Two or three? Clinical and proteomic perspectives on dolutegravir/lamivudine versus bictegravir/emtricitabine/tenofovir alafenamide as initial HIV treatment

Background While triple-drug regimens (3DR) have long been the standard of care for HIV infection, two-drug regimens (2DR), particularly dolutegravir/lamivudine (DTG/3TC), have emerged as viable first-line options. However, there is limited understanding of how baseline clinical profiles associated with regimen choice relate to underlying inflammatory states and long-term immune trajectories. Methods We performed a retrospective observational study using data from the Spanish CoRIS cohort, including ART-naive individuals who initiated either DTG/3TC or bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) between 2016 and 2023. We applied propensity score modeling to identify predictors of regimen choice. In a matched subset of participants with plasma samples at baseline and 24 months post-ART, we carried out longitudinal inflammatory profiling using the Olink Target 96 Inflammation panel. We then conducted differential expression and enrichment analyses and explored associations between clinical variables and proteomic changes over time. Results Among 3,145 participants (69.5% on BIC/F/TAF and 20.5% on DTG/3TC), those with higher baseline HIV-1 RNA and lower CD4+ T-cell counts were more likely to initiate BIC/F/TAF. In a matched subset (n=174), 11 proteins were significantly overexpressed at baseline in the BIC/F/TAF group, suggesting a heightened inflammatory state. Both regimens led to significant downregulation of inflammatory markers over two years, though each displayed distinct proteins and functional pathways. Baseline viral load and CD4+ counts correlated with specific proteomic profiles and predicted longitudinal changes, particularly in the BIC/F/TAF group. Conclusions Regimen selection was associated with baseline disease severity and inflammatory burden. Despite being used in patients with more advanced profiles, BIC/F/TAF effectively reduced systemic inflammation over two years. Both regimens attenuated inflammatory activity, though with distinct trajectories that may carry implications for immune recovery and long-term outcomes.