E.
      • Mulot M.
      • Peiffer-Smadja N.
      • Mahamat-Saleh Y.
      Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.
      ].
      • 5.
        The statement that we misrepresented four original works is fallacious.
      Nevertheless, we agree with Védrines et al. on one point: even if we carefully evaluated all studies of our systematic review following the Cochrane Review methods, and reported all results according to PRISMA guidelines, observational studies are not the reference standard for therapeutic evaluation. Since our work was published, several other randomized controlled trials have become available. Overall, the RECOVERY trial, the SOLIDARITY trial and recent meta-analyses confirmed our conclusion [
      • Fiolet T.
      • Guihur A.
      • Rebeaud M.E.
      • Mulot M.
      • Peiffer-Smadja N.
      • Mahamat-Saleh Y.
      Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.
      ,
      The RECOVERY Collaborative Group
      Effect of hydroxychloroquine in hospitalized patients with Covid-19.
      ,
      WHO Solidarity trial consortium. Repurposed antiviral drugs for COVID-19–interim WHO SOLIDARITY trial results.
      ,
      • Juul S.
      • Nielsen E.E.
      • Feinberg J.
      • Siddiqui F.
      • Jørgensen C.K.
      • Barot E.
      • et al.
      Interventions for treatment of COVID-19: a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).
      ,
      • Axfors C.
      • Schmitt A.M.
      • Janiaud P.
      • J van ’t Hooft
      • Abd-Elsalam S.
      • Abdo E.F.
      • et al.
      Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials.
      ,
      • Sarma P.
      • Kaur H.
      • Kumar H.
      • Mahendru D.
      • Avti P.
      • Bhattacharyya A.
      • et al.
      Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic review and meta-analysis.
      ,
      • Kashour Z.
      • Riaz M.
      • Garbati M.A.
      • AlDosary O.
      • Tlayjeh H.
      • Gerberi D.
      • et al.
      Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis.
      ]: hydroxychloroquine was not associated with a decrease in mortality for hospitalized patients. The Axfors et al. meta-analysis, based on 26 published and unpublished RCTs (including SOLIDARITY and RECOVERY trials), found a significant increased risk for mortality [
      • Axfors C.
      • Schmitt A.M.
      • Janiaud P.
      • J van ’t Hooft
      • Abd-Elsalam S.
      • Abdo E.F.
      • et al.
      Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials.
      ]. Thus, there is no need to reconsider our conclusion. We advise Védrines et al. to consider the last published articles and evidence. Védrines et al. stated that reality is complex. We agree, and we add that because reality is complex solid evidence of a favourable benefit–risk ratio is necessary. The COVID-19 crisis does not make the need for rigorous science obsolete: it reinforces this need.
      As stated by the author of a recent editorial on studies evaluating tocilizumab, another putative treatment for COVID-19 patients, “I plan to wait out the torrent of positive observational studies and reconsider tocilizumab's use in COVID-19 if, and only if, more compelling data from randomized trials emerges.” Regarding hydroxychloroquine, the torrent of positive observational studies, often of very low quality, has been shared, but compelling data from randomized trials have already been published and are univocal: hydroxychloroquine with or without azithromycin is not an effective treatment for patients with COVID-19 [
      • Parr J.B.
      Time to reassess tocilizumab’s role in COVID-19 pneumonia.
      ].

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Geleris J.
        • Sun Y.
        • Platt J.
        • Zucker J.
        • Baldwin M.
        • Hripcsak G.
        • et al.
        Observational study of hydroxychloroquine in hospitalized patients with covid-19.
        N Engl J Med. 2020; (In press)https://doi.org/10.1056/NEJMoa2012410
      1. Higgins J.P.T. Thomas J. Chandler J. Cumpston M. Li T. Page M.J. Cochrane handbook for systematic reviews of interventions. Cochrane, 2019 (version 6.0 (updated July 2019). Cochrane. Available on)
        • Magagnoli J.
        • Narendran S.
        • Pereira F.
        • Cummings T.H.
        • Hardin J.W.
        • Sutton S.S.
        • et al.
        Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19.
        Med. 2020; (In press)https://doi.org/10.1016/j.medj.2020.06.001
        • Qin J.
        • Shen Y.
        Statistical methods for analyzing right-censored length-biased data under cox model.
        Biometrics. 2010; 66: 382-392
        • Fiolet T.
        • Guihur A.
        • Rebeaud M.E.
        • Mulot M.
        • Peiffer-Smadja N.
        • Mahamat-Saleh Y.
        “Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients” – author’s reply.
        Clin Microbiol Infect. 2020; (In press)https://doi.org/10.1016/j.cmi.2020.10.002
        • Arshad S.
        • Kilgore P.
        • Chaudhry Z.S.
        • Jacobsen G.
        • Wang D.D.
        • Huitsing K.
        • et al.
        Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
        Int J Infect Dis. 2020; 97: 396-403
        • Malviya A.
        The continued dilemma about the usage of hydroxychloroquine: respite is in randomized control trials.
        Int J Infect Dis. 2020; 99: 310-311
        • 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.
        Int J Infect Dis. 2020; 98: 216-217
        • Varisco T.J.
        • Johnson M.L.
        • Thornton D.
        Comment on Arshad et al.: treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
        Int J Infect Dis. 2020; 99: 373
        • Fiolet T.
        • Guihur A.
        • Rebeaud M.E.
        • Mulot M.
        • Peiffer-Smadja N.
        • Mahamat-Saleh Y.
        Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.
        Clin Microbiol Infect. 2020; (In press)https://doi.org/10.1016/j.cmi.2020.08.022
        • The RECOVERY Collaborative Group
        Effect of hydroxychloroquine in hospitalized patients with Covid-19.
        New Engl J Med. 2020; (In press)https://doi.org/10.1056/NEJMoa2022926
      2. WHO Solidarity trial consortium. Repurposed antiviral drugs for COVID-19–interim WHO SOLIDARITY trial results.
        MedRxiv. 2020;
        • Juul S.
        • Nielsen E.E.
        • Feinberg J.
        • Siddiqui F.
        • Jørgensen C.K.
        • Barot E.
        • et al.
        Interventions for treatment of COVID-19: a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).
        PLOS Med. 2020; 17e1003293
        • Axfors C.
        • Schmitt A.M.
        • Janiaud P.
        • J van ’t Hooft
        • Abd-Elsalam S.
        • Abdo E.F.
        • et al.
        Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials.
        MedRxiv. 2020; https://doi.org/10.1101/2020.09.16.20194571
        • Sarma P.
        • Kaur H.
        • Kumar H.
        • Mahendru D.
        • Avti P.
        • Bhattacharyya A.
        • et al.
        Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic review and meta-analysis.
        J Med Virol. 2020; 92: 776-785https://doi.org/10.1002/jmv.25898
        • Kashour Z.
        • Riaz M.
        • Garbati M.A.
        • AlDosary O.
        • Tlayjeh H.
        • Gerberi D.
        • et al.
        Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis.
        J Antimicrob Chemother. 2020; (In press)https://doi.org/10.1093/jac/dkaa403
        • Parr J.B.
        Time to reassess tocilizumab’s role in COVID-19 pneumonia.
        JAMA Intern Med. 2020; (In press)https://doi.org/10.1001/jamainternmed.2020.6557