To mark World Ivermectin Day (29^th July 2023), in this article and videos we chart some of the highlights of the ongoing story of ivermectin use for covid-19.

In December 2020 a group of experienced intensivists (Professor Paul Marik, Dr Pierre Kory and Professor Joseph Varon) in the USA took the unusual step of holding a press conference and live streaming it to the world. The purpose was to describe experiences of using ivermectin to treat covid-19 infection and to issue a call to action to health authorities around the world. The message was clear – ivermectin hastens recovery and reduces mortality.  The pathway out of the pandemic seemed clear.

In January 2021 a rigorous, independent meta-analysis of ivermectin studies by Dr Tess Lawrie showed that there was an 83% reduction in the risk of death with ivermectin and this was graded as ‘moderate certainty’ evidence.  “The uncertainty is not related to whether or not ivermectin prevents death, but the estimate of effect size. We know  …..  it prevents death; the only uncertainly is by how much”, she emphasised.

In February 2021 Dr David Scheim described the mass treatment of the population in Peru with ivermectin. One state had started much later than the others and provided a natural control. This approach was associated with a 75% reduction in excess deaths by 30 days.

The next logical step was to interview a practising frontline clinician so that we could hear how ivermectin treatment is prescribed and managed in everyday practice. In a vivid and often moving interview Dr Jackie Stone in Zimbabwe described her experiences of ivermectin both as a clinician and patient.

In May 2021 IMI interviewed Dr Suryakant, a practising pulmonologist and adviser to the Indian Government. He is a strong advocate of mass prophylaxis with ivermectin and described in detail how ‘test, trace and treat’ schemes work in India. Dr Suryakant is based in Lucknow in Uttar Pradesh, a state that has been using ivermectin since August 2020 and contained and reduced the spread of SARS-CoV-2 very effectively.

In February 2023 Professor Colleen Aldous (Professor for Medical Research, University of KwaZulu-Natal, South Africa) explained why the SAIVE trial provided the highest quality trial evidence for ivermectin so far. She also argued that the pandemic could have been over sooner had the available evidence been evaluated correctly. “We should have been looking at the totality of evidence just as David Sackett – the father of evidence-based medicine – wanted it to be. Never once did he say a randomised, controlled trial was the gold standard – but you’ve got to look at the totality of evidence”, she said.

For more information and stories about ivermectin, see the World Ivermectin Day website.

Ivermectin had been in use on a compassionate basis for several months in Slovakia but now it is authorised for prophylaxis and treatment for SARS-CoV-2. This followed a formal request from the Slovak Ministry of Health infectious disease expert, Professor Ivan Schreter. Doctors in Slovakia may now prescribe ivermectin both in hospital and for outpatients and the drug can be dispensed in community pharmacies.

Supply challenges had been a problem whilst the drug was available for compassionate use because only animal products were available in Slovakia and the human drug had to be imported from Austria and India.  The formal approval means that ivermectin can now be imported and supplied through the normal official channels.

A group of physicians in Germany has recently treated elderly patients in a care home with ivermectin and reported sharp fall in mortality. This was not a formal clinical trial but ‘real world’ experience.

It is estimated that the use of ivermectin could save 60,000 lives per month in the USA and a quarter of a billion lives worldwide, according to data recently presented to the National Institutes of Health (NIH) in the USA.

Ivermectin is effective at all stages of SARS-CoV-2 infection, although it is better to use it early in the course of the disease. The longer that treatment is delayed, the harder it becomes to treat effectively.

Meta-analysis

https://www.youtube.com/watch?list=PLgA8niwnx035l6HLSoqmWNwX8SDwcH85Y&v=Qnjz0WlDxPc

A recent independent review and meta-analysis of controlled trials by Dr Tess Lawrie, Director of the Evidence-based Medicine Consultancy Ltd, showed that ivermectin reduced the risk of dying by 83% (95% CI 67-92%). Furthermore, ivermectin was also highly effective at preventing transmission of SARS-CoV-2. There was an 88% reduction in the risk of acquiring a covid infection amongst the people who had received ivermectin compared with controls. In absolute terms this amounts to an infection rate of about 4% in those who had received ivermectin compared with 35% infection rate in the control group.

Plan to eradicate SARS-CoV-2

A group of intensivists in the USA – the Front Line COVID-19 Critical Care (FLCCC) Alliance has called for the rapid introduction of ivermectin to stem the tide of infections. Furthermore, Marc Wathelet, a Belgian molecular biologist has argued that SARS-CoV-2 could be eradicated in Belgium in the space of six weeks if ivermectin were used appropriately.  Similar results could be expected in other countries if the same protocol was followed.

Wathelet’s proposal calls for the use of ivermectin at all stages of covid-19 infection – “a multi-pronged approach”, as advocated by the FLCCC Alliance.  For ivermectin prophylaxis he suggests two doses of 0.3 mg/kg 72 hours apart every month for health care workers and for family members of those who test positive for SARS-CoV-2.  Transmission within households in one of the major drivers of the pandemic and prophylactic ivermectin could cut this dramatically. Contacts of cases should also receive prophylactic treatment. The next step is ivermectin for early treatment of people with symptoms of covid-19 infection to reduce the severity and duration of the disease. At present only paracetamol is recommended. The third step is the use of ivermectin in severe covid-19 infection to reduce mortality.

https://www.youtube.com/watch?v=fh5iGkX8Vp4

Dr Lawrie is now trying to make an appointment with the Secretary of State for Health, Matt Hancock in order to share her findings so that ivermectin can be made available for British citizens as soon as possible.

There are many different ways that ivermectin use could be implemented. “I think firstly we need to get it to our health care workers and other frontline workers – they should be prioritised – and the other vulnerable people”, says Dr Lawrie. One way would be to have packs that contain ivermectin tablets, and sufficient vitamin, vitamin D and zinc for seven days’ treatment. Such packs could be posted to people to be kept at home until required, she suggests.  When people develop symptoms of covid-19 or they are exposed to someone else who has the disease then they could start taking the medicines.  Such approaches have already been used successfully in other countries such as India. Dr Lawrie’s message to GPs was simply that “ivermectin works” and she reminded them that doctors are entitled to prescribe the medicine that they regards as best for their patients.

Considering the types of trials that are needed for ivermectin now, Dr Lawrie suggested that trials to determine the optimum frequency of prophylactic doses would be helpful as would trials to compare different doses of ivermectin for covid treatment. It would also be useful to determine whether to give ivermectin alone or in combination with doxycycline or with other therapies such as vitamins D and C and zinc. There are comparative studies that can be done – but just not with a placebo, she emphasised.  “In this instance, where there’s such a massive effect and it is so consistent, doing a big trial is not going to come up with something different in the opposite direction”, she says.

Next steps

Clinical practice guidelines, the Government, that National Institute for Health and Care Excellence (NICE) and the World Health Organisation (WHO) have always relied on Cochrane reviews as the foundation for recommendations. For this reason Dr Lawrie has joined forces with Dr Andrew Hill in Liverpool to undertake a rapid Cochrane review of ivermectin for covid-19. They plan to complete the review in three weeks. “Hopefully, that will settle the question once and for all”, she says.

https://www.youtube.com/watch?v=WTTqKSYHOM8

The first finding was that ivermectin substantially reduces death amongst hospitalised patients with mild, moderate or severe covid-19. Six randomised controlled trials (RCTs) were included and the pooled estimate of reduction in the risk of death was 83% (95% CI 67-92%). “We don’t know what the precise estimate is, but even if it is on the lower estimate or even half as good it is still a substantial reduction in deaths”, say Dr Lawrie. This was graded as ‘moderate certainty’ evidence. The uncertainty is not related to whether or not ivermectin prevents death, but the estimate of the size of the effect. “We know – the evidence shows –  it prevents death; the only uncertainly is by how much”, emphasises Dr Lawrie.

“We found a substantial reduction in the risk of death if you receive ivermectin instead of receiving the control [treatment] and it was consistent across all of the studies that we included”, she says. Furthermore, the statistical measure that is used to measure the consistency of the data showed no inconsistency,  “so all the studies were showing the same thing – that ivermectin reduces death substantially in hospitalised patients…… whichever way you are looking at it, it is a massive reduction”, adds Dr Lawrie

Prophylaxis

The trials of ivermectin prophylaxis included both RCTs and observational trials.  “It doesn’t really matter whether you include OCTs and RCTs or RCTs only  –  all the studies are saying the same thing”,  comments Dr Lawrie,

There were four studies that reported data on covid prophylaxis with ivermectin. They were conducted amongst health care workers and people who had been exposed to covid-19.  The analysis found an 88% reduction, on average, in the risk of acquiring a covid infection amongst the people who had received ivermectin compared with controls In absolute terms this amounts to an infection rate of about 4% in those who had received ivermectin compared with 35% infection rate in the control group. This evidence was graded as ‘moderate certainty’, mainly because of study design limitations. However, the findings were consistent across all four studies. “So again it’s not a question of whether ivermectin reduces the risk of infection, but it’s just a question of how much”, says Dr Lawrie.

Placebo-controlled trials

Regarding future trials Dr Lawrie points out that placebo controlled trials for ivermectin treatment of covid are no longer ethical. The absolute risk of death in hospitalised covid-19 patients treated with ivermectin is 1.3% but for those who receive placebo as control treatment the risk of death is about 8%. “A doctor enrolling someone in a study would have to say,  “Well, the existing evidence shows that if you get ivermectin you’ll have a 1%  chance of dying and if we don’t give it to you you’ll have a 8% chance of dying”, so I can’t really imagine that anybody would be prepared to sign a form like that”, explains Dr Lawrie.

https://www.youtube.com/watch?v=Qnjz0WlDxPc

The Evidence-based Medicine Consultancy Ltd is an independent medical research company that specialises in evidence synthesis to support clinical practice guidelines.

On Boxing Day Dr Lawrie received a link to the video of Dr Pierre Kory’s testimony to the US Senate Committee on Homeland Security and Governmental Affairs – something that she found very moving. “Here’s a doctor having to ask permission to treat patients with a very well-known medicine that has been around for the past 40 years”, she says. As a doctor herself, who trained in South Africa she was used to not having the medicines that she needed. ”My heart went out to Dr Kory. I thought – I can see a desperate doctor there, and I‘ve been there, I know what it’s like to be able to save patients but just not have the tools to do so”, she says.

Dr Kory and his colleagues in the Frontline Covid-19 Critical Care (FLCCC) Alliance had reached the conclusion that ivermectin was very effective in preventing and treating covid-19. They then appealed to the international health care community and medicines‘ agencies to review their findings independently and take action. Sensing the urgency of the task and knowing that it could be a lengthy process Dr Lawrie decided to re-analyse the data herself over the Christmas holiday period. She downloaded all the papers and excluded those that were not of good enough quality for inclusion in a meta-analysis.  All the remaining trials were evaluated for risk of bias and the data were extracted and fed into Review Manager software.

Only clinical outcomes were included in the analysis (rather than biochemical outcomes).  In general, health outcomes are most important to people. They need to know whether a treatment will make them me feel better, prevent disease or prevent them from dying. Death was considered to be the most important outcome – and it has the advantage of being an objective endpoint [in trials].

“I was amazed at what I found”, she recalls. A total of ten trials is included in the analysis, but for the main outcome of death there are six randomised controlled trials (RCTs). Observational controlled trials were also included. Although these are not normally included in Cochrane reviews, on this occasion Dr Lawrie decided to use the trials that had been included in Kory’s original review. She emphasises that only the high-quality observational studies were included, the lower quality studies had already been excluded.