Fanned by despair and social media, there has been a massive movement, both locally and internationally, for the immediate repurposing of anti-parasitic drug Ivermectin to treat COVID-19 writes MedicalBrief. In South Africa, despite stern warnings from the medicines’ regulator and the Medical Advisory Committee, there is growing illegal use of the drug. There are also, this week, the first signs that the SA authorities are softening their position.
The clamour in the media on social engagement platforms like Twitter, Facebook, Instagram and YouTube around Ivermectin has been intense and growing. It echoes the hype that during the early days of the COVID-19 pandemic punted hydroxychloroquine, chloroquine and azithromycin, until hastily conducted trials proved not only were they not efficacious but potentially dangerous.
It also takes place against a shifting of position in the United States of the National Institutes of Health. On 15 January the NIH upgraded their recommendation, making Ivermectin an option for use in COVID-19. This new designation upgraded the status of ivermectin from "against" to "neither for nor against", which is the same recommendation given to monoclonal antibodies and convalescent plasma, both widely used across the US. This may clear its path towards emergency use approval.
The drive for immediate use of Ivermectin has been spearheaded world-wide by the the Front Line COVID-19 Critical Care Alliance (FLCCC). The thrust of the argument for emergency authorisation is essentially twofold: that Ivermectin has a long and safe history as repurposed veterinary medicine used in humans; that there is no time for randomised trials at a moment when the death toll from COVID-19 has exceeded two million and vaccines are only slowly being distributed.
Ivermectin has been trialled in treating the coronavirus SARS-CoV-2. An in vitro trial has shown ivermectin reduces the number of cell-associated viral RNA by 99.8 % in 24 hours. It is currently approved by the US Food and Drug Agency (FDA) as safe in humans for the treatment of intestinal worms.
The FLCC maintain that Ivermectin has a special combination of anti-viral and anti-inflammatory properties that make it useful preventively and for treating early and late-stage illness. The FLCC's Dr Paul Marik, chief of pulmonary and critical care medicine at Eastern Virginia Medical School, who co-authored the review and meta-analysis based mainly on studies from outside the US and his group, composed mostly of critical care doctors, don't see a need for more data, arguing that it would be unethical to give placebo to patients given Ivermectin's established safety.
In South Africa, a number of practitioners have campaigned for the South African Health Products Regulatory Authority (SAHPRA) to give immediate emergency authorisation for Ivermectin.
It is an indicator of the despair and anxiety sparked by the Second Wave and the government's unconvincing assurances on a vaccine rollout, that local doctors have acknowledge confidentially to MedicalBrief that they have acquired stocks of Ivermectin — they contradict a statement by MAC's Professor Salim Abdool Karim that only veterinary versions of the drug are available in SA — for the treatment of family and close friends.
There should be no doubt, whatever the position of officialdom: Ivermectin is already being used widely, both under medical supervision, as well as without. Usage and cost are increasingly exponentially as bootleggers rush to fill a booming demand, with "Ivermectin" drugs of sometimes dubious origin.
Among those calling for emergency authorisation is Dr Farida Amod, a specialist at the Lenmed Shifaa Hospital, who told SABC News that while the vaccine was being procured, Ivermectin, with its well-established safety profile, could help to reduce the number of coronavirus infections and COVID-19 related deaths. Writing Maverick Citizen, Dr Nathi Mdladla, an intensive care doctor at Dr George Mukhari Academic Hospital, argued that there were strong medical and evidentiary grounds to make ivermectin available for compassionate use:
"For a drug that has been dosed almost 3.5 billion times since it came to existence, its side-effects are obviously negligible. We have more dangerous drugs with way more common side-effects than Ivermectin that are being used routinely, including many of our antiretrovirals that save lives."
Mdladla wrote that it was “unacceptable and inadequate” of the Rapid Review by the National Essential Medicines List Committee (NEMLC) COVID-19 subcommittee, which recommended SA wait for more large randomised controlled trials. Similarly, the president's Ministerial Advisory Committee (MAC) conclusion that 'until more robust evidence is available, the routine use of Ivermectin for either the prevention or treatment of COVID-19 is not justified", he assesses as "Although a step in the right direction, it is too timid and less pragmatic about maximising on saving patients’ lives".
The Times reported that 11 local clinicians, public health specialists, community health workers and medical scientists called the Ivermectin Interest Group (IIG) on 2 January, sent a 41-page dossier to Health minister Dr Zweli Mkhize, asking that he "accelerate research of Ivermectin and fully explore its potential in the COVID-19 response in a responsible way".
