The goal of this clinical trial is to evaluate the safety, tolerability and Impact of low dose Dasatinib in People with Human Immunodeficiency Virus (PWH) on suppressive Combined Antiretroviral Therapy (cART),. The main question it aims to answer are: * How safe and tolerable is Dasatinib administered at low dose * To evaluate the on-target/biological effect of Dasatinib in "in vitro" T-cells activation and its durability after completion of the treatment * To evaluate the effect of Dasatinib on inflammation and immune activation, on the HIV-1 reservoir, and on cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) cell counts. * To characterize Dasatinib concentrations in plasma and its relationships with the observed effects. Participants will be treated with Dasatinib or matched Placebo once a day for 24 weeks. Suppressive cART will remain unchanged during the entire study. Participants will be followed until week 48, in a total of eleven visits.
This is a Phase II, single-center, randomized, double-blind, placebo-controlled clinical trial in People with Human Immunodeficiency Virus (PWH) on suppressive Combined Antiretroviral Therapy (cART). The aim is to assess safety, tolerability and Impact of low dose Dasatinib, during 24 weeks, on Viral Persistence and Inflammation in this population. Participants will be randomized (2:1) to receive oral Dasatinib 70 mg once daily or matched placebo for 24 weeks. At week 24, Dasatinib will be discontinued and participants will be followed until week 48, in a total of eleven visits. For all participants cART will remain unchanged during the entire study. The hypotheses of the study is that: * Daily administration of a low dose of dasatinib (70 mg once daily) to PWH for 24 weeks will be safe and well tolerated. * Dasatinib will interfere with HIV-1 persistence mechanisms contributing to chronic immune activation and inflammation status in both concordant and immune-discordant virologically suppressed PWH. * Dasatinib antiproliferative effect could have a significant impact on the HIV-1 reservoir size. The primary objective of the study is to evaluate the safety and tolerability of Dasatinib in this setting. Furthermore to evaluate the on-target/biological effect on the reduction of SAM Sterile Alpha-Motif (SAM) and histidine-aspartate (HD) Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 (SAMHD1) phosphorylation upon in-vitro T-cell activation, and its durability after completion of Dasatinib treatment. Secondary objectives are to evaluate the effect of the described intervention in the on-target/biological effects attributed to dasatinib, as well as on the Inflammation and immune activation, the HIV-1 reservoir, and CD4 and CD8 cell counts. Also to characterize dasatinib concentrations in plasma and its relationships with the observed effects, and to identify predictors of maintenance of dasatinib effects in HIV reservoir and inflammatory biomarkers after dasatinib interruption.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
60
Commercially available tablets containing 50 and 20 mg of dasatinib will be used. The tablets will be re-capsulated to keep the study blind
Maltodextrin capsules with identical size and appearance (shape, size, colour and flavour) as the dasatinib-containing capsules.
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
Grade 3 or 4 treatment-related adverse events or laboratory abnormalities during the study (based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading scale).
Proportion of participants (People with HIV on suppressive Combined Antiretroviral Therapy) that develop Grade 3 or 4 treatment-related adverse events or laboratory abnormalities during the study, based on the CTCAE v5.0 grading scale.
Time frame: From baseline (0) to week 48
Changes in SAMHD1 (SAM And HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1) phosphorylation in CD4+ T cells upon in-vitro T cell activation.
Proportion of SAM (Sterile alpha-motif ) and HD (histidine-aspartate) Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 (SAMHD1) phosphorylation in CD4+ T cells upon in-vitro T cell activation.
Time frame: From Baseline (0) to week 24
Changes in SAMHD1 (SAM And HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1) phosphorylation in CD4+ T cells upon in-vitro T cell activation.
Proportion of SAM (Sterile alpha-motif ) and HD (histidine-aspartate) Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 (SAMHD1) phosphorylation in CD4+ T cells upon in-vitro T cell activation.
Time frame: From Baseline (0) to week 48
Proviral reactivation capacity upon in-vitro T-cell activation: Proportion of intracellular HIV-1 core antigen in CD4+ T cells
Antiviral effect of Dasatinib and its durability: Proportion of intracellular HIV-1 core antigen in CD4+ T cells after in-vitro T-cell activation
Time frame: At weeks 0 (baseline) , 2, 24 and 48 weeks
Proviral reactivation capacity upon in-vitro T-cell activation: Frequency of HIV-1 p24 production
Antiviral effect of Dasatinib and its durability: Frequency of HIV-1 p24 production at a single-cell level, measured by viral protein spot (VIP-SPOT).
