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Effectiveness of hydroxychloroquine was

hiding in plain sight
By World Tribune on September 21, 2020

FPI / September 21, 2020

Analysis by R. Clinton Ohlers

During the past several weeks, major studies have claimed the drug hydroxychloroquine had
no effect on COVID-19 patients. Some even claimed it was harmful.

However, major studies out of New York, Spain, Switzerland, Michigan, Belgium and
elsewhere have provided compelling evidence that the drug, particularly in combination with
azithromycin and zinc, has been saving lives all along.

Perhaps most
surprising among these is a pivotal study that appeared in the Journal of the American
Medical Association (JAMA) online on May 11. It reported finding no evidence of the drug’s
having any positive effect on patients who were treated in New York during the early weeks
of the outbreak.
In reality, however, the study’s data actually confirms the positive findings of these recent,
thoroughgoing international studies that are reporting on hydroxychloroquine’s dramatic
effectiveness. It even affirms their precise statistics.

When the JAMA study’s data is re-analyzed in a manner congruent with recommended
treatment, that data demonstrates that hydroxychloroquine significantly and dramatically
improved patient survival during the early and chaotic weeks of the pandemic in New York.
Survival rates for hospitalized patients who received the drug approached 85%. When
hydroxychloroquine was combined with azithromycin the survival rate rose as high as 90%.
However, when hospitalized patients received neither drug, their survival fell to levels as low
as 53%.

The corresponding author of the JAMA study has not yet responded to requests for comment.

The author, Eli S. Rosenberg, PhD, is at the Department of Epidemiology and Biostatistics,
University at Albany School of Public Health in Albany, New York.

Rosenberg’s webpage at the University of Albany states: “Since March 2020, Rosenberg has
been providing technical assistance to the New York State Department of Health COVID-19
response across a broad portfolio of studies aimed at understanding critical aspects of SARS-
CoV-2 transmission, surveillance, and treatment.”

When historians revisit the early days of the pandemic in the United States, they will record
the importance of the May 11 JAMA study as the tipping-point study that effectively
terminated interest in hydroxychloroquine as a potential therapy in the larger medical
research community. It was this study that President Donald Trump looked to in mid-March
to confirm hopes for hydroxychloroquine as a sound therapy against COVID-19.

Instead, its authors asserted precisely the opposite.

They reported no significant difference in survival rates among patients who received
hydroxychloroquine, whether alone or in combination with azithromycin, versus those who
did not receive the drugs.

The impact was immediate.

No less a figure than Vanderbilt University Medical School’s Dr. William Schaffner, an
advisor to the CDC and a leader in the field of infectious diseases, announced on CNN, “the
nail has virtually been put in the coffin of hydroxychloroquine.” Schaffner previously had
been hopeful about the drug. A general consensus against hydroxychloroquine followed both
in the United States and internationally.

This consensus was further solidified by negative assessments in the Lancet (later retracted),
by the World Health Organization, and Oxford’s Center for Evidence Based Medicine.
Death rates in Switzerland when hydroxychloroquine was banned, then reinstated, in
response to Lancet study’s publication and then retraction. / Source: Dr. Stephen Hill, The
Federalist

Just how the same data in a single study may produce such diametrically opposed evidence is
the story that follows.

Any study on hydroxychloroquine coming out of New York in the early weeks of the
pandemic would have faced a daunting challenge. The reason has to do with how patients in
the state were treated under the guidelines laid out by Dr. Anthony Fauci, the FDA, and
Governor Andrew Cuomo’s executive order of March 23. Hydroxychloroquine was to be
administered only to those already hospitalized as part of a clinical trial or as “compassionate
care” for the most severely ill. Therefore, patients treated with hydroxychloroquine were
generally well advanced in the progress of the disease or were among the most severely ill,
the most aged, and possessing the most comorbidities, such as diabetes, obesity, or heart
disease.

