Over the last year, I’ve watched in horror as ivermectin went from a pet theory to a cultish fringe belief and a dangerous “vaccine alternative”. I put together a comprehensive post summarizing the evidence and why it does not support use of ivermectin outside of a clinical trial.
Conflict between in vitro data and pharmacokinetics -
Ivermania began in early 2020, when a group of scientists in Australia found that ivermectin, a widely used anti-parasitic drug, could apparently stop SARS-CoV2 from replicating in vitro. There are always limitations to in vitro studies, but especially in the early days of the pandemic, a repurposed medication to treat C-19 was an exciting prospect.
Unfortunately, from inception there appears to have been overreach. The original paper that found that ivermectin inhibited viral replication in cell culture used a 5 micromolar concentration. In vivo the drug has a Cmax of about 50 nanomolar. That means that dose that was required in vitro (IC50) is 100x higher than what can actually be achieved in vivo (Cmax). Even using a dose much higher than the safe/approved dose is unlikely to reach the level that was required in vitro.
Incredible results of early clinical trials -
Beginning just months into the pandemic there were a few hastily performed human studies of ivermectin. These studies had results that were simply incredible (and I mean this literally, as in “not credible”).
A large observational trial by Surgisphere found a strong association between ivermectin use and COVID survival. A randomized controlled trial by Elegazzar et al found that ivermectin treatment reduced COVID mortality by over 90%. And another RCT by Carvallo et al claimed that ivermectin prophylaxis was 100% effective in preventing SARS-CoV-2 infection in healthcare workers.
These early studies had implausibly large effect sizes, were mostly pre-prints (some such as Elegazzar were never peer reviewed despite being posted for over a year), and all had glaring methodologic flaws such as being non-randomized, having imbalanced allocation, unequal use of corticosteroids, and using HCQ and other disproven therapies as a control group, etc.
Higher quality RCTs don’t show benefit to Ivermectin -
This is not to say that all the studies are fake or methodologically flawed. In the last few months there have been some high quality ivermectin RCTs. Examples include the EPIC trial (published in JAMA), IVERCORCOVID (BMJ Infectious Disease), the TOGETHER trial (currently a pre-print), and the I-TECH trial (published in JAMA Internal Medicine). These more reputable studies have been uniformly negative.
Several ongoing trials should read out soon: PRINCIPLE in the UK, ACTIV-6 in the US, and many others. We will likely learn more in the coming months. In the meantime, I’d be cautious about interpreting the large number of ongoing trials as evidence of potential benefit, however. Recall that we also did a lot of trials of HCQ after it became popular.
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