Ivermectin Interest Group calls on SA government to consider drug

INTRODUCTION

The COVID-19 epidemic in South African has worsened. The current second wave is potentially compounded by the SARS-COV-2 variant N501Y that is just as lethal as the wild type but more readily transmitted, as well as human behavioural changes at a traditional time of celebration. Movement across provincial borders to be with families during the holidays has compounded the risk of transmission. Our resources, specifically healthcare resources in coping and dealing with the onslaught that the pandemic has brought, have been stretched beyond capacity across all sectors. .

The logistics of dealing with COVID-19 are proving difficult, with the government attempting to balance attempts to lower morbidity and mortality, with protecting the economy. While the vaccine rollout has been initiated in a number of countries, the pace of vaccination has been slower than anticipated. For example, in the United States by 28 December 2020, against a projected 20- million vaccinations by year-end, only 11-million doses have been distributed and 2.1 million vaccinations implemented. The rollout in the European Union

has only recently been initiated. The actual costs of logistical and human resource requirements, as well as timely and efficient implementation, are yet to be clarified. A critical issue to consider is that we need to roll the vaccine out to over 60% of the population before herd immunity snuffles the disease out. This could take several months, not enough time to prevent a third wave.

Lower and middle-income countries (“LMIC”), including South Africa, lag behind high-income countries in their ability to access the COVID-19 vaccines and enormous numbers of new infections can be anticipated prior to large-scale implementation of vaccination efforts. As a country, we need to keep an open mind to various immediately accessible options for prevention and treatment of COVID-19, to mitigate the impact of the pandemic until such time as we can roll out a comprehensive vaccination program.

Across the globe, and more especially many LMIC nations, have realised that the vaccine cannot be the only solution in the immediate future.

The impact of the second wave is felt largely at the frontline, namely at the general practitioner, clinic and hospital level. Therefore, the Country must explore every possible healthcare solution for COVID-19 prophylaxis and treatment to minimise morbidity and mortality, reduce the risks to health care workers, and reduce immense stress on our health system.

The search for preventative and curative solutions has presented a possible opportunity with the use of a well-established medicine listed on the WHO essential drug list. The latter is the antiparasitic drug, Ivermectin. It has changed the landscape of the scourge of parasite infections in many third world countries. The developers were recognised for their achievement by being awarded the Nobel Prize for Medicine in 2015.

Please note that a full list of references is available for this missive upon request. Extensive referencing is excluded for ease of reading this document.

WHO WE ARE AND WHAT ARE OUR INTERESTS

We are a group who are advocating for the principles of good critical science and flexibility of thought to be applied in looking at potential treatments in a pandemic, where our resources are exhausted and/or under considerable strain. We are not dismissive of any treatment that has shown benefit in treating COVID-19 but examine evidence to inform evidence-based medicine.

The Ivermectin Interest Group (“IIG”) is a grouping of clinicians, public health specialists, community health workers and scientists that have an interest in exploring the potential of the medicine Ivermectin to both prevent and treat COVID-19. While we fully endorse the pursuit and implementation of all available evidence-based vaccines, as they are essential to ending the pandemic, we wish to ensure that the potential of promising preventive and therapeutic measures, including drugs, be fully and urgently investigated.

As the world’s attention is focused on the rollout of vaccines, South Africa appears to be lagging behind in securing a stockpile, especially for the most vulnerable of our population. There is not much optimism that we can have any reasonable form of protection from a possible third wave in the forthcoming winter. The inability and lack of capacity in securing the vaccine and the uncertainty of its protection to new strains and variants demands a search for and implementation of alternative preventative measures in addition to the current benefit of physical distancing, masks and sanitiser.

This submission relates to the potential for Ivermectin as a prophylactic and therapeutic drug for COVID-19. The IIG does not endorse or endeavour to breach any laws or professional and ethical rules and regulations and distances itself from individuals who have made inflammatory and misleading statements about our local regulators and experts. As a group, we are aware of the information being presented from those advocating it’s use without research evidence. However, we strongly believe that an objective, unbiased and scientific approach is necessary.

IVERMECTIN

Currently, the use of Ivermectin is controversial for sound scientific reasons. We acknowledge that the drug has not been indicated for use in COVID-19 prophylaxis or treatment, either locally or by the major regulatory bodies globally. However, we must note that Ivermectin has been the subject of a number of studies and reviews, including a review funded by the World Health Organisation (WHO) as part of the ACT Accelerator and UNITAID programmes (Hill et al., 2020) that concluded that urgent further trials are required and that results anticipated from clinical trials currently underway will be available in January 2021 and could provide the numbers required for a meta-analysis to provide a reliable outcome.

