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1 minute ago, Newdoc said:

5,000 ius maybe on the high side if you are already normal. You’re probably safe at 1000 ius a day but if you happen to be really low then that may not move the needle. Vitamin D levels over 30 ng/ml seem to confer good immune response.

The data doesn’t appear to show it prevents infection but rather allows an effective initial and robust immune response.

Thanks!  And, since it can take weeks to show increased levels, sounds like this is something that builds up over time?  Is that how it works?

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I increased my vitamin D level from 17 to thirty-something by taking 2000 IUs per day.

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7 minutes ago, Newdoc said:

5,000 ius maybe on the high side if you are already normal. You’re probably safe at 1000 ius a day but if you happen to be really low then that may not move the needle. Vitamin D levels over 30 ng/ml seem to confer good immune response.

The data doesn’t appear to show it prevents infection but rather allows an effective initial and robust immune response.

my doc said 1000iu a day.  been doing that for 7 or 8 years plus a multivite.  I was only a bit low.

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Posted (edited)

There's a rule of thumb that for every 1000 IU of Vit D3 you take, you can expect an increase in blood level by 10 ng/mL.  So 5000 IU/d sustained will likely bump you significantly above the general normal level of 30 ng/mL, but not really near the standard toxic level considered to be above 150 ng/mL.  If you look at this graph I linked last page, you see that even at a normal level of 30 ng/mL, a pretty siginifcant percentage of folks experienced Covid associated fatal demise (with an average age of 60y/o).  

Spoiler

Ed4RsRaXkAEqAoA?format=png&name=medium

 

So having a blood level in the 40-50 ng/mL range might be preferable to swimming around the 'normal' level of 30 while still not approaching anything considered toxic D3 levels.  I'll probably back off to 5000 IU every other day since I've been taking it long enough to sustain the boost (5000 IU daily since March).

edit: also re-posting this 2 week old pre-print from Lancet:

Vitamin D Sufficiency Reduced Risk for Morbidity and Mortality in COVID-19 Patients

 

Edited by triplehorn

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On 7/29/2020 at 1:23 PM, Anastasis said:

I believe that @Fat Bastard is a cardiologist.  Perhaps he would care to comment on the relevance of the results in the JAMA publication linked up thread?

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It’s very sobering data, tbh, and it’s making big news in our community, especially considering the downstream sequelae younger CV19 patients may have who did not require hospitalization. The good news regarding this study (admittedly from the abstract that I read) is that it was just radiographic findings with really zero clinical significance. The mean LVEF was still >55%, which is very promising. Of course, knowing that a very common etiology for nonischemic cardiomyopathy (NICMP) is viral illness, it’ll be very interesting to see the downstream effects of this virus especially if they have other CV risk factors. 

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Posted (edited)

Why combine Azithromycin with HCQ, or add AZ at all?   This study shows a potentially very significant association that Azithromycin and CQ/HCQ have in common re cell physiology:

Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin

AZ and HCQ both have uniquely massive Volume of Distribution values and accumulate to massive concentrations inside cellular lysosomes due to the acid/base properties of their poly-amide groups.  I point this out as an extension of the post on the previous page as it relates to lysosomal roles in inflammasome activation.  Individual susceptibility to immune response dysregulation stemming from activation of the highly inflammatory inflammasome response is a key focus of the Yale collab findings on disease trajectories as a function of newly revealed immune signatures in covid patients. 

Does AZ share the same specific anti-inflammatory mechanisms as HCQ as described here and is it a function of very high intracellular concentrations in lysosomes?:

Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

In short, this association between AZ and HCQ could point to a shared role disrupting the activation pathways of inflammasomes and subsequent cascades contributing to late stage cytokine storm and death.  In other words, it points to AZ and HCQ both targeting and inhibiting/disrupting a very specific inflammatory pathway implicated in Covid demise.

 

 

 

Edited by triplehorn

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Posted (edited)

The trial I mentioned searching for on the CR thread was for IV zinc, which I don't think is practical for community use in the US. Also I couldn't tell if study is active or not.  While searching I did find an article about why zinc might be efficacious either alone or in combination w HCQ. Posting here instead of there because why derail a CR thread with reasoned, thoughtful discussion?  

n.b. I know nothing about the quality of the journal and this is labeled "opinion"

ETA IL-6 is a bad MF. anything that can suppress its activation as part of the immune response should help reduce likelihood of ARDS

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01736/full

 

Quote

Key Points

• Zinc deficiency may be common and associated with severe infection.

• Zinc helps to enhance the interferon type 1 response to the virus and participates in many regulatory pathways.

• Low levels of zinc have been associated with higher IL-6 responses.

• IL-6 plays an important role in severe lung injury due to COVID-19 infection.

• Zinc inhibits SARS-CoV RNA polymerase, and thus its replication capacity.

• Zinc may increase the efficacy of antimalarial agents, since they are zinc ionophores.

• Differences in mortality due to COVID-19 infection may be explained to some degree by−174 IL-6 gene polymorphism

 

 

Edited by Sawbonz

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https://www.nejm.org/doi/full/10.1056/NEJMoa2019014

 

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Abstract

BACKGROUND

Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.

METHODS

We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.

RESULTS

A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P=1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P=1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.

CONCLUSIONS

Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123. opens in new tab.)

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22 minutes ago, Sawbonz said:

The trial I mentioned searching for on the CR thread was for IV zinc, which I don't think is practical for community use in the US. Also I couldn't tell if study is active or not.  While searching I did find an article about why zinc might be efficacious either alone or in combination w HCQ. Posting here instead of there because why derail a CR thread with reasoned, thoughtful discussion?  

n.b. I know nothing about the quality of the journal and this is labeled "opinion"

ETA IL-6 is a bad MF. anything that can suppress its activation as part of the immune response should help reduce likelihood of ARDS

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01736/full

 

 

 

My company developed an anti-IL6 antibody but it didn't perform well in clinical trials. It would have probably done pretty well for this disease. It's buried somewhere in Amgen's vaults now.

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My wife’s 16 year old cousin had to go to ER last night with atrial fibrillation. He was just released and it was determine he had cardiac artery swelling due to a prior undiagnosed COVID-19 infection. They haven’t been social distancing.

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26 minutes ago, Sawbonz said:

The trial I mentioned searching for on the CR thread was for IV zinc, which I don't think is practical for community use in the US. Also I couldn't tell if study is active or not.  While searching I did find an article about why zinc might be efficacious either alone or in combination w HCQ. Posting here instead of there because why derail a CR thread with reasoned, thoughtful discussion?  

n.b. I know nothing about the quality of the journal and this is labeled "opinion"

ETA IL-6 is a bad MF. anything that can suppress its activation as part of the immune response should help reduce likelihood of ARDS

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01736/full

 

 

 

 

Add Zinc as playing an essential role in adaptive and innate immune response.  Quite the refresher, but I don't think I ever learned how integral Zinc is to immume regulation.  Having a robust innate T cell capacity is key for rapid response to novel pathogens.  This section from the article really jumps out:

Quote

Zinc homeostasis in immune system pathways is complex, since it participates both in pro-inflammatory and regulatory pathways, and much of the data comes from preclinical in vitro studies. Despite this, it seems clear that deficient or excessive zinc levels can lead to malfunction of the adaptive and innate immune systems. Zinc regulates the proliferation, differentiation, maturation and functioning of lymphocytes, and other leukocytes (6). It also regulates the immune response, and its deficiency increases susceptibility to inflammatory and infectious diseases, including pneumonia (50). Zinc sulfate supplementation at 20 mg/day for 5 months reduced acute lower respiratory tract infection morbidity vs. placebo in a clinical trial (51). Zinc is essential in both the adaptive and innate immune systems (52). For instance, the functionality of natural killer (NK) cells, which are essential for maintaining the immune response against viruses and tumors, is affected by low levels of zinc (53). Furthermore, zinc supplementation significantly increased NK cell numbers in whole blood cultures and NK cell activity in vivo (54, 55). In this latter study, zinc supplementation in subjects with low or borderline-normal circulating zinc increased the concentration of this ion and improved NK lytic activity, as well as modulating plasma IL-6. Zinc homeostasis directly influences the formation of lymphocytes and the secretion of cytokines and indirectly alters their stimulation by the innate immune system (56). There is also evidence that unregulated zinc homeostasis in macrophages impairs phagocytosis and results in an abnormal inflammatory response (57)

 

As an aside and not directly speaking to Zinc, a just published letter to the editor of Intl. J. of Infectious Disease reports a retrospective study from Italy (539 COVID-19 hospitalized patients were included in cohort in Milan) reporting "the use of hydroxycholoroquine + azithromycin was associated with a 66% reduction in risk of death as compared to controls" :  Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?   This is not a closed case by any stretch.

