A few weeks ago, healthcare workers and volunteers wearing masks and medical gloves began distributing an estimated 350,000 doses of ivermectin to residents of Trinidad in the northern Bolivian province of Beni. The ivermectin, a drug used for decades to treat parasitic worms, was being offered as a prophylactic to protect Bolivians from the novel coronavirus in a region hard hit by Covid-19.
Marco Antonio Aponte, the doctor who designed the treatment protocol for ivermectin in Beni, went on Bolivia’s Radio Uno recently to explain the drug distribution campaign. “My approach is that we use it as preventive medicine and for mild cases for home treatment,” Aponte said. The drug was approved by Bolivia’s Ministry of Health on May 12 to combat Covid-19. Ivermectin, originally found in a bacterium in Japanese soil, developed into an antiparasitic by the pharmaceutical company Merck and subsequently donated to treat river blindness, is now produced generically and used to treat elephantiasis, scabies and roundworm infections.
But the evidence of ivermectin’s efficacy in treating Covid-19 in humans is slim. Aponte’s rationale for using the drug, he explained to CNN Español, was based on a study conducted by Australian researchers that showed the drug inhibited SARS-CoV-2, the virus which causes Covid-19, in vitro, meaning the drug was tested not in humans or animals but on mammalian cells in a dish – monkey kidney cells to be precise. Soon after its publication in the journal Antiviral Research, though, the study prompted a letter of caution from the U.S. Food and Drug Administration (FDA) as well as substantial blowback from the scientific community.
“In vitro promise leads to clinical failure in the vast majority of cases,” warned one letter to the editor published in the journal in response to the study. A guest editorial published in the American Journal of Tropical Medicine and Hygiene (AJTMH) echoed that fact and also pointed out that severely ill patients could experience neurotoxicity if the drug crosses the blood-brain barrier.
“The discovery of ivermectin’s activity against SARS-CoV-2 gives reason for hope, but off-label and compassionate use requires careful risk–benefit considerations, especially in critically ill patients,” they wrote. The same point was raised by Doris Cully, an expert in ivermectin and former director of both Infectious Disease and Cardiovascular Research at Merck, in a recent episode of the podcast This Week in Virology. “When you get into this dose range, there is a lot unknown.”
Much of the ivermectin criticism from the scientific community boiled down to two simple facts: 1) in vitro and in vivo are vastly different universes when assessing a drug’s efficacy, and 2) administering any medication at high doses carries serious risks. In other words, showing antiviral activity in cells is one thing. Showing it works against SARS-CoV-2 in humans – and getting the dose right – is a much more complicated proposition and one that could lead to serious side effects. As Essalud, Peru’s social health insurance agency, recently concluded in a report discouraging the use of ivermectin for Covid-19: “the evidence available to date, on the viability of ivermectin as a Covid-19 treatment, is still in early stages of development; highlighting that pharmacokinetic predictions are theoretical and evidence from human studies is scarce.” Many of the doctors we spoke with expressed similar concerns.
“Several studies show that you can grow the virus in a test tube and then kill it off with high doses of various drugs we already have,” says Pranay Sinha, an infectious diseases physician and researcher at Boston Medical Center in Boston, Massachusetts. “But how does this translate to killing the virus in humans? If you’re going to give an innocuous FDA-approved drug like ivermectin at five or ten times the normal doses, of course you’re going to have toxicity.”
Drug development starts with in vitro tests followed by safety and efficacy tests in animals – such as rodents and primates – and finally clinical trials in humans. That process typically takes years and properly scaling up the dose without being toxic is highly complex. But in the face of a global pandemic, desperation has the public, politicians and even medical professionals seizing on early data and multiplying up the dose.
While Sinha understands these are desperate times, he thinks the medical community and the public need to better separate enthusiasm from evidence, faith from facts. “Hope is very important, but truth is necessary.”
Yet unproven treatments have become a hallmark of the Covid-19 pandemic. With drugs like hydroxychloroquine, azithromycin, remdesivir, tocilizumab and ivermectin, the scientific evidence they work for Covid-19 is limited and oftentimes shaky, and there exist serious risks of adverse reactions and side effects.
But news reports have heralded these drugs as panaceas and “game-changers,” often without citing studies or pointing out the risks. And, to make matters worse, politicians with no medical expertise are prescribing these drugs. Hydroxychloroquine and azithromycin, an antimalarial and antibiotic both produced generically, have been promoted by Brazilian president Jair Bolsonaro and U.S. president Donald Trump as being effective treatments against Covid-19. Yesterday, the FDA revoked its "emergency use authorization" for hydroxychloroquine and chloroquine for the treatment of Covid-19 due to a lack of scientific evidence.
These drugs are proliferating – especially across Latin America. In early May, ivermectin was approved by Peru’s Ministry of Health, along with hydroxychloroquine and azithromycin, to treat Covid-19. Last month, Brazil’s Ministry of Health released guidelines for the use of hydroxychloroquine in treating Covid-19 patients. Last week, the United States announced that it would be sending two million doses of hydroxychloroquine to Brazil for prophylactic use by nurses, doctors and other health care workers. And a few days ago, the city of Natal, in northeast Brazil, approved ivermectin, hydroxychloroquine and azithromycin for the treatment of Covid-19.
Many of these drugs, of course, were never meant to treat Covid-19. Hydroxychloroquine is an antimalarial, azithromycin is an antibiotic, ivermectin is an antiparasitic, tocilizumab is a cancer and rheumatoid arthritis drug, and remdesivir is an antiviral. Because they have other indications, clinical trial data with Covid-19 patients are sparse or nonexistent. Yet today, all five are being used to treat Covid-19 patients.
To fill the evidence gap, researchers around the globe are scrambling to launch and complete clinical trials to test these drugs for Covid-19 and accumulate evidence as to whether they do or don’t work. The timeline to completion for these clinical trials vary from later this year to as far away as 2023. In the meantime, however, patients in the clinic and people taking these drugs prophylactically risk serious side effects and potentially lethal adverse reactions, especially if they are taken without a doctor’s supervision, says César Ugarte, an epidemiologist at the Instituto de Medicina Tropical Alexander von Humboldt at the Universidad Peruana Cayetano Heredia.
“Ivermectin is not a drug that should be given without medical supervision,” says Ugarte, pointing out that the use of these drugs at home or in an outpatient setting compounds the risks. Indeed, ivermectin has been shown to have serious side effects in patients with multiple parasitic infections. That’s not a far-fetched scenario in Latin America, says Sinha, of Boston Medical Center. “In areas where there are multiple parasitic infections, receiving ivermectin could cause a Mazzotti reaction which can at times be lethal,” he explains.
“You can’t just hand ivermectin out like aspirin,” says Sinha. “There needs to be thoughtful use, especially in the tropics.”
Hydroxychloroquine and azithromycin
Hydroxychloroquine and azithromycin, meanwhile, can have serious side effects in patients with cardiovascular issues, which are widespread in Latin America. As the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society warned in a joint statement on April 8, “hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for Covid-19 infection. Both drugs are listed as definite causes of torsade de pointes,” an abnormal heart rhythm known as “twisting of the peaks” in French. Both drugs can increase the risk of other arrhythmias and sudden death, the authors wrote, and patients should be closely monitored with an electrocardiogram (EKG).
But that monitoring is not happening outside of the clinic. “Cardiac complications from the use of hydroxychloroquine and azithromycin are monitored daily in the hospitals I walk around,” says Letícia Kawano-Dourado, a pulmonologist and clinical trialist at Hospital do Coração and a clinical researcher at the University of São Paulo. “But that’s not real life. I may see that in São Paulo but people are using hydroxychloroquine at home. Noone’s doing an EKG on them.”
Hydroxychloroquine sales, though, have jumped in Brazil and health professionals and pharmacy groups have warned against Brazilians medicating themselves. Brazil’s public institute Oswaldo Cruz Foundation and the Brazilian Society of Infectious Diseases have issued warnings about hydroxychloroquine.
