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Effect of HIV Infection and Highly Active Antiretroviral Treatment (HAART) on Bone Homeostasis (OPG-2)

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ClinicalTrials.gov Identifier: NCT01020045
Recruitment Status : Completed
First Posted : November 25, 2009
Last Update Posted : October 19, 2015
Sponsor:
Collaborator:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
Ighovwerha Ofotokun, Emory University

Study Description
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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:

Advances in HAART have been a huge success story in the management of HIV infection. However, serious metabolic complications including osteoporosis and bone fractures are increasingly been seen with HAART, and the responsible mechanisms remain poorly elucidated.

The skeleton continually regenerates through homeostatic bone remodeling. Osteoclasts the cells responsible for bone resorption form under the influence of the key osteoclastogenic cytokine Receptor- Activator of NF-KB (RANKL). The osteoclastogenic and pro-resorptive activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG). Increase in the ratio of RANKL to OPG accelerates the rate of osteoclastic bone resorption leading to osteoporosis.

The investigators' preliminary studies have now demonstrated that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as observed in human patients. Furthermore, the investigators found that B cell expression of OPG is significantly downregulated, concurrent with a significant upregulation in production of RANKL.


Condition or disease
HIV Infection Osteopenia Osteoporosis

Detailed Description:

The investigators hypothesize that "immunological disruption of B cell number and/or function, may play a key causal role in the bone loss associated with HIV/AIDS, by driving a "switch" from OPG production to overproduction of RANKL". The investigators propose to determine the role of perturbations in B and T cells on OPG and RANKL production and on bone turnover.

This is a cross-sectional analysis of changes in BMD (DXA), and B cell and T cell function in HIV seronegative/seropositive subjects matched by known risk factors for osteoporosis. Serum will be collected for quantitation of total OPG and RANKL, and for biochemical markers of bone turnover (CTx, and TRAP5b), specific and sensitive markers of osteoclast activity, and for osteocalcin and P1NP, specific and sensitive markers of bone formation by commercial ELISAs. Peripheral blood mononuclear cells (PBMC) will be isolated and total and percentage frequency and absolute number (/mL) of B cells (CD19+) and T cells (CD3) and their subsets (CD4 and CD8). B cells (CD19) and T cells (CD3 and CD4 and CD8) will be immunomagnetically purified and OPG and RANKL mRNA and protein production quantitated by RT-PCR and ELISA respectively. As a secondary endpoint, B cells will be fractionated into subsets based on differential expression of the markers CD10, CD21 and CD27 and OPG and RANKL production quantitated by in each subset by intracellular staining and FACS analysis.


Study Design
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Study Type : Observational
Actual Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Effect of HIV Infection and HAART on Bone Homeostasis
Study Start Date : October 2010
Actual Primary Completion Date : May 2013
Actual Study Completion Date : October 2015

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U.S. FDA Resources

Groups and Cohorts
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Group/Cohort
HIV-seropositive, HIV seronegative
No intervention - biologic samples were collected from both HIV positive and HIV negative subjects
Treatment naive subjects
HIV-seropositive subjects naive to antiretroviral therapy. HIV-seronegative subjects otherwise healthy.


Outcome Measures
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Primary Outcome Measures :
  1. To correlate serum and B cell and T cell OPG and/or RANKL production in treatment-naïve HIV-infected patients, with indices of bone turnover and structure and with viral load. [ Time Frame: During entry visit ]

Eligibility Criteria
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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Healthy (HIV sero-negative) volunteers and otherwise healthy antiretroviral treatment naïve HIV-1 sero-positive patients, age >18 years.
Criteria

Inclusion Criteria:

  1. Healthy (sero-negative) volunteers and otherwise healthy treatment naïve HIV-1 sero-positive patient.
  2. Age >30<50 years and segregated into age and gender ranges as described above in section 3.2 (15 subjects per stratification based on Power Test).
  3. Ability and willingness of subject or legal guardian/representative to give written informed consent.
  4. Antiretroviral naivety.
  5. No CD4 T-cell counts requirement.

  6. Absence 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 imperfect
    • Osteomalacia
    • Osteosarcoma
    • Paget's disease
    • Postmenopausal osteoporosis
    • Rheumatoid arthritis
    • Systemic lupus erythematosus

  7. Laboratory values obtained within 90 days prior to study entry:

    • Hemoglobin >9.4 g/dl
    • Creatinine < 2 mg/dl
    • AST (SGOT) < 2 x ULN
    • ALT (SGPT) < 2 x ULN

Exclusion Criteria:

  1. Physical or biochemical evidence or a medical history of malignancy.
  2. 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, bisphosphonates).
  3. The patient is not fully ambulatory.
  4. Pregnancy or breast feeding.

Exclusion criteria are primarily centered on immunological aspects with bone related aspects secondary. This is because in our model immunological function is proximal to bone function. Consequently, use of vitamin D or calcium supplementation will not be exclusion criteria, but will be added as covariates in our analysis.

Contacts and Locations
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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01020045


Locations
United States, Georgia
Grady Infectious Diseases Program Clinic
Atlanta, Georgia, United States, 30308
Sponsors and Collaborators
Emory University
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators
Principal Investigator: Ighovwerha Ofotokun, MD, MSc Emory University
More Information
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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:
Dysregulated B Cell Expression of RANKL and OPG Correlates with Loss of Bone Mineral Density in HIV Infection  This link exits the ClinicalTrials.gov site

Publications of Results:

Responsible Party: Ighovwerha Ofotokun, Associate Professor of Medicine, Emory University
ClinicalTrials.gov Identifier: NCT01020045     History of Changes
Other Study ID Numbers: IRB00027210
R01AR059364-01 ( U.S. NIH Grant/Contract )
First Posted: November 25, 2009    Key Record Dates
Last Update Posted: October 19, 2015
Last Verified: October 2015

Keywords provided by Ighovwerha Ofotokun, Emory University:
HIV
Osteopenia
Osteoporosis

Additional relevant MeSH terms:
Infection
Communicable Diseases
HIV Infections
Acquired Immunodeficiency Syndrome
Osteoporosis
Bone Diseases, Metabolic
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
 Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases