Could This COVID Anti-Viral Pill Fuel the Emergence of New Variants?

Some scientists have expressed concerns that an anti-viral COVID-19 drug that is being rolled out across the United States may help to fuel the emergence of dangerous new variants.

The anti-viral pill molnupiravir, developed by Merck and Ridgeback Biotherapeutics, was authorized for emergency use in the United States by the Food and Drug Administration (FDA) on December 23, 2021, after an advisory panel narrowly endorsed the medication.

The pill is designed to treat adults with mild-to-moderate COVID-19 symptoms who are at high risk of severe disease.

Molnupiravir is available by prescription only and should be initiated as soon as possible after a COVID-19 diagnosis and within five days of symptom onset. The FDA was clear in announcing the authorization that use of the drug will be limited to high-risk people for whom alternative treatments are not "accessible or clinically appropriate." It should not be used for more than five consecutive days.

Initially hailed as a potential game-changer because it can be taken at home, the drug has been shown to cut the risk of hospitalization and death from COVID-19 by 30 percent in these patients—a lower efficacy than Merck had originally claimed.

Alongside the downgraded efficacy figures, some concerns have been raised about the drug's safety and the possibly that it might alter human genes. While the risk to adults, according to data from animal studies, is low, the FDA has not authorized the drug for under 18s or pregnant individuals as a result.

In addition, some experts have raised concerns about the possibility that the use of the drug could fuel the emergence of new COVID-19 variants, like Delta or Omicron, that are highly transmissible and/or may evade protection afforded by the vaccines to some extent.

Molnupiravir works by interfering with the replication of the SARS‑CoV‑2 virus—which causes COVID-19—after it has entered the cells of the body. It does this by introducing errors into the genetic code of the virus. Introducing enough errors eventually prevents the virus from replicating and the patient can clear the pathogen from their body.

But some scientists have warned that during this process of mutations, there is a possibility that new variants could emerge under certain circumstances—although other experts have downplayed such fears.

"I am very concerned about the potential consequences now that molnupiravir has been approved," Michael Lin, an associate Professor of neurobiology and bioengineering at Stanford University, told Newsweek. "It would only be a matter of time, perhaps a very short time, before a lucky set of mutations occurs to create a variant that is more transmissible or immunoevasive."

"Mutations are what naturally create variants of concern that are more contagious or immunoevasive, like Delta or Omicron," he said. "The drug simply speeds up that natural process. The hope is that over enough days all the viral copies will have so many mutations that none of the copies can function."

But Lin said he was concerned that in the real world, there is a possibility that a mutated virus could jump from a patient taking molnupiravir to another individual, citing the relatively modest efficacy of the drug.

"For cases that get worse so that people have to go to the hospital, this drug only prevents that from happening 30 percent of the time. That means 70 percent of the time the virus isn't being eliminated quickly enough to make a difference. And we know COVID patients going to hospitals are highly contagious."

Lin said the risks could be heightened when a patient does not comply exactly with the dosing schedule of the drug.

"This treatment is an oral one, so it is going to rely on the patients taking their pills. Patients are notoriously poor at completing a course of pills correctly. They'll forget, or they'll feel side effects and stop, or they'll feel better and think they don't need to finish the pills."

"In any of those situations viruses will have picked up some mutations but not enough to kill all the virus copies," he said. "The survivors are now mutated, perhaps have picked up immunoevasion, and can go on to infect others."

Merck has not supplied data showing that the drug eliminates the virus in those patients least likely to eliminate the virus and most likely to go to hospital—i.e. those who are immunocompromised. In their emergency authorization letter, the FDA requested that the company provide this data by April this year.

According to Lin, the "very low efficacy alone" should have disqualified the drug from approval given that it would only serve as an inferior option to other therapeutics such as fluoxetine, monoclonal antibodies or Pfizer's own oral COVID-19 anti-viral pill Paxlovid, which trials have shown to be 89 percent effective at preventing hospitalization and death for high-risk patients.

"Even if the drug were great we wouldn't take such a risk, but this drug is worse than any other drug that's sought approval for COVID19. It's completely not worth it."

Dr. William Haseltine, an expert of on the COVID-19 pandemic and former professor at Harvard Medical School who is known for his groundbreaking work on HIV/AIDS and cancer, is among other scientists who have raised concerns about molnupiravir and its potential to fuel the emergence of new variants.

Haseltine, the founder of several biotechnology companies who spent much of his early career working on HIV antivirals, told Newsweek: "I'm very concerned. And my concern is shared by a number of other scientists."

According to Haseltine, even under ideal conditions, patients treated with molnupiravir appear to shed viable live virus for two or three days into their treatment course.

"Unfortunately, the sequences of those viruses have not been made public," he said. "But despite that, it is a drug, which has the potential to seriously exacerbate an already bad situation."

