Maverick Citizen

MAVERICK CITIZEN: OP-ED

Potential to save lives: An intensive care doctor argues for ‘compassionate use’ of ivermectin for Covid-19

(Photo: geneonline.news / Wikipedia)

Debate is raging about the use of a long-established anti-parasitic drug, ivermectin, that shows strong evidence of efficacy in the treatment of Covid-19. Although SA’s regulatory authority continues to prohibit its use, as it fulfils its legal and ethical mandate to ensure efficacy and safety of all drugs in the country, it also recognises that it is being used widely ‘off-label’. 

We know that Maverick Citizen respects and protects the crucial role of the South Africa Health Products Regulatory Authority (SAHPRA) in ensuring efficacy and safety of medicines. However, where the need is urgent and immediate, we also think that public debate of the evidence on which its decisions are based is also important. The use of Ivermectin is a case in point. 

Here, a frontline intensive care doctor explains why he thinks there are strong medical grounds to make ivermectin available for compassionate use.

Between 21 December 2020 and 9 January 2021 South Africa recorded a further 8,100 deaths from Covid-19 and a total of 292,260 new cases. This means we have had: an average of 13,917 new cases daily and an average of 386 deaths per day.

I have chosen 21 December because that is when the Rapid Review by the National Essential Medicines List Committee (NEMLC) Covid-19 subcommittee recommended we wait for more large randomised controlled trials (RCTs) to be published to decide whether ivermectin is appropriate for South Africa. 

The scientists who put this review together need to be commended for producing it in a short period; that document became the basis for continued objection to the immediate granting of permission for ivermectin use for patients with Covid-19. Their document is at least slightly better than the initial from SAHPRA, released on 22 December, and whose improved 6 January statement is here.

But, in my view the Rapid Review was inadequate. It is also unacceptable, considering that since its publication there has been enough outcry and enough information has been shared on what it missed. More than three weeks later they have not reviewed their recommendation, which the Department of Health (DoH) continues to use to refuse the authorisation of this potentially life-saving medication.

It is interesting that the DoH, through its Ministerial Advisory Committee (MAC), released a follow-up memo, dated 7 January 2021. This memo acknowledges that the “unregulated use of ivermectin is evident in South Africa and increasing” and that, “at a community level it appears that ivermectin is being widely promoted for the treatment and/or prevention of Covid-19. There are numerous anecdotal reports from general practitioners and pharmacists of the widespread prescribing and sale of ivermectin for these purposes.” 

Although this memo is a step in the right direction, it is too timid and less pragmatic about maximising on saving patients’ lives. It reaches the same 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” while recognising that “emerging evidence must be actively sought and carefully reviewed”.

(Photo: trialsitenews.com/Wikipedia)

The authors of the Rapid Review based their decision on four small studies (with 632 patients) when there were an additional seven randomised controlled studies with more patients, including an Argentinian study with 1,370 patients already registered or ongoing. 

Dr Andrew Hill from Liverpool recently presented his meta-analysis data on the use of ivermectin in Covid-19, with a total of 7,100 patients from 53 available clinical trials. 

Hill’s preliminary data was available when the Rapid Review was published, which brings into question the resources available to the team and the meaningfulness of their review. This information is publicly available, so it is very concerning that we have not had a “rapid” follow-up to the Rapid Review.

Why do I care?

I work at Dr George Mukhari Academic Hospital north of Pretoria, the only tertiary hospital in the area, serving 1.7 million people with just 26 formal ICU beds and a single qualified ICU specialist. We have an additional 280 “isolation ICU-capable beds” which were recently upgraded with negative pressure/flow to enable us to manage a major contagious pandemic of Ebola proportions. Unfortunately, we do not have suitably qualified staff to look after patients in those beds, despite the recent employment of new nurses. 

