Raltegravir Cerebrospinal Fluid Pharmacodynamic Study in HIV-Infected Individuals

University of California, San Diego2 enrolled

Overview

The primary aim of this study is to determine the effects of the HIV integrase inhibitor, raltegravir, in cerebrospinal fluid (CSF). This will be accomplished by collecting CSF before and after initiation of either raltegravir or another antiretroviral, efavirenz, each in combination with two other antiretrovirals. Assessments will include HIV RNA levels (viral load), neuropsychological testing, mood assessments, and quality of life assessments.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

HIV

Interventions

RaltegravirDRUG

raltegravir 400 mg PO twice daily

EfavirenzDRUG

efavirenz 600 mg PO once daily

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (1)

UCSD Antiviral Research Center

San Diego, California, United States

Outcomes

Primary Outcomes

Cerebrospinal Fluid HIV RNA Levels

Slope of decline of HIV RNA levels in CSF over time

Time frame: 180 days

Secondary Outcomes

Neuropsychological Performance

Change in neuropsychological performance over 180 days

Time frame: 180 days

Measure of Mood

Change in mood over 180 days

Time frame: 180 days

Measure of Sleep

Change in self-reported sleep performance over 180 days.

Time frame: 180 days

Measure of Quality of Life

Change in self-report quality of life over 180 days

Time frame: 180 days

Data from ClinicalTrials.gov

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