A Tecovirimat-Resistant Mpox Cluster Spreads Across Five States, 2023–2024

Tecovirimat is the first-line antiviral for orthopoxvirus infections such as smallpox and mpox, and it has been used widely in the United States since the global mpox outbreak began in 2022. But mutations in the viral protein it targets — called F13 or VP37 — can arise during treatment and make the drug ineffective.

Such resistance mutations have been reported since 2022, mostly in severely immunocompromised patients who needed long courses of tecovirimat. Most people infected with resistant virus had been treated with the drug. But in late 2022 and early 2023, resistant virus spread in California among people who had never taken it. A CDC report in MMWR describes a second, unrelated cluster.

The cluster

Genetic surveillance found a new combination of F13 mutations — an N267 deletion (N267del) and an A184T substitution — in 20 specimens from 18 mpox patients in five states between October 6, 2023, and February 15, 2024:

During their incubation periods, two patients had traveled between states where the mutations were found, and two had traveled to other states — making this the first reported interstate spread of tecovirimat-resistant mpox.

The patients

• None of the 16 patients with treatment records had taken tecovirimat before their resistant sample was collected. One patient, with fewer than 10 large lesions, was prescribed a standard 14-day course afterward and recovered.
• All 17 patients with clinical data had mild disease, consistent with other clade IIb infections, though two were hospitalized for pain management.

Confirming resistance

• Lab tests on seven samples confirmed resistance: the half-maximal effective concentration (EC50) of tecovirimat rose 177- to 583-fold compared with a 2003 U.S. reference strain.
• Whole genome sequencing showed these viruses were distinct from the California cluster, which belonged to sublineage B.1.17 and carried N267del but not A184T. The new viruses formed a single branch within sublineage B.1.20, the dominant U.S. lineage in late 2023 and early 2024 — meaning the mutations arose in a common ancestor before any of these samples were collected.
• The resistance mutations made up 88%–100% of the virus population in each patient's samples, unusual for resistance acquired during treatment. Tecovirimat would likely have been ineffective for these patients.

The resistant viruses formed their own branch within sublineage B.1.20 (MMWR).

What it means

Because not every mpox case is sequenced, the true spread of this resistant variant is likely underestimated. The authors call for:

• more routine sequencing to find out whether the resistant virus is still circulating;
• following CDC's Investigational New Drug protocol for tecovirimat outside clinical trials — using it only when indicated, taking the full number of pills on schedule, and taking it with a fatty meal as instructed;
• preventing spread of potentially resistant virus to others.

Together with the PALM007 study, the findings show an urgent need for new mpox treatments, and for smallpox biothreat preparedness.

Sources

• Gigante CM, Takakuwa J, McGrath D, et al. "Notes from the Field: Mpox Cluster Caused by Tecovirimat-Resistant Monkeypox Virus — Five States, October 2023–February 2024," MMWR Vol. 73, No. 40, CDC; a work of the United States government in the public domain.