Thinking and Memory Problems in People With HIV

The natural history of neurocognitive impairment in human immunodeficiency virus (HIV)-
infected individuals remains poorly understood. While the advent of highly active
antiretroviral therapy (HAART) has led to a decreased incidence of the most severe form of
HIV associated neurocognitive disorders (HAND), HIV-associated dementia, it does not appear
to have impacted overall prevalence of HAND. Existing evidence suggests that the central
nervous system (CNS) could be an important reservoir for HIV regardless of cumulative time on
treatment. This 8 year multi-institute screening protocol will identify approximately 200
HIV-infected individuals and 100 healthy volunteers for enrollment in multiple HAND studies
at the National Institutes of Health (NIH). Subjects will undergo a one-time screening and
evaluation assessment, which will include history and physical, blood and urine collection,
neuropsychological testing, Client Diagnostic Questionnaire (CDQ), and brain magnetic
resonance imaging (MRI).

Those who meet eligibility criteria will be offered enrollment and co-enrollment into active
HIV-associated neurocognitive disorder protocols, including the natural history study
presented here. This observational study will characterize the natural course of HAND in
subjects with HIV viral loads <50 copies/mm3. Subjects will be followed yearly for 5 years.
Visits will include updated exam, blood and urine collection, neuropsychological testing,
brain MRI, optional lumbar puncture or drain, and optional ophthalmology exam. The option to
have a lumbar drain is only on the first visit and extended to HIV positive individuals only.
HIV- negative controls will have the option of doing a positron emission tomography/computed
tomography (PET/CT) imaging during the first visit. Cerebrospinal fluid (CSF) markers of
immune activation, chronic monocyte activation, cytomegalovirus/Epstein- Barr virus (CMV/EBV)
infection/reactivation, and neuronal injury will be collected. In addition, HIV viral load
and genotype, genetic susceptibility factors and CNS penetration- effectiveness score (CPE)
and CSF levels of antiretroviral drugs may be assessed. A repository of cryopreserved
biological samples will be developed and used for validation of candidate biomarkers in
future studies. Collection and analysis of these data will not only enhance understanding of
the CNS as a potential HIV reservoir in virally-controlled individuals but will further
define the association among cortical thickness, biomarkers and neurocognitive function in an
aging HIV-infected population.

- ELIGIBILITY CRITERIA FOR PART I SCREENING STUDY:

INCLUSION CRITERIA:

All Subjects (HIV-infected and HIV-negative Controls):

While different individual HIV neurocognitive studies have specific selection criteria,
especially related to HIV viral load and antiretroviral therapy, inclusion criteria for
this overarching protocol will be flexible in order to identify the broadest base of
potential enrollees possible. An upper age limit of 61 years old will be used because
changes in neurocognitive function occur more commonly in the general population after this
age.

1. Men and women, 18 years of age and older

2. Ability to sign informed consent by the subject

3. At least seventh grade educational level and ability to speak, read, and understand
English. Education level will be assessed by subject self-report. Because many of the
neuropsychological subtests were validated using United States norms, subjects must be
native English speakers or if foreign-born, demonstrate ability to understand the
English language at the time of screening protocol consent and neuropsychological
testing.

HIV-infected Only:

1. HIV-1 infection, as documented by OraQuick rapid test using venipuncture whole blood,
or fingerstick whole blood done at screening; or with HIV-1/HIV-2 Multispot rapid test
and Western Blot as determined by NIH Clinical Pathology Laboratory or Leidos
Biomedical Research. Monitoring Laboratory.

2. Outside primary medical doctor who provides care

HIV-negative Controls Only:

1.HIV-antibody negative

EXCLUSION CRITERIA:

Screening Study (all participants):

1. Illness or other condition that, in the opinion of the PI, may interfere with study
participation at the time of enrollment, including, but not limited to those listed
below:

1. CNS infections: this includes but is not limited to Varicella zoster virus (VZV)
encephalitis, CNS lymphoma and toxoplasmosis. Subjects who have recovered from
effectively treated CNS infections may be considered once they resume baseline
daily activities.

2. Non-CNS opportunistic infections: subjects who recovered from or are completing
treatment for non-CNS opportunistic infections (OIs) (e.g., Pneumocystis
pneumonia, Candida esophagitis, or pulmonary TB) can be enrolled if they have
returned to self-reported baseline activity and functional level.

2. Conditions other than HAND associated with cognitive impairment or dementia such as
Alzheimer s, Parkinson s disease, head injury with loss of consciousness >30 minutes,
untreated sleep apnea with day-time sleepiness, or seizure disorders. Subjects with a
history of seizure disorder with no seizure activity that are on a stable,
non-sedating anti-seizure regimen for >6 months may be enrolled.

3. Concurrent severe, unstable psychiatric illness that, in the opinion of the
investigators, may interfere with study participation and/or data interpretation.
Subjects on psychotropic anxiolytic, attention deficit-hyperactivity disorder (ADHD),
and other psychiatric medications may be included if clinically stable for >6 months.

