CCR5 Inhibitor Treatment Intensification on CD4+ T-Cell Recovery - Full Text View

Sponsor:	California Collaborative Treatment Group
Collaborators:	University of California, Los Angeles University of Southern California Pfizer California HIV/AIDS Research Program
Information provided by:	California Collaborative Treatment Group
ClinicalTrials.gov Identifier:	NCT00925756

Purpose

CCTG 590 is a open-label study to evaluate the impact of therapy intensification with Maraviroc (MVC) (a CCR5 inhibitor) to a stable suppressive HIV antiretroviral regimen on the rate of CD4+ T-cell recovery and gene expression profiles. Patients on a stable first-line HIV regimen with continued viral suppression and sub-optimal CD4+ T-cell counts will be eligible for this study. Those who are found to be eligible will have MVC (dose-adjusted to background HIV regimen) added to their current HIV regimen for 24 weeks. After the 24 week intensification, the MVC will be discontinued, the original antiretroviral regimen will be continued and the subjects will be followed for an additional 12 weeks.

The investigators hypothesize that MVC will improve the rate of CD4 recovery. This improved CD4 recovery will be associated with favorable changes in gene expression profiles of genes involved with CD4 maintenance and circulation.

Condition	Intervention	Phase
HIV Infections	Drug: Maraviroc	Phase IV

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Historical Control, Single Group Assignment
Official Title:	The Impact of CCR5 Inhibitor Treatment Intensification on CD4+ T-Cell Recovery and Gene Expression Profiles in HIV-Infected Patients With Viral Suppression

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: AIDS

Drug Information available for: Maraviroc

U.S. FDA Resources

Further study details as provided by California Collaborative Treatment Group:

Primary Outcome Measures:

Differences in gene expression profiles obtained at baseline and weeks 4 and 24. [ Time Frame: baseline and week 4 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

CD4+ T-cell absolute count and percentage at baseline, weeks 4 and 24. [ Time Frame: baseline, week 4 and 24 ] [ Designated as safety issue: No ]
The proportion of CD4+/CD8+ T-cell immune activation, maturation, regulatory and apoptosis markers at baseline and weeks 4 and 24. [ Time Frame: baseline, weeks 4 and 24 ] [ Designated as safety issue: No ]

Estimated Enrollment:	30
Study Start Date:	June 2009
Estimated Study Completion Date:	March 2011
Estimated Primary Completion Date:	June 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
maraviroc: Experimental Maraviroc will be added to patient's existing HIV treatment regimen dose-adjusted to background HIV medications	Drug: Maraviroc Maraviroc will be given dose-adjusted to background HIV treatment

Detailed Description:

Blunted CD4+ T-cell responses during viral control may be a consequence of on-going T-cell destruction in the regenerative phase of CD4 recovery from activation-induced apoptosis and/or reduced production from decreased thymic output. Maraviroc, a CCR5 inhibitor, may improve the clinical status of HIV-infected by two distinct mechanisms. First, by blocking HIV entry into CD4+ T-cells, CCR5 inhibitors have direct antiviral activity. Second, as the pro-inflammatory state of HIV infection up-regulates CCR5 ligands and receptors, this CCR5 receptor antagonist may abrogate immune activation and resultant T-cell apoptosis. Importantly, MVC binds CCR5 receptors without inducing intracellular signaling or altering cell-surface expression. Potentially, MVC intensification during viral suppression with ART may further decrease persistent activation-induced apoptosis and improve repair and remodeling of lymphoid tissue leading to increased CD4+ T-cell recovery and function.

The aim of this study is to evaluate a potentially therapeutic immunomodulatory effect of MVC. Several measures of immune homeostasis will be determined in this study, including functional genomic analysis and extended T-cell phenotyping. Genes responsive to MVC therapy will be identified and categorized into functional groups. Based upon existing literature of the identified genes and observed immune responses (change in CD4/CD8 subsets) during MVC therapy, a model of CCR5 responsive-genes and potential impact on immune recovery will be outlined. Potentially, individuals experiencing immune discordance during suppressive ART may be better treated by MVC antiretroviral intensification.

1. We hypothesize that expression will decrease among genes involved in immune activation (NF-kB, MAPK, nuclear factor of activated T-cells, MYD88 and STAT1), apoptosis (Fas ligand and TRAIL) and trafficking/repopulation of T-cells (CCR5, MIP-1α, MIP-1β and RANTES) and increase among genes involved in tissue repair (platelet-derived growth factor, insulin-like growth proteins and osteoblast-specific transcription factor).

