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Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.
- Source :
-
PLoS pathogens [PLoS Pathog] 2016 Jan 21; Vol. 12 (1), pp. e1005381. Date of Electronic Publication: 2016 Jan 21 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.
- Subjects :
- Adult
Alkynes
Anti-HIV Agents administration & dosage
Benzoxazines administration & dosage
Chromatography, High Pressure Liquid
Cyclohexanes administration & dosage
Cyclopropanes
Drug Combinations
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination administration & dosage
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
HIV Infections drug therapy
Humans
Lymphocyte Activation drug effects
Male
Maraviroc
Pilot Projects
Raltegravir Potassium administration & dosage
T-Lymphocyte Subsets immunology
Triazoles administration & dosage
CCR5 Receptor Antagonists administration & dosage
HIV Infections immunology
HIV Integrase Inhibitors administration & dosage
Immunity, Mucosal drug effects
T-Lymphocyte Subsets drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 26795282
- Full Text :
- https://doi.org/10.1371/journal.ppat.1005381