Not being able to to find toilet paper is annoying – not being able to find a prescription medication you rely on can be deadly serious. As I continue to hear stories of patients with autoimmune diseases like lupus unable to obtain the hydroxychloroquine they need while key authority figures tout this drugs’ miraculous Covid-19-fighting powers – WITHOUT SOLID EVIDENCE – I thought it was time for some tough treatment talk…
First off, I want to say that my thoughts are with everyone around the world as we struggle to cope with the global pandemic of Covid-19, the disease caused by the “novel coronavirus” SARS-Cov-2. It’s truly heartbreaking and anxiety-producing and, even if we haven’t been hit hard personally (knock on wood), it hurts to sit back and feel useless – so I’ve been trying to contribute by providing understandable resources on the science behind various aspects of testing, treatment, etc. which I hope help and which you can find here: https://bit.ly/covid19bbresources
I’ve been working on them from home and I hope that you, too, are practicing social distancing – avoiding gathering with others, working from home if you aren’t “essential” and only going out when you absolutely have to. Taking these measures helps slow the spread of the disease, keeps our healthcare systems from getting overwhelmed, and buys time for scientists to find vaccines and treatments. Speaking of which, a couple weeks ago, I wrote a post on some of the potential treatments in the works, and today I want to give you an update on where things stand as of today (April 6, 2020).
SARS-Cov-2 holds its genetic blueprint (genome) in a single strand of RNA. It gets host cells to make proteins based on the instructions it contains, including an RNA “copier” (RNA-dependent RNA polymerase) it uses to make copies of its genome. It wraps each copy up with nucleocapsid protein, and buds out of the host cell, getting enveloped in a membrane on the way out. Sticking out of the membrane are “crown-like” spike proteins which can bind to “matching” receptors on new cells. Then those cells take the virus in by kinda sucking in and pinching off the portion of membrane its bound to in a process called endocytosis, which leaves the virus in a sort of intracellular “bubble” called an endosome that the virus then has to escape from by fusing its membrane with the endosomal membrane.
So potential treatment targets include – stopping the RNA copying, stopping the protein producing, stopping the receptor binding, stopping the endosomal escape, and optimizing the immune response. And there are therapeutics being developed and tested for each of these.
I’m going to start with hydroxychloroquine (HCQ) – NOT because I think it has the most promise, but because I think it has the most (over) hype. HCQ is the more stable form of a drug called chloroquine (CQ). It’s an antimalarial treatment that’s been around for over half a century and it also has important immune response regulatory activity that makes it a staple treatment for autoimmune diseases like lupus and rheumatoid arthritis.
Malaria is a parasite, not a virus, but chloroquine also has some anti-viral activity. It is theorized to prevent viruses from getting into and/or out of cells by messing with their modes of transportation – raising the pH in endosomes, preventing the virus from getting out in its acid-dependent way (and it does some other stuff too). It’s been tested in the past as an anti-viral for other diseases but never really was very effective outside of a lab setting.
But, during this pandemic, anecdotal evidence started coming out about doctors “successfully” using HCQ to treat Covid-19 patients (that is – these doctors gave the patients HCQ and the patients got better, but the patients might have gotten better anyways but we can’t know without actual trials).
A big reason for all the hype is a VERY small (42 patient) “open-label” study (patients and doctors knew which patients were being treated with what) which show initial promising results, including when HCQ was combined with the antibiotic azithromycin (which might help combat secondary bacterial infections that can develop once the patient’s lungs are made vulnerable by the virus). BUT the study was majorly flawed. A great thread about it by Jason Pogue can be found here: https://bit.ly/2V566Sd
Some of the key red flags he points out:
- 6 of the initial 26 patients in the HCQ group weren’t included in the analysis because: 3 were transferred to ICU, 1 died, 1 left the hospital, and 1 withdrew because of treatment side effects
- only 6 patients received the combo treatment
- they used a really low threshold for success
- it wasn’t randomized so patients between the groups could have underlying differences (in age, disease severity, underlying conditions, etc.) that cloud compatibility
- their sample-taking method was non-ideal
Additionally, one of the co-authors was editor-in-chief of the journal it was published in, leading to a very fast and very questionable peer review process. And microbiologist Elisabeth Bik found that the lead author has a shady record when it comes to past publications, including what appears to be fabricated data in some of his old papers: https://bit.ly/2RfWTW1
Another (better-set up but still small) study out of China was pretty “not-sure-if-it-helped” results-wise. There wasn’t much of a difference between patients who did or didn’t take HCQ (so it certainly wasn’t a “miracle drug”): https://www.statnews.com/2020/03/27/we-dont-know-hydroxychloroquine/
So, I can’t say that there’s no effect (and no one can), but at this point, apart from in vitro (in a dish) findings, it’s basically just anecdotal evidence, and it’s too soon to really say this – or any drugs – are effective – and they can have SERIOUS side effects, including potentially fatal heart problems and psychiatric disturbances. So it is NOT a “nothing to lose” situation.
HCQ has become kinda like the presidential version of Goop’s jade eggs. But it’s way more dangerous because it comes from a higher authority source and capitalizes on people’s’ fears. Not to mention that if these eggs sell out no one is really harmed by not being able to buy one, whereas people *are* harmed if HCQ sells out.
Imagine if Gwenneth Paltrow said her jade eggs prevented or cured Covid-19. And do a bunch of people bought and “took” it. Most of those people wouldn’t get sick, and most who did would recover. So all those people might go give interviews about how the eggs are this miracle treatment. But those people would have had the same outcomes even if they hadn’t “taken” it. And with less side effects…
The situation isn’t this bad evidence-wise with HCQ because there is *some* evidence it might help. But the situation is way worse consequence-wise. Much worse. Because a lot of people NEED HCQ for proven purposes – like autoimmune diseases like lupus & rheumatoid arthritis, and for its “original purpose” – preventing and treating malaria. And now these people are having trouble getting the medication they really need. And these stories are heartbreaking too – especially because they’re unnecessary.
HCQ *may* help. But we don’t have near enough evidence to say that it does. And we don’t have anywhere near enough evidence to go hoarding it. A lot of people need HCQ for reasons that have a lot of evidence (and these people still get Covid-19 even though they’re on it!)
Before you start saying “just make more!” – firstly, people are and secondly, there can still be harm. Because the drug can be harmful, especially when used improperly. here’s part of a statement put out by the CDC on March 28: https://bit.ly/39MXRj9
“Chloroquine phosphate, when used without a prescription and supervision of a healthcare provider, can cause serious health consequences, including death. … these medications are being studied and evaluated as treatment for COVID-19; however, their efficacy to either prevent or treat this infection are unknown. In overdose situations or when used inappropriately, these medications can lead to severe toxicity, including cardiac rhythm disturbances such as prolonged QT, severe hypokalemia, cardiovascular collapse, seizures, coma, and death.”
Serious stuff. And it also has a really thin line between therapeutic amounts and toxic amounts – it’s easy to OD on it. Here are a couple of great articles if you want to find out more:
Now an update on a few other treatments.
Viruses like SARS-Cov-2 hijack their host cells’ protein-making machinery, but in addition to making some individual proteins, they also make “polyproteins” which basically means they make a bunch of proteins linked together and then cut them apart using protein-cutters called proteases. Since viruses need proteases to make functional proteins from polyproteins, some antivirals are protease inhibitors – including the HIV treatment combo Lopinavir/ritonavir (trademark Kaletra). Scientists had hoped that Kaletra also might help treat Covid-19 but the results of a small trial found it ineffective and side-effect-causing.
A more promising treatment target is RNA-copying. Our cells don’t have an RNA-to-RNA copier (RNA dependent RNA polymerase)(RdRP), so the virus has to use its own, offering up an “Achilles heel.” Nucleotide analogs mimic RNA letters but have something “messed up” about them. They’re able to trick the viral RdRP into adding them into the viral genome during copying, causing the viral RNA copying to screech to a halt or become gibberish. But our own RNA-users don’t get tricked so our cells can carry on as usual.
A couple of drugs in this class are Remdesivir and favipiravir, aka Avigan.
Remdesivir is a drug made by Gilead. It was a “failed” Ebola drug, so it never made it to mass production or FDA approval, but Gilead knows how to make it, has a lot of safety evidence on it, and is scaling up production & plans to donate over a million doses. It’s efficacy against Covid-19 (outside of a lab) is unproven, but there could soon be proof. There’s been a controlled trial of it going on at the NIH, with results potentially out at the end of this month: https://bloom.bg/2V7DJCX
Avigan is made by the Japanese company Fujifilm. It’s been used in Japan to treat certain types of flu. There are some preliminary findings out of China that it’s helpful and larger trials are underway. https://bit.ly/2XcmoLJ
Those were all examples of “small molecule” drugs – what you normally think of when you think of “pharmaceutical drugs” – but there are also efforts underway to develop so-called “biologics” including antibodies that bind to the spike proteins and keep them from docking onto cells. Antibodies are little proteins so they’re harder to produce and administer – plus you have to find ones that bind the virus’ spike proteins in the right place and don’t bind anything else anywhere else, so these treatments will take more time to develop. more on antibodies here: https://bit.ly/covid19testtypes
Importantly, (at least as of April 6, 2020) NONE of these drugs has been FDA-approved for the treatment of Covid-19. You might be saying “who cares if it’s FDA-approved or not?!” And I totally get that – it might just seem like semantics – if you’re dying and there’s some lifesaving treatment you don’t really care if it has the official stamp of approval right? But that stamp of approval represents a whole process of testing to show that a drug is SAFE and EFFECTIVE. more on that process here: https://bit.ly/clinicaltrialterms
The FDA issued an Emergency Use Authorization (EUA) for HQC – this is NOT the same as “FDA approval” – it just allows doctors to use it “off-label” on hospitalized patients outside of official trials if they feel it’s appropriate, even without data proving it works
While there is (as of today) no proven specific treatment for Covid-19, doctors can provide assistive therapies to treat the symptoms – like fluids, pain and/or fever reducers, & supplemental oxygen – including, in the most severe cases, through a tube into a patients lungs that also helps mechanically expand the lungs (they can get stiffened by the infection so some patients need help with this). This extreme therapy is provided by ventilators, which are in short supply, as are a lot of things that health care providers need.
So it’s really important we do our part to not overwhelm them. And, it isn’t a treatment, but there is a thing we have really good proof works: social distancing – so keep at it