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Background Although long-acting cabotegravir/rilpivirine (LA CAB/RPV) injections have demonstrated great adherence, broad safety and efficacy comparable to oral antiretroviral therapy (ART), limited data regarding its impact on the HIV viral reservoir and immune system status are available. Here, we investigated HIV-DNA levels, immune activation and senescence on peripheral blood mononuclear cells (PBMCs) of PLWH at baseline and after 48 weeks of LA-ART.Methods Blood samples were collected from 17 PLWH attending Umberto I hospital of Rome at baseline (T0) and 48 weeks following CAB/RPV LA treatment (T1) and 8 matched HIV-negative volunteers. Virological and clinical parameters were collected from medical records. DNA was extracted from PBMCs to evaluate HIV-DNA levels by quantitative RealTime-PCR. Phenotypes, immune activation and senescence were evaluated by multiparametric flow cytometry on PBMCs by the following monoclonal antibodies: CD3-PerCP, CD4-APC-Vio770, CD8-FITC, CD45RO-PE-Vio770, CD27-VioBlue, CD38-APC, HLA-DR-PE, CD56-PE-Vio770 and CD57-APC. Gating strategies and data analysis were performed using the software CytExpert. Statistical analyses were performed using GraphPad Prism and p<0.05 were considered statistically significant.Results HIV-RNA<200 copies/mL was maintained in all PLWH for the entire study period, but two individuals were returned to oral therapy as a preventive measure due to HIV-RNA blips. In one of them, a mutation associated with resistance to RPV was found, while the other experienced a dramatic increase in BMI, which could have been responsible for alterations of CAB/RPV concentration in plasma. After 48 weeks of CAB/RPV LA, PLWH showed a significant reduction in HIV-DNA levels from baseline (p=0.002). Compared to HIV- individuals, PLWH showed at both T0 and T1 higher CD38 expression on almost all CD4+ T cell subsets (p<0.05). However, PLWH had lower expression of CD38 on central memory CD4+CD38+ T cells and reduced frequency of effector memory CD4+CD38+HLA-DR+ T cell at T1 compared to T0 (p=0.008 and p=0.017, respectively). Moreover, PLWH showed increased frequency of CD8+CD57+ T cells at T0 compared to T1 (p=0.0005) and to HIV- controls (p=0.0009), while comparable values were observed between these latter (p>0.05). Similarly, CD57+ NK cell frequency was higher in PLWH at T0 compared to T1 and to HIV- volunteers (p=0.0003 and p=0.0008, respectively), but their value at T1 was still higher than HIV- controls (p=0.019).Conclusion CAB/RPV LA is a valid therapeutic strategy to maintain virological suppression and to reduce the HIV-DNA levels, suggesting a potential impact on the viral reservoir. In addition, this new treatment seems to partially improve the activation and senescence of the immune system that chronically characterize PLWH. Nevertheless, careful monitoring HIV drug resistance, as well as anthropometric factors such as BMI, is necessary to ensure the effectiveness of CAB/RPV injections.