Real-World Experience With Lenacapavir and/or Fostemsavir as Emerging Therapies for the Management of Multidrug-Resistant HIV-1 in Southeastern France.

Lenacapavir and fostemsavir, two recently approved anti-HIV-1 agents, are promising options for people with difficult-to-treat HIV; however, real-world data remain limited. This study aimed to describe the epidemiological, clinical, and virological profiles of people receiving combination antiretroviral regimens, including lenacapavir and/or fostemsavir. This retrospective study included adults living with HIV-1 treated by lenacapavir and/or fostemsavir in our center (Marseille, France), between January 2023 and June 2024, with follow-up continuing until July 2025. Clinical and biological data, including genotypic drug resistance testing and therapeutic drug monitoring, were extracted from electronic health records. The study included 21 people with HIV-1 (14 men; mean age, 56 years), representing 1.0% of our active HIV cohort in 2023 (n = 2,126). Virological and immunological failure and treatment intensification were the main reasons for switching therapy. Before switching, viral load was detectable in 11 persons; 8 (73%) achieved undetectable viral load at 24 months, whereas 3 (27%) nonadherent people with lower CD4 nadirs, higher baseline viral loads, and lower baseline CD4 counts remained persistently viremic. All three developed high-level genotypic resistance, including M426L and/or S375T for fostemsavir (two people) and Q67H, K70R, N74S, and/or A105AT for lenacapavir (two people). One developed resistance to both drugs. In one of these 3 persistently viremic PWH, a dual-injectable rescue regimen combining lenacapavir and cabotegravir achieved viral suppression at 33 months with maintenance through the end of follow-up, bringing the success rate to 9 out of 11 (82%) among PWH who were viremic at baseline. No severe lenacapavir- or fostemsavir-related adverse events were observed. This small real-world study supports the effectiveness and safety of lenacapavir and/or fostemsavir in people with multidrug-resistant HIV and variable adherence. All adherent people achieved viral suppression, whereas drug-resistant HIV-1 emerged in three people with poor adherence. A dual-injectable rescue regimen may represent a last-resort option in selected complex cases. Similar real-world studies should be expanded, and adherence support should be strengthened.