However, when I went to the link on the WHO site recently, that page is no longer there. Note the link I gave above is the one from the archive.org site, a site that archives previous web pages.
If you go to that link now though you’ll get an error message that WHO has been revamping its site since 2020 and some pages have been moved. However, I used the search function on the WHO site and that page no longer turns up.
So WHO acknowledges IVM’s safety for wide spread use. Then for a global epidemic it makes no logical sense to not allow its use under a doctors care, at least under an emergency use authorization.
Here’s a stunning fact when you think about it:
For COVID, IF your case is going to require hospitalization it will happen on average within 7 days of symptoms appearing.
Then IF a proposed medication really is successful for EARLY treatment of COVID-19, we will have evidence of that within days, indicated by the reduction of hospitalizations.
To me that is a stunning fact, if any of these proposed medications really is effective for EARLY treatment, then if they had been used wide-spread for EARLY treatment in the U.S. or other countries we would have knownwithin days that they had indeed been successful. We would not have had to suffer through the pandemic for 18 months. It’s extent could have been radically cut within just days.
This shows why the single-minded focus of relying on RCT’s is severely misguided in the midst of a pandemic. RCT’s take 3 months or more to complete. That’s too long during a pandemic undergoing exponential growth.
WHO and other public health agencies are not considering this fact in their risk-benefit analysis, especially for repurposed drugs with well-known side-effect profiles: the risk is small but the benefits are profoundly important and could be confirmed within just days.
Here’s another way of seeing this: suppose we just now instituted a national treatment guideline that EVERYONE be giving IVM or some other proposed drug for EARLY treatment on first signs of symptoms. And suppose then within days we saw a drop in hospitalizations by 80%, i.e., by 1/5th, across the board, for every city and state, and for every race and socio-economic group we saw this drop.
Then proponents of RCT’s would still say it wasn’t real because it wasn’t conducted under the guise of an RCT.
Note this is not just idle speculation. What we have seen in India may be an indication of such a rapid drop in cases and fatalities when IVM is put in wide spread use.
COVID-19 CASES PLUMMET IN INDIA AS THEY DISTRIBUTE IVERMECTIN AND HYDROXYCHLOROQUINE
Note now the Indian variant that was spreading rapidly then IS the delta variant predominant in the UK, Israel and building now in the U.S.
There was skepticism expressed by some that the effect in India could not be due to IVM because the drop occurred so rapidly after IVM being put in wide-spread use.
But that’s the ENTIRE point of the matter: since IF for a particular case COVID is to progress to the hospitalization stage, it will happen within days. Then if a medication can greatly cut this risk by EARLY treatment, its effectiveness will also be seen within just days.
Note too that such medications in their antiviral role if they really are effective as EARLY treatments quite likely will also be effective for prophylaxis. And that has indeed been seen to be the case for IVM. See for example this interview with a doctor actually treating patients with IVM in India:
Choosing and using ivermectin for covid-19 in India.
So imagine such a drug also being used wide-scale in a country for prophylaxis, and it cutting transmission also by, say, 80%, i.e., by 1/5th.
Then both these effects together prophylaxis and treatment will cut hospitalizations and fatalities by a factor of 1/25. This is now getting into the range of what vaccines can do, cutting severe cases and fatalities by double digits.
Since the effect can be seen so rapidly, to test it this doesn’t have to be put in effect across an entire country. Just put it in effect in some city of some size, for both treatment and prophylaxis.
I said WHO had earlier acknowledged ivermectins safety for mass treatment. But part of the reason it won’t grant its use for COVID treatment is the claim that not enough evidence supports its effectiveness. I have made this challenge to people I’ve corresponded with to perform their own judgement on this issue. The PubMed site has a listing of peer-reviewed published papers. Searching on there turns up literally dozens of published reports positive on ivermectins effectiveness:
As of now there are 210 reports listed under this search. That’s quite a lot of papers to review. So I’ve challenged anyone to pick any 10 at random. Here’s a random number generator page: random.org. Set the max range of numbers to pick from at 210. Use the generator 10 times to come up with 10 numbers at random from 1 to 210 and select those papers to review. Count now how many papers are positive, negative, and neutral. You’ll find the reports are overwhelmingly positive for ivermectins usefulness.
It is simply unreasonable to suppose all those reports are finding positive effects just by coincidence.
This is a graphic from an article published last May that showed Asian countries had radically reduced COVID-19 fatalities compared to Western ones, sometimes by two orders of magnitude.
That was then, what about now? The fatality rates in Asian countries are still radically reduced compared to Western ones. Only now, we also have data that shows fatality rates in Africa are also radically reduced compared to Western ones, again sometimes by two orders of magnitude.
But Asia and Africa make up 3/4th’s of the worlds population. Then the West is the outlier with these horrendous fatality rates.
