Article Review: Ivermectin

In the previous blog, we discussed the importance of a standardized format for scientific papers and touched on the material expected in each section. Building on this, I think it is a good idea to apply this knowledge to leading-edge research, and what better topic than something as polarizing as ivermectin. This post will cover a published, peer-reviewed article about the treatment of COVID-19 positive patients with ivermectin, with particular attention paid to the design of the experiment and the conclusions the authors present.

Article Referenced
A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness - International Journal of Infectious Diseases Feb 2021.

Immediately upon reading the title of this article, one word should jump out as the most important takeaway, and that is the qualifier 'may'. In this published work, the authors are claiming in their title that a five-day course of ivermectin has shown promising results and may be a potential treatment for COVID-19 positive patients.

Why is the qualifier 'may' so important? There are two reasons: first, one study is generally insufficient to make sweeping calls about the efficacy of any treatment for a human condition, and second, people often only read a title or a headline and usages of terms like 'may' help to mitigate overreaction.

As far as titles go, it is fine. It conveys the treatment, the treatment group, and the potential outcomes observed in their experimentation. There are no red flags or concerns about the quality of the study from simply reading the title.

Abstract
As mentioned in my Anatomy of a Journal Article blog post, the abstract can be thought of as the TLDR version of the full paper and must contain as much information as possible to accurately portray the experiment, the data, and the authors' conclusions.

In this paper, the authors do a very good job of condensing their work into a single paragraph. They describe their study cohort (72 patients at a hospital in Bangladesh with similar symptoms), the study design (three groups: one given ivermectin, one given ivermectin and doxycycline, and one given a placebo), and the authors' findings and conclusions.

Perhaps the most important line in the abstract is the last line, "larger trials will be needed to confirm these preliminary findings." The authors have presented data that indicates ivermectin could have a potential use in the treatment of COVID-19 positive patients but this study should serve to advise larger scale clinical trials, not be taken as evidence for ivermectin to be immediately prescribed.  

Introduction
The introduction to this paper explains what COVID-19 is and lists out the reasons they believe further investigation into the use of ivermectin as a COVID-19 treatment is warranted.

Their reasoning is based on a number of previous studies:
1. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, (Clay et al, 2020): Study shows that a specific cell line (Vero/hSlam, derived from African green monkey kidney tissue) has lower levels of virus after treatment with ivermectin. Note that cultured cells often react differently than cells in the body and these cells were not human or from the respiratory system and may not be an effective analog.
2. A case series of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline (Alam et al, 2020): This study seems to indicate that treatment with ivermectin and doxycycline is effective however based on this line from their conclusions, "our number is small and there is no control group," I would not use this study as evidence in favor of ivermectin.

There are a few other articles cited but we can move on. The point is that a number of studies exist looking into ivermectin as a treatment and they all seem to have the same caveats, small groups, poor controls, or very preliminary findings. Poor controls aside, the other two caveats are not problems, in fact they are common for studies into human treatments but they are by no means solid enough evidence to point to ivermectin as an effective treatment, yet.

Methods
This article claims to have conducted a "randomized, double-blind, placebo-controlled trial." Let's break this down really quickly:
1. Randomized: the patients chosen for the study were assigned to their group randomly.
2. Double-blind: the patients and the researchers do not know which patient is in which group
3. Placebo-controlled: one group is a control group given a placebo in place of ivermectin or ivermectin + doxycycline.

Patients were divided into three groups: the placebo control, a group given 12mg of ivermectin daily for five days, and a group given 12mg of ivermectin and 200 mg of doxycycline on day one and 100mg of doxycycline every 12 hours after for five days. To be eligible for the study the patients had to be admitted to the hospital less than 7 days prior to the study and present a fever (>37.5C), sore throat, and/or cough and be positively identified to have COVID via RT-PCR. Following the treatment, patients were tested for COVID via RT-PCR of nasal swabs at day 3, 7, and 14 and then weekly after until the virus had cleared.

Results
The research team highlights a number of findings but we will just touch on a few here:
1. Hospitalization Duration: The mean duration for hospital stays among the groups were: placebo 9.7 days, ivermectin + doxycycline 10.1 days, ivermectin alone 9.6 days. These results don't really highlight any benefit to ivermectin as there is no statistically significant difference between the groups.
2. Presented Symptoms: There was no observed difference in fever, cough or sore throat improvement between the groups.
3. Viral Clearance: The final aspect of COVID infection the team studied was the duration patients testing positive for COVID following the treatments. This was the only metric evaluated where the treatment groups appeared to benefit from ivermectin when compared to the placebo control. Mean clearance times were: 9.7 days for the ivermectin group, 11.5 days for the ivermectin + doxycycline group, and 12.7 days for the control.

In the attached figure, the authors show the results of testing each group on days 3, 7, and 14, with the x-axis (the horizontal axis) showing days and the y-axis (vertical axis) showing percentage of patients testing negative for COVID-19 via RT-PCR.

My immediate concern with the data presented here is the lack of data points between days 7 and 14. Each data point is a binary positive or negative value for COVID-19 infection, yet by only testing on three days, the researchers have essentially claimed that each patient who tests positive on day 3 or 7 is then considered positive until the next test. To me this renders their claims of "mean clearance time" inaccurate because patients only have three opportunities to test negative. It is entirely possible that patients were positive on day 7 but negative on day 8 or 9 and still counted as positive until day 14. While testing everyday may have been cost-prohibitive and resource intensive, it would have provided a much cleared picture to the true nature of viral clearance.

Looking at the raw numbers (which they call "Number at Risk" or patients still positive for COVID-19 infection), it does appear that ivermectin may play a role in viral clearance, particularly when comparing the placebo positive cases of 14 on day 14 to just 5 for the ivermectin group.

Discussion
The authors' main conclusion for this study is that ivermectin appears to play a role in reducing severity of COVID-19 infections while improving viral clearance time. I agree with the second half, time to viral clearance does appear to decrease in both ivermectin groups when compared to the control, I just wish the authors had more data points for more accurate conclusions.

The authors' then reiterate this is a small, pilot study but the evidence is enough to warrant further investigation. Again I agree with this statement, more investigation into ivermectin is warranted.

One final note on the study: the funding source for the study was from a pharmaceutical company who manufactures ivermectin. This is not a reason to discount the study, but important to note.

My Final Thoughts
All the evidence I read to prepare for this blog post indicates that ivermectin may have a role as a treatment for COVID-19. The effectiveness, dosage, and usage guidelines need to be studied further and larger human clinical studies are warranted.

Unfortunately, many have taken the positives from ivermectin studies as an indication that ivermectin is a wonder drug to treat COVID-19. This view is further amplified by a researcher who has published multiple review articles using the term "wonder drug," which I find distasteful in scientific research.

Based on my knowledge, ivermectin is one of many treatment options that should be investigated but expectations of its effectiveness should be tempered, as the most promising outcomes have been from small studies, studies lacking controls, or studies on non-human cultured cells. All the evidence points to ivermectin having effectiveness in patients with mild-to-moderate cases of COVID-19 who lack major co-morbidities, but may prove ineffective treatment for severe cases (patients on ventilators) or as a preventative treatment in place of the available vaccinations.

One thing that must be made abundantly clear is the ivermectin available over-the-counter is formulated for animals, such as horses, and cannot be safely administered to humans. I actually did calculate out the values for equine ivermectin paste compared to human dosage requirements but have decided to omit it here so people do not use those calculations for self-treatment.

The best way to combat COVID-19 infection, hospitalization, long-term disability or death remains a combination of vaccinations, wearing a mask, and staying home if you believe you may be sick. Ivermectin may prove an effective treatment for mild cases with further study but it is not a replacement for vaccination and will not rescue an individual with a severe infection. Ivermectin may be another tool to combat COVID-19 but it is not a "wonder" drug or a cure-all that is being withheld by medical professionals.

Perhaps most frustratingly, ivermectin and its potential usage for COVID-19 patients has brought out the worst from people on both sides of the political spectrum. One side laughs at desperate people taking "horse paste" and ignores any potential evidence that ivermectin could benefit some patients, while the other glorifies it as a miracle cure being withheld to force vaccinations on an unwilling public. The truth is, like most medication, it likely has a beneficial role in some cases and some patients and is ineffectual in others and for this reason larger-scale clinical trials should be supported.