Evaluation of Dasatinib Safety and Tolerability in Asymptomatic Patients with Recent HIV-1 Infection: A Pilot Clinical Trial

The primary objective of this study is to evaluate the **safety** and tolerability of dasatinib, an investigational tyrosine kinase inhibitor (ITK), in patients with recent asymptomatic HIV-1 infection. This is clinically relevant as it aims to establish the safety profile of dasatinib, which could potentially offer a new therapeutic strategy for managing HIV-1 infection.

Secondary objectives include:

• Assessing the in vivo antiretroviral capacity of dasatinib by quantifying plasma HIV-1 viral load during a 4-week administration of dasatinib monotherapy.
• Evaluating changes in the viral reservoirs of patients with recent HIV-1 infection induced by dasatinib administration.
• Assessing changes in markers of inflammation and immune activation induced by dasatinib administration.
• Evaluating changes in SAMHD1 phosphorylation levels and cytotoxic activity against HIV-1 induced by dasatinib.
• Assessing the tolerability and pharmacokinetic interactions of coadministration of non-boosted integrase inhibitor-based antiretroviral therapy with dasatinib.
• Evaluating the impact of dasatinib on markers of senescence.

The clinical trial involves **asymptomatic patients with recent HIV-1 infection**. The study population includes both male and female participants, aged between 18 to 65 years, who have documented asymptomatic HIV-1 infection of more than three months duration. Participants must not have received antiretroviral therapy (ART) and should have a CD4 T lymphocyte count greater than 350/μl. The trial population was selected based on these criteria, and all participants are required to provide written informed consent. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, as it involves individuals with a recent HIV-1 infection.

The clinical trial is designed to evaluate the **safety** and tolerability of **dasatinib** in patients with recent asymptomatic **HIV-1 infection**. This is a Phase II, randomized, double-blind, controlled trial involving the administration of dasatinib, an investigational tyrosine kinase inhibitor, compared to a placebo. The trial is expected to span approximately four years, with an estimated end date of October 30, 2026. Participants will be involved in the study for a maximum treatment period of 16 weeks, during which they will receive a daily oral dose of dasatinib or placebo, with a maximum daily dose of 70 mg.

The study will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age between 18 to 65 years, documented asymptomatic HIV-1 infection of more than three months, and a CD4 T lymphocyte count greater than 350/μl. Participants must not have received antiretroviral therapy (ART) previously and must provide written informed consent. Following the screening, eligible participants will be randomized to receive either dasatinib or placebo. The primary endpoint is to assess the safety and tolerability of dasatinib, with secondary endpoints including immunological, virological, and senescence markers.

Study visits will be scheduled at regular intervals to monitor participants' health and response to the treatment. These visits will include assessments of immune recovery, inflammatory markers, immune activation, bacterial translocation, and levels of NK-mediated cytotoxic activity. Virological assessments will focus on the decline in HIV viral load and the impact on the viral reservoir. The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the overall outcomes of the treatment.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to withdraw consent. The trial is not categorized as low intervention, and it is crucial to adhere to the protocol to ensure the integrity and validity of the study results. The trial's design and procedures are structured to provide comprehensive data on the potential benefits and risks associated with dasatinib in the specified patient population.

The clinical trial involves the administration of **dasatinib**, a chemical compound known for its role in blocking protein kinases. Dasatinib is provided in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dose of dasatinib is 70 mg, with a total maximum dose of 7840 mg over the course of the treatment. The treatment period is set for a maximum of 16 weeks. Dasatinib is administered orally, and its chemical structure is denoted by the synonyms BMS354825 and N-(2-CHLORO-6-METHYLPHENYL)-2-((6-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL)-2-METHYL-4-PYRIMIDINYL)AMINO)-5-THIAZOLECARBOXAMIDE. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group to serve as a comparator treatment. The placebo is not associated with any active pharmaceutical ingredient and is used to evaluate the efficacy and safety of dasatinib by comparison. The placebo is administered in a manner consistent with the dasatinib treatment to maintain the integrity of the trial's blinding process. The placebo does not have a specific pharmaceutical form or active substance, and its administration is designed to mimic the oral route used for dasatinib. The inclusion of a placebo group is critical for assessing the true therapeutic effects of dasatinib in patients with recent asymptomatic HIV-1 infection.

Efficacy in this clinical trial will be assessed through a series of secondary endpoints, focusing on immunological, virological, and senescence parameters. Immunological endpoints will include the evaluation of immune recovery by measuring CD4 subpopulation levels, inflammatory markers such as ultra-sensitive C-reactive protein (CRP), interleukin-6 (IL6), and tumor necrosis factor-alpha (TNF alpha), as well as immune activation markers including CD4/CD8, CD25, CD69, CD38, and HLA-DR+. Additionally, bacterial translocation will be assessed using rsCD163, and levels of natural killer (NK) cell-mediated cytotoxic activity will be determined through NK phenotyping and in vitro replication inhibition tests.

Virological endpoints will involve monitoring the decline in HIV viral load prior to the initiation of antiretroviral therapy (ART) during the 4-week period of **dasatinib** monotherapy. The impact on the viral reservoir will be evaluated by analyzing integrated DNA, genetically intact virus, residual and induced viral replication, and the determination of integration sites. Furthermore, SAMHD1 phosphorylation levels will be measured. Senescence endpoints will include the expression of beta-galactosidase, Bcl-2, Histone H2A, p16, and CD87 in peripheral blood lymphocytes (PBLs).