COVID-19 medical discussion

[triplehorn 2664]

Here's a correlation:

March 29th:  Italy Finally Starts Mass Treatment with Hydroxychloroquine

Quote

Doctors in Italy have finally began widely prescribing hydroxychloroquine in certain combinations in Rome and the wider region of Lazio with a population of around six million.

According to Corriere della Sera, a well known Italian daily newspaper, Dr. Pier Luigi Bartoletti, Deputy National Secretary of the Italian Federation of General Practitioners, explains that every single person with Covid-19 that has early signs, like a cough or a fever for example, is now being treated with the anti-malaria drug.

The drug “is already giving good results,” Bartoletti says while Malaysia reveals they have been using it since the very beginning. Bartoletti further adds that the drug:

“Must be used with all the necessary precautions, it must be evaluated patient by patient. It can have side effects. But those that take it are responding really well. 

We have just understood that the virus has an evolution in two phases and that it is during the second phase, after a few days (about a week), that the situation can suddenly, in 24 or 48 hours, worsen and leads to respiratory failure requiring intensive care.

The results that we are starting to accumulate suggest that hydroxychloroquine administered early, gives the possibility of avoiding this evolution in a majority of patients and is also helping us to prevent hospitals from filling up.”

Incredible. What is more incredible are the statements of Professor Christian Perronne, Head of the Infectious Diseases Department at the Garches University Hospital, made in an interview with a French weekly magazine.

Referring to the European Discovery trial in which UK is taking part with only 800 patients, Perronne says:

“I refused to participate because this study provides for a group of severely ill patients who will only be treated symptomatically and will serve as control witnesses against four other groups who will receive antivirals. It is not ethically acceptable to me.

We could perfectly well, in the situation we are in, evaluate these treatments by applying a different protocol. In addition, the hydroxychloroquine group (which was added to this study at the last minute), should be replaced by a hydroxychloroquine group plus azithromycin, the current reference treatment according to the most recent data.

Finally, the protocol model chosen will not provide results for several weeks. Meanwhile, the epidemic is galloping. We are in a hurry, we are at war, we need quick assessments.”

America is to start yet another study which is to take one month even while one thousand people or more are dying worldwide today. In Italy however doctors are finally not waiting anymore with Perronne saying:

“Even though the overwhelming evidence from large randomized studies is still lacking, I am in favor of a broad prescription for the following reasons:

1. We have a large body of evidence showing that in vitro hydroxychloroquine blocks the virus. We also have several clinical results indicating that this product is beneficial if administered early and we have no mention that it harms or is dangerous in this infection (only one study, poorly detailed, Chinese, on 30 patients with control group, did not observe any benefits but also no harmful effects). What is the risk of administering chloroquine straight away: nothing!

2. This drug is very inexpensive 3. It is well tolerated in long-term treatment. Personally, I have successfully used it clinically in the chronic form of Lyme disease for 30 years at a dose of 200 mg or even 400 mg/day.

I and hundreds of other doctors are able to judge its excellent tolerance in humans. The main contraindications are severe retinal and unbalanced heart disease.

Cardiovascular events remain exceptional if care is taken: to proscribe self-medication – to check with the elderly taking a lot of drugs that there are no drug interactions (with long-term diuretics in particular) and that the rate of blood potassium is within the norm.

Apart from these precautions, the undesirable effects are minor. They are even more so as the treatment is short, which is the case against Covid-19.

It would therefore be wise to produce hydroxychloroquine in very large quantities without further delay, to make it easily accessible to infected people…

I note that Italy has just authorized the wide distribution of hydroxychloroquine on medical prescription from the start of the infection and that other countries are preparing to do the same. What are we waiting for? To have more dead?”

Taken from the endcoronavirus.org website:

look at what has happened to Italy's graph after March 29th when Italy launched a national outpatient/in-home early intervention program incorporating HCQ

 

Edited May 13, 2020 by triplehorn

[Anastasis 23504]

I can't even. 

[triplehorn 2664]

Italy peak was about 3/22.  News of Italy's HCQ national policy came out 3/29.  I'm guessing they had good reason based on their observations/findings to go public with the news, hence the curve plunging before advertising it.  Crushing it is multifactorial.  We all know that.  But Italy's national curve didn't plateau before dropping, it just plunged.  Italy was less than 2 weeks ahead of us when their country blew up with the virus.  I'd love to look like Italy does two weeks from now.  They seem to think early intervention with HCQ for pre-symptomatic and uncomplicated cases is an important component, and today, it looks like they're not wrong.

[triplehorn 2664]

Now we get to watch and see if a similar trend is replicated in India, who is adopting a comparable approach to Italy with early outpatient/in-home HCQ intervention:

Published 10th May, 2020 : Revised guidelines for Home Isolation of very mild/pre-symptomatic COVID-19 cases

Quote

 

Right now, this is India's curve at the start of their national initiative for pre-test, pre-symptomatic application of HCQ.  So we'll get to watch in real time what happens.

It's important to realize that this approach necessarily involves a national coordinated effort with meaningful contact tracing and outpatient/in-home visits by health care providers to identify and administer HCQ safely and effectively.

[Brisketexan 105572]

27 minutes ago, triplehorn said:

Now we get to watch and see if a similar trend is replicated in India, who is adopting a comparable approach to Italy with early outpatient/in-home HCQ intervention:

Published 10th May, 2020 : Revised guidelines for Home Isolation of very mild/pre-symptomatic COVID-19 cases

 

Right now, this is India's curve at the start of their national initiative for pre-test, pre-symptomatic application of HCQ.  So we'll get to watch in real time what happens.

It's important to realize that this approach necessarily involves a national coordinated effort with meaningful contact tracing and outpatient/in-home visits by health care providers to identify and administer HCQ safely and effectively.

Quick question: the HCQ therapy you are discussing purportedly reduces MORTALITY.  The graphs you are citing measure not mortality, but CASES.  So, with respect to the thing that HCQ supposedly helps....how do those graphs tell us ANYTHING relevant?

[triplehorn 2664]

18 minutes ago, Brisketexan said:

Quick question: the HCQ therapy you are discussing purportedly reduces MORTALITY.  The graphs you are citing measure not mortality, but CASES.  So, with respect to the thing that HCQ supposedly helps....how do those graphs tell us ANYTHING relevant?

Re the graphs, correct, they reflect daily new cases of COVID-19 vs time with a 10-day average.  The outstanding question, which has been broached in some initial attempts to study the effects of HCQ on covid, is if early administration of HCQ results in smaller viral loads and a more rapid rate of the body's clearance of the virus.  It follows that this would reduce probability of transmission and reduce the number of daily new cases.  Individually it could mean a shorter milder course of illness less likely to progress to the crash/ICU phase.  Globally it could help reduce R0 to less than 1.0 leading to containment of the virus.

Edited May 13, 2020 by triplehorn

[triplehorn 2664]

Here's a different look at CV risk with use of HCQ :

Hydroxychloroquine Use and Cardiovascular Events Among Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis

"Conclusion: In this nested case-control study within an incident SLE/RA cohort, we found a 17% reduced risk of incident CV events overall associated with current HCQ use. We also identified trends towards reduced risks of MI, Stroke/TIA, and VTE associated with current HCQ use. By leveraging remote users as the comparison group, we reduced the potential for confounding by indication. These findings suggest a preventative benefit of HCQ use in reducing CV disease among patients with SLE and RA."

 

[Anastasis 23504]

So for something a little more reality based at the moment...crossposted from the DT thread.

https://blogs.sciencemag.org/pipeline/archives/2020/05/15/good-news-on-the-human-immune-response-to-the-coronavirus

Good News on the Human Immune Response to the Coronavirus

By Derek Lowe 15 May, 2020

One of the big (and so far unanswered) questions about the coronavirus epidemic is what kind of immunity people have after becoming infected. This is important for the idea of “re-infection” (is it even possible?) and of course for vaccine development. We’re getting more and more information in this area, though, and this new paper is a good example. A team from the La Jolla Institute for Immunology, UNC, UCSD, and Mt. Sinai (NY) reports details about the T cells of people who have recovered from the virus. To get into this, a quick explainer seems appropriate, so the next bit will be on the background of T cells and adaptive immunity – then we’ll get into these latest results.

So everyone’s heard of the broad category of white blood cells. One group of those are the lymphocytes (literally “lymph cells”, where they’re most easily found), and the lymphocytes include T cells, B cells, and NK cells. You’re looking at three big branches of the immune system right there. The NK (“natural killer”) cells are part of the innate immunity, the nonspecific kind, and they’re in the cell-mediated cytotoxic wing of that. The other side of the immune system is adaptive immunity. The B cells feature in my antibody background posts, because as part of the adaptive system they’re the ones that produce more of some specific antibody once one of the zillions of them present in the body turns out to fit onto a new antigen. The T cells are in the adaptive side as well, but they’re in the cell-mediated part of that army.

T cells come from the thymus (thus the “T”), so if you’ve been wondering what your thymus has done for you lately, that’s one good answer. They all have a particular surface protein, the T cell receptor. Similar to the way that the immune system generates a huge number of antibodies by shuffling and mixing protein expression, there are a huge number of different T cell receptors waiting to recognize what antigens may come along. The precursors of T cells come from the bone marrow and migrate to the thymus, where they branch out into different lines (and that branching out continues even once they leave the thymus and begin circulating in the lymph and in the blood.

The most direct of those are the cytotoxic T cells, also known as CD8+ T cells and by several other names. CD8 is another particular cell-surface protein that distinguishes this type. These cells aren’t going after viral particles; they’re going after the body’s own virus-infected cells and killing them off before they can break open and spread more viral particles. They’ll kill off bacterial cells in the same way. These are also the ones that the CAR-T therapies are trying to mobilize so that they’ll recognize cancer cells and do the same thing to them. How do they accomplish the deed? They’re thorough; there are several deadly mechanisms that kick in. One general one is to secrete cytokines, especially TNF-alpha and interferon-gamma, that alert other cellular systems to the fact that they’ve detected targets to attack. (The monoclonal antibody drugs for arthritis are actually aimed to shut down that TNF-alpha pathway, because in RA the T cells are – very inappropriately – attacking the body’s own joint tissue). A second CD8+ action is to release “cytotoxic granules”. These are payloads of destruction aimed at the target cell once the T cell is closely connected to it (the “immune synapse”). You need that proximity because cytotoxic granules are bad news – they contain proteins that open up pores in the target cell, and blunderbuss serine protease enzymes that slide in through them, whereupon they start vigorously cleaving intracellular proteins and causing general chaos (and eventually cell death). And the third killing mode is via another cell-surface protein the CD8+ cells have called FasL – it binds to a common protein on the target cells called Fas, and that sets off a signaling cascade inside the target cells that also leads to cell death. (Interestingly, the CD8+ cells use this system after an infection has subsided to kill each other off and get their levels back down to normal!)

And then there’s another crowd, the CD4+ T cells, also known as T-helper cells and by other names. They work with another class of immune cells, the antigen-presenting cells, which go around taking in all sorts of foreign proteins and presenting them on their cell surfaces. A CD4+ cell, when it encounters one of those, goes through a two-stage activation process kicks in (the second stage is sort of a verification check to make sure that it’s really a foreign antigen and not something already present in the body). If that’s successful, they start to proliferate. And you’re going to hate me for saying this, but that’s where things get complicated. Immunology! The helper T cells have a list of immune functions as long as your leg, interacting with many other cell types. Among other things, they help set off proliferation of the CD8+ cells just detailed, they activate B cells to start producing specific antibodies, and they’re involved with secretion of more cytokine signaling molecules than I can even stand to list here. These are in fact the cells targeted by HIV, and it’s the loss of such crucial players in the immune response that makes that disease so devastating.

OK, there’s some background for this new paper. What it’s looking at in detail are the virus-specific CD8+ and CD4+ cells that have been raised up in response to the infection in recovering patients. As you’ve seen, both of these subtypes are adaptive; they’re recognizing particular antigens and responding to those – so how robust was this response, and what coronavirus antigens set things off? You can see how important these details are – depending on what happens, you could have an infection that doesn’t set off enough of a response to leave behind B and T cells that will remember what happened, leaving people vulnerable to re-infection. Or you could set off too huge a response – all those cytokines in the “cytokine storm” that you hear about? CD4+ cells are right in the middle of that, and I’ve already mentioned the TNF-alpha problems that are a sign of misaligned CD8+ response. The current coronavirus is pretty good at evading the innate immune system, unfortunately, so the adaptive immune system is under more pressure to deliver. And one reason (among many) that the disease is more severe in elderly patients is that the number of those antigen-presenting cells decline with age, so one of the key early steps of that response gets muted. That can lead to a too-late too-heavy T cell response when things finally do get going, which is your cytokine storm, etc. In between the extremes is what you want: a robust response that clears the virus, remembers what happened for later, and doesn’t go on to attack the body’s own tissues in the process.

Comparing infected patients with those who have not been exposed to the coronavirus, this team went through the list of 25 viral proteins that it produces. In the CD4+ cells, the Spike protein, the M protein, and the N protein stood out: 100% of the exposed patients had CD4+ cells that responded to all three of these. There were also significant CD4+ responses to other viral proteins: nsp3, nsp4, ORF3s, ORF7a, nsp12 and ORF8. The conclusion is that a vaccine that uses Spike protein epitopes should be sufficient for a good immune response, but that there are other possibilities as well – specifically, adding in M and N protein epitopes might do an even more thorough job of making a vaccine mimic a real coronavirus infection to train the immune system.

As for the CD8+ cells, the situation looked a bit different. The M protein and the Spike protein were both strong, with the N protein and two others (nsp6 and ORF3a) behind it. Those last three, though, were still about 50% of the response, when put together, so there was no one single dominant protein response. So if you’re looking for a good CD8+ response, adding in epitopes from one or more of those other proteins to the Spike epitope looks like a good plan – otherwise the response might be a bit narrow.

