Vedolizumab (Anti-alpha4beta7) in Subjects With HIV Infection Undergoing Analytical Treatment Interruption

While combination antiretroviral therapy (cART) has improved the clinical outcome for
HIV-infected individuals, persistence of viral reservoirs in the peripheral blood and
lymphoid tissues remains a hurdle to complete eradication of virus and cure of the infection.
The concept that HIV preferentially infects discrete subsets of CD4+ T cells underscores the
need to develop therapeutics that exploit specific cell-virus interactions. T cells
expressing integrin alpha4beta7 not only regulate migration into the gutassociated lymphoid
tissue (GALT), but also concomitantly bind HIV, placing them in a prime position to
disseminate HIV throughout the tissue. Previously, it has been shown that the HIV envelope
protein gp120 binds to alpha4beta7 on CD4+ T cells in vitro, alpha4beta7high CD4+ T cells are
highly susceptible to productive HIV infection in vitro, and the administration of
anti-alpha4beta7 monoclonal antibody (mAb) prevents and/or delays transmission of SIV upon
repeated challenges and preserves CD4+ T cells in rhesus macaques. Furthermore, it has been
demonstrated that administration of anti-alpha4beta7 mAb in SIV-infected rhesus macaques
receiving cART suppresses plasma viremia for extended periods following discontinuation of
cART, collectively suggesting that sustained virologic remission in the absence of cART may
be achieved via direct targeting of alpha4beta7 integrin. It is well established that the
vast majority of HIV-infected individuals treated with cART experience plasma viral rebound
within weeks of cessation of therapy. Considering that current research on the treatment of
HIV-infected individuals has been heavily focused on developing strategies aimed at achieving
sustained virologic remission in the absence of cART, it is of great interest to investigate
whether administration of anti-alpha4beta7 mAb can prevent plasma viral rebound and allow
durable suppression of viral replication in HIV infected individuals after discontinuation of
cART. We propose to examine the effect of vedolizumab, an FDA approved anti-alpha4beta7 mAb
for the treatment of ulcerative colitis and Crohn s disease, on plasma viral rebound in
HIV-infected individuals following analytical treatment interruption (ATI).

-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.