
Study: Severe Covid-19 Cases Don't Respond to Hydroxychloroquine+Azithromycin - aazaa
https://www.sciencedirect.com/science/article/pii/S0399077X20300858
======
Cantbekhan
Nobody seems to be talking about the actual reason Chinese doctors found
chloroquine (and HCQ) interesting and it has nothing to do with it's
immunosuppressing effect:

1) Chloroquine (and HCQ) is a zinc ionophore:
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/)

2) Zinc seems to inhibit RNA polymerase of Coronaviruses in vitro
[https://www.researchgate.net/publication/47794995_Zn_Inhibit...](https://www.researchgate.net/publication/47794995_Zn_Inhibits_Coronavirus_and_Arterivirus_RNA_Polymerase_Activity_In_Vitro_and_Zinc_Ionophores_Block_the_Replication_of_These_Viruses_in_Cell_Culture)

Their conclusion was that chloroquine could indeed allow zinc to enter the
cell and then inhibit replication (and therefore that the treatment needed to
be administered early).

Nobody seems to be talking about a very easy way to verify chloroquine (and
HCQ) efficiency by just using the same method used in China:

Cross-check the list of patients infected with Lupus (lupus erythematosus) and
with chronic HCQ treatment (they take it for years) with the list of known
infected COVID19 patients.

In China (and specifically in Wuhan), this is how they (team of Dr Zhang Zhan)
found out about the efficiency of HCQ. They noticed that there were no
patients with chronic HCQ treatment for lupus (lupus erythematosus) infected
with covid19. This was in peoples Hospital of Wuhan University (source:
[https://www.jqknews.com/news/388543-The_novel_coronavirus_pn...](https://www.jqknews.com/news/388543-The_novel_coronavirus_pneumonia_has_short_term_curative_effect_on_the_treatment_of_new_crown_pneumonia.html))

This alone would be enough to prove some efficiency even as prophyalxis (as
they are advocating officially in India). This should be quite trivial to
check with the current amount of confirmed infection.

These details were all explained in this medcram vid:
[https://www.youtube.com/watch?v=Eeh054-Hx1U](https://www.youtube.com/watch?v=Eeh054-Hx1U)

~~~
majormajor
> Their conclusion was that chloroquine could indeed allow zinc to enter the
> cell and then inhibit replication (and therefore that the treatment needed
> to be administered early).

Where does the "if it inhibits replication it needs to be administered early"
line come from? I've seen it elsewhere too, but why wouldn't inhibit
replication lead to => continually declining amounts in the body => easier
recovery at any stage?

~~~
Cantbekhan
Because they didn't intend to use chloroquine as a way to reduce the immune
response to cytokine storms.

They intended to use it to prevent virus replication in the cells at the early
stages of the immune response to allow the immune system to build up a
response at a slower pace.

The amount of treatment proposed in Europe is around 5 days of HCQ with about
800mg on D1 and then 400mg on D2-5. This is an incredibly low dosage and will
have very little immunosuppressant effect. It takes a very long time to act as
an efficient immunosuppressant (1 to 3 months for Lupus).

Expecting HCQ to suppress the immune system for cytokine storms in a matter of
hours seems very strange.

As that controversial French doctor said in multiple interviews. If you are
already in need of a respirator then your issue is no longer the virus but
your own immune system killing you (cytokine storm or added bacterial
pneumonia). At that stage, HCQ is not very useful. Not in these dosages at
least.

Most people are only focusing on the immunosuppressing effect of HCQ for some
reason which is very strange to me.

It takes time for chloroquine to act as a zinc ionophore as well and for zinc
to enter the cells (and it needs to be in the cells to inhibit RNA
polymerase). As you can see in the studies I posted. Between 24 and 72 hours
it seems.

If the virus cannot replicate correctly (with the zinc idea), it might give
more time to "flatten the curve" for the immune system. To build up antibodies
and respond to the disease without inducing a cytokine storm.

This at least is their hypothesis. And it has not been confirmed in any other
way than by observing that those with chronic Lupus+HCQ treatment seemed to be
"immune" to the disease. And this was only done in Wuhan as far as I know.

Unfortunately Dr Zhan Zhang has not yet published his full results except for
this preliminary
[https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v...](https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.full.pdf)

Which doesn't go into much detail about anything except that "it seems to
work". Unfortunately ... Yet I do see logic in the idea.

I just wish people (with access to patient files in major hospital centers)
would also look into this and they could maybe confirm this "once and for all"
without even needing a full blown trial.

~~~
touisteur
Do we know of any case of severe covid-19 that was taking immunosuppresors
(post-transplant, so cyclosporine or tacrolimus?). Haven't heard of one and
the doctors my wife talks to (who follow hundreds of those) haven't heard of
one. Yet.

~~~
touisteur
Correction, sorry, seems we have (in France) over a 100 adult hospitalized
patients infected, that are post renal transplant (less than 5 years post
transplant it seems). Not heard of liver transplant cases, or even child
transplant cases (even more fragile).

------
OniBait
Nobody is going to point out that of the 11 patients, "8 had significant
comorbidities associated with poor outcomes (obesity: 2; solid cancer: 3;
hematological cancer: 2; HIV-infection: 1)"?

I don't even understand what the point of this study was except as a rebuttal
to the prior study. I mean, if people thought the prior study was cherry
picking results. I don't even know what I'd call this...

There's _some_ anecdotal evidence that it _may_ work if treated early.
Hopefully there are some real studies that are being done on that.

------
raphlinus
A really excellent review, published today, of the current state of knowledge
on HCQ:
[https://blogs.sciencemag.org/pipeline/archives/2020/04/06/hy...](https://blogs.sciencemag.org/pipeline/archives/2020/04/06/hydroxychloroquine-
update-for-april-6)

Note this is by Derek Lowe of "Things I won't work with" fame, an extremely
informative series about entertainingly dangerous chemicals.

And here's a new piece of candy for people who want to get their hopes up
about a promising treatment:
[https://stm.sciencemag.org/content/early/2020/04/03/scitrans...](https://stm.sciencemag.org/content/early/2020/04/03/scitranslmed.abb5883)

(h/t Helen Branswell of STAT news, who is very much worth following, who
retweeted Timothy Sheahan)

~~~
robocat
> a promising treatment
> [https://stm.sciencemag.org/content/early/2020/04/03/scitrans...](https://stm.sciencemag.org/content/early/2020/04/03/scitranslmed.abb5883)

That is frightening. Increasing the mutation rate must carry a large unknown
risk. Also surely the first thing to mutate will be self-defeating resistance
to that drug...

~~~
raphlinus
The thought occurred to me as well, I got a strong sense of "playing with
fire." However, viruses have a very high mutation rate as it is [1], so I'm
not sure how much difference it makes.

Btw, one of the best markers for overconfident but uninformed analysis is
overinterpreting the fact that we have all these strains of SARS-CoV-2 as
suggesting they have different degrees of infectiousness or health impacts.
Certainly the different flu strains do, and, thanks to fine-grained sequencing
efforts (Nextstrain in particular is doing awesome work) we can see lots of
strains of this one, but Trevor Bedford has estimated that we have about a
year or more before the variation in strains has an impact other than being
able to "fingerprint" the chains of transmission.

[1]:
[https://jvi.asm.org/content/92/14/e01031-17](https://jvi.asm.org/content/92/14/e01031-17)

~~~
robocat
Here is a paper which suggests they found a different strain:
[https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....](https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf)

“In this report we describe the first major evolutionary event of the SARS-
CoV-2 virus following its emergence into the human population. Although the
biological consequences of this deletion remain unknown, the alteration of the
N gene transcription would suggest this may have an impact on virus
phenotype.“

However they don’t speculate on whether that strain is more likely to spread
(it clearly is a viable mutation).

~~~
robocat
And another:
[https://www.medrxiv.org/content/10.1101/2020.03.10.20033944v...](https://www.medrxiv.org/content/10.1101/2020.03.10.20033944v2)

------
perl4ever
I have no medical expertise, but there's something that is confusing me. From
what I read, typically, you get the virus, then an opportunistic bacterium
gives you pneumonia, and that's what you die from. But this study seems to be
saying "someone else found these meds reduced the virus and we didn't". But
the meds are more or less antibiotics, aren't they? So could the explanation
simply be that while the virus is the same, the bacteria are not, in the two
tests?

~~~
Gibbon1
My understanding is what you said is true for influenza and to a lesser extent
colds. Those virus tend infect the upper respiratory system. COVID19 though
can infect the lower lungs and directly causes pneumonia. And viral pneumonia
is no joke even before COVID19.

------
sunsu
By the time it's severe, it's often too late:
[https://twitter.com/yishan/status/1244717172871409666?s=20](https://twitter.com/yishan/status/1244717172871409666?s=20)

------
uncoder0
I am not in any way qualified in the medical domain but these methods look
similar to the other Study that was viewed as flawed that showed it did work.
Seems there is no solid data either way.

~~~
archgoon
Which, in itself, is probably a valuable take-away.

------
podgaj
If the patients have a zinc deficient they can make all the zinc channels they
want, it won't matter.

It is one thing to inhibit the virus, but zinc is needed to reduce the over
active immune response,

------
webmobdev
Wonder when the Indian Council of Medical Research will release more papers -
there were a few patients who responded positively under their suggested
treatment plan:

> _“We used a combo of Lopinavir and Ritonavir drugs which are usually given
> as a second line of treatment for HIV with drugs meant for curing malaria
> and swine flu. We administered this line of treatment to a 70-year-old
> Italian woman, who had come as a tourist to Rajasthan, who tested positive
> and was being treated by us, as well as another Italian, who is 69-year-
> old,”_ said Dr Sudhir Bhandari.

> ... _“The team of doctors under the leadership of Dr Sudhir Bhandari,
> Principal of SMS Medical College held consultations with the ICMR and tried
> a combination medicines given for malaria, swine flu (Tamiflu) along with
> drugs for HIV and it worked well. All three persons including the Italians
> were cured this way,”_ said Rohit Kumar Singh, additional chief secretary,
> health of Rajasthan government.

Source: [https://www.nationalheraldindia.com/india/three-
coronavirus-...](https://www.nationalheraldindia.com/india/three-coronavirus-
afflicted-patients-recover-due-to-innovative-treatment-by-doctors-at-jaipur-
govt-hospital)

> ... The three persons who tested positive were administered a combination of
> 200mg Lopinavir and 50 mg of Ritonavir twice a day besides Oseltamivir and
> Chloroquine that are given to the swine flu and malaria patients.

> However, the doctors at the SMS Hospital warned that this was only an
> emergency treatment and the HIV medicines were used only as an emergency
> measure that could help in regaining normalcy.

