[Sivad]

NIH KNEW IN 2005 CHLOROQUINE WAS AN EFFECTIVE TREATMENT FOR SARS-CoV:

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Martin J Vincent, Eric Bergeron, [...], and Stuart T Nichol

Article information
Virol J. 2005; 2: 69.
Published online 2005 Aug 22

Authors
Martin J Vincent,1 Eric Bergeron,2 Suzanne Benjannet,2 Bobbie R Erickson,1 Pierre E Rollin,1 Thomas G Ksiazek,1 Nabil G Seidah,2 and Stuart T Nicholcorresponding author1

Abstract

Background
Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available.

Results
We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations.

Conclusion
Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

and here's a study from 2010 on Zinc:

PLoS Pathog. 2010 Nov 4

Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.


Abstract

Increasing the intracellular Zn(2+) concentration with zinc-ionophores like pyrithione (PT) can efficiently impair the replication of a variety of RNA viruses, including poliovirus and influenza virus. For some viruses this effect has been attributed to interference with viral polyprotein processing. In this study we demonstrate that the combination of Zn(2+) and PT at low concentrations (2 µM Zn(2+) and 2 µM PT) inhibits the replication of SARS-coronavirus (SARS-CoV) and equine arteritis virus (EAV) in cell culture. The RNA synthesis of these two distantly related nidoviruses is catalyzed by an RNA-dependent RNA polymerase (RdRp), which is the core enzyme of their multiprotein replication and transcription complex (RTC). Using an activity assay for RTCs isolated from cells infected with SARS-CoV or EAV--thus eliminating the need for PT to transport Zn(2+) across the plasma membrane--we show that Zn(2+) efficiently inhibits the RNA-synthesizing activity of the RTCs of both viruses. Enzymatic studies using recombinant RdRps (SARS-CoV nsp12 and EAV nsp9) purified from E. coli subsequently revealed that Zn(2+) directly inhibited the in vitro activity of both nidovirus polymerases. More specifically, Zn(2+) was found to block the initiation step of EAV RNA synthesis, whereas in the case of the SARS-CoV RdRp elongation was inhibited and template binding reduced. By chelating Zn(2+) with MgEDTA, the inhibitory effect of the divalent cation could be reversed, which provides a novel experimental tool for in vitro studies of the molecular details of nidovirus replication and transcription.

https://www.ncbi.nlm.nih.gov/pubmed/21079686

So the public health establishment down played the virus well into early March, encouraged everyone to mass congregate in Chinatowns across the country, told us not to wear masks, and then refused to acknowledge an effective treatment.

Fauci has even refused to fund research on chloroquine and he flat out lied when asked if there was any evidence for its effectiveness in treating coronavirus:

Trump says this drug has 'tremendous promise,' but Fauci's not spending money on it

Despite President Donald Trump's enthusiasm for the drug hydroxychloroquine to treat coronavirus, the federal funding powerhouse led by Dr. Anthony Fauci isn't spending any money on it, and clinical trials for it are lagging behind other drug studies, according to a CNN investigation.

But the National Institute of Allergy and Infectious Diseases isn't sponsoring any studies on hydroxychloroquine, according to a statement from the agency, which added that the agency is "considering" trials that examine the drug or its analogue chloroquine as a potential treatment for Covid-19. studies.

On its website, NIAID mentions several drug therapies it's supporting to fight coronavirus, but not hydroxychloroquine.

The Biomedical Advanced Research and Development Authority, another federal agency, also lists its coronavirus measures on its website, but hydroxychloroquine is not among them.
Hydroxychloroquine clinical trials

Last month, a Chinese study theorized that hydroxychloroquine might work against coronavirus by preventing it from binding to human cells.

Despite this enthusiasm, a federal government registry for clinical trials shows only two trials in the US for hydroxychloroquine to fight coronavirus, and only one of those is up and running.

Researchers for that trial, at the University of Minnesota, requested but did not receive any federal funding, according to Dr. David Boulware, the infectious disease expert running the study.

Boulware said he had to get funding from Silicon Valley tycoon David Baszucki for one part of his study, which looks at hydroxychloroquine to prevent development of the disease, and he still doesn't have funding for the other part, which studies the drug as a treatment for infection.

"With all the money being spent on coronavirus, we should spend funds on medical research on how best to treat people and prevent new infections," Boulware said.

The second study, at Columbia University Irving Medical Center, is expected to begin enrollment this week and is currently not funded, according to a hospital spokeswoman.

At the White House press briefing last week, Fauci tamped down Trump's enthusiasm for hydroxychloroquine when he was asked if there was any evidence to suggest the drug could be used to prevent coronavirus

"No. The answer is no," Fauci said, adding that there was only anecdotal evidence that hydroxychloroquine could be an effective therapy for people with coronavirus.

https://www.cnn.com/2020/03/28/health/c ... index.html

[ThirdTerm]

The drug was associated with heart complications, according to a new study (Mahévas et al. 2020). In the study, eight patients who took the drug developed abnormal heart rhythms and had to stop taking it. Hydroxychloroquine does not apparently treat patients with Covid-19 as there were side effects caused by the drug such as heart toxicities that required it be discontinued.

Abstract
Background Treatments are urgently needed to prevent respiratory failure and deaths from coronavirus disease 2019 (COVID-19). Hydroxychloroquine (HCQ) has received worldwide attention because of positive results from small studies. Methods We used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen ≥ 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day. The composite primary endpoint was transfer to intensive care unit (ICU) within 7 days from inclusion and/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47-1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation. Interpretation These results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.

Interpretation
These results do not support the use of HCQ in patients hospitalised for documented SARSCoV-2-positive hypoxic pneumonia.

https://www.medrxiv.org/content/10.1101 ... 20060699v1

Researchers at Monash University in Melbourne reported to the online journal Antiviral Research that they infected cells with Sars-CoV-2, the coronavirus that causes Covid-19, and then exposed them to ivermectin. The study showed that a single dose of ivermectin could kill Covid-19 in a petri dish within 48 hours, indicating potent antiviral activity.

Ivermectin is normally used for head lice treatments, as well as to treat roundworm, scabies and rosacea in tablet form. There is no reason to be buying lice treatment unless you’re going to be using it on your children’s hair. But Australians are reportedly stockpiling anti-parasitic drug ivermectin, which could be used as a home remedy in Australia. A single dose of ivermectin could kill Covid-19 in a petri dish slowly within two days but it could be dangerous to be used for Covid-19 patients without a clinical trial. 48 hours is a long time as we know that the coronavirus can be killed within an hour at 29 degrees Celsius (84.20 °F).

Abstract
Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
https://www.sciencedirect.com/science/a ... 4220302011

[Rancid]

What's up with the all caps title?

[XogGyux]

Once more you show that your grasp of science and the scientific process is primitive.
Read your own paper. Conclusion?

Chloroquine is effective in preventing the spread of SARS CoV in cell culture.

CELL CULTURE!
Last time I checked, the human body was a bit bigger than cell culture.
This is merely the bedrock upon which many more studies need to follow so that at some point at the very end you can find out whether it works or not it is a viably treatment in humans.
This is because things that work in a test-tube or in animal models do not mean they will work in humans. There are plenty of drugs that works in animals yet not humans.
There are plenty of drugs that work in-vitro yet not in humans.
Here is an example. Daptomycin is an antibiotic that is effective against Methicillin Resistance Staph Aureus. It is effective in vitro and it is effective in many different sites of infections in humans, however, this drug is not adecquate for the treatment for MRSA pneumonia. Why would you ask? Well it turns out that the lung tissue secretes sulfactant and this in turns inhibits the antibiotic.
We find cases like this all the time. We find drugs that work in a test tube are inhibited by certain molecules that exists in the human body, we find that drugs that work in a test tube do not achieve the appropriate concentrations in different parts of the body (for instance in CNS infection some antibiotics have higher penetrance than other, so meningitis by a bacteria might be treated with a different drug than the pneumonia caused by the same bacteria).
Point being, that if you wish to use this as some sort of scaffolding to develop a conspiracy theory, don't bother you are wasting your time.
This is obviously no new information and this is the reason why countries in asia that got hit by the coronavirus first started using the drug as "compassionate use" (meaning off-label, without evidence of work as a "let's try and hope it works" kind of approach with people that had a very high chance if not making it. Until appropriate randomized trials are performed it is nearly impossible to know whether they are effective. Because even very sick people can get better if you give them supportive treatment and allow their body to fight the disease on their own.
For hundreds of years doctors used stupid "treatments" (which do not work and in many cases actually caused harm!) such as bloodletting. Wonder why? well, because of this, lack of a systematic, unbiased, data-driven method to critically analyze the effectiveness (and safety) of treatment.

[Sivad]

The drug was associated with heart complications, according to a new study (Mahévas et al. 2020). In the study, eight patients who took the drug developed abnormal heart rhythms and had to stop taking it. Hydroxychloroquine does not apparently treat patients with Covid 19 as there were side effects caused by the drug such as heart toxicities that required it be discontinued.

Okay, so let's pretend that your study isn't junk science, an emulation that only looks at the effects of 600 mg/day on severe cases, provides no breakdown by age or medical history, doesn't augment HCQ with zinc, and arrives at a sweeping conclusion based on extremely limited evidence. Let's also pretend that a common drug that's been in use for decades all over the world is now suddenly too dangerous to use. And let's pretend that aren't larger studies that have gotten positive results. Let's pretend that it's a good study with a sound conclusion, that still wouldn't change the fact that NIH had science saying HCQ was a promising treatment and not only sat on it but actively discouraged anyone from studying it.

[Sivad]

Read your own paper. Conclusion?

CELL CULTURE!

You should read it more thoroughly, the authors say that it's "likely to have both prophylactic and therapeutic advantages". They even say that they have identified chloroquine as "an effective pre- and post-infection antiviral agent for SARS-CoV."

Once more you show that your grasp of science and the scientific process is primitive.

And here's the kicker, the shit actually is proving to be an effective treatment. The study said it was likely to be effective and it turns out that it is effective.

My grasp of science is just fine, your grasp of basic reasoning and reading comprehension is the problem here.

[Heisenberg]

There's a huge difference between a study of a drug in cell culture and live people.

The live studies that have been done have been stopped because of concerns about heart problems.
To say the NIH "knew it was an effective treatment" in 2005, based on one cell culture study, is simply wrong. That study is a good, promising starting point. It is not, by any stretch of the imagination, definitive.

Let's pretend that it's a good study with a sound conclusion, that still wouldn't change the fact that NIH had science saying HCQ was a promising treatment and not only sat on it but actively discouraged anyone from studying it.

They didn't discourage studying it. They discouraged Donald Trump, a man with absolutely no medical experience and very little regard for science, from irresponsibly telling people to take the drug before it had been properly studied.

[Sivad]

There's a huge difference between a study of a drug in cell culture and live people.

"The fact that chloroquine exerts an antiviral effect during pre- and post-infection conditions suggest that it is likely to have both prophylactic and therapeutic advantages."

"In this report, we describe the identification of chloroquine as an effective pre- and post-infection antiviral agent for SARS-CoV."

The live studies that have been done have been stopped because of concerns about heart problems.

An over-the-counter drug that's been used around the world for 70 years and is suddenly too dangerous to study.

To say the NIH "knew it was an effective treatment" in 2005, based on one cell culture study, is simply wrong. That study is a good, promising starting point. It is not, by any stretch of the imagination, definitive.

You're all missing the point here but okay, lets just add "likely". NIH knew in 2005 HCQ was likely an effective treatment for SARS-CoV. Why hasn't NIH been all over a likely effective treatment from the beginning? Why is NIH only just now at this late date starting clinical studies? That's the point here, your lame little semantic quibble doesn't address what's actually at issue.

They didn't discourage studying it.

Yes they did, they refused to fund it and Fauci lied when he said there was only anecdotal data supporting it. If you read the CNN piece I posted, independent researchers speculate that it's because there's no money to be made off HCQ and big pharma wants a more lucrative treatment.

They discouraged Donald Trump, a man with absolutely no medical experience and very little regard for science, from irresponsibly telling people to take the drug before it had been properly studied.

Trump never told anyone to just go take the drug, that's fake news. All Trump did was push for testing, Trump isn't responsible for mass imbecility.

[XogGyux]

:knife: You should read it more thoroughly, the authors say that it's "likely to have both prophylactic and therapeutic advantages". They even say that they have identified chloroquine as "an effective pre- and post-infection antiviral agent for SARS-CoV."

No, You should read it more closely.

Chloroquine is effective in preventing the spread of SARS CoV in [size=Courier New]cell culture[/size]. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.

This is a cell. Or more specific, a graphic representation of a stereotypical cell.


This is a human being (or a representation of one )

Notice any difference?

The fact that a drug or compound works in a cell culture does not mean it works in an animal or even a human as I explained previously.

