Background:
During the recent Mpox outbreak, Tecovirimat was used to treat patients with severe disease. There are few studies characterizing Tecovirimat resistance mutations and none describing concomitant drug plasma concentrations.
Methods:
Two HIV-1 infected patients hospitalized for severe and persistent Mpox clinical manifestations were studied. Sequential sampling of several anatomic compartments were screened for Mpox by PCR. Positive samples were sequenced using whole genome sequencing. Plasma concentrations of Tecovirimat were determined using LC-MS/MS (lower limit of quantification – LLOQ: 1 mg/L).
Results:
Patient 1 with a low CD4+ cells count (198 CD4+/mm3) despite an undetectable viral load, presented multiple Mpox skin lesions, evolving with fever and associated with extensive bilateral pulmonary, hepatic Mpox lesions and persistent Mpox viremia, motivating a Tecovirimat treatment. Mpox clinical evolution was very slow but favorable after 90 days of Tecovirimat (600mg BID). Whole genome sequencing showed no resistance associated mutations (RAMs) and Tecovirimat plasma concentrations were in the expected range (177 and 1635 mg/L) during all the follow-up. Patient 2 presenting an uncontrolled HIV-1 replication (30,000 copies/mL) and a deep immunodeficiency (43 CD4+/mm3) with a high BMI (48.5 kg/m2) was treated by Tecovirimat (600mg BID) during 14 days due to a disseminated mucocutaneous Mpox. Evolution during treatment was marked by a clear improvement of the cutaneous lesions. Nevertheless, three days after the tecovirimat cessation, two new cutaneous lesions appeared and evolved within abscess aspects. Whole genome sequencing showed the appearance of previously described Tecovirimat RAMs (A290V, D294V, I372N) and a new one (Y252C) with anatomic compartmentalization patterns. Tecovirimat plasma concentrations were always below the expected range or below the LLOQ during the treatment period.
Conclusions:
Persistent replication of Mpox under Tecovirimat pressure in an immunosuppressed patient harboring adequate plasma drug concentrations was not associated with RAM selection. However, in case of suboptimal Tecovirimat plasma concentrations, we observed in another patient a rapid selection of RAMs associated to a clinical and virological rebound. These low plasma concentrations could be due to adherence issues, malabsorption or high BMI. This study highlights the interest of the Therapeutic Drug Monitoring of Tecovirimat in special populations and raises the discussion of dose adjustment.