Source: [https://www.nationalheraldindia.com/india/covid-19-magic-
med...](https://www.nationalheraldindia.com/india/covid-19-magic-medicine-of-
jaipurs-hospital-cures-3-patients-draws-attention-in-medical-world)

~~~
webmobdev
Update: The Indian Council of Medical Research has also given the go ahead to
try out plasma therapy for the really serious, and some hospitals and
institute are waiting for clearance of the same from the Drug Controller
General of India:

> ... Blood for the plasma therapy will be collected from recovered patients
> at SCTIMST and the medical colleges and donated to critical patients with
> sanction from Blood Transfusion Council. Plasma would be separated from
> blood and taken to other hospitals under refrigeration.

> ... When a person suffers from COVID-19, antibodies are created in his or
> her body as defence. Such B lymphocytes would be present in plasma. After a
> patient recovers from the disease, these antibodies remain in blood to
> prevent another attack by the virus. The plasma collected from such people
> and given to another patient would have antibodies which target the virus
> and prevent the recipient from slipping into a more serious condition.
> According to researches, plasma taken from one donor would have sufficient
> doses for two patients.

Source:
[https://english.manoramaonline.com/news/kerala/2020/04/09/ke...](https://english.manoramaonline.com/news/kerala/2020/04/09/kerala-
plans-trials-in-convalescent-plasma-therapy-against-covid.html)

------
ruggi
An in-vitro pre-print study (
[https://www.biorxiv.org/content/10.1101/2020.03.29.014407v1](https://www.biorxiv.org/content/10.1101/2020.03.29.014407v1)
) showed that administering Hydroxychloroquine only after Covid-19 infection
is not helping much, while administering it both before the infection and
after the infection gives great outcomes. They tried different administration
modalities of HCQ to in-vitro infected cells: some cells got nothing
(control), some got HCQ only before infection, some got HCQ only after
infection, some got HCQ both before and after infection. THe cells that got
HCQ only before or only after infection had just slightly better outcome than
control (they appear as heavily infected), while cells that received HCQ both
before and after contagion were in much healthier conditions. If that would be
the same in vivo as in vitro, that would entail that it would be possible to
use HCQ as prophylaxis, given that the patients never stop taking the drug. Of
course the caveat is "IF that would be the same in vivo as in vitro", that
they didn't (yet) tested.

------
rpiguy
COVID-19 attacks hemoglobin and that is how it damages the lungs. With your
hemoglobin unable to exchange oxygen with blood in the lungs, it causes
terrible damage.

[https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surf...](https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173)

Chloroquine prevents the virus from affecting hemoglobin, or reduces the
effect. This is also how Chloroquine treats malaria.

The problem with a study on severe cases is that the damage is already done
and the hemoglobin is already compromised.

It is best to start treatment with chloroquine prior to reaching the severe
stage. By the time you are severe you’ve gotten permanent lung damage and the
immune system is in a race condition unable to keep up with the virus.

If you want to detour into tinfoil hat territory, you could posit that these
studies on severe patients were designed knowing it would show low or no
efficacy, because it’s too late to protect the patient’s hemoglobin.

Azithromycin slows ribosonal RNA replication in bacteria. It is unclear how it
helps with a Covid.

Antivirals are much more promising for severe cases, but even they can’t heal
ground glass in the lungs.

~~~
KaiserPro
> Chloroquine prevents the virus from affecting hemoglobin

This virus attacks the cells that live in the throat and lungs. The "spike" as
far as I'm aware does not attach to haemoglobin.

> damage is already done and the hemoglobin is already compromised.

Its the lungs that are damaged, not the blood. The reason why people die is
because they drown in thier own fluids, as the cells walls of the lungs are
broken down by the patient's immune system.

If Chloroquine was effective, it would stop the virus reproducing. This would
lead to a detectable change in viral load.

Sure, it could already be to late by then, the damage is done. But, the viral
load would have a measurable change. These studies don't really show anything
conclusive.

This means that its unlikley to work as a prophylactic as its not actually
stopping the virus from attaching or reproducing.

> Azithromycin

Thats there to stop any opportunistic bacteria from causing more damage.
Typically when someone is admitted to ICU for covid they have a lower than
expected white cell count.

> Antivirals are much more promising

yes because they actually disrupt the virus replicating. Chloroquine doesn't
appear to do that. This is the problem with making drugs. Something that works
in the petridish doesn't always work in the body. This is why Gilead's new
wonder drug wasn't in production, because it was designed to target ebola, but
didn't really work.

~~~
Threeve303
> as the cells walls of the lungs are broken down by the patient's immune
> system

If there is actually a real statistical anomaly that Lupus and other immune
comprised people are less susceptible to certain parts of the virus, perhaps
it's not the medication they take at all. It could simply be that someone who
is immune compromised would not have as strong as a reaction as a healthy
person and then may actually survive as a result. Less fluid, etc. Also, I am
in no way qualified medically, it's just a quarantine showerthought.

~~~
KaiserPro
I have heard of two patients in london who were immuno compromised and
recovered quicker than a "normal" person.

The real damage occurs when the immune system ramps up to attack the virus,
but ends up attacking the cells they are living in as well. Now, most of the
time this is fine an normal, but it can also trigger
[https://en.wikipedia.org/wiki/Cytokine_release_syndrome](https://en.wikipedia.org/wiki/Cytokine_release_syndrome)
which is a nasty feedback loop.

