Here is a dive into the study on “post-exposure prophylaxis” for COVID-19, recently published in the New England Journal of Medicine. The present article challenges the claim that it actually was a prophylaxis study and points at several key problems with the study, which most likely fails to be the “conclusive answer” about the role of hydroxychloroquine for COVID-19 prevention that its principal author claims it is.
The author Jean-Pierre Kiekens is an independent policy analyst. He is a former lecturer at the University of Brussels and a graduate of the universities of Oxford and Brussels.
Some time ago …
Some time ago, I did a few missions in West Africa, and even stayed one year in Côte d’Ivoire. Great memories. One of them was to have a drink after the sunset, typically a beer, on a terrace. And that was the place where I felt like transformed into feed for the numerous surrounding mosquitos.
Yes we would put on repellant, and wear long sleeves and trousers, yet, that was not enough. And pretty often, I could actually see the mosquito biting me. I would kill the bastard, but it was usually too late. Was the mosquito an Anopheles? Was it carrying Plasmodium falciparum or another parasite causing malaria?
Malaria causes tens of thousands of deaths every year across the world, and it’s why the use of antimalarial pills is so common not only in Africa, but also in Asia, Latin America, etc. For sure, antimalarial pills are just part of the answer, but an important one.
That might explain why in most countries, these are over the counter drugs, which was also the case, until very recently, in a number of European countries like France, from where there is lots of air travel to Africa.
For adults, the typical dosage for antimalarial prevention, when it comes to hydroxychloroquine, is 400 mg per week, taken the same day every week.
Importantly, when you travel to a region where there is malaria, you need to start your intake 2 weeks before arrival, and continue it 4 weeks after.
Now will this hydroxychloroquine sulfate in your blood prevent the Anopheles mosquitos from biting you? Of course not. But, unless you are unlucky to have a mosquito with a resistant Plasmodium strain, you should be OK and unlikely to get malaria.
Unlikely is the key word here – there is a large body of evidence to show that the drug significantly reduces the probability of acquiring malaria, but it is not a full-proof protection. Note that there are rare cases of people developing the disease years after having left infested regions, so it’s not a 100% guarantee either.
In short, the key feature of the drug is to be used as a prophylaxis; i.e. it is to be taken before exposure, as well as to be continued after. It does not stop the mosquito biting you and it does not prevent infection. But it reduces the likelihood of developing the disease.
What about that study by Boulware et al
Now what about that study by Boulware et al., which delivered the usual anti-hydroxychloroquine hype in the mainstream media even before the study was put online by the New England Journal of Medicine? The study looks at “post-exposure prophylaxis.”
Post-exposure prophylaxis sounds like an oxymoron. Either you have been infected, or you have not been infected by the virus before taking the drug.
You would think naïvely that those fearing for their lives after thinking to have been exposed to the virus would have gone to see a doctor, would have at least sought testing, and then would have been given the best available therapy to save their life. In the context of this study, the answer is no on all these counts.
- Those participating in the study were recruited through the Internet and social media. (6924 persons assessed for eligibility but only 821 retained for the study). Median age was relatively young: 41 in treatment group, 40 in placebo group – but there are no details about the precise age distribution.
- The participants were not seen by medical doctors. Instead, they had to “self-report” symptoms and disease severity status (see protocol at https://clinicaltrials.gov/)
- The amount of testing was extremely low: 11 tests out of 414 in the treatment group; and 9 tests out of 407 in the placebo group. So in average, only 2.4% of those participating in the study were tested!
- What therapy was received for those people fearing for their death? Half got placebo, and the other half hydroxychloroquine alone, even if the benefit of adding azithromycin to hydroxychloroquine was already known on March 20, with a publication by Gautret et al. from IHU Marseille — https://www.sciencedirect.com/science/article/pii/S0924857920300996
- Also to be noted is that the medications were shipped by courrier, so that between the time participants filled the form online, up to the time their file was processed and the medication was shipped by courrier and got to them, precious time was lost.
- The dosages were somewhat surprising for this therapy, and looked more like a short treatment after infection than a prophylaxis. Initial dosage was high, too high some will say. While the “observation” timeframe was 14 days, the treatment was only given for 5 days (post-exposure, not in anticipation of a possible other exposure in the following days).
- Despite all the buzz about the alleged dangers or side-effects of hydroxychloroquine, that the authors actually emphasize in their media release, and despite the pretty steep dosage on the first day, no cardiac screening was done via ECGs – contrary for example to the protocol of Professor Raoult in Marseille.
It’s actually important to contrast the approaches by IHU Marseille with what took place in the US and Canada in connection with this study.
At IHU Marseille, anyone who thought to have the disease could be tested. It’s how long lines developed in front of the hospital. Those who tested positive were pretty immediately taken care of medically, and seen by real doctors. There was no self-reporting. There was no diagnosis on the basis of self-reporting by some doctors being hundreds or maybe thousands of kilometres away.
In Marseille, many of those who tested positively were prescribed the hydroxychloroquine + azithromycin bi-therapy, already known to be more effective. There was medical monitoring of those taking the therapy, either as inpatients or outpatients, including with electrocardiograms. Tests were performed during and at the end of the therapy to assess progress and cure. PCR tests were quickly developed at the IHU-Marseille, and thousands and thousands were performed. Compare this with this North American study, at the same period, where only 20 participants were tested!
All the therapeutic efforts in Marseille were analyzed scientifically by Raoult and his collaborators, in the context of retrospective studies, as it was out of question for these medical doctors to give placebos to patients suffering from a deadly disease. The huge effort to provide treatment and save lives led to a series of studies, the latest one on 3,737 patients.
These could not have been randomized controlled trial studies, as the therapeutic approach was to treat all those patients suffering from the deadly disease, not to randomly just treat 50% of them.
It’s important to understand that the asymptomatic incubation period that takes place prior to developing symptoms for COVID-19, while typically considered to be about 5 days, can be much longer, up to around a month.
During that period, the person is infected, but does not have symptoms. Actually, some people get infected, and never get any significant symptoms that they are aware of. Others will get symptoms at some point, and things can go very fast from there.
The only way to know if someone is infected is to make a test, and if possible more than one, as these are not fully reliable.
What the researchers of the article did was to exclude by purpose from this study the symptomatic patients thought to have COVID-19. But that does not mean that those who were kept in the study were not infected. Even if asymptomatic, these were not necessarily “healthy” people, as described in the media release.
Zero Mortality Among Study Participants?
One of the most surprising aspects of this study is that there is no reported mortality, neither in the treatment group (414 participants) nor in the placebo group (407 participants). How could that be explained, for such a deadly disease? The number of hospitalized patients is also very low: 1 in each group.
According to the research protocol, in the Current Secondary Outcome Measures (submitted April 28 2020) death is assessed in a time frame of 90 days. The study itself started on March 16. https://clinicaltrials.gov/ct2/show/record/NCT04308668
It’s not clear what actual time frame was used in the research, as the 90 days stipulated in the research protocol is impossible, given that the research was released on June 3. The authors refer to a “survey at 4 to 6 weeks.” This is not the 90 days time frame stipulated in the protocol.
An obvious problem when one relies on self-reporting and the Internet is death. How to find out if a study participant died or not? And here is how the researchers say they proceeded.
“Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes.”
“When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status.”
“When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status.”
Yes … obituary searches, nothing less …
Table S10., provided in the “supplementary material” and titled “Baseline Demographics for those Lost to Follow-up with Unknown Vital Status,” indicates that there were 36 individuals in the treatment group and 33 in the placebo group of “unknown vital status.” All of those, but one, are from the US.
From this table, one finds that 69 participants in the study were lost in the follow up and have an “unknown vital status.”
These numbers can also be found in Table S1. Participant Status at Time of Trial.
How to reconcile this with the zero mortality and the extremely low hospitalization rate reported by the authors in Table 2, titled: “Outcomes of Hydroxychloroquine Therapy for Postexposure Prophylaxis against COVID-19”?
Actually, of those 69 individuals, some may be hospitalized, some may be dead. Maybe they are all fine. Maybe they are all dead. Nobody knows.
The authors chose to report zero mortality instead of highlighting that the “vital status” of nearly 10% of those participating in the study is actually unknown.
And obviously, an unsuccessful search for the name of a study participant in online obituaries is not a proof that he or she is alive.
Conflicts of Interest?
And well … in the disclosure forms, the principal author of the study does not mention his affiliation with the company Revive Therapeutics, which is
“exploring the use of Bucillamine as a potential novel treatment for infectious diseases including COVID-19.”
To the question: “Are there other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what you wrote in the submitted work?”, Boulware responds: No.
Another, and maybe more significant potential conflict, not disclosed by Boulware, is in respect with Gilead Sciences, the firm behind remdesivir. Here is how Boulware responded to a query about it …
This article did not look at the details of other possible conflicts of interest among the study authors. Yet, it can be noted that several authors have reported having ties with NIAID, whose position regarding hydroxychloroquine is pretty well known.
Mainstream Media Adores the Questionable Study
As the time of writing this, a search on Google News for “boulware” yielded about 24,800 results! Yes, there was a media buzz associated with this study.
Disappointingly, the media release describes the study as a prophylactic one, when we do not even know whether the people involved were actually infected or not.
“The randomized placebo-controlled trial, which rapidly launched on March 17, tested if hydroxychloroquine could prevent COVID-19 infection in healthy persons after exposure to someone with COVID-19.”
“hydroxychloroquine was not able to prevent the development of COVID-19 any better than a placebo”
“40% of trial participants taking hydroxychloroquine developed non-serious side effects — predominantly nausea, upset stomach or diarrhea.”
“Our objective was to answer the question of whether hydroxychloroquine worked to prevent disease or did not work,” Boulware said.
“While we are disappointed that this did not prevent COVID-19, we are pleased that we were able to provide a conclusive answer. Our objective was to find an answer.”
A particularly misleading feature of the media release is that it claims that those receiving the medication or placebo were healthy, while they may already have been infected yet be asymptomatic.
The media release does not mention the 69 out of 821 study participants that were lost track of by the authors and whose “vital status” remains unknown.
Reliance on self-reporting, absence of real medical monitoring, reliance on online obituaries and the near total absence of testing makes it a very questionable study indeed.
But how did the mainstream narrative / news media, so often eager to brag that hydroxychloroquine is a failure, report on the questionable study?
CNN: “On the heels of studies showing hydroxychloroquine doesn’t help patients in the hospital with Covid-19, a new study — the first of its kind — shows the drug doesn’t work to prevent infection with the virus, either. “
Washington Post: “Hydroxychloroquine, a drug promoted by Trump, failed to prevent healthy people from getting covid-19 in trial”
Global News Canada: “Hydroxychloroquine doesn’t prevent COVID-19 in people exposed to the virus, study finds”
NY Times: “The first carefully controlled trial of hydroxychloroquine given to people exposed to the coronavirus did not show any benefit.”
CNBC: “Hydroxychloroquine doesn’t prevent coronavirus infection, study with more than 800 people finds”
Even a more specialized media, Kaiser Heath News, didn’t see the pitfalls of the study: “Study Finds Malaria Drug Doesn’t Prevent COVID-19 In Latest Knock Against Controversial Treatment”
Oh, if you find an article in the media that analyzed the actual content of the study, please let us know … we may then write a follow-up.
Any Take Away Message?
Beyond the oxymoronic nature of the concept of “post-exposure prophylaxis,” the study reveals a new face of technocratic research in medicine: no doctors examining patients; self-reporting via the Internet; no real attempt to treat patients; “gold standard” randomized controlled trials relying on dubious data; hiding from the main text of significant information like study participants not known to be alive or dead, etc.
The study was mostly recruiting among health care workers and their relatives. These were rightly seen as high risk exposure individuals. About 60% of them were not wearing personal protection equipment. It shows how the lives of these high exposure individuals were needlessly put at risk, both in the US and in Canada.
With the reported risk of high exposure, a question worth asking is wether these potentially infected and contagious individuals were asked to go into isolation / quarantine. If not, there may actually have been new infections because of the lack of such precautions.
Add to this the quasi-absence of PCR testing, and the study actually contributes to understand how unprepared and disorganized the response to COVID-19 was, and how unprepared was also the medical research profession to respond in a useful manner to the challenge of the COVID-19 pandemic.
The contrast with the work done at the IHU-Marseille is astounding. Yet, who is the bad guy these days in many media? Professor Raoult, one of the world’s leading experts in infectious diseases, who contributed to considerably reduce the mortality rate from COVID-19 in Marseille, or Professor Boulware, who does not even know if people died in his study but reports that none did, in addition to misleading everyone about prevention and prophylaxis for COVID-19?
Of course, despite its flaws, the Boulware study was randomized. It was a randomized controlled trial – the gold standard! Incidentally, 46.5% of those in the hydroxychloroquine group thought they received hydroxychloroquine, while only 16.7% in the placebo group thought they received it. So even the masking was not very convincing …
The study may not be as flawed as the just retracted #Lancetgate one, where there are strong allegations of fabrication of data. Yet, this study by Boulware et al. should in my opinion not have been accepted for publication.
At this point, early hydroxychloroquine-based treatment, like implemented by Professor Raoult and his team in Marseille, is a pretty well established, yet still controversial, approach to deal with COVID-19 – but this must be done with real medical supervision, with real tests, not on the basis of self-diagnosis.
A recent article explaining why early treatment is so important was recently published by medical doctor and epidemiologist Prof. Harvey Rish from Yale University.
For an excellent introduction about early treatment, read our article or watch our video interview of Doctor J. Varon, Professor of Acute and Continuing Care at the University of Texas Health Science Center and Chief of Staff/Chief of Critical Care at United Memorial Medical Center in Houston, Texas.
As far as prophylaxis is concerned, in our view, this new study does not prove anything, contrary to what the authors claim in the study and even more in the media release.
The best available study for COVID-19 prophylaxis so far probably is “Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19.” by Pranab Chatterjee and collaborators, recently published in the Indian Journal of Medical Research.
According to the study, “consumption of four or more maintenance doses of HCQ was associated with a significant decline in the odds of getting infected.”
And for individuals not overly exposed, check the prophylaxis recommendations of Professor Marik, from the Eastern Virginia Medical Group, as explained in this interview video clip with Professor Varon.
See also this previous article:
NEJM Article: https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
Un. Minnesota Media Release: https://covidpep.umn.edu/