Bone Loss and Immune Reconstitution in HIV/AIDS (BLIR-HIV)
Condition: HIV Infection; Bone Loss; Osteopenia; Osteoporosis
MeSH terms: HIV Infections; Acquired Immunodeficiency Syndrome; Osteoporosis; Bone Diseases, Metabolic
Intervention: Zoledronic acid
Intervention description: A single dose of reclast containing 5 mg/100 mL ready-to-infuse zoledronic acid solution administered over 15-30 minutes.
A single dose of placebo containing 220 mg mannitol and 24 mg sodium citrate in a 100 mL ready-to-infuse solution, administered over 15-30 minutes.
Intervention MeSH terms: Zoledronic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 63.0
Sex: All
Minimum age: 30 Years
Maximum age: 50 Years
Healthy volunteers: No
Keywords: HAART; Antiresorptive drugs; HIV/AIDS; Bone loss

Summary:

      With the increasing age of people living with HIV/AIDS, age-induced osteoporosis is likely to
      be compounded by HIV/AIDS and HAART-associated bone loss. Mechanistically, osteoclasts the
      cells responsible for bone resorption form under the influence of the key osteoclastogenic
      cytokine receptor activator of nuclear factor kappa-Β ligand (RANKL). The osteoclastogenic
      and proresorptive activities of RANKL are moderated by its physiological decoy receptor
      osteoprotegerin (OPG). Imbalance in the ratio of RANKL to OPG alters osteoclastic bone
      resorption and lead to osteoporosis. Activated T- and B-cells are a major source of RANKL,
      while normal physiological B-cells are a major source of OPG. T-cells regulate the production
      of OPG by B-cells. Thus changes in the immune system induced by HIV/AIDS and/or by HAART
      could affect B-cell and T-cells RANKL and OPG production. Indeed, data from our group shows
      that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of
      osteoporosis is recapitulated as observed in HIV-infected patients, and B-cell OPG and RANKL
      production are concurrently down regulated and upregulated respectively. Furthermore,
      preliminary data in HIV-infected subjects suggests dramatic acute upswing in bone resorption
      following HAART initiation that peaks at 12 weeks and then declines. Based on these findings,
      the investigators hypothesize HAART associated bone loss is driven by immune reconstitution.
      Because this effect of HAART is dramatic in magnitude but short in duration, the
      investigators propose to apply antiresorptive agent (zoledronic acid, reclast®) to
      specifically spare patients from this dramatic but acute bone damage.
    

Eligibility criteria:

        Inclusion Criteria:

          1. HIV-1 infection, as documented by any licensed serologic test and confirmed by a
             western blot or by a positive plasma HIV-1 RNA performed by any laboratory that has a
             Clinical Laboratory Improvement Amendments (CLIA) certification.

          2. Meets Grady Infectious Disease Program (IDP) clinical criteria for antiretroviral
             therapy initiation, and subject and his/her provider are agreeable to subject
             initiating therapy with a regimen consisting of atazanavir (ATV)/ritonavir (RTV) +
             emtricitabine (FTC)/tenofovir (TDF) as part of his/her routine HIV management.

          3. Ambulatory men and women age ≥ 30 ≤ 50 years.

          4. Ability and willingness of subject or legal guardian/representative to give written
             informed consent.

          5. Antiretroviral (ARV) drug-naïve (defined as ≤ 10 days of antiretroviral therapy (ART)
             at any time prior to entry).

          6. Screening HIV-1 RNA ≥ 1000 copies/mL obtained within 90 days prior to study entry by
             any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA
             certification.

          7. Laboratory values obtained within 90 days prior to study entry.

               -  Absolute neutrophil count (ANC) ≥ 500/mm3

               -  Hemoglobin ≥ 8.0 g/dL

               -  Platelet count ≥ 40,000/mm3

               -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
                  phosphatase ≥ 3 x upper limit of normal (ULN)

               -  Total bilirubin ≥ 2.5 x ULN

               -  Calcium ≥ 8.0 mg/dL

               -  Serum vitamin D level ≥ 12ng/mL

               -  Creatinine clearance (CrCl) ≥ 50 mL/min as estimated by the Cockcroft-Gault
                  equation.

          8. Absence of history of non-HIV related active immunological or bone disorders such as:

               -  Bone marrow or organ transplantation

               -  Inflammatory bowel disease (ulcerative colitis, Crohn's disease)

               -  Multiple Myeloma

               -  Osteogenesis imperfecta

               -  Osteomalacia

               -  Osteosarcoma

               -  Paget's disease

               -  Postmenopausal osteoporosis

               -  Rheumatoid arthritis

               -  Systemic lupus erythematosus

               -  Thyroid disorders (hyper/hypothyroidism)

          9. Contraception requirements

               1. Female Subjects of Reproductive Potential:

                  Female subjects of reproductive potential, who are participating in sexual
                  activity that could lead to pregnancy, must agree to use at least one reliable
                  method of contraception while participating in the study. Acceptable methods of
                  contraception include:

                    -  Condoms (male or female) with or without a spermicidal agent

                    -  Diaphragm or cervical cap with spermicide

                    -  Intrauterine device (IUD)

                    -  Hormone-based contraceptive (must contain at ≥ 35 mcg of ethinyl estradiol)

               2. Female Subjects Who Are Not of Reproductive Potential.

        Exclusion Criteria:

          1. Pregnancy or breast feeding

          2. Physical or biochemical evidence or a medical history of malignancy.

          3. Currently (within the past 8 weeks) taking any medication with known influence on the
             immune or skeletal system (e.g. immune modulation therapy, glucocorticoids, steroid
             hormones, other bisphosphonates).

          4. Osteoporosis defined as T-score <-2.5 at the hip, or spine, or history of osteoporotic
             fracture.

          5. Prior or current use of zoledronic acid (reclast®)

          6. Recent (within the past 6 months) or planned (within the next 6 months) invasive
             dental procedure.

          7. Known allergy/sensitivity to study drugs or their formulations or mammalian cell
             derived drug products.

          8. Any condition that, in the opinion of the investigators, would compromise the
             subject's ability to participate in the study.

          9. Serious illness requiring systemic treatment and/or hospitalization until subject
             either completes therapy or is clinically stable on therapy, in the opinion of the
             investigators, for at least 7 days prior to study entry.

         10. Requirement for any current medications that are prohibited with any study drugs.
             Prohibited medications must be discontinued at least 30 days prior to entry.

         11. Current imprisonment or involuntary incarceration in a medical facility for
             psychiatric or physical illness.