COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

Comment: The main problem with this work is that the demographics of the control group are not reported, so we have no idea if they are similar. This them means that we have no idea if the differences in outcomes are because of the treatment, or if they would be expected because of the demographies of the groups. A subtler point is that the reported age profile of the treatment group is impossible. Group A is aged >60 years, and almost half of the treatment group was in that group. But the IQR was reported as 40-60, so only 25% of the treatment group had an age >60. I hope this was due to excessive rounding, or a similar error that can be corrected.

Comment: The paper is excellent and, as far as I, a mere engineer, am able to judge, it is well-founded, has been rigorously conducted and is clearly presented. The authors should justifiably take credit for a solid usable study, one that goes quite some way to counter the cynical efforts of a large and powerful body of self-interested persons and organisations who, in my humble opinion, have placed their own gain above the misery and tragedy of thousands of Covid-19 victims. Well done.

Comment: O presente artigo reforça a síntese de que a HCQ tem ação na redução da replicação viral, Seu uso no tratamento das artrites, a princípio era entendido como potencial amplificador dos efeito anti-inflamatórios dos corticoides no corpo humano. Alguns endocrinologistas, mais recentemente demonstravam conhecimento de que a droga sozinha sem associação com corticoide, agia efetivamente na redução dos efeitos inflamatórios de algumas artrites. E só mais recentemente como a pandemia do Covid-19, é que seu uso como antivirótico foi introduzido. Essa sequencia clínica, fora espelhada pelo Dr. Siddiqui, que tornou fácil o entendimento clinico das fases da doença em curso, levando de imediato a conclusão de que o tratamento das fases iniciais com HCQ, Zinc , Azitromicina e corticoides reduziam drasticamente a evolução da doença para fases mais tardias onde praticamento o sistema imunológico perderia para a tempestade citotóxica. Por outro lado, com a replicação viral reduzida pelo efeito comprovado da HCQ, problemas menores ocorreriam na troca gasosa alveolar, reduzindo a necessidade de entubação e mesmo se assim o fossem, haveria suficiente troca gasosa nos pulmões.
Desta forma quero deixa aqui meus elogios ao Ilustres colegas Scholz, M.; Derwand, R.; Zelenko, V, que tanto lutaram nessa guerra política que pela primeira vez, graças as Mídias Sociais , a Industria Farmacêutica perde sua hegemonia em impor medicações caras , e muitas vezes sem devido seguimento dos efeitos colaterais. Uma coisa nós sabemos, a HCQ tem 0 anos de uso no mundo sem nenhum relato de danos ao usuário necessitado.

Comment: Thank you Dr. Z and the others for publishing this paper that proves that the medicine works.

Comment: Dr Zelenko is one of hundreds and probably more like thousands of doctors who use this protocol with their patients and themselves. You doubters and your reasons for not trusting anything that could save the world from people like you wanting to put your trust in a vaccine called "WARP SPEED" is strange. The drug has been safe to use for other issues for the past 65 years which already proves is it safe and is still being used by MILLIONS today. Now it is being used off label for covid 19 with world saving success, so to use something that will probably save your life and inexpensive is a no brainer. It sure won't kill you to at least try it.

Comment: I have been closely following Dr. Zelenko and researching this combination protocol since March 2020. Congratulation to Dr. Zelenko et al for the hard work and courage in conducting this study. With politically tainted bias subtracted it is becoming easier to distinguish sincere HCQ studies from tainted HCQ studies that have been creatively constructed to discredit HCQ. Many HCQ studies didn't administer the treatment early, omitted zinc, administered unsafe dosing and/or included patients with comorbidities at a higher rate in the treatment group. This study should open the door for further HCQ and zinc studies, perhaps a HCQ and zinc prophylaxis study.

Comment: I am concerned with a number of biases in the data that seem to stack the deck in favor of the treatment group:

1) The inclusion of 37 cases substantiated by an antibody test is highly problematic, as in order to receive the antibody rest, each of these patients needed to survive covid. Any additional patients that died prior to otherwise receiving an antibody test are excluded. This stacks the deck in favor of the treatment group, and absent any intervention at all, we would still expect them to fare better than the control.

2) Separate from the study itself, I feel compelled to observe that the data described in the report seems to contradict public statements by one of the authors, Dr. Zev Zelenko. The author has publicly claimed to have treated more than 1500 patients with this treatment, but only provides data on 377.

The study states that the control group is based on laboratory results of patients in the same community - how big a population were these drawn from? If these are Dr. Zelenko’s patients, where are the rest of them? Why are we presented with no results from the other patients treated with this cocktail? If these are not Dr. Zelenko’s patients, who are they?

This is an interesting read, but in the public interest, the authors should publish results from the entirety of the patient population treated by Dr. Zelenko.

Comment: A very

A very interesting study. I would love to see a better designed study. There is not enough details in this prepublication study to reach any other conclusion. I would love to see the details about classification and data about the comparability of the groups. The age difference noted above is a big problem.
More research needed.

Comment: I am a retired engineer, and I am at a loss as to why the study does not headline every news outlet today. Maybe it plays as old, tired news? My Dad's explanation "It is always about the money. Unless they say it is not about the money, and then it is really all about the money"?
I have questions about the participants in the study. Maybe this is in the depth of the study but not clear to me from the extract.
335 candidates -- COVID-19 patients, not yet hospitalized when the selection for treatment was done.
127 treated with the protocol. How were these selected out of the 335 candidates? Some criteria? Randomly?
104 included in the analysis. Why were 23 treated patients excluded from analysis? That is a lot out of such a small sample size. I think hardly any would be found to have contraindications after the treatment was done. I assume all 23 didn't just die due to unrelated somethings. Maybe they got well and were just not seen on follow-up?

37 patients added to the treatment group with positive serum tests. Were these 37 out of the original 208 unselected candidates? Why were these patients added? It could be humanitarian reasons, I think.
141 treated patients included in the analysis.

Thank you and congratulations of your continued high-value contribution.

Comment: First of all congratulations for this wonderfully written article and sharing this extremely valuable evidence in these pandemic times. My question is about the rationale behind presence of at least 1 comorbidity in Group C? Would there be any data that may indicate positive evidence in symptomatic patients <60 without any co-morbidities? Thank you.

Comment: Dr Zelenko, I am so grateful for all you have done: first, doing the research to see what might help your patients; then putting together 2 treatments to create your protocol; then keeping a record of the outcome; then reaching out in a hundred different ways (interviews, letters including to Pres Trump), and on to this, with 2 world-class experts, to prove to the most science-centered that the protocol worked. Plus you have established a Crowd Protocol.
Congratulations,
And once again, much gratitude,
Elsa

Comment: The criticism of Dr. Zelenko’s original claim was that he treated many patients with HCQ+zinc+zpack who would not be expected to be hospitalized or die of COVID-19. This appears to be a response to that criticism by selecting a group of his patients who might not be expected to do well. Those patients did very well. However my criticism is that the paper left the impression that the untreated group were the stratified patients who did not meet the conditions of >60, SOB, or a comorbidity. They were not. This is a major weakness. How does the author know that these other COVID-19 patients did not receive the same medications or that these controls had a higher percentage of high risk attributes. I am disappointed as I touted the use of HCQ/zinc/Zpack based on this article and my incorrect assumptions of it. It would have been better to have eliminated the “control” group and let his results stand on their own.

Comment: A very important study.

@M. Scholz: How does your study compare to the recent Boulware NEJM study which found no PEP effect of HCQ regarding Covid onset in persons exposed to a confirmed patient? https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

Some differences I note: 1) Boulware didn't use zinc; 2) hospitalization was very low in both groups (0.2%), i.e. these were clearly not high-risk patients.

Do you expect HCQ or Zinc + HCQ to prevent symptom onset, or only prevent hospitalization?

Comment: The primary mandate is ," First DO NO Harm". At the early onset of covid 19 there are few , if any, alternatives. There is now a fair degree of " smoke" circulating among doctors that HCQ with zinc may offer some real benefits prophylactically. The real question has been, does the drug prolong the qt interval and therefore lead to a serious, and perhaps life-threatening ventricular arrhythmia. Two studies are now showing that the drug appears safe when given early in the course. To me, that's the main takeaway from this study.

Comment: I haven’t been able to find where the public reference data for the comparison comes from. If it is public, why isn’t the source provided? How do the authors know what people not seen by Dr Zelenko were treated with?

“In accordance with available public reference data, 712 confirmed SARS-CoV-2 PCR positively tested COVID-19 patients were reported for the respective community”

“Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control”

And from a comment by Martin Scholz

“For the analysis of the untreated patient group of the public reference (not of the respective practice and not treated with the triple therapy zinc, low dose HCQ, and azithromycin) unfortunately only the outcome data was available and so also a risk adjustment was not possible”

So, on the one hand, only outcome data is available, and on the other hand these people are included because they were not treated with HCQ/AZ/Zn. I don’t think these people can be both these things.

Comment: Here is a new video on mechanisms by which C-19 infects cells. It is hypothesised that a new route to infection also exists. Interestingly, they mention azithromycin as a possible treatment. This is actually part of the Zelenko protocol. While it is an antibiotic it also has the ability to block C-19 from entering cells via the CD147 spike protein. This may explain its efficacy in the protocol, apart from its role in treating secondary infection.

https://youtu.be/MUnTb3_mwTY

Comment: I very much appreciate that you have tabulated the data you have.
Many criticize the lack of controls and the lack of high numbers
of subjects. As people came to you and you selected the more ill
for treatment, and they almost all got markedly improved in 5 days.
That is terrifically valuable data and only needs repetition to certify
stronger statistics. Thank you for demonstrating the concept of zinc
as the real antiviral agent, (the RNA replicase inhibitor) and HCQS
as the ionophore (the transfer agent). The research using HCQS alone
is silly, like serving an empty package. The research using zinc alone
would be weak, as it would take too long to penetrate the infected cells.
The critics are unreasonably devoted to ignoring this important combination.
What I would love to see in future studies is to test RBC zinc levels in a
population of nasal swab positive PCR test subjects and follow them.
I hypothesize that the zinc deficient are the ones that go on to progress
to more severe respiratory distress cases. The zinc sufficient would never
get sick enough to need the Zelenko protocol as their ACE2 bearing cells
are already preloaded with the inhibitor.
I would also like to see studies using other ionophores such as picolinate,
or carnosinate tested clinically, so that we have more options beyond
total dependence on HCQS, which is often in short supply.
doctorhesselink.mysite.com/ResRef.htm

Comment: Unfortunately, the lack of information on the comparison population greatly weakens any statements regarding efficacy of the proposed treatment. There are many potential reasons for differences in hospitalizations and mortality between treated patients and an unmatched retrospective comparison group. The treated patients all evidently presented to a Family Physician office. If other patients in the community were presenting to Emergency Rooms or Urgent Care, one would naturally expect sicker patients and a higher percentage of admissions. Others have pointed out the potential higher ages within the comparison group, which would certainly slant that group toward worse outcomes. Other differences in risk factors between groups could do this as well.

Such criticisms do not diminish the possibility of benefit of the proposed treatment, which this report argues is a relatively safe one. However, it should not be considered substantial evidence of such.

Comment: Dear Dr. Shah (response 5 to comment 1 and comment 10),
The rationale behind presence of at least 1 comorbidity in group C is base on reference 35 in the paper. “(CDC) CoDCaP. People Who Are at Higher Risk for Severe Illness 2020 [Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.htmlaccessed 2020/05/23 2020]”. Syptomatic patients <60 years without any co-morbidity were not treated in this study according to the risk stratification approach described in the Methods section.

Comment: Dear Dr. Divito (response 6 to comment 1),
All potential repurposed drugs with sufficient evidence to be beneficial in treating COVID-19 patients should be considered. The MATH+ protocol is a strategy for hospitalized patients. The COVID-19 hyperinflammation ought to be limited as soon as possible. This is one of the key messages of our paper: Patients have to be treated early prior to the development of a cytokine storm which is extremely difficult to cure. When patients are admitted to the hospital it might be too late. However, in these cases the MATH+ protocol seems to be a feasible approach.

