Vedolizumab Treatment in HIV-Infected Subjects Without Previous Antiretroviral Therapy

Study Overview
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Brief Summary
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HIV cannot be eliminated and remains in the body despite the treatment that is used for HIV-infection called antiretroviral treatment (ART). Individuals undergoing ART interruption rapidly experience virus rebound in the blood. The current alternative therapeutic strategies to antiretroviral treatment have the aim to achieve the elimination of the virus in blood in the absence of ART. New drugs associated to ART that allow the elimination of the virus in the blood after ART withdrawn are needed. In monkeys infected with SIV, the analog of HIV, the virus has disappeared from the blood after administration of a compound and cessation of ART. There is an equivalent compound in humans called Vedolizumab. The aim of the present study is to research if Vedolizumab combined with ART, in subjects without previous ART, is able to eliminate the virus from the blood after ART is not taken.

Detailed Description
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HIV cannot be eradicated and keep latent in anatomical and cellular reservoirs. In fact, patients undergoing antiretroviral treatment (ART) interruption rapidly experience plasma viral load rebound. The current alternative therapeutic strategies to antiretroviral treatment have the aim to achieve the eradication or permanent remission of plasma viral load, also known as functional cure, in the absence of ART, as occurs in persistent HIV controllers. In this scenario, new drugs associated to ART that allow the achievement of permanent plasma viral remission after ART withdrawn are needed. The main targets of HIV infection are the memory CD4+ T-cells. This cell subset is mainly located in gut associated lymphoid tissue (GALT). These lymphocytes are recruited to the gut thanks to the expression of the integrin α4β7. The Env protein gp120 binds to α4β7 and enable the dissemination of HIV in the gut. At the same time the envelope of HIV is enriched in α4β7 coming from the plasma membrane of the host cells favoring its pathogenicity. Recently, the administration of a monoclonal antibody against α4β7 was shown to achieve significant protection for HIV transmission before and after low dose intravaginal inoculation of SIV in Rhesus Macaques. Surprisingly, long-term virological protection has been documented in SIV-infected macaques after ART interruption after administration and withdrawal of the monoclonal antibody against α4β7. The mechanisms through which this antibody has achieved the permanent remission of plasma viral load are not fully understood. The success of these findings in the simian model makes the antibody against α4β7 a good candidate as ART adjuvant with the aim to reach a functional cure and/or persistent virological remission in humans. Currently, there is a monoclonal antibody against α4β7 with known safety and security profiles in humans, this antibody is commercially available under the name of Vedolizumab. This antibody is used for the treatment of ulcerative colitis and Crohn Disease. In fact, there are already two clinical trials that are using Vedolizumab in HIV-infected patients (NCT02788175 y NCT03147859). In these clinical trials Vedolizumab is administered in the chronic phase of the infection in subjects with undetectable viral load during at least two years on ART. There are not clinical trials administering Vedolizumab in early stages of infection in naïve HIV-infected subjects for ART. Potentially, this strategy of early antibody treatment may increase the success of the therapy and decrease the time on ART of the individuals. The aim of the present clinical trial is to evaluate the safety and efficacy of Vedolizumab combined with ART to achieve permanent virological remission in naïve HIV-infected individuals after ART interruption.

Official Title
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Phase II Clinical Trial to Analyze the Safety and Efficacy of Vedolizumab Combined With Antiretroviral Therapy to Achieve Permanent Virological Remission in HIV-infected Subjects Without Previous Antiretroviral Therapy

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: Entyvio (Vedolizumab)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals with documented HIV-infection. Aged, 18 - 65 years. HIV-RNA >1x10e4 copies/mL. CD4+ T-cell counts >350 cells//μL To accept analytical ART interruption. Exclusion Criteria: Presence of major resistance mutations to the antiretrovirals used. Active opportunistic infections. Pregnancy or breastfeeding Active hepatitis C or B virus infection. Active or latent tuberculosis not treated. Cirrhosis, portal hypertension and/or hypersplenism of any etiology. Current or past neoplasia susceptible to be treated with steroids, immunotherapy or chemotherapy. Abnormal laboratory measurements grade 3 or 4. Concomitant use of drugs with pharmacological interactions with the treatment of the study based on the technical data sheet of the products. Creatinine clearance <50mL/min. Any type of vaccination (e.g., hepatitis B virus, influenza…) two weeks before the beginning of the study. Cardiovascular disease (e.g., acute coronary syndrome, heart failure…). Neurological or neuro psychiatric disorder which symptoms may interfere with the safety and tolerability analysis. Alcohol abuse and/or drugs that may interfere with the study treatment.

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
Intervention Model: Single Group Assignment
Interventional Model Description: HIV-infected subjects with no previous ART will begin ART together with Vedolizumab infusions at week 0, 4, 8, 12, 16, 20 and 24 weeks. At this time point ART and Vedolizumab treatment will be interrupted. Patients will be followed up until week 48. ART will be resumed if CD4+ T-cell levels drop below 350 CD4+/μL and/or viral load increases above 10e5 HIV-RNA copies/mL (two consecutive measurements).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single group<br>HIV-infected subjects with no previous ART will begin ART together with Vedolizumab infusions at week 0, 4, 8, 12, 16, 20 and 24 weeks. At this time point ART and Vedolizumab treatment will be interrupted. Patients will be followed up until week 48. ART will be resumed if CD4+ T-cell levels drop below 350 CD4+/μL and/or viral load increase above 10e5 HIV-RNA copies/mL (two consecutive measurements). | Biological: Entyvio (Vedolizumab)<br>* Antiretroviral treatment consisting in Dolutegravir (Tivicay) (50mg) + Tenofovir alafenamide (TAF) (25mg) / Emtricitabina (FTC) (200mg) (Descovy), once daily during 24 weeks. Entyvio (Vedolizumab) (300mg), 7 intravenous infusions at week 0 (baseline) (concomitant with ART onset), 4, 8, 12, 16, 20 and 24. At week 24 ART and Vedolizumab administration will be interrupted. ART will be resumed if CD4+ T-cell levels drop below 350 CD4+/μL and/or viral load increase above 10e5 HIV-RNA copies/mL (two consecutive measurements). Patients will be followed up until week 48.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | The number of adverse events and severity during Vedolizumab infusions and during all the follow up. | 48 weeks | 
| Plasma viral load rebound or remision after interrupting Vedolizumab infusions and ART | Quantitative plasma viral load (Roche HIV-1 RNA Viral Load Assay) measured before and after interrupting Vedolizumab infusions and ART. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, CD4+, T-cell, Reservoir, Cure, Antiretroviral therapy, Vedolizumab, Gut, Alpha4Beta7, gp120, Interruption