These have been our observations since 7 December 2020 when we decided to reactivate our “Resurgence Plan” (originally scheduled for 4 January 2021):

  • At the end of November 2020 our admitted cases doubled from between six and eight to more than 20 in a week;
  • That number increased to more than 40 by the next week and to more than 80 by 21 December. On this day we began mobilising all surgical departments to free their beds to accommodate a projected unmanageable surge;
  • The patients we were seeing with this resurgence were, worryingly, younger (40s) and sicker than our first surge;
  • By 28 December we had 110 admitted patients, and 133 by 4 January 2021 (a 17-fold increase in fewer than 30 days);
  • We were losing an average of four patients a day, including persons under investigation (PUI) with results unknown and Covid-19 patients (more than two per day);
  • The number of patients requiring oxygen grew exponentially compared with the first surge.
  • Our mortality for Covid and PUI patients has gone up 40-fold.

The situation at our institution holds true for the majority of state institutions except for the better-resourced “elites” – Groote Schuur Hospital (UCT), Charlotte Maxeke Academic (Wits), to a lesser degree Steve Biko Academic Hospital (Pretoria University), University of KwaZulu-Natal Academic Hospitals in Durban and Tygerberg Academic Hospital (Stellenbosch). 

We and the rest of the other academic hospitals represent a lower tier of academic hospitals, with poor infrastructure, weaker administration, fewer research capabilities and poorer systems. 

The district systems function on an even lower level than we do, which means if our systems are suboptimal, theirs are abysmal. They include Nelson Mandela Academic Hospital in Mthatha, Livingstone Hospital in Port Elizabeth, Limpopo Academic Hospital – Elim and Pietermaritzburg Complex. 

If we are in a bad situation, then the district and secondary hospitals are in even worse positions. 

Non-pharmaceutical interventions important but not sufficient

One of the things we learnt from the first surge was the limit to how effective our non-pharmaceutical interventions (NPIs) are. They are vitally important but insufficient because of the social and economic conditions in South Africa.

At the time of writing we are officially sitting at 33,579 deaths. The escalation in cases and mortalities in the past 40 days has surpassed the numbers from our initial surge. By 5 January the number of excess deaths was 83,918.

The first surge carried with it high infection numbers and very low mortality rates compared to the Northern Hemisphere countries. 

The new surge, fuelled by a mutated virus, has, unfortunately, changed our landscape and it almost feels as if we are dealing with a different virus altogether. The numbers are higher, and the disease seems more intense with the preponderance of the 40-49 age group being higher and characterised by more mortalities. 

Some provinces and districts that were spared during the first surge have suddenly been hit hard. Sadly, and more concerning, is that they are also the least-prepared and incapacitated provinces – they include the Eastern Cape (second surge), Garden Route (first surge), Limpopo (first surge), KZN (second surge) and parts of Mpumalanga (first surge). 

We are now experiencing a more severe pandemic than we did initially, in terms of cases, and possibly a higher mortality, but we’ll only know this for certain towards the tail-end of this surge when we are able to gather data. We know there is a delay in reported mortality cases as sick patients stay in hospital longer and this number is bound to increase in the next two to four weeks. 

The majority of South African hospitals have insufficient resources, the staff managing these patients often lack the means to do so, and the resources we have are limited in most settings, especially capacity for high-flow oxygen, which is the lifesaving intervention for these patients. Our interventions should always take this reality into consideration, and more resources need to be directed towards research on locally relevant projections and interventions.

It is appalling that we have such a disjointed strategy in tackling this pandemic, 27 years into our democracy. The DoH seems to be still battling to appreciate the fact that South Africa is a Third World country with a 10% First World component embedded in it. Any strategy that fails to recognise this will fail, every time. The HIV pandemic should have taught us this, but we seem to have missed the lessons. 

We now find ourselves at a desperate juncture where a vaccine is our only remaining “silver bullet”, if one believes in the mythology of werewolves. But for a virus with a penchant for mutation it only takes those heavily invested in seeing a worldwide rollout of vaccines to believe that mutations will not have an impact on vaccine efficacy. 

In any case, most Third World countries are a long way from universal vaccination while the virus rages, and they are facing conditions where if you are high risk and you contract Covid-19, your chances of survival are a toss of a coin (50:50 at best).

Pragmatic and rational steps to save lives

We need to be honest and find pragmatic ways of dealing with the reality we find ourselves in. We need to follow, and rapidly adopt, interventions researched and adopted by countries that have some resemblance to us. 

At the beginning of the pandemic the World Health Organisation (WHO), through Unitaid, decided to investigate cheap drugs that would be suitable for Third World countries because they are readily available, have a proven track record of efficacy and a tolerable side-effect profile. The WHO-Unitaid collaboration, known as the Access to Covid-19 Tools Accelerator (ACT-A), is co-chaired by Health Minister Zweli Mkhize, and the therapeutic investigation arm is driven by Unitaid and the Wellcome Trust.

Ivermectin, which is an anti-parasitic (anti-helminthic) used for a variety of parasitic diseases in humans and animals, has been extensively investigated in this regard (for questions and answers about ivermectin see here). The drug is not registered for human use in South Africa, but it is in many other countries, including the US, and “off-label” use is common. 

The drug has been in existence since 1975 and came to medical use in 1981. The common side-effects are red eyes, dry skin and burning skin. Its safety in pregnancy is uncertain, but it is probably acceptable for use during breastfeeding. 

The most feared complication is probably the one involving the brain. Interestingly, the most recent review from a Swedish group of researchers tasked with monitoring these neurological side-effects found only 48 such reports, with only 20 having a plausible cause related to ivermectin. Their review, Serious neurological adverse events after ivermectin – Do they occur beyond the indication of Onchocerciasis, is here

For a drug that has been dosed almost 3.5 billion times since it came to existence, these 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.

The preliminary results from the Unitaid meta-analysis have already been presented by many people, including Dr/Professor Pierre Kory and Professor Paul Marik of the Front Line Critical Care COVID (FLCCV) Alliance, and the principal investigator of the Unitaid-funded review, Dr Andrew Hill from the University of Liverpool. The findings, from more than 50 trials including 11 randomised control trials of good quality and significant numbers, have yielded 7,100 patients, enough for a robust meta-analysis. 

These were the impactful and statistically significant results from the meta-analysis in favour of ivermectin compared with a placebo. They showed:

  • Faster viral clearance – an obvious marker of drug effect;
  • Shorter hospital stay – a measure more relevant in resource-constrained environments;
  • 48% higher rates of clinical recovery;
  • An 83% increase in survival rates – the goal of most therapeutic interventions; and
  • The drug was effective in all the clinical stages of the disease – prevention/prophylaxis->out-of-hospital treatment – and treatment of severe disease.

Besides the available clinical evidence from clinical trials, there are also numerous anecdotal testimonials from respected colleagues who are clinicians in the frontline and managing Covid-19 patients. 

Some of the ones I have heard in a recent webinar from colleagues in Zimbabwe, which can be watched here, are: 

  • “It makes treating Covid-19 patients fun again.” I dare you to find any South African doctor in the frontline who can say this about treating these patients;
  • “Patients with very low oxygen saturations around 60-80% are discharged within a day of admission, off oxygen.” This is in a country poorer than South Africa, with an even worse challenge of resources.

To put this into context, none of the currently available and permitted drugs has shown similar benefits:

  • Steroids, which are advocated by everyone, have a very narrow window of effectiveness, with a modest 25% mortality reduction. The benefit of steroids is that they are cheap and readily available;
  • The antiretroviral combination of Lopinavir/Ritonavir has been declared ineffective. With our high HIV/Aids population, this was a reasonable drug to study if it was to be effective since it is readily available with a known side-effect profile;
  • Tocilizumab has been found ineffective in the large multicentre, randomised control trial by Solidarity, with a narrow window of purported benefit. The UK has authorised it for licensure and prescription in Covid-19, based on the results of the single REMAP-CAP trial. This is a drug that costs R55,000 ($3,600) for a patient course of treatment, with a modest benefit of 8.5% mortality reduction;
  • Hydroxychloroquine had to be quickly withdrawn due to side-effects and no benefit on mortality; it also had a narrow window of effectiveness;
  • Remdesivir is the last drug being studied by the Solidarity Trial, and is slowly also showing a lack of statistically significant effect on mortality, with a limited window of effectiveness. It also has a discouraging price tag, especially for low-income countries, of R10,000 per patient.

Source: P Marik, EVMC Critical Care Covid-19 Management Protocol

The reality is that our healthcare system is not adequate for the majority (85%) of the population because of limited resources, skills and capacity. 

Reports of hospital bed shortages abound in the media. What is never broken down and explained is why there is such a shortage. A survey I conducted of private hospitals during the first wave revealed many had been running at 25-40% capacity during this pandemic, in the initial and the current surges. This is no different to state hospitals, where only 25% of hospital beds will be allocated to Covid patients and the rest remain empty as surgical services and other elective admissions are stopped. 

The contributors to ICU bed shortages are:

  • Staff shortages – either endemic or from current illness with Covid-19;
  • Staff deaths from Covid-19;
  • High-risk staff who cannot work during a surge;
  • Fear that prevents staff from coming into work.

The other statistic that lacks detail is why Covid-19 patients die in South Africa. 

From personal experience in our unit, through speaking to other colleagues in similar set-ups as ours and reading distress calls from doctors in the districts and lower-level hospitals, it is clear that the majority of Covid-attributed deaths are not from Covid-19 directly but due to the numerous systemic failures that exist in our healthcare system. 

The RCTs (see definition here) we are waiting for are not going to resolve these problems in the short term, and definitely not before our next handful of surges unless the vaccine is ubiquitously available. 

Until then, what do we do?

It is in this context that it bewilders the mind why a drug like ivermectin should not be used for the management of Covid-19 patients for the benefit of its many phases of proven efficacy:

  • Prophylaxis using the I-Mask Protocol (shared here) to limit frontline staff infections – this can be extended to all frontline workers, including food industry staff, police, teachers, public transport drivers and hospitality industry workers. That way we can have a reasonable continuation of essential services.
  • It can be used to reduce or limit the need for hospital admissions and for early outpatient treatment protocols like this one. We are already overburdened, and ivermectin holds clear evidence of benefit for out-of-hospital treatment;
  • It can be used to reduce hospital stay in very sick patients and improve mortality overall using protocols like the MATH+ Protocol – which gives the opportunity to discharge patients earlier and for clinicians to focus on the more severe cases with less therapeutic response.

We are far from a universal vaccine in South Africa. There are many uncertainties, even with the rollout, considering our numerous unique challenges of storage, distribution and uptake. 

Patients are dying in droves in the meantime as a result of a system that has been failing them before this pandemic and is being laid bare now. 

We have been here before with the HIV pandemic. Weekends in the townships were marred by queues of hearses as young people were being buried in droves. The problem here is not denialism, thankfully, but the consequences of delay are the same. This makes the current situation seem like déjà vu for some of us who were interns more than 20 years ago. The private sector and civil society, through NGOs, intervened independently and turned the tide. Why are we repeating the same mistake now?

If ivermectin was 50% effective (compared with the published 83% improvement in survival rates reported in the meta-analysis by Dr Andrew Hill) it would have saved just more than 4,000 patients since December 21 2020. With a 75% reduction in mortality, we would have saved more than 6,000 lives (300 per day). 

In conclusion, the question then remains, what will it take for South Africa to give this cheap and effective drug a chance, and most importantly, what will it take to give the patients a fair shot and chance at survival? 

What would our justification be if ivermectin is eventually proven to be effective when the evidence has been around all along? Will the excuse for waiting for large multicentre RCTs be justifiable to the thousands of families who have lost their loved ones? 

It is obviously not a cost issue, it is also not a safety issue – it is only an academic evidence issue in Covid-19 specifically that is delaying a potential saving of frontline workers’ and patients’ lives. DM/MC

Dr Nathi Mdladla is associate professor and chief of ICU at Dr George Mukhari Academic Hospital and Sefako Makgatho University; deputy president of the Cardiac Anaesthesia Society of Southern Africa; and a reviewer for the Southern African Journal of Critical Care.

