Clinical trial NCT01852942: Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
Official title: Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infection
HIV Infections
Keywords: Infection
HIV 1
HIV
Losartan
Fibrosis
Immune Activation
Immune Reconstitution
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Merck Sharp & Dohme LLC
First posted: 2013-05-14
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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:

1. reverse existing lymphoid tissue fibrosis,
2. restore lymphoid tissue architecture,
3. increase the number and improve the function of peripheral and lymphatic CD4 T cells,
4. decrease levels of systemic immune activation (IA),
5. decrease size of the HIV reservoir, and
6. be safe and well tolerated.

Detailed description: 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).

Eligibility criteria: HIV infected participants:

1. Inclusion Criteria:

   Participants must meet all of the following inclusion criteria to participate in this study:
   * HIV-1 infected.

     -≥ 18 years of age.
   * Baseline peripheral CD4+ T cell count 200-600 cells/mm3 for at least two measures over the 6 months prior to study enrollment.

     -≥ 12 months of stable ART, defined as use of a given drug regimen without disruption lasting ≥ 1 week in the period leading up to study enrollment.
   * HIV viral load (VL) \< 50 copies/mL for at least two consecutive measures over the 6 months prior to study enrollment.
   * No contraindication to proposed study procedures.
   * Women of child-bearing potential must be willing to use a form of effective contraception for the duration of the study. Effective contraception includes hormonal injection, implant or oral medication, IUD, diaphragm, or cervical cap with spermicide. Condoms cannot be used as the sole form of contraception.
2. Exclusion Criteria: Participants meeting any of the following exclusion criteria at baseline will be excluded from study participation:

   * Use of any immunomodulator within the 12 months prior to study enrollment. An immunomodulator for the purposes of this study is defined as a drug known to either diminish or augment a patient's immune system. Examples of these include, but are not limited to, systemic corticosteroids (use of topical steroids will be permitted), TNF-inhibitors, rituximab, cyclophosphamide, abatacept,cyclosporine, azathioprine, 6-mercaptopurine, methotrexate, sulfasalazine, cyclosporine, tacrolimus,sirolimus, and intravenous immune globulin.
   * Current use of an ARB or ACEi.
   * Current use of rifaximin, fluconazole or lithium given potential for drug interactions with losartan.
   * Prior reaction or intolerance to an ARB or ACEi.
   * Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence as diagnosed by a primary care physician or specialist. Examples of these include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, mixed connective tissue disease, psoriasis, polymyositis, dermatomyositis, vasculitis, sarcoidosis, Wegener's granulomatosis, giant cell arteritis, polyarteritis nodosa, gastrointestinal pemphigoid, eosinophilic colitis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, and hepatitis C.
   * Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as diagnosed by a primary care physician or specialist (Marfan's syndrome, Ehlers-Danlos syndrome).
   * Baseline blood pressure \< 110/70.
   * Estimated Glomerular Filtration Rate (eGFR) of \< 30ml/min/1.73 m2 within 4 weeks of study initiation or history of advanced renal disease.
   * AST and/or ALT \> 3 times the upper limit of normal within 4 weeks of study enrollment.
   * Potassium \> 5.0 within 4 weeks of study enrollment.
   * Pregnancy.
   * In women of childbearing age, unwillingness to use birth control for the duration of the study.
   * Breast feeding.
   * Prior vaccination with an HPV vaccine, including Cervarix (GlaxoSmithKline) or Gardasil (Merck).
   * History of hypersensitivity or severe allergic reactions to yeast.

HIV-uninfected:

1. Inclusion Criteria

   Participants must meet all of the following inclusion criteria to participate in this study:
   * HIV uninfected.

     -≥ 18 years of age.
   * No contraindication to proposed study procedures.
2. Exclusion Criteria: Participants meeting any of the following exclusion criteria at baseline will be excluded from study participation:

   * Use of any immunomodulator within the 12 months prior to study enrollment (as defined above).
   * Current use of an ARB or ACEi.
   * Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence (as defined above).
   * Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as diagnosed by a primary care physician or specialist (Marfan's syndrome, Ehlers-Danlos syndrome).
   * Pregnancy.

Primary outcomes:
measure: Collagen Deposition in LT
timeFrame: 30 months
measure: Integrity of the Fibroblastic Reticular Cell Network (FRCn)
timeFrame: 30 months
Secondary outcomes:
measure: Frequency of CD4+ T Cells
timeFrame: 30 months
measure: Frequency TUNEL+CD3+CD8+ T Cells
timeFrame: 30 months
measure: Frequency of Cells Expressing TGF-beta and Lymphotoxin-beta
timeFrame: 30 months
measure: Serum Concentration of IL-7
timeFrame: 30 months
measure: Serum Concentration of TGF-beta
timeFrame: 30 months
measure: Immune Response to HPV Vaccination
timeFrame: 30 months
measure: Frequency of Activated T-cell Populations - Immunofluorescent Staining
timeFrame: 30 months
measure: Percent of Activated T Cells in PBMCs - Flow Cytometry
timeFrame: 30 months
measure: Percent of Activated Macrophages in PBMCs - Flow Cytometry
timeFrame: 30 months
measure: Percent of Activated Dendritic Cells in PBMCs - Flow Cytometry
timeFrame: 30 months
measure: Percent of Activated T Cells in LT - Flow Cytometry
timeFrame: 30 months
measure: Percent of Activated Macrophages in LT - Flow Cytometry
timeFrame: 30 months
measure: Percent of Activated Dendritic Cells in LT - Flow Cytometry
timeFrame: 30 months
measure: Intracellular Concentration of IL-17 in PBMCs
timeFrame: 30 months
measure: Intracellular Concentration of IFNg in PBMCs
timeFrame: 30 months
measure: Intracellular Concentration of IL-2 in PBMCs
timeFrame: 30 months
measure: Intracellular Concentration of TNF in PBMCs
timeFrame: 30 months
measure: Intracellular Concentration of IL-10 in PBMCs
timeFrame: 30 months
measure: Intracellular Concentration of GM-CSF in PBMCs
timeFrame: 30 months
measure: Intracellular Concentration of IL-17 in LT
timeFrame: 30 months
measure: Intracellular Concentration of IFNg in LT
timeFrame: 30 months
measure: Intracellular Concentration of IL-2 in LT
timeFrame: 30 months
measure: Intracellular Concentration of TNF in LT
timeFrame: 30 months
measure: Intracellular Concentration of IL-10 in LT
timeFrame: 30 months
measure: Intracellular Concentration of GM-CSF in LT
timeFrame: 30 months
measure: Plasma Concentration of LPS
timeFrame: 30 months
measure: Plasma Concentration of sCD14
timeFrame: 30 months
measure: Plasma Concentration of I-FABP
timeFrame: 30 months
measure: Plasma Concentration of IL-1b
timeFrame: 30 months
measure: Plasma Concentration of IL-1RA
timeFrame: 30 months
measure: Plasma Concentration of IL-6
timeFrame: 30 months
measure: Plasma Concentration of TNF
timeFrame: 30 months
measure: Plasma Concentration of Amyloid A
timeFrame: 30 months
measure: Plasma Concentration of CRP
timeFrame: 30 months
measure: Plasma Concentration of D-dimer
timeFrame: 30 months
measure: Frequency of HIV RNA+ and DNA+ Cells in LN - Radiolabeled ISH
timeFrame: 30 months
measure: Frequency of HIV RNA+ and DNA+ Cells in LN - RNAscopeTM in Situ Technology
timeFrame: 30 months
measure: Frequency of HIV RNA+ and DNA+ Cells in GALT - Radiolabeled in Situ Hybridization (ISH)
timeFrame: 30 months
measure: Frequency of HIV RNA+ and DNA+ Cells in GALT - RNAscopeTM in Situ Technology
timeFrame: 30 months
measure: Concentration of Losartan and Antiretrovirals (ARVs)
timeFrame: 30 months
measure: Intracellular Concentration of Losartan and Antiretrovirals (ARVs)
timeFrame: 30 months
Other outcomes:
measure: Frequency of Dendritic Cell and CD4 T Cell Interactions With the FRCn
timeFrame: 30 months
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota, Division of Infectious Diseases
state: Minnesota
Study officials:
affiliation: University of Minnesota
name: Timothy Schacker, M.D.
role: PRINCIPAL_INVESTIGATOR
References: