Background
Dasatinib (DASA) has been proposed as an HIV-1 latency promoter in “block and lock” strategies and as a senolytic drug, but clinical data in people with HIV (PWH) are scarce. BCN04-DASA trial evaluated the safety and effect of low-dose DASA on the antiviral protein SAMHD1, its primary target, and on HIV-1 reactivation capacity, viral persistence and markers of inflammation and senescence in PWH.
Methods
BCN04-DASA (NCT05780073) was a phase II, single-center, randomized, double-blind, placebo-controlled trial in 60 ART-suppressed PWH. Participants were randomized 2:1 to oral DASA 70 mg QD (n=39) or placebo (n=21) for 24 weeks. Primary analyses evaluated safety and changes from baseline in phosphorylated (inactive) SAMHD1 (pSAMHD1) expression in CD4+ T cells. Secondary endpoints included changes in HIV-1 reactivation upon T-cell activation, total and intact proviral HIV-1 DNA and cell-associated RNA (caRNA) in CD4+ T cells, 35 soluble inflammatory and senescence-associated secretory phenotype markers, and immune activation markers (CD69) in CD4+/CD8+ T cells.
Results
56 cis-men/4 cis-women on ART were included. Median (IQR) age was 45 (39-55) years. No drug-related serious adverse events (AEs) occurred. Five individuals (13%) in the DASA group, and none in the Control group, discontinued due to drug-related AEs (headache=3, facial edema=1, dyspepsia/diarrhea=1; all grade 2). DASA concentrations in plasma were within the expected range. At week 24, changes from baseline in pSAMHD1, HIV-1 reactivation, intact and total proviral DNA, caRNA levels or immune activation markers were similar between groups. Most cytokines and chemokines were unchanged, except for a significant decrease in matrix metalloproteinase 9 levels (MMP-9; linked to tissue degradation/inflammation) and an increase in MMP-3 (linked to tissue remodeling) in DASA, with no changes in Controls.
Conclusions
Low-dose DASA (70 mg QD for 24 weeks) did not alter SAMHD1 activity, HIV-1 reactivation, or viral reservoir measures in ART-suppressed PWH, but was associated with some drug-related discontinuations. Low dose and/or limited duration of DASA may have been insufficient to affect these pathways. However, these data provide clinical evidence to refine block-and-lock strategies. The reciprocal modulation of MMP-9 and MMP-3 suggests effects on tissue remodeling consistent with senescent-cell clearance, supporting further investigation of dasatinib as a senolytic drug.