Rethinking HIV treatment: How non‐integrase strand regimens may hold the key to better immune health

Abstract Purpose HIV outcome changed drastically with antiretroviral (ARV) therapy, especially after the introduction of second‐generation integrase strand transfer inhibitors (INSTIs). Despite these advances, however, chronic immune activation and exhaustion, marked by programmed cell death 1 (PD‐1) and programmed death ligand 1 (PD‐L1) upregulation, persist in patients. This study investigates the impact of various ARV regimens on these immune exhaustion markers in newly diagnosed HIV patients over 12 months, taking into consideration cardiovascular risk. Methods This study included 58 newly diagnosed patients with HIV at Pomeranian Medical University, Szczecin, Poland. Participants received ARV regimens classified as INSTI + tenofovir alafenamide, INSTI + tenofovir disoproxil fumarate, or non‐INSTI‐based (VARIA). Flow cytometry was used to assess PD‐1 and PD‐L1 expression on CD3+, CD3+CD4+, CD3+CD8+ and CD19+ lymphocytes. Statistical analyses included Wilcoxon paired tests, Kruskal–Wallis tests and multivariate regression, with validation through residual analysis and linear discriminant analysis (LDA). Results INSTI‐based regimens were linked to higher PD‐1 expression on CD3+ and CD3+CD4+ lymphocytes, indicating increased immune exhaustion. Conversely, non‐INSTI regimens were associated with lower PD‐1 levels, suggesting better retention of immune function. A positive correlation between cardiovascular risk a prediction model to estimate 10‐year fatal and non‐fatal cardiovascular disease (SCORE2) and PD‐1 expression was observed. However, the modest explanatory power of the models suggests variability in the effects of different ARV regimens. Conclusion This study challenges the assumption that INSTI‐based ARV regimens are universally superior, suggesting that non‐INSTI therapies may better preserve immune function by reducing PD‐1 expression. These findings highlight the potential benefits of non‐INSTI regimens in improving long‐term clinical outcomes in HIV treatment, warranting further research.