4. Concurrent substance abuse that, in the opinion of the investigators may interfere
with study participation and/or data interpretation. Active substance abuse includes
illegal drug use and/or excessive narcotic or alcohol use as determined by the
investigator. Urine drug screen will be performed on all subjects at screening. Use of
nicotine containing products will not be an exclusion criterion.

5. Contraindication to MRI/ MRS scanning, including pacemakers or other implanted
electrical devices, brain stimulators, some types of dental implants, aneurysm clips
(metal clips on the wall of a large artery), metallic prostheses (including metal pins
and rods, heart valves, and cochlear implants), implanted delivery pump, or shrapnel
fragments. Patients requiring a low dose oral benzodiazepine for mild to moderate
claustrophobia will be allowed to participate. Pregnancy testing will be performed in
enrolled female participants 48 hours prior to any MRI.

6. Medications: narcotics, psychiatric, and anti-seizure medications will not be allowed
except under certain conditions as noted above. Corticosteroids may be permitted for
subjects on stable short-term therapy without CNS disease (i.e., resolving
Pneumocystis pneumonia). Participants must be willing not to take the following

medications within 48 hours of neuropsychological testing : sedating antihistamines
such as diphenhydramine, zolpidem and other drugs identified by the study team that
are associated with altered alertness or impaired memory.

7. Pregnant or Lactating women: Women of childbearing potential must have a negative
serum or urine pregnancy test at the time of

screening. Pregnancy testing will also be performed in enrolled female participants prior
to any radiation exposure.

ELIGIBILITY CRITERIA FOR PART II NATURAL HISTORY STUDY:

INCLUSION CRITERIA:

Natural History Study (HIV-infected Only):

In addition to the inclusion criteria for the screening study (see above)

1. Plasma HIV-RNA <50 copies/mm(3) or BLD for greater than one year. Patients who
experience transitory episodes of an HIV viral load > 50 copies/mm (3) preceded and
followed by plasma viremia < 50 copies/mm(3) may be included.

2. At least one year of continuous ART

3. Consent to store blood and tissue

4. Willing to participate on this study for 5 years

Natural History Study (Healthy Controls Only):

1. Men and women, 18 years of age and older

2. Ability to sign informed consent by the subject

3. At least seventh grade educational level and ability to speak, read, and understand
English. Education level will be assessed by subject self-report. Because many of the
neuropsychological subtests were validated using United States norms, subjects must be
native English speakers or if foreign-born, demonstrate ability to understand the
English language at the time of screening protocol consent and neuropsychological
testing.

4. HIV-antibody negative

PARTICIPANT EXCLUSION CRITERIA:

In addition to the exclusion criteria from the screening protocol (see section above):

1. Inability to refrain from use of anticoagulant/antiplatelet medication, such as
dipyridamole (Persantine), clopidogrel (Plavix), dabigatran (Pradaxa), or warfarin
(Coumadin) for at least 72 hours prior to invasive procedures (lumbar puncture [LP],
lumbar drain).

2. Prior or planned/anticipated exposure to radiation due to clinical care or
participation in other research protocols, which would exceed the recommended
acceptable annual limit of radiation exposure once accounting for the requirements of
the current study.

3. Pregnant or Lactating females are excluded due to exposure to the radioactive compound
for PET/CT scans, which may be excreted in the breast milk and could be potentially
harmful to breast-fed infants. There is also exposure to radiation from the CT part of
the PET/CT scan and the lumbar puncture if done under fluoroscopy. Women of
childbearing potention must have a negative serum or urine pregnancy 48 hours prior to
any radiation exposure.

EXCLUSION OF PREGNANT OR LACTATING WOMEN:

The study requires exposure to high magnetic fields and irradiation, which could pose a
risk to the fetus. Futher, we will be studying growth factors and inflammatory mediators in
blood and CSF all of which will be affected by the state of pregnancy and then post partum
state. Women who are lactating are excluded because the study may result in transfer of
radioactive tracer in breast milk.

EXCLUSION OF CHILDREN::

Subjects younger than 18 years of age are excluded because the developing brain is not
within the scope of this study.

Department of Defense MRI-only Inclusion/Exclusion Criteria:

Due to the nature of the military population, the ALLHANDS DOD protocol has some notable
differences in the inclusion/exclusion criteria. Note that only HIV+ participants will come
from the DOD.

1. No ART use or HIV viral load level requirement.

2. Outside primary medical doctor requirement not included as subjects are military
beneficiaries who have primary medical care

3. Illicit drug testing will not be performed for this study to avoid risk of inadvertent
identification and disclosure of a positive result. Prior studies have shown drug use
to be very low in this population.

4. Head injury with loss of consciousness >30 minutes will be noted, but not an exclusion
criterion.

5. Untreated sleep apnea with daytime sleepiness will be noted, but not an exclusion
criterion Sleep disorders were found to be prevalent among this population.