Antiretroviral Therapy and Bone Loss in HIV-Infected Individuals 公开

Abstract

Background: Close to 6% loss in bone mineral density (BMD) is observed early on (1-2 years) with antiretroviral therapy (ART) - a loss that has recently been proposed to stem from ART-induced disease reversal and immune reconstitution. To validate this hypothesis we investigated the effect on the skeleton of an ART-regimen switch at the later phase of therapy in virologically suppressed patients with stable CD4 T-cell counts. The new regimen contained raltegravir (RAL), a new generation antiretroviral. We further investigated the direct actions on the skeleton of RAL in a murine model.

Methods: Longitudinal skeletal profiling was performed on a cohort of chronically treated virologically suppressed HIV-infected patients undergoing a regimen switch to lopinivir/ritonavir (LPV/r)+RAL. Plasma levels of C-terminal telopetide of collagen (CTx), a marker of bone resorption, osteocalcin (OCN), a marker of bone formation, receptor activator of NF-kB ligand (RANKL), the key osteoclastogenic cytokine, and osteoprotegerin (OPG), a RANKL moderator were quantified using ELISAs. BMD was quantified by dual energy X-ray absorptiometry (DXA). In a complimentary animal study, C57BL6 female mice were randomized to treatment with RAL or control group. BMD was measured every 4 weeks for 12 weeks at which time the mice were sacrificed for plasma CTx and OCN quantitation using ELISA.

Results: 29 patients were evaluated, median time on ART was 3.9 years, 69% male, 79% African Americans, 21% whites, and pre-study ART consisted of 2 nucleoside reserve transcriptase inhibitors (NRTI) + either a non-NRTI (38%) or a protease inhibitor (62%). Plasma levels of resorption, CD4 T-cell counts, and BMD were stable during the study. However, there was 26.2% ↓ (p=0.002) from baseline in plasma OCN. When RAL was administered to mice (n=15/group), BMD was markedly reduced by week 8 (5.3% ↓ lumbar spine, p=0.040; 2.6% ↓ femur, p=0.0002). These differences were consistent with a decline in bone formation (OCN 82% ↓, p=0.001).

Conclusions: These results suggest that bone resorption is stable beyond the early T cell reconstitution period. However, an incidental suppression of bone formation was identified. Interestingly, data from the animal study suggest that this suppression may be related to the RAL component of the switch regimen. Further corroborative studies in human are warranted.

Table of Contents

TABLE OF CONTENTS

List of Tables and Figures ..................................................................... i

Introduction ....................................................................................... 1

Background ....................................................................................... 3

Materials and Methods ......................................................................... 6

A. Clinical Study ................................................................................. 6

B. Animal Study .................................................................................. 9

Results ............................................................................................. 11

A. Clinical Study ................................................................................. 11 B. Animal Study ................................................................................. 13

Discussion ......................................................................................... 14

Conclusions ....................................................................................... 19

References ........................................................................................ 20

Tables and Figures .............................................................................. 24

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Pharmacology Health Sciences, Medicine and Surgery Health Sciences, Epidemiology
关键词	HIV ART Bone
Committee Chair / Thesis Advisor	Ofotokun, Igho, Emory University Weitzmann, M Neale, Emory University
Committee Members	Bruce, Beau Benjamin, Emory University Klein, Mitchel, Emory University

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