Comment: Dear Dr. Burrows (comment 9):
Thank you for your comment. The authors would like to refer to Figure 1 which explains the selection and exclusion procedure and our response to comment 7.

Comment: Let me just say while you people do your blind study with the proper control group... Yeh, yeh... If I get COVID I'll take Zinc HCQ and antibiotic and exercise my right to try as a patient before I will take anything else. Anyone coming out against this publically should be laughed out of the medical field because you all know it works... And have known since 2005 per the NIH.

Comment: The treatment population are patients who presented to their family doctor with mild symptoms. The paper presents this as a strength, as the 'first outpatient study,' which fair enough. It also means that these were almost certainly patients who were less sick than average at presentation. This needs to be clearly reflected in the control group.

There is no control group. There is a comparison group, selected ad hoc after the fact, from some source of data for patients in the same community. We don't know the severity at presentation, or the treatment history, of that comparison group. The paper seems to indicate that neither do the authors. That isn't a controlled study, it's a case series with a seemingly random comparison grafted on after the fact.

We have no idea what the data source for the comparison group is. Literally, none. The authors say it's publicly available community data, but they refuse to name the data source. We have no idea of the characteristics of patients in the control group. None, nada, zilch. All we know is how many there were, how many were hospitalised, and how many died. As one of the comments already points out, we don't even know whether some of the 'controls' might have also gotten the triple therapy.

The authors cite HIPAA to say they can't disclose the data source for the control group. This is confusing. If it's public data, it's public data. Cite the public data source. If it's not public data, that statement is at best misleading. One cannot simply say 'this data came from somewhere, but I can't tell you where,' and expect it to be taken as science.

In the comments, authors respond to this criticism by saying they selected the controls very conservatively. Which means they selected control patients from that undisclosed data source. They don't disclose the selection criteria. We have no idea how they selected the controls from the data source that they also won't disclose. They won't tell us. That's not science.

Given all this, it's entirely possible the 'control group' were patients presenting at the OR with severe disease, who received triple therapy and were hospitalized and died. A reader evaluating your data simply has no way to know.

They make a great deal throughout the paper that treated patients have a much lower death rate than controls. It's one of the major claims of the paper. We have no idea what the control group is, so we don't know if the difference is relevant. But more, that difference is not even statistically significant. The stats show that there is no significant difference in death rates.

Unless I missed something, the authors disclose this in only one sentence, and in one data table, where they show that for mortality, p=0.16, without flagging it as not significant. In fact, they attempt to excuse it, by saying in effect that the lack of significance is caused because they don't know enough about patients in the comparison group. That doesn't save the claim. Rather the opposite, in fact.

It's a case series, not a "case series study." The inclusion of the comparison group in this form is worse than useless, it's actively misleading. If HCQ in any treatment regime actually works, which seems increasingly unlikely based on randomized trials, this paper does a disservice to advancing our knowledge of that fact.

Comment: My biggest question with this study is the reason for using HCQ at all.


Chelated zinc is known to be the most effective and readily metabolized form of zinc. We also know zinc from red meat is more readily absorbed than it is from vegetables.


"Hydroxychloroquine's main function within this treatment approach is to allow zinc to enter the cell. *Zinc is the virus killer*, and azithromycin prevents secondary bacterial infection in the lungs and reduces the risk of pulmonary complications."


That said, again, how is HCQ proven to be more effective at promoting zinc absorption than what we already use? Is it even necessary?


Additionally, there’s a big question mark with the “public reference data” used for the control group. How did they verify these patients were “untreated”?


I *strongly* suggest this study be withdrawn until these key issues and biases are addressed.

Thank you.

Comment: I read through the draft and saw no demographic information on the race of the treated patients vs. the control patients. Since race appears to be a significant risk factor, it might be wise to include that information. If the treated patients came from the Hasidic community where Dr. Zelenko practices, then there may be substantial racial differences between that set of patients and the broader community.