The IIG noted that while the use of the drug was controversial for "sound scientific reasons", they highlighted promising research by Liverpool University's Dr Andrew Hill, "a respected academic and World Health Organisation (WHO) researcher who has been tasked, as part of the Unitaid ACT Accelerator initiative, to improve access to COVID-19 treatments and diagnostics".
SAHPRA response was that it had not approved Ivermectin, and that any attempt to import it to South Africa would be illegal. "Ivermectin is not indicated nor approved by SAHPRA for use in humans. There is no confirmatory data on Ivermectin available as yet for its use in the management of COVID-19 infections. Ivermectin has made headlines recently as a so-called 'miracle cure' for COVID-19. However, SAHPRA’s stance is unambiguous. This drug is not approved by SAHPRA and any attempt to import this drug into the country will be perceived as being unlawful," said CEO Dr Boitumelo Semete-Makokotlela.
SAHPRA highlighted the findings of the DoH review in December 2020, which found that the "evidence of efficacy and safety is very uncertain, early phase studies were of very low quality and there is very low certainty evidence".
SAHPRA also cited a report on the pharmacokinetics of the drug which found that while Ivermectin is considered generally safe, side-effects include nausea, vomiting, diarrhoea, stomach pain, facial or limb swelling, neurologic adverse events (dizziness, seizures, and confusion), a sudden drop in blood pressure, severe skin rashes potentially requiring hospitalisation and liver injury (hepatitis).
SAHPRA did say that although that Ivermectin was not registered as a drug for humans, doctors could use a Section 21 application in terms of the Medicines and Related Substances Act to apply to dispense it as an unregistered product for the treatment of patients with conditions such as scabies or head lice. No such applications, to date, had been granted.
Now SAHPRA seems to backing off its earlier hardline. On 20 January it issued a statement say that it would "revisit" the meta-analysis of Hill, which it had earlier dismissed. It would also review all existing Section 21 applications, "pending the review of new data to support the use of Ivermectin in the treatment or prevention of Covid-19 infections".
Further, SAHPRA will now "fast-track a sufficiently-powered randomised controlled clinical trial application and expedite a registration dossier for Ivermectin for the treatment or prevention of COVID-19 infection when submitted".
The science behind Ivermectin for COVID-19 continues to be debated. Writing in MedPage Today, Kristina Fiore notes that the FLCCC's Marik is known for developing the HAT protocol for sepsis, which "hasn't been without controversy". It's a combination of hydrocortisone, ascorbic acid (vitamin C) and thiamine. His group's 2017 observational study of the protocol, published in CHEST, garnered excitement about the combination. But that hasn't been borne out in subsequent trials, including the ADRENAL study (which looked at steroids alone), the CITRIS-ALI study (which looked at vitamin C alone) and the VITAMINS trial, which randomised patients to the full protocol but was open-label. The VICTAS study has completed enrolment but hasn't yet reported data.
Marik said the group adapted the protocol for COVID-19, using a more potent steroid and adding an anticoagulant, along with other elements. The new name was MATH+, for methylprednisolone, ascorbic acid, thiamine, and heparin, plus a statin, zinc, vitamin D, famotidine, melatonin, and magnesium. The group used steroids at a time when major public health agencies, including the World Health Organization and the National Institutes of Health, were cautioning against them.
"We said, we see that this works," Marik told MedPage Today. "Then lo and behold in June, the RECOVERY trial was published, and it showed that dexamethasone reduced the risk of dying in people with COVID in the hospital." Marik continues to advocate for methylprednisolone, which is more potent than dexamethasone.
The group published in the Journal of Intensive Care Medicine their observational experience with MATH+ in from two centres: Marik's and United Memorial Medical Center in Texas, where another FLCCC leader, Dr Joseph Varon, leads the critical care unit — in the Journal of Intensive Care Medicine. "The average hospital mortality at these two centres in over 300 patients treated is 5.1%, which represents more than a 75% absolute risk reduction in mortality compared to the average published hospital mortality of 22.9% among COVID-19 patients," the paper states.
"Everyone in medicine will yell and scream that this paper is not a randomised controlled trial," (RCT), said the third FLCCC leader, Dr Pierre Kory. "We didn't believe in an RCT. We believe we're supposed to doctor and use our expertise. If you've been doing this for decades, and you trust your assessment of the disease and your knowledge of medicine, it's OK to doctor."
Now Marik and colleagues have updated their protocols yet again, this time with a focus on early treatment. While the rationale for Ivermectin existed early in the pandemic, thanks to an Australian basic science paper, there weren't enough clinical data to advise on its use, Marik said. The FDA warned against using veterinary ivermectin in humans following interest in that paper. But since then, some governments and hospitals began using the drug in an attempt to prevent or treat COVID-19.
So arose the group's I-MASK+ protocol, which focuses on Ivermectin, but also includes vitamins C and D, quercetin, zinc, and melatonin for prophylaxis, and adding aspirin. The group also emphasises wearing masks and other public health measures to prevent transmission of the disease.
Regarding Ivermectin for prophylaxis, they cite four randomised controlled trials and three observational studies. Two of the RCTs were done in Egypt, one in Argentina, and one in Bangladesh, ranging in size from 100 to 300 patients. Marik and colleagues also cite "natural experiments" in Peru, Brazil, and Paraguay where Ivermectin was distributed widely, with "large decreases in case counts … soon after distribution began."
For Ivermectin in mild illness, they cite five RCTs: two in Bangladesh, and one each in Iraq, Brazil, and Spain, varying in size from 24 patients (Spain) to 722 patients (Brazil).
For Ivermectin in hospitalised patients, they cite four RCTs in Egypt, Iran, India, and Bangladesh, ranging from 72 to 400 patients. They also cite a host of observational studies and case series in both mild and severe illness.
Healio reports that the RCT in Egypt found that among health care and household contacts of COVID-19 patients, just 2% of those who received Ivermectin and wore PPE tested positive for the novel coronavirus, compared with 10% of contacts who were only given PPE.
Marik and colleagues also described a randomised controlled trial of hospitalised patients that was done concurrently with the prophylaxis study. The trial included 400 patients split into four groups – two consisting of patients with mild to moderate illness and two consisting of severely ill patients. Patients with mild to moderate illness received one dose of Ivermectin per day in addition to standard care or hydroxychloroquine twice a day in addition to standard care. The researchers determined that the rate of illness progression was significantly lower among those who received Ivermectin (1% vs. 22%). Severely ill patients were assigned to receive standard care plus Ivermectin or hydroxychloroquine. The researchers determined that in addition to lower rates of COVID-19 illness progression in the Ivermectin group (4% vs. 30%), the Ivermectin group also had a lower mortality rate (2% vs. 20%).
The lone study done in the US was a retrospective study, published in CHEST, of 280 hospitalised patients in Florida by Dr Juliana Rajter of Broward Health Medical Center, and colleagues, in which 173 patients who got Ivermectin were compared with 107 who didn't get the therapy. "Most patients in both groups also received hydroxychloroquine, azithromycin, or both," the study states.
Kory said an interview with MedPage Today that he was frustrated by criticism of the evidence. He emphasised that FLCCC members "are firm believers in evidence-based medicine. But we disagree with how most practice evidence-based medicine. We think they are way too biased toward randomised controlled trials and completely dismiss evidence from anything but RCTs. We think that's harmful and loses a lot of valuable data."
Writing in the New England Journal of Medicine's Journal Watch, Dr Paul Sax says that the clinical trials data for Ivermectin look stronger than they ever did for hydroxychloroquine, but "we’re not quite yet at the 'practice changing' level".
"But we have to guard against two important biases here. First, that because we were burned by hydroxychloroquine means that all other repurposed antiparasitic drugs will fail too. Second, that studies done in low- and middle-income countries must be discounted because, well, they weren’t done in the right places. That’s not just bias, it’s also snobbery."
While FLCCC members see their data as strong, but many experts disagree with their interpretation, writes MedPage Today. Dr Steven Joffe, a medical ethicist at the University of Pennsylvania, said he doesn't believe clinicians "should be lowering our standards of evidence because we're in a pandemic". "This group should be advocating strongly for a large, generalisable randomised trial if they believe so strongly in the efficacy of ivermectin," Joffe said. "If in fact it is effective, the only way to convince the clinical and scientific community and allow patients all over the world to benefit is to prove the case in such a trial."
Dr Zain Chagla, an infectious diseases physician at McMaster University, reviewed each of the trials in Hill's review in a Twitter thread. He called the overall evidence "very low grade" and was also unhappy that Hill disseminated it as a video. He said if there was indeed a signal for efficacy, he would have expected Ivermectin to be rolled into the SOLIDARITY or RECOVERY study by now.
Marik and Kory say they're frustrated that their work is now being championed by the political right, and that it's become politicised at all. The group has had to distinguish itself from America's Frontline Doctors, which gained notoriety for its pro-hydroxychloroquine, anti-lockdown rhetoric last summer.
US practitioners supporting the use of Ivermectin reject any comparisons with the earlier lobbying for hydroxychloroquine, arguing that Ivermectin is tried and tested, already approved for human use. Its measured use against COVID-19 is a typical off-label decision by frontline doctors. Some comments from the MedPage Today blog:
Dr Karl Buchanan writes: "I'm not anti-vaccine; They can and should work together. As outpatient physicians, it should be our goal to help our colleagues in the hospital by doing anything we can to keep our patients out. This includes a cheap, old medication with a low side effect profile. I've been using it for at least a month and believe it is helping [but] I have pharmacies refusing to fill prescriptions based on the fact that it's "off-label," which we all know is ridiculous since we use many medications that way.
Dr Brad Sparling writes: "The decision governing on-label or off-label standard or innovative therapeutic usage is between physician and patient PERIOD!
Critical care Dr John Weigandt warns that people taking Ivermectin are getting admitted to ICU, too "In fact, I admitted someone taking the aforementioned combo my most recent shift. His doctor called me, saying he had monitored this guy and he had been 'doing fine' with sats of 85% on 4L NC. That's not 'fine', that's a doctor with an anchoring bias and an unproven treatment."
Veterinarian Dr George Henderson warned against an overblown aversion to risk, with many drugs not used for this reason. "I have seen at least one drug (pimobendan) which literally saves heart failure dogs in acute decompensation, and doubles the lifespan of others with mitral valve disease. We have top tier evidence for it in the dog but it failed in human trials not because of lack of efficacy, but because the lawyers couldn't stomach "a small but not statistically significant trend toward arrhythmia" In short we let effective treatments fall through the cracks because we live in a society with a near total aversion to even the smallest risk, without factoring in the risk of doing nothing, which presently is massive. Drugs shouldn't be political, and we should not let the perfect get in the way of the good, while we continue to strive for perfection.
Dr Jennifer Greenhall points to a known side effect of Ivermectin, that it causes testicular dysfunction: "Ivermectin is usually given with selenium, or selenium + vitamin E, to protect against testicular (and also renal and hepatic) toxicity. Selenium is a strong independent risk factor for COVID-19 mortality and should be being tested for and supplemented anyway. Selenium is involved in the action of both vitamin D and dexamethasone, which redistribute it to the immune system from hepatic stores.
And therein lies the rub. If Dr Marik is supplementing vitamin D, C and zinc, and dexamethasone it is no wonder his patients have lower death rates, but this says nothing about Ivermectin. Similarly with others in comments using Ivermectin as additive to sensible and evidence-based supplement cocktails, was it needed?"
Dr Illini John writes that the arrogance of doctors discrediting the evidence for Ivermectin, though still in the early stages, is baffling. "Remdesivir has a worse side-effect profile than ivermectin, and the WHO study showed it did nothing. How can they possibly justify its continued, expensive use and not consider it worth trying Ivermectin to keep desperate patients out of the hospital?"
Dr Justus Hope writes that there is a significant difference between the goals of a clinician who is managing treatment for the best outcome (essentially risk management) and the goals of researchers. "From the perspective of the clinician, a treatment that has little downside risk significant upside potential and is not costly is worth pursuing. Researchers who deign clinicians who are practising good risk management should pause a moment to consider the human cost of pedanticism."
Pressure on SA regulator to authorise Ivermectin for immediate use/
MedicalBrief: Karim and SAHPRA warn against Ivermectin to treat COVID-19
MedicalBrief: Durban hospital and pharmacist charged over dispensing of Ivermectin
Full Daily Maverick report (Open access)
Full News24 report (Open access)
Full MedPage Today report (Open Access)
Full NEJM Journal Watch report (Open Access)
Dr Andrew Hill's meta-analysis (Currently available only on YouTube. Journal release imminent)
Lower mortality for hospitalised COVID-19 patients taking Ivermectin – ICON study (2020)
Ivermectin stops SARS-CoV-2 virus growing in cell culture within 48 hours – In vitro study (2020)
Lower mortality for hospitalised COVID-19 patients taking Ivermectin – ICON study (2020)
5-day course of Ivermectin may reduce duration of COVID-19 – Bangladesh study
Iranian trial announced into efficacy and safety of Ivermectin in patients with mild and moderate COVID-19
FLCCC Alliance's Review of emerging evidence on efficacy of Ivermectin
Math+ Protocol from FLCCC Alliance
I-Mask+ Protocol from FLCCC Alliance
Rapid review and meta-analysis in support of the Ivermectin recommendation of FCCC by UK Evidence-Based Medicine Consultancy Limited
Study on successful use of Ivermectin as an anti-malarial in West Africa (2017)
International study shows Ivermectin plus azithromycin 'highly effective' in scabies (2019)