Dr Andrew Hill Sr, 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, recently reported at an international ivermectin conference a meta-analysis of data from the first 11 randomised controlled trials that have been identified. This meta-analysis, while still ongoing, points towards the significant promise of Ivermectin as a low cost, widely available therapy potentially useful in COVID-19. His finding thus far, in the trials totalling 1452 patients, is that ivermectin treatment is associated with faster time to viral clearance, shorter duration of hospitalisation, 43% higher rates in clinical recovery (95% CI 21-67%), and a profound 83% improvement in survival (95% C.I. 65-92%). Other reviews that draw similar conclusions (Appendix 1) and national health authorities are also looking at Ivermectin (Appendix 2). The ivermectin studies stand out because there are virtually no studies showing a negative outcome.

There is a plethora of clinical research trial results supporting the efficacy of Ivermectin for COVID-19 prophylaxis and treatment, including both small and large randomised controlled trials and observational studies reported in peer- reviewed journals and pre-publication websites. A living systematic review of all papers is required in South Africa, to monitor this literature and further support meta-analysis data to gain a clearer picture of the effect of Ivermectin on COVID- 19.

THE SCIENCE BEHIND IVERMECTIN

Properties of Ivermectin

Many existing drugs have been investigated for their potential to be re- purposed, Ivermectin is one such drug. However, Ivermectin is unique in that it possesses both anti-viral and anti-inflammatory properties. For example, since 2012, a growing number of cellular studies have demonstrated that Ivermectin has anti-viral properties against an increasing number of RNA viruses, including influenza, Zika, HIV, Dengue, and most importantly, SARS-CoV-2. Insights into the mechanisms of action by which Ivermectin both interferes with the entrance and replication of SARS-CoV-2 within human cells are mounting.

Caly et al. first reported that Ivermectin significantly inhibits SARS-CoV-2 replication in a cell culture model, observing the near absence of all viral material 48h after exposure to Ivermectin. However, some questioned whether this observation is generalisable clinically given the inability to achieve similar tissue concentrations employed in their experimental model using standard or even massive doses of Ivermectin. It should be noted that the concentrations required for effect in cell culture models bear little resemblance to human physiology given the absence of an active immune system working synergistically with a therapeutic agent such as Ivermectin. Further, prolonged durations of exposure to a drug likely would require a fraction of the dosing in short term cell model exposure. Most importantly, the belief that 100 fold concentration would be required for clinical effects has been disproven by the rapidly increasing numbers of studies showing efficacy at standard dosing. This is reassuring in light of safety concerns.

Furthermore, it is also possible that co-existing or alternate mechanisms of action explain the clinical effects observed, such as the competitive binding of Ivermectin with the host receptor-binding region of SARS-CoV-2 spike protein, as proposed in six molecular modelling studies. In four of the studies, Ivermectin was identified as having the highest or among the highest of binding affinities to spike protein S1 binding domains of SARS-CoV-2 among hundreds of molecules collectively examined, with Ivermectin not being the particular focus of study in four of these studies. This is the same mechanism by which viral antibodies, in particular, those generated by the Pfizer and Moderna vaccines, contain the SARS-CoV-2 virus. The high binding activity of Ivermectin to the SARS-CoV-2 spike protein could limit binding to either the ACE-2 receptor or sialic acid receptors, respectively either preventing cellular entry of the virus or preventing hemagglutination, a recently proposed pathologic mechanism in COVID-19.

Ivermectin has also been shown to bind to or interfere with multiple essential structural and non-structural proteins required by the virus in order to replicate. Finally, Ivermectin also binds to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication.

Safety of Ivermectin

he discovery of Ivermectin in 1975 was awarded the 2015 Nobel Prize in Medicine given its global impact in reducing onchocerciasis (river blindness), lymphatic filiariasis, and scabies in endemic areas. It has since been included on the WHO’s List of Essential Medicines. Beyond the massive, global reductions in morbidity and mortality achieved in many low-and middle-income populations, the knowledge base establishing its high margin of safety and low rate of adverse effects are nearly unparalleled given it is based on the experience of

billions of doses dispensed. Numerous studies report low rates of adverse events, with the majority mild, transient, and largely attributed to the body’s inflammatory response to the death of the parasites and include itching, rash, swollen lymph nodes, joint pains, fever and headache. In a study which combined results from trials including over 50,000 patients, serious events occurred in less than 1% and largely associated with the administration in Loa.

