Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

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:

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.

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).

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.