The Wandering and Demise of Ivermectin for COVID-19: (Part 1) Developments Abroad
The Wandering and Demise of Ivermectin for COVID-19 (Part 1): International Developments
Ever since the start of the COVID-19 pandemic in early 2020, numerous drug candidates have been proposed in simulations. Many people will remember that the anti-HIV drug Kaletra® was among the first to be suggested. Humanity sought to combat this emerging infectious disease with existing drugs that could be used immediately. Besides Kaletra®, serine protease inhibitors® (Fusan®), asthma medication (Orvesco®), and a novel influenza treatment (Avigan®) were also proposed, but they failed to demonstrate efficacy in clinical trials and vanished from the list of candidate drugs. The parasitic treatment drug Ivermectin (and the anti-malarial drug hydroxychloroquine) were similarly proposed, but these drugs had a peculiar trajectory. Numerous instances of research misconduct occurred, and the resultant calamity surpassed even that of the STAP cell controversy. Furthermore, despite not demonstrating efficacy in numerous large-scale clinical trials, adherents of these drugs now exhibit the characteristics of an anti-medical cult. This article summarizes these developments. The international and Japanese situations will be explained in two separate parts.
1. The Start of the Ivermectin Frenzy
In 2020, an in vitro study at Monash University in Australia [1] reported that adding IVM 5μM just once to Vero-hSLAM cells (a cell line derived from Vero cells of African Green Monkey, expressing member 1 of the human signaling lymphocyte activation molecule family A (SLAMF1) or Signaling Lymphocyte Activation Molecule (SLAM)) infected with SARS-CoV-2 reduced virus RNA by about 5000 times after 48 hours. The Ivermectin concentration of 5μM (equivalent to about 9660ng/mL) used in this study is more than 100 times the peak blood concentration (50-80ng/mL for a weight of 60kg) at the dosage of 200μg/kg used for parasite treatment. The IVM dose required to achieve this, according to past animal experiment data, would correspond to a lethal dose (LD 50).
On December 8, 2020, at a U.S. Senate committee hearing, Pierre Kory claimed that "Ivermectin is virtually a 'miracle drug' against COVID-19 and could potentially end the pandemic." This assertion was based on the aforementioned in vitro study [1] and small-scale observational studies [2]. This led to media exaggeration and the spread of information by influencers. Subsequently, some small-scale studies reported efficacy for COVID-19, and demand for Ivermectin increased in early 2021 [3]. However, in a situation where no high-quality clinical trial had yet proven Ivermectin's effectiveness against COVID-19, it was difficult for medical institutions to recommend or use this drug. This situation was amplified when Brett Weinstein appeared on Tucker Carlson Today on Fox Nation on July 9, 2021, claiming he had been "censored for raising concerns about opposition from medical institutions," which fueled conspiratorial associations with Ivermectin [4].
2．Unusual Recommendations by Ivermectin Advocacy Groups and Associated Health Damage
Then emerged American organizations promoting Ivermectin (such as AFLDS and FLCCC). Their assertions were mostly irrational with scant evidence. In 2022, the number of visits to the FLCCC website declined as large-scale clinical trials consistently failed to show effectiveness. However, they are now making unfounded claims that Ivermectin is effective against influenza and RSV, desperately trying to sell it. Also characteristic of these doctors and groups is the spreading of false information about other drugs and vaccines to prevent their use, all to sell Ivermectin.
Such promotion of Ivermectin led the general public to obtain it without going through medical institutions, and health damage began to be observed. Normally, Ivermectin is used as an antiparasitic drug, with a dosage of 200μg/kg given twice at two-week intervals for intestinal ascariasis and once for scabies. But the promoting groups were recommending far higher doses, involving daily intake. Pierre Kory, the representative of FLCCC, even changed his recommendation to 24mg/day for himself when he contracted COVID-19, despite taking a preventive dose of Ivermectin (12mg/day). Naturally, this dosage has not been properly studied for safety.
Reports of neurological symptoms and visual abnormalities are prominent among those who take Ivermectin. In a report by Campillo et al. [5], of the 1777 COVID-19 patients administered Ivermectin, serious adverse events were reported in 53 cases (only 4 of which were overdoses), most of which were neurological symptoms. Adverse event reports related to the therapeutic or preventive use of Ivermectin for COVID-19 in 15 U.S. facilities reported to the FDA [6] show 40 reports (including 18 self-administrations of veterinary preparations), 33 emergency visits, 19 hospitalizations, 15 mild cases, 25 severe cases, with neurological toxicity being the most common. A U.S. cohort study of 1.3 million cases [7] reported that Ivermectin administration for COVID-19 significantly increased the risk of death compared to non-administration in both outpatient (7.7% vs 2.2%) and inpatient (15.6% vs 7.2%) settings, according to a propensity score matching analysis.
Also, in a prison in Arkansas, when a COVID-19 cluster occurred, an Ivermectin-promoting physician falsely explained (describing Ivermectin as a steroid or vitamin) and administered Ivermectin without consent to prisoners [8,9]. Some prisoners were given six times the authorized amount of Ivermectin, and four prisoners suffered side effects such as vision impairment, diarrhea, and stomach cramps, and are suing the doctor.
3. Confusion Caused by Overseas Epidemiological Data
Claims began to appear frequently on social media that ivermectin was effective against COVID-19 and that the spread of the disease had been successfully controlled in certain overseas cases. These assertions continue to be made based on those cases, but they are fundamentally mistaken.
(1) India
There is a widely spread argument among ivermectin supporters that, "During the massive wave of the COVID-19 outbreak in India in spring 2021, the Indian government recommended the use of ivermectin in its guidelines as an emergency measure, and immediately thereafter, the epidemic decreased, and the number of deaths declined in Uttar Pradesh, where ivermectin was used, proving its effectiveness."
However, there are fundamental errors in this argument. First of all, ivermectin use in Uttar Pradesh started in August 2020 [10], which means that it completely failed to prevent the major wave of COVID-19 in the spring of 2021. Furthermore, in populous areas of the state, the system collapsed entirely, and all deaths, COVID-19 and otherwise, ceased to be counted for several months [10]. Additionally, it is acknowledged by the state's health department that the state has underreported its coronavirus fatalities by a factor of 1/43, not counting deaths among those in home isolation [11,12]. The mortality rate in Uttar Pradesh among confirmed infected individuals (1.3%) is no different from the Indian average (1.4%), and there are numerous states with lower mortality rates than Uttar Pradesh [13]. Since then, ivermectin has been removed from India's guidelines [14], and two clinical trials conducted in India have not demonstrated its efficacy [15,16].
(2) Africa
Some African countries have been administering ivermectin to their populations on a regular basis for the purpose of preventing parasitic infections, long before the outbreak of COVID-19. The Tokyo Medical Association president has noted the argument that the low prevalence of COVID-19 in these countries is due to the efficacy of ivermectin, but this is also a significant misconception. There are many confounding factors between countries that administer ivermectin and those that do not, including climate, economic conditions, healthcare systems, population density, age distribution, education level, and religion. For instance, parasitic diseases tend to be prevalent in rural areas with low population densities. In countries with inadequate healthcare systems, they often lack the ability to conduct proper testing. In reality, a model constructed from various background factors estimates that the number of coronavirus infections in 47 African countries is 71 times the actual reported number [17].
Additionally, in terms of education level and religion, there are many cases where it is difficult to raise awareness of diseases or provide medical cooperation, such as beliefs that diseases are a curse (this was the case during the Ebola outbreak in West Africa). The administration of ivermectin to residents for the prevention of parasitic diseases in Africa is done only once or twice a year, and it is highly unlikely that this could significantly reduce the number of infected individuals. Furthermore, in these countries, regular administration of ivermectin to the population was interrupted due to the chaos caused by the COVID-19 outbreak, so they were not actually taking ivermectin [18].
(3) Peru
For some reason, there are claims that Peru managed to control the COVID-19 outbreak with ivermectin, but this is simply not the case. While Peru approved ivermectin as a treatment and preventative for COVID-19 in the spring of 2020, by June 2020, the mortality rate from coronavirus in Peru was the highest in the world [19]. Moreover, there have been reports of increased health damage (particularly liver damage) due to ivermectin in Peru [20], and even a report stating that those who took ivermectin had a higher risk of death [21]. The spread of misinformation that ivermectin and other drugs were good for treatment and prevention resulted in inadequate infection control measures and a false sense of security, which are thought to be factors that increased the risk of death among ivermectin users [22].
4. Rampant Misconduct in Ivermectin Clinical Research
What happened in the clinical trials? On June 8, 2020, a paper showing the effectiveness of ivermectin against COVID-19, compiled by the University of Utah and others, was retracted for fabrication. However, this was due to the fabrication of fictitious big data by Surgisphere, a US data analysis company, and not only ivermectin but also several other papers on drugs were retracted. The company did not respond to inquiries from journals such as The Lancet and deleted its homepage. This was done by a specific clinical trial outsourcing company. After that, from the summer of 2021, misconduct occurred one after another from RCTs that showed the effectiveness of ivermectin, leading to a spate of retractions.
Andrew Hill, et al conducted a meta-analysis to examine ivermectin for COVID-19. Initially, it showed effectiveness [23], but it was temporarily withdrawn due to numerous allegations of misconduct in the ivermectin paper [24]. When they excluded the papers pointed out for misconduct, the revised results did not show effectiveness [25]. Ivermectin supporters excessively bashed this revised meta-analysis result, and even threats to kill Hill and his family were rampant, leading to widespread media reports that the movement around ivermectin has taken on the aspect of a cult religion. The number of ivermectin prescriptions in the United States peaked in August 2021 and rapidly declined thereafter as misconduct in the papers became rampant [26].