And here’s something to think about: in the unexposed patients, 40 to 60% had CD4+ cells that already respond to the new coronavirus. This doesn’t mean that people have already been exposed to it per se, of course – immune crossreactivity is very much a thing, and it would appear that many people have already raised a response to other antigens that could be partially protective against this new virus. What antigens those are, how protective this response is, and whether it helps to account for the different severity of the disease in various patients (and populations) are important questions that a lot of effort will be spent answering. As the paper notes, such cross-reactivity seems to have been a big factor in making the H1N1 flu epidemic less severe than had been initially feared – the population already had more of an immunological head start than thought.

So overall, this paper makes the prospects for a vaccine look good: there is indeed a robust response by the adaptive immune system, to several coronavirus proteins. And vaccine developers will want to think about adding in some of the other antigens mentioned in this paper, in addition to the Spike antigens that have been the focus thus far. It seems fair to say, though, that the first wave of vaccines will likely be Spike-o-centric, and later vaccines might have these other antigens included in the mix. But it also seems that Spike-protein-targeted vaccines should be pretty effective, so that’s good. The other good news is that this team looked for the signs of an antibody-dependent-enhancement response, which would be bad news, and did not find evidence of it in the recovering patients (I didn’t go into these details, but wanted to mention that finding, which is quite reassuring).

Onward from here, then – there will be more studies like this coming, but this is a good, solid look into the human immunology of this outbreak. And so far, so good.

 

[triplehorn 2664]

Keep an eye on these folks using therapeutic monoclonal antibodies spearheaded by a San Diego based group doing initial work in conjunction with UTMB and Mount Sinai:

Sorrento IDs Antibody Against COVID-19 That Appears 100% Effective

 

Quote

As the world battles the COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2, biopharma and biotech companies are approaching the fight with various weapons—repurposed drugs, antivirals, vaccines and clinical antibodies. One of the companies deeply involved in clinical antibody development against COVID-19 is San Diego-based Sorrento Therapeutics.

A week ago, Sorrento announced it was teaming up with New York City-based Mount Sinai Health System to develop an antibody cocktail called COVI-SHIELD to treat COVID-19. The partnership is aimed at creating antibody products that could act as a “protective shield” against infection by the virus that causes COVID-19, SARS-CoV-2. COVI-SHIELD is expected to deliver a mixture of three antibodies that combined recognize three specific regions of the SARS-CoV-2 Spike protein.

The company announced on Friday that one of its antibodies, STI-1499, has shown 100% inhibition of SARS-CoV-2 in laboratory tests. Henry Ji, Sorrento’s co-founder, director, president and chief executive officer, and Mark Brunswick, vice president of Regulatory Affairs and Quality, took time out to speak with BioSpace ahead of the announcement.

Ji indicates that Sorrento began screening its own library of fully human antibodies about three months ago, as well as partnered with Mount Sinai on acquiring B-cells from recovering COVID-19 patients to identify neutralizing antibodies. The leading antibody, STI-1499, came from the company’s extensive library.

“We screened about a billion antibodies,” Ji said. “And we found about 100 of them to characterize further. From them we selected about a dozen that had neutralizing activity.”

Then, working with collaboration partners at the University of Texas Medical Branch, which has access to the live virus, they were able to screen the dozen antibodies for the most promising ones.

“We’re actually so impressed with the data,” Ji said. “One of the antibodies is so powerful that at a very low concentration it is able to 100% completely prevent infection or inhibit the infection. In our studies, not even one virus escaped from the antibody.”

That was STI-1499. Currently, Sorrento believes STI-1499 will be the first antibody in the three-antibody cocktail, COVI-SHIELD, which it is developing with Mount Sinai. Additionally, because of its high potency, it plans to develop the antibody as a stand-alone therapy, COVI-GUARD.

“The pathway we’re following right now is quite similar to the pathways used in antibody therapies for oncology indications, where an antibody is discovered that is reactive to a specific cancer marker, grown up in culture, and given to patients,” Brunswick said. “So what we’ve done is identified an antibody that recognizes the COVID-19 virus and completely inhibits its binding to the specific receptor. This is grown up in vitro, in tissue culture, in cell fermenters.”

Sorrento is now growing the clones up and will create a single-clone cell bank and inoculate a fermenter.

“We anticipate having enough material to start a Phase I trial in patients in the ICU within two months. If that is successful, we will expand that trial using our cGMP facility which can produce 2,000 liters of material, which is enough for approximately 100,000 patients, based on what we think the dose will be,” Brunswick said.

The antibody is potentially both a preventative and a treatment. It prevents the virus from binding to the cell it wants to bind to, which means it can’t enter the cell and reproduce.

“The difference between an antibody and a vaccine is that a vaccine takes either a protein from the virus, or—some of them aren’t real vaccines, but people are calling them vaccines—where DNA or RNA is being injected into patients’ arms and making material in the patient that then the patient’s immune system responds to what’s being made,” Brunswick said. “The problem with that is not every patient will respond to a vaccine. Some will have 10% efficacy, some will have 20% efficacy, some will have 90% efficacy. But until you’ve gone into large trials and assessed everyone, you won’t know the full extent a vaccine works. An antibody gives instantaneous protection against the virus.”

“The elderly or an immunocompromised person will have a lack of immune response to a vaccine, but the antibody should provide the instant immunity,” Ji said.

If the Phase I trial starts by the beginning of July, they will know within a week or two whether the antibody is having an effect. If it is effective and safe in the patients, they would expect to start a larger Phase II trial in August or possibly September.

“Hopefully we will be able to submit for approval before the end of the year or beginning of next year,” Brunswick added.

If approved, Sorrento expects very large demand. Ji indicates that they can produce hundreds of thousands of doses per run, but the demand could climb into the tens of millions of doses needed. As a result, they are looking for manufacturing partners.

Meanwhile, they are in the process of identifying additional antibodies for the cocktail version.

“Our hope is to have two or three antibodies eventually that cover different epitopes, different regions of the virus, so if one portion of the virus mutates and affects one of the neutralizing activity but won’t affect the other,” Ji said.

Sorrento is an antibody-centric biopharma company typically focused on therapies for cancer and infectious diseases. Its immuno-oncology platforms include fully human antibodies (G-MAB library), clinical stage immuno-cellular therapies such as CAR-T and DAR-T, Intracellular targeting antibodies (iTAbs), antibody-drug conjugates (ADC) and clinical stage oncolytic virus, Seprehvir. Its antiviral therapies include COVIDTRAP, ACE-MAB, COVI-MAB, COVI-SHIELD and COVI-CELL.

Ji concluded by saying, “Sorrento is in the therapeutic antibody space, and we know it inside out. We have a cGMP facility to get the product onto the market quickly.”

 

[Brisketexan 105572]

Okay, so tell me if I'm wrong for being mildly hopeful about this scenario.

We are currently at mid-May.

Several therapeutic treatments (including some that have some overlap with how vaccines may work) are showing some promise (the above-referenced one, for example).  While it takes time to develop them, and get production ramped up so that it's reasonably widely available....that time may be less than it takes to have a vaccine developed and fully produced.

