The OFFICIAL 'Wuhan' Coronavirus outbreak information and tracking thread. NARRATIVE CHANGE. "Endemic, just like the cold". Cuomo regrets lockdown.
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If this situation is turned around this will be the footage that CNN will use for their news cast about the virus up to an including election day to blame it on Trump.
I just watched the Sunday coronavirus pandemic White House briefing. America is very quickly reaching the point to where the Government has done about all it can do for the average American. That was not verbalized, but watching the body language, it was evident. Appearing they will compartmentalize America and fight the major battles on a regional engagement. You guy's see anything differently?
Hobo
Hobo
I viewed it through a similar lens. When our prior administrations and congressional leaders ignore the CDC/WHO/AHA/APA recommendations for decades on end, specifically on how to prepare and react to such a pandemic, one could argue this is what happens.
And now we are playing National GDP Balance gymnastics, leveraging 2+ billion of the future of follow-on generations to stop the bleeding we have today.
I wonder how soon interstate travel will get shut down.
Didn’t you hear, “its going down tonight!”
I would imagine someone with any of the State Highway Patrol's could give some insight as to what is being planned.
13 CLICKS IN MILS.
Ssh! Don’t give them any ideas.
No! Stay away from whores and homeless junkies!
I hear it's those mil guys that have to multiply by 100 so they can understand numbers.
Was reading through this article and found it to be enlightening. Apparently, its been posted a few times on various social media platforms and taken down. The two pictures are excerpts.
www.zerohedge.com
Zerohedge
ZeroHedge - On a long enough timeline, the survival rate for everyone drops to zero
www.zerohedge.com 
I think the issue is that the courts are currently closed/quarantined.
The preference is always for summons but right now even more so.
Shit that previously would be an arrest is now being handled by summons.
If there is an arrest they are trying to figure how to video arraign from the holding police station so the arrested never goes to court.
Im thinking they are just trying to head off the issues with the fact the already fucked up courts will now be doing motor vehicle violation appeals three years after the incident.
For those who really want to dive into the nerdery of my life, some of the more recent published literature on the current strategies countries are deploying:
The numbers on the news this morning.
34400 positive tests and 414 deaths.
Today's number is .01203 and for those that are number challenged multiply by 100 and the number will still be dropping.
The offer still stands. One months pay. Any takers?
34400 positive tests and 414 deaths.
Today's number is .01203 and for those that are number challenged multiply by 100 and the number will still be dropping.
The offer still stands. One months pay. Any takers?
Was reading through this article and found it to be enlightening. Apparently, its been posted a few times on various social media platforms and taken down. The two pictures are excerpts.
Zerohedge
ZeroHedge - On a long enough timeline, the survival rate for everyone drops to zero
View attachment 7279470
View attachment 7279471
This article does have something worth exploring. We don't know the true impact or average outcomes of the "mild cases" well enough in current day, and we also have a "denominator" problem. I.e, there are a lot of people who are walking around right now with the virus with barely any symptoms at all who will never be captured in the data set, thus making the fatality/morbidity rate skewed.
Brian Stelter. Is that you? Weren't you and CNN pushing Impeachment during the Jan/Feb time period? Weren't you criticizing the president for being racist for shutting down travel from China on Feb. 2? Boy, you and your leftist compadres showed the President when Florence Italy held a "hug a Chinese" initiative in Feb. and New York City Health Commissioner encouraged folks to gather together at the Chinese New Year festivities to show the world that Orange Man bad. You and Jim Acosta's open border advocacy likely seeded our nation with this virus. You had us focused on climate change, not pathogens from China.
Stop your hatred of the man from blinding you from seeing the huge challenges the man has to overcome. There are no easy black and white decisions. To suggest otherwise, is BS. We could end the virus spread if we shut down the economy but that leads to downstream issues, ie poverty, starvation, economic collapse. It's a balancing act and one I think he's doing amazing at. If he wasn't undercut every step by the corrupt media and leftist politicians, we would be on the other end of this.
Donald Trump is the exact leader we need at this time because of his life experience. Think about every policy that he talked about and how that would have kept us safe: the wall, rebuild American industry, reduce government regulation, etc. Step back and think about who could have handled this better. Hillary? Obama? Give me break.
We will get through this. We will be stronger. We now clearly see the dangers of Leftism and corrupt media. We are Americans. We don't run. We don't quit. We aren't cup-cakes.
When I was in the military we studied the effect of a panic on the civilian population. The salient point on that factor in any political-military scenario is that an enemy can achieve his objective with very little application of force.
It is against the Geneva Convention rules to counterfeit money in order to sew chaos in a countries economic system. Now that our economy is in a free-fall and the value of 401Ks dropping like bird shit, the Chinese could not have conceived of a better outcome in their wildest dreams. They didn't need to hang any paper.
As more and more people are tested we are sure to see significantly large segments of the populations infected with the Chinese virus. As we all know, most of the people infected are asymptomatic. Even though it is tragic, there is only a sliver of those infected that have serious or fatal outcomes.
Nevertheless, statistics are like loose women. You can do anything you want with them. The mainstream media will continue to ring the death knell because:
1) It sells advertising space on their newscasts, newspapers or online articles.
2) The hate Trump and will blame him for any negative consequences of the Chinese virus.
3) Like an enemy force, they hope to achieve their objective by psychological methods rather than the application of force.
4) The MSM's objective is to get a Communist in the White House and a leftist majority in both legislative branches - with the ultimate goal of changing the judiciary.
The MSM will not report the low percentage of serious or fatal COVID-19 cases. They will only report the actual number of people dying; which on the surface, would make it look like a replay of the black plague.
I will largely agree our news media outlets, on BOTH SIDES, are contributing largely to the mass panic. If I could force news outlets to report only scientifically verified data, 99.9% of the time, I would pay to see that.
Your other conclusions, I remain unconvinced.
Local radio reporting Fauci was in the Wikileaks emails.....
A fawning Hillary Clinton fan.
A fawning Hillary Clinton fan.
One upside of the corona that it might wipe out some of forever lawmakers ,most are pushing 70+
Same metrics skews the mortality rate for flu and host of other viral infections so its a not realy a good point .
Same metrics skews the mortality rate for flu and host of other viral infections so its a not realy a good point .
Guessing Dems will be having someone in the midst of full blown CV visit Joe Biden soon and tongue kiss him.
Id suggest they send a child if they want to be successful in enticing him.
What I need to know.....
I just bought a Kestrel from @gr8fuldoug at a great price, should be shipping today......
Will I survive to use it?
I just bought a Kestrel from @gr8fuldoug at a great price, should be shipping today......
Will I survive to use it?
We are taking, processing and shipping orders. No worries.
Give us a call with any questions.
Stay healthy and safe
Give us a call with any questions.
Stay healthy and safe
I agree, this problem exists with the flu as well, but I still think it matters especially in the early onset of a very new data set of virus behavior and the subsequent national policies that are being implemented from these data sets.
Regarding COVID-19, what is your profession/experience? Just a question, not an attack.
While I wouldn't make bets on how many people die, I did notice this morning that it's 471/35000
Still 1.35%
But, we do see your point. The death rate will probably go way way down. Probably, someday, since we're guessing.
