Long‐Acting Cabotegravir/Rilpivirine Reduces Immune‐Activation and ‐Senescence in People With <scp>HIV</scp> With <scp>CMV</scp> Co‐Infection

Despite the effectiveness of combined antiretroviral therapy (ART), HIV infection remains a chronic condition characterised by persistent inflammation and immune activation, likely associated with viral persistence and other factors such as cytomegalovirus (CMV) co-infection. Long-acting (LA) injectable formulations, a newer class of ART with improved and sustained bioavailability, may help modulate the HIV-associated immunoinflammatory state. Therefore, we analysed dynamic changes in lymphoid immune-activation and -senescence markers in people with HIV (PWH) switching to LA injectable cabotegravir and rilpivirine (CAB/RPV-LA), compared with PWH who continued oral ART by choice. The relationship between CMV-specific immune responses and phenotypic T-cell alterations was also evaluated. T-cell immune-activation (CD38 + HLA-DR+) and -senescence (CD28-CD57+) were measured at baseline (T0), at 4 (T4), 28 (T28), 48 (T48) and at 72 (T72) weeks after switching to CAB/RPV-LA. A control group (CG) of PWH (PWH-CG) on daily oral ART was studied at T0 and at 48 weeks (T48). Furthermore, CMV-specific cellular and humoral immune responses were assessed. Thirty-seven PWH switching to CAB/RPV-LA and nine PWH-CG were enrolled. In PWH-LA, total CD4 levels remained stable over time, while CD8 levels decreased significantly at T72 versus T0 and T4. In CG, an increasing CD4 and decreasing CD8 trend was observed. The CD4/CD8 ratio remained stable in both PWH-LA and -CG and showed a nonsignificant increase at T48 in PWH-CG. Immune-activation decreased in PWH-LA: CD4 activation levels were significantly lower at T48 and T72 versus earlier time points and CD8 activation was reduced at T72 versus T0 and T4. Immune-senescence declined in both compartments, with a significant reduction in CD8 senescence at T28, T48 and T72 compared to earlier time-points. Delta analysis confirmed a greater reduction in immune-activation and -senescence in PWH-LA compared to PWH-CG. Regarding CMV immune response, anti-CMV antibody levels remained stable with only a minor decline over time, whereas CMV-specific T-cell responses transiently increased at T28 before returning to baseline at T48 and T72. Switching to CAB/RPV-LA is associated with reduced T-cell activation and senescence, particularly in CD8 T-cell, suggesting improved immune homeostasis beyond viral suppression alone. However, despite these promising immunological changes, CMV coinfection remains a key driver of residual immune dysfunction.