A Pilot Project of Virologic, Pharmacologic and Immunologic Correlates of Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution Following Maraviroc Therapy

Study Overview
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Brief Summary
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This research study is being done to find out how the immune system in the small intestines improves after taking antiretroviral (anti-HIV) medications. Biopsies (small snips of tissue) will be taken from the part of the intestines just below the stomach, and will be studied in the laboratory. The main purpose of this study is to measure the increase in the numbers of immune cells in the intestines to see if this number is related to the amount of medication that reaches the intestinal tissue, and the amount of virus that is still hiding there. Subjects are either normal control subjects without HIV or, are HIV positive and are about to start HIV medications. As part of this study, HIV positive patients will be randomized to receive one of three possible combinations of medications. maraviroc (Selzentry) in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) or maraviroc PLUS raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) or efavirenz (Sustiva) in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) Both Maraviroc and Raltegravir each represent new classes of medications in the way that they interfere with HIV making copies of itself. Maraviroc attaches to the surface of the T-cell that the virus uses to get into the cell and is therefore known as an entry inhibitor. Raltegravir blocks the virus from inserting itself into the DNA of the infected cell's nucleus and is therefore known as an Integrase Inhibitor. We hope to learn more about how antiretroviral drugs affect T cells and how immune function restores itself when HIV infection is treated.

Detailed Description
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Despite improved survival, durable virologic suppression, and increases in peripheral CD4+ T-cell counts in patients receiving potent antiretroviral therapy (ART), immune reconstitution remains incomplete as measured by a number of additional surrogate markers. Perhaps critically important among areas of apparent incomplete immune recovery is the gastrointestinal-associated lymphoid tissue (GALT), where CD4+ T-cells repopulate very slowly if at all. Several new classes of antiretrovirals (ART) have recently been approved by the FDA that offer potential advantages in terms of immune reconstitution and/or the kinetics viral suppression over traditionally available treatment regimens. Maraviroc is a new ART agent from a novel class of HIV inhibitors, entry inhibitors, that results in rapid suppression of HIV and recovery of peripheral CD4+ T-cells. This project proposes to examine whether volunteers receiving maraviroc recover GALT immune cells more completely that those taking comparator ART. Raltegravir is an integrase inhibitor that blocks incorporation of the proviral HIV DNA into the host chromosomes leading to more rapid declines in plasma HIV load than has previously been observed. This project proposes to examine whether volunteers receiving maraviroc or maraviroc plus raltegravir recover GALT immune cells more completely that those taking comparator ART. An additional attraction of the use of maraviroc and raltegravir together is that they may provide a potent combination that is also lipid neutral and thereby constitute a 'Heart friendly HAART' (Highly Active Antiretroviral Therapy).

Official Title
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A Pilot Project of Virologic, Pharmacologic and Immunologic Correlates of Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution Following Maraviroc Therapy

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: maraviroc in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)
* Drug: maraviroc plus raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)
* Drug: efavirenz [or other NNRTI (non-nucleoside reverse transcriptase inhibitor)]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females ages 18 years to 60 years inclusive HIV positive (no anticipated antiretroviral therapy adjustments/changes) CD4 count greater than or equal to 50 cells/ml within 30 days of screening CCR5 tropism by Trofile ES(TM) Can be on secondary prophylaxis with a history of AIDS defining illness All females of child-bearing potential must agree to use barrier methods to prevent pregnancy or be abstinent from sexual activity while on study. willing to sign consent form HIV Negative individuals will also be recruited for this study as a Control Group Exclusion Criteria: allergy to peanuts or soya (maraviroc contains soya lecithin) abnormal coagulation parameters (PT greater than or equal to 1.2 ULN) thrombocytopenia (platelet count less than 50,000 within 6 weeks) known GI pathology contra-indications to upper endoscopy or conscious sedation anemia greater than grade 1 any active acute opportunistic infection (OI) or therapy for acute OI within 30 days of entry into study positive pregnancy test aspirin, ibuprofen, warfarin, or other agents that interfere with the coagulation cascade taken within 1 week of endoscopy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>maraviroc in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician | Drug: maraviroc in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)<br>* maraviroc 300mg 1 tablet taken twice a day without regard to food taken in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician<br>* Other names: Selzentry;|
| Active Comparator: 2<br>maraviroc PLUS raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician | Drug: maraviroc plus raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)<br>* maraviroc 300mg 1 tablet taken twice a day without regard to food PLUS raltegravir 400mg 1 tablet taken twice a day without regard to food in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician<br>* Other names: Selzentry (maraviroc);|
| Active Comparator: 3<br>efavirenz or other NNRTI (non-nucleoside reverse transcriptase inhibitor) in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician | Drug: efavirenz [or other NNRTI (non-nucleoside reverse transcriptase inhibitor)]<br>* efavirenz 600mg 1 capsule is taken once a day without regard to food in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician<br>* Other names: Sustiva;|
| No Intervention: 4<br>HIV-negative | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Density of CD3+/CD4+ Cells Per Cubic Millimeter at the Effector Sites in the Duodenal Tissues Following Antiretroviral Therapy Regimen | immunohistochemistry for CD3+/CD4+ cells counted manually within the lamina propria | Baseline and nine months for 3 treatment cohorts and Baseline for the control group, which was only assessed at one time point | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Plasma and Tissue Drug Levels in Volunteers at the Time of the Upper Endoscopy | The reported drug level is for the primary ART agent for that cohort. For the maraviroc arm, maraviroc plasma and tissue levels are reported. For the maraviroc plus raltegravir arm, the raltegravir plasma and tissue levels are reported. For the efavirenz arm, the efavirenz plasma and tissue levels are reported. HIV negative controls were not on ART and did not have drug levels measured. | nine months | 
| Change in HIV DNA Per 10^6 Cells in Duodenal Tissue Versus PBMC by Drug Regimen Received | single-cell suspension of digested duodenal tissue and Ficol-Hypaque separated PBMC underwent HIV-DNA PCR | Baseline and nine months | 
| Change in GALT CD4+ and CD8+ T-cell Subpopulations (naïve and Memory Subsets) |  | nine months | 
| Lymphocyte Immune Function and Activation at Two Time Points Approximately Nine Months Apart in GALT; and Four Timepoints (Month 0, 3, 6, and 9) in Peripheral Blood |  | nine months | 
| Changes in CD4+ T-cell Numbers by Treatment Regimen | peripheral absolute CD4+ T-cell counts increase from baseline to 9 months of cART by commercial assay | Baseline and nine months | 
| Immune Reconstitution With Respect to Absolute Numbers of CD4+ T-cells, the Relative Proportion of T-cell Subpopulations in the Tissue, and Immune Activation to a Cohort of Normal Controls |  | nine months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HIV positive, Gastrointestinal Associated Lymphoid Tissue (GALT), GALT Immune Reconstruction, treatment naive