Ivermectin for COVID: How Do We Know What to Believe?

[Music] welcome to impact factor your weekly dose of commentary on a new medical study i'm dr f perry wilson of the yale school of medicine this week it's time we talk about ivermectin since the first days of the coven 19 pandemic various existing drugs have been touted as near miracle cures for the disease often the discussion of agents like hydroxychloroquine lopinovir and their ilk veered into the conspiratorial squelching reasonable scientific discussion boosters would accuse detractors of hiding the truth of a safe and effective treatment at the behest of big pharma or the deep state detractors would accuse boosters of bad data analysis and wishful thinking enter ivermectin and this meta-analysis of randomized trials by andrew hill and his colleagues in open forum infectious diseases that seem to show that the drug has pretty remarkable efficacy against covet 19. but before we dig in let's put the mechanistic cards on the table this is ivermectin it's an anti-parasitic agent that has been used to treat scabies river blindness and filiarism among others you may give it to your dog to prevent heartworm discovered in 1975 the drug has been in worldwide use for nearly five decades and appears on the who list of essential medicines ivermectin binds to certain chloride channels on nerve and muscle cells paralyzing the creature exposed to it these channels are present in worm and insect nervous systems which is why the drug works humans have the channels too but only in our brains and spinal columns and since ivermectin can't cross the blood-brain barrier we are spared from its effects but you will note that sars-cov2 has no muscles or nerves so why the interest in this drug for this virus well a lot of the enthusiasm comes from this study by a group that has done nice work showing that the drug may have antiviral properties by affecting a protein called importin that a lot of viruses hijack for their own nefarious uses researchers infected a cell culture with sars kov2 and added various concentrations of ivermectin they then measured viral replication and found that the drug in a petri dish at least could dramatically inhibit the ability of the virus to reproduce but there's a problem the inhibitory concentration of the drug around 2.5 micromolar is not achievable in real life humans in fact standard ivermectin dosing achieves blood concentrations of about 25 nanomolar a hundred fold less than what was needed in vitro lung concentrations are a bit higher than blood concentrations but still 50 fold less than what is needed to inhibit the virus in cells in culture so if ivermectin is going to work in humans with coven 19 it has to be via some other mechanism anti-inflammation or something but as a starting point biological plausibility here is not high that never stopped us before multiple clinical trials at this point have evaluated the drug in covin 19 and according to this meta-analysis at least the results are compelling the authors combine data from 24 randomized trials of ivermectin a total of 3 328 patients to examine a variety of outcomes ranging from resolution of symptoms to death i'm going to focus on mortality because it's a pretty important endpoint but the results for other outcomes are broadly similar 11 trials with about 2 000 patients total had death data available combining them gave a death rate of 3 percent in the ivermectin arm and 8.7 percent in the comparator arm a statistically significant result these forest plots can be a bit tough to read but basically each bar represents the effect of a single study and the diamond is the overall effect anything that crosses the line at one is not statistically significant so you have several studies trending towards significance that when combined give you that overall final result this is how meta-analyses work but there's a bit of a problem here remember that the data you get out of a meta-analysis is only as good as the data you put in and there are some things to criticize about this data the authors aggregated data from studies that were peer-reviewed those that were hosted on pre-print servers and those whose results they obtained through a network of researchers interested in ivermectin even if the studies hadn't been published elsewhere i broke down the mortality results by publication status here i'm worried about a few things here first inclusion of completely unpublished studies is really problematic since there's no way for anyone to vet the results it's possible that those people running trials with promising data are even more likely to provide that to the meta analyzers than those whose trials turned up nothing now i do get why you might want to include pre-prints in your meta-analysis peer review is slow and the pandemic is happening fast but peer review really does have a purpose some of these studies will probably never get published and not because dark forces are conspiring against ivermectin they just have some real problems one study driving the mortality benefit is this one out of iran hosted on a pre-print server it's a six-armed randomized trial of patients hospitalized with covid19 but it's weird according to table 1 29 of them were pcr negative for sars cov2 what's worse this percentage is much higher in the two control groups 47 percent compared to the ivermectin groups 20 my math suggests that such a discrepancy would occur only 2 out of 10 000 times if randomization was well random i'm not saying this is fake or anything but this is exactly the sort of thing that peer review would pick up on and give the authors a chance to correct and yet here this trial is given equal weight to all the others the other trial that seems to drive these results also not yet peer reviewed is the el gazar trial out of egypt here ivermectin was compared with hydroxychloroquine in 400 individuals with coven 19. the results were pretty stark in terms of death in the moderately ill group there were no deaths in the ivermectin group four in the hydroxychloroquine group in the severely ill group two deaths in the ivermectin group 20 in the hydroxychloroquine group now you'll note that hydroxychloroquine is not placebo so there's some chance that what we're seeing is a sign that hydroxychloroquine is bad not that ivermectin is good but inspired by the iran paper i went ahead and looked at table 1 again multiple statistically significant imbalances across baseline characteristics again this is very unlikely if there wasn't some failure of randomization now all i'm doing is some peer review of a study that has not yet been peer reviewed i'm not saying it's wrong but review would allow the authors to provide an explanation or maybe even reanalyze their results mistakes get made all the time in research it helps to have a critical eye others have noted that if you remove the iran and elgazar papers the protective effect of ivermectin in this meta-analysis disappears which doesn't mean ivermectin isn't useful what it means is we still don't know we don't have ironclad evidence the meta-analysis authors note that there are multiple large clinical trials going on right now that should seal the deal one way or the other but what do we do until then well the easy answer is to say just cut the gordian knot and get vaccinated then you won't even need ivermectin but there are plenty of places around the world where vaccines are not available and ivermectin is so here's my pitch all of these trialists should in the interest of public health release not just their results but their analytic data sets in a de-identified format to a site like datadryad.com so the community can review them directly instead of trying to parse what the authors mean in this or that sentence in the manuscript just share the data we'll know right away if we should believe it or not this is easy transparent and perfectly legal all of us ivermectin boosters or ivermectin detractors should speak with one voice on this we are in a public health emergency release the data so we can know for sure what to believe for medscape i'm perry wilson [Music] you

Channel: Medscape

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Length: 8min 46sec (526 seconds)

Published: Mon Sep 13 2021