A Few Questions (and Answers, I Hope) about Hydroxychloriquine

Apologies for what is likely to be a very, very dry post today. We are living in strange days; better ones are coming. The comments to follow are not political. They should not be seen as endorsing one political narrative versus another.

As Queen Elizabeth (channeling Vera Lynn circa 1939), we will meet again.

CAVEAT: I am not a medical doctor. I am an epidemiologist. It is (and has been, for 26 years) my day to day job to build, run, and abstract the results from disease models. I've run analytics of randomized clinical trials. I have helped prepare (and been a subject matter expert for questions from) the United States Food and Drug Administration (FDA).

But I am not a "scientist." I would not question the medical expertise of a doctor, whose job it is to make medical decisions.

Let me say, with no ambiguity or equivocation, that ANY decision (yes or no) people make about medical care absolutely should be made in consultation with a doctor.

In the past few days, there has been a lot of talk in the news and the popular press about the use of hydroxychloroquine (with or without azithromycin) to treat people suffering from infection with the SARS-CoV-2 virus. The US president has made many statements in support of it. People in the press have attacked his comments.

There is, I think, a lot of misinformation and misunderstanding about these medicines, why there is some belief that they help treat COVID-19 (the illness associated with SARS-CoV-2), the risks of the medications, and frankly, what is going on.

What is COVID-19? 

First, you hear "COVID-19," "coronavirus," and, to a lesser extent, "SARS-Cov-2" used interchangeably. They aren't.

COVID-19 is a terminology resulting from the abbreviation resulting from "coronavirus disease" (COVID), concatenated with 19, the year (2019) it was identified. This is a standard way that the World Health Organisation (whose job it is to come up with the nomenclature) assign.

Coronavirus is a heuristic to describe a family of viruses (of which this particular strain is included) that are so called due to their physical structure - a central structure that houses the RNA (essentially, viruses are primitive structures of genetic material) with spiky projections that make the virus look like a crown. The word "corona" means "crown," in the original Latin.

SARS-CoV-2 is an abbreviation for "SARS-CoV" (severe, acute respiratory syndrome, of the coronavirus type). It is a strongly believed to be a close genetic cousin of the virus that caused the outbreak of SARS in 2005, hence the "2." The name was implemented by the International Committee on the Taxonomy of Viruses.

So briefly, the virus is SARS-CoV-2; the illness it provokes is COVID-19. Think of it in parallel that HIV is the virus that causes people to get sick. AIDS was the disease that resulted. It's not a perfect metaphor (and thankfully, with highly effective treatment, these days, people with HIV infection can suppress infection and avoid AIDS).

What is hydroxychloroquine?

Hydroxychlorquine is a medication that was first approved for use by the FDA in 1955. It is in the family of antimalarial drugs called aminoquinolines. Its first use was for treating malaria; later, it was approved by FDA for use in treating Lupus (SLE), and rheumatoid arthritis. Its activity against infection was well-established in its early days against malaria. How, exactly, it works with RA is still not well understood.

Hydroxychloroquine is known under a brand name called "Plaquenil."

It is on the WHO List of Essential Medicines - a list of what the WHO describes as the safest and most effective medications that are essential to basic health for a health system. These represent well-established and basic for the key population health needs. There are currently approximately 500 medications on this list.

What is azithromycin?

Azithromycin is an antibiotic (medications that are used to kill bacterial infections) called a macrolide antibiotic. It has broad activity against a host of GRAM positive (and some, more serious GRAM negative) bacteria, and is widely used for inner ear infections, community acquired bacterial pneumonia, skin infections, and some respiratory and throat infections. It was first approved for use in the USA in 1988.

Azihtromycin is marketed under the brand name Zithromax; often, it is sold in seven or 10 days packages called "Z Pack."

Azithromycin is, like hydroxychoroquine, on the WHO list of essential medications.

Why has hydroxychloroquine been suggested for COVI-19?
There are several problems with Dr Raoult's study. The first is that the sample size is very small. Only 42 patients is too small a sample for any regulatory body to approve a medication for use.

The results are encouraging.

One of the controversies not said in the US media is that Dr Raoult is not without controversy. He is a highly respected infectious disease doctors. He was named one of the ten leading researchers in all of France by Nature magazine, and has published two thousand peer-reviewed manuscripts in his career. He was awarded, in 2010, with the Grand Prix de l'INSERM (Institut National de la Sante et de la Receherce Medicale), the French national institute for health research.

ALL medications have adverse events. When FDA approve drugs, it is implicitly understood that there are risks. When medicines are approved, FDA (and other regulators) are asked to balance the risk/benefit calculus - is the benefit that the medication greater than the risk associated?

Frequent complaints on the news are about how the use of hydroxychloroqine as an intervention represents bad, or at the least incomplete, science. Dr Anthony Fauci, who, with Dr Deborah Birx, are the medical experts informing our government's response to the outbreak of SARS-CoV-2. Dr Fauci is one of the leading experts in the country on infectious disease. He earned his bona fides over the years working in HIV disease, as did Dr Birx. His opinion absolutely must be respected.

Medications are "approved" for use by regulators - in the US, by the FDA. When they are approved, there is a very detailed "label," and more in what is called a package insert - the little paper in six point Courier type in the bottle - that describe the indication (the disease its use is "approved" for), side effects observed by more than 1% of patients in the trial, the clinical trial data, dosing, and other details.

COVID-19 is a very serious problem. As of this writing, 400,000 Americans have been diagnosed. 13,000 have lost their lives.

A small, observational study was conducted by the French infectious disease expert called Didier Raoult at his hospital in Marseille, France (Institut Hospitalo-Universitaire, or IHU) in which he treated 42 patients who had been admitted to his hospital with COVID-19, at various severity of disease. 26 of the patients received hydroxychloroqine. 16 received 'standard of care,' which is to say, palliative care. Six of the 26 in the treatment arm had azihtromycin added to their treatment.

The results were published by Dr Raoult in the International Journal of Antimicrobial Agents in mid-March 2020.

Dr Raoult reported that 14/20 (70%) of the treatment arm were reported free of viral loads at six days following inclusion. In the control arm, just two had this outcome (12.5%).

This is a stark result, and is certainly, from the perspective of statistics, an encouraging number.

So, what is the controversy?

Second, the study was not a 'randomised control trial' (RCT). This is the gold-standard for the research and approval of medications in the US (FDA), the EU (European Medicines Agency, or EMA), Canada (Health Canada), and most other industrialised nations on earth. It involves "double blinding" (enrolling patients into the trial into arms that neither the subject nor the investigator knows is which) that are broken only at the end to control for biases. Dr Raoult's study was "open label" (subjects and doctors knew who was in the treatment arm, and who was in the control arm), and it was observational (meaning that there was no attempt, through randomisation, to allocate patients into the two arms to balance things like underlying health, age, and other factors that can bias results).

Third (and in my view an under-reported problem) is that the study was not an intent to treat (or modified intent to tread) analysis. Dr Raoult reported that 14/20 patients (and 6/6 of those on both hydroxychloroquine AND azithromycin) recovered. In fact, there were six patients lost to follow up, and not included in the calculations. Three of these in fact died (of their infection, not side effects). Three others did not complete treatment. So the results reported (70% efficacy) represent a sort of survivor bias. In fact, 14/26 (54%) recovered. That's much less exciting than the numbers broadcast.

The study in effect was very small, uncontrolled, and had design issues. People are right to be sceptical of these results.

Who is Dr Raoult

A significant part of the backstory that frequently remains unsaid in the US media is that Dr Raoult is not without controversy. He is a highly respected infectious disease doctors. He was named one of the ten leading researchers in all of France by Nature magazine, and has published two thousand peer-reviewed manuscripts in his career. He was awarded, in 2010, with the Grand Prix de l'INSERM (Institut National de la Sante et de la Receherce Medicale), the French national institute for health research.

He is, in short, an acclaimed doctor and researcher.

But he is idiosyncratic. In 2013, he ventured outside his lane and questioned climate change, which drew widespread ire and scorn.

What role is there in the arguments about safety?

Both hydroxychloroquine and azithromycin are among the most prescribed medications in the world. If you are over the age of five, it is almost certain that you have taken azithromycin at some point. Of course it has risks - the most significant, perhaps, is that it causes QT prolongation - a heart condition that can result in irregular heartbeat. This is a real, but rare risk.

It is not zero.

The reality is, most of the "side effects" of the treatment are things like nausea, rash, and headache. These are the types of common 'adverse events' reported in most clinical trials. Anecdotally, of the trials I have run analyses on, nausea, headache, diarrhoea, and rash have in every case been the most common events reported.

What about the 'science?'

But people, I think, are either misunderstanding what Dr Fauci is saying, or they are distorting it.

He is a scientist as well as a doctor. His comments reflect that the only way, really, to establish the efficacy of a treatment right now is via RCTs. Randomisation is simply the best way to mitigate sampling and other biases. Using control arms are the best way to establish placebo effects.

In a perfect world, of course we would conduct multiple RCTs. And I suspect that we will. Many are right now going on, and the results will be in.

The problem is, we simply do not have the luxury of time.

I am old enough to remember life before the advent of effective HIV therapies (in fact, not that long ago). 25 years ago, when antiretroviral therapies (ARV) had not been discovered, the criticisms of FDA among others were that they were too slow to react and were obstructing treatments.

HIV activists were, at the time, highly critical of Dr Fauci for just this reason.

Dr Fauci's is right to be conservative. It is part of his job to question whether this approach will work.

But people need to listen to what he is actually saying rather than what they think he is.

Basically, the treatments have side effects, but they have been in use for decades, and are on the whole, pretty safe. They don't have no risk, but the risks are well-known. What we don't know is the actual efficacy, which the RCTs will establish.

Thus, in deciding whether or not to treat, patients should consult their doctors; medical expertise should decide.

In short, talk with your doctor.

Both hydroxychloroqine and azithromycin require a doctor's prescription. You cannot walk into Safeway and pick it up as if it were aspirin.

What does it mean for a drug to be "approved?" What is off-label use?

Medications are not "approved." They are approved for specific diseases. Adalimumab (Humira), for example, is "approved" for rheumatoid arthritis, psoriasis, ulcerative colitis, and a few other autoimmune disorders.

Doctors can - and frequently do - prescribe medications for disease not specifically indicated in the label. This is called "off label use."

The laws of the US presume that the best person to decide care for a patient is his or her doctor - a medical expert who knows the specifics of the patient before him or her - and is best positioned to understand the nuances, risks, and benefits to make the best medical decision.

This is, again, why it is critical for patients to talk to - and listen to - the opinions of their doctors.

Right now, you cannot get access to hydroxychloroquine - whether for an approved use (Lupus) or off-label (COVID-19) without your doctor.

Bottom Line

The reality is, those numbers are going to end up being much higher.

I don't know that hydroxychloroquine (with or without azithromycin) is effective. The initial evidence is encouraging, but it remains to be seen if this will be borne out in larger studies.

I do know that both have some risks, but those risks are pretty small. The risk of death from SARS-CoV-2 is many orders of magnitude higher.

We hear, every day, about ventilators. And it's true that they are essential. Without them, virtually all of those who require invasive ventilation would die.

But they are not a cure. Data right now indicate that, of those going in ventilators, mortality is 30-50%.

I worked, 10 years ago, in Phase II (dose-ranging) studies for a novel treatment of Lupus. One of the comparators we used was Plaquenil. Safety for Plaquenil was something we evaluated versus our treatment. But it was not the driving factor. Not close.

If I were to test positive for the virus, I personally would not immediately turn to this unproven therapy. But if I were to be put in the hospital, I would seriously talk to my doctor about it. And I would absolutely listen to what the doctor said.

The claims by the president that "you have nothing to lose" by trying hydroxychoroquibe are false.

But given that we have nothing else in the armamentarium right now means that I would think long and hard about the novel treatments before I required a ventilator.