HIV Infections
Conditions
Keywords
raltegravir, central nervous system (CNS), HIV-1, AIDS, cerebrospinal fluid (CSF), immunoactivation, antiretroviral therapy, suppression
Brief summary
This pilot study focuses on the persistence of central nervous system (CNS) immune activation that has been observed in the presence of 'effective' combination antiretroviral therapy (cART). Attention to this issue is based on the fear that chronic CNS immunoactivation can cause indolent brain injury that will eventually compromise brain function as patients survive for years on treatment. A leading hypothesis explaining this continued immunoactivation is that viral replication continues within the brain at a level too low for detection in cerebrospinal fluid (CSF), yet sufficient to stimulate local immunoactivation. Based on this hypothesis, we propose to use augmented treatment with raltegravir to test whether additional suppression of this hypothesized CNS HIV-1 replication will reduce continued CNS immunoactivation.
Interventions
DRUGraltegravir
400 mg two times daily for three months
Sponsors
National Institute of Mental Health (NIMH)
Merck Sharp & Dohme LLC
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Capacity to provide informed consent. * Documented HIV-1 infection. * History of continuous cART treatment (with at least three drugs) for at least 2 years. * Documentation of 'undetectable' plasma HIV-1 RNA for at least 1 year. * HIV-1 RNA \<50 copies/mL in plasma and CSF at screening visit.
Exclusion criteria
* Contraindication to LP (suspicion of CNS mass lesion, bleeding diathesis, etc.). * Prior experience with raltegravir or contraindication to raltegravir treatment, including medication interactions that might compromise ongoing antiretroviral therapy or treatment of other conditions. * Active opportunistic infections or neurological diseases. * Other conditions or treatments likely to interfere with treatment or evaluation. * Hemoglobin \< 10 Gm/dL. * Pregnant or anticipating pregnancy during study. * Active substance abuse. * Subjects taking rifampin, phenytoin, Phenobarbital or other drugs that accelerate raltegravir metabolism and might decrease its tissue concentrations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in CSF Concentrations of Neopterin After 12 Weeks | three months (Rollover subjects were assessed for a second baseline after the initial 12 week period) | CSF markers of immuno¬activation and inflammation after 12 weeks compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CD8+ T Cell Co-expression of CD38 and HLA-DR | three months (Rollover subjects were assessed for a second baseline after the initial 12 week period) | Blood CD8+ T cell activation as indicated by percentage of cells in fresh specimens coexpressing surface CD38 and human leukocyte antigen (HLA)-DR. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir Group The raltegravir dosing will be 400mg twice daily by mouth. Subjects will continue all of their regular medications throughout the protocol. | 9 |
| No Augmented Treatment Subjects randomized not to receive augmented treatment will continue in the study with their regular antiretroviral regimen. | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | No Augmented Treatment | Raltegravir Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 18 Participants |
| Age Continuous | 54.3 years STANDARD_DEVIATION 5.3 | 52.7 years STANDARD_DEVIATION 6.4 | 53.9 years STANDARD_DEVIATION 6.1 |
| Region of Enrollment United States | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 9 |
| serious Total, serious adverse events | 0 / 15 | 0 / 9 |
Outcome results
Primary
Change in CSF Concentrations of Neopterin After 12 Weeks
CSF markers of immuno¬activation and inflammation after 12 weeks compared to baseline.
Time frame: three months (Rollover subjects were assessed for a second baseline after the initial 12 week period)
Population: One subject in the raltegravir group was censored when a pharmacological study showed no drug in either plasma (n=9) or CSF. Six subjects randomized to no drug later rolled over to receive raltegravir. Primary analysis treated the rollover subjects as independent and compared 14 intensified to 9 nonintensified subject experiences.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raltegravir Group | Change in CSF Concentrations of Neopterin After 12 Weeks | 0.1 nmol/L | Standard Deviation 0.3 |
| No Augmented Treatment | Change in CSF Concentrations of Neopterin After 12 Weeks | 0.3 nmol/L | Standard Deviation 1.1 |
Secondary
Change From Baseline in CD8+ T Cell Co-expression of CD38 and HLA-DR
Blood CD8+ T cell activation as indicated by percentage of cells in fresh specimens coexpressing surface CD38 and human leukocyte antigen (HLA)-DR.
Time frame: three months (Rollover subjects were assessed for a second baseline after the initial 12 week period)
Population: One subject in the raltegravir group was censored when a pharmacological study showed no drug in either plasma (n=9) or CSF. Six subjects randomized to no drug later rolled over to receive raltegravir. Primary analysis treated the rollover subjects as independent and compared 14 intensified to 9 nonintensified subject experiences.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raltegravir Group | Change From Baseline in CD8+ T Cell Co-expression of CD38 and HLA-DR | 0.51 percentage of cells | Standard Deviation 1.03 |
| No Augmented Treatment | Change From Baseline in CD8+ T Cell Co-expression of CD38 and HLA-DR | 0.66 percentage of cells | Standard Deviation 1.2 |