PET Imaging and Lymph Node Assessment of IRIS in People With AIDS

Immune reconstitution inflammatory syndrome (IRIS) in HIV infection represents a paradoxical,
frequently inflammatory, immune response after initiation of antiretroviral (ART) therapy.
The immunopathogenesis of IRIS remains elusive partially due to a lack of tissue sampling and
a lack of detailed screening, including imaging, for subclinical opportunistic infections in
many studies. Most pathogenesis studies to date have been performed in peripheral blood with
a few notable exceptions of cryptococcal IRIS studies in which cerebrospinal fluid (CSF)
samples were obtained and evaluated.

This is a 2-arm natural history study intended to evaluate the incidence, predictors and
pathogenic mechanisms of IRIS in HIV-1 infected adults (age >18 years). A ART Naive arm will
enroll 100 patients who are ART-naive with CD4+ T cell counts <100 cells/mm(3). These
participants will initiate ART according to the clinical standard of care. Any opportunistic
infections (OIs) or AIDS-defining illnesses identified prior to, during screening or at any
point during the study, will also be treated according to standard of care. The IRIS arm will
enroll 20 participants who are ART-treated and meet criteria suspicious for IRIS (Appendix
D), with any CD4+ T cell count. The ART Naive arm will be followed for 48 weeks, with an
optional extension up to week 96. The IRIS arm will be followed for 48 weeks after enrollment
if the IRIS event is confirmed, also with an optional extension up to week 96. In both arms,
subjects must have adequate venous access and will undergo collection of whole blood by
phlebotomy, leukapheresis, lymph node biopsy, and fluorodeoxyglucose-positron emission
tomography (FDG-PET/CT) at designated study visits.

- ELIGIBILITY CRITERIA:

ART NAIVE ARM INCLUSION CRITERIA:

1. Documentation of HIV-1 infection. Results from outside facilities will be accepted for
enrollment.

2. No recent (within the past two years) treatment with combination anti-retroviral
therapy (ART). Patients with limited (no more than 2-3 weeks) recent use of potent
combination ART may be eligible for study participation if, the opinion of the
investigator, the ART usage will not impact the scientific validity of the protocol

3. Documented CD4+ cell count less than or equal to 100 cells/mm(3) within the past 8
weeks.

4. Residence within the wider Washington D.C. area (within a 100-mile radius from the NIH
Bethesda campus) and plans to stay in the area for 48 weeks

5. Men or women age greater than or equal to 18 years.

6. Ability and willingness of subject (or legal guardian/representative) to understand
study requirements and give informed consent.

7. Willingness to allow storage of blood or tissue samples for future research

8. Willingness at time of screening to undergo study procedures (phlebotomy, apheresis,
optional FDG-PET/CT and lymph node biopsy*)

9. Willingness to have genetic testing

10. Participants should have a primary care physician or will need to agree to have one
established by 24 weeks on study.

- In the event of an estimated reversible inability to consent, patients may enroll
via a legally authorized representative (DPA) if they have the ability to assign
a DPA. For these participants, baseline lymph node biopsy will not be performed
however the week 4-8 lymph node biopsy may be performed if the participant
regains the capacity to consent prior to that time.

IRIS ARM INCLUSION CRITERIA:

1. Documentation of HIV-1 infection. Results from outside facilities will be accepted for
enrollment.

2. Meet criteria suspicious for IRIS (Must meet 4/5 following criteria):

I. Initiation (reintroduction or change) in antiretroviral therapy/regimen

II. Evidence of:

1. an increase in CD4+ cell count defined as greater than or equal to 50cell/mm(3)
or a greater than or equal to 2 fold rise in CD4+ cell count, and/or

2. decrease in the HIV-1 viral load of greater than or equal to 0.5 log10

III. Symptoms and/or signs consistent with an infectious/inflammatory condition.

IV. Theses symptoms and/or signs cannot be explained by a newly acquired infection,
the expected clinical course of a previously recognized infectious agent, or the side
effects of antiretroviral therapy itself.

V. The infectious/inflammatory condition must be attributable to a specific pathogen
or condition.

*Criteria IV or V may not be met for suspected IRIS definition.

3. Residence within the wider Washington D.C. area (within a 100-mile radius from the NIH
Bethesda campus). **Participants from outside of the 100 mile radius may be enrolled
on a case by case basis to diagnose or manage IRIS.

4. Men or women age greater than or equal to 18 years.

5. Ability and willingness of subject to understand study requirements and give informed
consent.

6. Willingness to allow storage of blood or tissue samples for future research

7. Willingness at time of screening to undergo study procedures (phlebotomy, apheresis,
an optional FDG-PET/CT, and lymph node biopsy*)

8. Willingness to have genetic testing

9. Participants should have a primary care physician who will initiate the referral.

- In the event of an estimated reversible inability to consent, patients may enroll
using a legally authorized representative (DPA) if they have the ability to
assign a DPA. lymph node biopsy will not be performed in these occasions.

SUBJECT EXCLUSION CRITERIA:

1. Active drug or alcohol use or dependence that, in the opinion of the investigator,
would interfere with adherence to study requirements.

2. Pregnancy will be an exclusion criterion for study entry given the intense nature of
the protocol regarding blood draws, apheresis, biopsies and FDG-PET/CT imaging.

3. Inadequate venous access for phlebotomy and apheresis procedures as assessed by the
study team.

4. Women who are breastfeeding.

5. A life-threatening underlying illness that according to the study team requires
immediate intervention such as PML requiring initiation of ARVs or lymphomas requiring
chemotherapy initiation.

6. An inability to consent that is estimated by the study team to be irreversible.

7. History of significant medical non-adherence which would, in the opinion of the
investigator, interfere with study participation