Medical science, hydroxychloroquine and the mainstream media

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Prior to the year 2020, hydroxychloroquine (HCQ) was an uncontroversial treatment for malaria, lupus, rheumatoid arthritis, and porphyria cutanea tarda. Then COVID-19 became a concern and Donald Trump decided to promote HCQ as a possible cure. Ever since, views on its effectiveness have been politicized without much regard to the underlying science. While you might know it if your only source of news is the mainstream media, a handful of studies have emerged that suggest Trump was right... HCQ works (see also: Vladimir Zelenko's coronavirus treatment).

What is Hydroxychloroquine?

HCQ is one of a group of drugs related to quinine, a natural compound found in the bark of the Cinchona tree. In 1632, Spanish Jesuit missionaries 'discovered' quinine as a malarial treatment, though it was probably used by the indigenous Peruvian cultures well before then. Precisely how the quinine group of drugs are able to combat malaria hasn't been fully resolved, but the prevailing theory for chloroquine is that the drug kills the parasite by interfering with its digestive process. When the parasite that causes malaria enters the body, it begins to eat hemoglobin. Normally, the parasite digests most of the protein and discards hemoglobin's heme unit by biocrystallizing it into a nontoxic and insoluble molecule called hemozoin. Chloroquine disrupts this process by accumulating in the parasite's food vacuole and binding with the heme unit to form the highly toxic FP-chloroquine complex. FP-chloroquine then kills the parasite.[1]

Hydroxychloroquine and chloroquine are highly similar (they only differ by one oxygen atom), but hydroxychloroquine has the advantage of being less toxic which is why it is more extensively studied as a treatment option for diseases.[2] Like its cousin chloroquine, HCQ is highly effective against malaria. However, in order for it to be effective against SARS-CoV-2, HCQ must also possess anti-viral properties as SARS-CoV-2 is a virus and not a parasite. An article published in 2003 by Savarino postulated that HCQ was able to have an antiviral effect by increasing intracellular ph which results in "decreased phago-lysosome fusion, impairing viral receptor glycosylation." It also was postulated to have immune-modulating effects by inhibiting toll-like receptor signaling.[3] HCQ is also a known zinc ionophore and proponents of HCQ will often include zinc as part of their recommended treatment protocol as they believe HCQ is effective by enabling zinc to enter an infected cell where the ion inhibits viral replication. One study which supports this conclusion is Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture This study was published in 2010 in the journal PLOS Pathogens, which is well before any of the controversy surrounding hydroxychloroquine and COVID-19 occurred.[4] Another study, Hydroxychloroquine (HCQ) and azithromycin (AZ) plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients, examined the role zinc played and discovered that the number of patients discharged home significantly increased and the number of patients needing ICU, ventilation, or hospice care significantly decreased when zinc was added to the HCQ treatment regiment.[5]

HCQ and Covid 19

Prior to 2020, chloroquine (hydroxychloroquine's close cousin) was shown to be effective against SARS-CoV, a pathogen that is related to SARS-CoV-2. A study published on August 22, 2005 in the Virology Journal, almost 15 years before COVID-19 concluded Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.[6] Other journal articles which suggested chloroquine could be effective against coronavirus were Effects of chloroquine on viral infections: an old drug against today's diseases? (2003), In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine (2004), and New insights into the antiviral effects of chloroquine (2006).[7] Doctors familiar with medical research began prescribing hydroxychloroquine to combat SARS-CoV-2 because it was a less toxic alternative to chloroquine and the aforementioned studies meant that both drugs were treatment options worthy of serious consideration. Two of the first countries to use HCQ were South Korea, who used hydroxychloroquine + zinc, and France, who used hydroxychloroquine + azithromycin. In the case of the USA, HCQ achieved prominence when Donald Trump promoted the drug as a treatment for COVID-19. This view was inline with some of his political advisers such as Rudy Giuliani, but certainly not all, Dr. Anthony Fauci being the principal skeptic. In the case of Rudy Giuliani, he conducted an interview with Dr. Vladimir Zelenko on his podcast Common Sense where Dr. Zelenko promoted the three drug regiment he was using to treat patients in New York - hydroxychloroquine (HCQ) + zinc + azithromycin (AZ). This was a combination of the South Korean and French approaches to treating the disease. Zelenko concluded that his treatment protocol was being effective based off of the results he was having treating his patients.[8]

More evidence supporting HCQ's effectiveness emerged as time progressed. Didier Raoult, the French doctor whom administered HCQ + azithromycin, was having a mortality rate under .5% with patients showing up at the hospital. Costa Rica, which began administering HCQ countrywide to treat patients, was having a lower case mortality rate when compared with the rest of the world.[9] Brazil, which began treating patients with hydroxychloroquine and azithromycin, studied their treatment protocol and determined that HCQ's benefit was highly statistically significant (p< 0.001).[10] Spain was also having similar results (p=0.002).[11] Even a Texas nursing home had positive results using HCQ. None of these were double blind, randomized, placebo-controlled studies, but they were certainly enough evidence to suggest that a casual relationship between HCQ and COVID-19 recovery could be occurring, and that the relationship deserved to be researched further.

The scientific studies that said hydroxychloroquine was harmful

Prior to 2020, HCQ was seen as safe. According to a WHO report conducted in 2016 on the cardiotoxicty of antimalarial drugs, "there have been no reports of sudden unexplained death associated with quinine, chloroquine or amodiaquine, although each drug causes QT/QTc interval prolongation."[12]. As for the known side effects of HCQ prior to Covid 19, they include skin rashes, nausea, diarrhea, headaches, hair loss, tinnitus, and visual problems.[13] In other words, nothing particularly harmful when compared to things like the complete destruction of one's lungs. Even after COVID-19, HCQ has remained standard of care for diseases such as lupus and rheumotoid arthritis, and continues to be prescribed to children and women who are pregnant or are nursing even though those patients are often excluded from drugs that aren't as safe as HCQ.[14] And yet, once it was touted as a potential cure for COVID-19, HCQ was suddenly seen as harmful by many media outlets and health organizations. So how did this come to be?

The VA study

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 was one of the first studies to suggest a positive correlation between HCQ treatment and death from COVID-19. In the results section, the paper stated there were 27 deaths (27.8%) in the HCQ group, 25 deaths (22.1%) in the HCQ + azithromycin group, and 18 deaths (11.4%) in the no HCQ group.[15] Even before the paper had a chance to be peer reviewed (it was a preprint when it first appeared in the media), journalists from organizations such as the Washington Post, CNN, and the AP used this information to write articles with attention grabbing headlines such as More deaths, no benefit from malaria drug in VA study.[16][9][17][18]

An obvious question readers may ask after reading such a headline is "Why did more deaths occur?" If one's job was to report the news, one might try to find the answer to that question by reading the paper they were reporting on. If one had done that, one would have come across this paragraph in the discussion section.

Baseline demographic and comorbidity characteristics were comparable across the three treatment groups. However, hydroxychloroquine, with or without azithromycin, was more likely to be prescribed to patients with more severe disease, as assessed by baseline ventilatory status and metabolic and hematologic parameters. Thus, as expected, increased mortality was observed in patients treated with hydroxychloroquine, both with and without azithromycin.[15]

In other words, several doctors at the VA were using HCQ in a last ditch effort to try and save critically ill patients, it didn't work, and their efforts skewed the data as less seriously ill patients weren't being treated as often with HCQ. Problems such as this highlight why it is so important to have randomized clinical trials and control for variables such as when HCQ was administered. The VA study wasn't designed in that manner. To its credit, it said exactly that.

Our study has certain limitations including those inherent to all retrospective analyses such as non-randomization of treatments... Despite propensity score adjustment for a large number of relevant confounders, we cannot rule out the possibility of selection bias or residual confounding... Data from ongoing, randomized controlled studies will prove informative when they emerge.[15]

Neither the greater use of HCQ in critically ill patients nor the study limitations were discussed in the news article mentioned earlier. Instead the author wrote that the study didn't track side effects and then implied HCQ's side effects caused the increased death rate![16]

None of that seemed to matter to the news organizations that copy and pasted her work though.

To be fair, the "authors" did mention that the VA study was not a rigorous experiment. To be fair to the study, it might have been more rigorous than the reporting on it.

Surgisphere

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis[26] was one of the next studies to suggest HCQ was dangerous. According to its authors, hydroxychloroquine had a 18% mortality rate when used to treat COVID-19 and the mortality rate raised to 23.8% when it was combined with an antibiotic, whereas the control group only had a 9.3% mortality rate. Media organizations such as US News and World Report,[27]The Verge,[28] NBC News,[29] TIME,[30] CBS News,[31]The Wall Street Journal,[32] FOX News,[33] and CNN[34] were quick to promote this study and its findings. There was only one problem...the study was a complete fraud. Thankfully, medical professionals who actually understand science, logic, and reasoning were not fooled and mentioned problems with The Lancet article before it had been retracted. The Guardian also managed to see The Lancet article for what it was. So what were the red flags that revealed the study to be fraudulent?

1. The data was too clean

About the paper published in The Lancet: Data coming from five different continents cannot be so homogeneous. There is either data manipulation (not mentioned in Material and Methodes), or incorporation of faked data. - Dr. Didier Raoult[35]
People from different countries have different cultures and this results in different behaviors and lifestyles among their citizens. One example mentioned by both Dr. Didier Raoult and Dr. Chris Martenson was smoking. In North America and Australia, rates of smoking are closer to 14% and in Europe it is closer to 20 - 30%.[36][37] One would expect this variation in smoking prevalence to be reflected in the study's data set, but the authors claimed that 10% of North Americans, 9.7% of South Americans, 9.7% of Europeans, 10.3% of Africans, 9.4% of Asians, and 10.0% of Asians in the study smoked.[26] This discrepancy made the data appear fake, which was the point Dr. Raoult was making in his tweet.

Another problem with clean data was pointed out by the twitter user arkancideisreal.

This (Table S7B) gives more of a breakdown of the data and uses something called "propensity matching". This is a method of matching up similar patients. So for instance you want to get the same proportions of black/white patients in each group. Same for BMI, smoking, etc.

Each time you do this for each factor you reduce the pool of patients to compare. So to get the same number of black, non-smoking, BMI 25, hypertensive people in each group is really tough (5 factors) This group did it with 23 factors, all matched up "perfectly". This is pretty much statistically impossible.[38]

The objective of propensity matching is to try and account for the influence of confounding variables. For example, one doesn't want more obese people to be in the HCQ group when compared to the non-HCQ group because obesity is a comorbidity and any observed increase in deaths could be due to this confounding variable. To try and eliminate this problem, researchers will reduce the number of patients they are comparing so that they have patient groups that are highly similar. Once one gets out to 23 factors, the likelihood that a large number of patients in the HCQ group will have similar statistics as a large number of patients in the control group is vanishingly small, thus table S7B strongly suggests that the authors lied.

2. Impossible to collect the data in a month and a half without violating privacy laws

Usually to submit to a database like Surgisphere you need ethics approval, and someone from the hospital will be involved in that process to get it to a database. - Dr. Allen Cheng[39]
Pretty much all countries except China have strict privacy laws. This is particularly true for western countries in regards to their citizen's health data and yet The Lancet study said that patient data had been collected from Europe, Australia, and North America in a really short time frame. This fact leads inquiring minds to ask "How did they get the data?" Surgisphere, the company behind the paper, said they questioned existing repositories of data. While some electronic repositories of health data do exist, each hospital system has their own repository that is not linked to the repositories of other hospital systems and access to each repository requires its own ethical approval. Obtaining such approval is not easy, particularly when one has to do it for multiple different countries, each of whom has their own unique set of rules and regulations surrounding access to patient records. Even if one were to gain access, all the information one wishes to include (such as whether or not a patient was a former smoker) may not have been entered into the database by the hospital. Moreover, one would need to gain access to pathology databases which are complete separate from hospital record databases and be able to match the information from pathology databases to a particular individual's hospital record.[38][39] Maybe in China that is possible, but not in western countries unless one is a doctor or nurse of that particular patient.

3. Only four authors

Usually with studies that report on findings from thousands of patients, you would see a large list of authors on the paper. Multiple sources are needed to collect and analyse the data for large studies and you usually see that acknowledged in the list of authors.” - Dr. Allen Cheng[39]
The Lancet study had only four authors, three of whom were heart specialists and therefore were not responsible for data collection or statistical analysis.

4. Too many Australian deaths

The following was also revealed in The Guardian article the quotes from Dr. Allen Cheng came from.

The study, led by the Brigham and Women’s Hospital Center for Advanced Heart Disease in Boston, examined patients in hospitals around the world, including in Australia. It said researchers gained access to data from five hospitals recording 600 Australian Covid-19 patients and 73 Australian deaths as of 21 April.

But data from Johns Hopkins University shows only 67 deaths from Covid-19 had been recorded in Australia by 21 April. The number did not rise to 73 until 23 April. The data relied upon by researchers to draw their conclusions in the Lancet is not readily available in Australian clinical databases, leading many to ask where it came from.[39]

Yep. That is a problem, but it gets worse for Surgisphere...

5. Two of the authors were related

And the story is not that I am related to Dr. Desai by marriage. That’s old news. Many people from the Brigham were at that wedding and media knew about it. Despite this I still do not have the information of what happened at Surgisphere. But there has to be locals who do.[40] - Dr. Amit Patel
No conflict of interest there...

6. And there were even more problems...

This study led doctors from around the world to sign an open letter to its authors and Richard Horton (the editor of The Lancet) essentially asking for its retraction. Among the reasons given were "not adhering to standard practices in the machine learning and statistics community", "no mention of the countries or hospitals that contributed to the data source", "implausible ratios of chloroquine to hydroxychloroquine use", and "mean daily doses of hydroxychloroquine that are 100 mg higher than FDA recommendations."[41] The Lancet eventually caved and retracted the paper just like they had done with their publication of Andrew Wakefield's paper. Unfortunately, just like with the vaccine and autism scare, the damage had already been done. As the open letter points out, "the WHO has paused recruitment to the hydroxychloroquine arm in their SOLIDARITY trial. The UK regulatory body, MHRA, requested the temporary pausing of recruitment into all hydroxychloroquine trials in the UK (treatment and prevention), and France has changed its national recommendation for the use of hydroxychloroquine in COVID-19 treatment and also halted trials."

The RECOVERY Trial

Another study commonly cited by the media is the UK's RECOVERY Trial[42], which is a comprehensive evaluation of possible treatment options for COVID-19. HCQ was one of the drugs tested, but the results were not statistically significant. The following is how Professor Peter Horby and Professor Martin Landray presented their findings.

A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. ‘These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19. Full results will be made available as soon as possible.[43]
That statement is not correct. If the study convincingly ruled out HCQ, it would have a p value less than .05.[44] It didn't. It had a p value of .10.

In any case, the researchers were correct to conclude that the study only applies to hospitalized patients and therefore can't be used to conclude that HCQ won't work for people who use the drug closer to the time they were infected. A useful analogy is thinking of COVID-19 like a car crash and HCQ as an airbag. In order for for an airbag to be effective, it has to be deployed after the car crash but before the occupant crashes through the windshield. In the case of COVID-19, the argument is that anti-virals such as HCQ must be deployed after catching the virus but before it causes massive damage... having the airbag deployed after one hits the windshield just doesn't work. By focusing only on hospitalized patients, the RECOVERY trial failed to address the more pertinent issue of whether HCQ can be used to treat the disease before one has to be hospitalized.

Failure to address early treatment options was not the RECOVERY trial's biggest limitation, however. All drugs, when taken in the wrong doses, can become toxic. A good example of this is warfarin. In low doses, it is an effective and medically useful anticoagulant. In high doses, it is known as rat poison. In the case of HCQ, the maximum recommended daily dose is 800 mg,[45] but the RECOVERY trial used a daily dose of 2400 mg of HCQ[42], a dose that is three times higher than the recommended maximum daily dose![46][47] When Martin Landray was asked why he used such a high dose in his trial, he said "the chosen dosage is in line with the dosages used for other diseases such as amoebic dysentery." That was a curious response considering hydroxychloroquine isn't used to treat amoebic dysentery. Diiodohydroxyquinoline is. This has lead to speculation that the doctors of the RECOVERY trial confused the two drugs.[44][46][48]

Th University of Minnesota studies

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 is a study authored by David Boulware and published in the New England Journal of Medicine. Unlike the prior studies mentioned, this study did not say HCQ was harmful. Rather it is often cited by the media to suggest that HCQ has no net benefit. There are several studies that come to the same conclusion, most of whom administered HCQ too late in the disease progression for the anti-viral to be effective.[7] Boulware's study is different in that it aimed to examine the effects of HCQ on a random selection of people shortly after they were exposed to COVID-19, which is a good methodology. Unfortunately, the study also had major limitations.

  1. Almost all data was reported by the participants - Self-reported data is extremely unreliable which is why most studies are done with researchers administering the drugs. Self-reporting adds variables such as 'forgetting if one took the drug or not' that wouldn't occur in a more controlled setting.[49][50]
  2. A lack of testing for COVID-19 - Only 3% of the participants were tested for COVID-19 as the study was conducted when test kits weren't widely available. Instead they were declared to be COVID-19 positive even if their only symptom was a cough or if they had two symptoms of common things like headache and myalgia. Moreover, participants didn't have to have a known exposure to SARS-CoV-2 (such as a COVID-19 significant other). Instead they could have simply traveled to an area where SARS-CoV-2 was transmitting and thought they caught the pathogen. That is not rigorous diagnostics as other pathogens such as the common cold or the flu can cause the same symptomology.[49][50]
  3. The patient cohort was young - It is well established that the elderly are most at risk and therefore most likely to see benefit from HCQ.[49][50]
  4. The treatment was delayed - The authors were trying to prove whether or not HCQ can prevent the incidence of COVID-19 and that requires drugs to be taken quickly after exposure. Placebos and HCQ were delivered to participants through the mail.[49][50]

The following is how the authors presented their results.

The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35).[51]
Dr. Cohen counterargues-
In the current trial, the long delay between perceived exposure to SARS-CoV-2 and the initiation of hydroxychloroquine (≥3 days in most participants) suggests that what was being assessed was prevention of symptoms or progression of COVID-19, rather than prevention of SARS-CoV-2 infection."[49]
In other words, the study cannot be used to assess HCQ's ability to prevent incidence like Boulware claimed because the participants weren't given the drugs quickly enough.

The French newspaper France Soir looked at the study's data and concluded HCQ had some benefit for individuals treated for COVID-19 1-2 days after exposure (at 90% confidence, which doesn't quite make it to p <.05). France Soir also reported that Dr. Boulware scheduled a presentation for October 5, 2019 where he disclosed having received a research grant from Gilead Sciences.[52] Gilead is the maker of remdesivir. To Boulware's credit, he recognizes the study's flaws. According to Dr. Lewis, "He also points out that day 1-3 use had statistical significance and he’s gearing his other studies accordingly. He intends to investigate this significance further."[53]

The University of Minnesota conducted another study entitled Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial with a similar trial design, with Boulware as a co-author. Like its predecessor, it used internet surveys and overnight shipping of the drugs. During the trial, a major problem occurred... "the low event rate of hospitalizations or deaths in the trial would have required increasing the sample size to 6000 participants" and they only had 491 participants. Instead of making the study more robust by adding more participants, the study incorporated "overall symptom severity" instead of hospitalization as an endpoint. While more people had PCR confirmed COVID-19 than the earlier study, only 58% of participants received SARS-CoV-2 testing.

The study failed to reach statistical significance which should be unsurprising given its limitations. The results were positive, however, with HCQ having a P value of .21 for lower rate of ongoing symptoms and a P value of .29 for a lower rate of hospitalization.[54]

Retrospective studies from New York

There is no question that retrospective studies are not the best science. One has to use statistics to try and account for all kinds of variables such as delayed onset of treatment, not giving a patient a drug due to a patient's risk factors, and other variables such as differences in comorbidities. Some of these factors can be controlled for in certain situations. For example, if patients are seen by the same group of doctors, then differences such as when a particular drug is administered may not vary widely, but even in that situation other variables will persist such as screening for risk factors. The main advantage of retrospective studies is that ethical concerns are limited to protecting patient privacy as no patients are being given placebos or potentially harmful drugs. In the case of New York, three large, retrospective studies for hosptilized patients were conducted, two of which said HCQ treatment had no effect, and a third which said HCQ had a net benefit.

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Joshua Geleris studied the patients who came to the New York–Presbyterian Hospital (NYP)–Columbia University Irving Medical Center (CUIMC). Having the results come from one hospital could mean that some of the variables one might encounter with a multi-hospital analysis are controlled for, but that doesn't hold true in this case. While the hospital initially recommended dosing for HCQ at 400 mg, these recommendations were subsequently removed and treatment was left to the doctor's discretion. Moreover, it was only until after patients reached the emergency room that they were given HCQ (see figure S3), and even then only 45.8% received it within 24 hours. That is pretty late to be giving HCQ. In any case, what did they find?

Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses.[55]
In short, the researchers found that if you give HCQ in an ER preferentially to patients who were more severely ill at baseline, there is no significant difference between those given HCQ and those who weren't given it. It is difficult to figure out how to interpret that result. Is there no effect in an ER setting as evidenced by the similarity of outcomes between the two groups? Does it mean that there was a net positive effect to HCQ because the sicker patients weren't dying as often as one might otherwise expect?

The short answer? Nobody really knows because there are too many variables not being accounted for.

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Eli Rosenberg analyzed the data from 25 different hospitals in the New York Metropolitan area, a situation that is far from ideal. As there was no guidebook for doctors to go by for treating COVID-19, different doctors at different hospitals had different ways of treating the same disease. Rosenberg tried to account for this problem by randomizing the hospitals, but randomization is not a substitute for controlling the variables one can control such as when HCQ is administered. That having been said, having randomization is better than not having it.

Because of the study's inherent problems (and the inherent problems of all retrospective studies), the confidence intervals of their findings were large. "HQ + AZ" had a hazard ratio that ranged from .76 (meaning net benefit) to 2.40 (meaning net harm). "HCQ alone" ranged from .63 to 1.85 and "AZ alone" ranged from .26 to 1.21. This study also showed a higher prevalence of heart problems with HCQ (hazard ratio from 0.96 to 3.81), but no statistical significance was obtained for HCQ, either negative or positive.[56]

No findings does not mean that HCQ doesn't work and/or is harmless. It just means that there are no findings. One explanation could be that HCQ didn't work and/or is safe. Another explanation was that the trial was poorly designed. A third factor could be that the trial wasn't large enough to achieve statistical significance. Only after the likelihood of the later two factors are seen as small (usually through the use of multiple, well-executed studies that consistently come up with the same result), can one begin to make the case that the null hypothesis is correct.

Risk Factors for Mortality in Patients with COVID-19 in New York City

The third study was conducted by Takahisa Mikami and it analyzed the medical records of the Mount Sinai Health System. One of the first things that stands out in this study was its sheer size - it analyzed the results of 6493 patients whom had laboratory-confirmed COVID-19. By contrast, Geleris's study had 1446 patients, Rosenberg's study had 1438 patients, and the VA study had only 368 patients. When it comes to statistics, size definitely matters, and this one was even larger than the RECOVERY trial (not larger than Surgisphere though). While size is important, it is not a substitute for skill so let's take a more in-depth look at the study.

The study divided patients into ambulatory and hospitalized sub-groups. Ambulatory was defined as "patients whose encounter was an office visit, emergency department (ED) visit, or telehealth/telemedicine." Hospitalized was defined as "inpatients and ambulatory patients who were subsequently admitted to the hospital." This subdivision is important as it helps control for two of the most important factors, namely the timing of HCQ use and the overall health of the patients using the drug. Because of its sheer size, the study was able to do this subdivision without impacting its ability to achieve statistically significant results... even the subdivisions were larger than the studies conducted by Geleris and Rosenberg. The subgroups were then further subdivided into survivors and non-survivors, with the end date being April 17, 2020 (meaning a patient had to have died or discharged by that date to be included in the study). Then they did a whole bunch of statistical stuff (Cox Regression analysis, inverse probability weighting (IPTW) based on propensity scoring) to determine what the statistical results were.[57] So what did they find?

A total of 858 of 6493 (13.2%) patients in our total cohort died: 52/2785 (1.9%) ambulatory patients and 806/3708 (21.7%) hospitalized patients. Cox proportional hazard regression modeling showed an increased risk of in-hospital mortality associated with age older than 50 years (hazard ratio [HR] 2.34, CI 1.47–3.71), systolic blood pressure less than 90 mmHg (HR 1.38, CI 1.06–1.80), a respiratory rate greater than 24 per min (HR 1.43, CI 1.13–1.83), peripheral oxygen saturation less than 92% (HR 2.12, CI 1.56–2.88), estimated glomerular filtration rate less than 60 mL/min/1.73m2 (HR 1.80, CI 1.60–2.02), IL-6 greater than 100 pg/mL (HR 1.50, CI 1.12–2.03), D-dimer greater than 2 mcg/mL (HR 1.19, CI 1.02–1.39), and troponin greater than 0.03 ng/mL (HR 1.40, CI 1.23–1.62). Decreased risk of in-hospital mortality was associated with female sex (HR 0.84, CI 0.77–0.90), African American race (HR 0.78 CI 0.65–0.95), and hydroxychloroquine use (HR 0.53, CI 0.41–0.67).[57]
The confidence interval for HCQ in this study ranged from .41 to .67, which indicates that HCQ was associated with decreased risk of in-hospital mortality. If we use the .53 hazard ratio, people given HCQ were 47% less likely to die. As shown by the supplementary figure four of the study, the survival of patients was significantly higher for patients taking HCQ. (P < 0.001). That is a highly significant finding and a strong indicator that HCQ works. There were no statistical results presented for HCQ among the ambulatory patients, though it was reported that the majority of them did not receive the drug.[57]

Scientific studies that say hydroxychloroquine has a statistically significant net benefit

One of the arguments raised by individuals wishing to dismiss HCQ as a treatment option for COVID-19 is that the evidence supporting its efficacy is anecdotal. That actually isn't the case. Research studies such as the one conducted at Mount Sanai hospital have be done and statistically significant results have been achieved. That is science not anecdote. Of course, like with any scientific analysis, the conclusions could be wrong and the results need to be scrutinized (unlike what The Lancet did with Surgisphere's data). So here is a novel thought. Why don't we scrutinize the data logically instead of doing whatever Richard Horton thinks passes as empiricism?

Prevent Senior Institute in Brazil

One of the early studies published on HCQ as a possible treatment for COVID-19 was Empirical treatment with hydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up by telemedicine which was published as a preprint on April 15[7] by the Prevent Senior Institute in São Paulo, Brazil. The study had several limitations that made it less than ideal... it wasn't randomized and it had to assume that patients who were exhibiting flu-like symptoms during São Paulo's SARS-CoV-2 pandemic had contracted SARS-CoV-2 (testing wasn't widely available at the time), but the study also had several strengths. Unlike retrospective studies like the VA study, it had a natural control group - it offered to give HCQ and azithromycin to 636 symptomatic outpatients, 412 of whom accepted the treatment (the treatment group) and 224 of whom refused the medications (the control group). It also used HCQ early which is when antivirals are most effective and the patients were monitored by telemedicine[10] (unlike Boulware's study). So what where the results?

Need for hospitalization was 1.9% in the treatment group and 5.4% in the control group (2.8 times greater) and number needed to treat was 28. In those who started treatment before versus after the seventh day of symptoms, the need for hospitalization was 1.17% and 3.2%, respectively. Conclusion: Empirical treatment with hydroxychloroquine associated with azithromycin for suspected cases of COVID-19 infection reduces the need for hospitalization (p< 0.001).[10]
That is a highly significant result, not "anecdote". Actually, highly significant results as the study showed two things.
  1. Need for hospitalization is substantially reduced (2.8 times less) when patients are treated with HCQ.
  2. Patients who are treated with HCQ before the seventh day of symptoms do significantly better than patients who receive the treatment late.

These are potentially life-saving results in a study that was in a preprint before the VA study was in a preprint and yet is almost completely ignored by the mainstream media. It was also slightly larger than the VA study.

Gómez Ulla in Spain

Another early study with highly significant results was Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study (published as a preprint on May 5). This study is unique in that it was an observational study that actually acted more like a case-control study. The following is how the researchers described the situation at the hospital. "During the first days of the pandemic, HCQ was not considered in the local protocol. Afterwards, there were shortages in HCQ distribution. Because of that, we had two populations of patients treated and not treated with HCQ although they had similar characteristics. That gave us the opportunity to investigate the differences observed between the two groups."[11] Thus it has a control group, namely patients before HCQ was considered and patients that were treated after they ran out of HCQ, and it had a treatment group, namely patients who received the drug when it was available. The study also had the advantage of enrolling "all 18-85 years old inpatients from Central Defense Hospital “Gómez Ulla”, Madrid, Spain, who were hospitalised for COVID-19 and had a definitive outcome'." The enrollment of everyone reduces the likelihood of selection bias, although it doesn't completely eliminate it (some people were excluded because of things like pre-existing arrhythmias or drug interactions).

This study focused on a different patient cohort than the Brazil study as these were people presenting to the hospital rather than people seeking treatment right after they were infected which means it is closer to the Mount Sanai study. So what did they find?

We analysed first 220 medical records. 166 patients met the inclusion criteria. 48.8 % of patients not treated with HCQ died, 22% of those treated with hydroxychloroquine (p=0.002). According to clinical picture at admission, hydroxychloroquine increased the mean cumulative survival in all groups from 1.4 to 1.8 times. This difference was statistically significant in the mild group. Conclusions: in a cohort of 166 patients from 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with 800mg added loading dose increased survival when patients were admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will have to be clarified in subsequent studies.[11]

P=0.002 is another highly significant result with potentially life saving implications that was in a preprint after the VA study but before Surgisphere. The main disadvantage of this study was that it was small... 166 patients is not a high number.

This study is also ignored by the mainstream media.