 

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Thanks to all for your contributions to this thread. It's really enlightening.

 

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1 hour ago, Anastasis said:

 

https://www.nejm.org/doi/full/10.1056/NEJMoa2019014

 

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Abstract

BACKGROUND

Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.

METHODS

We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.

RESULTS

A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P=1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P=1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.

CONCLUSIONS

Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123. opens in new tab.)

I honestly have a lot of respect for the medical profession. They perform near miracles on a daily basis. But to say they can be hard headed on occasion is an understatement. When an Australian doctor figured out that antibiotics cured ulcers in almost 100% of his patients, and he published a paper to that effect in 1985, it took TEN YEARS for the medical community to accept it.  What is surprising given the low cost and safety of the treatment, and the fact that virtually 100% of patients were being cured, is that very few doctors just tried it.  Thousands, maybe hundreds of thousands, of patients suffered and some died while this treatment was being proven in RCT's.  The incentives for doctors to try unproven treatments is very low, and I can understand that.  HCQ is particularly tough, given that most patients will recover without it, and some may die with it.  It's very hard to tease out the real signal from all the noise.

However, it makes sense to me as a patient (without heart issues) to try HCQ plus zinc as an outpatient when covid is first suspected. Very low risk, and possible to probable benefit, and there is nothing else anyway. If I have to play Russian roulette, I'd like as few bullets in the chamber as possible.  From a doctor's perspective prescribing it, it's all risk and no benefit. You could get sued if the patient has a heart problem, and there is no upside to them recovering without hospitalization, which they will likely do anyway.

 

 

 

 

 

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1 hour ago, CooterBrown said:

My wife’s 16 year old cousin had to go to ER last night with atrial fibrillation. He was just released and it was determine he had cardiac artery swelling due to a prior undiagnosed COVID-19 infection. They haven’t been social distancing.

Damn, that's frightening, and a pretty good argument against opening high schools right now.

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14 minutes ago, JohnLocke said:

However, it makes sense to me as a patient (without heart issues) to try HCQ plus zinc as an outpatient when covid is first suspected. Very low risk, and possible to probable benefit, and there is nothing else anyway.

There is some evidence that HCQ counteracts the antiviral effect of remdesivir.  I by no means think that remdesivir has shown itself to be a particularly outstanding treatment, but it is one of the few options available. In vitro data suggests that HCQ antagonizes the antiviral activity of remdesivir. The half-life of HCQ is very long (~40 days), so if you end up in the hospital after a course of HCQ, and remdesivir becomes a necessary treatment, it's effectiveness may be reduced. 

I don't really care if you take HCQ or not, to be honest. I understand that in the anxiety of the situation, people are looking for any hope to cling to. I was optimistic based on the early information coming out. That was in like March.  But it just hasn't shaken out. That said, I have recently helped people who were insistent obtain HCQ. I tried to talk them out of it and gave them the whole run down, but ultimately I think that people should be able to make their own decisions with the information at hand.  If in July where we sit now, people want to take HCQ based on the very low quality and level of the evidence, bad epidemiology, and a shot in the dark, that's on them.  Just don't pump the decision making with backasswards epidemiological analysis.  

https://www.fda.gov/media/137566/download

Antiviral Activity Remdesivir exhibited cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. The EC50 values of remdesivir against SARS-CoV-2 in Vero cells was 137 nM at 24 hours and 750 nM at 48 hours post-treatment. The antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in normal human bronchial epithelial cells.

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2 hours ago, Bevo said:

My company developed an anti-IL6 antibody but it didn't perform well in clinical trials. It would have probably done pretty well for this disease. It's buried somewhere in Amgen's vaults now.

Roche just had a negative trial with tocilizumab.  Results of combo trial with remdesivir pending. 

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18 minutes ago, JohnLocke said:

I honestly have a lot of respect for the medical profession. They perform near miracles on a daily basis. But to say they can be hard headed on occasion is an understatement. When an Australian doctor figured out that antibiotics cured ulcers in almost 100% of his patients, and he published a paper to that effect in 1985, it took TEN YEARS for the medical community to accept it.  What is surprising given the low cost and safety of the treatment, and the fact that virtually 100% of patients were being cured, is that very few doctors just tried it.  Thousands, maybe hundreds of thousands, of patients suffered and some died while this treatment was being proven in RCT's.  The incentives for doctors to try unproven treatments is very low, and I can understand that.  HCQ is particularly tough, given that most patients will recover without it, and some may die with it.  It's very hard to tease out the real signal from all the noise.

However, it makes sense to me as a patient (without heart issues) to try HCQ plus zinc as an outpatient when covid is first suspected. Very low risk, and possible to probable benefit, and there is nothing else anyway. If I have to play Russian roulette, I'd like as few bullets in the chamber as possible.  From a doctor's perspective prescribing it, it's all risk and no benefit. You could get sued if the patient has a heart problem, and there is no upside to them recovering without hospitalization, which they will likely do anyway.

Re the study involved in the quote you responded to, pay close attention to the fine print:  "The primary outcome was clinical status at 15 days."  This is a departure from mortality outcomes and it represents an arbitrary(?)  "15 day window" that neglects the potential for outcome measures between groups to diverge after 15 days.  Just saying it's a very peculiar design that has built-in outcome omissions where positive findings exist in other studies.  Also for all the talk about QT prolongation, in public discourse there's been no accounting for just how many commonly prescribed medications are associated with QT prolongation.  Anyone doing a quick search realizes it's a whole lot, many of which are being taken/have been taken by posters right here without having an EKG.  The vast, vast majority of the time, for all those meds, the associated QT prolongation does not justify getting an EKG, and in the outpatient setting, typically none are ordered because even with measurable QT prolongation, it doesn't approach clinical relevance.  Elevated LFT's?  To the extent it even happens for an individual, it would be transient and harmless given that clinical exposure to HCQ in this context amounts to a duration lasting from 5 days to 2 weeks (at the extreme end).  Check LFT's after a couple nights of beer and 'rita's and good chance you'll see elevated LFT's in a healthy person that completely subside within 72 hrs of not drinking.  This is everyday stuff.

With Covid, Quinine derivatives appear to be a two-fer; increased intracellular Zinc (slowing early viral replication rates) and targeted anti-inflammatory effects significantly upstream from associated end-stage cytokine storm with Covid.  The unique anti-inflammatory effects (and likely AZ too) wrt covid loom really large right now.

Re viral replication, realize that the RATE at which a virus can enter a cell, replicate, and leave the cell is an adaptive trait subject to natural selection.  In this case a successful virus can accomplish this cycle faster than innate immunity (ie NK 'killer" T cell / non-antibody mediated) can neutralize infected cells/kill virus.  If simply increasing intracellular Zn concentration slows activity of coronavirus RdRp (viral RNA polymerase) - which it does -suddenly the virus is running with its feet in cement blocks and it gets overwhelmed by existing innate T cell immune function from viral inception. 

If intracellular Zn is optimized prior to or right after infection occurs, it follows you impact disease trajectory.  Doesn't mean you prevent detectable infection, but altering the trajectory in this fashion could render it essentially harmless, is is being observed in numerous studies.  But again, it's the unique mechanistic anti-inflammatory fit of Quinine derivatives that likely is playing a larger role when taken for about 5 days duration at onset of signs of infection with this coronavirus.

 

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So it sounds like you're saying I should double my gin and tonic intake?

 

BOOM, SCIENCE!

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6 minutes ago, triplehorn said:

Re the study involved in the quote you responded to, pay close attention to the fine print:  "The primary outcome was clinical status at 15 days."  This is a departure from mortality outcomes and it represents an arbitrary(?)  "15 day window" that neglects the potential for outcome measures between groups to diverge after 15 days. 

HCQ has such a profound clinical effect that we can't even observe it within 15 days! 

 

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52 minutes ago, Anastasis said:

Roche just had a negative trial with tocilizumab.  Results of combo trial with remdesivir pending. 

Thanks. It looks like there are some anti-IL-6 antibodies on the market now. I'm kind of surprised. I wasn't too thrilled with the target for complex reasons that I thought would lead to too many unintentional consequence ie side effects/toxicity.

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41 minutes ago, Anastasis said:

HCQ has such a profound clinical effect that we can't even observe it within 15 days! 

And just so nobody is misled by nonsense. Mortality was baked into the primary outcome measure in that study, and in-hospital death was a stand-alone secondary outcome measure.  There was likewise no difference between groups on the secondary endpoint.  Mortality as a standalone can't be the primary outcome because the study would be futile and hopelessly underpowered. You would have to have a study with approximately N=30,000 to achieve 80% power to detect the observed between group difference in mortality.  There is nothing peculiar about it at all, unless you have a strange religious affiliation to quinine derivatives.

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Posted (edited)

Here's a story yesterday on tocilizumab negative findings:  Roche bid to retool arthritis drug for COVID-19 fails

Quote

 

"ZURICH (Reuters) - Roche's attempt to retool its rheumatoid arthritis drug Actemra/RoActemra to treat patients hospitalised with severe COVID-19-related pneumonia has failed in a late-stage trial, the Swiss company said on Wednesday.

[...]

The "COVACTA trial did not meet its primary end-point of improved clinical status in patients with COVID-19 associated pneumonia, or the key secondary end-point of reduced patient mortality," Roche said.

The news follows an Italian study that showed the drug failed to help patients with early-stage COVID-19 pneumonia."

 

Tocilizumab (Actemra) targets IL-6 for inhibition.  Someone else may be able to offer some detailed clarification, but IL-6 seems to be recognized as a relatively late-appearing cytokine prominent after illness progression to pneumonia  Targeting IL-6 may be helpful applied to the timeline of rheumatoid arthritis, but the Covid timeline for progression is far more rapid.  By the time you've got pneumonia and you're trying to block IL-6, it's too late. 

Targeting early mechanisms of inflammation that now appear associated with early Covid immune dysregulation, like IL-1b and IL-18 are likely to offer more help in preventing onset of pneumonia and death.  But again, the big difference maker across the board is early recognition and initiation of treatment.

Rheumatologists target IL-1b, TNF-a, and IL-6 with quinine derivatives:  

Chloroquine inhibits production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes

 

 

 

Edited by triplehorn

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Posted (edited)

Two very good threads from a pharmacist specializing in infectious disease.  They a) outline the trajectory of the HCQ experience; and b) explain the issues with observational data analysis in this particular setting.

 

 

Edited by Anastasis

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4 hours ago, JohnLocke said:

If I have to play Russian roulette,

The problem is I don’t like to play Russian roulette with the hypocratic oath, my state license and a liability lawsuit.

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^^^ I looked at that post above.  Those two twitter threads are a beating.  Of Note, he completely omits any consideration of viral RNA polymerase inhibition in any time frame.  He's talking about effects on pH values related to inhibiting viral invasion of a cell.  So the pH/endosomal pathway is a no go?  Ok, that's ignoring a lot of other considerations.  He doesn't even whiff any anti-inflammatory mechanisms of quinines in this context as a function of mitigating risk of progressing to cytokine storm and death.  There are enough studies out now that people can pick and choose in isolation.  He's good at that.

I did notice he referenced the negative Boulware Minnesota post-exposure prophylaxis study.  I saw this critical review of the data and what Boulware failed to recognize about his own data set:

Efficacy of Hydroxychloroquine as Prophylaxis for Covid-19:

The entire article is in pdf form at the link

"Limitations in the design of the experiment of Boulware et al[1] are considered in Cohen[2]. They are not subject to correction but they are reported for readers' consideration. However, they made an analysis for the incidence based on Fisher's hypothesis test for means while they published detailed time dependent data which were not analyzed, disregarding an important information. Here we make the analyses with this time dependent data adopting a simple regression analysis.
We conclude their randomized, double-blind, placebo-controlled trial presents statistical evidence, at 99% confidence level, that the treatment of Covid-19 patients with hydroxychloroquine is effective in reducing the appearance of symptoms if used before or right after exposure to the virus. For 0 to 2 days after exposure to virus, the estimated relative reduction in symptomatic outcomes is 72% after 0 days, 48.9% after 1 day and 29.3% after 2 days. For 3 days after exposure, the estimated relative reduction is 15.7% but results are not statistically conclusive and for 4 or more days after exposure there is no statistical evidence that hydroxychloroquine is effective in reducing the appearance of symptoms.
Our results show that the time elapsed between infection and the beginning of treatment is crucial for the efficacy of hydroxychloroquine as a treatment to Covid-19."

^^^ Boulware's data suggest you have about 48hrs post-exposure to get a meaningful observable effect.  The sooner the better. 

 

Or better yet, do pre-exposure prophylaxsis.  India is pleasantly surprised with their large scale prophylaxis results:

'Pleasant surprise' with antigen test of BMC staff, 16 of 2,400 +ve

 

Mumbai has been using hydroxychloroquine prophylaxis on its essential civic employees --> expecting to find 360 positive cases in a test campaign, it finds only 16.  
 
 
 

 

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This is the part where the psychiatrist critiques the work of an infectious disease pharmacist and a randomized placebo controlled trial by posting word salad and a link to a lay press article in the Times of India.  

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So, back when one of these threads started, there was a long conversation about ARBs and ACEI for hypertension.  Idea being that since the virus latches on to ACE-2, and people taking these drugs express a lot more ACE-2 than other folks, they would be more at risk for catching and/or more severe symptoms.  

I, for one, switched from an ARB to a CCB (amlodipine) for this reason-with my doctor's OK, if not encouragement.

Well, several studies have been done in the last few months - pretty robust-looking to my non-scientist eye, and it looks like that may not be a concern.  Peer review and all that, but it doesn't look so far like there's any statistical correlation between ARB/ACEI use and higher infection rates or more severe courses of COVID.

https://www.acc.org/latest-in-cardiology/articles/2020/07/15/13/12/covid-19-and-use-of-drugs-targeting-the-renin-angiotensin-system

https://jamanetwork.com/journals/jama/fullarticle/2767669

https://www.nejm.org/doi/full/10.1056/nejmoa2006923

https://scopeblog.stanford.edu/2020/07/14/high-blood-pressure-drugs-dont-increase-covid-19-risk-stanford-study-finds/

https://jasn.asnjournals.org/content/early/2020/07/14/ASN.2020050667

https://www.nejm.org/doi/10.1056/NEJMoa2008975

Amlodipine isn't really working for me, so I think I might switch back to olmesartan.

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I started Lisinopril back in March, proud of myself for finally taking on my BP.  Then a few weeks later the concern started, my PCP said it was up to me as the evidence wasn’t convincing yet, and I decided to stay on my ACEI.  Glad to hear it’s likely overblown as 10mg a day keeps me in check and I don’t want to start hunting for something new.  

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I am still taking my lisinopril. Paused for a bit on the early reports but restarted a long time ago. 

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50 minutes ago, Newdoc said:

The problem is I don’t like to play Russian roulette with the hypocratic oath, my state license and a liability lawsuit.

I completely understand that stance.  I wouldn't go so far as to call it roulette, but the national and social conflict over it is like bullets rolling around on a table.  Someone may be swept up by the conflict, pick one up, and fire it back at you under adverse conditions.  I'd just stay open-minded listening to patients if they bring it up to gauge how well they understand the relative risks of enduring Covid with supportive care only versus off-label use of a drug(s) with a solid safety index (even pregnant women and children take it safely at proper dose).  TX permits off-label use, so it's a professional and personal choice as a treating physician.  I've found a lot of people understand the relative unknowns of intervention as well as the potential consequences of Covid, and to them it's an easy choice to have on hand.  Unfortunately my state currently precludes off-label use for covid but I'm not sure how hard it's being enforced.  I know a couple primary docs who are responding to their patients' serious requests for intervention, but it's not being pushed or promoted at all, and no adverse events or bad outcomes have occurred to date.

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Former clinical instructor from Yale School of Medicine Dr David Katz.  We depend on level headed discourse like this.  I'd say this is a must watch

 

 

I wonder how aware he is of his Yale peers' findings last week on defining Covid disease trajectory clusters and predictive early immune signatures with implications for targeted therapy early on. #Inflammasomes

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Posted (edited)

YouTube is where I always go for my daily dose of level headed medical advice. #inflammasomes. 

Edited by Anastasis
Why not?

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12 hours ago, triplehorn said:

Former clinical instructor from Yale School of Medicine Dr David Katz.  We depend on level headed discourse like this.  I'd say this is a must watch

 

 

I wonder how aware he is of his Yale peers' findings last week on defining Covid disease trajectory clusters and predictive early immune signatures with implications for targeted therapy early on. #Inflammasomes

This guy again.  He was the “lockdowns don’t work” and the “cure is worse than the disease” guy from March.  He wanted everyone but the very oldest and very sickest to go out and catch it on purpose to build herd immunity.


I guess they’re like weathermen.  Doesn’t matter how wrong or how often, they’re still experts. 

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Posted (edited)
23 minutes ago, Liquor and Poker said:

This guy again.  He was the “lockdowns don’t work” and the “cure is worse than the disease” guy from March.  He wanted everyone but the very oldest and very sickest to go out and catch it on purpose to build herd immunity.


I guess they’re like weathermen.  Doesn’t matter how wrong or how often, they’re still experts. 

I don't agree with those takes in general, but I'd be interested to hear an argument from someone with his credentials and ability to articulate on these matters.  Are you sure it's the same person?

What you describe above says nothing about the pragmatic explanation he provides of where we stand on understanding mechanisms and timing for efficacy, and patient selection and safety.  There is ample evidence suggesting early therapeutic benefits are significant and real, and safety has not been an issue.  Note also the rationale provided around why HCQ/Azithromycin or doxycycline plus Zn as opposed to monotherapy. 

Taking (H)CQ is not playing Russian roulette.  The real roulette is what happens when this virus takes you for a ride.  

 

Edited by triplehorn

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1 minute ago, triplehorn said:

Are you sure it's the same person?

I'm 100% sure.

About halfway down in this article is a summary:

https://www.buzzfeednews.com/article/stephaniemlee/ioannidis-trump-white-house-coronavirus-lockdowns

Or you can read his Op-Ed from the NYT.

https://www.nytimes.com/2020/03/20/opinion/coronavirus-pandemic-social-distancing.html?searchResultPosition=2

Or his interview with Bill Maher:

 

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Thanks.  The Maher interview is the best representation.  It's a good listen.  He uses a lot of public health and epidemiologic nuance in describing and discussing the "Lose/Lose" predicament of Covid, but "lockdowns don't work" and "cure is worse than the disease" does not accurately capture or reflect what he is communicating.  

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1 hour ago, triplehorn said:

Thanks.  The Maher interview is the best representation.  It's a good listen.  He uses a lot of public health and epidemiologic nuance in describing and discussing the "Lose/Lose" predicament of Covid, but "lockdowns don't work" and "cure is worse than the disease" does not accurately capture or reflect what he is communicating.  

He had definitely walked back a bit by then because he was the guy Trump cited for his reopen by Easter rhetoric. 
 

More on that in this Zakaria debate:

https://www.cnn.com/videos/tv/2020/03/29/exp-gps-0329-c-blk-web.cnn

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1 hour ago, Liquor and Poker said:

He had definitely walked back a bit by then because he was the guy Trump cited for his reopen by Easter rhetoric. 

...by Easter?  No wonder @triplehorn has a hard on for the guy.  They share the same spirit animals. 

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5 hours ago, triplehorn said:

Taking (H)CQ is not playing Russian roulette.

It can be when you combine it with Zithromax. 

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20 hours ago, Newdoc said:

It can be when you combine it with Zithromax. 

Odds of bad outcome summarized:  "This fact is proven by an Oxford University study of more than 320,000 older patients taking both hydroxychloroquine and azithromycin, who had arrhythmia excess death rates of less than 9/100,000 users [0.00009%] as I discuss in my May 27 paper cited above. A new paper in the American Journal of Medicine by established cardiologists around the world fully agrees with this."

