A Phase II Randomized, Double‑Blind, Placebo‑Controlled Study of Dasatinib to Reduce HIV‑1 Reservoir, Chronic Inflammation and Immune Senescence in ART‑suppressed Adults

Primary objective: To assess the effect of dasatinib on the counts of CD4, CD8 and CD56+ lymphocytes and on their activation/exhaustion markers, thereby evaluating its potential to reduce the viral reservoir and modulate immune dysregulation in people with HIV‑1 infection. Secondary objectives include: • Evaluation of CD4⁺, CD8⁺, and CD56⁺ cell dynamics and activation/exhaustion profiles at additional study time points. • Determination of safety and tolerability of 50 mg/day dasatinib combined with ART over 24 weeks. • Monitoring of T‑cell activation markers CD25 and CD69 throughout treatment and follow‑up. • Assessment of SAMHD1 phosphorylation changes during therapy. • Characterization of the viral reservoir during and after dasatinib administration. • Quantification of the proviral reservoir decay rate using mathematical modeling. • Measurement of proinflammatory and homeostatic cytokine levels. • Analysis of immune exhaustion and senescence markers. • Investigation of CD4⁺ T‑cell distribution and trafficking biomarkers as indicators of lymphocyte mobilization from secondary lymphoid tissues. • Evaluation of susceptibility of monocyte‑derived macrophages to infection. • Examination of NK‑cell trained immunity.

The trial enrolled adult participants of both sexes who had confirmed HIV-1 infection and were receiving suppressive antiretroviral therapy (ART) for 1–10 years with plasma HIV‑1 RNA consistently below the detection limit for at least six months. Eligible individuals were required to have a CD4⁺ T‑cell count greater than 500 cells/mm³ (or a CD4/CD8 ratio of approximately 1.0 ± 0.2), a stable ART regimen for a minimum of six months, and to demonstrate reliable adherence to both ART and the study medication over a 24‑week period. All participants were ≥ 18 years old; the sponsor did not provide the total number of enrolled subjects. Both male and female subjects of childbearing potential were required to use highly effective contraception throughout the study. The population thus comprised generally healthy, virologically controlled patients with preserved immune function.

The study is a Phase II, single‑center, randomized, double‑blind, placebo‑controlled trial evaluating the safety and efficacy of dasatinib 50 mg tablets versus microcrystalline cellulose placebo in adults with confirmed HIV-1 infection who have been on suppressive antiretroviral therapy for 1–10 years. After obtaining written informed consent, participants undergo a screening visit to confirm eligibility criteria, including CD4 count >500 cells/mm³ and stable ART regimen. Eligible subjects are then randomized in a 1:1 ratio to receive either dasatinib or placebo daily for 24 weeks; both participants and investigators remain blinded to allocation. Study visits are scheduled at baseline (day 0), pharmacodynamic assessments on days 2–3, and follow‑up assessments at weeks 4, 12, 24 (end of treatment), 28, 36, and 48 (end‑of‑study). Each visit includes collection of blood for immunologic, virologic, and inflammatory markers, safety laboratory tests, and adverse‑event monitoring. The total participant involvement spans approximately 48 weeks from randomization to the final assessment. Early termination may occur if a participant experiences a grade 3 or higher adverse event deemed related to study medication, violates major protocol requirements, becomes pregnant, demonstrates persistent non‑adherence to the study drug, or is lost to follow‑up.>

The investigational product is Dasatinib Teva 50 mg coated tablets, containing dasatinib as the sole active substance. Each tablet provides a dose of 50 mg and is administered orally. The tablet is supplied in a film‑coated form and is taken according to the study‑defined dosing schedule.

The comparator is a placebo composed of microcrystalline cellulose, manufactured as tablets that are identical in appearance to the active product. The placebo contains no active pharmaceutical ingredient and is administered by the same oral route as the investigational drug.

Both study arms are double‑blind; participants receive either the active tablet or the matched placebo. Medication intake is recorded at each study visit, and adherence is assessed by pill count and review of participant dosing logs in accordance with the protocol requirements.

Efficacy will be evaluated primarily by measuring changes in CD4, CD8 and CD56+ cell counts and associated activation/exhaustion markers from baseline to the early timepoint of 2–3 days and to week 24 of treatment with dasatinib or placebo. Blood samples will be collected at these predefined visits, and flow cytometry will be employed to quantify cellular subsets and marker expression.

Secondary efficacy assessments will include:

• Serial determination of CD4⁺, CD8⁺ and CD56⁺ cell counts and activation/exhaustion markers at weeks 4, 12, 28, 36 and 48.
• Evaluation of the activation markers CD25 and CD69 at days 2–3 and at weeks 4, 12, 24, 28, 36 and 48.
• Quantification of phosphorylated SAMHD1 (Thr592) expression at weeks 4, 12, 24, 28, 36 and 48.
• Characterization of the viral reservoir—including size, composition, reactivation capacity, integration sites, and HIV evolution—at weeks 4, 12, 24, 28, 36 and 48.
• Model‑based estimation of proviral reservoir decay using longitudinal proviral DNA measurements obtained at the same timepoints.
• Assessment of inflammatory biomarkers such as IL‑6, CRP, TNFα and sCD163 at weeks 4, 12, 24, 28, 36 and 48.
• Measurement of immune exhaustion and senescence markers at weeks 4, 12, 24, 28, 36 and 48.
• Analysis of CD4⁺ T‑cell trafficking markers (CCR7, CD45RA, CD49a, CD103, CD101, CXCR6, CX3CR1, PD‑1) on CD69⁺ tissue‑resident memory and CD69⁻ memory subsets at day 2–3 and weeks 4, 12, 24, 28, 36 and 48.
• Evaluation of monocyte‑derived macrophage susceptibility to HIV‑1 infection at weeks 4, 12, 24 and 48 using luminescence and flow cytometry for intracellular HIV‑1 core protein and phosphorylated SAMHD1.
• Determination of NK‑cell cytotoxic activity and activation/exhaustion status at weeks 4, 12, 24, 28, 36 and 48 by microscopy and flow cytometry.