Despite treatment with antiretroviral therapy, women living with HIV continue to experience cognitive impairment. Psychological risk factors, including stress, impair cognition more in HIV-infected women than HIV-uninfected women. This study plans to examine a novel intervention for cognitive dysfunction that targets the mechanisms by which stress negatively affects cognitive functioning.

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).

The only entity knowledgeable of randomization is the Johns Hopkins University Investigational Drug Service Pharmacy. They are responsible for randomizing and encapsulating the drug and placebo tablets