title: Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.
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.
authors.affiliation: University Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Serrano-Villar
authors.affiliation: University Hospital La Paz, Madrid, Spain.
authors.forename: Talia
authors.initials: T
authors.lastname: Sainz
authors.affiliation: California National Primate Research Center, Davis, California, United States of America.
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Ma
authors.affiliation: University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Netanya S
authors.initials: NS
authors.lastname: Utay
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America.
authors.forename: Tae
authors.initials: T
authors.lastname: Wook-Chun
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Surinder
authors.initials: S
authors.lastname: Mann
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: Rush University, Chicago, Illinois, United States of America.
authors.forename: Basile
authors.initials: B
authors.lastname: Siewe
authors.affiliation: Veterans Administration Northern California Health Care System, Mather, California, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Albanese
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Troia-Cancio
authors.affiliation: University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.affiliation: University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Anoma
authors.initials: A
authors.lastname: Somasunderam
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Tammy
authors.initials: T
authors.lastname: Yotter
authors.affiliation: University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Rush University, Chicago, Illinois, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Landay
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
authors.affiliation: California National Primate Research Center, Davis, California, United States of America.|University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: University Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Asmuth
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage; D048588:Benzoxazines / Q000008:administration & dosage; D065100:CCR5 Receptor Antagonists / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid; D003510:Cyclohexanes / Q000008:administration & dosage; D003521:Cyclopropanes; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D000077592:Maraviroc; D010865:Pilot Projects; D000068898:Raltegravir Potassium / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D003521:Cyclopropanes; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D019428:HIV Integrase Inhibitors; D014230:Triazoles; D000068898:Raltegravir Potassium; C098320:efavirenz; D000077592:Maraviroc