Tecovirimat Resistance in Mpox Patients, United States, 2022-2023

Abstract

During the 2022 multinational outbreak of monkeypox virus (MPXV) infection, the antiviral drug tecovirimat (TPOXX; SIGA Technologies, Inc., https://www.siga.com) was deployed in the United States on a large scale for the first time. The MPXV F13L gene homologue encodes the target of tecovirimat, and single amino acid changes in F13 are known to cause resistance to tecovirimat. Genomic sequencing identified 11 mutations previously reported to cause resistance, along with 13 novel mutations. Resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment, whereas most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive. The frequency of resistant viruses remains relatively low (<1%) compared with the total number of patients treated with tecovirimat.

Keywords: ST-246; TPOXX; United States; antimicrobial resistance; antivirals; monkeypox virus; mpox; orthopoxvirus; tecovirimat; viruses.

Figure 1

Geographic distribution of patients with mpox who had samples received for tecovirimat resistance testing (A) and who had samples confirmed resistant (B) June 2022–July 2023, United States.

Figure 2

Examples of tecovirimat resistance in mpox patients, United States, 2022–2023. Patient samples were sequenced, cultured, and subjected to tecovirimat sensitivity testing in a cytopathic effect assay. A) Different samples from the same patient showed different F13 amino acid substitutions that result in different levels of resistance compared with the wild-type control (MPXV clade IIa, collected in the United States in 2003 [GenBank accession no. ON563414]). B) Samples from the same patient at different times before and after starting tecovirimat treatment in August 2022, showing sensitivity before drug treatment and increasing resistance after drug treatment. Abs₅₇₀, absorbance at 570 nm.