Effects of Glucocorticoids on Cognition in HIV-infected Women

The overall aim of this study is to contribute important foundational knowledge of the
utility of targeting neuroinflammation and the hypothalamic-pituitary-adrenal (HPA) axis to
improve cognition in HIV and will provide key clinical insights into the mechanisms
underlying any cognitive benefit. The investigators are conducting a single-dose study of low
dose hydrocortisone (LDH) followed by a 4-week study of daily LDH as a probe of the
mechanisms of neuroinflammation including myeloid-lineage cells and the HPA axis in
HIV-infected (HIV+) women demonstrating cognitive dysfunction and reporting high levels of
stress, trauma history, and mental health risk factors which commonly occur in this
population. The use of a pharmacological challenge may aid in the identification of: 1) a
putative biomarker of stress- and psychiatric disorder-related neurocognitive complications
in HIV-infected women and/or 2) an adjunctive, cost-effective therapy for the treatment of
cognitive deficits in HIV

The design is a two-phase study of HIV+ women who: 1) first participate in a double-blind,
placebo-controlled cross-over study of a single, low dose (10 mg) of hydrocortisone versus
placebo on cognition; and 2) then participate in a mechanistic, randomized, double-blind,
placebo controlled trial of daily LDH for 4 weeks on cognition and side effects. The clinical
trial will include 100 virally suppressed HIV+ women who show elevated stress and cognitive
impairment and who represent the range of psychological risk factors characteristic of this
population. Next, to understand the mechanism and broader clinical significance of LDH on
cognition, investigators will conduct a 4-week randomized study of the effects of daily
treatment with LDH versus placebo on cognition in HIV+ women (targeted n=80).

Women meeting enrollment criteria will complete three cognitive assessments. The first and
second assessments will be embedded in the double-blind, placebo-controlled, cross-over study
of a single administration of LDH versus placebo (targeted n=100). Investigators will measure
cognitive performance 30 minutes and 4 hours post-dosing, because an emerging literature
shows that the cognitive effects of LDH depends on timing of the assessment post-dosing. The
30-minute assessment addresses how the maximal cortisol levels following LDH affect
cognition. This immediate assessment is standard in studies of stress and cognition and
allows for comparisons with the broader literature. More novel and clinically important is
the 4-hour assessment which occurs post-peak, when cortisol levels are more steady state and
typical of the broader daily cortisol profile following LDH. The third assessment will take
place after 4 weeks of treatment with LDH or placebo. That assessment addresses the clinical
significance and safety of longer-term LDH treatment. Lastly, the investigators will explore
glucocorticoids and inflammation and immune activation as mechanisms by which LDH might
affect cognition.

Objective 1 To examine immediate and delayed effects of a single administration of LDH on
cognition in HIV+ women.

Objective 2 To examine the effects of a 4-week course of daily LDH on cognition in HIV+
women.

Objective 3 To investigate potential mechanisms of LDH effects on cognition in HIV+ women.

Inclusion Criteria:

- Females only;

- HIV-infected;

- Able to give informed consent;

- Able to travel to study site for study participation;

- Age between 18 and 65;

- English as a first language;

- Above-average self-reported levels of perceived stress (>14 on the perceived stress
scale (PSS-10)) and/or current SCID-V diagnosis of mood and/or anxiety disorder;

- Meet criteria for HIV-associated cognitive dysfunction (based on Neurocognitive test
battery and instrumental activities of daily living assessment-impairment on only 1
cognitive domain is required)

- Virally suppressed and on combination antiretroviral therapy (Plasma HIV RNA<1000cp/ml
and bring in medications)

Exclusion Criteria:

- Current use of hormone-based contraceptives (birth control pills or patch);

- Currently pregnant, post-partum or lactating;

- Currently regular use of steroids;

- History of closed head injury resulting in loss of consciousness greater than 1 hour;

- History of schizophrenia or schizoaffective disorder;

- Current untreated hypertension or diabetes*;

- History of dementia or any other neurologic central nervous system (CNS) or
AIDS-defining disorder;

- Positive urine toxicology screen (except marijuana) or breathalyzer and/or any
evidence of acute intoxication or withdrawal.

- History of substance abuse/dependence in the past six months.

Participants who present with a heretofore untreated condition (e.g., hypertension) will be
excluded; however, they may be rescreened for eligibility after receiving appropriate
treatment for the condition in the course of their standard medical care (at least 6
months).