Here is an New York Times article that discusses it:
March 8, 2021 By David Leonhardt Good morning. Why has Covid’s toll been surprisingly low across much of Africa and Asia? ‘An epidemiological whodunit’ It’s one of the biggest mysteries about Covid-19: Why has the death toll been relatively low across much of Africa and Asia? The virus has killed a fraction of as many people on those continents — despite their relative lack of resources — as it has in Europe or the U.S.:
The article links to a well-written article by physician Dr. Siddhartha Mukherjee that examines the mystery. But Mukherjee’s article, once again, does not address a key question: what are the treatment strategies in those countries with radically reduced fatality rates?
This is a doctor writing this, mind you. A doctor who’s job is to treat people. Yet he doesn’t even ask of these countries something you would think would occur to any doctor to ask: how do you treat your sick?
By the way, the title is a bit misleading. It is also rich Asian countries that have radically reduced fatality rates compared to the West. The only common denominator is that they either treat COVID-19 with antivirals EARLY or drugs with antiviral capability are already in wide use in these countries as antimalarials or anti-parasiticals.
In these articles once again nowhere did they even ask the question what treatments are they using in these countries with the radically reduced fatality rates. These are doctors investigating this remember, doctors whose job is to treat people, and they never ask the question how do you treat your sick.
The national treatment protocols for COVID of giving antivirals EARLY for some of the Asian countries go all the way back to last year to March. It’s stunning when you think about it but if the question had been asked of them of what treatment strategies do you use, the researchers would have gotten the answer over and over again, “We use antivirals EARLY”, “We use antivirals EARLY”, “We use antivirals EARLY”, “We use antivirals EARLY”. It would then have been apparent that EARLY treatment with antivirals is important for bringing the virus under control.
This study also concludes countries using anti-malarials are much better at keeping the epidemic under control:
National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study.
“COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group.”
COVID-19 treatment: Antivirals, anti-inflammatory drugs, blood thinner and mechanical ventilation
Updated 22:28, 26-May-2020
Antiviral treatment Ranko Škrbić, dean of the Department of Pharmacology at University of Banja Luka, asked about the most effective antiviral therapy that has been used in the Chinese hospital against the coronavirus. Hou Xinguo, Deputy Director of Endocrinology Department at Qilu Hospital, said that several antiviral drugs including alpha-interferon, ribavirin and abidol have been recommended in the COVID-19 diagnosis and treatment guideline issued by China's health authorities. But based on their clinical experience, the antivirals could be useful on patients only at the early stage of infection, as they did not have significant effects on severely ill patients. He added that according to the guideline, no more than two antiviral drugs should be used in combination.
Gov't recommends use of antiviral drugs for COVID-19 treatment
Published on Feb 13, 2020
'고령•중증에에이즈치료제권장'…코로나19 치료원칙나왔다
South Korea has unveiled a set of treatment guidelines for COVID-19. It consists of administering an anti-HIV medication twice a day. This is the nation's first treatment protocol for those who show severe symptoms. Kim Jae-hee has our top story. Infectious disease experts in South Korea have agreed to the use of antiviral drugs in the treatment of severe coronavirus cases, senior patients, and those with underlying diseases. On the other hand, it was concluded that young patients, or those with mild symptoms, seemed to have improved after 10 days and without any antiviral treatment. "Young and healthy people have mostly shown improvement without any special treatment. But older patients or those with underlying diseases are in need of the medication from an early stage." Expert says differences in treatment depending on a patient's age is actually quite normal. "Most viral infections tend to heal even without any treatment... thanks to our body's immune system. But old age in itself can raise risks,... and many senior patients have underlying diseases, so it's recommended that they undergo antiviral treatment." The government's guidelines recommend Kaletra, an anti-retroviral medication used to treat AIDS for a duration of 7 to 10 days. Chloroquine or Hydroxychloroquine, a medication used to prevent and treat Malaria can be used as an alternative. But experts says, while the government's announcement may sound promising, it might not make much of a difference to current treatment metThere won't be a significant difference in the treatment methods. It's an antiviral drug that we are already using, and its effectiveness has not been fully proven. It's still just a recommendation." But the expert is optimistic, saying that the recurrence rate of the novel coronavirus is low. "It seems unlikely that a recovered patient will catch the virus again. In fact, there are very few reports of patients being re-infected when they've recovered from other coronavirus diseases such as SARS and MERS." He added that all seven of the patients who have made full recoveries in South Korea had no serious underlying diseases, and are unlikely to be re-infected.
Hong Kong public hospitals to revise Covid-19 treatment guidelines, highlight effective drugs behind low mortality rates.
Victor Ting
27 August 2020·3-min read
Hong Kong’s public hospitals will revise clinical treatment guidelines for Covid-19 patients to better highlight the effectiveness of an antiviral drug that has helped achieve one of the lowest coronavirus death rates in the world. Dr Owen Tsang Tak-yin, medical director of the Hospital Authority’s infectious disease centre at Princess Margaret Hospital, made the revelation at a media briefing on Thursday as the city’s third wave of infections showed signs of easing, with health officials reporting 21 new cases, taking the local tally to 4,755, with 81 related deaths. “The third wave has been very rapid and fierce,” Tsang said. “But despite that, we have one of the lowest mortality rates worldwide, at about 1.6 per cent.” One factor that helped suppress the death rate was effective treatment, which centred on a cocktail therapy involving antiviral drug Interferon; Kaletra, a drug originally used for HIV/Aids, and Ribavirin, which was also used for hepatitis C, according to Tsang. The treatment guidelines, which were last updated in June, would be revised “very soon”, Tsang said, and would highlight Interferon as the major medication for Covid-19, combined with Ribavirin. But Kaletra may lead to some side effects and has proved to be unsuitable for some patients, causing liver problems in such cases. Another antiviral drug, Remdesivir, was found to be most effective among patients in severe condition requiring oxygen support, but less effective in those who are critically ill and requiring intubation, while Hydroxychloroquine and Chloroquine have been ruled out as overseas research have shown their ineffectiveness.
It’s notable that Hong Kong decided against HCQ following Western studies. But those studies did not test it for EARLY treatment which is essential for antivirals. But no matter. COVID-19 is a virus easy to treat. Multiple antivirals are effective treating if given EARLY.
In Thailand:
Am J Trop Med Hyg. 2020 Jul; 103(1): 48–54.
Published online 2020 May 18. doi: 10.4269/ajtmh.20-0442
PMCID: PMC7356442
PMID: 32431287
Critical Care Management of Patients with COVID-19: Early Experience in Thailand
Ranistha Ratanarat,1,* Chaisith Sivakorn,2 Tanuwong Viarasilpa,1 and Marcus J. Schultz3,4,5
Antiviral treatment before ICU admission. Thailand has set national guidelines for antiviral treatment. Patients with mild symptoms receive chloroquine or hydroxychloroquine plus a boosted protease inhibitor, lopinavir or darunavir plus ritonavir. Favipiravir is not recommended in mild cases because of its limited availability.8 Favipiravir is an antiviral RNA polymerase inhibitor for which most preclinical data are derived from its influenza and Ebola activity.16 It is given to all patients with proven COVID-19 who have symptoms or signs consistent with pneumonia, or when there is hypoxemia (SpO2 < 95% on room air).8
Interim Treatment Guidelines for COVID-19 (Version 1.0, dated 2 April 2020)
ABSTRACT Background In December 2019, pneumonia cases caused by a novel coronavirus occurred in Wuhan, Hubei Province. As of 11th February 2020, the World Health Organisation has officially named the disease “COVID-19”. In addition, virologists in the coronavirus study group have officially announced the name of the virus to be “SARS-CoV-2”. This guideline provides evidence-based recommendations on the therapeutic management of patients with COVID-19 in Singapore.
There has been a present
push to reopen the economies and the schools. Unfortunately, there has been a
present surge in COVID-19 cases. Some
countries particularly the Asian countries have COVID-19 death rates at 1/100th
those in Western countries:
Researchers ponder why covid-19 appears
deadlier in the U.S. and Europe than in Asia.
We suggest an
international conference on the treatments being used that have been found
effective throughout the world. Such a conference could even be conducted
online.
Very few researchers
seem to be giving this difference in COVID-19 fatality rates by country
comparisons sufficient attention. It's importance though becomes even more clear
when it's noted this radical reduction in fatality rates also applies in the
African countries:
The pandemic appears to have spared Africa so far.
Scientists are struggling to explain why.
Many even
knowledgeable researchers in the medical field are not even aware of it. I
think the cross-country comparisons should be made to various influencing
factors such as population age, obesity levels, mask wearing, lockdowns,
prevalence of vaccines, medications common in a region due to endemic
illnesses, and treatments.
Commenters on this
difference have mentioned the first few of these as the cause. But quite
puzzling is the aversion of those who have commented on the question to
consider the possibility that difference in treatments might at least be a part
of cause.
For instance one
explanation offered is mask wearing common in Asian countries. But maskwearing is not common in India or the African
countries, with the low fatality rates. Another explanation given is the
greater testing in Asian countries, but Indonesia has one of the lowest rates
of testing:
Yet still Indonesia
counts with the other Asian countries as among the lowest in fatality rates.
Asia and Africa
together account for 3/4ths of the world's population. That they have orders of
magnitude lowered death rates suggest all factors including treatment
strategies should be considered in evaluation which of these to adopt in
Western countries.
Antivirals.
It is a well-known fact that antiviral therapies are
best applied soon after infection, for example, for influenza and HIV. And this
had been the recommendation of the CDC against the flu and thepandemic H1N1:
Revised CDC guidance on flu antivirals stresses early
treatment. Filed Under: Influenza, General; H1N1 2009 Pandemic
Influenza; Public Health By: Robert Roos| Sep
08, 2009 Sep 8, 2009
(CIDRAP News)Revised recommendations
from federal health officials on the use of influenza antiviral drugs suggest
that clinicians consider providing prescriptions over the phone for high-risk
patients as a way to start treatment faster if they come down with flu
symptoms.
