Vedolizumab (Anti-alpha4beta7) in Subjects With HIV Infection Undergoing Analytical Treatment Interruption
Condition: HIV
MeSH terms: HIV Infections
Intervention: Entyvio (Vedolizumab)
Intervention description: A humanized monoclonal antibody that specifically binds to the alpha4beta7 integrin with MAdCAM-1, which in turn inhibits the migration of T-lymphocytes across the endothelium into GALT
Intervention MeSH terms: Vedolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: HIV Immune Therapy; Monoclonal Antibody; Integrin

Summary:

      Background:

      In most people infected with human immunodeficiency virus (HIV), their immune system cannot
      control HIV infection. They need drugs called combination antiretroviral therapy (cART) to
      control the HIV. When people stop cART treatment, their immune system cannot control the
      infection again. They can also become resistant to cART and have lasting side effects.
      Researchers want to test if the drug vedolizumab is effective at controlling HIV infection
      without the need for cART.

      Objective:

      To test if vedolizumab is safe and can control the amount of HIV in the blood when cART is
      not taken.

      Eligibility:

      People ages 18-65 who have HIV and are being treated with cART

      Design:

      Participants will be screened with:

      Physical exam

      Medical history

      Electrocardiogram: Soft, sticky patches on the chest, arms, and legs measure heart activity.

      Blood and urine tests

      Participants will have a baseline visit. This will be 2-5 hours each day for 1-2 days. It
      will include repeats of the screening tests and:

      Leukapheresis: Blood is removed through a needle in the arm. A machine separates the white
      blood cells from the blood. The rest of the blood is returned to the participant.

      Neurologic exam: The nerves and reflexes are tested.

      First vedolizumab infusion through an arm vein

      Participants will have visits every 4 weeks for 30 weeks. These will include:

      Vedolizumab infusions

      Repeats of baseline tests

      Participants will have more visits for blood draws.

      Participants will keep taking cART until after the week 22 infusion.

      After discontinuing cART at study week 22, participants will be seen every two weeks to
      monitor the CD4 count and the level of HIV in the blood. Some of these visits will occur in
      between infusion visits and will only take about 1 hour to complete. cART will be restarted
      if a participant's HIV levels go up to high, or if their CD4 cell counts decreases by too
      much.

      For the follow-up phase, participants will have visits every 4 weeks for 24 weeks. These will
      include blood tests and a physical exam.

      ...
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Age, 18 - 65 years

          2. Documented HIV-1 infection and clinically stable

          3. In general good health, with an identified primary health care provider for medical
             management of HIV infection and willing to maintain a relationship with a primary
             health care provider for medical management of HIV infection while participating in
             the study

          4. CD4+ T cell count >450 cells/mm3 at screening

          5. Documentation of continuous cART treatment with suppression of plasma viral level
             below the limit of detection for more than or equal 2 years. Subjects with blips
             (i.e., detectable viral levels on cART) prior to screening may be included provided
             they satisfy the following criteria:

               1. The blips are <400 copies/mL, and

               2. Succeeding viral levels return to levels below the limit of detection on
                  subsequent testing

          6. Willingness to undergo ATI

          7. Laboratory values within pre-defined limits at screening:

               -  Absolute neutrophil count >1,000/mm3

               -  Hemoglobin (Hgb) levels >10.0 g/dL for men and >9.0 g/dL for women

               -  Platelet count >100,000/mm3

               -  Prothrombin time (PT) and partial thromboplastin time (PTT) <1.5 upper limit of
                  normal (ULN)

               -  Estimated glomerular filtration rate (eGFR) of greater than or equal to 50 mL/min
                  as determined by the NIH Clinical Center laboratory

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of
                  <1.1 x ULN. Total bilirubin <1.1 x ULN (unless subject is taking atazanavir or
                  has Gilbert s Syndrome)

          8. Willingness to have samples stored for future research

        Participation of Women:

        Contraception: The effects of vedolizumab on the developing human fetus are unknown. For
        this reason, men and women of childbearing potential must agree to use adequate
        contraception (hormonal or barrier method of birth control; abstinence) prior to study
        entry and for the duration of study participation.

        EXCLUSION CRITERIA:

          1. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen
             (HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced by a positive test
             for HCV RNA. Subjects with a positive test for HCV antibody and a negative test for
             HCV RNA are eligible.

          2. Documented nadir CD4+ T cell count <200 cells /mm3

          3. Documented multiclass antiretroviral drug resistance that, in the judgment of the
             investigator, would pose a risk of virologic failure should additional mutations
             develop during the study

          4. HIV immunotherapy or vaccine(s) received within 1 year prior to screening

          5. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza,
             pneumococcal polysaccharide) received within 2 weeks prior to study enrollment

          6. Receipt of other investigational study agent within 28 days of enrollment

          7. Any active malignancy that may require systemic chemotherapy or radiation therapy

          8. Systemic immunosuppressive medications received within 3 months prior to enrollment.
             The following are not excluded: [1] corticosteroid nasal spray or inhaler; [2] topical
             corticosteroids for mild, uncomplicated dermatitis; and [3] oral/parenteral
             corticosteroids administered for non-chronic conditions not expected to recur (length
             of therapy less than or equal to 10 days, with completion in more than or equal to 30
             days prior to enrollment)

          9. History or other clinical evidence of:

               -  Significant or unstable cardiac disease (e.g., angina, congestive heart failure,
                  recent myocardial infarction)

               -  Severe illness, chronic liver disease, malignancy, immunodeficiency other than
                  HIV, active systemic infection other than HIV, or any other condition that, in
                  the opinion of the investigator, would make the subject unsuitable for the study

               -  Active or latent tuberculosis, regardless of treatment history

         10. Neurologic or neuropsychiatric disorder, the symptoms of which mimic PML and could
             interfere with the assessment of safety (e.g. history of encephalitis with motor
             sequela, stroke with sequela, severe major depressive disorder, severe bipolar
             disorder, seizure disorder)

         11. Active drug or alcohol abuse or any other pattern of behavior that, in the opinion of
             the investigator, would interfere with adherence to study requirements

         12. Pregnancy or breast-feeding

        Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than
        enrollment on observational studies. Study staff should be notified of co-enrollment as it
        will require the approval of the Principal Investigator.