A sound approach: Hydroxychloroquine reduces mortality in severe COVID-19

In response: We thank those submitting letters. It is important to critically review COVID-19 experience in a peer-reviewed, non-politicized process, and we fully support appropriately powered double-blind, randomized trials to address questions on COVID-19 clinical management. Many letters discussed several similar points, which we will address jointly. Corticosteroids (MPD) were controlled for in the multivariate and propensity analyses as were age and comorbidities, including cardiac disease and severity of illness. Age was an independent risk factor associated with mortality. We do feel that steroids have a role in reducing mortality for COVID-19 and were first to publish this (Fadel et al., 2020Fadel R. Morrison A.R. Vahia A. Smith Z.R. Chaudhry Z. Bhargavaet P. et al.Early short course corticosteroids in hospitalized patients with COVID-19.Clin Infect Dis cia. 2020; ([published online ahead of print, 2020 May 19]): a601https://doi.org/10.1093/cid/ciaa60Crossref Google Scholar), however in this study, HCQ was independently associated with decreased mortality, a distinct benefit from the steroid effect. We agree with Wiseman that prospective evaluation of a stage-and-age-nuanced approach to COVID-19 that exploits the multiple mechanisms of HCQ and synergy with MPD is needed. In response to Malviya, we reported 91% of all patients began treatment within two days of admission. We agree that early therapy is of most benefit; however, we do not have information on the duration of symptoms prior to hospitalization. The mSOFA has been validated in other studies (de Grooth et al., 2017de Grooth H.-J. Geenen I.L. Girbes A.R. Vincent J.-L. Parienti J.-J. Heleen M. Oudemans-van Straaten SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis.Crit Care. 2017; 21: 38https://doi.org/10.1186/s 13054-017-1609-1Crossref PubMed Scopus (0) Google Scholar, Grissom et al., 2010Grissom C.K. Brown S.M. Kuttler K.G. Boltax J.P. Jones J. Jephson A.R. et al.A modified sequential organ failure assessment (MSOFA) Score for Critical Care Triage Disaster.Med Public Health Prep. 2010; 4https://doi.org/10.1001/dmp.2010.40 paperCrossref Google Scholar); moreover, we also used hypoxia as an independent marker of disease severity. In response to Thornton, HCQ was used throughout the study period, limiting time bias. We used dosages that followed FDA guidelines, with monitoring for cardiac arrhythmias. All centers used the same treatment guideline minimizing treatment bias. The protocol we used was previously published (Fadel et al., 2020Fadel R. Morrison A.R. Vahia A. Smith Z.R. Chaudhry Z. Bhargavaet P. et al.Early short course corticosteroids in hospitalized patients with COVID-19.Clin Infect Dis cia. 2020; ([published online ahead of print, 2020 May 19]): a601https://doi.org/10.1093/cid/ciaa60Crossref Google Scholar). In response to Atkinson, patients assigned to the HCQ group had a moderate and severe illness at presentation, which would favor worse outcomes with HCQ. The exclusion of patients with premorbid risk for cardiac toxicity is similar to clinical trials of many other drugs such as remdesivir, where individuals with severe liver or kidney disease were excluded (Clinical Trial, 2020https://clinicaltrials.gov/ct2/show/NCT04280705Google Scholar). Importantly, in response to Rosenberg, our study differed from other studies, including randomized controlled trials (RCTs), in a variety of ways, including the number of patients, comorbidities, the severity of illness and dosage and timing of administration of HCQ (WHO, 2020https://www.who.int/publications/m/item/informal-consultation-on-the-dose-of-chloroquine-and-hydroxychloroquine-for-the-solidarity-clinical-trial---8-april-2020Google Scholar, New Indian Express, 2020https://www.newindianexpress.com/nation/2020/may/29/icmr-writes-to-who-disagreeing-with-hcq-assessment-officials-say-international-trial-dosage-four-ti-2149702.htmlGoogle Scholar, Mikami et al., 2020Mikami T. Miyashita H. Yamada T. Harrington M. Steinberg D. Dunn A. et al.Risk factors for mortality in patients with COVID-19 in New York City.J Gen Intern Med. 2020; Crossref PubMed Scopus (144) Google Scholar). Prior studies have major limitations with timing, dosing, cardiac AE monitoring, and therapeutic windows. To date, there has been no properly designed and powered RCT that evaluates HCQ treatment for COVID-19. Concerning our comments about the Rosenberg paper, a variety of serious limitations in that paper should be corrected on the record. The critical limitation, among many others, is that patients receiving HCQ with or without azithromycin (AZM) were overall sicker on presentation and had multiple other risk factors; Black or Hispanic patients were likely to receive HCQ or AZM (mortality is significantly higher in these groups). Patients receiving HCQ were more likely to be obese, diabetic, have chronic lung disease, and cardiovascular conditions, yet these sicker patients had approximately the same mortality rates compared to patients with a milder course of the disease and fewer risk factors. However, the authors incorrectly conclude that “there are no significant benefits.” It is noteworthy that HCQ was associated with a significant survival benefit in a larger cohort of patients from New York City, as reported by Mikami et al., 2020Mikami T. Miyashita H. Yamada T. Harrington M. Steinberg D. Dunn A. et al.Risk factors for mortality in patients with COVID-19 in New York City.J Gen Intern Med. 2020; Crossref PubMed Scopus (144) Google Scholar. In these unprecedented times, the role, cost-benefit, and availability of repurposed agents such as HCQ and newer drugs such as remdesivir should be urgently evaluated in an impartial manner. Remdesivir is a novel drug with a novel approach and has a place in the COVID-19 treatment formulary; however, it is expensive, and there is limited availability outside of the United States (Forbes, 2020https://www.forbes.com/sites/iainmartin/2020/07/01/us-buys-the-world-supply-of-breakthrough-coronavirus-drug-remdesivir/#7556f0cf547Google Scholar, Finley, 2020Finley, A. The Politics of Hydroxychloroquine: Trump touted it, so Biden denounces it. The FDA has suspended a permit for its use. Let doctors decide.Google Scholar). Our paper's overarching theme is that a safe dosage and early utilization of hydroxychloroquine reduced mortality in hospitalized patients. Similar published large cohort studies support our findings from New York City and France (Mikami et al., 2020Mikami T. Miyashita H. Yamada T. Harrington M. Steinberg D. Dunn A. et al.Risk factors for mortality in patients with COVID-19 in New York City.J Gen Intern Med. 2020; Crossref PubMed Scopus (144) Google Scholar, Lagier et al., 2020Lagier J.C. Million M. Gautret P. Colson P. Cortaredona S. Giraud-Gatineau A. et al.Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis.Travel Med Infect Dis. 2020; 1017: 91Google Scholar) As stated in our paper, further prospective studies are needed. No conflict of interest to declare. Approval was not required. 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 AccessHydroxychloroquine in COVID-19: Taking care of statistics to take care of patientsInternational Journal of Infectious DiseasesVol. 99PreviewI read with great interest the article published by Arshad and the Henry Ford COVID-19 Task Force. They evaluated the role of hydroxychloroquine (HCQ) therapy alone and in combination with azithromycin in hospitalized COVID-19 patients. They included a total of 2.541 patients divided into four groups: HCQ alone, HCQ + azithromycin, azithromycin alone, and neither drug. The authors performed propensity score matching to control for confounding factors, using the parameters included in the Cox regression model. Full-Text PDF Open AccessProblems with the analysis in “Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19”International Journal of Infectious DiseasesVol. 99PreviewI am writing to comment on the article “Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19” by Samia Arshad et al. (Arshad et al., 2020). In this observational study, the patients were deliberately assigned to the treatment protocols based on their underlying medical conditions. This introduces a bias into the study, and as with all observational studies, there is the hope that the subsequent adjustments, based on a regression model in this instance, will compensate for this bias. Full-Text PDF Open AccessEffectiveness of hydroxychloroquine in COVID-19 disease: A done and dusted deal?International Journal of Infectious DiseasesVol. 99PreviewArshad 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., 2020). Data on the effectiveness and toxicity of hydroxychloroquine are controversial (Liu et al., 2020; Devaux et al., 2020; Gautret et al., 2020; Tang et al., 2020; Geleris et al., 2020). Full-Text PDF Open AccessPossible synergistic effects of hydroxychloroquine and steroids in COVID-19, time for a nuanced approach. Comment on Arshad et al.International Journal of Infectious DiseasesVol. 99PreviewAs its accompanying editorial (Lee et al., 2020) perceives, Arshad’s report (Arshad et al., 2020) indeed fuels the fire of the hydroxychloroquine (HCQ) controversy. It also fans the steroid controversy (Salton et al., 2020). Full-Text PDF Open AccessComment on Arshad et al.: Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19International Journal of Infectious DiseasesVol. 99PreviewWe read, with great interest, the results published by Arshad and colleagues concerning the potential association between treatment with hydroxychloroquine with or without azithromycin and in-hospital mortality in patients with COVID-19 (Arshad et al., 2020). The reported treatment benefit contradicts that reported elsewhere, including a recent study at US Veterans Affairs Hospitals that showed an almost perfectly inverse risk of mortality (HR = 2.61; 95% CI, 1.10–6.10) (Magagnoli et al., 2020). Full-Text PDF Open AccessThe continued dilemma about the usage of hydroxychloroquine: Respite is in randomized control trialsInternational Journal of Infectious DiseasesVol. 99PreviewI read with interest the retrospective cohort study published in the International Journal of Infectious Diseases by Arshad et al., who report that treatment with Hydroxychloroquine (HCQ) alone and in combination with Azithromycin was associated with a reduction in COVID-19 associated mortality. I congratulate the authors, but I have noted a few limitations in the study, which may constrain the application of the study's results in routine clinical practice. Full-Text PDF Open AccessClarifying the record on hydroxychloroquine for the treatment of patients hospitalized with COVID-19International Journal of Infectious DiseasesVol. 99PreviewThe study from Arshad et al. on the use of hydroxychloroquine, with and without azithromycin, for the treatment of inpatients with COVID-19 in one healthcare system (Henry Ford Health System), is a new entrant into the rapidly expanding literature on the treatment of this disease (Arshad et al., 2020; Sattui et al., 2020). The study's findings of a significant beneficial effect of hydroxychloroquine in the reduction of in-hospital mortality are not consistent with several recent studies, and as authors of one of those studies, we wish to share a few observations (Sattui et al., 2020; Geleris et al., 2020; Rosenberg et al., 2020). Full-Text PDF Open Access

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