Safety, Tolerance and Antiretroviral Activity of Dasatinib: a Pilot Clinical Trial in Patients With Recent HIV-1 Infection

Study Overview
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Brief Summary
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Study to evaluate the safety, tolerability and antiretroviral activity of a new therapeutic strategy, based on the administration of dasatinib, an ITK, in patients with recent (3-12 months) asymptomatic HIV-1 infection.

Official Title
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Safety, Tolerance and Antiretroviral Activity of Dasatinib: a Pilot Clinical Trial in Patients With Recent HIV-1 Infection

Conditions
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Recent HIV-1 Infection

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 65 years. Documented asymptomatic HIV-1 infection of 3-12 months duration (all patients must have a positive Western blot, including the p31 band whose appearance indicates infection of more than 90 days duration). Not having received ART CD4 T-lymphocyte count> 350 / μl Patient giving written informed consent Exclusion Criteria: HBV positive serology (any marker except HBsAb after vaccination) or HCV positive RNA. ALT> 2 UNL, glomerular filtration rate <70 mL / 1.73 m2, leukocytes <4000 / mm3, total lymphocyte count <1000 / mm3, platelets <100,000 / mm3 or Hg <12g / dL. Pregnancy or active breastfeeding Ongoing or previous pleural effusion Chronic obstructive pulmonary disease, bronchial asthma or recent chest trauma. History of gastrointestinal or other bleeding. Any concomitant treatment with potentially dangerous drug interaction with dasatinib. Any clinical condition, at the opinion of the investigator, contraindicating participation (for example, Active neoplastic disease, active concomitant infection, etc.) Resistance to integrase inhibitors (raltegravir, dolutegravir, bictegravir) or analogues

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib<br>Dasatinib monotherapy (70 mg/day) will be given for 4 weeks. Antiretroviral therapy (ART) based on unboosted integrase inhibitors will be initiated at week 4 (S4) and dasatinib will be continued with ART until week 12. | Drug: Dasatinib<br>* Dasatinib monotherapy 70 mg/day, during 16 weeks.<br>|
| Placebo Comparator: Placebo<br>Placebo monotherapy will be given for 4 weeks. Antiretroviral therapy (ART) based on unboosted integrase inhibitors will be initiated at week 4 (S4) and placebo will be continued with ART until week 12. | Drug: Placebo<br>* Placebo during 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerance of dasatinib with and without antiretroviral therapy, measured by number of AEs and SAEs | Measured by number of AEs and SAEs | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antiretroviral capacity of dasatinib | Measured by quantification of plasma HIV-1 viral load during 4-week administration of dasatinib monotherapy. | at week 0 and 4 | 
| Changes in the viral reservoirs of patients with recent HIV-1 infection induced by dasatinib administration. | Measured by changes in the viral reservoirs (integrated DNA, genetically intact virus, residual and induced viral replication and determination of integration sites) | at week 0, 4, 16 and 52 | 
| Changes in markers of inflammation and immune activation induced by dasatinib administration. | Measured by changes in ultra-sensitive CRP, IL6, TNF alpha and CD4/CD8, CD25, CD69, CD38, HLA-DR+. | at week 0, 4, 16 and 52 | 
| Changes in SAMHD1 phosphorylation levels and cytotoxic activity against HIV-1 induced by dasatinib. | Measured by NK phenotyping and in vitro replication inhibition tests. | at week 0, 4, 16 and 52 | 
| Pharmacokinetic interactions of coadministration non-boosted integrase inhibitor-based antiretroviral therapy with dasatinib. | Measured by Cmax | at week 1, 2, 3, 4, 8, 12, 16 | 
| Pharmacokinetic interactions of coadministration non-boosted integrase inhibitor-based antiretroviral therapy with dasatinib. | Measured by Cmin | at week 1, 2, 3, 4, 8, 12, 16 | 
| Impact of dasatinib on markers of senescence | Measured by expression in PBLs of beta-galactosidase, Bcl-2, Histone H2A, p16 and CD87. | at week 0, 4, 16 and 52 |