So, perhaps we have some slate of treatments (antibody products, remdesivir, simply better treatment protocols for respiratory distress, etc.) that is generally available by sometime in the fall (Sept-Oct seems early, Nov-Dec may be more likely).

And perhaps we're on track for a vaccine by early 2021.

My thought is -- and this is in terms of making public health decisions -- that once we reach a point where we are confident that we can reduce the "serious acute illness/death" rate with therapeutic treatments, then we can relax transmission-reducing measures even more.  Maybe not open up venues where 1,000 people are pressed up against each other, but full restaurant reopenings with no real restrictions, etc.

Then, once there's a vaccine, we can begin to treat COVID like the seasonal flu -- get your shot, if you're sick, stay home.

The mix was always going to have to be blunt-force measures that are readily available (social distancing, masks), then improved therapies etc., then a vaccine.

SUMMARY: I think maybe I have reason to be hopeful that COVID, as a looming deadly threat, can be largely reduced or neutralized by sometime this fall.  All in all, that will put us in a position where as a pandemic of heavy global economic impact, we can be past the bulk of the impact within 6-9 months of feeling the impact (outside of China).

[SizzleChest 8292]

1 hour ago, triplehorn said:

Keep an eye on these folks using therapeutic monoclonal antibodies spearheaded by a San Diego based group doing initial work in conjunction with UTMB and Mount Sinai:

Sorrento IDs Antibody Against COVID-19 That Appears 100% Effective

 

 

It's fine to keep an eye on stuff like this, but these statements from the CEO are, shall we say, a bit too attention-horsey.  The tell was the statement about greater efficacy than a vaccine, thus rendering a vaccine unnecessary.  I hope to hell it's true, though.

Seems like the big questions would be safety and how long protective immunity lasts.  Even if it's safe, but you need something like a monthly booster to maintain immunity, that presents a host of other challenges, not the least of which is manufacturing / supply.

[triplehorn 2664]

28 minutes ago, SizzleChest said:

It's fine to keep an eye on stuff like this, but these statements from the CEO are, shall we say, a bit too attention-horsey.  The tell was the statement about greater efficacy than a vaccine, thus rendering a vaccine unnecessary.  I hope to hell it's true, though.

Seems like the big questions would be safety and how long protective immunity lasts.  Even if it's safe, but you need something like a monthly booster to maintain immunity, that presents a host of other challenges, not the least of which is manufacturing / supply.

Suggesting vaccines are rendered unnecessary wasn't my takeaway from what the CEO said:

“The problem with that is not every patient will respond to a vaccine. Some will have 10% efficacy, some will have 20% efficacy, some will have 90% efficacy. But until you’ve gone into large trials and assessed everyone, you won’t know the full extent a vaccine works. An antibody gives instantaneous protection against the virus.”

The observation made above probably contributes in part to why it can take up to 10 years to develop effective vaccines.  Vaccines depend on a human response that can be quite variable across populations.  Vaccines still have advantages, but development time to safe and effective implementation isn't one.  Monoclonal antibodies are simply a direct hit on virus particles.  It appears this mAB, STI-1499, has both active treatment (akin to convalescent plasma infusion) and preventative capacities. 

[SizzleChest 8292]

37 minutes ago, triplehorn said:

Suggesting vaccines are rendered unnecessary wasn't my takeaway from what the CEO said:

“The problem with that is not every patient will respond to a vaccine. Some will have 10% efficacy, some will have 20% efficacy, some will have 90% efficacy. But until you’ve gone into large trials and assessed everyone, you won’t know the full extent a vaccine works. An antibody gives instantaneous protection against the virus.”

The observation made above probably contributes in part to why it can take up to 10 years to develop effective vaccines.  Vaccines depend on a human response that can be quite variable across populations.  Vaccines still have advantages, but development time to safe and effective implementation isn't one.  Monoclonal antibodies are simply a direct hit on virus particles.  It appears this mAB, STI-1499, has both active treatment (akin to convalescent plasma infusion) and preventative capacities. 

I think you missed my point.  The statement RE: vaccines comes off as PT Barnum.  Not every drug or vaccine works for every patient.  

The absolutist, super-definitive nature of his statement reeks of spin.

[triplehorn 2664]

1 hour ago, Brisketexan said:

The mix was always going to have to be blunt-force measures that are readily available (social distancing, masks), then improved therapies etc., then a vaccine.

SUMMARY: I think maybe I have reason to be hopeful that COVID, as a looming deadly threat, can be largely reduced or neutralized by sometime this fall.  All in all, that will put us in a position where as a pandemic of heavy global economic impact, we can be past the bulk of the impact within 6-9 months of feeling the impact (outside of China).

Yep.

Factors that support your timeline: blunt measures absolutely work.  They are known and well defined, readily employable, and there are multiple other nations we can point to who have already successfully inverted their national curves using multimodal approaches.

Factors that work against your timeline: we can't point to another country's success where the pandemic got as out of hand as it has in the US.  Until we get a true national Zeitgeist with appropriate coordinated messaging and responses, it's going to be rough.  For now, it's still two steps forward, one step backward.

Personally I think things will look a lot better in the US by this fall, even late summer by way of continued improvement in public acceptance of and voluntary adherence to blunt force measures combined with ongoing improvements in medical management and mitigation of illness severity.  The US operates differently than other nations which cuts both ways, but the tools are available.  The thing to always keep in mind is the epidemiological math in play - relatively quick and small changes in bending the curve have very dramatic effects on absolute numbers visible within 2 weeks of changes being made (works both ways).  The heavy lifting for ongoing success remains psychological.

[triplehorn 2664]

1 minute ago, SizzleChest said:

I think you missed my point.  The statement RE: vaccines comes off as PT Barnum.  Not every drug or vaccine works for every patient.  

The absolutist, super-definitive nature of his statement reeks of spin.

He is talking about a silver bullet, after all.  100% kill rate is what it is.  You can be skeptical.  You are not misreading him.

Monoclonal antibodies make it to lung epithelium where they could have both preventative and treatment functions, and they can go pretty much everywhere in the body where Covid can go, with limits on crossing the blood brain barrier (Covid is thought to also have direct effects on the brain).

[BradInATX 9208]

Okay, so tell me if I'm wrong for being mildly hopeful about this scenario.
We are currently at mid-May.
Several therapeutic treatments (including some that have some overlap with how vaccines may work) are showing some promise (the above-referenced one, for example).  While it takes time to develop them, and get production ramped up so that it's reasonably widely available....that time may be less than it takes to have a vaccine developed and fully produced.
So, perhaps we have some slate of treatments (antibody products, remdesivir, simply better treatment protocols for respiratory distress, etc.) that is generally available by sometime in the fall (Sept-Oct seems early, Nov-Dec may be more likely).
And perhaps we're on track for a vaccine by early 2021.
My thought is -- and this is in terms of making public health decisions -- that once we reach a point where we are confident that we can reduce the "serious acute illness/death" rate with therapeutic treatments, then we can relax transmission-reducing measures even more.  Maybe not open up venues where 1,000 people are pressed up against each other, but full restaurant reopenings with no real restrictions, etc.
Then, once there's a vaccine, we can begin to treat COVID like the seasonal flu -- get your shot, if you're sick, stay home.
The mix was always going to have to be blunt-force measures that are readily available (social distancing, masks), then improved therapies etc., then a vaccine.
SUMMARY: I think maybe I have reason to be hopeful that COVID, as a looming deadly threat, can be largely reduced or neutralized by sometime this fall.  All in all, that will put us in a position where as a pandemic of heavy global economic impact, we can be past the bulk of the impact within 6-9 months of feeling the impact (outside of China).