At the same
time, the recommendations released today from the Centers for Disease Control
and Prevention (CDC) suggest that clinicians try "watchful waiting"
when high-risk patients have been exposed to flu but remain healthy, rather
than prescribing a preventive antiviral right away. The recommendations cover
both pandemic H1N1 and seasonal flu. https://www.cidrap.umn.edu/news-perspective/2009/09/revised-cdc-guidance-flu-antivirals-stresses-early-treatment
Oddly, this lesson
seems to have been forgotten for COVID-19.
This article argues for going back to that well-known
principal of antiviral therapies:
Recently, the NIH in
an article co-authored by Fauci advocated for finding medications effective for
early treatment for COVID-19:
November 11, 2020 Therapy for Early COVID-19 A Critical Need Peter S. Kim, MD1; Sarah W. Read, MD, MHS1; Anthony S.
Fauci, MD2 JAMA. 2020;324(21):2149-2150. doi:10.1001/jama.2020.22813 https://jamanetwork.com/journals/jama/fullarticle/2773058
Note they are making
this recommendation even considering the vaccines now coming into use. However,
it is utterly mystifying why the NIH came so late to this realization since it
is a well-fact about antivirals that they are most effective early. Indeed, in
the early part of the year, before the vaccines were developed, it was even
more important to have such early antiviral treatments but the NIH made no such
recommendations to find them.
So we have had
numerous clinical studies supported by the NIH on late treatment using antivirals such as HCQ, Remdesivir,
lopinavir/ritonavir, interferon, ribavirin, etc. When these were shown
ineffective in studies for late
treatment, the unfortunate inference drawn by many was that they were in general ineffective against COVID-19.
This led to their not even being tried for the scenario they from the beginning
should have been tried for, early treatment, soon after symptoms appear.
There have been many antivirals that have been shown
effective against the coronavirus in vitro, but have been disappointing in
vivo. But almost all such studies have been looking at patients at advanced
disease. But key would be to do the treatment soon after symptoms first appear.
Because testing sometimes takes days for the results to come back, the treatment
should be applied immediately even before a positive test confirmation.
Because there are sometimes false negatives, the
medication should continue to be taken during the time symptoms are apparent.
And even if after repeated testing it is likely the person is negative for
COVID-19, if the medication is effective than it should be protective during
the period the medication is taken. This in fact will be another method of
testing its effectiveness, by determining if it has a protective effect.
Since such treatments are taking place before serious
disease develops it necessarily would be on an outpatient basis. Then for those
antivirals being taken among the teams administering the medications there
should be experts on the possible side effects.
To be able to find which medications are most
effective, clinical practices and hospitals within the same general vicinity
could be using different medications. That would be able to make it easier to
compare their effectiveness, without various confounding factors coming into
play. And the effectiveness of the medications should be shared in real
time.
A difficulty with respect to COVID-19 though is that
most subjects recover on their own making it difficult to see if a medication
is having a real effect or not. However, the experience of some doctors in
Italy with hydroxychloroquine shows a key and important method by which the
effectiveness could be detected: cut in hospitalizations.
Success in Italy reported in early treatment of COVID-19
using hydroxychloroquine.
Since most deaths
come after hospitalizations a dramatic cut in hospitalizations would result in
a dramatic cut in the death rates. And the experience of those particular doctors
in Italy using it was of a dramatic cut in the hospitalizations. Unfortunately,
restrictions on its use are in place in Italy as it is in U.S. and most Western
countries so it cannot be determined for sure if the effectiveness seen by
these doctors will be a general phenomenon.
The importance of this early use, for HCQ and other
proposed antivirals, is not just for the cut in the hospitalizations but also
the speed at which this drop will
become apparent. If you are only judging by death counts, then that can take
weeks to months to determine the medications effectiveness because patients can
remain hospitalized for weeks to months, before it is determined if they
recover or not from the disease.
But because for COVID-19 whether the disease
progresses to the serious stage requiring hospitalization is determined within
a matter of days, doctors using the medication would know within days if it is
effective in cutting the hospitalizations they observed.
If an
antiviral is effective against COVID-19 then the same should be true also for
that antiviral, a cut in hospitalizations that becomes apparent within days.
Given the success those particular doctors in Italy
using it for early treatment have
found in cutting hospitalizations, hydroxychloroquine should be among the
antivirals being tried. However, the FDA has a policy in place that is
interpreted as banning it in general for treating COVID-19. But actually the
policy allows it within clinical trials against COVID-19. But any doctor can
apply for a clinical trial. So the doctors wanting to use it should apply to
conduct a clinical trial. Such trials don't have to be paid for by government
grants or pharmaceutical companies. And the medication itself is quite cheap.