Also note in this study of 200 hospitalized Covid patients while there is observed QT prolongation (as would be normally expected), there were zero instances of TdP and no deaths.  While this is only one study, what's important recognize is that these are really sick Covid patients already hospitalized.  Perhaps even more significantly, look at the baseline demographics of the participating subjects: 60% had pre-existing HTN, 42% dislipidemia, 32% diabetes, 7% a.fib., 11% CAD, 15% COPD, CHF 7.5%.  Yet no TdP and no deaths with these agents alone or in combination.  Given that, keep in mind available evidence points to best use of quinine derivatives in Covid as being targeted for application as soon as possible following exposure/onset of infection, which represents a substantially more medically stable window than hospitalization after crashing from severe illness.  So early outpatient initiation would be expected to further reduce a risk that is already orders of magnitude lower under the worst circumstances than rolling the dice with Covid alone. 

 

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India is now all in.  In the Spring, they started prophylaxis of health care workers and expanded it to frontline civil workers.  Not only are they continuing it, they're aggressively expanding it.  India releases 42 millions pills of hydroxychloroquine directed for use as prophylaxis and treatment of Covid-19 patients.

Quote

"This drug (HCQ) should be used as early in the disease course as possible to achieve any meaningful effects and should be avoided in patients with severe disease. An ECG should ideally be done before prescribing the drug to measure QTc interval (and HCQ avoided if QTc is >500 ms). The dose should be given 400 mg twice on day 1 followed by 400mg daily for the next 4 days," stated clinical management protocol for COVID-19.

Prophylaxis protocols are essentially the same once weekly dosing regimen as is already dosed for malaria prevention.  On any given day, our own VA system uses 42,000 doses of hcq across all purposes.  

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1 hour ago, triplehorn said:

So early outpatient initiation would be expected to further reduce a risk that is already orders of magnitude lower under the worst circumstances than rolling the dice with Covid alone. 

 

We could cherry pick studies all day long. You have obviously put a lot of research into this topic.

For example, here is a JAMA Cardiology article that states the significant increase in QT when combining the drugs.

Jama Cardiology Azithromycin and HCQ

"Patients who were hospitalized and receiving hydroxychloroquine for COVID-19 frequently experienced QTc prolongation and ADEs, including a case of torsades de pointes with administration of hydroxychloroquine and azithromycin, which to our knowledge has yet to be reported elsewhere in the literature. There is a critical need for rigorous, large-scale studies and risk-benefit assessment prior to initiating COVID-19 therapeutics, with careful attention to medication interactions, cardiac manifestations, routine electrocardiograms, and electrolyte monitoring."

Until the benefit clearly outweighs risk then I will proceed with caution. I have not seen enough consensus to warrant wide spread use of this regimen.  I would like to see the bulk of studies and evidence moving towards this as a solution but I just don't think it's there yet.

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Baylor Cardiologists Support Hydroxychloroquine Emergency Use Authorization by FDA

"Dr. Kevin R. Wheelan, chief of cardiology at Baylor Heart and Vascular Hospital in Dallas and Dr. Peter McCullough, a clinical cardiologist and professor at the Texas A&M School of Medicine, issued a letter supporting the emergency use authorization (EUA) of hydroxychloroquine for outpatient treatment and prophylaxis for COVID-19."

 

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I'll listen to Baylor and Aggy grads when I am researching how to sexually assault women or sheep.

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Posted (edited)

I'm curious:  what is the chief driver of disagreement when it comes to evaluating evidence, clinical or otherwise, among medical and pharmaceutical professionals?

Watching @Anastasis, @triplehorn, et al go back and forth on HCQ for months is fascinating.  Is the disagreement in the scientific community related to noisy data, overreliance on bad tests, human nature, inconclusive evidence, or what?

I'm an engineer.  If I correctly evaluate the level of material stress in a dynamically loaded part, there could be reasonable disagreement between myself and other professionals about the ultimate cycle life of that part, because to a certain extent experience and good judgment come into play in determining what factors to consider.  But, when all is said and done, we should all land within maybe a 20% window on estimated life.  These trials being touted by various people to support their positions seem all over the map.

Edited by jimmyjazz

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