Time frame: At weeks 0 (baseline), 2, 24 and 48 weeks
Resistance to HIV infection: Frequency of CD4+ T cells infection by NL4-3_wild type strain
Antiviral effect of Dasatinib and its durability: Frequency of CD4+ T cells infection by NL4-3\_wild type strain of HIV in vitro.
Time frame: At weeks 0 (baseline), 2, 24 and 48 weeks
Plasma levels of homeostatic cytokines (interleukin-IL) IL-2, IL-7, IL-15, IL-21
Antiviral effect of Dasatinib and its durability: Homeostatic proliferation
Time frame: At weeks 0 (baseline), 2, 24 and 48 weeks
Antiviral effect of Dasatinib and its durability (Immunomodulatory effects) (Presence of cytotoxic activity in natural killer (NK) and CD8+ T cells).
Direct cytotoxicity measured in natural killer (NK)- specific K562 cells and HIV-infected TZM cells as targets (DCC), and antibody-mediated cellular cytotoxicity (ADCC) assay using rituximab-coated Raji cells as target
Time frame: At weeks 0 (baseline) , 24 and 48 weeks
Functionality of NK and CD4/CD8 T cells and its durability (Immunomodulatory effects of Dasatinib)
Percentage of AIM+ CD4 and CD8 T cells measured by AIM (activation induced marker) multiparametric flow cytometry and percentage of polyfunctional CD4 and CD8 T cells measured by ICS (intracellular cytokine staining) assay after HIV and CMV peptide stimulation.
Time frame: At weeks 0 (baseline), 24 and 48 weeks
Impact of Dasatinib and its durability on Inflammation and immune activation: plasma levels of proinflammatory biomarkers
Plasma levels of proinflammatory biomarkers: Polymerase Chain Reaction (PCR), d-dimer, IL-6, IL-32, IL-8, (Tumor Necrosis Factor alpha) TNFa, interferon-gamma (IFNg), and sCD14.
Time frame: At weeks 0 (baseline), 2, 24 and 48 weeks
Impact of Dasatinib and its durability on Inflammation and immune activation: plasma levels of anti-inflammatory biomarkers
Plasma levels of anti-inflammatory biomarkers: IL-10, transforming growth factor beta (TGFb)
Time frame: At weeks 0 (baseline), 2, 24 and 48 weeks
Impact of Dasatinib and its durability on Inflammation and immune activation: T cell frequencies with activation, exhaustion and senescence markers
Measured by multiparametric flow cytometry assays. * Activation markers: chemokine receptor 7 (CCR7), cluster of differentiation 45RA (CD45RA), Human Leukocyte Antigen-DR (HLA-DR), cluster of differentiation 38 (CD38), cluster of differentiation 25 (CD25) and cluster of differentiation 69 (CD69) * Exhaustion markers: PD-1/LAG-3 (Programmed cell Death 1 / Lymphocyte Activation Gene 3) and TIGIT * Senescence markers: cluster of differentiation 28 (CD28) and cluster of differentiation 57 (CD57)
Time frame: At weeks 0(baseline) , 24 and 48 weeks
Impact of Dasatinib and its durability on HIV-1 reservoir: proviral HIV-1 DNA quantification
Total and intact (IPDA) proviral HIV-1 DNA in purified CD4 T cells
Time frame: At weeks 0 (baseline), 24 and 48 weeks
Impact of Dasatinib and its durability on HIV-1 reservoir: viral load quantification
Ultrasensitive plasma viral load quantification (usVL)
Time frame: At weeks 0(baseline) , 24 and 48 weeks
Impact of Dasatinib and its durability on HIV-1 reservoir: Cell-associated HIV-RNA quantification
Quantification of Cell-associated HIV-RNA (caHIV-RNA) in CD4+ T cells
Time frame: At weeks 0 (baseline), 2, 24 and 48 weeks
Impact of Dasatinib and its durability on CD4+ T cell populations: number of CD4 T cells
Peripheral CD4 T cell counts
Time frame: At weeks 0 (baseline), 2, 12, 24, 28, 36 and 48 weeks
Impact of Dasatinib and its durability on CD4+ T cell populations: percentage of CD4 T cells
Peripheral CD4 T cell percentage
Time frame: At weeks 0 (baseline), 2, 12, 24, 28, 36 and 48 weeks
Impact of Dasatinib and its durability on CD4+ T cell populations: CD4/CD8 T cells ratio
Peripheral T cell CD4/CD8 ratio
Time frame: At weeks 0 (baseline), 2, 12, 24, 28, 36 and 48 weeks
Pharmacokinetics of Dasatinib (plasma concentrations)
Concentrations in plasma of Dasatinib.
Time frame: At weeks 0 (baseline), 2, 12 and 24 weeks
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