The gene expression profiles induced by MVC will be associated with a favorable increase in the rate of CD4+ T-cell recovery.
The rate of CD4 recovery (cells/month) will be greater during MVC compared to before.
The proportion of cells expressing activation/ apoptosis markers will decrease from baseline and this decrease will be associated with improved CD4 recovery.
The proportion of naïve cells will increase from baseline and this increase will be associated with improved CD4 recovery.
The rate of CD4 recovery will be greater among those subjects receiving PI-containing treatment regimens compared to those receiving NNRTI-containing treatment regimen.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

HIV-1 infection
All available CD4+ T cell counts within the last 12 months of screening below 350 cells/mm3 (minimum of 3 values obtained > 30 days apart).
HIV treatment with a stable (for at least 6 months) antiretroviral regimen consisting of at least 2 NRTIs and either a protease inhibitor boosted with low dose ritonavir or an NNRTI. A stable regimen is defined as no additions or deletions for more than 14 cumulative days.
Patient considered to be receiving initial HIV regimen (history of medication substitution for toxicity is allowed).
All available plasma HIV RNA levels within the last 12 months are below the level of detection. Isolated values that are detectable but < 1000 copies will be allowed as long as the plasma HIV RNA levels before and after this detectable time point are undetectable - The subject should have a minimum of 3 values obtained > 30 days apart.
Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
Men and women age ≥ 18 years.

Exclusion Criteria:

Current antiretroviral regimen contains tenofovir disoproxil fumarate AND didanosine in combination.
History of chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable).
History of chronic active hepatitis B (defined as surface antibody negative, surface antigen positive and HBV DNA detectable).
Concurrent use of G-CSF or GM-CSF.
Prior or concurrent use of IL-2.
Prior or concurrent use of a CCR5 inhibitor.
Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry.
Use of human growth hormone within 30 days prior to study entry.
Initiation of testosterone or anabolic steroids within 30 days prior to study entry. (Exception: Chronic replacement dosages in patient's with diagnosed hypogonadism is allowed).
Evidence of splenic sequestration or suppressed bone marrow function:
- Clinical or radiographic evidence of significant splenomegaly.
- History of leukemia or lymphoma.
- History of myelosuppressive chemotherapy or irradiation

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00925756

Contacts

Contact: Miguel Goicoechea, MD	619-543-8080 ext 274	mgoicoechea@ucsd.edu
Contact: Linda Meixner, RN	619-543-8080 ext 217	lmeixner@ucsd.edu

Locations

United States, California
University California San Diego	Recruiting
San Diego, California, United States, 92103
Contact: Linda Meixner, RN 619-543-8080 ext 217 lmeixner@ucsd.edu
Principal Investigator: Miguel Goicoechea, MD
Harbor-UCLA	Recruiting
Torrance, California, United States, 90502
Contact: Angela Gbric 310-222-3848 agrbic@labiomed.org
Sub-Investigator: Eric Daar, MD
University Southern California	Recruiting
Los Angeles, California, United States, 90033
Contact: Connie Funk 323-226-7194 funk@usc.edu
Sub-Investigator: Michael Dube, MD

Sponsors and Collaborators

California Collaborative Treatment Group

University of California, Los Angeles

University of Southern California

Pfizer

California HIV/AIDS Research Program

Investigators

Study Chair:

Miguel Goicoechea, MD

California Collaborative Treatment Group

More Information

Additional Information:

organization's website This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	California Collaborative Treatment Group ( Miguel Goicoechea, MD )
Study ID Numbers:	CCTG 590
Study First Received:	June 18, 2009
Last Updated:	July 8, 2009
ClinicalTrials.gov Identifier:	NCT00925756 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by California Collaborative Treatment Group:

HIV
low CD4 recovery
Low CD4 recovery despite HIV control
Treatment experienced

Additional relevant MeSH terms:

Virus Diseases
Sexually Transmitted Diseases, Viral
RNA Virus Infections
Slow Virus Diseases
Immune System Diseases
HIV Infections

Sexually Transmitted Diseases
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Infection
Retroviridae Infections
Immunologic Deficiency Syndromes

ClinicalTrials.gov processed this record on February 08, 2010