CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery

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.

• 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.

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