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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of California, Davis
ClinicalTrials.gov Identifier:
NCT00870363
First received: March 25, 2009
Last updated: May 24, 2017
Last verified: May 2017
March 25, 2009
May 24, 2017
April 2009
April 2013   (Final data collection date for primary outcome measure)
Change in the Density of CD3+/CD4+ Cells Per Cubic Millimeter at the Effector Sites in the Duodenal Tissues Following Antiretroviral Therapy Regimen [ Time Frame: Baseline and nine months for 3 treatment cohorts and Baseline for the control group, which was only assessed at one time point ]
immunohistochemistry for CD3+/CD4+ cells counted manually within the lamina propria
To correlate the increase in frequency of CD3+/CD4+ cells per cubic millimeter at the effector sites in the duodenal tissues to the antiretroviral therapy regimen over time [ Time Frame: nine months ]
Complete list of historical versions of study NCT00870363 on ClinicalTrials.gov Archive Site
  • Trough Plasma and Tissue Drug Levels in Volunteers at the Time of the Upper Endoscopy [ Time Frame: nine months ]
    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.
  • Change in HIV DNA Per 10^6 Cells in Duodenal Tissue Versus PBMC by Drug Regimen Received [ Time Frame: Baseline and nine months ]
    single-cell suspension of digested duodenal tissue and Ficol-Hypaque separated PBMC underwent HIV-DNA PCR
  • Change in GALT CD4+ and CD8+ T-cell Subpopulations (naïve and Memory Subsets) [ Time Frame: 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 [ Time Frame: nine months ]
  • Changes in CD4+ T-cell Numbers by Treatment Regimen [ Time Frame: Baseline and nine months ]
    peripheral absolute CD4+ T-cell counts increase from baseline to 9 months of cART by commercial assay
  • 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 [ Time Frame: nine months ]
  • To measure the trough plasma and tissue drug levels in volunteers at the time of the upper endoscopy [ Time Frame: nine months ]
  • To correlate the level of HIV RNA per gram of duodenal tissue versus plasma HIV load and drug regimen received [ Time Frame: nine months ]
  • To measure the change in GALT CD4+ and CD8+ T-cell subpopulations (naïve and memory subsets) [ Time Frame: nine months ]
  • To assess 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 [ Time Frame: nine months ]
  • To explore whether the treatment regimen correlates with the changes in CD3+/CD4+ T-cell numbers [ Time Frame: nine months ]
  • To compare the level of 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 [ Time Frame: nine months ]
Not Provided
Not Provided
 
A Pilot Project of Virologic, Pharmacologic and Immunologic Correlates of Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution Following Maraviroc Therapy
A Pilot Project of Virologic, Pharmacologic and Immunologic Correlates of Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution Following Maraviroc Therapy

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.

  1. maraviroc (Selzentry) in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) or
  2. maraviroc PLUS raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) or
  3. 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.

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).
Interventional
Phase 4
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
HIV Infections
  • Drug: maraviroc in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)
    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
    Other Name: Selzentry
  • Drug: maraviroc plus raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)
    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
    Other Name: Selzentry (maraviroc)
  • Drug: efavirenz [or other NNRTI (non-nucleoside reverse transcriptase inhibitor)]
    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
    Other Name: Sustiva
  • Active Comparator: 1
    maraviroc in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician
    Intervention: Drug: maraviroc in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)
  • Active Comparator: 2
    maraviroc PLUS raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor) pre-determined with primary care physician
    Intervention: Drug: maraviroc plus raltegravir in combination with 2 NRTIs (dual nucleoside reverse transcriptase inhibitor)
  • Active Comparator: 3
    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
    Intervention: Drug: efavirenz [or other NNRTI (non-nucleoside reverse transcriptase inhibitor)]
  • No Intervention: 4
    HIV-negative

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
44
April 2013
April 2013   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years to 60 Years   (Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00870363
200816535
No
Not Provided
Not Provided
University of California, Davis
University of California, Davis
Not Provided
Principal Investigator: David M. Asmuth, MD University of California, Davis Health System
University of California, Davis
May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP