The Food and Drug Administration (FDA) is warning there is potential for the monkeypox virus to change significantly enough that the treatments currently being used to fight the outbreak could be rendered ineffective.

In updated guidance on Thursday, the FDA noted that viruses are subject to change over time — the SARS-CoV-2 virus being an all too perfect example — and these changes can result in treatments becoming less effective.

TPOXX, the smallpox antiviral that has been authorized to treat cases of monkeypox, works through the inhibition of the VP37 protein found in orthopoxviruses, the family of viruses that both smallpox and monkeypox belong to.

“However, as noted in the drug label, TPOXX has a low barrier to viral resistance. This means small changes to the VP37 protein could have a large impact on the antiviral activity of TPOXX,” the FDA said.

The efficacy of TPOXX against monkeypox infections is still not known, with little to no human data available. The drug was approved to treat smallpox by the FDA based on data from animal studies and there is currently no safety or efficacy data for monkeypox treatment.

Most people who contract monkeypox will recover within two to four weeks with no lingering symptoms apart from scarring left over from lesions caused by the infection. Anecdotally, physicians have reported that many patients are hospitalized for pain caused by these lesions, but not necessarily due to severe illness.

As with most viral infections, immunocompromised individuals are at a higher risk of developing severe illness when infected with monkeypox. According to recent data from the Centers for Disease Control and Prevention (CDC), 38 percent of people infected with monkeypox also have HIV, a condition that affects patients’ immune systems.

In accompanying CDC guidance updated on Thursday, the agency explicitly stated “healthcare providers should not prescribe TPOXX to people with milder monkeypox symptoms.”

“When TPOXX is prescribed too often to people with milder monkeypox symptoms, it may increase the chance that the monkeypox virus develops resistance to the medication. This means the drug might no longer work for monkeypox,” said the CDC.

The CDC is monitoring for changes to the monkeypox virus that could make it better at evading potential protection from TPOXX. The FDA advised similarly that “the drug be used in a judicious manner,” due to the potential of monkeypox becoming resistant.

The National Institute of Health has recently announced clinical trials to determine TPOXX’s efficacy. One will be conducted in the U.S. and another in the Democratic Republic of the Congo, where monkeypox is endemic. NIH researchers are currently recruiting adult and child volunteers for the study, with White House medical advisor Anthony Fauci saying they are aiming to recruit over 500 people in the U.S.

Nearly 23,000 monkeypox cases have been confirmed in the U.S. so far. Of these cases, at least 2,600 patients have been reported to have been treated with TPOXX, though this number is likely an undercount as physicians can begin treatments before reporting to the CDC. Nearly all patients who have been treated with TPOXX for monkeypox have been male, as most cases of infection have been among men who have sex with men.