In vitro susceptibility to fostemsavir is not affected by long-term exposure to antiviral therapy in MDR HIV-1-infected patients. (28th May 2020)

• Record Type: Journal Article
• Authors: Saladini, Francesco; Giannini, Alessia; Giammarino, Federica; Maggiolo, Franco; Vichi, Francesca; Corbelli, Giulio M; Galli, Andrea; Bigoloni, Alba; Poli, Andrea; Santoro, Maria M; Zazzi, Maurizio; Castagna, Antonella
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 75:Number 9(2020)
• Page Start: 2547
• Page End: 2553
• Publication Date: 2020-05-28
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkaa178
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: Fostemsavir is the prodrug of the HIV-1 attachment inhibitor temsavir and is currently under clinical assessment in heavily treatment-experienced patients with limited therapeutic options. We evaluated the genotypic and phenotypic susceptibility to temsavir in a panel of samples collected from patients harbouring MDR strains enrolled in the Italian PRESTIGIO Registry. Methods: Plasma samples from 24 patients were used for HIV-1 gp120 sequencing, while viral tropism and susceptibility to temsavir were assessed through a homemade phenotypic assay with pseudotyped viruses expressing patient-derived Env protein. Results: Of the 24 patients enrolled, 18 (75%) were male, median (IQR) age was 55 years (52–61), time since HIV-1 diagnosis was 27 years (24–30), time on ART was 26 years (23–27) and 11 (46%) had a previous AIDS diagnosis. Exposure to entry inhibitors (maraviroc and/or enfuvirtide) had occurred in 19 (79%) patients. Among 23/24 gp120 sequences obtained, temsavir resistance-associated mutations (RAMs) were detected in three cases (two M426L and one S375N). Pseudotyped viruses were obtained from 23/24 samples and viral tropism was CXCR4-tropic, CCR5-tropic and dual/mixed-tropic in six, nine and eight cases, respectively. Phenotypic susceptibility to temsavir was comparable to the reference WT viruses NL4-3 and AD8 in all samples, irrespective of RAMs. Viral tropism and exposure to entry inhibitors did not impact temsavir susceptibility. Conclusions: These data support the use of fostemsavir as a valuable therapy option in patients harbouring MDR virus. The role of laboratory testing in optimal screening of patients eligible for fostemsavir treatment remains to be investigated.