Identification of Tecovirimat Resistance-Associated Mutations in Human Monkeypox Virus - Los Angeles County
Abstract
Tecovirimat (also known as TPOXX or ST-246) is a drug available for the treatment of mpox through the Centers for Disease Control and Prevention’s Expanded Access Investigational New Drug “compassionate use” protocol (https://www.cdc.gov/poxvirus/ monkeypox/clinicians/Tecovirimat.html). In Los Angeles County, a fatal case of mpox with tecovirimat resistance was previously reported (1). Epidemiologic surveillance in Los Angeles County has since identified additional cases of severe mpox that did not improve after multiple rounds of tecovirimat treatment, including one involving a person who succumbed to infection (Table 1). Consistent with reports describing severe manifestations of mpox within the current global outbreak (1, 2), the identified cases involved host immunodeficiency due to advanced HIV infection. Tecovirimat targets the conserved orthopoxvirus VP37 envelope protein required for extracellular virus particle generation, and previous studies from monkeypox virus (MPXV) and other orthopoxviruses identified more than 20 mutations in VP37 associated with tecovirimat resistance (https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/ fda-mpox-response#therapeutics) (1, 3). To determine whether these identified cases involved tecovirimat resistance, MPXV specimens were subjected to whole-genome sequencing and examined for mutations in the homolog of the vaccinia virus Copenhagen F13L gene that encodes VP37 protein (1, 4). All specimens encoded lysine at…
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