There are experiments to give immuno-suppressants at key times to try and
limit the damage. But its tricky and dangerous.

------
sdiq
[https://abc7news.com/amp/coronavirus-drug-
covid-19-malaria-h...](https://abc7news.com/amp/coronavirus-drug-
covid-19-malaria-hydroxychloroquine/6079864/)

Not a study but just another anecdote. Using zinc this time round rather than
azithromycin.

~~~
snapetom
Yeah, I don't know what's the point of these studies that don't look at
HCQ+zinc when the hypothesis is that HCQ promotes zinc absorption.

~~~
HarryHirsch
The hypothesis is that hydroxychloroquin interferes with glycosylation of cell
surface proteins that are essential for entry of the virus into the cell. The
zinc notion is total bunk, intracellular zinc concentration is tightly
controlled. Random zinc excursions just don't happen, if they did they would
result in death.

~~~
podgaj
This is so wrong I do not know where to start.

ADAM17 is responsible for shedding of ACE2 from the cell which creates soluble
ACE2. If ACE2 is not ON the cell the virus cannot infect the cell.

ADAM17, like ACE2 is a zinc finger protein and uses zinc as a cofactor.

Also, zinc is widely understood to lower the immune response by affecting
interferon levels.

It is not only about intracellular zinc. But in a deficiency intracellular
zinc has even less chance of being brought into the cell, right?

To say that zinc does not matter because hydroxychloroquin is absurd.

------
anigbrowl
The lack of productive discussion around a potential treatment tells us more
about our bad decision-making under anxiety conditions than it does about the
efficacy or not of the medical proposal. Although I posted a preprint of the
French micro-study to HN a few weeks ago when this first became a topic of
discussion, I now regret doing so due to the subsequent public confusion and
imho very irresponsible promotion of it as a harm-free prophylactic by Trump.

------
sna1l
n = 11?

~~~
michael_storm
Believe it or not, it's pretty hard to conduct a large-scale study in the
middle of the largest pandemic in modern history.

~~~
SpicyLemonZest
I don’t believe it. Studying how to effectively treat coronavirus patients is
literally the most important problem in the world right now, and I’m sure a
lot more than 11 severe cases are being treated with hydrochloroquine.

~~~
kilbuz
While your point is a good one, meaningful clinical research is hard enough
under normal conditions. Forms, enrollment, protocols, data collection,
statistical analysis plans, reporting, etc. It's an entire industry used to
operating in scales that often span years for a single meaningful study.

~~~
SpicyLemonZest
And I agree with that as far as it goes, but I think it reflects the problem -
clinical research contains a bunch of hurdles that have nothing to do with
uncovering the truth. So in a sudden emergency, where clinical research starts
to diverge from the treatment decisions of doctors and the drug supply actions
of governments, I'm not going to put much weight on clinical research.

------
SrslyJosh
Not very surprising given the quality of the studies that this fad is based
on:

[https://respectfulinsolence.com/2020/04/03/zelenko-smith-
aba...](https://respectfulinsolence.com/2020/04/03/zelenko-smith-abandoning-
evidence-based-medicine-for-covid-19/)

That's a long read, but it's pretty damning.

TL;DR: China says "hey, this stuff might work". French doctor conducts two
very sketchy rapid-fire studies, then starts promoting himself on TV,
including on Dr. Oz. No red flags there, right?

~~~
gridlockd
Pretty much every virologists I listened to said "this stuff might work",
because it's entirely plausible that it might work.

> That's a long read, but it's pretty damning.

It actually isn't. All it says is that the evidence is poor and done by people
with questionable reputation. It doesn't say "it doesn't work". What if it
_does work_ , but only in the early stages, when symptoms aren't severe (yet)?
You wouldn't know.

Chloroquine and hydroxychloroquine are somewhat dangerous drugs and are
therefore far more likely to only be given as a "last resort" rather than as a
"precautionary measure", given their unproven status.

What are the odds that a _reputable_ person is going to put their reputation
on the line, doing such a dangerous trial on patients that aren't at high
risk? Early on, a _disreputable_ person is way more likely to do it. There
won't be any good evidence for a while, in the meantime it's all a gamble.

