Raltegravir Cerebrospinal Fluid Pharmacodynamic Study in HIV-Infected Individuals

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.

Study Overview

• Status: Terminated
• Conditions: HIV
• Intervention / Treatment: Drug: Raltegravir; Drug: Efavirenz

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • UCSD Antiviral Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Raltegravir	Drug: Raltegravir; raltegravir 400 mg PO twice daily; Other Names: tenofovir disoproxil fumarate 300 mg PO once daily; emtricitabine 200 mg PO once daily
ACTIVE_COMPARATOR: Efavirenz	Drug: Efavirenz; efavirenz 600 mg PO once daily; Other Names: tenofovir disoproxil fumarate 300 mg PO once daily; emtricitabine 200 mg PO once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal Fluid HIV RNA Levels	Slope of decline of HIV RNA levels in CSF over time	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychological Performance	Change in neuropsychological performance over 180 days	180 days
Measure of Mood	Change in mood over 180 days	180 days
Measure of Sleep	Change in self-reported sleep performance over 180 days.	180 days
Measure of Quality of Life	Change in self-report quality of life over 180 days	180 days

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Scott Letendre, MD, University of California, San Diego

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): December 1, 2013

Study Registration Dates

• First Submitted: February 9, 2011
• First Submitted That Met QC Criteria: February 9, 2011
• First Posted (ESTIMATE): February 10, 2011

Study Record Updates

• Last Update Posted (ACTUAL): October 31, 2019
• Last Update Submitted That Met QC Criteria: October 8, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: HIV; raltegravir; cerebrospinal fluid
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Emtricitabine; Raltegravir Potassium; Efavirenz
• Other Study ID Numbers: 11-0067