Further, according to the pharmaceutical reference standard Lexicomp, the only medications contraindicated for use with Ivermectin are the concurrent administration of anti-tuberculosis and cholera vaccines while the anticoagulant warfarin would require dose monitoring. A longer list of drug interactions can be found on the drugs.com database, with nearly all interactions leading to a possibility of either increased or decreased blood levels of Ivermectin. Another special caution is that immunosuppressed or organ transplant patients who are on calcineurin inhibitors such as tacrolimus or cyclosporine or the immunosuppressant sirolimus should have close monitoring of drug levels when on Ivermectin given that interactions exist which can affect these levels. In studies showing tolerance and lack of adverse effects in human subjects who received escalating high doses of Ivermectin, toxicity was found to be unlikely, although a reduced efficacy due to decreased levels may be a concern. Finally, Ivermectin has been used safely in pregnant women, children, and infants.

Studies Demonstrating Anti-Inflammatory Properties of Ivermectin in COVID-19

The beneficial impacts reported from treatment studies on hospitalised and ICU patient populations suggest that potent anti-inflammatory properties of Ivermectin could play a major role given that little viral replication occurs in the later phases of COVID-19, nor can the virus be cultured, and only in a minority of autopsies can viral cytopathic changes be found. Thus, it appears that the increasingly, well-described in-vitro properties of Ivermectin as an inhibitor of inflammation are far more clinically potent and significant than previously recognised. The growing list of studies demonstrating the anti-inflammatory properties of Ivermectin includes its ability to; inhibit cytokine production after lipopolysaccharide exposure, downregulate transcription of NF-kB, and limit the production of both nitric oxide and prostaglandin E2.

Summary of studies demonstrating the clinical evidence in prophylaxis and treatment

A categorical summary of the statistically significant results found from controlled trials included are as follows:

Controlled trials in the prophylaxis of COVID-19 (n=6)

• 4 RCT’s with large statistically significant reductions in transmission rates, N=851 patients
• 3 OCT’s with large statistically significant reductions in transmission rates, N=1,688 patients Controlled trials in the early, outpatient treatment of COVID-19 (n=5)
  • 2 RCT’s with large, statistically significant reductions in rates of deterioration or hospitalisation, N=1,085
  • 1 RCT with a near statistically significant decrease in time to recovery, p=.07, N=130
  • 1 RCT with a statistically significant decrease in viral load, days of anosmia and cough Controlled trials in late phase treatment of the hospitalised patient (n=12)
    • 2 RCT’s with large, statistically significant reductions in mortality (N=580)
    • 1 RCT with a near statistically significant reduction in mortality, p=0.052
    • 3 OCT’s with large, statistically significant reductions in mortality (N=1,688)

IVERMECTIN USE AND/OR APPROVAL FOR COVID-19 GLOBALLY

0. Regulatory approval has been provided in Belize and Macedonia. Bulgaria and India are anticipated to follow shortly along with several other LMICs. Widespread use of Ivermectin, often uncontrolled, has occurred in a number of regions and specifically in Latin America, Bangladesh, and Uttar Pardesh Ivermectin has also been used in a controlled environment, such as in the Front Line COVID-19 Critical Care Alliance (“FLCCC”) MATH+ study, with excellent results.

THE DoH AND SAHPRA STATEMENTS ON THE USE OF IVERMECTIN FOR COVID19 TREATMENT

On the 21st and 22nd of December, both the DoH and SAHPRA put out public statements warning against the use of Ivermectin in COVID-19 treatment. The drug is currently not registered for human use in South Africa, and although evidence is building on the potential efficacy of the drug, there have been no large randomised controlled trials for its use in COVID-19 treatment providing a definitively positive outcome. However, it is receiving increased attention in various parts of the world, with smaller countries such as Belize and Macedonia regulating for its use.

We contend that South Africa, as a Country, should explore the promise that Ivermectin use presents for us as a nation, using an objective, unbiased and scientific approach.

Ivermectin is a drug that is out of patent and therefore lacks any incentive for a pharmaceutical company to invest in large clinical trials. This creates a unique opportunity for the South African Government. Through its various institutions to pioneer its own local research into what is potentially game-changing addition to our limited arsenal of medicines to treat COVID-19.

Despite a proliferation of publications on the use of Ivermectin globally, most of these studies, have been hastened to publication, particularly positive ones, under the global urgency to assuage the virus’s effects. In many of these studies, the numbers are small and the researchers, in doing their best to help in the pandemic and with limited resources, have resulted in the trials being underpowered. Despite some underpowered studies having shown no statistical significance because the sample sizes have been small, a number of these show a positive trend. For this reason, expert meta-analysis is required to ensure sufficient statistical power to find and validate the true efficacy of Ivermectin in COVID-19 prevention and treatment. The current meta-analyses of existing data give enough reason not to dismiss Ivermectin as a potential drug for use in COVID-19 yet.
Ivermectin has not been registered for use in COVID-19 treatment, neither have Hydroxycholoroquine, Remdesivir, Doxycycline, Melatonin, and many others used regularly as a standard of care. Remdesivir in particular is a costly drug. The combination of these drugs adds much to the cost of treatment, both from the pill burden, intravenous administration of remdesivir, and nursing role.In addition melatonin needs to be used for 14 days. The biggest interest in COVID- 19 therapy has, understandably been the development of a vaccine. Vaccines are being rolled out now, almost a full year since the identification of COVID-19 in China. The vaccine rollout will not happen in time in South Africa to save those susceptible to succumbing to COVID-19 in the next few months. Even when the vaccine becomes available, the limited supply will mean that an estimated 90% of our population will be without vaccine protection and this will delay prospects of herd immunity being a reality in the foreseeable future. In reality, what South Africa has in its arsenal to protect the population at present is non- pharmaceutical interventions (NPIs) (which has limited success in a population prone to flouting the rules) and the option of exploring novel treatment options.

In a time of pandemic, where the promise of vaccine is remote, clinicians and the population at large, in desperation will resort to using any treatment or a combination of treatments with some promise. This, unfortunately, is what is happening on the ground with some of our clinicians already using Ivermectin, reportedly with success, for COVID-19. Both veterinary and illegally imported human use products are being used, based on anecdotal evidence and the proliferation of small unconnected studies coming from across the globe. Although this is seen by some as anarchical, the motives are noble and based on the need to treat patients effectively.

Whilst it is was true that weeks back the evidence of efficacy and safety of the drug in COVID-19 treatment was tentative and that individual studies did “not demonstrate any clear evidence of efficacy or safety”, comprehensive meta- analyses of studies have arguably provided a proof of concept. These have been dismissed by the NDoH, prematurely we believe, as having “insufficient data available for review and evidence synthesis”. They have ignored a large number of trials with over 7000 patients in total. Dr Andrew Hill’s summary of a meta- analysis on the available data found that there was an 83% reduction in mortality, reduced hospital stay, a faster viral clearance, and a 43% higher rate of clinical recovery. Also, most of the 27 studies available at present show Ivermectin is beneficial in treatment.
SAHPRAs statement that “The use of such a drug could potentially lead to harmful effects or even death” appears to be unfounded. In our literature search, we have found mention of some mild side effects and rare adverse reactions, but Ivermectin has proven to be one of the safest drugs in the world.

We would like to urge the NDoH to develop a living, ongoing systematic review of all potential drugs, in particular Ivermectin, so that South Africans do not miss out on the opportunity to access a drug that could mitigate the effects of the Cov-2-virus in the immediate term, before the vaccine rollout has been completed. It is important to state, that the signatories to this submission advocate for the introduction and use of a vaccine when one is available, but hold the view that Ivermectin is an important stop-gap in the interim.

IVERMECTIN IN SOUTH AFRICA

The desperate situation that South Africa finds itself in with a second, unrelenting wave coupled with the fact that the full benefit of a vaccine is still distant, has spurred local clinicians to explore the potential of Ivermectin. The challenge that local clinicians face is that Ivermectin is not registered for human use in South Africa.

However, it appears that there has been some use, particularly of the veterinary preparations, in humans which is continuing to feed the anecdotal evidence for the efficacy of the drug. This anecdotal evidence, along with the publications being released, and the need for as many useful drugs to be included in our armamentarium for fighting this pandemic, especially when facing a second and more severe second wave, demands that we look at this drug through the lens of legal, ethical and scientific pragmatism and are not simply dismissive of it.

