CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

disease disseminated by sexual fluids. We established a pathophysiological model of Mpox with symptoms similar to human that will allow to assess vaccines and therapeutics against this emerging disease. Tecovirimat Plasma Concentrations, Mpox Resistance Mutations Selection, and Clinical Outcomes Stephane Marot 1 , Minh P. Le 2 , Nicolas Visinoni 1 , Claire Perillaud-Dubois 3 , Ruxandra-Oana Calin 4 , Vincent Berot 1 , Valentin Leducq 1 , Cécile Pouderoux 1 , Olivier Ferraris 5 , Laurence Morand-Joubert 3 , Vincent Calvez 1 , Gilles Pialoux 6 , Gilles Peytavin 2 , Anne-Genevieve Marcelin 1 , Valerie Pourcher 1 1 Hôpitaux Universitaires Pitié Salpêtrière, Paris, France, 2 Hôpital Bichat-Claude-Bernard, Paris, France, 3 Saint-Antoine Hospital, Paris, France, 4 Tenon Hospital, Paris, France, 5 Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France, 6 Assistance Publique–Hôpitaux de Paris, Paris, France 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+/mm 3 ) 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+/mm 3 ) with a high BMI (48.5 kg/m 2 ) 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. Conclusion: 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.

insufficient daily nutrition affecting oral tecovirimat absorption and another lacking consistent housing and wound care that led to recurrent presentations that required extended tecovirimat (5-16 weeks) and cidofovir (1-12 doses). We stopped cidofovir after 7 months on one patient based on IgG+/IgM– orthopoxvirus serology. Ocular lesions were treated with trifluridine (3 weeks). Two patients required adjustments of ART. After ART, all cases had markedly lower HIV load (0-138 copies/ml). All patients had improved mpox lesions at follow-up and renal function remained stable. Conclusion: This report illustrates that prolonged cidofovir with tecovirimat can be safely administered to manage severe mpox infections in people with advanced HIV. Our case series underscores the multifaceted challenges this population faces, extending beyond clinical manifestations, to include social determinants such as housing stability, nutritional intake essential for effective tecovirimat absorption and presence of concurrent infections. Our findings advocate for a comprehensive approach integrating ART with multiple antivirals, while simultaneously addressing contextual and socio-environmental factors.

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Poster Abstracts

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Mpox Virus Model of Sexual Transmission in Cynomolgus Macaque Cecile Herate 1 , Audrey Ferrier Rembert 2 , Francis Relouzat 1 , Hélène Letscher 1 , Quentin Pascal 1 , Benoît Delache 1 , Olivier Ferraris 3 , Roger Le Grand 4 , Jean-Nicolas Tournier 2 1 Université Paris-Saclay – Site de Fontenay-aux-Roses, Fontenay-aux-Roses, France, 2 Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France, 3 Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France, 4 Vaccine Research Institute, Fontenay-aux-Roses, France Background: The Monkeypox virus (MPXV) responsible for 2022 outbreak belongs to clade IIb which derives from the less virulent clade and whose exact mode transmission needs to be established. Monkeypox (Mpox) mainly affects male population and evidence suggest that Mpox could be a sexually transmitted disease. Today, the animal models of Mpox and more particularly the non-human primate models (NHP) available remains limited; and do not fully reflect the pathophysiology of the virus infection. In particular, there are no precise evidence and model on the potential sexual transmission of MPox. Methods: We mimicked virus transmission during sexual activities by challenging Cynomolgus macaques by intradermal (ID) or intrarectal (IR) route alone or in combination with a MPXV strain isolated on a French patient in 2022. Infection of NHPs was documented clinically (clinical score and photographs) and monitored by blood count. Virus dissemination was tested by qRT-PCR and viral isolation, and the humoral immune response was assessed by specific IgG quantification and seroneutralisation. The virus was tested in various compartments, including blood, seminal fluid, rectal secretions and saliva. In a second time, we focused on the IR transmission and have mapped the virus infected organs and performed large histology analysis. Results: We observed a moderate disease whatever the route of infection with clinical symptoms similar to human including fever episodes, lymphodenomegaly and skin lesions. Interestingly, the kinetics of clinical symptoms appearance is also very similar to human. The infection was characterized by marked lymphopenia, combined with monocytosis and a drop in Hemoglobin as reported in patients. Virus was detected in skin lesions, blood, rectal mucosa and semen. Sexual fluids contain infectious virus during 2 weeks after IR transmission. We also observed that IR challenge provoked a systemic infection with virus dissemination in organs including digestive tract and genital tract but a very limited seroconversion. Histological analysis also revealed remarkable inflammation and infiltration in the infected organs such as rectum and genital tract. Conclusion: We have set up a non-lethal model of MPox in NHPs by intrarectal route and validated that Mpox can be considered as a sexually transmitted

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