Clinical trial NCT01293123: Raltegravir Cerebrospinal Fluid Pharmacodynamic Study in HIV-Infected Individuals
Official title: Raltegravir Cerebrospinal Fluid Pharmacodynamic Study in HIV-Infected Individuals
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: HIV
Keywords: HIV
raltegravir
cerebrospinal fluid
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2011-02-10
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cerebrospinal Fluid HIV RNA Levels
timeFrame: 180 days
Secondary outcomes:
measure: Neuropsychological Performance
timeFrame: 180 days
measure: Measure of Mood
timeFrame: 180 days
measure: Measure of Sleep
timeFrame: 180 days
measure: Measure of Quality of Life
timeFrame: 180 days
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Antiviral Research Center
state: California
Study officials:
affiliation: University of California, San Diego
name: Scott Letendre, MD
role: PRINCIPAL_INVESTIGATOR
References: