Early in the pandemic, based on poor-quality studies, hydroxychloroquine was touted as a potential treatment for COVID-19. Then, once well designed studies evaluated it, we found out it has no effect. Is ivermectin the next hydroxychloroquine, or is it the miracle cure that some are proclaiming it to be?
What is ivermectin?
Ivermectin is a drug used to treat parasitic infections (predominantly used for the treatment of tropical diseases, like Strongyloidiasis). It’s normally pretty well tolerated when it’s used at the normal doses, and has been used to treat millions.
Why use an anti-parasitic drug against a virus?
The theory is that because ivermectin has activity against the SARS-CoV-2 virus (the virus that causes COVID-19) in vitro (i.e. in a test tube under lab conditions), then it should be effective. Others think it may have some anti-inflammatory properties that could help in the same way steroids were shown to help.
One problem with the theory of antiviral effect is that the amount of drug that actually gets into the body is nowhere near enough to have any antiviral effect like the in vitro studies. In fact, we would need to give 100 times the usual dose for it to reach the theoretical threshold for virus killing activity.
And, even if we did give this toxic dose of ivermectin, there’s still no guarantee that it will work. Many drugs that had plausible mechanisms for them to work (e.g. hydroxychloroquine, lopinavir/ritonavir) failed when used in clinical trials. This is because in vitro results don’t always translate to clinical results in people.
Why are people bashing a Nobel Prize winning medication?
Many internet memes and misinformation campaigns are touting the fact that ivermectin won a Nobel Prize as why it should be used to treat COVID-19 and that this puts it above questioning (somehow).
However, they often fail to specify that the Nobel Prize was won with regards to the treatment of parasitic infections (not for COVID-19). To use this as an argument that we should be using it is completely nonsensical. Organ transplant also has won a Nobel Prize, but this doesn’t mean we should start doing kidney transplants to treat COVID-19.
Are there studies that show ivermectin works in COVID-19?
Many groups that promote ivermectin cite several studies that have shown staggeringly positive results.
A major problem is that the overall quality of the studies is VERY low:
- One (the study by Elgazzar et al. in Egypt) was retracted after some investigations discovered that the entire study was almost certainly completely made up, and even plagiarized other studies by using a thesaurus app.
- Detailed investigations by Gideon Meyerowitz-Katz and Dr. Kyle Sheldrick have uncovered that several of the other studies also had major flaws. A 5 part series of articles on Medium details all the problems with the trials; ranging from odd patterns suggesting that the data were manipulated, improper randomization, major risks of bias, and potentially some data being falsified or made up.
Reminder: It’s absolutely essential to get results from properly done randomized controlled trials (RCTs).
How an RCT works is that participants are randomly allocated to one of two groups (experimental group vs control group) and then they are followed going forward. By randomly allocating people, we are essentially trying to eliminate as many other variables as possible to see if the main difference between the groups (treatment vs no treatment) had any impact.
Without randomization, you could get into a scenario where the treatment and control groups are very different. Do you think a chemotherapy trial with one group having more young patients with early cancer (compared to another group that had more elderly patients with advanced cancer) would be a fair way to compare a treatment? Probably not.
Bonus points if the participants and researchers are blinded (i.e. they don’t know) which group a participant has been placed in; this is usually done by using a placebo in the control group. This makes it less likely that someone could be influenced by knowing if someone received a treatment of not.
Another important point is that the studies should preferably measure an actual real-world outcome. Some studies earlier on measured things like COVID-19 viral load, or time-to-negative test. While these things are interesting (and potentially important), they aren’t what the ultimate goal is.
What we really want is a treatment that can prevent hospitalizations/death, reduce transmission, or at the very least reduce the duration of illness. Some of the studies being promoted as “proof” that ivermectin works don’t really have these real-world outcomes, and instead focus on things like viral load.
What did the randomized trials studying ivermectin show?
An excellent starting point for looking at evidence is to look at things like a meta-analysis or systematic review. These are essentially studies of studies, where they take a bunch of studies and then look at all of them side by side (or together) to look at the big picture to eliminate/reduce variations that can occur by chance.
The Cochrane Library (one of the biggest names in systematic reviews) has published a systematic review on ivermectin in the treatment or prevention of COVID-19. Here’s a rapid-fire summary of what they found:
- After excluding studies that did not meet basic criteria, they had a total of 14 trials
- Many of the studies had a high risk of bias (i.e. they had many uncontrolled aspects/variables that had a high risk of skewing the results)
- In hospitalized patients, they found:
- No statistical benefit for reducing death, need for ventilation, need for supplementary oxygen, viral clearance, duration of hospitalization, or side effects,
- In non-hospitalized patients with mild illness, they found:
- No statistical benefit for reducing death, need for ventilation, viral clearance, duration of illness, or side effects.
- In the prevention of COVID-19, they found:
- No statistical benefit for reducing death
- They saw a reduction of COVID-19 symptoms in the treatment group (but they didn’t even test all of them to confirm that it was actually COVID-19…)
So, not exactly great stuff to support the use of ivermectin in COVID-19. If it was the “game-changer” that is being promoted by some charlatans, this would not be the case.
The NIH also did a review of the evidence, and concluded there wasn’t enough evidence to support the use of ivermectin.
You may see two other reviews referenced by people claiming ivermectin is a “game-changer”. The first review includes the fraudulent study I mentioned earlier (that was apparently literally made up), along with several of the other ones with potential problems. Because of these reasons, I don’t personally trust their conclusions. (To be clear, I am not accusing them of any wrongdoing for citing the article; at the time of their work much of this information on potential fraud was not available).
The other commonly cited review by Andrew Hill and colleagues also initially cited the same article. But he has recently clarified that they retracted their initial report due to the fraudulent study. They have since updated their analysis (also adding results from 2 large trials) and now have concluded that there is no benefit to using ivermectin for COVID-19. They go on to say, quite clearly, that ivermectin “is not a viable option to treat patients with COVID-19”.
More (yet to be published) results from a large, well-designed, randomized (double blind) placebo-controlled trial from Brazil (TOGETHER) have also been shared. During a presentation to the NIH, a lead investigator of the TOGETHER trial presented their results showing that there was no observable benefit to using ivermectin for COVID-19.
If ivermectin probably doesn’t work, then why does the NIH still say it should be studied?
This statement has been made to me a few times recently; and it’s important to clarify something: when there isn’t much high quality data, the NIH will almost always say that “well-conducted clinical trials are needed”.
But in this instance, the statement is being slightly quote-mined (i.e. taken out of context). The NIH guidelines will only use published high-quality evidence to make recommendations. So, when it comes to ivermectin, because the quality of evidence is just so bad, they go on to say:
There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.– NIH COVID-19 Treatment Guidelines – Ivermectin
This statement is clearly not a recommendation that ivermectin must be studied, nor is it any indication that there is promise to be seen with ivermectin. It’s just saying that because there isn’t much quality published information that they can’t take any official position.
*Note that there are other studies that are already underway, so their results should help NIH and other groups to make a final call on ivermectin.
One last comment
I think it’s important to tell people that I really wanted to be wrong about ivermectin. We need to keep discovering therapies that can help treat those who suffer from COVID-19 (either when in hospital or to prevent severe illness in the first place). A cheap and usually well tolerated drug would be great. But, as this post details, ivermectin is not looking very promising in well done studies.
If we keep wasting our time on things that have a low likelihood of making any impact, the longer we will have to wait before we find something that actually works.
The Bottom Line
Does ivermectin work for COVID-19?
Based on current evidence, ivermectin is very unlikely to be effective for the treatment of COVID-19. While some preliminary data from small poorly-done studies showed a potential for its use, many of these trials have now been shown to have major problems (ranging from suspicious data patterns to outright scientific fraud). A recent large placebo controlled randomized controlled trial in Brazil failed to observe any benefit with the early use of ivermectin in the treatment of COVID-19.
Let’s see what the Rxplanation Bullsh*t Meter reads:
The BS meter reads: “Almost BS”.
I can’t bring myself to say total BS, since, as I’ve said, the quality of evidence is not very high. However, the higher-quality evidence we do have suggests it has no significant impact.
I think we can be decently certain that ivermectin doesn’t have a role in treating COVID-19 outside of a research setting. If it was the game-changer that is being promoted, we would have seen it in the well designed larger trials.
Since we have other treatments (e.g. dexamethasone, monoclonal antibodies, tocilizumab, baricitinib, budesonide, etc.) that have been shown to work in well done studies, it would be unethical in my opinion to give something like ivermectin in their place.