I gave you one example amongst hundreds of why this could be. Let me give you another example:

It is clear that part of the pathology that occurs during the sickest patients affected COVID 19 is that there is a degree of damage to the body that is caused by the body itself. An overwhelming inflammatory response by the body. Under this circumstances it would be unclear what degree of benefit, if any, could be obtained on a patient already infected. Removing the virus out of the equation might not have a significant effect if the inflammatory reaction in the body is what is driving the damage.

So yeah... this applies to cells and for SARS-CoV (version 1.0) of this virus. Extrapolating this to the newest generation of the virus, COVID 19 (Version 2.0) and humans rather than cells requires lots of investigation and testing.

[Sivad]

No, You should read it more closely.

I did, you're just playing a retarded game of gotcha to score a pofo point.


Here's what the authors say:

It recently was speculated that chloroquine might be effective against SARS and the authors suggested that this compound might block the production of TNFα, IL6, or IFNγ [15]. Our data provide evidence for the possibility of using the well-established drug chloroquine in the clinical management of SARS.

Conclusion
Chloroquine, a relatively safe, effective and cheap drug used for treating many human diseases including malaria, amoebiosis and human immunodeficiency virus is effective in inhibiting the infection and spread of SARS CoV in cell culture. The fact that the drug has significant inhibitory antiviral effect when the susceptible cells were treated either prior to or after infection suggests a possible prophylactic and therapeutic use.

So it's pretty clear that they thought they were onto something which makes it more than a little strange that NIH has refused funding for HCQ studies.

[Sivad]

It's fascinating that nobody here is interested in the actual issue and the only comments so far are desperate flailing attempts to dismiss it.

[late]

It's fascinating that nobody here is interested in the actual issue and the only comments so far are desperate flailing attempts to dismiss it.

Why is you can't pay attention.

"The malaria drugs touted by President Trump as potentially “the biggest game changers in the history of medicine” have received a decidedly more sober assessment of their coronavirus-fighting potential from researchers in China, France and Brazil.

Both chloroquine and its close relative hydroxychloroquine offered signs that they may ease some of the hallmark symptoms of coronavirus infection in patients who were hospitalized with COVID-19. But the drugs largely failed to deliver improvements on other key measures when evaluated in rigorous research studies."

If you had watched the news, the medical types have been saying the trials weren't going well for at least a week.


https://www.latimes.com/science/story/2020-04-17/malaria-drugs-fails-to-help-coronavirus-patients-in-controlled-studies

[XogGyux]

I did, you're just playing a retarded game of gotcha to score a pofo point.


Here's what the authors say:



So it's pretty clear that they thought they were onto something which makes it more than a little strange that NIH has refused funding for HCQ studies.

This is ignorant and inflammatory. Why don’t you stick with Bigfoot, flat earth and moonlight conspiracy theories?
Google ORCHID study.
Actually let me do that for you.
https://clinicaltrials.gov/ct2/show/NCT04332991

It's fascinating that nobody here is interested in the actual issue and the only comments so far are desperate flailing attempts to dismiss it.

What is the actual issue? Because from my perspective the actual issue is that a grown man, with a bit of delusional paranoia and tendencies for conspiracy theories and with the scientific understanding of an 8th grade seems to have the delusions of being some sort of expert and goes around forums posting random studies with a very poor understanding of the results.
Is there any other issue?

[Donna]

All-caps inferiority complex

[Sivad]

All-caps inferiority complex

More like a hasty copy paste issue.

[XogGyux]

More like a hasty copy paste issue.

www.conspirancy_theory.org?

[Hindsite]

The drug was associated with heart complications, according to a new study (Mahévas et al. 2020). In the study, eight patients who took the drug developed abnormal heart rhythms and had to stop taking it. Hydroxychloroquine does not apparently treat patients with Covid-19 as there were side effects caused by the drug such as heart toxicities that required it be discontinued.