Comment: Excellent work!
I'm a Computer Scientist, not a Physician, but a medical degree is not needed to discern what makes sense from what doesn't.
Fact: HQC has not provided a double-blind, randomized study.
Fact: Remdisivir can offer a double-blind, randomized study.
But here are some additional facts.
Fact: In the Ford Health System study of the effectiveness of the HQC protocol vis-a-vis Remdesivir, HQC showed better results than Remdesivir
Fact: Remdesivir has some significantly more long term adverse effects than the HQC protocol.
https://www.drugs.com/sfx/remdesivir-side-effects.html
Fact: enough data is now available to unequivocally affirm that the death rate in countries that have been using the HQC protocol is 80% lower than those who have not. And the number of studies now available on the use of HQC is large and overwhelmingly supportive of Dr. Zelenko's claims.
A compilation of them is available at
https://c19study.com/ It is imperative that the FDA rescind all restrictions on the prescription and dispensation of HQC and allow it to be used at the discretion of physicians and patients.
We must take politics and financial gain out of a decision-making process that can save tens of thousands of lives in the coming months.

Comment: The control group is a consecutive series of covid-19 patients, of all levels of severity.

The study patients should also be a consecutive series encountered by him, but it is not. During this study, Dr Zelenko doubtless had consultations with some patients reporting such urgent symptoms that he sent them directly to hospital for in-patient treatment, notably oxygen in some form. By excluding these severe cases, he has selected milder cases for treatment. Dr Zelenko's records are good, and he should give the number of sick patients he sent for immediate hospital care during the study period. If any of his patients went directly to hospital emergency departments on their own initiative, he would see them on discharge and/or get a summary letter from the hospital. Their number should also be given.

Comment: Was strain typing performed? Could that be the reason behind the both the severity of disease and response to treatment? This in turn begs another question - could the severity of the disease confounded the patients' outcome in the study as Group A has both symptomatic and asymptomatic patients?

Comment: I am not in the public health. However, I have followed closely public the discussions by Dr. Zelenko in recent months. I have also followed the positive case and death counts on websites of my local counties. I presume one needs to make a request to the public health agencies of local counties through proper channel to examine the records. On Aug 11, I heard Dr. Zelenko say that his data is available for examination by anyone via legal means.

That said, I want to address this question on the demand for the gold standard RCT. First, I want to state that no experiments in physical sciences that I know of does any randomization for canceling of confounding factors or biases. In health sciences involving patients, to my knowledge the randomization is an efficient way for cancellation of biases and confounding factors. However, it is not clear to me that a placebo RCT can be performed on every segment of covid-19 patients and stages of illness. I cannot think that high risk patients can be given apart from the best of cares in light of available treatments.

Absent of an RCT study on high risk patients at the early stage of illness, here, I want emphasize that the paper's results of N=141 high risk patients is not insignificant. I am speaking not as a statistician. For background, I looked at the binomial distributions for mean frequency p=0.99 for cases N=10, 100 and 1,000. At 100, the peak is from 98 to 100. In other words, if one saw 99 patients of 100 survived, then when repeated the likely outcomes can be 98 to 100. The distribution allows for even lower numbers to 95 with very low probabilities. If patient count were 1,000, the distribution peak gets sharper and the results are even more solid. If non-randomized results are statistically solid, then any randomization in sampling (i.e. RCT) will not change outcomes.

Granted that there can be confounding factors, we can look at what the possibilities are. Out of the 35,000 population in the community of one square mile [per Dr. Zelenko], assume the positive cases in the duration from Mar to May were of 10%, that is 3,500.

all patients 335+37(10.6%) out of 3,500
high risk 104+37(37.9%) out of 335+37

If we assume 40% to be the community wide number out of the 3,500, then there were 1,400 high risk patients. So, the number of high risk patients in the community is in the ball park of 1,500.