The whole picture of the ivermectin misconduct became clear on October 6, 2021 [27]. In clinical studies claiming that ivermectin prevented deaths from COVID-19, not a single one was found to be without "obvious signs of fabrication or serious errors that invalidate the study". Of the 26 major trials, five were suspected of data fabrication (such as virtually impossible numbers of data, non-randomized, copied & pasted rows of the same patient's data), and five more had serious issues such as inconsistent numbers, incorrect calculations of proportions, and local healthcare institutions not recognizing the implementation of the trial. More than one-third of the studies had serious errors or potential misconduct, and the remaining trials did not find convincing evidence of ivermectin's effectiveness. Adding to these flawed studies, 14 paper authors did not return raw data when requested, strongly suggesting possible misconduct.
In the annual edition of The Scientist's top 10 papers retracted for misconduct and other reasons [28], three COVID-19 related ones made it to the top 10 in 2021, one of which was an ivermectin paper (the other two were anti-vaccine papers and anti-mask papers). Ultimately, 14 ivermectin papers were retracted, an unusually high number. There are also several preprint papers not retracted but pointed out for suspected misconduct. As will be mentioned later, all subsequent large-scale trials resulted in negative outcomes, and no reproducibility was obtained. It was indeed a storm of misconduct that engulfed the world, far beyond the STAP cell uproar.
5. Large-scale Trials that All Ended Up Negative
Given all the misconduct so far, and considering that no efficacy could be shown in studies where no misconduct was pointed out, one would predict as a physician that "ivermectin may not work for the novel coronavirus." And indeed, all subsequent large-scale trials conducted in various countries around the world failed to show efficacy.
Entering 2022, the 490-case I-TECH trial in February, the 1358-case TOGETHER trial in March, the 983-case trial in Thailand, the 1158-case trial in Iran, the 476-case trial in China in July, the 1431-case COVID-OUT in August, the 1519-case ACTIV-6 (standard dose) in October, and the 1206-case ACTIV-6 (high dose) in December were all published, but not a single study showed efficacy. The verification of ivermectin for patients with COVID-19 is now essentially complete, and it is now judged as ineffective for COVID-19. On March 6, 2023, the revised COVID-19 treatment guidelines of the U.S. National Institutes of Health (NIH) changed the description to "recommend not using ivermectin," including even the clinical trials that were exceptionally allowed. Currently, there are no physicians specializing in infectious diseases who are vocally advocating for the use of ivermectin for COVID-19.
This concludes the summary of ivermectin for COVID-19 abroad. Next time, I will discuss the situation within Japan.
[1] Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178: 104787
https://doi.org/10.1016/j.antiviral.2020.104787
[2] Pierre Kory. HOmeland Security Committee Meeting Focus on Early Treatment of COVID-19. 2020 Dec. 8
https://www.hsgac.senate.gov/wp-content/uploads/imo/media/doc/Testimony-Kory-2020-12-08.pdf
[3] Ostrovsky MA, et al. Impact of misinformation on ivermectin internet searches and prescribing trends during COVID-19. J Pub Health 2022 Dec.18
https://doi.org/10.1093/pubmed/fdac152
[4] Baker AS, Maddox A, et al. From COVID-19 Treatment to Miracle Cure; The Role of Influencers and Public Figures in Amplifying the Hydroxychloroquine and Ivermectin Conspiracy Theories during the Pandemic. Media Culture J 2022;25
https://openaccess.city.ac.uk/id/eprint/27960/
[5] Campillo JT, Faillie JL. Adverse drug reactions associated with ivermectin use for COVID-19 reported in the World Health Organization's pharmacovigilance database. Therapies 2022; 77: 747-9
https://doi.org/10.1016/j.therap.2022.03.002
[6] Farah R, Kazzi Z, Brent J, et al. Ivermectin associated adverse events in the treatment and prevention of COVID-19 reported to the FACT pharmacovigilance project. Clin Toxicol (Phila) 2022; 60: 942-6
https://doi.org/10.1080/15563650.2022.2070187
[7] Annie FH, Campbell J, Searls L, et al. The Effect of Ivermectin on Cases of COVID-19. Cardiovasc Revasc Med 2022; 44 :98-100
https://doi.org/10.1016/j.carrev.2022.06.004
[8] InmatesInmates Weren't Told They Were Given An Anti-Parasite Drug Instead Of COVID-19 Meds. npr 2021 Sep.2
https://www.npr.org/2021/09/02/1033586429/anti-parasite-drug-covid-19-ivermectin-washington-county-arkansas?utm_campaign=storyshare&utm_source=twitter.com&utm_medium=social
[9] Migdon B. Arkansas inmates unknowingly given ivermectin to treat COVID-19, lawsuit says. Changing America 2022 Jan.17
https://thehill.com/changing-america/respect/equality/590046-arkansas-inmates-unknowingly-given-ivermectin-to-treat/
[10] Ramos TJ. There is no scientific basis for claims of ivermectin’s success in Uttar Pradesh, India; Recorded cases of COVID-19 in Uttar Pradesh have fallen, but there is no consensus about why. Poynter Fact Check 2021 Nov.16
https://www.poynter.org/fact-checking/2021/there-is-no-scientific-basis-for-claims-of-ivermectins-success-in-uttar-pradesh-india/
[11] Siddiqui P. Uttar Pradesh: Corona casualties under-reported by 43 times, says Akhilesh Yadav. 2021 Jun.23
https://timesofindia.indiatimes.com/city/lucknow/corona-casualties-under-reported-by-43-times-akhilesh/articleshow/83762453.cms
[12] Lalchandani N. Uttar Pradesh: No data on Covid deaths in home isolation, says health minister Jai Pratap Singh. 2021 Aug.20
https://timesofindia.indiatimes.com/city/lucknow/no-data-on-covid-deaths-in-home-isolation-health-min/articleshow/85473261.cms
[13] Das NK. Kerala's COVID-19 lessons for India and Modi's government. 2021 Aug.29
https://www.japantimes.co.jp/news/2021/08/29/asia-pacific/kerala-cornavirus-lessons-india-modi/
[14] Yhacker T, Bureau ET. HCQ, another drug dropped from Covid treatment protocol. 2021 Sep.24
https://economictimes.indiatimes.com/news/india/hcq-another-drug-dropped-from-covid-treatment-protocol/articleshow/86469107.cms
[15] Ravikirti, Roy R, Pattadar C, et al. Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India. J Pharm Pharm Sci 2021; 24:343-50
https://doi.org/10.18433/jpps32105
[16] Mohan, Tiwari P, Suri TM, et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. J Infect Chemother 2021; 27: 1743-9
https://doi.org/10.1016/j.jiac.2021.08.021
[17] Cabore WJ, Karamagi CH, Kiproto KH, et al. COVID-19 in the 47 countries of the WHO African region: a modelling analysis of past trends and future patterns. Lancet Glob Health 2022; 10: E1099-114
https://doi.org/10.1016/S2214-109X(22)00233-9
[18] Hamley IDJ, Blok JD, Walker M, et al. What does the COVID-19 pandemic mean for the next decade of onchocerciasis control and elimination? Trans R Soc Trop Med Hyg 2021; 115: 269-80
https://doi.org/10.1093/trstmh/traa193
[19] Artikel D. Beispiel Peru: Ivermectin kein Covid-19-Mittel. 2022 Jan.10
https://science.orf.at/stories/3210743/
[20] Oscanoa JT, Amado J, Romero-Ortuno R, et al. Hepatic disorders associated with the use of Ivermection for SARS-CoV-2 infection in adults: a pharmacovigilance study in VigiBase. Gastroenterol Hepatol Bed Bench 2022; 15: 426-9
https://doi.org/10.22037/ghfbb.v15i4.2383
[21] Soto A, Quiñones-Laveriano MD, Azañero J, et al. Mortality and associated risk factors in patients hospitalized due to COVID-19 in a Peruvian reference hospital. PLoS One 2022; 17: e0264789
https://doi.org/10.1371/journal.pone.0264789
[22] Schwalb A, Armyra E, Méndez-Aranda M, et al. COVID-19 in Latin America and the Caribbean: Two years of the pandemic. J Intern Med 2022; 292: 409-27
https://doi.org/10.1111/joim.13499
[23] Hill A, Garratt A, Levi J, et al. Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection. Open Forum Infect Dis 2021; 8: ofab35
https://doi.org/10.1093/ofid/ofab358
[24] Hill A, Garratt A, Levi J. Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection. Open Forum Infect Dis 2022; 9: ofac056
https://doi.org/10.1093/ofid/ofac056
[25] Hill A, Mirchandani M, Pilkington V, et al. Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud. Open Forum Infect Dis 2022; 9: ofab645
https://doi.org/10.1093/ofid/ofab645
[26] Ostrovsky AM, Parikh C. Impact of misinformation on ivermectin internet searches and prescribing trends during COVID-19. J Pub Health 2022 Dec.18
https://doi.org/10.1093/pubmed/fdac152
[27] Schraer R,Goodman J. Ivermectin: How false science created a Covid 'miracle' drug. BBC Reality Check 2021 Oct.6
https://www.bbc.com/news/health-58170809
[28] Retraction Watch. The Top Retractions of 2021. The Scientists 2021 Dec.21
https://www.the-scientist.com/news-opinion/the-top-retractions-of-2021-69533
Ever since the start of the COVID-19 pandemic in early 2020, numerous drug candidates have been proposed in simulations. Many people will remember that the anti-HIV drug Kaletra® was among the first to be suggested. Humanity sought to combat this emerging infectious disease with existing drugs that could be used immediately. Besides Kaletra®, serine protease inhibitors® (Fusan®), asthma medication (Orvesco®), and a novel influenza treatment (Avigan®) were also proposed, but they failed to demonstrate efficacy in clinical trials and vanished from the list of candidate drugs. The parasitic treatment drug Ivermectin (and the anti-malarial drug hydroxychloroquine) were similarly proposed, but these drugs had a peculiar trajectory. Numerous instances of research misconduct occurred, and the resultant calamity surpassed even that of the STAP cell controversy. Furthermore, despite not demonstrating efficacy in numerous large-scale clinical trials, adherents of these drugs now exhibit the characteristics of an anti-medical cult. This article summarizes these developments. The international and Japanese situations will be explained in two separate parts.
1. The Start of the Ivermectin Frenzy
In 2020, an in vitro study at Monash University in Australia [1] reported that adding IVM 5μM just once to Vero-hSLAM cells (a cell line derived from Vero cells of African Green Monkey, expressing member 1 of the human signaling lymphocyte activation molecule family A (SLAMF1) or Signaling Lymphocyte Activation Molecule (SLAM)) infected with SARS-CoV-2 reduced virus RNA by about 5000 times after 48 hours. The Ivermectin concentration of 5μM (equivalent to about 9660ng/mL) used in this study is more than 100 times the peak blood concentration (50-80ng/mL for a weight of 60kg) at the dosage of 200μg/kg used for parasite treatment. The IVM dose required to achieve this, according to past animal experiment data, would correspond to a lethal dose (LD 50).
On December 8, 2020, at a U.S. Senate committee hearing, Pierre Kory claimed that "Ivermectin is virtually a 'miracle drug' against COVID-19 and could potentially end the pandemic." This assertion was based on the aforementioned in vitro study [1] and small-scale observational studies [2]. This led to media exaggeration and the spread of information by influencers. Subsequently, some small-scale studies reported efficacy for COVID-19, and demand for Ivermectin increased in early 2021 [3]. However, in a situation where no high-quality clinical trial had yet proven Ivermectin's effectiveness against COVID-19, it was difficult for medical institutions to recommend or use this drug. This situation was amplified when Brett Weinstein appeared on Tucker Carlson Today on Fox Nation on July 9, 2021, claiming he had been "censored for raising concerns about opposition from medical institutions," which fueled conspiratorial associations with Ivermectin [4].
2．Unusual Recommendations by Ivermectin Advocacy Groups and Associated Health Damage
Then emerged American organizations promoting Ivermectin (such as AFLDS and FLCCC). Their assertions were mostly irrational with scant evidence. In 2022, the number of visits to the FLCCC website declined as large-scale clinical trials consistently failed to show effectiveness. However, they are now making unfounded claims that Ivermectin is effective against influenza and RSV, desperately trying to sell it. Also characteristic of these doctors and groups is the spreading of false information about other drugs and vaccines to prevent their use, all to sell Ivermectin.
Such promotion of Ivermectin led the general public to obtain it without going through medical institutions, and health damage began to be observed. Normally, Ivermectin is used as an antiparasitic drug, with a dosage of 200μg/kg given twice at two-week intervals for intestinal ascariasis and once for scabies. But the promoting groups were recommending far higher doses, involving daily intake. Pierre Kory, the representative of FLCCC, even changed his recommendation to 24mg/day for himself when he contracted COVID-19, despite taking a preventive dose of Ivermectin (12mg/day). Naturally, this dosage has not been properly studied for safety.
Reports of neurological symptoms and visual abnormalities are prominent among those who take Ivermectin. In a report by Campillo et al. [5], of the 1777 COVID-19 patients administered Ivermectin, serious adverse events were reported in 53 cases (only 4 of which were overdoses), most of which were neurological symptoms. Adverse event reports related to the therapeutic or preventive use of Ivermectin for COVID-19 in 15 U.S. facilities reported to the FDA [6] show 40 reports (including 18 self-administrations of veterinary preparations), 33 emergency visits, 19 hospitalizations, 15 mild cases, 25 severe cases, with neurological toxicity being the most common. A U.S. cohort study of 1.3 million cases [7] reported that Ivermectin administration for COVID-19 significantly increased the risk of death compared to non-administration in both outpatient (7.7% vs 2.2%) and inpatient (15.6% vs 7.2%) settings, according to a propensity score matching analysis.
Also, in a prison in Arkansas, when a COVID-19 cluster occurred, an Ivermectin-promoting physician falsely explained (describing Ivermectin as a steroid or vitamin) and administered Ivermectin without consent to prisoners [8,9]. Some prisoners were given six times the authorized amount of Ivermectin, and four prisoners suffered side effects such as vision impairment, diarrhea, and stomach cramps, and are suing the doctor.
3. Confusion Caused by Overseas Epidemiological Data
Claims began to appear frequently on social media that ivermectin was effective against COVID-19 and that the spread of the disease had been successfully controlled in certain overseas cases. These assertions continue to be made based on those cases, but they are fundamentally mistaken.
(1) India
There is a widely spread argument among ivermectin supporters that, "During the massive wave of the COVID-19 outbreak in India in spring 2021, the Indian government recommended the use of ivermectin in its guidelines as an emergency measure, and immediately thereafter, the epidemic decreased, and the number of deaths declined in Uttar Pradesh, where ivermectin was used, proving its effectiveness."
However, there are fundamental errors in this argument. First of all, ivermectin use in Uttar Pradesh started in August 2020 [10], which means that it completely failed to prevent the major wave of COVID-19 in the spring of 2021. Furthermore, in populous areas of the state, the system collapsed entirely, and all deaths, COVID-19 and otherwise, ceased to be counted for several months [10]. Additionally, it is acknowledged by the state's health department that the state has underreported its coronavirus fatalities by a factor of 1/43, not counting deaths among those in home isolation [11,12]. The mortality rate in Uttar Pradesh among confirmed infected individuals (1.3%) is no different from the Indian average (1.4%), and there are numerous states with lower mortality rates than Uttar Pradesh [13]. Since then, ivermectin has been removed from India's guidelines [14], and two clinical trials conducted in India have not demonstrated its efficacy [15,16].
(2) Africa
Some African countries have been administering ivermectin to their populations on a regular basis for the purpose of preventing parasitic infections, long before the outbreak of COVID-19. The Tokyo Medical Association president has noted the argument that the low prevalence of COVID-19 in these countries is due to the efficacy of ivermectin, but this is also a significant misconception. There are many confounding factors between countries that administer ivermectin and those that do not, including climate, economic conditions, healthcare systems, population density, age distribution, education level, and religion. For instance, parasitic diseases tend to be prevalent in rural areas with low population densities. In countries with inadequate healthcare systems, they often lack the ability to conduct proper testing. In reality, a model constructed from various background factors estimates that the number of coronavirus infections in 47 African countries is 71 times the actual reported number [17].
Additionally, in terms of education level and religion, there are many cases where it is difficult to raise awareness of diseases or provide medical cooperation, such as beliefs that diseases are a curse (this was the case during the Ebola outbreak in West Africa). The administration of ivermectin to residents for the prevention of parasitic diseases in Africa is done only once or twice a year, and it is highly unlikely that this could significantly reduce the number of infected individuals. Furthermore, in these countries, regular administration of ivermectin to the population was interrupted due to the chaos caused by the COVID-19 outbreak, so they were not actually taking ivermectin [18].
(3) Peru
For some reason, there are claims that Peru managed to control the COVID-19 outbreak with ivermectin, but this is simply not the case. While Peru approved ivermectin as a treatment and preventative for COVID-19 in the spring of 2020, by June 2020, the mortality rate from coronavirus in Peru was the highest in the world [19]. Moreover, there have been reports of increased health damage (particularly liver damage) due to ivermectin in Peru [20], and even a report stating that those who took ivermectin had a higher risk of death [21]. The spread of misinformation that ivermectin and other drugs were good for treatment and prevention resulted in inadequate infection control measures and a false sense of security, which are thought to be factors that increased the risk of death among ivermectin users [22].
4. Rampant Misconduct in Ivermectin Clinical Research
What happened in the clinical trials? On June 8, 2020, a paper showing the effectiveness of ivermectin against COVID-19, compiled by the University of Utah and others, was retracted for fabrication. However, this was due to the fabrication of fictitious big data by Surgisphere, a US data analysis company, and not only ivermectin but also several other papers on drugs were retracted. The company did not respond to inquiries from journals such as The Lancet and deleted its homepage. This was done by a specific clinical trial outsourcing company. After that, from the summer of 2021, misconduct occurred one after another from RCTs that showed the effectiveness of ivermectin, leading to a spate of retractions.
Andrew Hill, et al conducted a meta-analysis to examine ivermectin for COVID-19. Initially, it showed effectiveness [23], but it was temporarily withdrawn due to numerous allegations of misconduct in the ivermectin paper [24]. When they excluded the papers pointed out for misconduct, the revised results did not show effectiveness [25]. Ivermectin supporters excessively bashed this revised meta-analysis result, and even threats to kill Hill and his family were rampant, leading to widespread media reports that the movement around ivermectin has taken on the aspect of a cult religion. The number of ivermectin prescriptions in the United States peaked in August 2021 and rapidly declined thereafter as misconduct in the papers became rampant [26].