Not surprisingly, death rates among patients who received the drug were actually much
higher than for those who did not. Among the hydroxychloroquine + azithromycin group, the
death rate was 25.7%. For those receiving only hydroxychloroquine, the death rate was
19.9%. For those given neither drug, it was 12.7%. Those, however, are unadjusted death
rates.

How a study of this kind handles such disparities has to do with very powerful and effective
statistical tools. Cox adjusted modeling, for example, helped correct for differences among
patient groups such as age, sex, and greater numbers of comorbidities. Calculating standard
deviations enabled researchers to determine how much difference between groups simply
might be the result of chance or factors other than whether or not the drug worked.
In medicine, the threshold at which the effectiveness of a drug is considered significant, all
else being equal, begins at two standard deviations. If the differences were to rise as high as
three standard deviations, the efficacy of the drug would be very strongly confirmed.

An analogy here is a coin toss. If two players flip a coin, how does the losing player know
something else has not affected the outcome, such as the coin being weighted? The losing
player might demand that the coin be tossed 300 times and note the numbers of heads versus
the number of tails. Ideally, the ratio would be 50/50. However, in only 300 tosses, that ideal
is unlikely to be achieved exactly. One might easily get more than 150 heads. Nonetheless,
the results can still render a conclusion. By calculating the percentage of heads to tails against
the number of tosses one can test the outcome against the normal plausible range of results.
In medicine, that range is two standard deviations or less.

Presumably, the Cox adjusted modeling and standard deviations accounted sufficiently for
the significant differences in base-line health and severity of illness, bringing the authors to
the conclusion that hydroxychloroquine had no discernible effect.

An initial concern arises when one examines just how much more severely ill or
compromised the hydroxychloroquine patients were, compared with the control group.
Among those receiving the drug in combination with azithromycin, for example, 30.7%
entered the intensive care unit (ICU) at some point in their stay. Less than half, only 12.2%,
of patients given no drugs did so.

This suggests a rate of greater severity of illness of 2.5x. By contrast the rate of death of the
paired-drug group was only 2x that of the control. In other words, a group that had 2.5x the
rate of severely ill patients had only 2x the rate of death, but was somehow brought to parity
using a statistical tool designed to account for that group’s greater (not lesser) incidence of
comorbidities. On the surface, at least, this would appear to imply the drug had imparted
some benefit.

The first major red flag appears when the authors discuss the study’s limitations. They
explain that “the rapidity with which patients entered the ICU and underwent mechanical
ventilation, often concurrently with initiating hydroxychloroquine and azithromycin, rendered
these outcomes unsuitable for efficacy analyses.”

Nevertheless, these “unsuitable” patients were included in the study as it attempted to analyze
efficacy. No attempt to understand how their presence might adversely influence the study’s
conclusions was presented.

This disclosure is profound for several reasons. The first of these has to do with how anti-
viral drugs function.

By mid-March, proponents of hydroxychloroquine universally agreed that for the drug to be

effective it had to be administered very soon after the first onset of symptoms. This was true
of the doctors in Wuhan and Shanghai, such as Dr. George F. Gao, Director General of the
Chinese Center for Disease Control and Prevention and his colleagues who pioneered the
treatment, those in Costa Rica such as Dr. Mario Ruiz, Director of the Caja Costarricense de
Seguro Social, and his colleagues, who adopted their advice, Dr. Didier Raoult, Director of
the Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes at Aix-
Marseille University, and his colleagues in France, and Dr. Vladimir Zelenko in New York,
who later teamed with doctors in Germany, as well as many other physicians in the United
States.

In his White House press briefing on March 19, FDA Chairman Dr. Stephen Hahn could
hardly have stated more clearly what was needed to discover a real treatment for COVID-19:

“We need to make sure that the sea of new treatments will get the right drug to the right
patient at the right dosage at the right time.”

With antiviral therapies early treatment is important. The best known example of this is the
over-the-counter drug Abreva. Cold sore sufferers are instructed to apply Abreva as soon as
they sense a tingling, before a cold sore actually appears and the virus has achieved its florid
state. A further reason for early treatment in COVID-19 is to win the race against the
cytokine storm that emerges in response to the virus, when the immune system actually
attacks the patient’s own cells. This is why proponents of the drug universally recommended
its use early, before hospitalization, rather than late when hospitalization is required.

Dr. Steven Hatfill, a veteran epidemiologist who teaches mass casualty medicine at the
George Washington University Medical Center, identifies this as an ideal “seven-day
window” after the onset of first symptoms. This window had been well identified by April.

In late May, after this study appeared, Yale epidemiologist Dr. Harvey Risch wrote with deep
concern in the American Journal of Epidemiology, emphasizing the importance of early
treatment, which major studies like this one had overlooked:

“Early outpatient [COVID-19] illness is very different than later hospitalized florid disease
and the treatments differ,” he warned.

Early outpatient community treatment with hydroxychloroquine compared with late/none.

By analogy, to study the effectiveness of an antiviral medication like hydroxychloroquine by
assessing patients treated so late that they were already in the ICU would be like testing the
effectiveness of air bags by looking at cases where the air bag had only deployed after the
driver made impact with the steering wheel or was thrown through the windshield.

At the same time, one of the most interesting elements of the studies out of Europe has been
the effectiveness of hydroxychloroquine among patients who were already hospitalized and
which also appears when the data of the JAMA study is reanalyzed. Apparently, what appears
to be occurring with hydroxychloroquine, particularly when it is given with azithromycin
(and even more so with zinc) is that the ideal time to initiate treatment is that seven-day
window. After that point benefits still occur, but appear increasingly to decline the later in the
progress of the disease that the drug therapy is begun. Where the cut-off area occurs, that
zone within the progression of the disease that the window of opportunity closes, is an open
question for science to address in the future.

For our purposes of analysis here, it is enough simply to assume the same cut-off that the
authors of the JAMA study noted as too late to be suitable for efficacy: when a patient has
already entered the ICU before or at the same time as starting treatment.

The second reason the red flag is so significant has to do with the sizable number of the
unsuitable cases.
Patients who received hydroxychloroquine +azithromycin represent the largest group in the
study. Of them, 17.1% were transferred to ICU in less than one day. That number is equal to
66.5% of the paired-drug group’s death rate.

This is particularly troubling because other data in the report indicates that mortality among
those rapidly transferred to ICU was also extremely high. Possibly approaching 100%, for
example, in the no-drug control group. In such a scenario, these unsuitable cases contributed
as much as 66.5% of the deaths in that group.

A third reason the red flag is so profound is that it is reasonable to believe this large number
of unsuitable patients were placed in the wrong test group.

It is reasonable to view such late treatment as equal to receiving no drug at all. That is, in
essence, what doctors from Wuhan and Shanghai reported when in March they shared their
frontline treatment recommendations with doctors in Costa Rica. If such late treatment is
equivalent to no treatment at all, then these patients may have belonged in the no-drug control
group, not in the hydroxychloroquine test groups.

To use the airbag analogy, the purpose of the study was to determine whether the airbag
(hydroxychloroquine) had the capability of cushioning passengers from fatal impact. The
unsuitable cases are equivalent to passengers who received no airbag protection because the
airbag was not deployed, not because airbags that did deploy had no effect.

To include in the analysis passengers for whom the airbag was deployed only after the crash
occurred does much more than merely muddy the results. It actually lessens the appearance
of the risk of driving without an air bag. It does so at the very same time that it attributes an
increased number of lethal crashes to airbags.

Alternatively, researchers might remove these unsuitable cases from consideration altogether.
However, that would also distort the data. That too would make it appear that crashes without
airbags resulted in death less often than actually occurred.

Given that this scenario comprises such a large portion of the JAMA study, the inclusion of
rapid ICU transfers in the hydroxychloroquine group drastically inclined the study’s
conclusion toward a negative assessment.

It is fair to ask, then, what happens to the data when these patients are instead included where
arguably they belong, in the no-drug control group. This is not the only way to view this data,
rather it is a highly relevant and necessary one.

Doing so could also improve the integrity of the data. The authors report that the study’s final
sampling included fewer patients in the no-drug group than the authors originally intended
for their proposed ratio. Such a transfer moves the treated to non-treated ratio closer to the
original proposal. Doing so may also distribute more evenly patients with severe illness and
comorbidities between the two groups. One risk, of course, is that if the drugs were
beneficial, death rates among the no-drug group would be artificially lowered. However, if
hydroxychloroquine truly provides no benefit, as the authors report, then no such concern
exists.
What happens when this transfer is made? The unadjusted death rates favor the effectiveness
of the paired drugs to a stunning degree.

The realistic death rate for patients receiving hydroxychloroquine + azithromycin drops as
low as 10.3%. By contrast, the death rate among the control group rises as high as 44.4%.
That is a difference of up to 77% lower mortality when hydroxychloroquine and
azithromycin were taken together. This increase is significant: the difference between the
outcomes with and without treatment stands at 12 standard deviations.

A study from Spain published on July 29 examined 9,644 patients who received only
hydroxychloroquine showed similar results. That study found “no serious side effects,” and
when adjusted odds ratios were applied, it “shows a 66 percent reduction in COVID mortality
in patients taking hydroxychloroquine.”

Therefore, one might expect that application of adjusted odds ratios, to account for
comorbidities in the JAMA study, could demonstrate greater results for hydroxychloroquine
+ azithromycin, as occurred in the Spanish study.

Without access to the study’s raw data, the actual death rates among patients who rapidly
transferred to the ICU can only be approximated. However, even when tested against
significantly lower rates of death than those suggested by the published data, the results
remain significant. When the actual death rates that future, detailed re-examinations of the
study’s data may render, the evidence of significant effect will hold and will continue to
affirm the Spanish study.

As a note to future researchers who may pursue this question, it is important to point out that
the May 11 JAMA study tracked patient outcomes more comprehensively than did an earlier
JAMA study published on April 24. That earlier study made a projection concerning death
rates among ventilated patients. However, the May 11 study demonstrates that those
projections did not bear out.

What about the results among patients in the JAMA study who received only
hydroxychloroquine?

The unsuitable cases here comprised 8.1% of the group. When transferred, the
hydroxychloroquine death rate falls as low as 12.9% compared with 20.6% for the no-drug
group. These results also meet the threshold of significance at 2.85 standard deviations.
These numbers are similar to the unadjusted death rates of 14.7% and 29.2% in the Spanish
study. They are also of larger importance.

On August 24, a group of Belgian researchers published a nationwide study in the

International Journal of Antimicrobial Agents. It included 8075 patients, compared with 1482
in the JAMA study, and was also a randomized retrospective observational study. The
Belgian team examined hydroxychloroquine alone versus treatment without the drug.
Importantly, they studied patients across the vast majority of Belgian hospitals in order to
compare like groups of patients with similar levels of comorbidities and other risk factors.

The Belgian team reported a rate of death among patients who received hydroxychloroquine
in the hospital as 17.7% versus 27.1% for those who did not. When compared, the results of
the Belgian study are virtually identical to those found in this reanalysis.
These numbers also support the findings of a Henry Ford Health System study of 2541
patients that was released on July 2. That study found a death rate of only 13% for patients
treated with hydroxychloroquine alone, compared with 26.4% among patients not treated
with the drug. The Henry Ford rates also support the Belgian study and are virtually identical
to those of the Spanish study.

The most dramatic effect is found when all patients in the JAMA study receiving
hydroxychloroquine, whether with or without azithromycin, are considered once the
unsuitable cases are transferred. These results demonstrate a rate of death as low as 11%
versus 47.7% in the no-drug group. This difference was confirmed well above three standard
deviations.

These results far exceed those of the Belgian study. With mortality approaching less than
one-quarter the mortality of the no-drug group, the JAMA study’s data further demonstrates
the enormous advantage of adding azithromycin to hydroxychloroquine—something
proponents of the drug asserted in March.

One more finding remains.

Here benefit of hydroxychloroquine + azithromycin is revealed by examining survival rates

among patients transferred to the ICU and also their length of stay in the hospital. Although
these data do not contain enough detail to allow analysis by transferring out the unsuitable
cases, they are revealing nonetheless. In other words, in spite of the distortion created by
including those severely ill patients “unsuitable for efficacy analyses” there was still evidence
hydroxychloroquine + azithromycin had a significant effect.
The signal still broke through the noise if one knows where to look.

In a hospital setting, most patients who die of COVID-19 do so only after first transferring to
the ICU. A small number may expire too quickly, unexpectedly, or en route to ICU.
Therefore, comparing death rates to ICU transfer rates can be telling, as can the length of the
hospital stay of patients who nonetheless died.

Only patients treated with hydroxychloroquine and azithromycin showed any improved rate
of survival when compared with the number who transferred to ICU. Among patients
receiving no drugs, for example, the number who required transfer to the ICU was 12.2%.
The death rate for the no-drug group was 12.7%. This indicates that a small number of
patients died outside of ICU and that scant few survived after entering ICU. By contrast,
among hydroxychloroquine + azithromycin patients 30.7% entered ICU and only 25.7% of
the total group died. That is a 16.4% greater rate of survival compared against ICU transfer,
in spite of the inclusion of the most severely ill in the calculations.

When tested for statistical significance, that number shows 6 standard deviations. Even if
using a hypothetical death rate of only 90% among ICU patients treated without the drug
combination, significance is still demonstrated at 2.3 standard deviations.

Not surprisingly then, the study also shows that among hydroxychloroquine + azithromycin
patients who did die, their length of stay in hospital was longer, congruent with lengthening
of survival. One recalls, for example, the cause of interest in Remdesivir, even when that
drug failed to produce any improvement in survival—Remdesivir shortened the hospital stays
of patients.

These findings should be a source of hope.

It now appears that the disregard of hydroxychloroquine that followed the JAMA publication
was gravely premature. Although the authors’ own conclusions about the drug were negative,
their data actually contains potent indicators of the drug’s effectiveness, even when
administered under far less than ideal circumstances.

Even more importantly, when that data is re-examined in scenarios that better approximate
how proponents have asserted the drug should be administered, the numbers fall directly in
line with the major studies performed in locales as diverse as Michigan, New York, France,
Spain, and most recently Belgium.

These findings provide further important evidence that a highly effective, inexpensive, and
widely available treatment for COVID-19 is already in hand. It should provide needed
impetus to get these valuable drugs to those currently ill with the disease as rapidly as
possible.

[List of JAMA authors: Eli S. Rosenberg, PhD; Elizabeth M. Dufort, MD; Tomoko Udo,
PhD; Larissa A. Wilberschied, MS; Jessica Kumar, DO; James Tesoriero, PhD;
PattiWeinberg, PA; James Kirkwood, MPH; Alison Muse, MPH; Jack DeHovitz, MD; Debra
S. Blog, MD; Brad Hutton, MPH; David R. Holtgrave, PhD; Howard A. Zucker, MD.]
[Special thanks to Dr. Mike Brownnutt, Associate Director of the Faith and Science
Collaborative Research Forum at the University of Hong Kong (PhD, Physics, Imperial
College London), for his valuable help with statistical calculations and critique. Special
thanks also to Dr. Chis Martenson (PhD, Pathology, Duke) whose scientific reporting on
COVID-19 since the beginning of the outbreak motivated this reanalysis. Thanks also to two
MDs who provided valuable consultation and insight.]

R. Clinton Ohlers, PhD is a historian of science and religion and a contributing editor for
the FreePressMediaGroup. Previously, he held the position of Research Assistant Professor
in the Humanities at the University of Hong Kong. His book, The Birth of the Conflict
Between Science and Religion, is scheduled to appear in 2021. He received his PhD in
history from the University of Pennsylvania.