It is remarkable that Dr. Zelenko's clinic saw ~10% of the high risk patients in that time period early in the pandemic. Apart from the paper, Dr. Zelenko has frequently mentioned publicly of his team having seen ~2,200 covid-19 patients. And, the paper presents only 4(2.8%) out of 104+37 high risk patients got hospitalized compared to 58(15.4%) out of 377 in the community from public reference data. From this, the hospitalization rate is bracketed between 2.8% and 15.4%. Suppose, we form a binomial distribution for N=1,500 with mean frequency p=0.154 for hospitalization. At the 1,500, the peak is practically zero at below p=0.13 with the sum from p=0 to 0.13 giving only probability of 0.004. There is not much probability for below p=0.13 that is around p=0.028 and is almost zero from p=0 to 0.06, that is 1.4E-29 or 1.4x10^-29.

Having done this analysis, it appears to me that if the community hospitalization rate were 0.154 among high risk patients, the probability is zero for a local clinic to be seeing a rate of only 0.028 unless an external influence is present.

Comment: This is an excellent article and I am very happy to see more and more studies underway to explore hydroxychloroquine, zinc, and azithromycin combo therapy for treating people with COVID-19. What baffles me is how much money and effort is being poured into fast-tracking novel, untested, and possibly expensive vaccines and how very little comparative effort and resources are being allocated to studies of this inexpensive and readily accessible alternative to vaccines. It appears that proponents of hydroxychloroquine are in an uphill battle to garner support for the use of this medication for COVID-19. A course of treatment for Remdesivir is $3500. The combo therapy of hydroxychloroquine, zinc, and azithromycin run less than $100. The bigger question to investigate would be “who has an investment in a vaccine solution (or expensive prescription antiviral medication) versus who stands to benefit from the hydroxychloroquine/zinc option.” Another question that might be raised is, why is there such tremendous resistance to the use of hydroxychloroquine? When faced with a life-threatening illness, who in their right mind would not employ what has been a safe, accessible, and inexpensive course of treatment for many decades?

Comment: I find it very disturbing that Zalenko repeatedly stated on his channel and in interviews that he treated hundreds well over 1000 patients for COVID, and that now all he can produce is a study that contains 104+37 patients. I no longer feel I can trust him. If the hundred of patients not included here never took a test to prove that they had the covid, then he should never have said he treated hundreds of patients who had covid! That is extraordinarily unethical. The president was making decisions based on feedback from doctors on the front line and him in particular. I feel he misled the president and the nation, and ppl like me who have been defending him at great cost to our reputation. Shame on him!

Comment: A huge congratulations and many thanks for sharing this information!

So, reading between the lines, we basically have highly effective prophylaxis treatment for COVID-19 comprised of just 3 OTC supplements:

1. Elemental Zinc.
2. Quercetin OR Epigallocatechin-gallate (EGCG) from Green Tea.
3. Vitamin C.

All available in the local chemist without prescription and all perfectly safe and good for the health supplements regardless of COVID-19!

I'm sure his excellency Dr. Zelenko would agree that the best way to reduce the pandemic as quickly and as safely as possible would be for as many adults as possible to take the above supplement combination for a period of time.

Once again, enormous gratitude!
MF

Comment: Thank you for all your comments. I am a family physician and not a researcher. I was not doing research, rather I was trying to keep my patients alive and out of the hospital. In early March, there was NO out-patient treatment recommended or even suggested. I was the FIRST in this country (perhaps even the world) to suggest and implement successful out-patient treatment of high risk patients. To suggest that the control group may of also received treatment is intellectually dishonest. At that time I was attacked from every direction and had no support from anyone. Thus, it is reasonable to assume that I was the ONLY one treating patients in this manner.

Regarding selection bias of the control group: there was absolutely a bias but it was against me. I only treated high risk and patients (most of which were over the age 60) whereas the control group had both low and high risk patients. It is reasonable to assume that the average age of the control group was lower than the patients that I treated.

Comment: I really liked the article and its methodology, within the expected limitations due to only indirect access to patients in the control group.

I have a question not entirely related to the article, but I think that it's worth an answer from one the authors.

How do you think the use of Ivermectin compares with the use of Hydroxychloroquine, in the sense that it is even rarer that there are side effects with the use of Ivermectin?

With Ivermectin, it is possible that even patients with less risk could take it with litlle risk.

Would it make sense to add zinc to those prescribed to use Ivermectin with Azithromycin or Doxicillin?