The whole picture of the ivermectin misconduct became clear on October 6, 2021 [27]. In clinical studies claiming that ivermectin prevented deaths from COVID-19, not a single one was found to be without "obvious signs of fabrication or serious errors that invalidate the study". Of the 26 major trials, five were suspected of data fabrication (such as virtually impossible numbers of data, non-randomized, copied & pasted rows of the same patient's data), and five more had serious issues such as inconsistent numbers, incorrect calculations of proportions, and local healthcare institutions not recognizing the implementation of the trial. More than one-third of the studies had serious errors or potential misconduct, and the remaining trials did not find convincing evidence of ivermectin's effectiveness. Adding to these flawed studies, 14 paper authors did not return raw data when requested, strongly suggesting possible misconduct.
In the annual edition of The Scientist's top 10 papers retracted for misconduct and other reasons [28], three COVID-19 related ones made it to the top 10 in 2021, one of which was an ivermectin paper (the other two were anti-vaccine papers and anti-mask papers). Ultimately, 14 ivermectin papers were retracted, an unusually high number. There are also several preprint papers not retracted but pointed out for suspected misconduct. As will be mentioned later, all subsequent large-scale trials resulted in negative outcomes, and no reproducibility was obtained. It was indeed a storm of misconduct that engulfed the world, far beyond the STAP cell uproar.
5. Large-scale Trials that All Ended Up Negative
Given all the misconduct so far, and considering that no efficacy could be shown in studies where no misconduct was pointed out, one would predict as a physician that "ivermectin may not work for the novel coronavirus." And indeed, all subsequent large-scale trials conducted in various countries around the world failed to show efficacy.
Entering 2022, the 490-case I-TECH trial in February, the 1358-case TOGETHER trial in March, the 983-case trial in Thailand, the 1158-case trial in Iran, the 476-case trial in China in July, the 1431-case COVID-OUT in August, the 1519-case ACTIV-6 (standard dose) in October, and the 1206-case ACTIV-6 (high dose) in December were all published, but not a single study showed efficacy. The verification of ivermectin for patients with COVID-19 is now essentially complete, and it is now judged as ineffective for COVID-19. On March 6, 2023, the revised COVID-19 treatment guidelines of the U.S. National Institutes of Health (NIH) changed the description to "recommend not using ivermectin," including even the clinical trials that were exceptionally allowed. Currently, there are no physicians specializing in infectious diseases who are vocally advocating for the use of ivermectin for COVID-19.
This concludes the summary of ivermectin for COVID-19 abroad. Next time, I will discuss the situation within Japan.
[1] Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178: 104787
https://doi.org/10.1016/j.antiviral.2020.104787
[2] Pierre Kory. HOmeland Security Committee Meeting Focus on Early Treatment of COVID-19. 2020 Dec. 8
https://www.hsgac.senate.gov/wp-content/uploads/imo/media/doc/Testimony-Kory-2020-12-08.pdf
[3] Ostrovsky MA, et al. Impact of misinformation on ivermectin internet searches and prescribing trends during COVID-19. J Pub Health 2022 Dec.18
https://doi.org/10.1093/pubmed/fdac152
[4] Baker AS, Maddox A, et al. From COVID-19 Treatment to Miracle Cure; The Role of Influencers and Public Figures in Amplifying the Hydroxychloroquine and Ivermectin Conspiracy Theories during the Pandemic. Media Culture J 2022;25
https://openaccess.city.ac.uk/id/eprint/27960/
[5] Campillo JT, Faillie JL. Adverse drug reactions associated with ivermectin use for COVID-19 reported in the World Health Organization's pharmacovigilance database. Therapies 2022; 77: 747-9
https://doi.org/10.1016/j.therap.2022.03.002
[6] Farah R, Kazzi Z, Brent J, et al. Ivermectin associated adverse events in the treatment and prevention of COVID-19 reported to the FACT pharmacovigilance project. Clin Toxicol (Phila) 2022; 60: 942-6
https://doi.org/10.1080/15563650.2022.2070187
[7] Annie FH, Campbell J, Searls L, et al. The Effect of Ivermectin on Cases of COVID-19. Cardiovasc Revasc Med 2022; 44 :98-100
https://doi.org/10.1016/j.carrev.2022.06.004
