Raltegravir Cerebrospinal Fluid Pharmacodynamic Study in HIV-Infected Individuals

Cognitive disorders continue to be a common complication of HIV disease even though potent
antiretroviral drugs can reduce HIV below detectable levels and restore immune function.
Concentrations of most antiretrovirals in the nervous system are only a fraction of
concentrations in blood. As a result, HIV can continue to be present in the nervous system
when it is below detection in blood. A recently approved drug, raltegravir, reaches
therapeutic concentrations in cerebrospinal fluid and may be effective at controlling HIV
replication in the primary target cells in the brain, macrophages and microglia. Based on
this, raltegravir may be a particularly effective drug for treating HIV disease in the
nervous system. The purpose of this study is to determine the effects of raltegravir in the
nervous system by measuring HIV in the CSF (via lumbar puncture, also known as spinal taps)
before and after initiation of raltegravir-containing antiretroviral therapy. CSF is an
accessible fluid that provides a window into brain processes, including HIV replication and
inflammation. The potency of raltegravir will be estimated by calculating the change in HIV
viral load in CSF over time. These changes will be compared to those following initiation an
efavirenz-containing regimen in a separate group of individuals. Two additional drugs
(tenofovir disoproxil fumarate, emtricitabine) will be combined with either raltegravir or
efavirenz. Neuropsychological performance, mood, sleep and quality of life assessment will
also be compared. Participants will be randomly assigned to either raltegravir- or
efavirenz-containing therapy.

Inclusion Criteria:

1. Men and women aged 18-65 years;

2. Integrase inhibitor-naive subjects with clinical indication to initiate RAL under the
supervision of their HIV care provider;

3. Baseline detectable HIV-1 RNA levels ≥ 5000 copies/mL in plasma and ≥ 500 copies/mL
in CSF;

4. Absolute T-cell CD4+ subset between 200-500/mm3

5. Individual willing to undergo serial lumbar punctures as outlined in study
evaluations;

6. Subject able to give informed consent to all study procedures (if cognitively
impaired, the individual must pass an evaluation to ensure adequate comprehension of
the consent document and procedures);

7. Susceptibility to all study drugs on Monogram Biosciences PhenoSense GT assay.

Exclusion Criteria:

1. Contraindication to lumbar puncture, such as current coagulopathy, thrombocytopenia
(platelets below 50,000/µL), or use of anticoagulants;

2. Cognitive, psychiatric, or substance use disorders or any other medical conditions
that would interfere with study participation, in the opinion of the investigator;

3. Major opportunistic infections (e.g., pneumonia, tuberculosis) within 30 days;

4. Use of prescribed drugs with known substantial interactions with the study drugs;

5. Positive HCV serology;

6. HIV-associated dementia/Global Deterioration Scale ≥4;

7. Pregnancy;

8. Serum creatinine higher than 2.0 mg/dL;

9. Total bilirubin or alanine or aspartate transaminases more than 3 times the upper
limit of normal