As the drug is given to millions of people across the country—the U.S. pre-ordered 3.1 million courses although supply is currently tight and access limited—the risks increase, he said.

"Of all the antiviral drugs I have ever seen, this is by far the most potentially dangerous. The more people that take it, the more more dangerous it will be," Haseltine said.

There is some evidence from experiments conducted prior to the pandemic that other coronaviruses—the family which SARS-CoV-2 belongs to—could become resistant to molnupiravir. The development of the drug, which was initially intended to be a treatment for influenza, began in the mid 2010s.

When the anti-viral was tested against two other coronaviruses—MERS-CoV and the mouse hepatitis virus (MHV)—researchers found an increase in mutations, including in the key spike protein, which enables the pathogens to bind to and enter living cells.

In fact, for MERS, which is closely related to SARS-CoV-2, researchers found more than 100 mutations on the genome of the virus. This is more mutations than the highly-mutated Omicron COVID-19 variant has.

While these experiments did demonstrate a replication disadvantage, the MERS and MHV viruses could still survive and replicate.

"While it's possible that at the optimal concentration, the drug may very well cause enough mutations to prevent replication and onward transmission of [SARS-CoV-2,] the impact of suboptimal doses is still very much unknown," Haseltine wrote in an article for Forbes.

In the FDA analysis of Merck's molnupiravir clinical trial results for the treatment of SARS-CoV-2, officials found that virus mutations appeared to be more prevalent among people who were given the drug, compared to those who received a placebo.

FDA researchers told the advisory panel—which voted 13 to 10 in favor of recommending emergency authorization—that some of these structural changes were similar to those seen in major COVID-19 variants, such as Delta. But the FDA researchers said the risk of new variants emerging in individual patients was low.

One of the panel members who voted no, James Hildreth—president of Meharry Medical College in Tennessee—said Merck should do more to quantify the risk of such an event.

"Even if the probability is very low, one in 10,000 or 100,000, that this drug would induce an escape mutant which the vaccines we have do not cover, that would be catastrophic for the whole world," he told the panel.

In a statement provided to Newsweek, a Merck spokesperson said: "There is no evidence to indicate that any antiviral agent has contributed to the emergence of circulating variants. Over the course of the pandemic, variants have emerged due to uncontrolled viral replication and continued transmission caused by an absence of widely available treatment options and low levels of vaccination. Antivirals such as molnupiravir, because they help to address these issues, can form an important part of the solution."

Several other scientists that Newsweek contacted for this article said they were not overly worried about the potential for molnupiravir to generate new and potentially dangerous variants.

Dr. Douglas Richman, a professor of pathology and medicine at the University of California San Diego, told Newsweek: "I am personally not concerned that molnupiravir presents a risk for the emergence of resistant viruses of concern."

The researcher said the theoretical risk of the drug potentially being able to damage human genes and its "less than optimal efficacy" are the "real concerns."

Dr. John Williams, a professor of pediatrics at the University of Pittsburgh School of Medicine, told Newsweek the risk of drug-resistant viral mutations is "low."

"I and the scientists I am in contact with are not particularly concerned that this drug will fuel the emergence of a new variant of concern. In testing of the drug against SARS-CoV-2 in cells and animals, as well as against other RNA viruses, the drug causes lethal mutations in the viruses and there was a high barrier to developing resistance."

Even if drug-resistant mutants did arise, Williams said, there is no reason to think that they would behave differently to variants that are already circulating.

"In fact, drug-resistant viruses are often 'weaker' than the 'wild type' viruses," he said.

Sankar Swaminathan, an infectious disease specialist at the University of Utah School of Medicine, said the emergence of new variants in patients taking molnupiravir was "not likely to happen," at least on a large scale, for a variety of reasons.

"The high rate at which mutations are induced in the viral genome are likely to lead to so-called catastrophic mutation, which renders the virus incapable of replicating. It is therefore generally unlikely to generate viable viruses capable of surviving and being transmitted at a higher rate than normally occurs during normal untreated infection."

"We have no evidence that such [new variants] survived treatment in the normal individuals in the study. But the frequency at which these may exist is not known for certain."

Nevertheless, Swaminathan said the risk of generating new variants could be higher in immunocompromised patients who are taking the pill, even if the risks are still low.

"Under circumstances where viral elimination is impaired, as we have seen in patients with compromised immune systems, viruses persist and come through each round of antiviral therapy or antibody treatment, having escaped elimination, and with mutations that have been selected to be resistant," he said. "We simply do not know if this is likely or how often it may happen in the immunocompromised patient."

COVID-19 antiviral pills
Stock image showing COVID-19 anti-viral pills. Molnupiravir is designed to treat adults with mild-to-moderate COVID-19 symptoms who are at high risk of severe disease. iStock