The evolution of tecovirimat resistance in an immunocompromised individual with severe mpox infection.

Tecovirimat is widely used for severe mpox, but resistance is increasingly reported, particularly in immunocompromised hosts. We describe a case of persistent clade IIb mpox in a 43-year-old man with advanced HIV (CD4 23 cells/µL) and disseminated necrotising disease. Despite prolonged tecovirimat therapy, lesions progressed. Serial viral isolates (n=8) obtained over 45 days underwent phenotypic susceptibility testing and whole-genome sequencing. Tecovirimat susceptibility declined markedly, with a ∼3 log10 increase in IC50 in late isolates. Sequencing identified distinct resistance-associated VP37 mutations (A290V, A295E), emerging in parallel within heterogeneous viral populations. In vitro passaging confirmed rapid enrichment of resistant phenotypes under drug pressure. Susceptibility to cidofovir and brincidofovir was preserved, and initiation of cidofovir was associated with clinical improvement and cessation of new lesions. This case demonstrates rapid intra-host evolution of multi-lineage tecovirimat resistance in severe mpox, highlighting the need for resistance surveillance and alternative or combination antiviral strategies in immunocompromised patients.