A cautionary tale? After hydroxychloroquine, attention turns to ivermectin

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A box of Ivermectine, made by Biogaran, at a counter of a pharmacy in Paris, France. Photo by: Benoit Tessier / Reuters

The Philippines is one of the latest countries to be swept by the ivermectin quandary, caught in a debate between doctors and experts who are aggressively pushing for the drug’s immediate uptake, and those calling for caution noting uncertainties on the drug’s efficacy and safety when used as treatment for COVID-19.

Dr. Benigno Agbayani, an orthopedic surgeon in Manila, has taken ivermectin both as treatment and prophylaxis. Suffering from long COVID, he said his symptoms gradually went away after taking ivermectin.

While he read about ivermectin — an antiparasitic drug used to treat several neglected tropical diseases in humans, and is also used in veterinary medicine — Agbayani’s personal experience was his “biggest proof” that the drug works for COVID-19, launching him as a vocal advocate in the Philippines. As president of a group calling for the uptake of the drug, he petitioned the country’s leadership to issue a directive allowing for the manufacture, import, and distribution of human-grade ivermectin in the country.

Resty Arrelano, a car painter, has been taking one capsule of ivermectin every three weeks since February 2021 as well to protect him from COVID-19. At 64, he is considered high-risk for COVID-19 but is hesitant to receive a vaccine over reported side effects.

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Such anecdotes can be a powerful convincing tool in a country experiencing a deadly surge of COVID-19 cases. Over the past week, the Philippines reported a 400% increase in COVID-19 deaths, the highest since March 2020. Amid the gloomy situation, veterinarians have reported increased inquiries for ivermectin purchases.

In many ways, experts said ivermectin’s story shares similarities with hydroxychloroquine. Both drugs are cheap, widely available, and have been used to treat other diseases prior to COVID-19. Interest in both drugs’ ability to treat COVID-19 was driven by early studies with questionable data. Both have also created hype and hope in the middle of a pandemic where people are seeking a cure or means to protect themselves.

But unlike hydroxychloroquine, which has received a strong recommendation in March from World Health Organization experts that it should no longer be a research priority, the jury is still out on ivermectin. More large-scale, randomized trials are considering including the drug to fill the gaps in evidence, but if the story of hydroxychloroquine is anything to go by, such studies are unlikely to settle the debate.

“There are still people around the world who are saying, ‘Oh, you're murderers for saying this, depriving people of treatment.’ And there are many countries in which hydroxychloroquine is still being used as standard treatment,” Dr. Jeffrey Aronson, a clinical pharmacologist at the University of Oxford and president emeritus of the British Pharmacological Society, told Devex.

The debate could be settled if the results of upcoming studies on ivermectin turn out to be positive. But he sees large-scale, randomized trials as the only way forward.

“There is a kind of angst, internal panic, people feeling we need to do something, and we need to do it now,” he said. But “you can't substitute [that] for proper science,” said Aronson.

Finding a middle ground

Two publications drove the initial interest in ivermectin in 2020: a preprint study that has since been taken down, and an in vitro study that never progressed to clinical trials, Devex has learned.

“I think the story with ivermectin in Peru is an unfortunate story, in an environment with much need, and you can see that need arising from very, very big impacts of the pandemic … I think that tells us that good science and good intentions need to stick to the evidence.”

— Dr. Jaime Miranda, director, CRONICAS Center of Excellence in Chronic Diseases

More studies have since been published on the drug, but as treatment, WHO has recently issued a statement recommending its limited use in clinical trials, until the availability of more data. Those who’ve been aggressively pushing for the drug’s immediate uptake, however, have said there is already enough evidence that ivermectin works, and delaying its uptake could cost more lives.

“It remains a highly contentious topic, with people really convinced on one side … [that] it's worthless and it will be a waste of effort and time. On the other side, people are convinced that there's a huge conspiracy, and Big Pharma wants to push vaccines when we have this miracle cure sitting on the shelves. That's very difficult to [reconcile],” said Dr. Carlos Chaccour, assistant research professor at the Barcelona Institute for Global Health.

“There is a potential for it, just like there was a potential for hydroxychloroquine. But now hydroxychloroquine is shown that it doesn't work. So could ivermectin help in low-resource areas where there's a shortage of other treatments ... in general? It could. But that's not proven,” he added.

Ivermectin has a good safety profile based on its use for some neglected tropical diseases, but there are risks to its indiscriminate and unregulated use for COVID-19. Those who are using the drug as a prophylactic could also have a false sense of protection. In addition, there are uncertainties about the drug’s impact on a patient’s immune response, or its potential interaction with COVID-19 vaccines, Chaccour said.

“I don't judge policymakers or MDs working on the frontlines of care who take care of patients who are very sick and desperate for measures. But we might be giving out something with unknown consequences,” he said.

Aronson said there were early assumptions too that hydroxychloroquine was safe for COVID-19, but it’s hard to pick up adverse effects until one has done large-scale studies.

But safety concerns around COVID-19 vaccines are also driving others to look for other means to protect themselves from the disease. As a doctor, Agbayani is eligible for a COVID-19 vaccine but chose not to due to lack of evidence for long-term safety studies. Hospitals are also at full occupancy in the Philippine capital, he said.

Philippine health authorities, however, maintain that the COVID-19 vaccines are safe and effective, and say there haven’t been any incidents in the Philippines reporting blood clots from the Oxford-AstraZeneca vaccine. The European Medicines Agency recently listed blood clots as very rare side effects of the Oxford-AstraZeneca vaccine.

Filling the evidence gap

Renewed interest in ivermectin has led large institutions to consider the drug in further trials.

UNITAID is adding ivermectin in the ANTICOV trial conducted in 13 countries in Africa. The U.S. National Institutes of Health is also mulling including the drug in a planned randomized clinical trial. Canada’s McMaster University is also leading a large-scale study evaluating ivermectin’s impact on COVID-19 disease progression.

In Peru, a randomized clinical trial is recruiting to determine the impact of ivermectin given daily for three consecutive days to nonsevere COVID-19 patients.

The study could help provide evidence for the drug in a country often touted as a model for ivermectin uptake. Peru is one the earliest adopters of both ivermectin and hydroxychloroquine in 2020, and there were papers linking ivermectin use to decline in mortality in some Peruvian states.

But Dr. Jaime Miranda, director at the CRONICAS Center of Excellence in Chronic Diseases at Universidad Peruana Cayetano Heredia in Lima, expressed caution in these observations, saying they’re at risk of “ecological fallacy” or where assumptions are made on an individual based on group data analyses.

But countries could learn a few things from Peru’s story on ivermectin, he said. Lacking social protection and suffering from a weak health system, Peru, seeing a rise in cases in the second quarter of 2020, was under pressure to do something.

So in May 2020, the Ministry of Health approved the use of ivermectin as COVID-19 treatment. Months later, finding the drug has shown no beneficial effect, the health ministry removed the drug, as well as hydroxychloroquine and azithromycin, from the treatment of hospitalized patients for COVID-19, although it appears to still be included for ambulatory cases in Peru, per doctors’ discretion.

The effect was the drugs caused people to self-medicate, were used as a political tool, and physicians dispensed the treatments without any proper guidelines.

“I think the story with ivermectin in Peru is an unfortunate story, in an environment with much need, and you can see that need arising from very, very big impacts of the pandemic,” Miranda told Devex.

“I think that tells us that good science and good intentions need to stick to the evidence,” he said.

About the author

  • Jenny Lei Ravelo

    Jenny Lei Ravelo is a Devex Senior Reporter based in Manila. She covers global health, with a particular focus on the World Health Organization, and other development and humanitarian aid trends in Asia Pacific. Prior to Devex, she wrote for ABS-CBN, one of the largest broadcasting networks in the Philippines, and was a copy editor for various international scientific journals. She received her journalism degree from the University of Santo Tomas.