Jose Caro, a Peruvian-born infectious disease physician at Tufts Medical Center in Boston, Massachusetts, also worries about hydroxychloroquine’s side effects. Though the drug has been safely used for decades to treat malaria and lupus, its efficacy in treating Covid-19 remains to be seen. Indeed, the scientific debate surrounding hydroxychloroquine is probably the drug being used most fervently for Covid-19 today, in part due to its heavy promotion by politicians like Trump and Bolsonaro.
Caro says he is worried about hydroxychloroquine’s use without medical supervision, especially in Latin America. “Hydroxychloroquine has been used for decades. It’s in general a very safe drug,” he says. “But it’s never been used for Covid up until recently. We don’t recommend it. I would caution doctors in Latin America to not use them in the outpatient setting because patients cannot be monitored. I’d caution not to use it in people over the age of 65. And I would not use it in people with cardiac arrhythmias.” For those reasons, Caro says his hospital system in Boston no longer uses the drug for treating Covid-19 patients. “We’re not using hydroxychloroquine anymore for several reasons, one of them being that there are various signals pointing at the fact that the side effects outweigh the potential benefits.”
The intravenous drugs
Tocilizumab, traditionally used with patients with rheumatoid arthritis and undergoing cancer treatments, is a drug that Caro says he is using very frequently to treat Covid-19. “Covid patients experiencing what’s called a cytokine storm may have that ameliorated by this cytokine inhibitor,” he explains. Developed by Japanese immunologist Tadamitsu Kishimoto in the 1990s, tocilizumab has been approved in more than 100 countries and is marketed by the pharmaceutical company Roche as Actemra and RoActemra, tocilizumab works by quelling the storm of immune activity, characterized by an overproduction of inflammatory cytokines, cells of the immune system, in very sick Covid-19 patients. But the data is early on tocilizumab in Covid-19 patients, Caro warns. “We haven’t seen major issues. Results are yet to be seen.”
Sinha, of Boston Medical Center, agrees that data on tocilizumab in Covid-19 patients still needs to emerge – but his early results excite him. “We found that timing matters. If the patients have already suffered immune damage and are critically ill, the effectiveness of these drugs is reduced. The horse is already out of the barn. But it is also important not to give these drugs too early when the immune system is needed to kill the virus. To be clear, these conclusions are based on observational data. We need randomized controlled trials to make definitive conclusions.”
Nicholas Mark, a critical care physician in Seattle, Washington, has also seen promising results with tocilizumab – or “toci” as he calls it – if a bit cautious in his optimism. “Anecdotally, toci is no magic bullet but it definitely resolves fever quickly,” says Mark. “It may help get patients extubated faster. Overall I’m optimistic that it helps.”
Remdesivir, an antiviral shown to inhibit SARS and MERS viruses but useless against the Ebola virus, has been in the spotlight in recent months thanks to a string of clinical studies from the U.S. National Institutes of Health, the U.S. National Institute of Allergy and Infectious Diseases and Gilead, the company that owns the drug. Remdesivir has shown different reductions in recovery times in Covid-19 patients. On May 1, the drug was given “emergency use authorization” by the FDA for hospitalized Covid-19 patients in light of those early data.
But doctors remain skeptical.
“Does remdesivir make a difference? The answer is we actually don’t know,” says Sinha. “Although the studies show a slightly faster time to clinical improvement, we haven’t seen an incredible antiviral response or clear mortality benefit.” That uncertainty was recently echoed by Lindsey Baden, deputy editor of the New England Journal of Medicine (NEJM), in an episode published on May 28 of the NEJM podcast. “We, as a community, have been struggling with how do we use this agent over the last two, three weeks without data to tell us how it works, or the nature of the side effects,” said Baden. “How do we now use remdesivir? How much is available? How is it deployed? Many, many questions, even the adverse events are not fully explained or fully known.”
The limited evidence on remdesivir’s side effects, according to a NEJM study of the drug on severe Covid-19 patients, lists diarrhea, rash, kidney impairment, hypotension and, most seriously, potential damage to the liver. The FDA reports that most patients receiving remdesivir for Covid-19 have elevated levels of the enzyme alanine transaminase (ALT) in the bloodstream, which is an early warning sign for liver damage and liver disease. The problem is further complicated by the fact that elevated ALT levels is already a common abnormality in Covid-19 patients, according to an April 13 study in the Journal of Hepatology. Sinha warns: “Remdesivir is associated with reversible liver injury, but people with pre-existing liver damage from alcoholism, viral infections or other causes could face more severe consequences, particularly if their liver function cannot be monitored closely.”
Tocilizumab and remdesivir are both administered intravenously, which means they’ll be nearly impossible for people to access outside of the clinic, says Kawano-Dourado, who doesn’t foresee government approvals of these anytime soon. “For remdesivir and tocilizumab, I don’t think we’ll see government approvals because they’re IV drugs. The access will be much lower.” That issue of access is stark in Latin America, says Kawano-Dourado. In her country, she’s only seen tocilizumab used in private hospitals, and “in Brazil we don’t have remdesivir.” That may be one reason populist leaders like Bolsonaro have seized on cheaper treatments, in spite of a lack of clinical evidence. “It’s much easier to say that a cheap drug like ivermectin or hydroxychloroquine are the solution,” says Kawano-Dourado.
Gilead, the company that owns the patent on remdesivir, has exhibited some troubling behavior since the Covid-19 pandemic started. In March, Gilead sought to designate remdesivir as an "orphan” drug, a status that would give the company tax credits and seven years of market exclusivity to box out competition from other manufacturers. The company later withdrew their request but only after receiving a wave of criticism.
Should a drug like remdesivir prove to make a significant difference in Covid-19 recovery time, both access and cost will need to be worked out if Latin American is to benefit. Some could be in line: Gilead signed voluntary licensing agreements that permit five generic pharmaceutical manufacturing companies, all in Pakistan and India, to produce and supply remdesivir to 127 countries, including Cuba, Dominican Republic, El Salvador, Guatemala, Guyana, Honduras, Nicaragua, Panama, Suriname in Latin America. The current licensing agreement's exact details are not public but Gilead has indicated the countries on the list are either "low-income and lower-middle-income" or have "significant obstacles to healthcare access." Countries without an ability to deliver remdesivir (or similar intravenous medications) reliably to their citizens would also be less likely to purchase the drug, regardless of cost.
However, many larger, comparatively richer, Latin American countries didn't make Gilead's list: Brazil, Peru, Argentina and Mexico among them. In these countries, a course of remdesivir could end up costing thousands of dollars, according to one analysis, though ultimately whatever price Gilead decides. Another wrinkle to keep in mind: While the current Gilead deal sounds generous, it's essentially an expiring offer. The 'royalty-free' agreement ends either when the WHO declares Covid-19 is not an international concern or if another medicine gets approved to treat or prevent Covid-19; whichever comes first.
Booting up clinical trials
More research is crucial in the context of these novel treatments for a novel disease. In an effort to collect better data on these drugs in the Covid-19 context, Ugarte is currently preparing two clinical trials: one with hydroxychloroquine as a preventative measure for health professionals; and one with ivermectin for mass distribution. The idea with the latter is to put the Bolivia case to the test. Kawano-Dourado, for her part, is currently working on “Coalizão Covid Brasil,” where she’s launched two randomized control trials: one assessing hydroxychloroquine, and the other hydroxychloroquine and azithromycin.
Indeed, there are dozens of clinical trials on hydroxychloroquine, azithromycin, ivermectin, remdesivir and tocilizumab that have been initiated around the world. Like Ugarte and Kawano-Dourado’s trials, many are in Latin America, including “Ivermectin Effect on SARS-CoV-2 Replication in Patients With COVID-19” in Argentina, “Hydroxychloroquine and Ivermectin for the Treatment of COVID-19 Infection” in Mexico, and “Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19)" in Colombia. The time to completion varies substantially for these trials; some will be finished before the end of the year, while others have not yet recruited patients.
While they wait for that clinical data to roll in, physicians and the public will continue to struggle to decide how to treat Covid-19 with incomplete information, while risking serious side effects. But in a sense, this uncertainty has been the overriding theme of this pandemic. Covid-19 is a lesson in how medicine works in real-time and under a climate of unpredictability. As Sinha puts it: “This pandemic is an x-ray of our institutions and ourselves.”