IHU Méditerranée Infection hospital in France

Dr. Didier Raoult is a French microbiologist, doctor, and professor who heads the Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (Emerging Infectious and Tropical Disease Research Unit) at Aix-Marseille University and is affiliated with the IHU Méditerranée Infection hospital.[58] When SARS-CoV-2 reached France and COVID-19 patients began showing up at the IHU Méditerranée Infection hospital, Dr. Raoult promoted hydroxychloroquine + azithromycin as a treatment protocol. As he is a director of a lab that specializes in emerging infectious diseases, his research team collected a lot of data in order to study the effectiveness of the treatment. His team provided the media and the medical community preliminary evidence that HCQ + AZ was working throughout the research process and published a small study on March 20, but his much larger retrospective analysis study wasn't published until June 25. Entitled Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis, it is a thorough examination of the HCQ treatment option and it is most definitely not anecdote... this is medical science done with a high level of precision.

While the study had less patients than Mount Sanai's (it had 3,737 patients), the fact that it had researchers involved throughout the process gave them a lot of data to work with and use in their analysis. For example, 2,065 low-dose CT scan characteristics were performed among the patients in order to evaluate the effect the virus was having on the lungs. They also "recorded lymphocyte, eosinophil and platelet counts; fibrinogen; D-dimer and other coagulation factors; electrolytes; zinc; lactate dehydrogenase (LDH); creatine phosphokinase (CPK); C-reactive protein; and HCQ serum dosage. Viral load was analysed by qPCR from nasopharyngeal swabs at admission and during the follow-up." The studies main problems was that it was an observational study whose control group consisted mostly of people who had risk factors for HCQ or patients who where seen before HCQ + AZ became the go-to treatment.[59] So what did they find?

The patients’ mean age was 45 (sd 17) years, 45% were male, and the case fatality rate was 0.9%. We performed 2,065 low-dose computed tomography (CT) scans highlighting lung lesions in 592 of the 991 (59.7%) patients with minimal clinical symptoms (NEWS score = 0). A discrepancy between spontaneous dyspnoea, hypoxemia and lung lesions was observed. Clinical factors (age, comorbidities, NEWS-2 score), biological factors (lymphocytopenia; eosinopenia; decrease in blood zinc; and increase in D-dimers, lactate dehydrogenase, creatinine phosphokinase, troponin and C-reactive protein) and moderate and severe lesions detected in low-dose CT scans were associated with poor clinical outcome. Treatment with HCQ-AZ was associated with a decreased risk of transfer to ICU or death (Hazard ratio (HR) 0.18 0.11–0.27), decreased risk of hospitalization ≥10 days (odds ratios 95% CI 0.38 0.27–0.54) and shorter duration of viral shedding (time to negative PCR: HR 1.29 1.17–1.42). QTc prolongation (>60 ms) was observed in 25 patients (0.67%) leading to the cessation of treatment in 12 cases including 3 cases with QTc> 500 ms. No cases of torsade de pointe or sudden death were observed.[59]
A case fatality rate of 0.9% is really low when compared to other studies, although the fact that patients with milder symptoms were included in the study certainly helped. For comparison, across the channel, the RECOVERY trial's case fatality rate was 25.7% for hydroxychloroquine and 23.5% for usual care.

The study also showed that HCQ was associated with a shorter duration of viral shedding, as one might expect when an antiviral is working as an antiviral. 10.6% of patients using HCQ and AZ had the virus persist longer than ten days versus 20.6% of patients using other treatments. That result had a statistical significance of P<0.001. HCQ was also associated with decreased "risk of transfer to the ICU or death" and decreased "risk of hospitalization", both of which were statistically significant results (P<.001). The study also had zero cases of torsades de pointes despite having treated over 3000 patients. That is a critically important finding as the main argument opponents of HCQ use is that it causes torsades de pointes which can lead to sudden death. It must be noted that Raoult's numbers are helped by the fact that he screened out people who had risk factors for HCQ and QTc prolongation was monitored through EKGs in hospitalized patients.[59][60]

Dr. Raoult is too prominent of a figure for the mainstream media to ignore. The following are some examples of how they have portrayed him and his work.

Raoult, a distinctive figure with his shoulder-length shaggy grey hair, ended the video by repeating another controversial claim that "this is the end of the epidemic". Looking at the records of 96,000 patients across hundreds of hospitals, the study published in The Lancet found that administering the drugs actually increased the risk of dying.[61]
The study Dr. Raoult was defiant of was Surgisphere's...

The title says it all. There are some legitimate concerns contained within the article such as the research not being a double-blind placebo controlled trial, but the coverage was hardly balanced. For example, it failed to mention that the drug chloroquine was shown to have efficacy against SARS CoV before Dr. Raoult promoted HCQ as a cure.[62]

The results from two new drug trials have failed to find evidence that hydroxychloroquine works to treat Covid-19... One was the RECOVERY trial, supported by a grant to the University of Oxford in the U.K. The other was from researchers at the University of Minnesota.[63]
So a travel writer is arguing that the doctors in the RECOVERY trial who prescribed three times the maximum recommended dose for HCQ and had a 25.7% case fatality rate are the ones being responsible and the doctors whom ceased treatment in 12 patients with QTc prolongation and had a 0.9% case fatality rate are the ones being irresponsible? Interesting. As for the Minnesota study she mentioned, the author failed to state that Boulware believed day 1-3 HCQ use had enough statistical significance to warrant further investigation. She also defended Surgisphere after their study had been retracted, citing the company's claim that the release of their data would violate third party client confidentiality agreements.

USA

Dr. Zelenko

Before Dr. Immanuel's video went viral, the medical professional most prominently associated with HCQ in the United States was Dr. Vladimir Zelenko, a general practitioner who treats patients in the state of New York. Since the time he first told Rudy Giuliani about the positive results he was having with HCQ + AZ + zinc, he has coauthored a preprint entitled COVID-19 outpatients – early risk-stratified treatment with zinc plus low dose hydroxychloroquine and azithromycin: a retrospective case series study. The study has some problems in its current form, the most glaring of which is that "only outcome data for hospitalization and all cause death was available" for the untreated control group.[64] Ideally, one would wish to use propensity matching with these results, with age being one of the factors being accounted for, but that simply isn't possible with the data the researchers had available to them. This having been said, the study is notable due to its incorporation of zinc, its study of outpatients, and Dr. Zelenko's prominence in the media. So what were the results?

In the treatment group 4 of 141 patients were hospitalized, which was significantly less than in the untreated group with 58 of 377 patients (15.4%), (fig 2.), (OR 0.16; [95% CI, 0.06 to 0.5]; p<0.001), (table 7, fig 4). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated patients... One of the 141 patients (0.71%) who belonged to treatment group A (age > 60 years) died after being hospitalized. This patient had a history of cancer and did only take one daily dose of the triple therapy before hospital admission. With 13 of 377 patients (3.5%, fig 3) more patients died in the untreated group (OR 0.2; [95% CI, 0.03 to 1.5]) (table 7, fig 4). The odds of all-cause death of treated patients were 80% less (p=0.16) than in the untreated group.[64]

It is a small study with serious questions concerning its control group, but Dr. Zelenko was able to find a statistically significant reduction in the hospitalization rate of patients treated with HCQ.

Dr. Zelenko is another figure who is too prominent to be ignored.

A misstatement by Zelenko about a randomized clinical trial being conducted by St. Francis Hospital "drew scrutiny of federal prosecutors"... Zelenko had thought the St. Francis's study had FDA approval when it had only been approved by the hospital's internal review board.[65] Thankfully, prosecutors don't appear to be treating the misstatement too seriously. The Daily Beast article Controversial Doc in Trump’s Ear Calls Malaria Drug Study ‘Garbage' was far less kind and used the misstatement (as well as the time-machine based Lancet paper) to attack Dr. Zelenko's credibility.[66]

Vanity Fair was also highly critical and accused Dr. Zelenko of using his political connections to commit the unfathomable crime of helping St. Francis Hospital's outpatient primary care to obtain:

"1. Hydroxychloroquine 200mg. 10000 pills"

"2. Azithromycin 500mg 5000 pills"

"3. Zinc sulfate 220 mg 5000 pills."[67]

A Hasidic Jew helping a Catholic hospital get life saving drugs? Scandalous. The author clearly deserves a Pulitzer.

The Henry Ford Health System

When SARS-CoV-2 hit Detroit, the Henry Ford Health System set up a COVID-19 task force and established uniform treatments across all of its 6 hospitals in order to assess what their treatment protocol should be. The "patient population received aggressive early medical intervention", which means that treatments were given early, and the treatment of hydroxychloroquine + azithromycin was reserved "for selected patients with severe COVID-19 with minimal cardiac risk factors." The fact that hospitalized patients were studied means that the study is closer to Mount Saini's study than it is with Brazil's study of outpatients.[3][68] Before we get to the results, the study also mentioned why HCQ + AZ was chosen as a potential treatment option. Given the political controversy surrounding HCQ, what they had to say is particularly important.

Hydroxychloroquine, an antimalarial and immunomodulatory agent and a safer analogue of chloroquine, has demonstrated antiviral activity against SARS-CoV-2 (Wang et al., 2020a; Liu et al., 2020; Yao et al., 2020; WHO, 2017). It is postulated to exert a direct antiviral activity by increasing intracellular pH resulting in decreased phago-lysosome fusion, impairing viral receptor glycosylation. In addition, it has immune-modulating effect by inhibiting toll-like receptor signaling, decreasing production of cytokines especially IL-1 and IL-6 (Savarino et al., 2003). Prior data also suggests a potential anti-thrombotic effect (Jung et al., 2010). Azithromycin, a macrolide antibiotic, has in vitro antiviral properties such as decreased viral replication, blocking entrance into host cells, and a potential immunomodulating effect (Tran et al., 2019). An in vitro study demonstrated synergistic activity of the combination of hydroxychloroquine and azithromycin against SARS-CoV-2 (Andreani et al., 2020). A small non-randomized, open-label trial from France reported higher frequency of SARSCoV-2 clearance after six days of treatment with hydroxychloroquine alone or hydroxychloroquine in combination with azithromycin versus untreated control group (70% vs 12.5%; P<0.001) (Gautret et al., 2020a)[3]
There is no mentioning of Donald Trump or Rudy Giuliani. Or patients with lupus and rheumatoid arthritis struggling to get HCQ. Or COVID-19 patients self-medicating with fish-tank cleaner. Or Surgisphere. And if you didn't know who Andreani and Gautret worked for, no mentioning of Dr. Didier Raoult. All they cared about was the science.

Without further ado, here are the results.

Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4–10 days), median age was 64 years (IQR:53–76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3–53). Overall in-hospital mortality was 18.1% (95% CI:16.6%–19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%–23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%–15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%–30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%–31.0%]). Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age>65 years (HR:2.6 [95% CI:1.9–3.3]), white race (HR:1.7 [95% CI:1.4–2.1]), CKD (HR:1.7 [95%CI:1.4–2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1–2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4–3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p <0.001).[3]
In other words, HCQ cut the death rate by over half.

This study is not without its own problems. It is similar to Dr. Raoult's study in that the control group consisted mostly of people with risk factors for HCQ and it is an observational study.

USA Today attempted to "Fact-check" the article, correctly pointing out that it showed a 50% reduction in death rates, HCQ had no safety problems, and the study was limited by being an observational study, but then it made assertions that were more misleading. The following was what they had said:

A study this month out of the Henry Ford Hospital System in southeast Michigan found death rates were 50% lower among the patients treated with hydroxychloroquine. The study's authors noted the drug posed no safety problems. The research was criticized as an observational study – much less rigorous than a randomized trial – and because patients who received hydroxychloroquine also got steroids shown to be clinically beneficial in treating COVID-19. “You want to look at the totality of the data,” said Eric Topol, director of the Scripps Research Translational Institute, in an interview with The Washington Post. “The totality is overwhelmingly in the opposite direction. You have to conclude with the Henry Ford study is an outlier, and there’s some kind of confounder that is skewing the data and not representing the truth.”[69]

Some counterpoints.

  • The study is not an outlier. Spain's study had very similar results and had control groups. Mount Sanai's study also had similar results and it is the largest study of its kind to date. Brazil's study, France's study, Dr. Zelenko's study, India's study, and even the Boulware study the article cited to defend its position, have all had positive results, and only Boulware's study failed to reach statistical significance. The outliers are the studies which haven't had positive results, all of which had inherent problems such as the drug being given late, the drug being given in toxic doses, or the study being a complete fraud.
  • The following is how John MeComb described the problem of randomized trials with control groups (in regards to COVID-19 and Zelenko's study).
The control group would have to be people with symptoms at high risk for progression of disease. Would this not be unethical for this kind of study? I for one would not want to be in such a control group and, as a patient, if informed as such would decline. As a physician, under the current circumstances, it would violate my hippocratic oath to place people in such a control group... The "control group" has to be a preponderance of the evidence at this point.[64]
  • While steroids do work and were given about twice as often to patients given HCQ in the study[3], steroid use doesn't explain the 66-71% hazard reduction - steroids only reduce one's risk by about a third[70] and the net effect would only be about 1/6th once one considers the percentage of people not being treated with HCQ but still given steroids. If one was so compelled, one could go through the data and account for the confounding variable of steroids... if it wasn't already done for you. The HCQ and non-HCQ propensity-matched patients of the study both received steroids 44.2% of the time. As the study states, "The Cox regression result for the two propensity matched groups (Table 4) indicates that treatment with hydroxychloroquine resulted in a mortality hazard ratio decrease of 51% (p = 0.009)."[3] 51% hazard reduction is not as good as 71%, but it is still pretty freaking good.
  • In the same USA Today article - "Remdesivir and COVID-19: New data suggests the experimental drug can shorten how long people are sick."[69] Shorter duration of sickness is not as good as 51% reduction of death... The lady doth protests too much, methinks.

The ICMR COVID-19 Research Team in India

In the studies we have mentioned so far, HCQ has been taken after the patient was infected, but what if the drug was taken before a person was exposed to SARS-CoV-2? Could it still work? India studied that very question among its healthcare workers and published their findings in a study entitled Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19. So what did they find?

It worked. (They also found PPE worked.)

Compared to controls, cases were slightly older (34.7 vs. 33.5 yr) and had more males (58 vs. 50%). In multivariate analyses, HCWs performing endotracheal intubation had higher odds of being SARS-CoV-2 infected [adjusted odds ratio (AOR): 4.33, 95% confidence interval (CI): 1.16-16.07]. Consumption of four or more maintenance doses of HCQ was associated with a significant decline in the odds of getting infected (AOR: 0.44; 95% CI: 0.22-0.88); a dose-response relationship existed between frequency of exposure to HCQ and such reductions (χ[2] for trend=48.88; P <0.001). In addition, the use of PPE was independently associated with the reduction in odds of getting infected with SARS-CoV-2.[71]
AOR stands for adjusted odds ratio and it represents how likely a certain outcome will occur given exposure to the variable of interest. In this case, the outcome is SARS-CoV-2 infected and the variable of interest is the use of HCQ. Odds ratios above 1 mean that that outcome is more likely to occur given exposure to the variable. In the above results, "Performing endotracheal intubation" was associated with a high likelihood of being SARS-CoV-2 infected (4.33). Odds rations that are below 1 mean that the outcome is less likely to occur. In the above results, "4 or more maintenance doses of HCQ" was associated with a significant decline in the odds of health care workers becoming SARS-Cov-2 infected (0.44). This means that people who took HCQ were about half as likely to become infected than those who didn't take the drug (the confidence interval ranged from .22 to .88). India's researchers also found that HCQ's dose-response relationship had statistical significance (P <0.001).[71][50]

Other Studies

There are even more studies that could be cited and, if one is interested, one can go to C19study.com which has a fairly comprehensive list of all of the studies involving HCQ and COVID-19. The overall consensus of these studies is that when HCQ is taken early, it works. If instead it is taken late in the disease progression, the data is more inconclusive.[7]

HCQ, QT elongation, and torsades de pointes

One of the recurring arguments opponents of HCQ make is that is it is dangerous because it could lead to sudden death visa vi QT elongation. This is a valid concern if there is evidence that HCQ actually causes death through QT elongation. So why don't we evaluate the evidence?

The clinical name for sudden death caused by excessive lengthening of the QT interval is torsades de pointes and it is monitored through EKGs. Some people have long QT intervals due to genetic factors, but QT elongation can also be acquired through medications.[72] There are several medications that have this effect, including Abarelix, Aclarubicin, Alfuzosin, Alimemazine, Amiodarone, Anagrelide, Apalutamide, Apomorphine, Aripiprazole, Arsenic trioxide, Artemether, Artenimol, Asenapine, Astemizole, Atomoxetine, and Azithromycin (and those are just the A's).[73]. Because of the concern of torsades de pointes, people taking these medications in a hospital setting will be monitored and the course of their medication may be altered due to perceived risk. The following is how the Henry Ford study described their procedure.

"Apart from halofantrine, the oral antimalarial drugs, particularly chloroquine and piperaquine, have been used extensively with very few reports of cardiotoxicity...Despite hundreds of millions of doses administered in the treatment of malaria, there have been no reports of sudden unexplained death associated with quinine, chloroquine or amodiaquine, although each drug causes QT/QTc interval prolongation."[12][13]
People with naturally long QT intervals or other cardiac risk factors may also be excluded from the use of drugs that prolong QT due to the risk of torsades de pointes.

The largest study to monitor cardiac risk in regards to COVID-19 and HCQ use was the one conducted by Didier Raoult's team where 3,119 patients were treated with HCQ and AZ. Of those patients, QT prolongation was only observed in 25 of them (0.67%) and this led to cessation of treatment in 12 of the cases. There were zero cases of torsades de pointes.[59] The Henry Ford Health System study was somewhat smaller (1985 patients treated with HCQ) and they reserved the HCQ + AZ treatment to people with minimal cardiac risk factors. They also had zero cases of torsades de pointes.[3] Thus, the likelihood of HCQ-induced torsades de pointes in two large studies was zero, with the caveat that the researchers screened out patients with HCQ risk factors and used EKGs to monitor their patients for risk.

Alright, one may argue, but that was in hospitalized patients. What about people who aren't monitored at a hospital? According to Dr. Zelenko, the question "Has there been any cardiac arrhythmias using the combination of HCQ and AZ?" has been addressed by electrophysiologists in the USA who used their equivalent of "WhatsApp" to discuss the problem amongst themselves. The answer was no in the outpatient setting. In the ICU setting, the answer becomes more muddled as COVID-19 can cause cardiomyopathy which, in turn, can cause QT elongation. Thus it is uncertain whether it is HCQ or COVID-19 that is the cause.[14]

As HCQ is commonly used in outpatient settings for diseases such as malaria, the likelihood of sudden death from its use has already been addressed. A massive study entitled The cardiotoxicity of anti-malarials was conducted by the WHO in 2016 and found the following:

"Apart from halofantrine, the oral antimalarial drugs, particularly chloroquine and piperaquine, have been used extensively with very few reports of cardiotoxicity...Despite hundreds of millions of doses administered in the treatment of malaria, there have been no reports of sudden unexplained death associated with quinine, chloroquine or amodiaquine, although each drug causes QT/QTc interval prolongation."[12][13]
So out of hundreds of millions of doses being administered, the likelihood of sudden death is zero? Well not quite zero as shown by this case report, although that person didn't die due to medical intervention. But the risk is still really low, particularly when compared to the risk associated with being harmed by SARS-CoV-2 (or malaria, for that matter). If one has risk factors such as a naturally long QT interval, HCQ may still pose some risk, which is probably why it is not an over-the-counter medication. But if one is healthy, it is difficult to beat HCQ's safety profile. Just don't expect to hear that from the mainstream media as they are in the business of promoting a false narrative.

Motivated reasoning among the mainstream media?

AP

British researchers on Friday published their research on the only drug shown to improve survival — a cheap steroid called dexamethasone. Two other studies found that the malaria drug hydroxychloroquine does not help people with only mild symptoms... the only other therapy that’s been shown to help COVID-19 patients is remdesivir, an antiviral that shortens hospitalization by about four days on average.[74]
The above quote was taken from Marilynn Marchionne's New studies clarify what drugs help, hurt for COVID-19, an article rife with errors.

Error/Claim #1 - Dexamethasone is the only drug shown to improve survival.

That's not true. All drugs which have studies that have statistically significant correlations (p<.05) linking their use to increased survival are drugs "shown to improve survival" and HCQ has a lot of those studies. Granted, one can take issue with the results and argue that there are reasons not to believe them (like with Surgisphere, for example), but the onus of proof is on the person seeking to refute the studies. You can't just ignore the fact that the studies exist. In addition to HCQ, there are other drugs the author failed to mention that have shown to improve survival.

  1. The drugs in what is known as MATH+ protocol - Methylprednisolone (another steroid), Ascorbic acid, Thiamine, Heparin, and plus (melatonin, zinc, vitamin D, atorvastatin, famotodine (a.k.a. pepsid) and magnesium). Oral prednisone is used as a substitute for methylprednasone on day 8 of the treatment.[75] That protocol has been known since at least May 11,[76] which is a full month before the RECOVERY trial discovered that the steroid dexamethasone also works.[77][48]
  2. Vitamin D[78][79][80][48]
  3. Pepsid (preliminary, but encouraging, optional part of the MATH plus protocal)[81][48]
  4. Ivermectin[82][83][84][85]
  5. Tocilizumab (Published in The Lancet, but promising)[86][60]
  6. Anakinra (Published in The Lancet, but promising)[87][60]

Error/Claim #2 - Two other studies found that the malaria drug hydroxychloroquine does not help people with only mild symptoms.

The two studies referenced were a small study from Spain and the Minnesota study Boulware co-authored. Like the Minnesota study, the Spain study had positive results that supported HCQ use but it failed to reach statistical significance, likely due to its small sample size (it only had 293 people which is much smaller than the 6000 people the Minnesota study said were needed to reach statistical significance).[88] The fact that these were the two studies chosen as evidence "against" HCQ is a clear-cut case of cherry picking. The fact that studies with statistically significant positive results such as the ones conducted at Prevent Senior Institute in Brazil, Gómez Ulla in Spain, IHU Méditerranée Infection in France, the Henry Ford and Mount Sanai hospitals in the USA, and by the ICMR COVID-19 Research Team in India were not mentioned in the article are fallacies of omission.

Error/Claim #3 - The only other therapy that’s been shown to help COVID-19 patients is remdesivir.

What about the plasma therapy that was covered on 60 minutes and analyzed in this study?[89][90] (Actually, the study is really small and other studies have shown that plasma therapy doesn't work late in the disease progression, but if the criterion of proof is "as good as or better than remdesivir," then it has been shown to help.)

Error/Claim #4 - HCQ is harmful

The article goes on to report "Now, details published on a research site for scientists show that the drug may have done harm. Patients given hydroxychloroquine were less likely to leave the hospital alive within 28 days — 60 percent on the drug versus 63 percent given usual care."[74]

Any reporter worth their salt would then say something to the effect of "That may have been due to the fact that the researchers treated their patients with toxic levels of HCQ," but that isn't mentioned. Moreover, inclusion of the RECOVERY data is a double standard. If one argues that the not statistically significant positive results in the Boulware and Spain studies don't support HCQ use, then one can't logically argue that the not statistically significant negative results from the RECOVERY trial refute HCQ use.

The article goes on to make other unsubstantiated claims, all in what appears to be a concerted effort to promote remdesivir over other treatment options (including the new inhaled version Gilead is working on). Get it now... "supplies are very limited."[74] (That phrase was actually said).

The aforementioned flaws didn't stop NBC,[91] Yahoo,[92] US News and World Report,[93] MSN,[94] The Daily Mail,[95] and ABC[96] from copying and pasting it (among others).

Marilynn Marchione is the same author who wrote More deaths, no benefit from malaria drug in VA study[16] and conveniently omitted the part where the VA study says "hydroxychloroquine, with or without azithromycin, was more likely to be prescribed to patients with more severe disease."[15]

BBC

If it was just Marilynn Marchione shading the truth, then other independent journalists could correct the misinformation by pointing out the flaws in the argument and provide the public with strong, fact-based, counter-arguments. Unfortunately, Marilynn Marchione's reporting style is par for the course. Another example is Coronavirus: Dexamethasone proves first life-saving drug, written by Michelle Roberts, which says the following:

The Recovery Trial, running since March, also looked at the malaria drug hydroxychloroquine, which has subsequently been ditched amid concerns it increases fatalities and heart problems. The antiviral drug remdesivir, meanwhile, which appears to shorten recovery time for people with coronavirus, is already being made available on the NHS.[77]
There is no reason for the antiviral drugs remdesivir and HCQ to be mentioned in an article about the steroid dexamethasone unless one was trying to make a comprehensive analysis of the medical literature, which this article wasn't doing. If one wanted to add context, then the author could have instead talked about the closely related drug methylprednasone and the MATH+ protocol. And, in order to inform the reader, one could explain that the MATH+ protocol has a 6.6% mortality rate in one hospital and a 3.3% mortality rate in another[75] whereas the RECOVERY trial is rocking a 41% mortality rate among patients on a ventilator, 25% mortality rate among those on oxygen therapy, and a 13% mortality rate on those patients who did not require respiratory intervention.[70]

CNN

Dr. Chris Martenson, a pathologist and YouTube podcaster, provided another example of how the media has covered HCQ, this time from CNN and their Senior Medical Correspondent, Elizabeth Cohen. The first article she wrote, Yet another study shows hydroxychloroquine doesn't work against Covid-19, was published at 4:57 PM ET on Monday, May 11.[97] That was prime time news coverage and the article covered Rosenburg's retrospective study. The second article she wrote, "Study finds hydroxychloroquine helped coronavirus patients survive better," covered the Henry Ford study's results and was published at 11:24 PM on Thursday, July 2 (right before July 4 celebrations).[68] Apparently that title and publishing time wasn't enough so CNN updated the article on July 3, 1:31 PM so that it reads "Study finds hydroxychloroquine may have boosted survival, but other researchers have doubts" and they added some criticisms, such as screening patients for HCQ risk factors may have skewed the results.[98] That is a valid point, and one needed for balance, but no such "balanced" treatment was given to the New York study. If the author had added a counterpoint from other scientists, it would read something like this:

"Among a number of limitations, this study included patients who were initiated on hydroxychloroquine therapy at any time during their hospitalization... Because treatment regimens likely varied substantially (including delayed initiation) across the 25 hospitals that contributed patients to the study, it is not surprising that the case-fatality rate among the New York patients was significantly higher than in our (the Henry Ford) study.[3]"

As of August 1, 2020, CNN's coverage of the VA study also made no attempt at "balance".[99] Heck, they didn't even bother to update their article on Surgisphere's study even though The Lancet had retracted it.[34]

The media truly hates HCQ

On July 28, 2020, Dr. Stella Immanuel promoted HCQ in a video that went viral, but what is more telling than her belief in the virtues of the drug was the social and news media's response to it.

  • Twitter banned Donald Trump Jr.'s account for his posting of the video and deleted Donald Trump's retweet of it.[100]
  • Facebook took the video down “for sharing false information about cures and treatments for COVID-19.”[100]
  • Youtube removed the video for violating its "Terms of Service" or "Community Guidelines.”[100]
  • The video could still be found on the website for America's Frontline Doctors, but then Squarespace decided that the website violated their acceptable use policy and suspended their account.[101]

You could still see the video at Daily Motion... but then it was taken down.

Several news networks also contributed to the onslaught (just google Dr. Immanuel), including NBC Nightly News which incorporated ad hominem attacks against Dr. Immanuel and America's Frontline Doctors rather than any in-depth analysis of the science (apparently Dr. Anthony Fauci's medical opinion is the only one that matters). The title of the news's segment was "Trump under fire for sharing coronavirus misinformation on social media,"[102] which leads one to ask "What misinformation?" She didn't talk about demons or the other ideologies the media has dredged up in order to demonize her. Instead the essence of what she said was that she believed HCQ works based off of the results she was seeing with her patients and her staff. How does saying that warrant the extreme measures taken by both the social media giants and the news networks? It is not a crazy idea to believe that HCQ works when it has multiple scientific studies that support this conclusion, and yet Dr. Immanuel deserves to be portrayed as a lunatic for stating that belief? One must ask oneself why? Why has the media done this to a woman whose only crime appears to be believing in a drug that Donald Trump also happens to believe in?

Dr. James Todaro, a popular twitter user who was involved in exposing the Surgisphere article to be a fraud, also happens to be one of the America's Frontline Doctors featured in the video. He provided a link of the video that, as of August 1, was still up on Vimeo.[103]

The future of HCQ

In her viral video, Dr. Immanuel reported seeing patients from far away because their local doctors were too afraid to prescribe the drug and being reported to the medical review board, a threat Dr. Immanuel also received.[104] Yale's Epidemiology Professor Dr. Harvey Risch also reported that doctors were being threatened by their state medical licensing boards for prescribing HCQ.[105] This represents a public health concern and is a violation of patient rights.

On July 29, the state of Ohio officially banned pharmacies from fulfilling HCQ prescriptions to patients with COVID-19. Dr. James Todaro reported that this was "a direct infringement on the patient-doctor relationship." Ohio governor Mike DeWine reversed the decision at 9:30 A. M. on July 30, presumably due to public outrage. Dr. Todaro subsequently had "a great meeting with Vice President Mike Pence and his Chief of Staff. We are doing everything to restore the power of medicine back to doctors. Doctors everywhere should be able to prescribe Hydroxychloroquine without repercussions or obstruction."[103]

Dr. Simone Gold was fired shortly after appearing as one of the America's Frontline Doctors in favor of HCQ.

The Henry Ford Health System filed for permission with the FDA to continue using HCQ and were denied after they had shown that the drug cuts the death rate by about 50% in hospitalized patients.[106]

Dr. Anthony Fauci has repeatedly said “The overwhelming evidence of properly conducted randomized clinical trials indicate no therapeutic efficacy of hydroxychloroquine (HCQ)”. A group of doctors wrote him an open letter questioning this statement, outlining several key facts concerning the science behind HCQ and its efficacy for treating COVID-19 patients. Dr. Fauci has yet to respond.[107]

External links

References

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