Raltegravir Augmentation on Persistent Central Nervous System (CNS) Immunoactivation in Treated HIV-1 Patients

Pilot Study of Raltegravir Augmentation on Persistent Central Nervous System (CNS) Immunoactivation in Treated HIV-1 Patients

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: raltegravir

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • Ucsf Ccrc, Sfgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: raltegravir group; The raltegravir dosing will be 400mg twice daily by mouth. Subjects will continue all of their regular medications throughout the protocol.	Drug: raltegravir; 400 mg two times daily for three months; Other Names: Isentress
No Intervention: No augmented treatment; Subjects randomized not to receive augmented treatment will continue in the study with their regular antiretroviral regimen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CSF Concentrations of Neopterin After 12 Weeks	CSF markers of immuno¬activation and inflammation after 12 weeks compared to baseline.	three months (Rollover subjects were assessed for a second baseline after the initial 12 week period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	three months (Rollover subjects were assessed for a second baseline after the initial 12 week period)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Mental Health (NIMH); Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Richard Price, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Dahl V, Lee E, Peterson J, Spudich SS, Leppla I, Sinclair E, Fuchs D, Palmer S, Price RW. Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis. 2011 Dec 15;204(12):1936-45. doi: 10.1093/infdis/jir667. Epub 2011 Oct 21.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: April 29, 2008
• First Submitted That Met QC Criteria: May 2, 2008
• First Posted (Estimate): May 6, 2008

Study Record Updates

• Last Update Posted (Estimate): July 5, 2013
• Last Update Submitted That Met QC Criteria: May 29, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: HIV-1; AIDS; raltegravir; antiretroviral therapy; cerebrospinal fluid (CSF); central nervous system (CNS); suppression; immunoactivation
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Raltegravir Potassium
• Other Study ID Numbers: CCRC5004; R01MH062701 (U.S. NIH Grant/Contract)