Science

Ivermectin’s Covid-19 failure: When initial clinical data does not give the full story

Drug failed to deliver Covid-19 benefits shown in flawed studies

The best choice for Covid-19 remains vaccination. Photograph: Alan Betson

Anthony King
Thu Aug 25 2022 - 07:00

Dr Andrew Hill has decades of experience with HIV studies yet ended up with egg on his face after he published a study on ivermectin. There was nothing wrong with how he went about his own research, where he concluded existing studies showed ivermectin helped with Covid-19 patients.

But, over a period of a few months in 2021, it emerged that the studies on Covid-19 patients that Hill had analysed were flawed, fraudulent, or non-existent. “If you take clinical trials at face value, you can be led astray,” says a chastened Hill, a virologist at the University of Liverpool. A clinical trial in Egypt seems to have included data on patients that didn’t exist. Other studies had the same patient data copy and pasted over and over.

Ivermectin is an essential drug used against debilitating parasitic diseases present especially in the Tropics. Trinity College graduate Prof William Campbell won a Nobel Prize for research linked to ivermectin. But the Covid-19 trials raised red flags.

Something strange was noticed about the last numbers in one study. The numbers were non-random (people are not good at making up numbers in a random way). They looked made up. Another seemed to have enrolled too many patients in a short amount of time.

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Hill redid his analysis and found that without the dodgy studies, there was no benefit from ivermectin. He rewrote his paper, without the flawed studies, and came to a different conclusion. Ivermectin gave no benefit in reducing symptoms, nor in preventing infection.

The ivermectin horse though had bolted. Supporters of ivermectin took to social media to tout it as a ready-made cure and alternative to vaccines. Hill began to receive death threats after his reappraisal. There were videos of people spreading veterinary pastes – with content pictures of horses – on to their arms to protect themselves against Covid-19.

This was not harmless quackery. “Throughout the pandemic, patients have sometimes taken various different medications, and some proved to be harmful,” says ICU doctor Prof Alistair Nichols, who is based at St Vincent’s University Hospital, Dublin. An example was hydroxychloroquine, an antimalarial medication that showed some initial promise, which was then much used in March to April 2020. It subsequently showed no benefit in patient studies.

“Physicians advocated for some medications for Covid-19 and some patients took medication themselves,” notes Nichols, who ran a clinical trial on ivermectin in severely ill patients. “A high-quality clinical trial is the only way that doctors and patients and their families can know if a treatment is effective.” The more desperate patients are, the more vulnerable to unproven treatments.

The Irish trial on ivermectin has not yet completed, but “recent high-quality publications from other groups have further questioned the benefit of ivermectin,” notes Nichols. There is growing consensus that this treatment is unlikely to be effective in ICU patients despite initial claims, he explains. As Covid-19 becomes endemic, it is likely that we will continue to need treatments for patients with severe Covid-19, he adds – and hopefully that number will stay much lower than during earlier surges in infection.

Hype factor

Ivermectin’s gallop began when an Australian university issued a press release on ivermectin killing viruses in a dish. It gained ground from there, though the lab study proved nothing about the drug’s relevance to Covid-19 patients. Hype and desperation then prematurely pushed ivermectin out front as a possible solution to the pandemic.

“The concentrations they were using in dishes to kill viruses were way too high. You would never give that to humans,” says David Brayden, professor of advanced drug delivery at University College Dublin. Also, he was left wondering how it would act as an antiviral.

After the Aussie lab results, ivermectin gathered some loyal supporters and multiple studies on Covid-19 patients subsequently reported positive effects of ivermectin. These were carried out by individual clinicians or researchers in Egypt, Iran and Brazil. There was a desperate need for antiviral medicines and pressure to find a cure. But ivermectin as a cure was an illusion.

It is not the first time the medical community has been misled. In the late 1980s, patients with advanced breast cancer received an aggressive treatment involving chemo and bone marrow surgery. There was a strong push for this approach from patients and doctors, until the influential study turned out to be untrustworthy.

The trial backing up this treatment approach was shown to be a fraud. In the meantime, patients had wanted the supposed “treatment” rather than take part in studies where they might not receive it. Very ill patients were later found to have suffered from an approach that offered no benefit.

All human medicines must vault the hurdle of a phase three trial before gaining regulatory approval. This can involve thousands of patients on the new treatment plus standard card, and the same number on standard treatment. Doctors record the outcome of all patients and uncover statistically whether one group did better than the other.

The system is expensive, but drug regulators require this to show a treatment is safe and effective. It can sometimes be hobbled by fraud, especially when mixed with patient desperation.

Now, with ivermectin, once again some unscrupulous people engaged in creative dishonesty that probably cost lives. “I’m worried that there are people who were led astray thinking that these treatments worked and did not get vaccinated,” says Hill. “Some may have got Covid and died.”

Predictably, some ivermectin doses used for farm animals were unsuitable for people. This led the Food and Drug Administration in the United States to issue a warning about the dangers of people taking veterinary medications. Strange that this was needed, but the pandemic brought with it strange times and openings for hype around snake oil solutions.

Slow lane, fast lane

Issues have arisen around how pharma has communicated results from large clinical trials. Many scientists are wary when pharma companies released results as succinct press releases.

In defence of this practice, early sight of results might be justifiable during a deadly pandemic. Clinicians needed to know if there really was a life-saving treatment. For example, in September 2021, researchers found that a cheap steroid drug could help treat severely ill patients. This was immediately used to save lives.

But some medicines fell short of initial press release lift-off. The antivirals have exercised Hill at the University of Liverpool. “I think we have seen a two-speed process, where you have negative results coming out much more slowly than positive results.”

Merck issued a press release last October on its antiviral drug (molnupiravir) showing a 50 per cent reduction in hospitalisations and fewer deaths, based on 700 patients. “But the next half of the patients in the study, about 500 to 600, actually did worse than placebo, and that information took months to come out,” Hill adds.

The full set of results showed hospital admission and deaths were about 30 per cent lower. “Press releases,” he complains, “just gives this perception that all these drugs are working”.

What would help is the publication of a larger study, this time including vaccinated people. One is under way in the United Kingdom.

Antivirals must be taken within five days of Covid-19 symptoms, which can sometimes be impractical. It might seem wise to allow easier access, but it is prescription only for good reason. Molnupiravir can cause birth defects in animals, and some scientists worry that men or women taking this drug could in future see a rise in birth abnormalities. The best choice for Covid-19 remains vaccination.

Covid-19