This is sort of where I'm at, and I think it's basically the thought process of the early open states. Sort of a gamble on beating the late q3 resurgence to an antiviral or cocktail type thing. Which I think is reasonable. I'm pretty fine with most of the Texas plan. Would have liked to see masks mandatory, and maybe have waited another couple weeks to see actual downward trends. But I think we'll largely be fine through summer.
My concern is that if the gamble doesn't work, it's going to be tough to get the cat back in the bag on a resurgence. It's all so politicized (by everyone) that I'm not sure people will abide by a re-tightening.
But that's a Q3 problem if at all; I'm rooting for the bet the governor made to hit. And I've got four months to drink beer in the pool until then.

[Liquor and Poker 3659]

So honest question-what does it mean for the whole antibody/immunity thing that 13 sailors on the Theodore Roosevelt retested positive this past week after recovering and testing negative twice, with some of them having real symptoms the second time like body aches, fever, headaches and cough?

https://www.politico.com/news/2020/05/16/uss-theodore-roosevelt-sailors-test-positive-coronavirus-261873

13x2 seems like a lot for just plain false negatives.  Is there a reason to think this disease is like malaria - some people never get rid of it?  

[GreenspointTexas 9867]

33 minutes ago, Liquor and Poker said:

So honest question-what does it mean for the whole antibody/immunity thing that 13 sailors on the Theodore Roosevelt retested positive this past week after recovering and testing negative twice, with some of them having real symptoms the second time like body aches, fever, headaches and cough?

https://www.politico.com/news/2020/05/16/uss-theodore-roosevelt-sailors-test-positive-coronavirus-261873

13x2 seems like a lot for just plain false negatives.  Is there a reason to think this disease is like malaria - some people never get rid of it?  

Based on this plus stories out of china and south korea of the exact same thing happening are pretty crazy

[gmr548 16635]

So honest question-what does it mean for the whole antibody/immunity thing that 13 sailors on the Theodore Roosevelt retested positive this past week after recovering and testing negative twice, with some of them having real symptoms the second time like body aches, fever, headaches and cough?
https://www.politico.com/news/2020/05/16/uss-theodore-roosevelt-sailors-test-positive-coronavirus-261873
13x2 seems like a lot for just plain false negatives.  Is there a reason to think this disease is like malaria - some people never get rid of it?  

Not an expert at all so just speculating with these: Could it be possible that those 13 have weaker or compromised immune systems in some way that limited the production of antibodies?

With a supposed false negative rate of 20 percent or so, the odds a positive would test negative twice are ~4 percent. And that's assuming false negatives are truly random, not that there's something specific that would cause it (seems likely there would be, no?). With the volume of sailors tested, is 13 really out of line?

[Bevo 13635]

1 hour ago, gmr548 said:

Not an expert at all so just speculating with these: Could it be possible that those 13 have weaker or compromised immune systems in some way that limited the production of antibodies?

With a supposed false negative rate of 20 percent or so, the odds a positive would test negative twice are ~4 percent. And that's assuming false negatives are truly random, not that there's something specific that would cause it (seems likely there would be, no?). With the volume of sailors tested, is 13 really out of line?

False negative rate of antibody tests are approximately 5%, I believe.

[gmr548 16635]

False negative rate of antibody tests are approximately 5%, I believe.

But we're talking diagnostic tests, no? Cause if these sailors tested negative for antibodies twice... then no shit they got reinfected.

[Bevo 13635]

9 hours ago, gmr548 said:

9 hours ago, Bevo said:

False negative rate of antibody tests are approximately 5%, I believe.

But we're talking diagnostic tests, no? Cause if these sailors tested negative for antibodies twice... then no shit they got reinfected.

I don't know what test was done at each visit, but the false negative rate is lower with PCR than with an antibody test. So the false negative rate is lower than 5% regardless of which test was conducted. So your use of a 20% false negative rate is wrong.

[triplehorn 2664]

Treatment Response to Hydroxychloroquine, Lopinavir–Ritonavir, and Antibiotics for Moderate COVID-19: A First Report on the Pharmacological Outcomes from South Korea     

(full text with charts and graphs visible clicking the 'preview .pdf' at the link)

Methods: A retrospective cohort study of the 358 laboratory-confirmed SARS-CoV-2 – or COVID-19 - patients was conducted. Of these patients, 270 adult patients met inclusion criteria and were included in our analyses. The primary endpoints were time to viral clearance and clinical improvement. The mean duration to viral clearance and clinical improvements were displayed as bar-plots to visualize treatment responses.

Conclusion: This first report on pharmacological management of COVID-19 from South Korea revealed that HQ with antibiotics was associated with better clinical outcomes in terms of viral clearance, hospital stay, and cough symptom resolution compared to Lop/R with antibiotics or conservative treatment. The effect of Lop/R with antibiotics was not superior to conservative management. The adjunct use of the antibiotics may provide additional benefit in COVID-19 management but warrants further evaluation.

Quote

Quote

 

Important consideration is that "mild" and "moderate" cases were given the regimens, but again these are all people who were hospitalized.  And hospitalization is an important indicator of duration of illness before treatment initiation.  What happens when people get the treatments as soon as they test positive, as opposed to progressing to requiring hospitalization ? 

If viral loads and time to viral clearance are reduced with treatment, it suggests there's an opportunity to reduce probability of transmission within a population, particularly in asymptomatic people.  But without adequate testing in place, none of this matters nearly as much.

[Anastasis 23504]

13 minutes ago, triplehorn said:

But without evidence from a trial with randomized assignment adequate testing in place, none of this matters nearly as much.

FIFY. 

Edited May 19, 2020 by Anastasis

[triplehorn 2664]

Punjab directs all its frontline healthcare workers to take HCQ tablets

the lede:

"A MONTH after ICMR recommended use of hydroxychloroquine as prophylaxis (preventive treatment) for frontline healthcare workers and high risk population amid the COVID-19 outbreak, Punjab has directed all frontline healthcare workers across the state to take the recommended weekly dose of HCQ." 

"...the government is considering giving the medicine to other frontline workers as well, including police and government officials etc."

---> After a full month of doing this, they're not ditching the approach, they're expanding it.  On the face of it, it suggests that not only are they not experiencing negative events, they're seeing some associated good.  Also note their prophylactic regimen is once weekly dosing - the same regimen that has been dosed tens of millions of times for over half a century (established safety).

On one hand, there is a need for RCT's, on the other hand we're in a war. A war where, if you wait and realize what's happening in real time, it's too late.

 

[Anastasis 23504]

Speaking of controlled trials with random assignment...

https://www.bmj.com/content/369/bmj.m1849

Abstract

Objective To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19).

Design Multicentre, open label, randomised controlled trial.

Setting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.

Participants 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone).

Interventions Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).

Main outcome measure Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.

Results Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.

Conclusions Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.

Trial registration ChiCTR2000029868.

[triplehorn 2664]

 "The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days"

Over 2 weeks mean duration from symptom onset to randomization ?  That ship has sailed. 

[Anastasis 23504]

https://www.statnews.com/2020/05/19/vaccine-experts-say-moderna-didnt-produce-data-critical-to-assessing-covid-19-vaccine/

 

Vaccine experts say Moderna didn’t produce data critical to assessing Covid-19 vaccine

Heavy hearts soared Monday with news that Moderna’s Covid-19 vaccine candidate — the frontrunner in the American market — seemed to be generating an immune response in Phase 1 trial subjects. The company’s stock valuation also surged, hitting $29 billion, an astonishing feat for a company that currently sells zero products.

But was there good reason for so much enthusiasm? Several vaccine experts asked by STAT concluded that, based on the information made available by the Cambridge, Mass.-based company, there’s really no way to know how impressive — or not — the vaccine may be.

While Moderna blitzed the media, it revealed very little information — and most of what it did disclose were words, not data. That’s important: If you ask scientists to read a journal article, they will scour data tables, not corporate statements. With science, numbers speak much louder than words.

Related: 

Moderna carries a big-boy market valuation now, so it shouldn’t act like a biotech penny stock

Even the figures the company did release don’t mean much on their own, because critical information — effectively the key to interpreting them — was withheld.

Experts suggest we ought to take the early readout with a big grain of salt. Here are a few reasons why.

The silence of the NIAID

The National Institute for Allergy and Infectious Diseases has partnered with Moderna on this vaccine. Scientists at NIAID made the vaccine’s construct, or prototype, and the agency is running the Phase 1 trial. This week’s Moderna readout came from the earliest of data from the NIAID-led Phase 1.

NIAID doesn’t hide its light under a bushel. The institute generally trumpets its findings, often offering director Anthony Fauci — who, fair enough, is pretty busy these days — or other senior personnel for interviews.

But NIAID did not put out a press release Monday and declined to provide comment on Moderna’s announcement.

The n = 8 thing

The company’s statement led with the fact that all 45 subjects (in this analysis) who received doses of 25 micrograms (two doses each), 100 micrograms (two doses each), or a 250 micrograms (one dose) developed binding antibodies.

Later, the statement indicated that eight volunteers — four each from the 25-microgram and 100-microgram arms — developed neutralizing antibodies. Of the two types, these are the ones you’d really want to see.

We don’t know results from the other 37 trial participants. This doesn’t mean that they didn’t develop neutralizing antibodies. Testing for neutralizing antibodies is more time-consuming than other antibody tests and must be done in a biosecurity level 3 laboratory. Moderna disclosed the findings from eight subjects because that’s all it had at that point. Still, it’s a reason for caution.

Separately, while the Phase 1 trial included healthy volunteers ages 18 to 55 years, the exact ages of these eight people are unknown. If, by chance, they mostly clustered around the younger end of the age spectrum, you might expect a better response to the vaccine than if they were mostly from the senior end of it. And given who is at highest risk from the SARS-CoV-2 coronavirus, protecting older adults is what Covid-19 vaccines need to do.

There’s no way to know how durable the response will be

The report of neutralizing antibodies in subjects who were vaccinated comes from blood drawn two weeks after they received their second dose of vaccine.

Two weeks.

“That’s very early. We don’t know if those antibodies are durable,” said Anna Durbin, a vaccine researcher at Johns Hopkins University.

There’s no real way to contextualize the findings

Moderna stated that the antibody levels seen were on a par with — or greater than, in the case of the 100-microgram dose — those seen in people who have recovered from Covid-19 infection.

But studies have shown antibody levels among people who have recovered from the illness vary enormously; the range that may be influenced by the severity of a person’s disease. John “Jack” Rose, a vaccine researcher from Yale University, pointed STAT to a study from China that showed that, among 175 recovered Covid-19 patients studied, 10 had no detectable neutralizing antibodies. Recovered patients at the other end of the spectrum had really high antibody levels.

So though the company said the antibody levels induced by vaccine were as good as those generated by infection, there’s no real way to know what that comparison means.

STAT asked Moderna for information on the antibody levels it used as a comparator. The response: That will be disclosed in an eventual journal article from NIAID, which is part of the National Institutes of Health.

“The convalescent sera levels are not being detailed in our data readout, but would be expected in a downstream full data exposition with NIH and its academic collaborators,” Colleen Hussey, the company’s senior manager for corporate communications, said in an email.

Durbin was struck by the wording of the company’s statement, pointing to this sentence: “The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera.”

“I thought: Generally? What does that mean?” Durbin said. Her question, for the time being, can’t be answered.

Rose said the company should disclose the information. “When a company like Moderna with such incredibly vast resources says they have generated SARS-2 neutralizing antibodies in a human trial, I would really like to see numbers from whatever assay they are using,” he said.

Moderna’s approach to disclosure

The company has not yet brought a vaccine to market, but it has a variety of vaccines for infectious diseases in its pipeline. It doesn’t publish on its work in scientific journals. What is known has been disclosed through press releases. That’s not enough to generate confidence within the scientific community.

“My guess is that their numbers are marginal or they would say more,” Rose said about the company’s SARS-2 vaccine, echoing a suspicion that others have about some of the company’s other work.

“I do think it’s a bit of a concern that they haven’t published the results of any of their ongoing trials that they mention in their press release. They have not published any of that,” Durbin noted.

Still, she characterized herself as “cautiously optimistic” based on what the company has said so far.

“I would like to see the data to make my own interpretation of the data. But I think it is at least encouraging that we’ve seen immune responses with this RNA vaccine that we haven’t seen with previous RNA vaccines for other pathogens. Whether it’s going to be enough, we don’t know,” Durbin said.

Moderna has been more forthcoming with data on at least one of its other vaccine candidates. In a statement issued in January about a Phase 1 trial for its cytomegalovirus (CMV) vaccine, it quantified how far over baseline measures antibody levels rose in vaccines.

[Anastasis 23504]

Remdesivir study finally hits the press.

 

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2007764?

BACKGROUND Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.

METHODS We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infectioncontrol purposes only.

RESULTS A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The KaplanMeier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).

CONCLUSIONS Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.)

 

 

[Brisketexan 105572]

Sounds like we oughta get us some of that Remdesivir...

[Captainant 27972]

Serious adverse side effects in 1 out of 5 is concerning. Would that normally be good enough to make it to the next round of trials?

