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

May 24, 2017 updated by: University of California, Davis

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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).

Study Type

Interventional

Enrollment (Actual)

44

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Sacramento, California, United States, 95811
        • CARES Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
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)
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 Names:
  • Selzentry
Active Comparator: 2
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)
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 Names:
  • Selzentry (maraviroc)
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
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 Names:
  • Sustiva
No Intervention: 4
HIV-negative

What is the study measuring?

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
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
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
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.
nine months
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
Baseline and nine months
Change in GALT CD4+ and CD8+ T-cell Subpopulations (naïve and Memory Subsets)
Time Frame: nine months
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
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
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
Time Frame: nine months
nine months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, Davis

Investigators

  • Principal Investigator: David M. Asmuth, MD, University of California, Davis Health System

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2009

Primary Completion (Actual)

April 1, 2013

Study Completion (Actual)

April 1, 2013

Study Registration Dates

First Submitted

March 25, 2009

First Submitted That Met QC Criteria

March 26, 2009

First Posted (Estimate)

March 27, 2009

Study Record Updates

Last Update Posted (Actual)

May 30, 2017

Last Update Submitted That Met QC Criteria

May 24, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 200816535

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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