Abstract
BACKGROUND: Currently, integrase strand-transfer inhibitors (INSTIs) are the cornerstone of antiretroviral therapy (ART), providing potent viral suppression and good tolerability. Emerging evidence suggests that INSTI-based regimens may exert different effects on immune and metabolic pathways, potentially influencing inflammation and comorbidity risk. This study aimed to evaluate the impact of various first-line INSTI-based regimens on a panel of circulating biomarkers in treatment-naïve individuals with HIV. METHODS: We included ART-naïve adults (≥18 years) with confirmed HIV-1 infection initiating a non-boosted INSTI according to the treating physicians' decisions. The regimen included were bictegravir/emtricitabine/tenofovir alafenamide (BIC/TAF/FTC or Group 1 [G1]), dolutegravir/lamivudine (DTG/3TC or Group 2 [G2]), and dolutegravir/abacavir/lamivudine (DTG/ABC/3TC or Group 3 [G3]). Participants receiving DTG/ABC/3TC were enrolled via the Spanish CoRIS cohort, with samples from the HIV BioBank. Blood samples were collected at baseline and after 48 weeks. Biomarkers were grouped into six categories: pro- and anti-inflammatory cytokines, immune activation, endothelial dysfunction, metabolic markers, and tryptophan catabolism. Changes from baseline were analyzed using Kruskal-Wallis and Dunn's tests; linear mixed-effects models assessed longitudinal trends. RESULTS: We included 62 participants. All regimens achieved viral suppression and increased CD4 + counts, with the greatest CD4 + gain in G3. At baseline, G3 had higher TNF, CD40, ICAM-1, and lower IL-10 and leptin levels. After 48 weeks, G3 showed a significant increase in IL-10 and greater declines in CD163 and ICAM-1. Mixed models confirmed distinct longitudinal patterns in CD4 + counts, CD163, and IL-10 in G3. CONCLUSIONS: All INSTI-based regimens led to immune restoration, but modest differences in biomarker trajectories suggest distinct immunomodulatory effects. The clinical relevance of these differences remains unclear and warrants further study to assess their role in long-term comorbidity risk.