[Bevo 13635]

4 minutes ago, Captainant said:

Serious adverse side effects in 1 out of 5 is concerning. Would that normally be good enough to make it to the next round of trials?

The overall number of serious adverse events were pretty much equivalent to the placebo. To get a better idea, you would have to look up the occurrence of each specific side-effect and compare it to placebo.

[Anastasis 23504]

Yeah, many of the side effects are probably related to the underlying disease.  

I thought the subgroup analysis by baseline score is interesting. Does not appear to do any good once they are on invasive vent.

Also the symptom duration and age group subgroup analyses.  Wouldn't make a whole bunch out of it, but will be something interesting to look for in the next wave of RCT data. 

 

Edited May 23, 2020 by Anastasis

[Mitch Cumsteen 18658]

1 hour ago, Captainant said:

Serious adverse side effects in 1 out of 5 is concerning. Would that normally be good enough to make it to the next round of trials?

All SAE are reported, regardless of whether they are treatment-related. So, an increase in disease severity in this case is considered an SAE, which you would consider par for the course in this disease. It looks like very few of the SAE were treatment related. You would think with an already approved drug, they would have a  pretty good idea of side effects and SAE.

Quote

Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3); 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators.

 

Edited May 23, 2020 by Mitch Cumsteen

[ChiTownDoc 21219]

4 hours ago, Anastasis said:

Yeah, many of the side effects are probably related to the underlying disease.  

I thought the subgroup analysis by baseline score is interesting. Does not appear to do any good once they are on invasive vent.

Also the symptom duration and age group subgroup analyses.  Wouldn't make a whole bunch out of it, but will be something interesting to look for in the next wave of RCT data. 

 

Dr. Anastasis is pretty prettttyyyy good. 

[Anastasis 23504]

 

Reports of adverse events associated with MRNA's vax in their phase I trial:

https://www.statnews.com/2020/05/26/moderna-vaccine-candidate-trial-participant-severe-reaction/

In the 45-person Moderna study, four participants experienced what are known as “Grade 3” adverse events — side effects that are severe or medically significant but not immediately life-threatening. Neither the company nor the National Institute of Allergy and Infectious Diseases, which is running the trial, have previously detailed the nature of those incidents, but Moderna did disclose that three, likely including Haydon, received the highest dose of the vaccine that was tested, and had reactions that involved their whole bodies. A fourth received a lower dose and had a rash at the injection site. 

[Brisketexan 105572]

36 minutes ago, Anastasis said:

 

Reports of adverse events associated with MRNA's vax in their phase I trial:

https://www.statnews.com/2020/05/26/moderna-vaccine-candidate-trial-participant-severe-reaction/

In the 45-person Moderna study, four participants experienced what are known as “Grade 3” adverse events — side effects that are severe or medically significant but not immediately life-threatening. Neither the company nor the National Institute of Allergy and Infectious Diseases, which is running the trial, have previously detailed the nature of those incidents, but Moderna did disclose that three, likely including Haydon, received the highest dose of the vaccine that was tested, and had reactions that involved their whole bodies. A fourth received a lower dose and had a rash at the injection site. 

Well, looks like it was to the high dose (that is, higher than they would  anticipate using in actual treatment).

[ChiTownDoc 21219]

49 minutes ago, Anastasis said:

 

Reports of adverse events associated with MRNA's vax in their phase I trial:

https://www.statnews.com/2020/05/26/moderna-vaccine-candidate-trial-participant-severe-reaction/

In the 45-person Moderna study, four participants experienced what are known as “Grade 3” adverse events — side effects that are severe or medically significant but not immediately life-threatening. Neither the company nor the National Institute of Allergy and Infectious Diseases, which is running the trial, have previously detailed the nature of those incidents, but Moderna did disclose that three, likely including Haydon, received the highest dose of the vaccine that was tested, and had reactions that involved their whole bodies. A fourth received a lower dose and had a rash at the injection site. 

Definitely not good.  They're the shittiest horse in this race imo.  Had fun with STONKS thanks to them.  

[Skipper 6315]

It's a little disappointing that we're almost to June and appears we haven't made much progress finding a therapeutic to help until we get a vaccine.   I remember reading about Remdesivir when this first started blowing up in late February early March and it seemed the thought then was that it may help but not close to a magic bullet.  Seems like we're still at the same place unless I've missed something.

[XYZ 2154]

I thought hydroxychloroquine plus zinc was a pretty good treatment option. Has that been disproved, or there hasn’t been proper trials yet?

Edited May 28, 2020 by XYZ

[triplehorn 2664]

On 5/27/2020 at 6:36 PM, XYZ said:

I thought hydroxychloroquine plus zinc was a pretty good treatment option. Has that been disproved, or there hasn’t been proper trials yet?

The past couple weeks have been pretty wild with the criticized Lancet publication spurring the WHO pronouncement on Wednesday to temporarily suspend the testing of HCQ in Covid-19 patients following safety concerns.  It resulted in nations around the globe taking sides this week as to whether they were abandoning use of HCQ and halting study trials, or forging ahead with it based on their own medical community determinations of safety and benefit through first hand treatment of their populations. 

India's ICMR finds it safe and is forging ahead with HCQ

Lancet spooked Canada, but after a pause, found no safety issues and resumed their 9 ongoing trials.

German clinical trial of HCQ paused even though director sees "no evidence of side effects" and is confident that it will resume shortly. (subscription)

More responsive to your question - treatment benefits beyond primary safety questions - Turkey is also forging ahead with HCQ and appears to have it dialed in:

 

The article has a section dedicated debate over HCQ.  From the article:

"Chief doctor Nurettin Yiyit - whose art work is on the hospital walls - says it's key to use hydroxychloroquine early. "Other countries are using this drug too late," he says, "especially the United States. We only use it at the beginning. We have no hesitation about this drug. We believe it's effective because we get the results."

They are all saying early application is key, not after you've been symptomatic for a week or had progression of severity requiring hospitalization.  This is the common observation and practice in Italy, India, Turkey, other European countries, and in various nations in SE Asia.  So far Zinc is not even a part of MSM reporting on this matter.  However, there has been one study (non-gold standard) to date out of NYU the other week suggesting Zn added to the HCQ appeared to have a sizable benefit.

 

Edited May 30, 2020 by triplehorn

[triplehorn 2664]

Pre-print article on findings in India using HCQ only as prophylaxis to prevent Covid-19 infection (no Azithromycin):

Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19
 

Date of Submission28-May-2020

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmr.IJMR_2234_20

   Abstract 

Background & objectives: Healthcare workers (HCWs) are at an elevated risk of contracting COVID-19. While intense occupational exposure associated with aerosol-generating procedures underlines the necessity of using personal protective equipment (PPE) by HCWs, high-transmission efficiency of the causative agent [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] could also lead to infections beyond such settings. Hydroxychloroquine (HCQ), a repurposed antimalarial drug, was empirically recommended as prophylaxis by the National COVID-19 Task Force in India to cover such added risk. Against this background, the current investigation was carried out to identify the factors associated with SARS-CoV-2 infection among HCWs in the country.

Methods: A case-control design was adopted and participants were randomly drawn from the countrywide COVID-19 testing data portal maintained by the ICMR. The test results and contact details of HCWs, diagnosed as positive (cases) or negative (controls) for SARS-CoV-2 using real-time reverse transcription-polymerase chain reaction (qRT-PCR), were available from this database. A 20-item brief-questionnaire elicited information on place of work, procedures conducted and use of PPE.

Results: Compared to controls, cases were slightly older (34.7 vs. 33.5 yr) and had more males (58 vs. 50%). In multivariate analyses, HCWs performing endotracheal intubation had higher odds of being SARS-CoV-2 infected [adjusted odds ratio (AOR): 4.33, 95% confidence interval (CI): 1.16-16.07]. Consumption of four or more maintenance doses of HCQ was associated with a significant decline in the odds of getting infected (AOR: 0.44; 95% CI: 0.22-0.88); a dose-response relationship existed between frequency of exposure to HCQ and such reductions (χ2 for trend=48.88; P<0.001). In addition, the use of PPE was independently associated with the reduction in odds of getting infected with SARS-CoV-2.

Interpretations & conclusions: Until results of clinical trials for HCQ prophylaxis become available, this study provides actionable information for policymakers to protect HCWs at the forefront of COVID-19 response. The public health message of sustained intake of HCQ prophylaxis as well as appropriate PPE use need to be considered in conjunction with risk homoeostasis operating at individual levels.

 

---> I didn't download the .pdf of the full text, but evidently there was a loading dose followed by HCQ 400mg once per week. 

[triplehorn 2664]

Here's an article about the ICMR's positive findings for HCQ prophylaxis: 80% reduction in odds of HCW's developing Covid infection.

4 or more hydroxychloroquine doses reduced risk of coronavirus in healthcare workers: ICMR study

"The ICMR study indicates that "simply initiating HCQ prophylaxis did not reduce the odds of acquiring Covid-19 infection among HCWs. However, with the intake of four or more maintenance doses of HCQ, the protective effect started emerging. A significant reduction of about 80 per cent in the odds of Covid-19 infection in the HCWs was identified with the intake of six or more doses of HCQ prophylaxis. This dose-response relationship added strength to the study outcomes."

"Biologically, it appears plausible that HCQ prophylaxis, before the onset of infection, may inhibit the virus from gaining a foothold," researchers said in the study.

The National Task Force for coronavirus in India recommended once a week maintenance dose for seven weeks i.e., 400 mg once every week, following the loading dose of 400 mg. Adherence to this recommended regimen is underlined by the findings of the study, researchers said.

[...]"

 

Need more studies, but damn.

 

 

 

[South Austin 52688]

On ‎5‎/‎19‎/‎2020 at 9:48 AM, triplehorn said:

Punjab directs all its frontline healthcare workers to take HCQ tablets

You said Punjab. [snortle]

[WithoutAClue 15558]

Coronavirus May Be a Blood Vessel Disease, Which Explains Everything

Interesting theory of how COVID-19 attacks the body.

In April, blood clots emerged as one of the many mysterious symptoms attributed to Covid-19, a disease that had initially been thought to largely affect the lungs in the form of pneumonia. Quickly after came reports of young people dying due to coronavirus-related strokes. Next it was Covid toes — painful red or purple digits.

What do all of these symptoms have in common? An impairment in blood circulation. Add in the fact that 40% of deaths from Covid-19 are related to cardiovascular complications, and the disease starts to look like a vascular infection instead of a purely respiratory one.

[Newdoc 3465]

1 hour ago, WithoutAClue said:

Add in the fact that 40% of deaths from Covid-19 are related to cardiovascular complications,

This really does make sense as most of the high risk conferred is in people with pre-existing cardiovascular disease. As the authors admit, they are not sure if the cytokine storm or direct vascular infection is causing the complications in these patients.

We maybe able to greatly reduce death if we can effectively treat these high risk individuals prior to their coagulopathy and/or infarction.

[Victor Lazlo 1788]

3 hours ago, Newdoc said:

This really does make sense as most of the high risk conferred is in people with pre-existing cardiovascular disease. As the authors admit, they are not sure if the cytokine storm or direct vascular infection is causing the complications in these patients.

We maybe able to greatly reduce death if we can effectively treat these high risk individuals prior to their coagulopathy and/or infarction.

I have a question about “people with pre-existing cardiovascular disease”.

Does that include people like me, not overweight but diagnosed with high blood pressure years ago that is being controlled effectively with medication? The high blood pressure runs in my family.

I’ve never been able to pin down exactly what “pre-existing cardiovascular disease” means in the context of Covid-19 comorbitities.

 

[Newdoc 3465]

7 hours ago, Victor Lazlo said:

I have a question about “people with pre-existing cardiovascular disease”.

Does that include people like me, not overweight but diagnosed with high blood pressure years ago that is being controlled effectively with medication? The high blood pressure runs in my family.

I’ve never been able to pin down exactly what “pre-existing cardiovascular disease” means in the context of Covid-19 comorbitities.

 

Cardiovascular or atherosclerotic disease  indicates a buildup of plaques in arteries that supply critical organs like the heart and the brain.  These plaques can become unstable especially with an inflammatory process and cause a hypercoagulable state where clots form along the plaques inside the arteries and then block blood flow or cause a clot to move to another part of the body and block blood flow (e.g. a stroke).

High blood pressure itself causes several changes to the arteries that can also lead to reduced blood flow and inflammatory changes in the arteries that lead to blockages as well. The hypertension itself is not necessarily an immediate risk unless it puts significant pressure on a weakening vessel and causes a rupture. The same concept is true for diabetes and even obesity. The disease state itself doesn't necessarily kill you, it's the long term changes the disease creates that kill you.  There are many people with these disease processes that don't know they have these vascular end changes from their long term disease process.

Covid has become a tipping point as it causes significant stress to systems that are already compromised by chronic disease. If you hypertension is well controlled it is likely that you do not have significant risks as compared to someone who has vessel disease included with their hypertension, obesity, diabetes, etc.

[Armybrat 40993]

12 hours ago, Newdoc said:

This really does make sense as most of the high risk conferred is in people with pre-existing cardiovascular disease. As the authors admit, they are not sure if the cytokine storm or direct vascular infection is causing the complications in these patients.

We maybe able to greatly reduce death if we can effectively treat these high risk individuals prior to their coagulopathy and/or infarction.

Hope so, as I have 4 heart stent implants and a clot in my leg (not deep vein).

had a mild heart attack in January 2019, but no damage to speak of. Still obese.

Edited June 2, 2020 by Armybrat

[Armybrat 40993]

8 hours ago, Victor Lazlo said:

I have a question about “people with pre-existing cardiovascular disease”.

Does that include people like me, not overweight but diagnosed with high blood pressure years ago that is being controlled effectively with medication? The high blood pressure runs in my family.

I’ve never been able to pin down exactly what “pre-existing cardiovascular disease” means in the context of Covid-19 comorbitities.

 

See my last post.