This is misleading. It was not the Hydroxychloroquine that cause the heart complications in people with heart problems. It was the drug that is often used with it. President Trump mentions that in this video:

In the following video President Trump has several people that recovered from the virus and two of them credit taking Hydroychloroquine:

Coronavirus outbreak: Trump meets with recovered COVID-19 patients at the White House

[XogGyux]

This is misleading. It was not the Hydroxychloroquine that cause the heart complications in people with heart problems. It was the drug that is often used with it. President Trump mentions that in this video:

In the following video President Trump has several people that recovered from the virus and two of them credit taking Hydroychloroquine:

Coronavirus outbreak: Trump meets with recovered COVID-19 patients at the White House

The plural of anecdote is not data.
The problem with all of this reports here and report there is that people tend to either die or get better on their own, sometimes even without intervention. You can put a heart tattoo on people, and then when they get better you can claim the heart tattoo is healing COVID 19 people.
We have a famous president, not Trump, a real president. George Washington... he got sick once. They called the doctors and the doctors prescribed what was believed to be the treatment for pneumonia. Do you know what this treatment was? Bloodletting (we call it phlebotomy today) which means to take blood out of the patient’s body. In the case of Washington, this practice likely was a major contributor to his death. Perhaps if he had gotten some warm soup, water to drink, some bed rest he might have survived that pneumonia (antibiotics were not used at that time).
The point is not that the drug doesn’t work, it might work. We simply don’t know if it does because it has not been tested in the way every other drug gets tested. What do we know for sure is that it has side effects and some of them could be lethal. As any other drug, most common side effects are usually mild and tolerable, a bit of nausea, maybe some abdominal pain, vomiting. In the case of hydrochloroquine we also have rarer but more severe adverse effects such as bone marrow suppression, heart arrhythmias, Steven johnson’s Syndrome among others.
An otherwise healthy patient that gets this drug for malaria prophylaxis is different from a very sick patient in the ICU that gets it for compassionate treatment of COVID.
The patient in the ICU is receiving a multitude of drugs (sedation, paralytic, antibiotics, medications to prevent blood clots and gastrointestinal bleeding) which means interactions can occur. Sick patients also have different degrees of organ dysfunction, kidneys, livers, heart, lungs etc so they might not necessarily react to a drug in the same way as those that are healthy or at least healthier (stable).
What he is done is irresponsible. In the event the appropriate studies are done and shows no statistical benefit (or worse, harm) of this drug, you will not only end up with a drug that is not helpful in the treatment of covid but you will also have millions of people that will think that there is some kind of conspiracy. It is not hard to imagine that you will get patients or patient’s family requesting this medication even if it is proven to have no benefit.
This is not very different that when moron trump decided to open his big mouth to say hurricane Dorian was going to hit Alabama. Rather than admit that he was mistaken or misspoke (something that btw is very common and easily forgivable) he decided to escalate, because the moron cannot admit he was wrong.
Except the price in this situation is far greater. Hopefully the drug works, as much as I dislike the idiot, I rather we have a drug that we can use to help people than not. However, if we end up finding that unfortunately it does not work, I suspect that he will continue to praise this and that it will make for a rather awkward situation for the NIH/FDA as well as health providers and I guarantee that we will see hundreds of cases of patients or their family demanding this and it will be a shit show because most doctors will never prescribe a drug proven to be ineffective. Now we can under the umbrella that it is “experimental, compassionate usage” but this option goes away the minute that there is evidence that it does not work. Like I said, my hope is that it does. The fact remains, highly, highly inappropriate what he has been doing.

[Ter]

As any other drug, most common side effects are usually mild and tolerable, a bit of nausea, maybe some abdominal pain, vomiting. In the case of hydrochloroquine we also have rarer but more severe adverse effects such as bone marrow suppression, heart arrhythmias, Steven johnson’s Syndrome among others.

I was rather interested to use this in case I or my dear ones get infected but if it can affect my johnson I will pass.

By the way I took chloroquine as a malaria prophylaxis when I was in Africa but that was on a weekly, not a daily dosage.

[ThirdTerm]

Trump mentioned azithromycin in the interview and he was briefed on the subject. Short-term HCQ treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, according to Lane et al. (2020). Trump suggested hydroxychloroquine was behind African nations’ low COVID-19 counts in a March 23 coronavirus press briefing. Hydroxychloroquine is used to prevent or treat malaria caused by mosquito bites. The classified DHS study found that the risk of “transmission from surfaces outdoors is lower during daylight” and under higher temperature and humidity conditions, while sunlight destroys the virus quickly. This is why COVID-19 spreads slowly in tropical countries and I expect the current outbreaks in colder countries will be contained by the end of June.

Abstract
Background: Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin. Methods: New user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine-azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%. Results: Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45]) Conclusions: Short-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.
https://www.medrxiv.org/content/10.1101 ... 20054551v1