[8] InmatesInmates Weren't Told They Were Given An Anti-Parasite Drug Instead Of COVID-19 Meds. npr 2021 Sep.2
https://www.npr.org/2021/09/02/1033586429/anti-parasite-drug-covid-19-ivermectin-washington-county-arkansas?utm_campaign=storyshare&utm_source=twitter.com&utm_medium=social
[9] Migdon B. Arkansas inmates unknowingly given ivermectin to treat COVID-19, lawsuit says. Changing America 2022 Jan.17
https://thehill.com/changing-america/respect/equality/590046-arkansas-inmates-unknowingly-given-ivermectin-to-treat/
[10] Ramos TJ. There is no scientific basis for claims of ivermectin’s success in Uttar Pradesh, India; Recorded cases of COVID-19 in Uttar Pradesh have fallen, but there is no consensus about why. Poynter Fact Check 2021 Nov.16
https://www.poynter.org/fact-checking/2021/there-is-no-scientific-basis-for-claims-of-ivermectins-success-in-uttar-pradesh-india/
[11] Siddiqui P. Uttar Pradesh: Corona casualties under-reported by 43 times, says Akhilesh Yadav. 2021 Jun.23
https://timesofindia.indiatimes.com/city/lucknow/corona-casualties-under-reported-by-43-times-akhilesh/articleshow/83762453.cms
[12] Lalchandani N. Uttar Pradesh: No data on Covid deaths in home isolation, says health minister Jai Pratap Singh. 2021 Aug.20
https://timesofindia.indiatimes.com/city/lucknow/no-data-on-covid-deaths-in-home-isolation-health-min/articleshow/85473261.cms
[13] Das NK. Kerala's COVID-19 lessons for India and Modi's government. 2021 Aug.29
https://www.japantimes.co.jp/news/2021/08/29/asia-pacific/kerala-cornavirus-lessons-india-modi/
[14] Yhacker T, Bureau ET. HCQ, another drug dropped from Covid treatment protocol. 2021 Sep.24
https://economictimes.indiatimes.com/news/india/hcq-another-drug-dropped-from-covid-treatment-protocol/articleshow/86469107.cms
[15] Ravikirti, Roy R, Pattadar C, et al. Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India. J Pharm Pharm Sci 2021; 24:343-50
https://doi.org/10.18433/jpps32105
[16] Mohan, Tiwari P, Suri TM, et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. J Infect Chemother 2021; 27: 1743-9
https://doi.org/10.1016/j.jiac.2021.08.021
[17] Cabore WJ, Karamagi CH, Kiproto KH, et al. COVID-19 in the 47 countries of the WHO African region: a modelling analysis of past trends and future patterns. Lancet Glob Health 2022; 10: E1099-114
https://doi.org/10.1016/S2214-109X(22)00233-9
[18] Hamley IDJ, Blok JD, Walker M, et al. What does the COVID-19 pandemic mean for the next decade of onchocerciasis control and elimination? Trans R Soc Trop Med Hyg 2021; 115: 269-80
https://doi.org/10.1093/trstmh/traa193
[19] Artikel D. Beispiel Peru: Ivermectin kein Covid-19-Mittel. 2022 Jan.10
https://science.orf.at/stories/3210743/
[20] Oscanoa JT, Amado J, Romero-Ortuno R, et al. Hepatic disorders associated with the use of Ivermection for SARS-CoV-2 infection in adults: a pharmacovigilance study in VigiBase. Gastroenterol Hepatol Bed Bench 2022; 15: 426-9
https://doi.org/10.22037/ghfbb.v15i4.2383
[21] Soto A, Quiñones-Laveriano MD, Azañero J, et al. Mortality and associated risk factors in patients hospitalized due to COVID-19 in a Peruvian reference hospital. PLoS One 2022; 17: e0264789
https://doi.org/10.1371/journal.pone.0264789
[22] Schwalb A, Armyra E, Méndez-Aranda M, et al. COVID-19 in Latin America and the Caribbean: Two years of the pandemic. J Intern Med 2022; 292: 409-27
https://doi.org/10.1111/joim.13499
[23] Hill A, Garratt A, Levi J, et al. Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection. Open Forum Infect Dis 2021; 8: ofab35
https://doi.org/10.1093/ofid/ofab358
[24] Hill A, Garratt A, Levi J. Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection. Open Forum Infect Dis 2022; 9: ofac056
https://doi.org/10.1093/ofid/ofac056
[25] Hill A, Mirchandani M, Pilkington V, et al. Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud. Open Forum Infect Dis 2022; 9: ofab645
https://doi.org/10.1093/ofid/ofab645
[26] Ostrovsky AM, Parikh C. Impact of misinformation on ivermectin internet searches and prescribing trends during COVID-19. J Pub Health 2022 Dec.18
https://doi.org/10.1093/pubmed/fdac152
[27] Schraer R,Goodman J. Ivermectin: How false science created a Covid 'miracle' drug. BBC Reality Check 2021 Oct.6
https://www.bbc.com/news/health-58170809
[28] Retraction Watch. The Top Retractions of 2021. The Scientists 2021 Dec.21
https://www.the-scientist.com/news-opinion/the-top-retractions-of-2021-69533
by DrMagicianEARL
| 2023-06-08 09:44
| 感染症
