Tecovirimat treatment of clade II mpox: a virological analysis of a randomised, double-blind, phase 3 trial.

Abstract

Monkeypox virus (MPXV) has emerged as a global public health threat. Three phase 3 trials of tecovirimat showed no substantial clinical benefit. We report virus isolation and sequencing results from the Advancing Clinical Therapeutics Globally (ACTG) A5418-The Study of Tecovirimat for Human Mpox (A5418-STOMP). ACTG A5418-STOMP was a phase 3 randomised, placebo-controlled, double-blind trial (NCT05534984) with an additional open-label arm enrolling paediatric, pregnant, severely immunosuppressed, or severe-disease participants. Day 1 (baseline), day 8, and day 15 index lesion skin swabs were used for virus isolation. Deep sequencing of the F13L gene was performed on index and new skin lesions, and on rectal, oral, vaginal, blood, and urine specimens through day 57. A predefined list of resistance-associated mutations (RAMs) was used to classify participants as having no RAMs, transmitted RAMs, or treatment-emergent RAMs. Proportions were compared using Fisher's exact tests; duration-normalised log₁₀ MPXV DNA copies were compared using Mann-Whitney U tests. P values were adjusted using Benjamini-Hochberg corrections where applicable. Among participants who were culture-positive on day 1 with available day 8 swabs, five (9%) of 53 in the randomised tecovirimat arm, three (12%) of 25 in the placebo arm, and eight (12%) of 67 in the open-label arm were culture-positive on day 8 (p=0·71). Among participants with day 1 and longitudinal sequencing data available, treatment-emergent resistance was observed in one (2%) of 54 of the randomised tecovirimat arm, zero of 29 of the placebo arm, and six (65%) of 92 of the open-label arm. Participants with treatment-emergent resistance had significantly higher longitudinal viral loads (p=0·0014) and lower clinical resolution rates by day 57 (28·6% vs 94·7%; p=3·8 × 10^-5) than those without resistance mutations. Six of seven individuals with treatment-emergent variants were living with HIV; all five with available baseline CD4⁺ T-cell counts recorded values below 80 cells per μL. Among 23 immunocompromised participants living with HIV, five (22%) developed treatment-emergent RAMs, with markedly lower clinical resolution rates than those who did not (one [20%] of five vs 17 [94%] of 18; p=0·0027). Although treatment-emergent resistance to tecovirimat was rare overall, it was observed more often in participants living with advanced HIV and profoundly impaired cellular immunity, leading to persistently higher viral loads and delayed clinical recovery. Tecovirimat therapy of mpox infection did not reduce the frequency of MPXV isolation from skin swabs. Novel therapeutic options are needed to address mpox infection. Advancing Clinical Therapeutics Globally and the National Institute of Allergy and Infectious Diseases, US National Institutes of Health.