Monkeypox Has the Potential to Mutate and Resist Antiviral Treatment, FDA Warns

As the global monkeypox outbreak lingers on, health officials are warning that the virus is mutating at a pace that may soon allow it to become resistant to an antiviral drug used to treat patients at risk of serious illness.

The Food and Drug Administration (FDA) is urging that providers be “judicious” in prescribing the drug tecovirimat—or TPOXX—due to the potential for immune resistance.

“Viruses can change over time. Sometimes these changes make antiviral drugs less effective at combating the virus they are targeting, meaning those drugs won’t work as well or might not work at all,” the FDA said in guidance published online and as part of updated labeling for TPOXX.

The FDA’s new guidance added that TPOXX has a “low barrier to viral resistance” and that even small changes to a monkeypox viral protein known as VP37, could “have a large impact on the antiviral activity of TPOXX.”

Here’s a closer look at what that means for the future of monkeypox and treating at-risk patients.

In its new guidance, the FDA explained that the antiviral drug TPOXX works by inhibiting the VP37 protein that orthopoxviruses like smallpox and monkeypox all possess. However, studies have identified several genetic pathways for orthopoxviruses to become resistant to tecovirimat or TPOXX, the FDA added.

In light of such concerns, “CDC scientists are actively monitoring for changes in the monkeypox virus that could make the virus less susceptible to TPOXX,” the FDA warning adds.

It takes just a “single mutation” in a DNA sequence that codes for a particular amino acid for the virus to develop resistance to tecovirimat, Monica Gandhi, MD,MPH, told Health.

“In layman’s terms, this just means it won’t be that difficult for the monkeypox virus to evolve resistance to tecovirimat, a process that will most likely occur if we use tecovirimat broadly so the virus has ‘pressure’ to evolve this resistance in order to still replicate when tecovirimat is given,” Dr. Gandhi added.

The big concern surrounding the FDA’s warning is that “tecovirimat resistance will develop quickly, Eleftherios Mylonakis, MD, PhD, the Charles C.J. Carpenter, MD professor of infectious diseases, professor of medicine, assistant dean of medicine, and professor of molecular microbiology and immunology at the Alpert Medical School of Brown University, told Health.

If that were to occur, it would have larger implications, Dr. Mylonakis said. Given that there are limited monkeypox vaccine supplies, the resistance threat posed by mutations is real and could even mean monkeypox is here to stay, said Dr. Mylonakis.

Who Should and Should Not Get TPOXX?

The FDA warning raises questions about who should and who should not get TPOXX moving forward.

The FDA suggests that those who are not at risk for more serious illness —in other words those who have a healthy immune system already—but might still contract monkeypox, should not pursue use of the medication.

When asked who he prescribes TPOXX to, Dr. Mylonakis, from Brown, said he usually discusses use of the antiviral drug with patients who have severe pain or are at risk for severe disease spread, such as a course of disease that would impact the central nervous system, or result in comorbid conditions like pneumonia.

In general, when looking at the new guidance, providers “should not be using tecovirimat broadly” in people who “do not have multiple lesions or severe monkeypox disease,” Dr. Gandhi added.

Instead, she suggests they be referred to a randomized, controlled clinical trial being conducted by National Institutes of Allergy and Infectious Diseases (NIAID) that is further testing the drug’s use for monkeypox. This would allow for better monitoring of the safety and effectiveness of the drug in those using it, as well as observation of a potential “resistance profile” for TPOXX.

“A randomized trial is necessary for us to determine how well tecovirimat works for monkeypox,” she said. The trial will also help health officials more accurately gauge the virus’ rate of resistance before disseminating TPOXX more widely.

In its guidance, the FDA writes that the agency “believes releasing this additional information will further facilitate the ability to monitor for the development and spread of tecovirimat-resistant virus and therefore is important in promoting public health.”

For the average reader seeing this news, the revelation about potential drug-resistant mutations of monkeypox might seem similar to what took place during the COVID-19 pandemic. For the past two years, there’s been constant updates about resistance to vaccines meant to protect people against COVID-19.

However both Dr. Gandhi and Dr. Mylonakis stressed that monkeypox and COVID-19 are very different viruses.

Dr. Mylonakis said it’s necessary to keep in mind that the respiratory spread that occurred with COVID-19 is far less likely with monkeypox, making the dynamic of the monkeypox outbreak significantly different.

However, Dr. Mylonakis added that it will be important to continue to monitor how monkeypox evolves and mutates.

Dr. Gandhi expressed similar sentiments noting that monkeypox is a “DNA virus” that tends to mutate much more slowly than “RNA viruses like SARS-CoV-2.”

“We saw very little variability in the monkeypox endemic outbreaks in terms of different variants in West and Central Africa over the past 20 years,” Dr. Gandhi explained, adding that the monkeypox outbreaks have seen the development of just “two major clades,” or different types.

“However, when we start using antivirals—or antibacterials in the case of bacteria— for an infection, we can see mutations in that virus,” Dr. Gandhi said. “So, we are watching this closely and will be able to monitor if tecovirimat resistance occurs.”

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