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    11 Comments for this article
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    Hydroxychloroquine-Treated Patients Were Sicker at Baseline
    David Chappell, MD | Private Internist/Endocrinologist
    This study in JAMA and another appearing in the May 11, 2020 issue of NEJM (1) both show no clear benefit in treating Covid-19 infected patients with hydroxychloroquine. However, in both studies the treated patients were significantly sicker at baseline than the untreated groups. Both studies were observational; neither had a control group.

    Today CNN posted a headline entitled "Yet another study shows hydroxychloroquine doesn't work against Covid-19". On the contrary, neither study was robust enough to draw definitive conclusions as CNN proposes. It is unfortunate that the authors of neither study make this clear. The statement that
    "interpretation of these findings may be limited by the observational design" is a cop-out. At the very least the word "may" should be replaced with the word "is". Of note, the editorial by Rubin et. al. in the NEJM May 11 issue was more balanced and left open the possibility that hydroxychloroquine could have had a modest effect to bring the mortality rate of sicker patients down closer to the mortality rate of those less sick. A good clinical study is needed here, not "multiple sensitivity analyses" as done by Rosenberg et. al.

    A separate study involving remdesivir was stopped early by The National Institute of Allergy and Infectious Diseases without achieving statistical significance due to ethical issues revolving around using a placebo for Covid-19 patients (2). This occurred despite the fact that many cancer treatment trials carry a higher mortality than does Covid-19. Now we have another study that fails to meet basic scientific standards and a difficult path forward to overcome this failure.

    Scientists and health care providers need to guard against the inevitable politicization of scientific data and investigations. False interpretations of scientific data are rampant these days, and the public suffers from this. I like to ask my patients who have formed their own, often erroneous, medical opinions, "which is more complicated, a nuclear reactor or the physicists who designed it?" Most of us would not presume to offer advice on the design of nuclear reactors, but we sure like to opine on scientific issues surrounding, for example, Covid-19.

    REFERENCES

    1. https://www.nejm.org/doi/full/10.1056/NEJMoa2012410
    2. https://www.statnews.com/2020/05/11/inside-the-nihs-controversial-decision-to-stop-its-big-remdesivir-study/ 
    CONFLICT OF INTEREST: None Reported
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    Comparing the Incomparable.
    Olga Goodman, MD | Rheumatology, Internal Medicine, Pediatrics
    -"Patients receiving hydroxychloroquine with or without azithromycin were overall sicker on presentation."
    --The were significantly sicker given available information (table 1) and had
    multiple other risk factors:
    - Black or Hispanic patients were as likely to receive hydroxychloroquine and/or azithromycin (mortality is significantly higher in these groups)
    - Patients receiving hydroxychloroquine + azithromycin and hydroxychloroquine alone were more likely to be obese and have diabetes;
    - Patients receiving hydroxychloroquine alone had the highest levels of chronic lung disease (25.1%) and cardiovascular conditions (36.5%);

    But after receiving treatment much sicker patients had approximately the same mortality rates vs
    patients with a milder course of the disease and less risk factors. However, the authors conclude that "there are no significant benefits."

    Really? No benefits?
    CONFLICT OF INTEREST: None Reported
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    Hydroxychloroquine/Azithromycin in COVID 19 Treatment
    Dr Mubarak M Khan, MBBS,DLO,DNB(ENT) | Sushrut ENT Hospital & Dr khan’s Research Centre, Pune, india
    This is a good retrospective observational study of the effects of HCQ and HCQ+AZT in the treatment of COVID19-infected hospitalized patients but it will be very much premature to conclude these drugs' role in treatment based on short experience and the following questions and concerns:

    1. This is an observational study to determine outcomes in the sickest admitted patients
    2. Selection criteria are hospitalised COVID19 patients. At which stage drugs were administered is not clear in all three groups
    3. Outcome criteria are either death or discharge. What happened to those who got discharged ? Was there any
    hastening in improvement due to these drugs? Was there shortening of duration of illness due to drugs, from COVID positive to negative?
    4. Were the drugs tried as prophylaxis? Or only used in hospitalised patients?
    5. All patients included are mean age at 70 and with many comorbidities
    6. What dosages were used for HCQ and azythromicin? How many days was treatment given? Were different dosages tried?
    7. What type of safety pharmacovigilance was there, beyond noting increased cardiac complications?
    8. Were drugs discontinued due to side effects? Did discontinuation lead to any improvements?
    9. What side effects were obvious during the treatment period in patients free from any morbidity? 
    10. When patients succumbed to mechanical ventilation, how and what type of dosages of these drugs were given?
    11. Were blood levels of hydroxychloroquine and azythromycin measured and related to increased complications?

    Sincere regards
    Dr Mubarak khan DLO, DNB(ENT)
    Dr Sapna Parab MS, DNB(ENT)
    CONFLICT OF INTEREST: None Reported
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    Irrational use of Hydroxychloroquine and Azithromycin
    Muhammad Sikandar Aslam, MBBS,MPH | Shaikh Zayed Hopsital Lahore Punjab Pakistan
    In countries like Pakistan these drugs are freely available to everyone from local pharmacies and out of fear, with or without mild/severe symptoms of COVID-19, they are taken by people prophylactically, which may aid in antibiotic resistance (azithromycin) and can lead to arrhythmias (hydroxychloroquinine). There is not enough data available where these drugs might prove to be helpful in COVID-19 patients. So their irrational use must be stopped and clearcut guidelines should be provided regarding their use.
    CONFLICT OF INTEREST: None Reported
    Cumulative Incidence Plot
    Luis Pinheiro, MEpi | Data Science and Epidemiology
    This is an interesting and useful paper. While I have some detailed comments, I will only focus on the cumulative incidence plot. Is the overlap of the lines for "HCQ alone" and "neither alone" correct? By my calculations, the lines should clearly separate by day 7. Does this affect any other calculation?
    CONFLICT OF INTEREST: None Reported
    Hydrochloroquine Study
    Alton Thomson, MD | Retired
    It's well know that most drugs don't work when given at inappropriate times. Do a study using them for early intervention.
    CONFLICT OF INTEREST: None Reported
    QTc From a Medical Toxicology Fellowship.
    Gary Ordog, MD, DABMT, DABEM | County of Los Angeles, Department of Health Services (Physician Specialist retired)
    Thank you for the valuable information that you and your study have provided. I can still see my teacher and mentor Dr. Matthew J. Ellenhorn almost 40 years ago, during his weekly Medical Toxicology Grand Rounds*, "never add two QTc prolongators together." This point added to many years of study of the effects of multiple similar toxins added to the system at the same time. Similar, though not identical toxins, operating with similar but not identical mechanisms of injury, not only have an addition of their toxic effects, but the physiological injury is usually multiple times that of the individual toxin.

    *These recorded Rounds led to the text books: Medical Toxicology: Diagnosis and Treatment of Human Poisoning.
    CONFLICT OF INTEREST: None Reported
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    Role of Zinc
    Manuel Datiles, MD | Special Volunteer Ophthalmologist, National Institutes of Health, Bethesda, MD 20892
    A recent trial available as a preprint from NYU Grossman School of Medicine by Infectious Disease specialist Dr. Joseph Rahimian (NYU Langone Health) which included Zinc treatment with the Hydrochloroquine and Azithromycin showed efficacy in early stage CoVid-10 patients (1). Perhaps Zinc is the missing ingredient.

    Reference

    1. https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v1
    CONFLICT OF INTEREST: None Reported
    First Try Simple Things To Do Less (or No) Harm Later
    Flavio Dantas, M.D. , D.Sc | Retired Professor, Federal University of Uberlândia (Brazil)
    Given that early results in France and China suggested that chloroquine and hydroxychloroquine could reduce viral load in COVID-19 patients, it follows that these drugs should primarily be tested in patients soon after their exposure to coronavirus (or in the very initial phase) before getting hospitalized. This was done in São Paulo (Brazil), after a pandemic was officially declared, with patients from a health care provider dedicated to attending old people (1). Using telemedicine resources, 636 patients with flu-like or COVID-19 symptoms were asked if they consented to use hydroxychloroquine (800 mg first day and 400 mg for 6 days) plus azithromycin (500 mg for 5 days). Despite the fact that patients treated with hydroxychloroquine and azithromycin had higher prevalence of comorbidities, only 8 (in 412) needed hospitalization (no deaths), whereas in the non-treated patients 12 (out of 224) were hospitalized, and 5 died. The percentage of hospitalization for patients treated early (<7 days from onset of disease) was 1,17% (for late treatment was 3.2%). The paper was taken out from a preprint site after CONEP (Brazilian Committee of Ethics in Human Research) allegations that patients were enrolled before the study protocol already was approved by CONEP, in the midst of a growing politicization of chloroquine use in Brazil for COVID-19.

    Reference

    1. https://www.preprints.org/manuscript/202004.0381/v1
    CONFLICT OF INTEREST: None Reported
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    HCQ & COVID 19
    Sam Mansour, MD, FRCS(C), FACS | Virginia Retina Center / George Washington University
    Unless any current COVID 19 therapeutic study is able to provide disease severity stratification of study participants (ie. early, intermediate, severe) at entry, meaningful conclusions as to the efficacy of the therapy in question will be very limited. This study is a good example of this quandary. The proposed mechanisms for HCQ in the management of COVID 19 are as follows:

    1. Intracellular alkalinization
    a. Reduction in cell membrane permeability>>inhibition of SARS-CoV-2 cellular entry
    b. Reduction in endosome membrane permeability>>inhibition of SARS-CoV-2 endosomal entry
    c. Inhibition of secondary viral replication enzymatic processes
    2. Zinc ionophore (elevate intracellular Zn
    levels>> inhibition of viral replicase enzyme)
    3. Inhibition of SARS-CoV-2-ACE2 receptor binding

    There is ample published in vitro data to substantiate these antiviral mechanisms in HCQ & coronaviruses dating back to 2011.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Dose and Duration of Azithromycin
    Joanne Tobacman, M.D. | University of Illinois at Chicago
    In treating patients, including patients >65 y, I have often found that the Z-pak duration of azithromycin (5 d) is not long enough. What was the dose and duration of azithromycin used in the 211 patients treated with azithromycin alone?
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    May 11, 2020

    Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

    Author Affiliations
    • 1University at Albany School of Public Health, State University of New York, Rensselaer
    • 2New York State Department of Health, Albany
    • 3IPRO, Lake Success, New York
    • 4Downstate Health Sciences University, State University of New York, Brooklyn
    JAMA. Published online May 11, 2020. doi:10.1001/jama.2020.8630
    Key Points

    Question  Among patients with coronavirus disease 2019 (COVID-19), is there an association between use of hydroxychloroquine, with or without azithromycin, and in-hospital mortality?

    Findings  In a retrospective cohort study of 1438 patients hospitalized in metropolitan New York, compared with treatment with neither drug, the adjusted hazard ratio for in-hospital mortality for treatment with hydroxychloroquine alone was 1.08, for azithromycin alone was 0.56, and for combined hydroxychloroquine and azithromycin was 1.35. None of these hazard ratios were statistically significant.

    Meaning  Among patients hospitalized with COVID-19, treatment with hydroxychloroquine, azithromycin, or both was not associated with significantly lower in-hospital mortality.

    Abstract

    Importance  Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events.

    Objective  To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19.

    Design, Setting, and Participants  Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020.

    Exposures  Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither.

    Main Outcomes and Measures  Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation).

    Results  Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.

    Conclusions and Relevance  Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.

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