Ferumoxytol-enhanced Brain MRI in HIV-associated Neurocognitive Disorders

The continued existence of cognitive dysfunction in HIV infected individuals in the era of
effective antiretroviral therapy may be, in part, secondary to the failure of current
antiretroviral regimens to eradicate the pool of HIV-infected and activated monocytes within
the bloodstream. Trafficking of such HIV infected and activated blood monocytes into the
brain parenchyma is believed to introduce HIV into the brain and precipitate immune
activation and inflammation, ultimately leading to neuronal degeneration.

Ferumoxytol is an ultrasmall superparamagnetic iron-oxide (USPIO), which is FDA-approved for
intravenous iron-replacement therapy in anemic patients with chronic kidney disease. The
paramagnetic properties of ferumoxytol also allow it to be used as a MRI contrast agent.
Ferumoxytol is avidly taken up by circulating monocytes and reactive astrocytes, microglia,
and dendritic cells within the brain, making it potentially a novel biomarker for
HIV-associated cognitive impairment given the role of monocytes in its pathogenesis.

This proposal intends to investigate the possible use of ferumoxytol (a new MRI contrast
agent) as a biomarker for HIV-associated cognitive impairment and to assess the safety and
tolerability of ferumoxytol in HIV-infected individuals.

Hypotheses to be tested:

- HIV-infected subjects with undetectable plasma HIV RNA levels and detectable levels of
HIV DNA in CD14+ peripheral blood mononuclear cells (PBMCs) and impairment on
neurocognitive testing will demonstrate ferumoxytol contrast enhancement in the
perivascular regions of the brain consistent with monocyte/macrophage infiltration in
these regions.

- Ferumoxytol can be safely administered to HIV-infected subjects.

Inclusion Criteria:

- HIV-1 infection as documented by ELISA and confirmed by Western blot, HIV-1 culture,
HIV-1 antigen, plasma HIV-1 RNA by RT-PCR or DNA at any time prior to study entry.

- Receipt of antiretroviral (ARV) medication uninterrupted for at least 6 months leading
up to the screening period with demonstrated plasma HIV RNA < 48 copies/ml within the
last 6 months.

- Willingness for both males and females of childbearing potential to utilize 2
effective contraception methods (2 separate forms, one of which must be an effective
barrier method), be non-heterosexually active or have a an exclusive vasectomized
partner from screening throughout the duration of the study treatment and for 30 days
following the last dose of study drugs.

- Age >18 years.

- Ability and willingness to provide written informed consent

- HIV DNA > 10 copies/106 CD14+ PBMCs

- Mild or greater cognitive impairment as indicated by global NPZ8 z-score < -0.5 with a
neurocognitive abnormality (defined as a z-score < -0.5) in at least one cognitive
domain characteristic of HAD (i.e., executive function, psychomotor speed, memory).

Exclusion Criteria:

- Requirement for acute therapy for other AIDS-defining illness or other serious medical
illnesses (in the opinion of the site investigator) within 14 days prior to study
entry.

- Known allergic or hypersensitivity reaction to FERAHEME, parental iron, parental
dextran, parental iron-dextran, or parental iron-polysaccharide preparations

- Known history of an iron overload syndrome (e.g., hereditary hemochromatosis,
porphyria cutanea tarda)

- Medical conditions (e.g., chronic hemolytic anemia) which requires frequent blood
transfusions

- Taking oral iron supplementation

- Any factor that precludes MRI scan including presence of metal or exposure to metal
work (e.g. metal grinder/worker) and claustrophobia

- Past or present HIV opportunistic infection of the brain, learning disability, head
injury with prolonged loss of consciousness or cognitive sequelae, or other non-HIV
risk factor that in the opinion of the principal investigator (PI) may impact
cognitive performance.

- History of epilepsy requiring treatment with an antiepileptic

- Other chronic illnesses including insulin-dependent diabetes, autoimmune diseases, and
endocrinopathies, except subjects on stable physiologic replacement therapy for low
testosterone or thyroid levels

- Current active substance or alcohol dependence or positive urine toxicology screen.

- Pregnancy or breast-feeding, intent to become pregnant during the course of the study.

- Any condition which, in the opinion of the investigator, would compromise the
subject's ability to participate in the study

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) greater than 2x upper
limits of normal on pre-entry baseline laboratory safety assessment prior to study
enrollment.

- Elevated iron levels on pre-entry baseline laboratory safety assessment prior to study
enrollment.

- Hematocrit > 52% or Hemoglobin > 18 g/dL on pre-entry baseline laboratory safety
assessment prior to study enrollment.