Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure

Study Overview
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Brief Summary
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Many people with HIV fail to regain normal CD4 counts despite effectively suppressing HIV replication with medications. Blocking the co-receptor for HIV might decrease inflammation of the immune system, potentially providing an immune benefit. The goal of the current trial is to determine whether adding maraviroc, a new CCR5 co-receptor blocker, decreases inflammation, providing an immune benefit for patients with low CD4 counts despite undetectable viral loads on HIV medications. In this study, HIV-infected patients who are receiving antiretroviral therapy for HIV will receive either maraviroc or a placebo (sugar pill) each day for 24 weeks. After 24 weeks, the study medication will be stopped and all subjects will be followed for 12 more weeks. Blood tests measuring the extent of inflammation, low-level viremia, and immune function will be measured throughout the trial and compared between treatment arms.

Detailed Description
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Our primary hypothesis is that CCR5 inhibitors may have protective immunomodulatory effects independent of their impact on HIV replication. Specifically, we predict that maraviroc will reduce the persistent T cell activation that prevents normal immune reconstitution during HAART-mediated viral suppression. This hypothesis will be tested in the context of a placebo controlled pilot study assessing the impact of maraviroc in antiretroviral-treated patients with a CD4+ T cell count less than 350 cells/mm3. In order to address the immunologic activity of this drug independent of plasma HIV RNA levels, we will study individuals who have undetectable viral loads (< 75 copies RNA/mL). Subjects will be randomized to maraviroc for 24 weeks or matching placebo for 24 weeks, followed by a 12 week washout period. We will use as our primary endpoint the proportion of CD8+ T cells that co-expresses CD38 and HLA-DR, as these outcomes have been well validated in prior studies. The primary outcome will be change in the percentage of activated CD8+ T cells at week 24. Change in CD4+ T cell counts, HIV RNA levels (using ultra-sensitive techniques), and other more experimental immunologic measurements will be assessed as secondary outcomes.

Official Title
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Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Placebo
* Drug: Maraviroc


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test. Stable antiretroviral therapy for at least 12 months Screening CD4+ T cell count below 350 cells/mm3 All available CD4+ T cell counts in the last year and at screening < 350 cells/mm3 Screening plasma HIV RNA levels below level of detection (< 50 copies RNA/mL using Roche Amplicor or < 75 copies/mL using Bayer bDNA) All available plasma HIV RNA levels within past year below the level of detection. Isolated values that are detectable but < 500 copies will be allowed as long as the plasma HIV RNA levels before and after this time point are undetectable. > 90% adherence to therapy within the preceding 30 days, as determined by self-report. Both male and female subjects are eligible. 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. Ability and willingness of subject or legal guardian/representative to provide informed consent Exclusion Criteria: Increase in CD4 count of > 100 cells/mm3 in past year. Patients who are intending to modify antiretroviral therapy in the next 24 weeks for any reason. Serious illness requiring hospitalization or parental antibiotics within preceding 3 months. Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks. HBVsAg+ or active hepatitis C or hepatitis B which will require treatment in the subsequent 24 weeks. Prior exposure to CCR5 inhibitors Screening absolute neutrophil count <1,000 cells/mm3, platelet count <50,000 cells/mm3, hemoglobin < 8mg/dL, estimated creatinine clearance <40 mL/minute. Pregnant or breastfeeding women Use of both Tenofovir and Didanosine in current antiretroviral therapy regimen.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maraviroc<br>Maraviroc (dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens). | Drug: Maraviroc<br>* Dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.<br>* Other names: Selzentry;|
| Placebo Comparator: Placebo<br>Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens). | Drug: Placebo<br>* Dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.<br>* Other names: Placebo for Maraviroc;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 24 Change in Percentage of CD8+ T Cells That Co-express CD38 and HLA DR (Week 24 %CD38+HLA-DR+ CD8+ T Cells Minus Baseline %CD38+HLA-DR+ CD8+ T Cells) |  | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD4+ T Cell Count |  | Baseline and Week 24 | 
| Change in Ultra-sensitive Plasma HIV RNA Level (Single Copy/ml Assay) |  | Baseline and Week 24 | 
| Change in Brachial Artery Flow-mediated Dilatation (UCSF Site Only) |  | Baseline and Week 24 | 
| Change in Gut-associated Lymphoid Tissue HIV RNA Level (UCSF Site Only) |  | Baseline and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CCR5, HIV infection, T cell activation, Antiretroviral Therapy, Maraviroc