II-017 Jeremie Guedj

Early administration of tecovirimat shortens the time to mpox clearance in a model of human infection

Jeremie Guedj

INSERM

Introduction: In the 2022 outbreak, mpox has been reported in more than 80,000 cases, predominantly among men who have sex with men[1]. Few data are available on the natural history of mpox infection, and findings rely on scarce samplings from small cohorts [2–4]. The most commonly used treatment for mpox infection, tecovirimat, was approved based on results from animal studies and pharmacokinetic findings in healthy volunteers, lacking data on its efficacy in mpox-infected patients[5–9]. Several randomized, placebo-controlled, double-blind trials are ongoing but the assessment of the virological and clinical benefits of tecovirimat will be hampered by the ethical challenges in conducting randomized trials, as well as the rapid decline in the number of cases in most parts of the world. We therefore predicted tecovirimat efficacy in mpox-infected patients, using a unique set of reported data in nonhuman primates (NHPs) and humans.

Objectives: (i) to characterize mpox blood viral kinetics & determine tecovirimat antiviral effect in NHPs, (ii) to describe mpox viral kinetics in human lesions, (iii) to predict tecovirimat antiviral effect with different dosing regimens in infected humans.

Methods: To characterize the concentration-effect relationship in NHPs, we use a target cell-limited (TCL) model to analyze data from 24 macaques infected with 5´107 pfu of mpox Zaire 79 strain and administered vehicle or oral tecovirimat at 3, 10, or 20 mg/kg/day for 14 days, starting from Day 4[10]. Next, we used a pharmacological model developed in healthy volunteers[8] to project its antiviral efficacy in humans. Using data in a prospective study from 77 individuals enrolled shortly after symptom onset and followed until viral clearance, we then characterized mpox viral dynamics in skin lesions[11] to characterize viral dynamics in mpox infection. Finally, this model was bridged with NHP model of tecovirimat efficacy to predict the impact of tecovirimat on viral clearance in skin lesions.

Results: Tecovirimat antiviral efficacy in NHPs was associated with an EC50 of 1.6 ng/mL. At human-recommended doses, tecovirimat could inhibit viral replication from infected cells by more than 90% after 3 to 5 days of drug administration and achieved over 97% efficacy at drug steady state. With an estimated mpox within-host basic reproduction number in humans, R0, equal to 5.6, tecovirimat could therefore shorten the time to viral clearance if given before viral peak. We predicted that initiating treatment at symptom onset, which on average occurred 2 days before viral peak, could reduce the time to viral clearance by about 6 days. Immediate postexposure prophylaxis could reduce not only the time to clearance, but also lower peak viral loads by more than 1.0 log10 copies/mL and shorten the duration of positive viral culture by about 7 to 10 days.

Conclusion: This is the first model of mpox viral dynamics and treatment in humans. Using a unique set of preclinical and clinical data, we found that tecovirimat administered either as a post-exposure prophylaxis or upon symptom onset may reduce peak viral load and shorten the time to negative PCR or viral culture. Our findings support early administration of tecovirimat against mpox infection, ideally starting from the infection day as a postexposure prophylaxis, to reduce the risk of infection and transmission.

References:

  1. WHO. Multi-country outbreak of mpox, External situation report #19 – 30 March 2023. [cited 5 Apr 2023]. Available: https://www.who.int/publications/m/item/multi-country-outbreak-of-mpox–external-situation-report–19—30-march-2023
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  11. Suñer C, Ubals M, Tarín-Vicente EJ, Mendoza A, Alemany A, Hernández-Rodríguez Á, et al. Viral dynamics in patients with monkeypox infection: a prospective cohort study in Spain. Lancet Infect Dis. 2022;23: S1473-3099(22)00794–0. doi:10.1016/S1473-3099(22)00794-0

Reference: PAGE 32 (2024) Abstr 10945 [www.page-meeting.org/?abstract=10945]

Poster: Drug/Disease Modelling - Other Topics