Bone Loss and Immune Reconstitution in HIV/AIDS (BLIR-HIV) (BLIR-HIV)

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Osteoporosis; Bone Loss; Osteopenia
• Intervention / Treatment: Drug: Zoledronic acid

Detailed Description

In a prospective, blinded placebo-controlled randomized trial, treatment naïve HIV-infected subjects initiating HAART will be assigned to HAART + zoledronic acid or HAART + placebo. Serial assessment of serum levels of bone markers, cellular expression of OPG/RANKL and other cytokines, cellular immune activation markers, serum bone regulating hormones, and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) scan will be undertaken at pre-defined time points from baseline through week 144 of HAART.

In the primary analysis, changes in serum C-Terminal Telopeptide (CTx) level, BMD, and cellular OPG/RANKL expression from baseline through week 24 will be quantitated and subsequently compared between treatment arms. In addition, the impact of zoledronic acid administration on these covariates will be assessed at various study time points. The relationship between OPG/RANKL expression, immune activation, serum bone regulating hormonal levels, and bone turnover will be evaluated.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Grady Infectious Diseases Clinic (Ponce Center)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zoledronic acid; Subjects in this arm will receive 5 milligram (mg) per 100 milliliter (mL) solution of zoledronic acid infused intravenously over 15-30 minutes under the supervision of study personnel.	Drug: Zoledronic acid; 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.; Other Names: Reclast
Placebo Comparator: Placebo; Subjects in the placebo arm will receive placebo containing 220 mg mannitol and 24 mg sodium citrate in a 100 mL ready-to-infuse solution administered iv over 15-30 minutes under the supervision of study personnel.	Drug: Zoledronic acid; 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.; Other Names: Reclast

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels	Serum C-terminal telopeptide of collagen (CTx) levels through week 144 were examined by evaluating the baseline-adjusted means. The baseline-adjusted CTx mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at each scheduled clinical visit. The expected outcome is that HIV-infected individuals will display increased indices of bone resorption (CTx) as a result of diminished bone mineral density (BMD). Lower CTx values indicate that better maintenance of bone mineral density.	Baseline, Week 12 through Week 144

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-Adjusted Means of Osteocalcin	Osteocalcin was evaluated to examine the inhibitory effect of single dose zoledronic acid on HAART associated changes in markers of bone turnover. Osteocalcin is released from bone during resorption and higher levels in the circulatory system indicate increased bone turnover. HIV-infected individuals are expected to have increased bone resorption. The baseline-adjusted osteocalcin mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at the Week 144 clinic visit. Baseline-adjusted means of osteocalcin at week 144 are presented.	Baseline, Week 144

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA)	Development of osteoporosis was assessed by examining bone mineral density (BMD) by DXA scan. Baseline-adjusted means of DXA scan Z-scores are presented for the lumbar spine (L1-L4), left hip, and femur neck. The baseline-adjusted BMD mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at the Week 144 clinic visit. Bone density Z-scores tell how close to the average that a person is (adjusted for age, race, and gender). A Z-score of 0 means the value matches that of the average person. Z-score values below 0 indicate lower than average bone density while values above 0 indicate higher bone density than the average person.	Baseline, Week 144

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Mervyn N Weitzmann, PhD, Emory University

Publications and helpful links

General Publications

• Vikulina T, Fan X, Yamaguchi M, Roser-Page S, Zayzafoon M, Guidot DM, Ofotokun I, Weitzmann MN. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13848-53. doi: 10.1073/pnas.1003020107. Epub 2010 Jul 19.
• Ofotokun I, Weitzmann MN. HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture. Curr Opin Endocrinol Diabetes Obes. 2010 Dec;17(6):523-9. doi: 10.1097/MED.0b013e32833f48d6.
• Ofotokun I, Titanji K, Lahiri CD, Vunnava A, Foster A, Sanford SE, Sheth AN, Lennox JL, Knezevic A, Ward L, Easley KA, Powers P, Weitzmann MN. A Single-dose Zoledronic Acid Infusion Prevents Antiretroviral Therapy-induced Bone Loss in Treatment-naive HIV-infected Patients: A Phase IIb Trial. Clin Infect Dis. 2016 Sep 1;63(5):663-671. doi: 10.1093/cid/ciw331. Epub 2016 May 18.
• Ofotokun I, Collins LF, Titanji K, Foster A, Moran CA, Sheth AN, Lahiri CD, Lennox JL, Ward L, Easley KA, Weitzmann MN. Antiretroviral Therapy-Induced Bone Loss Is Durably Suppressed by a Single Dose of Zoledronic Acid in Treatment-Naive Persons with Human Immunodeficiency Virus Infection: A Phase IIB Trial. Clin Infect Dis. 2020 Oct 23;71(7):1655-1663. doi: 10.1093/cid/ciz1027.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): April 13, 2017
• Study Completion (Actual): April 13, 2017

Study Registration Dates

• First Submitted: October 23, 2010
• First Submitted That Met QC Criteria: October 25, 2010
• First Posted (Estimate): October 26, 2010

Study Record Updates

• Last Update Posted (Actual): June 26, 2018
• Last Update Submitted That Met QC Criteria: June 21, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: HIV/AIDS; HAART; Bone loss; Antiresorptive drugs
• Additional Relevant MeSH Terms: Metabolic Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Musculoskeletal Diseases; Bone Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Osteoporosis; Bone Diseases, Metabolic; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: IRB00038739; BLIR-HIV (Other Identifier: Other)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No