Only, those doctors wanting to use it should have doctors on their teams or be
in consultation with doctors who are experts in their use and possible side
effects such as those specializing in rheumatic diseases.
Note that what is being argued for here is a
process for finding and testing medications known as Real World Experience(RWE).
In
the midst of an epidemic during its exponential growth phase, RWE's might be
the best approach to take rather than RCT's for finding treatments.
Randomized Controlled
Trials(RCT's) commonly take 3 months or more to complete, and then there still
can be complaints it didn't have enough study participants to form firm
conclusions. Here I'm arguing for RWE's, but conducted nationwide.
An advantage of RCT's is their randomized
nature allows confounding factors to be accounted for. But RWE's conducted
nationwide can accomplish the same thing because of the large number of cases
and circumstances of the studies.
Indeed several authors have argued for these
reasons for RWE's:
May
11, 2018,12:25am EDT
Will
Real World Performance Replace RCTs As Healthcare's Most Important Standard?
The
Beneficial Impacts of Real-World Evidence in Drug Development
Posted
on August 1st, 2019 by Xuanyan Xu in Pharma R&D
Real-world evidence, which is based on
data that is gathered during routine clinical practice, has the potential to
make a meaningful impact in nearly every phase of the life of a drug. That
means RWE is relevant to:
Early discovery – “RWE has the potential
to be used early in drug discovery and development programs, facilitating
product development by identifying diseases or indications that represent a
significant burden in populations,” explains this paper on real-world evidence,
also noting the example of the NIH using electronic health records to support
differentiation of patients’ needs.
Version 2. F1000Res. 2018; 7: 111. Published online 2018 Aug 29. doi:
10.12688/f1000research.13585.2 Real world evidence (RWE) - a disruptive innovation or the
quiet evolution of medical evidence generation? Sajan Khosla 1, Robert White 2, Jesús Medina 3, Mario Ouwens
4, Cathy Emmas 5, Tim Koder 6, Gary Male 6, Sandra Leonard 2 PMID: 30026923 PMCID: PMC6039945 DOI:
10.12688/f1000research.13585.2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039945/
Note with doctors nationwide using their own judgement and
experience about which medications to use, we would have orders of magnitude
greater insight about which medications could be effective rather than just
restricting to a few doctors on a few teams conducting RCT’s.
Doctors whose expertise is in rheumatic diseases for example could prescribe HCQ. They would be intimately familiar with its side effects and would know what to look for. And doctors for example who routinely prescribe interferon would know its side effects and contraindications. This way you could have a maximal safety approach while allowing a wide variety of different medications to be tested at the same time.
There are about a
million doctors in the U.S. Imagine all that knowledge, all that experience,
all that creativity, all being brought to bear in toto in finding effective
treatments for this, and other diseases as well. Furthermore, imagine this all
happening in real time, critically
important in the midst of a pandemic.
It is notable then
there have been antivirals found effective in trials for early treatment. One is interferon:
International Journal of Infectious Diseases. November 16, 2020 Efficacy and Safety of Favipiravir, an Oral RNA-Dependent
RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized,
Comparative, Open-Label, Multicenter, Phase 3Clinical Trial Zarir F.Udwadiaa, et.al. https://www.sciencedirect.com/science/article/pii/S120197122032453X
It is notable, and unfortunate, that these
successful trials showing effective antiviral use when used early occurred in trials overseas.
Even more dismaying is that there
were published reports early on in the timeline of the disease in the U.S. that
showed early treatment was effective
using antivirals, such as this report from May from China:
ARTICLES| VOLUME 395, ISSUE 10238,
P1695-1704, MAY 30, 2020 Triple combination of interferon
beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients
admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial Prof Ivan Fan-Ngai Hung, MD et al. Published:May 08, 2020 https://doi.org/10.1016/S0140-6736(20)31042-4
Most of these reports were from Asian
countries, but that's hardly a reason to disregard their validity. It is truly
puzzling that these successful results on early
treatment in Asia were not followed up upon with American and European studies
also on early treatment. Instead,
mystifyingly, the studies taken up in the West using these antivirals were for
patients under late stages of the disease,
where it was already known antivirals were not likely to be effective.
Anti-inflammatories for serious disease.
Some anti-inflammatories have shown to be effective
for patients that need oxygen such as those on ventilators, including
dexamethasone and tocilizumab. But the reduction in lung inflammation can be
measured in real time by detecting
markers such as IL-6 and CRP and even in CT scans. Then the effectiveness of
these anti-inflammatories can also be observed on short time scales. See the
discussion in the update dated from 6/26/2020 here:
Research Paper Published: 15 May 2020 Low dose of hydroxychloroquine reduces fatality of
critically ill patients with COVID-19. Bo Yu, Chenze Li, Peng Chen, Ning Zhou, Luyun Wang, Jia Li,
Hualiang Jiang & Dao-Wen Wang Science China Life Sciences (2020) Abstract ... These data
demonstrate that addition of HCQ on top of the basic treatments is highly
effective in reducing the fatality of critically ill patients of COVID-19
through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for
critically ill COVID-19 patients, with possible outcome of saving lives. hydroxychloroquine, IL-6, mortalities, COVID-19 https://link.springer.com/article/10.1007/s11427-020-1732-2
Quite notably the
authors observed in real time a
reduction in the level of IL-6, a key marker for inflammation, during the
treatment with HCQ. So from both CT imaging and inflammation marker readings we
could tell if HCQ or other anti-inflammatories were having a beneficial effect
on patients under severe disease.
It is important to
understand the reason why it was that several studies from Asian countries
showed positive effects for HCQ while several studies in the Western countries
did not.
After we examined several of the negative reports on HCQ
published on Western studies, we observed multiple times that the effectiveness
ofHCQ was obscured in the presentation
of their data. We will offer no hypotheses as to the reasons why its
effectiveness was obscured in the reports on the Western studies.
For example, two of the most widely-cited negative HCQ
reports by Geleris et al. and Rosenberg et al. omitted from the conclusions
that the data showed HCQ cut mortality in half for ventilated patients. Adverse
events for a medication must be reported, and this has been done extensively
for HCQ. But by the same token, subcases with benefit for the medication should
also be reported.
The report by Geleris et. al. here:
Observational
Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.
June 18,
2020
Editor’s
Note: This article was published on May 7, 2020, at NEJM.org.
You see the mortality in the HCQ group for
intubated patients, i.e., those on invasive mechanical ventilation, was 49/154
= .318, or 31.8%. But the mortality for intubated patients for the non-HCQ
group was 17/26 = .654, or 65.4%. So the mortality was halved in the HCQ group
for intubated patients.
Actually, it may even be better than this. As
an observational trial, the treated patients are likely not evenly distributed
among patients with different comorbidities or with level of disease compared
to the controls. Quite often the treatments are given to the sicker patients.
Then usually in such observational studies as in this one statistical
adjustments have to be made to compensate for the fact the sicker patients were
given the medication which would skew the results against the treated group.
But in the Table S1 this appears to be just
the raw data. Then after the statistical adjustments for HCQ being given to the
sicker patients the mortality benefit for HCQ over the controls for ventilated
patients might be even higher.
The Rosenberg et. al.
paper is here:
May 11, 2020 Association of Treatment With Hydroxychloroquine or
Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York
State Eli S. Rosenberg, PhD1; Elizabeth M. Dufort, MD2; Tomoko
Udo, PhD1; et al JAMA. 2020;323(24):2493-2502. doi:10.1001/jama.2020.8630 https://jamanetwork.com/journals/jama/fullarticle/2766117
The table showing the
mortality specifically for ventilated patients from the supplementary file here:
You see HCQ used alone reduced mortality
specifically for ventilated patients by a factor of 0.60 and HCQ used with AZT
by a factor of 0.53.But once again this
appeared not in the paper itself but only in a supplementary file.
It's dismaying
that this data wasn't discussed among the conclusions the authors made in their
articles. First of all appearing only in the supplementary files, not in the
articles proper, very few people would have taken the time to find and read
these tables, certainly not the science journalists reporting on the research
and not even most doctors disseminating this information to the public at large
and to the policy makers making decisions on use of HCQ.
But what's
really dismaying is both of these took place in New York. In New York at the
time the mortality for patients on ventilators was in the range of 80%:
Doctors were desperate to find a treatment to
help save ventilated patients lives, but the effectiveness of HCQ for those on
ventilators was not made apparent to them.
The usefulness of HCQ for those on mechanical
ventilation would have been even more apparent because of that report appearing
in a Chinese journal that we cited above by Bo Yu et al., "Low dose of hydroxychloroquine
reduces fatality of critically ill patients with COVID-19".
That report showed mortality cut by 60% for ventilated patients taking HCQ. But with
the two widely cited American papers making a blanket statement of "no
benefit", this Chinese report barely registered.
It's possible the authors and/or reviewers
and/or editors calculated the significance levels and decided they didn't rise
to the standard significance level of 0.05. If they did calculate the
significance levels then they should have been reported in the papers. But in
any case, all medical researchers are aware of the fact that a result not
rising to statistical significance level does not mean the result is wrong. It could also simply mean the sample size
wasn't large enough for it to rise to statistical significance.
All too often
this qualifier is left out of reports on medical studies, and it is certainly
left out on news reports on the studies. Then the public and other doctors are
simply left with the incorrect conclusion that the treatment has been proven not to work.
With a
difference this large of the deaths being cut in half for those on ventilators,
the significance levels should have been reported in the papers. And it should
have been acknowledged in the papers if the significance level wasn't at the
standard level of 0.05 for the sample size used, that larger studies would be
needed to determine if the result was real or just a statistical artifact.
As we mentioned, studies have shown multiple
different anti-inflammatories such as steroids can be beneficial for COVID-19.
Indeed this happened with dexamethasone in the RECOVERY trial, among others. It
is simply unreasonable then to suppose HCQ as a very effective
anti-inflammatory is not. It’s probably the reason so many HCQ studies,
including ones claiming “no benefit”, did
show benefit.
An astonishing instance of this occurred in
the RECOVERY trial. The RECOVERY trial was a randomized-controlled trial (RCT),
which are called the "gold-standard" of medical studies. Because it
was negative towards HCQ, it was frequently cited as evidence of HCQ having no
effect.
RCT's aren't perfect of course. There can be
flaws in interpreting the data, there may not be sufficient numbers of subjects
to draw a strong conclusion. They can use the wrong dosage, etc. And
unfortunately there can also be cases where researchers falsify data.
We do not consider this last possibility
likely to be the case with the RECOVERY trial. However, what we found did
happen in the RECOVERY trial was nearly as bad in regards to accurately assessing the effectiveness of HCQ: while
the data presented was correct, the way it was presented obscured the HCQ
effectiveness.
Here's the HCQ report from the RECOVERY trial:
Editor’s Note: This
article was published on October 8, 2020, at NEJM.org. ORIGINAL ARTICLE Effect of Hydroxychloroquine
in Hospitalized Patients with Covid-19 The RECOVERY
Collaborative Group November 19, 2020 N Engl J Med 2020;
383:2030-2040 DOI:
10.1056/NEJMoa2022926 https://www.nejm.org/doi/full/10.1056/NEJMoa2022926
Here's the
relevant table:
You see
instead of deaths on mechanical ventilation being given directly, it is
combined with all deaths into one category. This is called a "composite
endpoint" or "composite outcome". So, we need to do the
calculation to find the proportion of the ventilated patients who died on HCQ
and then calculate the proportion for those not on HCQ who died, since these
are not given directly. Use the formula for counting the number of elements in
the union of two sets with possible overlap:
which simply means you add together the number in each
set, then subtract off the number in the overlap.
What's given in
the report is the union of the two
sets of the ventilated and of the deaths. But what we want is the intersection, those who were ventilated
that died. So we'll turn around that formula for the number in the union to get
the number in the intersection as, | A ⋂ B | = |A| +
|B| - | A ⋃ B |.
So in this
case, |ventilated ⋂ deaths|= |ventilated| + |deaths| - |ventilated ⋃ deaths|. First look at the cases
on HCQ. From Table 2, for those on
HCQ,|ventilated⋂deaths| = |ventilated| + |deaths| - |ventilated ⋃ deaths|
=128+311- 399 = 40. So on HCQ, the rate of deaths on ventilator 40/128 = 0.312,
31.2%.
Now calculate
it for the non-HCQ group, i.e., the usual care group. The numbers appear in the
"Usual care" column in the table. So in this case, |ventilated ⋂ deaths|= |ventilated| + |deaths| - |ventilated ⋃ deaths|. First look at the cases
on HCQ. From Table 2, for those
HCQ,|ventilated⋂deaths| = |ventilated| + |deaths| - |ventilated ⋃ deaths| =
225 + 574 - 705 =94, so the rate of deaths on ventilator is 94/225 = 0.417, or 41.7%. This difference between the number of
ventilated patients on HCQ who died of 32.2%
and those not on HCQ who died of 42.3% is large enough that it should have been
reported.
The RECOVERY
trial made headlines world-wide when it sent out a news release on the
"breakthrough" that the steroid dexamethasone could cut mortality for
ventilated patients by 30%.
In the Results section the mortality for
ventilated patients on dexamethasone is given as 29.3%, while for those not on
dexamethasone it's given as 41.4%. Note these numbers are quite close to those
for HCQ. Yet the RECOVERY trial described HCQ as offering "no
benefit" while dexamethasone was described as a "breakthrough".
Note that all of the Geleris et al., Rosenberg
et al., and the RECOVERY trials could legitimately report that overall there was no statistical
difference by using HCQ. But this was because for the important subcase of
ventilated patients, their numbers were a small proportion of the total number
of cases. However, the large difference using HCQ for that key subcase of ventilated
patients should have been reported.
Another
instance where positive effects of HCQ were obscured was in a paper by Tang et
al. In this case though the positive effects weren't just obscured, they were actually deleted:
Research Hydroxychloroquine in patients with mainly
mild to moderate coronavirus disease 2019: open label, randomised controlled
trial BMJ 2020; 369 doi:
https://doi.org/10.1136/bmj.m1849 (Published 14 May 2020) https://www.bmj.com/content/369/bmj.m1849
Tang
et al. is regarded as a negative HCQ paper, but deleted from the published
version was this passage in the preprint:
Title: Hydroxychloroquine in patients with
COVID-19: an open-label, randomized, controlled trial. "In
addition to virus infection, acute inflammation response is another hallmark of
COVID-19.19 Recent
findings in clinical series have shown that the systemic inflammation or
cytokine storm is the
driver of disease progression and death.20,21 Substantially decrease of
lymphocyte count and increase of inflammatory response marker, e.g., CRP were
both observed in the early stage of patients who eventually progressed and
died.21 These results highlighted the importance of the recovery of lymphopenia
or anti-inflammation in preventing the development of systemic inflammation
in critically ill COVID-19 patients. Such abilities and benefits were observed
from HCQ
in our current trial, showing that patients with SOC plus HCQ had a
significantly greater reduction
of CRP level and a moderate elevation of blood lymphocyte count at the last
assessment comparing to patients with SOC only. These effects were observed
after 5-day of HCQ treatment and maintained until the withdraw of HCQ. These encouraging results suggested clinical
benefits of adding HCQ into the current standard management to limit
inflammatory response, which is the key to prevent systemic inflammation and
subsequent multiple organ failure and death." https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1.full.pdf
The
extensive list of benefits of HCQ seen by the Tang et al. research group, that
were deleted from the published report was discussed by Dr. Didier Raoult here:
It is
extremely unfortunate these details were deleted from the final report. Note
this study appeared around the same time as the Geleris et al. and Rosenberg et
al. reports in May. Since it shows HCQ effectiveness as an anti-inflammatory,
if the Tang published report and the two
Geleris and Rosengberg published reports had revealed these positive effects of
HCQ, then coupled with the positive results of the Bo Yu et al. report, doctors
would have had an effective treatment approach to ventilated patients.
Some
Western doctors and researchers may choose to believe the Western studies
rather than the Asian studies. But given the fact the death rates in the Asian
countries are 1/100th those in the West, I would not be so sanguine about that
choice.
As with the antivirals, the Real World Experience
approach should be used, with nearby hospitals testing different anti-inflammatories
so the comparisons can be made to their effectiveness without confounding
factors. And as with the antivirals the comparisons among the various hospitals
should be done in real time. And also as with the antivirals the effectiveness
of the anti-inflammatories might be seen within days by looking in real-time
the presence of the inflammation markers such as IL-6 and CRP, and at the CT
scans. The importance of the CT scans is that the improvement in the degree of
lung inflammation can literally be seen
by the doctors as the treatment progresses:
CT Provides Best Diagnosis for Novel Coronavirus (COVID-19) CT scans can detect coronavirus in patients before RT-PCR
lab testing NEWS | COMPUTED TOMOGRAPHY (CT) | FEBRUARY 26, 2020 |
MELINDA TASCHETTA-MILLANE AND DAVE FORNELL In a study of more than 1,000 patients published in the
journal Radiology, chest CT outperformed lab testing in the diagnosis of 2019
novel coronavirus disease (COVID-19)
Chest CT images of a 29-year-old man
with fever for 6 days. RT-PCR assay for the SARS-CoV-2 using a swab sample was
performed on Feb. 5, 2020, with a positive result. (A column) Normal chest CT
with axial and coronal planes was obtained at the onset. (B column) Chest CT
with axial and coronal planes shows minimal ground-glass opacities in the
bilateral lower lung lobes (yellow arrows). (C column) Chest CT with axial and
coronal planes shows increased ground-glass opacities (yellow arrowheads). (D
column) Chest CT with axial and coronal planes shows the progression of
pneumonia with mixed ground-glass opacities and linear opacities in the
subpleural area. (E column) Chest CT with axial and coronal planes shows the
absorption of both ground-glass opacities and organizing pneumonia. Image
courtesy of Radiology https://www.itnonline.com/content/ct-provides-best-diagnosis-novel-coronavirus-covid-19
Research | Open Access |
Published: 12 August 2020 Rapid identification of
COVID-19 severity in CT scans through classification of deep features. Zekuan Yu, Xiaohu Li,
Haitao Sun, Jian Wang, Tongtong Zhao, Hongyi Chen, Yichuan Ma, Shujin Zhu &
Zongyu Xie BioMedical Engineering
OnLine volume 19, Article number: 63 (2020) https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-020-00807-x
The observational
difference in the appearance of coronavirus inflamed areas of the lung are made
apparent in this 3DCT scan:
CT scan shows damaged tissue from a covid-19 patient's lungs.
Apr 1, 2020
CT scans however use much more radiation than usual X-rays. Since this approach would require taking frequent CT scans of patients, methods of using reduced radiation as by Dr. Marcus Chen, may be preferred:
NHLBI Bethesda Labs @TheBethesdaLabs Dr. Marcus Chen's research involves making #CT scans safer by reducing the amount of radiation by over 90%. This chest CT shows a stunning view of a #COVID19 patient's lungs. The yellow areas represent normal lung tissue, while the blue areas are damaged tissue. #ImageOfTheWeek