Time will tell. I'll be checking back in here for quite awhile as the numbers change. Im eager to see who ends up being right, and who ends up being full of shit.
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In the medical field. I just got the first aid classes.
Military experience: Air Force and Army. That's all that I want to say about myself right now.
I did stay at a Holiday Inn Express
No offence taken.
More reports indicating the erratic and tornado-like damage pattern of COVID-19 through the entire population...
36 year old nurse in the UK. Healthy and no underlying conditions.
amp.theguardian.com
In the US, there is a 12 year old girl still in very critical condition. A 40 year old New Orleans DJ with no health issues also died, a 29 year old social worker also from New Orleans, and scores of other cases. Apparently, many of those who were relatively young and fit are dropping like flies from this thing...
Still thought that big spring break beach party was a good idea???
36 year old nurse in the UK. Healthy and no underlying conditions.
'Fit and healthy' 36-year-old UK nurse in intensive care with coronavirus | Coronavirus | The Guardian
Areema Nasreen is on a ventilator at Walsall Manor hospital in West Midlands
amp.theguardian.com In the US, there is a 12 year old girl still in very critical condition. A 40 year old New Orleans DJ with no health issues also died, a 29 year old social worker also from New Orleans, and scores of other cases. Apparently, many of those who were relatively young and fit are dropping like flies from this thing...
Still thought that big spring break beach party was a good idea???
Thanks VERY much for your service. I HATE the mainstream media as much as anyone. That being said, being on the front lines of dealing with this pandemic as a ER doctor who intubated 4 patients with COVID-19 in less than 10 hours yesterday, this is VERY much a different deal than Influenza and far, far more virulent. 2 of the 4 patients were less than 40 years old and no prior medical history.In the medical field. I just got the first aid classes.
Military experience: Air Force and Army. That's all that I want to say about myself right now.
I did stay at a Holiday Inn Express
No offence taken.
More reports indicating the erratic and tornado-like damage pattern of COVID-19 through the entire population...
36 year old nurse in the UK. Healthy and no underlying conditions.
'Fit and healthy' 36-year-old UK nurse in intensive care with coronavirus | Coronavirus | The Guardian
Areema Nasreen is on a ventilator at Walsall Manor hospital in West Midlands
In the US, there is a 12 year old girl still in very critical condition. A 40 year old New Orleans DJ with no health issues also died, a 29 year old social worker also from New Orleans, and scores of other cases. Apparently, many of those who were relatively young and fit are dropping like flies from this thing...
Still thought that big spring break beach party was a good idea???
I would still agree that "random" is not the correct way to think about it. There is an underlying pattern to uncover.
I agree that the disease should be taken seriously. For the most part I don't have a problem with the precautions that are being implemented.
What now seems to be the bigger problem is the panic from this situation.
When people are told not to panic, that is the first thing they do.
When people are told not to hoard, they make a run on all the stores like a pack of wild dogs on a fresh piece of carrion.
When people were told to keep their money in the banks after the crash of 1929, they worsened the collapse. That's how we got the FDIC.
Even worse than the panic is the doom & gloom the MSM is spreading. IMHO, it will not stop even if this "crisis" [term used loosely] is turned around until Trump and the Republicans are defeated.
'This week, it's going to get bad': U.S. Surgeon general says people need to take coronavirus seriously
The disease is spreading, the surgeon general said, because many people are not following the guidance to stay at home.
www.nbcnews.com 
Yes, the same ~1% that we've seen in every country where the health system wasn't overrun. So if that is the best case scenario, and there is no immunity and it could infect half the population...that's a problem.
And the cases may be increasing partly because of increased testing capacity, that is true. But that doesn't explain the deaths:
Source: https://www.worldometers.info/coronavirus/country/us/
Agreed. Putting deaths aside, roughly 20% of the infections are resulting in SOME TYPE of hospitalization according to the early data (subject to change as we get more). Let's just blindly assume that statistic applies to America at varying degrees:
340,000,000 people * 20% = 68 million people who need medical attention.
340,000,000 people * 15% = 51 mil
340,000,000 people * 10% = 34 mil
340,000,000 people * 5% = 17 mil
(and so on).
None of that is good.
Doesn't look like fun..
Horrifying images show coronavirus patients in Madrid hospital
The scenes were reportedly recorded at the Infanta Leonor Hospital and the Severo Ochoa de Leganes Hospital in the Spanish capital Madrid.
Here in SE AZ, we've shut down our VFW Post with a tentative reopening April 1; but my thinking is at least another week, and it could go to months. Our volunteer weekly cleaning crew showed up on schedule at 7:15am today, and cleaned/disinfected all floors and preparation/serving surfaces; vacuuming the carpets as well. All door and faucet handles were disinfected, and the sign out front was changed to "Closed for Now".
We have fixed expenses that continue to accrue, and our only paid staff is the bar tenders. We are doing what we can to ease the staff' financial burdens, mainly through individual donations to the Post funds, etc. This Post is our family, and without it we are pretty much without any place to meet and unwind. Same for our churches, Community Centers, and Library. Dollar General is the main source for most things we need, and they're doing a surprisingly good job of keeping up with family needs. The hardware store is open, and it provides an ATM during open hours.
No raving maniacs in the streets, increased foot/exercise traffic on the side streets, and a general, but somewhat distant, cheer on what faces show themselves. We're seeing it work, and we're glad about it.
I'm new here (going on four years), and pleasantly surprised at how sensible and cheerful my neighbors are. I anticipate that whatever happens, we'll stand through it together.
Greg
We have fixed expenses that continue to accrue, and our only paid staff is the bar tenders. We are doing what we can to ease the staff' financial burdens, mainly through individual donations to the Post funds, etc. This Post is our family, and without it we are pretty much without any place to meet and unwind. Same for our churches, Community Centers, and Library. Dollar General is the main source for most things we need, and they're doing a surprisingly good job of keeping up with family needs. The hardware store is open, and it provides an ATM during open hours.
No raving maniacs in the streets, increased foot/exercise traffic on the side streets, and a general, but somewhat distant, cheer on what faces show themselves. We're seeing it work, and we're glad about it.
I'm new here (going on four years), and pleasantly surprised at how sensible and cheerful my neighbors are. I anticipate that whatever happens, we'll stand through it together.
Greg
BREAKING:
More direct on-the-ground reports regarding the use of hydrochloroquine and azithromycin in resolving acute COVID-19 is coming in now as the first US hospitals begin using the drug cocktail for treatment of serious and critical patients. Some of the hospitals had already started trials of the cocktail even before President Trump had made his official announcement for the country to begin the treatment regimen. World Health Organization begins global mega trial of multiple drugs and drug cocktails with majority emphasis on Plaquenil+Zithromax (commercial brand names for hydroxychloroquine and azithromycin). Article in third entry of this post.
CASE 1:
53-year old nurse from New Jersey.
Sex: Female.
Nonsmoker.
No underlying conditions.
The progression of her COVID-19 infection took a track much like some of the other worrisome cases in much younger people that we have been seeing all over the world. A period of mild flu-like symptoms in the beginning. A light dry cough, spiking fever similar to regular influenza, aches and pains, and general malaise which rapidly escalated into ARDS (acute respiratory distress syndrome) by the eighth day of the illness. Doctors initially misdiagnosed her with bacterial pneumonia and prescribed her copious amounts of antibiotics, which obviously would not work. It was not until she had been brought to the ICU in critical respiratory distress that the diagnosis of COVID-19 was made. One quick thinking doctor on her team immediately placed an order for hydrochloroquine and azithromycin to be started, citing effective results from Chinese, Korean, and French doctors. Within a day, her fever went down and her respiratory symptoms began to ease, although it will be up to another week before her body is able to clear the virus completely. Without the cocktail drug therapy, this case was very much likely fatal.
www.forbes.com
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Margaret Novins talked to me on her cellphone from a hospital bed at CentraState Medical Center in Freehold, N.J.
She had been ill since March 8, toughing it out through fatigue, a cough and fevers that brought on vicious chills for five evenings straight.
Finally, on March 15, she went to an urgent care center and, on March 16, to an emergency room. The attending there called it “conversational dyspnea.”
“I couldn’t breathe,” she said.
Novins, who shared her lab tests and medication list, got her diagnosis March 19. Next to the entry for SARS-CoV-2 were the words “Detected Critical.” She had the coronavirus, or COVID-19.
To that point, Novins had been a pneumonia patient for three days, treated mainly with antibiotics. But within an hour, a new drug was added to her med list: hydroxychloroquine, a decades-old malaria-turned-autoimmune drug, also called by its brand name Plaquenil. President Trump is touting the drug, some say overselling it, as the possible answer to the COVID-19 crisis.
Novins’ responded to the treatment. She was better, though surely not well, the next day.
“The fever,” which was still spiking when she was on other meds, “is now gone, which is fantastic,” she said on Saturday March 21, coughing at times but able to speak.
A 53-year-old nurse who described herself as a nonsmoker with no medical issues, Novins spoke to me from the hospital that had cared for some of the seven members of a family ravaged by COVID; two adult brothers, a sister and their mother died from the infection.
“The doctor insisted the pharmacy get it to me the minute we got the positive,” she said of hydroxychloroquine. “It seemed like their go-to right away.”
After three nights in the hospital, Margaret Novins' COVID test came back positive: "Detected ... [+] Critical," the result said.
There are other anecdotal successes like Novins’, including one in which end-of-life discussions for an older parent had been broached — until Plaquenil apparently kicked in. In that case, the family had to plead for, rather than being offered, the drug.
Anecdotes are surely not science, which for now is limited and new.
Trump is basing his optimism mostly on one small study from Marseilles, France, that, combined with laboratory findings, has prompted ongoing trials in France and the United States. The just-released French study reported that 70 percent of hydroxychloroquine-treated patients, or 14 of 20, were negative for the virus at day 6, as were all six patients who were treated with hydroxychloroquine and the antibiotic azithromycin (which Novins also received). But the study was small – 20 treated patients and 16 controls – and had other serious limitations.
Of concern, six patients dropped out and were not considered in the reported efficacy rates. Three went to intensive care; one died; one left the hospital testing negative, and one opted out due to nausea.
Two scientists at major university centers reviewed the French trial for me. They agreed, separately, that while the study is preliminary, small, and not without flaws, its findings were strong enough, given the drugs’ known safety records, to guide treatment decisions in a crisis.
“Despite the limitations of this study, in the absence of any effective treatment, in this urgent situation, this Plaquenil and Azithromycin combination therapy should be given to patients with COVID-19 as a treatment option,” Ying Zhang, a professor of microbiology at Johns Hopkins Bloomberg School of Public Health, wrote in an email. “For now, there is no time to wait.”
Working against the study, in Zhang’s view: It was not a randomized trial, which would avoid bias; the sample size was small, and the treatment and followup duration was too short. The findings are nonetheless “potentially interesting and justified,” he wrote.
Brian Fallon, a research scientist and clinical trials investigator at the Columbia University Irving Medical Center, agreed on the study’s overall merit despite the patients who dropped out. After analyzing the data and counting all six dropouts as treatment failures, he said the overall rate of improvement was still statistically significant for the entire group, though not for the hydroxychloroquine group alone.
He too had reservations, in particular that the combination therapy group was very small, six patients, and that high doses of the two drugs together carry “serious risk of cardiac arrhythmias.” Physicians must be warned of this, he suggested.
Nonetheless, he wrote in an email, “Given the life and death situation of hospitalized patients with COVID-19 and the possibility that hydroxychloroquine plus azithromycin may be helpful, it was valuable and ethical for the authors to report these promising, preliminary results.”
Others agreed. Lorraine Johnson, who has published on the use of collected data to improve health care outcomes, said, “It is important right now to take the gloves off clinicians and give them access to all available tools; patients are dying and can’t wait for clinical trials.”
At the same time, she and Zhang, who has published on treatments for difficult infections like tuberculosis and Lyme disease, said a database should be set up to track patients, like Margaret Novins, in order to document drug performance. “I would recommend real-time online posting of treatment evaluation results of the Plaquenil+Azithromycin at multi-center sites across the US and the Globe,” Zhang wrote. “Someone has to coordinate this online registry and resources.” He added that other treatments should be included.
Supply issues raised
In a 1982 drug bulletin, the FDA encouraged so-called off-label use of approved drugs: “Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations.”
In the real world, however, a rush to put a relatively safe approved drug to a vastly expanded new use may reduce supplies for others who need it, including lupus, rheumatoid arthritis and Lyme disease sufferers.
Kenneth Farber, president of the Lupus Research Alliance, said there were shortages of Plaquenil throughout the United States and especially in New York and California.
Asked about supplies, a spokesperson for CVS Health, T.J. Crawford, said the drug-store chain has an “adequate supply on-hand” of hydroxychloroquine but supply of a related drug, chloroquine, “is tight across the marketplace.”
Jane Marke, a New York City psychiatrist who takes Plaquenil for Lyme disease, said she had trouble getting her prescription filled at several city chains. After reading the French study, she understands why. “It is really possible that this is a major breakthrough,” she said, envisioning a time when a good test could pick up early infections and the drug would stop the epidemic in its tracks.
In that vein, the University of Minnesota is organizing a trial to treat 1,500 people with hydroxychloroquine who were exposed to the virus from infected family members or as healthcare workers but are not yet ill. The study relied on laboratory experiments in China that found hydroxychloroquine inhibited the infection.
“If effective, this may become a worldwide standard of care for helping prevent disease in other healthcare workers and people exposed,” Dr. David Boulware, a U of M professor of medicine, said in announcing the study.
A key advantage of an off-patent generic drug like hydroxychloroquine: “A five-day treatment course would cost approximately $12,” Boulware said.
Novins, meantime, is expecting to leave the hospital in a day or two. As a nurse for a medical equipment company, she believes she contracted the infection not from a patient but while conducting a day-long training session.
Nonetheless, she said in a text, “I feel fortunate.”
“From my notes it is clear that my fevers and horrible chills I fought hard from 3/8-3/18 turned the corner the day I started Plaquenil 3/19,” she wrote.
While she said COVID is a “violent illness,” Novins never was in intensive care or on a respirator. The French study offers a mere glint of hope for more serious cases too. Of five patients with lower respiratory infection, four turned negative by day 6, three of them on both drugs.
In the meantime, scientists said larger, more rigorous studies must be launched to answer questions of efficacy, dosing, duration, and potential adverse drug interactions — for this and other COVID treatments.
