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

• ClinicalTrials.gov Identifier: NCT00870363
• Recruitment Status: Completed
• First Posted: March 27, 2009
• Results First Posted: February 10, 2017
• Last Update Posted: May 30, 2017
• Sponsor: University of California, Davis
• Information provided by (Responsible Party): University of California, Davis

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infections	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)]	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Project of Virologic, Pharmacologic and Immunologic Correlates of Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution Following Maraviroc Therapy
• Study Start Date: April 2009
• Actual Primary Completion Date: April 2013
• Actual Study Completion Date: April 2013

Arms and Interventions

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 Name: 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 Name: 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 Name: Sustiva
No Intervention: 4; HIV-negative

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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.
2. 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
3. Change in GALT CD4+ and CD8+ T-cell Subpopulations (naïve and Memory Subsets) [ Time Frame: nine months ]
4. 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 ]
5. 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
6. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, California

CARES Clinic

Sacramento, California, United States, 95811

Sponsors and Collaborators

University of California, Davis

Investigators

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

More Information

Publications of Results:

Serrano-Villar S, Sainz T, Ma ZM, Utay NS, Chun TW, Mann S, Kashuba AD, Siewe B, Albanese A, Troia-Cancio P, Sinclair E, Somasunderam A, Yotter T, Deeks SG, Landay A, Pollard RB, Miller CJ, Moreno S, Asmuth DM. Correction: Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial. PLoS Pathog. 2016 Mar 25;12(3):e1005540. doi: 10.1371/journal.ppat.1005540. eCollection 2016 Mar.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Serrano-Villar S, de Lagarde M, Vázquez-Castellanos J, Vallejo A, Bernadino JI, Madrid N, Matarranz M, Díaz-Santiago A, Gutiérrez C, Cabello A, Villar-García J, Blanco JR, Bisbal O, Sainz T, Moya A, Moreno S, Gosalbes MJ, Estrada V. Effects of Immunonutrition in Advanced Human Immunodeficiency Virus Disease: A Randomized Placebo-controlled Clinical Trial (Promaltia Study). Clin Infect Dis. 2019 Jan 1;68(1):120-130. doi: 10.1093/cid/ciy414. Erratum in: Clin Infect Dis. 2018 Oct 30;67(10):1641.

Asmuth DM, Thompson CG, Chun TW, Ma ZM, Mann S, Sainz T, Serrano-Villar S, Utay NS, Garcia JC, Troia-Cancio P, Pollard RB, Miller CJ, Landay A, Kashuba AD. Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy. J Infect Dis. 2017 Oct 17;216(7):813-818. doi: 10.1093/infdis/jix418.

Ellis CL, Ma ZM, Mann SK, Li CS, Wu J, Knight TH, Yotter T, Hayes TL, Maniar AH, Troia-Cancio PV, Overman HA, Torok NJ, Albanese A, Rutledge JC, Miller CJ, Pollard RB, Asmuth DM. Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribosomal DNA (rDNA) quantification and correlations with immune activation. J Acquir Immune Defic Syndr. 2011 Aug 15;57(5):363-70. doi: 10.1097/QAI.0b013e31821a603c.

• Responsible Party: University of California, Davis
• ClinicalTrials.gov Identifier: NCT00870363
• Other Study ID Numbers: 200816535
• First Posted: March 27, 2009
• Results First Posted: February 10, 2017
• Last Update Posted: May 30, 2017
• Last Verified: May 2017

Keywords provided by University of California, Davis:

HIV; HIV positive; Gastrointestinal Associated Lymphoid Tissue (GALT); GALT Immune Reconstruction; treatment naive

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Efavirenz; Reverse Transcriptase Inhibitors; Raltegravir Potassium; Maraviroc; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors