Be careful of that article. HCQ ie HC was only given late stage, preferentially to the neutropenic and we know that Hydroxychloroquine and Zinc work best in early treatment not late treatment. https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf full study information
Response to Magagnoli, MedRxiv, 2020
Matthieu MILLION, Yanis ROUSSEL, Didier RAOULT
In the current period, it seems that passion dominates rigorous and balanced scientific analysis and may lead to scientific misconduct. The article by Magagnoli et al. (Magagnoli, 2020) is an absolutely spectacular example of this. Indeed, in this work, it is concluded, in the end, that hydroxychloroquine (HCQ) would double the mortality in patients with COVID with a fatality rate of 28% (versus 11% in the NoHCQ group), which is extraordinarily hard to believe. The analysis of the data shows two major biases, which show a welling to be convinced before starting the work :
The first is that lymphopenia is twice as common in the HCQ groups (25% in the HCQ, 31% in the HCQ+AZ group versus 14% in the no HCQ group, p =.02) and there is an absolute correlation between lymphopenia (<0.5G/L) and fatality rate, which is well known (Tan, 2020) and confirmed here : 28% deaths, 22% and 11% in the HCQ, HCQ+AZ and No HCQ group, respectively. Lymphopenia is the most obvious criterion of patient severity (in our cohort, lymphocytes in dead individuals (n=22, mean ± standard deviation, 0.94 ± 0.45), versus in the living (n=2405, 1.79 ± 0.84, p < .0001)). As the authors acknowledge, the severity of the patients in the different groups was very different, and their analysis can only make sense if there is a selection of patients with the same degree of severity, i.e. the same percentage of lymphopenia.
The second major bias is that in an attempt to provide meaningful data, by eliminating the initial severity at the time of treatment, two tables are shown: one table where drugs are prescribed before intubation, and which shows no significant difference in the 3 different groups (9/90 (10%) in the HCQ group, 11/101 (10. 9%) HCQ+AZ, and 15/177 (8.5%) in the group without HCQ, chi-square = 0.47, ddl = 2, p = 0.79), and one table, where it is not clear when the drugs were prescribed, where there are significant differences. These differences are most likely related to the fact that the patients had been intubated for some before receiving hydroxychloroquine in desperation. It is notable that this is unreasonable at the time of the cytokine storm, as it is unlikely that hydrochloroquine alone would be able to control patients at this stage of the disease.
Moreover, incomprehensibly, the “untreated” group actually received azithromycin in 30% of cases, without this group being analyzed in any distinct way. Azithromycin is also a proposed treatment for COVID (Gautret, 2020) with in vitro efficacy (Andreani, 2020), and to mix it with patients who are supposedly untreated is something that is closer to scientific fraud than reasonable analysis.
Altogether these 3 voluntary biases are all pushing to the idea of dangerosity of hydroxychloroquine safest drug as reported on nearly 1 million people (Lane, 2020).
All in all, this is a work that shows that, in this period, it is possible to propose things that do not stand up to any methodological analysis to try to demonstrate that one is right.
Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, Wurtz N, Rolain JM, Colson P, La Scola B, Raoult D. In vitro testing of combined Hydroxychloroquine and Azithromycin on SARS-CoV-2 shows synergistic effect. Microbial pathogenesis. 2020. In press.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949. doi: 10.1016/j.ijantimicag.2020.105949.
Lane JCE, Weaver J, Kostka K, et al. Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study. medRxiv 2020.04.08.20054551; doi: https://doi.org/10.1101/2020.04.08.20054551
Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv 2020.04.16.20065920; doi: https://doi.org/10.1101/2020.04.16.20065920
Tan, L., Wang, Q., Zhang, D. et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Sig Transduct Target Ther 5, 33 (2020). https://doi.org/10.1038/s41392-020- 0148-4.
In reviewing the article it seems the risk of ventilation need if was on HC +AZ was half of the control group and they did not use Zinc. Is this true?
Then if there was a similar death rate of HC+AZ that means far more of those not on ventilators in the HC+AZ group died. Why?
How do they explain the high risk of death of those not ventilated in the HC+AZ group?
How much Hydroxychloroquine was give per patient in the HC and HC&AZ groups? It was not clear the amount of HC given, and no zinc seems to be given.
There is a group of approximately 50 patients that was given Azithromycin and was grouped into those not given Hydroxychloroquine… as one large control group.
It is notable that 50pts in the no HC group received AZ… How many of those who received AZ died or were on ventilator etc was not elucidated?
The study lists authors conflicts including author SSS and Gilead.
A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%,
respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.
1. There were less ventilator patients in the HCQ(HC) group 13.3/14.1 (6% less) and even less in the HC+AZ group 6.9/14.1(51% less ventilator use than control). So why did they die? We need all the deaths to analyze EKGs, esp QT intervals, but also direct cause of death (e.g. sudden death arrhythmia? hypoxemia with no ventilator? advanced age?)
2. The study lists authors conflicts including one author(SSS) and Gilead. It may be helpful for Senators to have some background on the invention of Remdesivir at Ft Dietrich in Maryland and the subsequent research on Gilead at Boston University and where the research for the Coronavirus was done and what research at Boston University was stolen or was allowed to be stolen by China.
3. There is a group that was given Azithromycin and was grouped into those not given Hydroxychloroquine… as one large control group. It is notable that 50pts in the no HC group received AZ… How many of those who received AZ died or were on ventilator etc was not elucidated?
4. HC was not given with Zinc? We don’t know. They did not say. HC works best with Zinc.
5. HC was not given early. This is a hospital and they may have waited for the (poor) standard of Covid 19 PCR testing (late in the course of disease PCR turns positive) which in patients with lots of comorbidities is a poor standard of care “bad medicine.”
To: <firstname.lastname@example.org> Cc: <email@example.com> Subject: veterans Hydroxychloroquine and azithromycinDear S. Scott Sutton, Pharm.D.1,2, Jayakrishna Ambati, M.D.,
In reviewing your article, it seems the risk of ventilation was half of your control group and you did not use Zinc. Is this true?
How much Hydroxychloroquine was given per patient in the HC vs HC&AZ vs none groups?
It is notable that 50pts in the no HC group received AZ… How many of those who recived AZ died or were on ventilatior etc?
How do you explain the high risk of death of those not ventilated in the HC+AZ group?
Are you aware other countries are giving HC or HCQ early with very good results?
We have also found those who did not get Zinc in combination with Hydroxychloroquine did not fare as well as those who did and the combination must be given earlier, best prior to test positive or at least prior to waiting for test to come back positive.
Have you considered designing a study that uses early and low dose hydroxychloroquine?
Are you aware of these low dose HCQ protocols?
As a Veteran having a vested interest in your exact protocols. Have you considered reviewing for earlier intervention with low dose HCQ and Zinc?
Would you please provide your outpatient as well as hospitalization and ICU protocols for those with or suspected of having Covid-19 and treatment with all options including HCQ and/or Remdesivir if possible?
Have you considered giving low dose HCQ and Zinc earlier using clinical acumen rather than relying on a test that may only turn positive after some days or may not turn positive due to mutations?
It may be helpful for Senators to have some background on the invention of Remdesivir at Ft Dietrich in Maryland and the subsequent research on Gilead at Boston University and where the research for the Coronavirus was done and what research at Boston University was stolen or was allowed to be stolen by China.