Read this analysis piece by Maverick Citizen Editor Mark Heywood here:

Using ivermectin for Covid-19: what to do when caution and crisis clash?

 

Further reading: American Journal of Tropical Medicine and Hygiene: Ivermectin and Covid-19: Keeping Rigor in Times of Urgency.

 

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All Comments 17

  • A brilliant article and about time. We arranged a supply of this for our family a while ago.

    I cannot help but find it strange how vaccines which were developed in under a year are being pushed out to pretty much the entire planet’s population, and at a high cost per dose, but a drug which is already available and can now be produced fairly cheaply as a generic drug in a number of global factories and which has literally BILLIONS of doses already safely used globally was blocked by the SA government.

    I cannot help but smell a very large profit scented rat!

  • This article states that Dr Hill reviewed studies covering 7 100 patients, however, in the video linked in this article, Dr Hill clearly states that his meta-analysis is only based on 11 randomized trials covering 1 452 patients. The 7 100 number refers to trials that are currently ongoing, but for which there are no results yet. Also he clearly states several limitations on some of the original 11 trials, many of which were not double blind trials and therefore are more susceptible to bias. People are scared to use a vaccine tested in a trial of 45 000 people, but want to rush to use a drug tested on ~1 500 people. Dr Nathi also points out how several other drugs that were rushed into use have shown or are beginning to show a lack of efficacy as more results from widespread use have become available.

    • Unlike the vaccine, Ivermectin is not a new drug. It has been in use for 40 years and is approved for human use in several other countries including the USA. I don’t see why it shouldn’t be approved for use here in S.A. If I was critically ill from Covid I would very happily take this drug.

      • Ivermectin could prove to be a miracle drug and if I was critically ill I might also be likely to try any drug that shows some promise, however to argue that this drug has been scientifically proven to show efficacy is patently false. Also by that argument we could be putting all sorts of drugs into people with Covid. Even if not approved for treatment of Covid, South Africa could easily lead its own clinical trials to test the efficacy of Ivermectin. Ultimately I am neither for nor against the use of Ivermectin, I am for presenting the truth of the facts that are out there.
        Here is a link to a list of published results on the FLCCC website:
        https://covid19criticalcare.com/medical-evidence/ivermectin/
        which also has a link to their review of the data. And this link, https://www.covid19treatmentguidelines.nih.gov/statement-on-ivermectin/ describes some of the limitations of the studies that have been published so far.

        • I am all for rigorous scientific research, however; how about some plain old common sense? Ivermectin and other known drugs have been tested safe for human use. Period. The specific disease or ailment is not related to or is a determinant in the safety of the drug. Watch this for a real wake up call; https://www.c-span.org/video/?c4929043/user-clip-dr-jean-jacques-rajter-opening-statement/. Dr Rajter testifies to specific actions and results seen in the real world i.e. hospital wards. In the 1960’s a young engineer asked an old site foreman what formula to use to test if the abnormal load truck will carry the megaton steel silo without breakdown. The old man replied; “Fill it with water and see if it holds”.

    • Jason : I think people do not believe our government has the ability to get and roll out meaningful numbers of the vaccines in a time frame that will stop the virus killing thousands more (and stop the devastating economic effects). You can’t extrapolate what a few nut cases say about the vaccine to all of us. Since Ivermectin seems safe – what is the harm in trying? What worries me most is that “illegal” use is going to lead to tragic outcomes. At least we are now starting to see guidelines https://documentcloud.adobe.com/link/track?uri=urn:aaid:scds:US:0e8f0c4e-b19e-4aae-8114-3aea5350b457

    • Jason, note that Dr Hill has just updated his meta-analysis data and conclusions to reflect more than 2100 patients. He shared it with The Minara Chamber of Commerce on a Zoom call on 19th Jan and answered the questions of many SA doctors on the call; including Dr Nathi Mdladla who wrote the above article. I have written a summary of Dr Hill’s latest findings below as a response to the scientifically uninformed comments of “Tods the Toad”, but you can also view the whole interview on the Facebook page of Minara Chamber of Commerce.

  • This doctor is on some skunk lined path that we should not follow. His article is big on sentiment but little science. Anecdotal word of mouth stories from his contacts in Zimbabwe and ‘proof’ from studies he clearly misrepresented does not make it the tip of the spear that will solve our problems with saving lives. This is not HIV . If you have to extrapolate from our experience with HIV then call it turbocharged HIV because it’s not like we experienced even in the early days of AIDS. This drug paralyses invertebrate nerve and muscles by blocking glutamate gated chloride ion channels. How does it work to inhibit an RNA virus from replicating??!. Hog wash

    • I’m afraid your comments are entirely uninformed with regard to the latest scientific evidence. Professor Andrew Hill, the specialist consultant from Liverpool University hired by the WHO to perform a meta analysis on ivermectin trials for COVID-19, presented his most updated findings on 19th Jan to a group of South African doctors over Zoom and answered their questions. He now has 2100 reliable data points showing that ivermectin improves outcomes by 75%. He will have more than 7100 data points by mid February and is expecting the final result to come in in the range between 48% and 85%. (For comparison, he says the best current treatment, dexamethasone, is at 20% improvement in outcomes). He says there is now only a one in 5000 chance that the final trials results will prove ivermectin to be unhelpful. Given that it is well know to be totally safe at anti-parasitic dosage levels (routinely taken by 250 million people a year already) there are no real risks in using it at what currently looks like the most effective dosage of 0.4mg per kg for 5 days. But he notes that many countries like South Africa currently have no stock, so he recommends ordering ivermectin “at risk” immediately (just like Britain did with ordering and paying for vaccines that looked promising but were not yet fully proven), knowing that by the time the stock arrives in the country it will be possible to make a final decision on use because by mid Feb evidence will have reached the threshold for reliable conclusions. (He says in the unlikely event that it proves ineffective the stock can always be resold to countries that need it to treat all the existing conditions it is good for).

      He says it is up to every country’s regulator to decide but he thinks it makes no sense to delay placing orders until all the trials are completed, then approve it, and then wait another 6 weeks for stock while 1000s more people die. Also, based on his extensive experience in HIV treatments, he outlines a strategy for the combined use of vaccines plus ivermectin across a population which would rapidly stamp out Covid altogether (and far more quickly than even the best possible outcome expected from using vaccines only). No wonder that this is what India is already doing.
      The only remaining question seems to be: What do we have to do to get the SA regulators to wake up and act on this?

  • There is a much wider polemic on this afoot. I cannot find the Youtube vid on Dr Pierre Corey testifying before the american Senator Ron Johnson on Invermectin. However; he cites numerous studies and other anecdotal evidence form medical practitioners on the drug’s efficacy. In one study they administered Invermectin against CoVid-19 to 400 patients. Not one became sick. In the control group of 400 which were treated “conventionally” 58% or 238 became sick. See more here; https://trialsitenews.com/us-senate-hearing-explores-ivermectin-as-miracle-drug-for-covid-19-while-mainstream-media-outlets-ignore/. Thus there are many more and larger studies than just the locals. Now, since this “until more robust evidence is available . . . ” is SAHPRA’s aproach, when will it happen and who will actually show initiative to do the work? Don’t call us, we’ll call you. We’re on Africa time again. The problem’s aproblem ‘causit’s aproblem. And oh yes, Invermectin does not have to be stored at -70 Celsius. Find comment on Dr Corey’s testimony on no less than 30 studies here; https://www.worthynews.com/54705-lung-specialist-tells-senate-committee-that-ivermectin-anti-parasite-medicine-is-wonder-drug-for-covid-19. He advocates Invermectin to be re-purposed as it is a known drug with known properties.

  • If the virus is parasitic in nature, why can the anti-prasitic drug Invermectin not be used against it? Side effects have been shown as insignificant. Besides that it will remove the stress of deciding between the economy or death.