We are aware of two avenues that can be implemented in order to investigate the use of Ivermectin for COVID-19. The first is to grant Ivermectin Section 21 approval for use in COVID-19, noting that it is approved for human use elsewhere, albeit for other indications. For example, according to the United States Federal Drug Administration:

Ivermectin tablets are approved for use in humans for the treatment of some parasitic worms (intestinal strongyloidiasis and onchocerciasis) and Ivermectin topical formulations are approved for human use by prescription only for the treatment of external parasites such as headlice and for skin conditions such as rosacea.

Writing in the World Health Bulletin, Speare and Durheim (2004) highlight the relevance and use of Ivermectin globally for There is currently some approved use of Ivermectin on Section 21 in private hospitals in South Africa. It is our understanding that SAHPRA collates data on certain aspects of section 21 use and that the outcome of such analysis should
scabies (by breaking the infection cycle through its therapeutic effect) and
controlling strongyloidiasis and filariasis, through its effect on transmission.

be made available or published as an interim report. We request that the State sector also has access to Ivermectin through a section 21 approval, based on the positive meta-analysis and global use/registration of Ivermectin.

Secondly, a Phase 2/3 double-blinded clinical trial, which would produce definitive data either supporting or not supporting the clinical efficacy of this drug for COVID-19 is required. This will provide a good scientific evidence base that will either put to rest the claims of Ivermectin being useful in the treatment of COVID-19, or vice versa. For this to occur as quickly as possible, given our current high transmission rate, we need guidance from the MAC, SAMRC, NICD and SAHPRA on how to expedite approval for such research and to obtain the requisite funding thereof. It would be a source of great national pride if South Africa were to spearhead a cost-effective treatment breakthrough for COVID- 19.

CONCLUSION
Both the Section 21 approval and the clinical trial approval and implementation will ensure that any local use of Ivermectin occurs in a controlled manner, in accordance with protocols or the best empirical evidence and where adverse events can be properly monitored and recorded. The failure to adopt this approach will have the consequence that practitioners, in desperation and under intense pressure from patients and families, will resort to experimentation. The IIG is concerned that if some avenue is not opened for the controlled use of Ivermectin, that there may be dire consequences for patients, practitioners and the Country as a whole. More worrying still, is the possible loss of opportunity to save lives.
Our request is to explore Ivermectin for prophylaxis and treatment of COVID-19. We also recommend that, as with vaccines, particular priority groups be identified for trials. For example, health care workers who are at immediate risk, and the central priority in responding to COVID-19 remains to minimise the extent of hospitalisations following infection. To this end, vaccinations have been prioritised for health care and other frontline workers, followed by persons older than 65 and persons of younger ages who have comorbidities. A similar strategy should be explored in trials, and for potential rapid implementation should trials elsewhere demonstrate efficacy for either prophylactic or treatment purposes. It would also be relevant to explore supply lines, logistics and costs for procuring Ivermectin dosages suitable for human use. We note that Ivermectin is available as a generic at a low cost.

Its scientific properties and low cost could potentially benefit millions in our Country and other parts of the world as an addition to the vaccine. The most urgent consideration should be to allow it’s use on a section 21 basis with the evidence being presented in the meta-analysis from Dr Andrew Hill from Liverpool university. His work is being funded by Unitaid, part of the WHO’S ACT accelerator initiative to provide and improve access to treatment for Covid 19.
We urge the Department of Health and the relevant regulatory institutions, such as SAHPRA to pay urgent attention to this request. Whilst we note the recent rapid review from the Department, we hold the view that this, was inadequate as the meta-analysis has not been looked at objectively or comprehensively as a number of clinical trials were overlooked. We request that the NDoH review their decision and monitor the evidence closely, allowing clinical trials, Section 21 use and potentially emergency use of Ivermectin.

The IIG urges the Minister through the MAC and the regulatory bodies listed above to accelerate research of Ivermectin and fully explore its potential in the COVID-19 response in a responsible way. The IIG would like to remind the Minister of Health, the MAC and all other leadership bodies, that it has a public duty to protect the health of the citizens of this county and that it may not be remiss in doing so. It MUST act in the public interest, and the IIG is of the belief that it has a duty to properly and expediently explore the potential of medicines such as Ivermectin.

We eagerly await an urgent and favourable response that will potentially benefit millions in our Country and beyond our borders and will be happy to engage further in this regard.

SIGNATORIES.
Prof Colleen Aldous
Prof Yunus Moosa
Ravin Singh
Warren Parker
Dr Yakub M Essack
Dr Shoyab Wadee
Dr Riyas Fadal
Dr Yasmin Goga
Dr Humza Bawa
Dr Zainab Goondiwala Solly Suleman