This study is important, but limited in its scope. It shouldn't poison the
well.

------
rodgerd
So a bunch of people who have medical conditions which actually respond to HCQ
have lost access to it, for no benefit to anyone else.

Great.

~~~
transreal
Unfortunately, I'm one of those people. My last refill ran out last week, and
my pharmacist doesn't think I can get a refill anytime soon :-(

Fortunately my condition is not life threatening or severe, but it's something
I've been living with for many years, and the HCQ was just finally getting it
under control, so it's a bummer that there is so much hoarding going on before
we even know if it really works for Covid-19.

Also, it is not a risk free medication. While it's generally safe, my doctor
makes me get frequent lab work & a vision test because the side effects can be
pretty bad for a small minority of people.

------
tgafpc2
Maybe don't let them get that severe? One can still starve after eating.

~~~
orwin
Thank you, i'm sure they are incompetent idiots that could not prevent their
patients to die, after all they have graduated from a third world country and
are probably not capable doctors. /s

~~~
ReptileMan
Some of the best medical minds with best education rejected evidence that
washing hands before surgery saves lives for like 50 years.

Anyway X doesn't work on severe cases when there is compelling anecdotal
evidence that X helps on medium cases to not progress to severe is, so give
them X earlier is what I read in the OP word.

------
trhway
[IANAD] hydroxychloroquine is an immunosuppressant and shouldn't be combined
even with vaccines (
[https://www.medicinenet.com/hydroxychloroquine/article.htm#w...](https://www.medicinenet.com/hydroxychloroquine/article.htm#which_drugs_or_supplements_interact_with_hydroxychloroquine_plaquenil)
), so using it when immune system is really fighting an infection may happen
to be very antiproductive unless it is a case of COVID triggered cytokine
storm (hyperinflammation) when such immunosuppressant is probably what you'd
really want. May be it is a reason why in come cases of COVID it works and in
some doesn't.

[https://www.thelancet.com/journals/lancet/article/PIIS0140-6...](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736\(20\)30628-0/fulltext)

"However, in hyperinflammation, immunosuppression is likely to be beneficial.
Re-analysis of data from a phase 3 randomised controlled trial of IL-1
blockade (anakinra) in sepsis, showed significant survival benefit in patients
with hyperinflammation, without increased adverse events.8 A multicentre,
randomised controlled trial of tocilizumab (IL-6 receptor blockade, licensed
for cytokine release syndrome), has been approved in patients with COVID-19
pneumonia and elevated IL-6 in China "

Notable fact is that majority of the deaths of the second wave (the deadliest,
which in addition to children/weak/elderly was also strongly hitting healthy
25-35 years old) of Spanish flu was due to cytokine storm.

~~~
orwin
Yes, obviously in case of hyperinflammation doctor are giving
immunosuppressing drugs, HCQ or other depending on the stocks (and of course
the patient history and other drugs given prior). They are very capable people
in most cases, urgentists are often very knowledgable, and reanimation doctors
are probably the best at interfering/preventing coktail effect. They are not
available in all cases, but they try to be there for the most important ones.

No one, no scientist is saying with certainty that HCQ does not work at all.
However, the maxim is primum non nocere. Are HCQ effects important enough to
use it in every case when you can do otherwise? Well, according to the last
Raoult study on 80 mild cases, no. 3 hospitalisation, 1 death for 80 cases is
around the same result as German/S.K. mild cases who are given no treatment at
all (a bit superior, even, but n=80 is clearly not enough).

Maybe HCQ reduce contagiosity. In this case, is HCQ more efficient than
interferon? I know that i would prefer interferon as my liver and kidneys can
take more hit than my heart atm (i already have a medication that cause
tachycardia when i overdose it a little + some minor heart issues). Is HCQ
more efficient than rinovir? this particular article seems to say that it's
not but why should i trust this article more than Raoult and some French
articles? Should i take everything (interferon, rinovir, HCQ, CQ) and hope for
the best? Or, since i can afford to as i live in a rich country, should i wait
the different study results?

