Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
This study was designed to test the hypothesis that treatment of HIV infected subjects with losartan, an agent with specific anti-inflammatory and anti-fibrotic actions, will:
- reverse existing lymphoid tissue fibrosis,
- restore lymphoid tissue architecture,
- increase the number and improve the function of peripheral and lymphatic CD4 T cells,
- decrease levels of systemic immune activation (IA),
- decrease size of the HIV reservoir, and
- be safe and well tolerated.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV|
- The primary endpoint is to determine the impact of losartan treatment on lymphoid tissue (LT) fibrosis. [ Time Frame: 30 months ] [ Designated as safety issue: No ]This will be determined by measuring the amount of collagen deposition in LT and the integrity of the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA). LT will be obtained at baseline, month 12 and month 30.
- We will assess the impact of losartan on immune reconstitution and function. [ Time Frame: 30 months ] [ Designated as safety issue: No ]
This will be determined by measuring:
- Frequency of CD4+ T cells, TUNEL+CD3+CD8+ T cells and cells expressing TGF-beta and lymphotoxin-beta in LT using IHC.
- Serum levels of IL-7 and TGF-beta using ELISA.
- The immune response to HPV vaccination using flow cytometry to identify cells stimulated by specific HPV peptides.
- We will determine the impact of losartan on immune activation in HIV infected, treated individuals. [ Time Frame: 30 months ] [ Designated as safety issue: No ]
This will be determined by measuring:
- Frequency of activated T-cell populations (specifically CD3+CD4+CD38+, CD3+,CD8+CD38+,CD4+Ki67+ and CD8+Ki67+ T cells) in LT using immunofluorescence staining.
- Percentage of activated T cells, macrophages and dendritic cells in PBMCs and LT using flow cytometry.
- Intracellular levels of the inflammatory cytokines IL-17, IFNg, IL-2, TNF, IL-10, and GM-CSF in PBMCs and LT using cytokine staining.
- Plasma levels of additional inflammatory markers including LPS, sCD14, I-FABP, IL-1b, IL-1RA, IL-6, TNF, amyloid A, CRP, and D-dimer using limulus assay (sCD14) and ELISA (all others).
- We will assess the potential for losartan to reduce the size of the viral reservoir. [ Time Frame: 30 months ] [ Designated as safety issue: No ]This will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in LN and GALT using both radiolabeled in situ hybridization (ISH) and RNAscopeTM in situ technology.
- We will assess for any potential drug-drug interactions between losartan and antiretrovirals (ARVs). [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
This will be determined by:
- Performing an intensive pharmacokinetics experiment in all HIV infected subjects at month 1 of the study (when losartan is at steady state).
- Measuring levels of ARVs and losartan in plasma and peripheral blood mononuclear cells (PBMCs) quarterly over the 30-month study period.
- Measuring intracellular levels of losartan and ARVs in LT at month 30.
- As an exploratory endpoint, we will determine the impact of losartan on frequency of dendritic cell and CD4 T cell interactions with the FRCn. [ Time Frame: 30 months ] [ Designated as safety issue: No ]This will be determined using two-photon microscopy in sections on LN obtained from study subjects. Given that this is an exploratory endpoint, these assays will be performed in a subset of subjects (5 losartan treated, 2 placebo treated and 5 HIV uninfected controls).
|Study Start Date:||September 2014|
|Estimated Study Completion Date:||July 2018|
|Estimated Primary Completion Date:||July 2018 (Final data collection date for primary outcome measure)|
We will start with 50 mg of losartan by mouth daily. We will increase the dosage to 100 mg by mouth daily after 14 days. The maximal tolerable dosage (up to 100mg by mouth daily) will be continued for a total of 30 months.
Other Name: Cozaar
|Placebo Comparator: Sugar Pill||
one tablet by mouth daily
This is a randomized, double-blind, placebo-controlled trial of 50 HIV-1 infected individuals on stable ART randomized in a 1:1 ratio to losartan (50 mg orally daily titrated to 100 mg daily) vs placebo for 30 months. We plan to enroll a total of 63 HIV infected subjects to ensure that 50 complete the protocol. All HIV infected subjects will undergo biopsies of inguinal lymph node (LN) and gut associated lymphatic tissue (GALT) for primary endpoint analysis at baseline, 12 and 30 months after study enrollment. Blood will be collected at least quarterly throughout the study and an intensive blood pharmacokinetic (PK) study will be conducted at month 1. All HIV infected subjects will be vaccinated with the quadrivalent human papillomavirus (HPV) vaccine at months 23, 25 and 29.5 to measure immune function. 5 HIV uninfected control subjects will also be enrolled.
The primary endpoint is to determine the impact of losartan on lymphoid tissue fibrosis in HIV infected, ART treated adults. This will be determined by measuring the amount of collagen deposition in lymphoid tissues and the integrity of the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01852942
|Contact: Ann Thorkelson, RNfirstname.lastname@example.org|
|United States, Minnesota|
|University of Minnesota, Division of Infectious Diseases||Recruiting|
|Minneapolis, Minnesota, United States, 55455|
|Contact: Ann Thorkelson, RN 612-625-7472 email@example.com|
|Principal Investigator: Timothy Schacker, M.D.|
|Sub-Investigator: Gregory Beilman, M.D.|
|Sub-Investigator: Cavan Reilly, Ph.D.|
|Sub-Investigator: Jeffrey Chipman, MD|
|Sub-Investigator: Jason Baker, MD|
|Sub-Investigator: Brian Fife, PhD|
|Sub-Investigator: Courtney Fletcher, PharmD|
|Sub-Investigator: Daniel Douek, MD, PhD|
|Sub-Investigator: Richard Koup, MD|
|Sub-Investigator: Jacob Estes, PhD|
|Principal Investigator:||Timothy Schacker, M.D.||University of Minnesota - Clinical and Translational Science Institute|