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CASE 2:
TV actor Daniel Kim attributes his rapid recovery from acute COVID-19 infection to the cocktail of hydroxychloroquine and azithromycin.
www.washingtontimes.com
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Television star Daniel Dae Kim said he feels “practically back to normal” after taking a combination of drugs that include hydroxychloroquine, the anti-malarial drug President Trump has touted, calling it his “secret weapon.”
Mr. Kim, who starred in the network shows “Lost” and “Hawaii Five-O,” said in a Saturday post on Instagram that he has almost no symptoms after taking Tamiflu; the antibiotic azithromycin, or Z-Pak; an inhaler, and hydroxychloroquine.
“I’m happy to report that my progress has continued and I feel practically back to normal,” said Mr. Kim in a video from his home in Hawaii, where he has self-isolated. “I am lucky enough to be in the 80% of diagnosed cases that have not required hospitalization. That’s an important statistic.”
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WHO to begin worldwide mega trials of the drug cocktail.
www.sciencemag.org
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A drug combo already used against HIV. A malaria treatment first tested during World War II. A new antiviral whose promise against Ebola fizzled last year.
Could any of these drugs hold the key to saving coronavirus disease 2019 (COVID-19) patients from serious harm or death? On Friday, the World Health Organization (WHO) announced a large global trial, called SOLIDARITY, to find out whether any can treat infections with the new coronavirus for the dangerous respiratory disease. It’s an unprecedented effort—an all-out, coordinated push to collect robust scientific data rapidly during a pandemic. The study, which could include many thousands of patients in dozens of countries, has been designed to be as simple as possible so that even hospitals overwhelmed by an onslaught of COVID-19 patients can participate.
With about 15% of COVID-19 patients suffering from severe disease and hospitals being overwhelmed, treatments are desperately needed. So rather than coming up with compounds from scratch that may take years to develop and test, researchers and public health agencies are looking to repurpose drugs already approved for other diseases and known to be largely safe. They’re also looking at unapproved drugs that have performed well in animal studies with the other two deadly coronaviruses, which cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
Drugs that slow or kill the novel coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could save the lives of severely ill patients, but might also be given prophylactically to protect health care workers and others at high risk of infection. Treatments may also reduce the time patients spend in intensive care units, freeing critical hospital beds.
Scientists have suggested dozens of existing compounds for testing, but WHO is focusing on what it says are the four most promising therapies: an experimental antiviral compound called remdesivir; the malaria medications chloroquine and hydroxychloroquine; a combination of two HIV drugs, lopinavir and ritonavir; and that same combination plus interferon-beta, an immune system messenger that can help cripple viruses. Some data on their use in COVID-19 patients have already emerged—the HIV combo failed in a small study in China—but WHO believes a large trial with a greater variety of patients is warranted.
Enrolling subjects in SOLIDARITY will be easy. When a person with a confirmed case of COVID-19 is deemed eligible, the physician can enter the patient’s data into a WHO website, including any underlying condition that could change the course of the disease, such as diabetes or HIV infection. The participant has to sign an informed consent form that is scanned and sent to WHO electronically. After the physician states which drugs are available at his or her hospital, the website will randomize the patient to one of the drugs available or to the local standard care for COVID-19.
“After that, no more measurements or documentation are required,” says Ana Maria Henao-Restrepo, a medical officer at WHO’s Department of Immunization Vaccines and Biologicals. Physicians will record the day the patient left the hospital or died, the duration of the hospital stay, and whether the patient required oxygen or ventilation, she says. “That’s all.”
The design is not double-blind, the gold standard in medical research, so there could be placebo effects from patients knowing they received a candidate drug. But WHO says it had to balance scientific rigor against speed. The idea for SOLIDARITY came up less than 2 weeks ago, Henao-Restrepo says, and the agency hopes to have supporting documentation and data management centers set up next week. “We are doing this in record time,” she says.
Arthur Caplan, a bioethicist at New York University Langone Medical Center, says he likes the study’s design. “No one wants to tax the frontline caregiver who’s overwhelmed and taking risks anyway,” Caplan says. Hospitals that aren’t overburdened might be able to record more data on disease progression, for instance by following the level of virus in the body, Caplan suggests. But for public health, the simple outcomes WHO seeks to measure are the only relevant ones for now, says virologist Christian Drosten of the Charité University Hospital in Berlin: “We don’t really know enough about this disease to be sure what it means when the viral load decreases in the throat, for instance.”
On Sunday, INSERM, the French biomedical research agency, announced it will coordinate an add-on trial in Europe, named Discovery, that will follow WHO’s example and will include 3200 patients from at least seven countries, including 800 from France. That trial will test the same drugs, with the exception of chloroquine. Other countries or groups of hospitals could organize add-on studies as well, Heneo-Restrepo says. They are free to do additional measurements or observations, for instance on virology, blood gases, chemistry, and lung imaging. “While well-organized additional research studies of the natural history of the disease or of the effects of the trial treatments could well be valuable, they are not core requirements,” she says.
The list of drugs to test was first put together for WHO by a panel of scientists who have been assessing the evidence for candidate therapies since January, Heneo-Restrepo says. The group of selected drugs that had the highest likelihood of working, had the most safety data from previous use, and are likely to be available in supplies sufficient to treat substantial numbers of patients if the trial shows they work.
Here are the treatments that SOLIDARITY will test:
Remdesivir
The new coronavirus is giving this compound a second chance to shine. Originally developed by Gilead Sciences to combat Ebola and related viruses, remdesivir shuts down viral replication by inhibiting a key viral enzyme, the RNA-dependent RNA polymerase.
Researchers tested remdesivir last year during the Ebola outbreak in the Democratic Republic of the Congo, along with three other treatments. It did not show any effect. (Two others did.) But the enzyme it targets is similar in other viruses, and in 2017 researchers at the University of North Carolina, Chapel Hill, showed in test tube and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.
The first COVID-19 patient diagnosed in the United States—a young man in Snohomish county in Washington—was given remdesivir when his condition worsened; he improved the next day, according to a case report in The New England Journal of Medicine (NEJM). A Californian patient who received remdesivir—and who doctors thought might not survive—recovered as well.
Such evidence from individual cases doesn’t prove a drug is safe and effective. Still, from the drugs in the SOLIDARITY trial, “remdesivir has the best potential to be used in clinics” says Jiang Shibo of Fudan University, who has long worked on coronavirus therapeutics. Jiang particularly likes that high doses of the drug can likely be given without causing toxicities.
However, it may be much more potent if given early in an infection, like most other drugs, says Stanley Perlman, a coronavirus researcher at the University of Iowa. “What you really want to do is give a drug like that to people who walk in with mild symptoms,” he says. “And you can’t do that because it’s an [intravenous] drug, it’s expensive and 85 out of 100 people don’t need it.”
Chloroquine and hydroxychloroquine
At a press conference on Friday, President Donald Trump called chloroquine and hydroxychloroquine a “game changer.” “I feel good about it,” Trump said. His remarks have led to a rush in demand for the decades-old antimalarials. (“It reminds me a little bit of the toilet paper phenomenon and everybody’s running to the store,” Caplan says.)
The WHO scientific panel designing SOLIDARITY had originally decided to leave the duo out of the trial, but had a change of heart at a meeting in Geneva on 13 March, because the drugs “received significant attention” in many countries, according to the report of a WHO working group that looked into the drugs’ potential. The widespread interested prompted “the need to examine emerging evidence to inform a decision on its potential role.”
The available data are thin. The drugs work by decreasing the acidity in endosomes, compartments inside cells that they use to ingest outside material and that some viruses can coopt to enter a cell. But the main entryway for SARS-CoV-2 is a different one, using its so-called spike protein to attach to a receptor on the surface of human cells. Studies in cell culture have suggested chloroquines have some activity against SARS-CoV-2, but the doses needed are usually high—and could cause serious toxicities.
Encouraging cell study results with chloroquines against two other viral diseases, dengue and chikungunya, didn’t pan out in people in randomized clinical trials. And nonhuman primates infected with chikungunya did worse when given chloroquine. “Researchers have tried this drug on virus after virus, and it never works out in humans. The dose needed is just too high,” says Susanne Herold, an expert on pulmonary infections at the University of Giessen.
Results from COVID-19 patients are murky. Chinese researchers who report treating more than 100 patients with chloroquine touted its benefits in a letter in BioScience, but the data underlying the claim have not been published. All in all, more than 20 COVID-19 studies in China used chloroquine or hydroxychloroquine, WHO notes, but their results have been hard to come by. “WHO is engaging with Chinese colleagues at the mission in Geneva and have received assurances of improved collaboration; however, no data has been shared regarding the chloroquine studies.”
Researchers in France have published a study in which they treated 20 COVID-19 patients with hydroxychloroquine. They concluded that the drug significantly reduced viral load in nasal swabs. But it was not a randomized controlled trial and it didn’t report clinical outcomes such as deaths. In guidance published on Friday, the U.S. Society of Critical Care Medicine said “there is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.”
Hydroxychloroquine, in particular, might do more harm than good. The drug has a variety of side effects and can in rare cases harm the heart. Because people with heart conditions are at higher risk of severe COVID-19, that is a concern, says David Smith, an infectious disease physician at the University of California, San Diego. “This is a warning signal, but we still need to do the trial,” he says. What’s more, a rush to use the drug for COVID-19 might make it harder for the people who need it to treat their rheumatoid arthritis or malaria.
Ritonavir/lopinavir
This combination drug, sold under the brand name Kaletra, was approved in the United States in 2000 to treat HIV infections. Abbott Laboratories developed lopinavir specifically to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses. Because lopinavir is quickly broken down in the human body by our own proteases, it is given with low levels of ritonavir, another protease inhibitor, that lets lopinavir persist longer.
The combination can inhibit the protease of other viruses as well, specifically coronaviruses. It has shown efficacy in marmosets infected with the MERS virus, and has also been tested in SARS and MERS patients, though results from those trials are ambiguous.
The first trial with COVD-19 was not encouraging, however. Doctors in Wuhan, China, gave 199 patients two pills of lopinavir/ritonavir twice a day plus standard care, or standard care alone. There was no significant difference between the groups, they reported in NEJM on 15 March. But the authors caution that patients were very ill—more than one-fifth of them died—and so the treatment may have been given too late to help. Although the drug is generally safe it may interact with drugs usually given to severely ill patients, and doctors have warned it could cause significant liver damage.
Ritonavir/lopinavir and interferon-beta
SOLIDARITY will also have an arm that combines the two antivirals with interferon-beta, a molecule involved in regulating inflammation in the body that has also shown an effect in marmosets infected with MERS. A combination of the three drugs is now being tested in MERS patients in Saudi Arabia in the first randomized controlled trial for that disease.
But the use of interferon-beta on patients with severe COVID-19 might be risky, Herold says. “If it is given late in the disease it could easily lead to worse tissue damage instead of helping patients,” she cautions.
Thousands of patients
The design of the SOLIDARITY trial can change at any time. A global data safety monitoring board will look at interim results at regular intervals and decide whether any member of the quartet has a clear effect, or whether one can be dropped because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by Japan’s Toyama Chemical, may be added to the trial.
To get robust results from the study, several thousands of patients will likely have to be recruited, Henao-Restrepo says. Argentina, Iran, South Africa, and several other non-European countries have already signed up. WHO is also hoping to do a prevention trial to test drugs that might protect health care workers from infection, using the same basic protocol, Henao-Restrepo says.
The trial’s European counterpart, Discovery, will recruit patients from France, Spain, the United Kingdom, Germany, and the Benelux countries, according to an INSERM press release today. The trial will be led Florence Ader, an infectious diseases researcher at the University Hospital Center in Lyon.
Doing rigorous clinical research during an outbreak is always a challenge, Henao-Restrepo says, but it’s the best way to make headway against the virus: “It will be important to get answers quickly, to try to find out what works and what doesn’t work. We think that randomized evidence is the best way to do that.”
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More direct on-the-ground reports regarding the use of hydrochloroquine and azithromycin in resolving acute COVID-19 is coming in now as the first US hospitals begin using the drug cocktail for treatment of serious and critical patients. Some of the hospitals had already started trials of the cocktail even before President Trump had made his official announcement for the country to begin the treatment regimen. World Health Organization begins global mega trial of multiple drugs and drug cocktails with majority emphasis on Plaquenil+Zithromax (commercial brand names for hydroxychloroquine and azithromycin). Article in third entry of this post.
CASE 1:
53-year old nurse from New Jersey.
Sex: Female.
Nonsmoker.
No underlying conditions.
The progression of her COVID-19 infection took a track much like some of the other worrisome cases in much younger people that we have been seeing all over the world. A period of mild flu-like symptoms in the beginning. A light dry cough, spiking fever similar to regular influenza, aches and pains, and general malaise which rapidly escalated into ARDS (acute respiratory distress syndrome) by the eighth day of the illness. Doctors initially misdiagnosed her with bacterial pneumonia and prescribed her copious amounts of antibiotics, which obviously would not work. It was not until she had been brought to the ICU in critical respiratory distress that the diagnosis of COVID-19 was made. One quick thinking doctor on her team immediately placed an order for hydrochloroquine and azithromycin to be started, citing effective results from Chinese, Korean, and French doctors. Within a day, her fever went down and her respiratory symptoms began to ease, although it will be up to another week before her body is able to clear the virus completely. Without the cocktail drug therapy, this case was very much likely fatal.
This Coronavirus Patient Dodged A Bullet With Hydroxychloroquine. Is She A Harbinger Or Outlier?
Margaret Novins is on the leading edge of a real-time experiment to see what works for COVID-19.
www.forbes.com ----------
Margaret Novins talked to me on her cellphone from a hospital bed at CentraState Medical Center in Freehold, N.J.
She had been ill since March 8, toughing it out through fatigue, a cough and fevers that brought on vicious chills for five evenings straight.
Finally, on March 15, she went to an urgent care center and, on March 16, to an emergency room. The attending there called it “conversational dyspnea.”
“I couldn’t breathe,” she said.
Novins, who shared her lab tests and medication list, got her diagnosis March 19. Next to the entry for SARS-CoV-2 were the words “Detected Critical.” She had the coronavirus, or COVID-19.
To that point, Novins had been a pneumonia patient for three days, treated mainly with antibiotics. But within an hour, a new drug was added to her med list: hydroxychloroquine, a decades-old malaria-turned-autoimmune drug, also called by its brand name Plaquenil. President Trump is touting the drug, some say overselling it, as the possible answer to the COVID-19 crisis.
Novins’ responded to the treatment. She was better, though surely not well, the next day.
“The fever,” which was still spiking when she was on other meds, “is now gone, which is fantastic,” she said on Saturday March 21, coughing at times but able to speak.
A 53-year-old nurse who described herself as a nonsmoker with no medical issues, Novins spoke to me from the hospital that had cared for some of the seven members of a family ravaged by COVID; two adult brothers, a sister and their mother died from the infection.
“The doctor insisted the pharmacy get it to me the minute we got the positive,” she said of hydroxychloroquine. “It seemed like their go-to right away.”
After three nights in the hospital, Margaret Novins' COVID test came back positive: "Detected ... [+] Critical," the result said.
There are other anecdotal successes like Novins’, including one in which end-of-life discussions for an older parent had been broached — until Plaquenil apparently kicked in. In that case, the family had to plead for, rather than being offered, the drug.
Anecdotes are surely not science, which for now is limited and new.
Trump is basing his optimism mostly on one small study from Marseilles, France, that, combined with laboratory findings, has prompted ongoing trials in France and the United States. The just-released French study reported that 70 percent of hydroxychloroquine-treated patients, or 14 of 20, were negative for the virus at day 6, as were all six patients who were treated with hydroxychloroquine and the antibiotic azithromycin (which Novins also received). But the study was small – 20 treated patients and 16 controls – and had other serious limitations.
Of concern, six patients dropped out and were not considered in the reported efficacy rates. Three went to intensive care; one died; one left the hospital testing negative, and one opted out due to nausea.
Two scientists at major university centers reviewed the French trial for me. They agreed, separately, that while the study is preliminary, small, and not without flaws, its findings were strong enough, given the drugs’ known safety records, to guide treatment decisions in a crisis.
“Despite the limitations of this study, in the absence of any effective treatment, in this urgent situation, this Plaquenil and Azithromycin combination therapy should be given to patients with COVID-19 as a treatment option,” Ying Zhang, a professor of microbiology at Johns Hopkins Bloomberg School of Public Health, wrote in an email. “For now, there is no time to wait.”
Working against the study, in Zhang’s view: It was not a randomized trial, which would avoid bias; the sample size was small, and the treatment and followup duration was too short. The findings are nonetheless “potentially interesting and justified,” he wrote.
Brian Fallon, a research scientist and clinical trials investigator at the Columbia University Irving Medical Center, agreed on the study’s overall merit despite the patients who dropped out. After analyzing the data and counting all six dropouts as treatment failures, he said the overall rate of improvement was still statistically significant for the entire group, though not for the hydroxychloroquine group alone.
He too had reservations, in particular that the combination therapy group was very small, six patients, and that high doses of the two drugs together carry “serious risk of cardiac arrhythmias.” Physicians must be warned of this, he suggested.
Nonetheless, he wrote in an email, “Given the life and death situation of hospitalized patients with COVID-19 and the possibility that hydroxychloroquine plus azithromycin may be helpful, it was valuable and ethical for the authors to report these promising, preliminary results.”
Others agreed. Lorraine Johnson, who has published on the use of collected data to improve health care outcomes, said, “It is important right now to take the gloves off clinicians and give them access to all available tools; patients are dying and can’t wait for clinical trials.”
At the same time, she and Zhang, who has published on treatments for difficult infections like tuberculosis and Lyme disease, said a database should be set up to track patients, like Margaret Novins, in order to document drug performance. “I would recommend real-time online posting of treatment evaluation results of the Plaquenil+Azithromycin at multi-center sites across the US and the Globe,” Zhang wrote. “Someone has to coordinate this online registry and resources.” He added that other treatments should be included.
Supply issues raised
In a 1982 drug bulletin, the FDA encouraged so-called off-label use of approved drugs: “Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations.”
In the real world, however, a rush to put a relatively safe approved drug to a vastly expanded new use may reduce supplies for others who need it, including lupus, rheumatoid arthritis and Lyme disease sufferers.
Kenneth Farber, president of the Lupus Research Alliance, said there were shortages of Plaquenil throughout the United States and especially in New York and California.
Asked about supplies, a spokesperson for CVS Health, T.J. Crawford, said the drug-store chain has an “adequate supply on-hand” of hydroxychloroquine but supply of a related drug, chloroquine, “is tight across the marketplace.”
Jane Marke, a New York City psychiatrist who takes Plaquenil for Lyme disease, said she had trouble getting her prescription filled at several city chains. After reading the French study, she understands why. “It is really possible that this is a major breakthrough,” she said, envisioning a time when a good test could pick up early infections and the drug would stop the epidemic in its tracks.
In that vein, the University of Minnesota is organizing a trial to treat 1,500 people with hydroxychloroquine who were exposed to the virus from infected family members or as healthcare workers but are not yet ill. The study relied on laboratory experiments in China that found hydroxychloroquine inhibited the infection.
“If effective, this may become a worldwide standard of care for helping prevent disease in other healthcare workers and people exposed,” Dr. David Boulware, a U of M professor of medicine, said in announcing the study.
A key advantage of an off-patent generic drug like hydroxychloroquine: “A five-day treatment course would cost approximately $12,” Boulware said.
Novins, meantime, is expecting to leave the hospital in a day or two. As a nurse for a medical equipment company, she believes she contracted the infection not from a patient but while conducting a day-long training session.
Nonetheless, she said in a text, “I feel fortunate.”
“From my notes it is clear that my fevers and horrible chills I fought hard from 3/8-3/18 turned the corner the day I started Plaquenil 3/19,” she wrote.
While she said COVID is a “violent illness,” Novins never was in intensive care or on a respirator. The French study offers a mere glint of hope for more serious cases too. Of five patients with lower respiratory infection, four turned negative by day 6, three of them on both drugs.
In the meantime, scientists said larger, more rigorous studies must be launched to answer questions of efficacy, dosing, duration, and potential adverse drug interactions — for this and other COVID treatments.
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CASE 2:
TV actor Daniel Kim attributes his rapid recovery from acute COVID-19 infection to the cocktail of hydroxychloroquine and azithromycin.
Daniel Dae Kim credits hydroxychloroquine for coronavirus recovery
Television star Daniel Dae Kim said he feels “practically back to normal” after taking a combination of drugs that include hydroxychloroquine, the anti-malarial drug President Trump has touted, calling it his “secret weapon.”
www.washingtontimes.com ----------
Television star Daniel Dae Kim said he feels “practically back to normal” after taking a combination of drugs that include hydroxychloroquine, the anti-malarial drug President Trump has touted, calling it his “secret weapon.”
Mr. Kim, who starred in the network shows “Lost” and “Hawaii Five-O,” said in a Saturday post on Instagram that he has almost no symptoms after taking Tamiflu; the antibiotic azithromycin, or Z-Pak; an inhaler, and hydroxychloroquine.
“I’m happy to report that my progress has continued and I feel practically back to normal,” said Mr. Kim in a video from his home in Hawaii, where he has self-isolated. “I am lucky enough to be in the 80% of diagnosed cases that have not required hospitalization. That’s an important statistic.”
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WHO to begin worldwide mega trials of the drug cocktail.
AAAS
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A drug combo already used against HIV. A malaria treatment first tested during World War II. A new antiviral whose promise against Ebola fizzled last year.
Could any of these drugs hold the key to saving coronavirus disease 2019 (COVID-19) patients from serious harm or death? On Friday, the World Health Organization (WHO) announced a large global trial, called SOLIDARITY, to find out whether any can treat infections with the new coronavirus for the dangerous respiratory disease. It’s an unprecedented effort—an all-out, coordinated push to collect robust scientific data rapidly during a pandemic. The study, which could include many thousands of patients in dozens of countries, has been designed to be as simple as possible so that even hospitals overwhelmed by an onslaught of COVID-19 patients can participate.
With about 15% of COVID-19 patients suffering from severe disease and hospitals being overwhelmed, treatments are desperately needed. So rather than coming up with compounds from scratch that may take years to develop and test, researchers and public health agencies are looking to repurpose drugs already approved for other diseases and known to be largely safe. They’re also looking at unapproved drugs that have performed well in animal studies with the other two deadly coronaviruses, which cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
Drugs that slow or kill the novel coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could save the lives of severely ill patients, but might also be given prophylactically to protect health care workers and others at high risk of infection. Treatments may also reduce the time patients spend in intensive care units, freeing critical hospital beds.
Scientists have suggested dozens of existing compounds for testing, but WHO is focusing on what it says are the four most promising therapies: an experimental antiviral compound called remdesivir; the malaria medications chloroquine and hydroxychloroquine; a combination of two HIV drugs, lopinavir and ritonavir; and that same combination plus interferon-beta, an immune system messenger that can help cripple viruses. Some data on their use in COVID-19 patients have already emerged—the HIV combo failed in a small study in China—but WHO believes a large trial with a greater variety of patients is warranted.
Enrolling subjects in SOLIDARITY will be easy. When a person with a confirmed case of COVID-19 is deemed eligible, the physician can enter the patient’s data into a WHO website, including any underlying condition that could change the course of the disease, such as diabetes or HIV infection. The participant has to sign an informed consent form that is scanned and sent to WHO electronically. After the physician states which drugs are available at his or her hospital, the website will randomize the patient to one of the drugs available or to the local standard care for COVID-19.
“After that, no more measurements or documentation are required,” says Ana Maria Henao-Restrepo, a medical officer at WHO’s Department of Immunization Vaccines and Biologicals. Physicians will record the day the patient left the hospital or died, the duration of the hospital stay, and whether the patient required oxygen or ventilation, she says. “That’s all.”
The design is not double-blind, the gold standard in medical research, so there could be placebo effects from patients knowing they received a candidate drug. But WHO says it had to balance scientific rigor against speed. The idea for SOLIDARITY came up less than 2 weeks ago, Henao-Restrepo says, and the agency hopes to have supporting documentation and data management centers set up next week. “We are doing this in record time,” she says.
Arthur Caplan, a bioethicist at New York University Langone Medical Center, says he likes the study’s design. “No one wants to tax the frontline caregiver who’s overwhelmed and taking risks anyway,” Caplan says. Hospitals that aren’t overburdened might be able to record more data on disease progression, for instance by following the level of virus in the body, Caplan suggests. But for public health, the simple outcomes WHO seeks to measure are the only relevant ones for now, says virologist Christian Drosten of the Charité University Hospital in Berlin: “We don’t really know enough about this disease to be sure what it means when the viral load decreases in the throat, for instance.”
On Sunday, INSERM, the French biomedical research agency, announced it will coordinate an add-on trial in Europe, named Discovery, that will follow WHO’s example and will include 3200 patients from at least seven countries, including 800 from France. That trial will test the same drugs, with the exception of chloroquine. Other countries or groups of hospitals could organize add-on studies as well, Heneo-Restrepo says. They are free to do additional measurements or observations, for instance on virology, blood gases, chemistry, and lung imaging. “While well-organized additional research studies of the natural history of the disease or of the effects of the trial treatments could well be valuable, they are not core requirements,” she says.
The list of drugs to test was first put together for WHO by a panel of scientists who have been assessing the evidence for candidate therapies since January, Heneo-Restrepo says. The group of selected drugs that had the highest likelihood of working, had the most safety data from previous use, and are likely to be available in supplies sufficient to treat substantial numbers of patients if the trial shows they work.
Here are the treatments that SOLIDARITY will test:
Remdesivir
The new coronavirus is giving this compound a second chance to shine. Originally developed by Gilead Sciences to combat Ebola and related viruses, remdesivir shuts down viral replication by inhibiting a key viral enzyme, the RNA-dependent RNA polymerase.
Researchers tested remdesivir last year during the Ebola outbreak in the Democratic Republic of the Congo, along with three other treatments. It did not show any effect. (Two others did.) But the enzyme it targets is similar in other viruses, and in 2017 researchers at the University of North Carolina, Chapel Hill, showed in test tube and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.
The first COVID-19 patient diagnosed in the United States—a young man in Snohomish county in Washington—was given remdesivir when his condition worsened; he improved the next day, according to a case report in The New England Journal of Medicine (NEJM). A Californian patient who received remdesivir—and who doctors thought might not survive—recovered as well.
Such evidence from individual cases doesn’t prove a drug is safe and effective. Still, from the drugs in the SOLIDARITY trial, “remdesivir has the best potential to be used in clinics” says Jiang Shibo of Fudan University, who has long worked on coronavirus therapeutics. Jiang particularly likes that high doses of the drug can likely be given without causing toxicities.
However, it may be much more potent if given early in an infection, like most other drugs, says Stanley Perlman, a coronavirus researcher at the University of Iowa. “What you really want to do is give a drug like that to people who walk in with mild symptoms,” he says. “And you can’t do that because it’s an [intravenous] drug, it’s expensive and 85 out of 100 people don’t need it.”
Chloroquine and hydroxychloroquine
At a press conference on Friday, President Donald Trump called chloroquine and hydroxychloroquine a “game changer.” “I feel good about it,” Trump said. His remarks have led to a rush in demand for the decades-old antimalarials. (“It reminds me a little bit of the toilet paper phenomenon and everybody’s running to the store,” Caplan says.)
The WHO scientific panel designing SOLIDARITY had originally decided to leave the duo out of the trial, but had a change of heart at a meeting in Geneva on 13 March, because the drugs “received significant attention” in many countries, according to the report of a WHO working group that looked into the drugs’ potential. The widespread interested prompted “the need to examine emerging evidence to inform a decision on its potential role.”
The available data are thin. The drugs work by decreasing the acidity in endosomes, compartments inside cells that they use to ingest outside material and that some viruses can coopt to enter a cell. But the main entryway for SARS-CoV-2 is a different one, using its so-called spike protein to attach to a receptor on the surface of human cells. Studies in cell culture have suggested chloroquines have some activity against SARS-CoV-2, but the doses needed are usually high—and could cause serious toxicities.
Encouraging cell study results with chloroquines against two other viral diseases, dengue and chikungunya, didn’t pan out in people in randomized clinical trials. And nonhuman primates infected with chikungunya did worse when given chloroquine. “Researchers have tried this drug on virus after virus, and it never works out in humans. The dose needed is just too high,” says Susanne Herold, an expert on pulmonary infections at the University of Giessen.
Results from COVID-19 patients are murky. Chinese researchers who report treating more than 100 patients with chloroquine touted its benefits in a letter in BioScience, but the data underlying the claim have not been published. All in all, more than 20 COVID-19 studies in China used chloroquine or hydroxychloroquine, WHO notes, but their results have been hard to come by. “WHO is engaging with Chinese colleagues at the mission in Geneva and have received assurances of improved collaboration; however, no data has been shared regarding the chloroquine studies.”
Researchers in France have published a study in which they treated 20 COVID-19 patients with hydroxychloroquine. They concluded that the drug significantly reduced viral load in nasal swabs. But it was not a randomized controlled trial and it didn’t report clinical outcomes such as deaths. In guidance published on Friday, the U.S. Society of Critical Care Medicine said “there is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.”
Hydroxychloroquine, in particular, might do more harm than good. The drug has a variety of side effects and can in rare cases harm the heart. Because people with heart conditions are at higher risk of severe COVID-19, that is a concern, says David Smith, an infectious disease physician at the University of California, San Diego. “This is a warning signal, but we still need to do the trial,” he says. What’s more, a rush to use the drug for COVID-19 might make it harder for the people who need it to treat their rheumatoid arthritis or malaria.
Ritonavir/lopinavir
This combination drug, sold under the brand name Kaletra, was approved in the United States in 2000 to treat HIV infections. Abbott Laboratories developed lopinavir specifically to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses. Because lopinavir is quickly broken down in the human body by our own proteases, it is given with low levels of ritonavir, another protease inhibitor, that lets lopinavir persist longer.
The combination can inhibit the protease of other viruses as well, specifically coronaviruses. It has shown efficacy in marmosets infected with the MERS virus, and has also been tested in SARS and MERS patients, though results from those trials are ambiguous.
The first trial with COVD-19 was not encouraging, however. Doctors in Wuhan, China, gave 199 patients two pills of lopinavir/ritonavir twice a day plus standard care, or standard care alone. There was no significant difference between the groups, they reported in NEJM on 15 March. But the authors caution that patients were very ill—more than one-fifth of them died—and so the treatment may have been given too late to help. Although the drug is generally safe it may interact with drugs usually given to severely ill patients, and doctors have warned it could cause significant liver damage.
Ritonavir/lopinavir and interferon-beta
SOLIDARITY will also have an arm that combines the two antivirals with interferon-beta, a molecule involved in regulating inflammation in the body that has also shown an effect in marmosets infected with MERS. A combination of the three drugs is now being tested in MERS patients in Saudi Arabia in the first randomized controlled trial for that disease.
But the use of interferon-beta on patients with severe COVID-19 might be risky, Herold says. “If it is given late in the disease it could easily lead to worse tissue damage instead of helping patients,” she cautions.
Thousands of patients
The design of the SOLIDARITY trial can change at any time. A global data safety monitoring board will look at interim results at regular intervals and decide whether any member of the quartet has a clear effect, or whether one can be dropped because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by Japan’s Toyama Chemical, may be added to the trial.
To get robust results from the study, several thousands of patients will likely have to be recruited, Henao-Restrepo says. Argentina, Iran, South Africa, and several other non-European countries have already signed up. WHO is also hoping to do a prevention trial to test drugs that might protect health care workers from infection, using the same basic protocol, Henao-Restrepo says.
The trial’s European counterpart, Discovery, will recruit patients from France, Spain, the United Kingdom, Germany, and the Benelux countries, according to an INSERM press release today. The trial will be led Florence Ader, an infectious diseases researcher at the University Hospital Center in Lyon.
Doing rigorous clinical research during an outbreak is always a challenge, Henao-Restrepo says, but it’s the best way to make headway against the virus: “It will be important to get answers quickly, to try to find out what works and what doesn’t work. We think that randomized evidence is the best way to do that.”
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No silver bullet yet , lots of hype out there
The claim that the anti-malaria drug (hydro-)chloroquine helps in SARS-CoV-2 infection cases comes from two Chinese studies which are only based on in-vitro tests on the virus and human cells. The doses were relatively high and chloroquine is known to have some bad side effects. There is also no sound way yet to get chloroquine into the lower lungs where the virus resides and where it would be actually needed.
There is also a small French trial with chloroquine based on real patients but which is unfortunately invalid. It was a non-randomized study with only 42 patients of which 6 dropped out.
The researches counted the number of viruses before and after the medication to see if it works. But they only took swabs in the throat to look for viruses. During the cause of a SARS-CoV-2 infection the virus does start to multiply in the throat but it then migrates down into the lower lung. Only there does the virus begin to grow in really big numbers and to cause serious damage. While that happens the virus count in the throat region goes down. The French researchers did not know that.
The above details are from the daily podcast no. 17 by Professor Dr. Christian Drosten, the chief of the virology department at the Charité in Berlin. German transcripts are available ( https://www.ndr.de/nachrichten/info...-Folgen-als-Skript,podcastcoronavirus102.html.) Drosten was involved in several clinical case studies with Covid-19 cases during which every development was measured and detailed. He knows how the disease proceeds.
There is more to be criticized in that French study. Gaetan Burgio, a geneticist at the Australian National University, summarizes his own critique:
The claim that the anti-malaria drug (hydro-)chloroquine helps in SARS-CoV-2 infection cases comes from two Chinese studies which are only based on in-vitro tests on the virus and human cells. The doses were relatively high and chloroquine is known to have some bad side effects. There is also no sound way yet to get chloroquine into the lower lungs where the virus resides and where it would be actually needed.
There is also a small French trial with chloroquine based on real patients but which is unfortunately invalid. It was a non-randomized study with only 42 patients of which 6 dropped out.
The researches counted the number of viruses before and after the medication to see if it works. But they only took swabs in the throat to look for viruses. During the cause of a SARS-CoV-2 infection the virus does start to multiply in the throat but it then migrates down into the lower lung. Only there does the virus begin to grow in really big numbers and to cause serious damage. While that happens the virus count in the throat region goes down. The French researchers did not know that.
The above details are from the daily podcast no. 17 by Professor Dr. Christian Drosten, the chief of the virology department at the Charité in Berlin. German transcripts are available ( https://www.ndr.de/nachrichten/info...-Folgen-als-Skript,podcastcoronavirus102.html.) Drosten was involved in several clinical case studies with Covid-19 cases during which every development was measured and detailed. He knows how the disease proceeds.
There is more to be criticized in that French study. Gaetan Burgio, a geneticist at the Australian National University, summarizes his own critique:
Chinese researcher believe they will have more success with interrupting the bonding process with which the virus sneaks into the cell:
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Agreed, we should be skeptical of the in vitro application. I'd rather see it work in-vitro than NOT work, but to then conclude it will work elsewhere is bad science.
This trial below I think is the largest/highest power RCT that finishes the SOONEST (July 2020) that I/we should keep our eyes on:
ClinicalTrials.gov
clinicaltrials.gov Some interesting stats
https://www.ft.com/coronavirus-latest
https://www.ft.com/coronavirus-latest
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