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Author Notes:

Address Correspondence to: Ighovwerha Ofotokun, Infectious Diseases, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303; Tel: (404) 616-0659; Fax: (404) 616 0592; iofotok@emory.edu. M. Neale Weitzmann, Division of Endocrinology & Metabolism & Lipids, Emory University School of Medicine, 101 Woodruff Circle, 1305 WMRB, Atlanta Georgia 30322-0001. Tel: (404) 727-1389; Fax: (404) 727-1300; mweitzm@emory.edu.

Ighovwerha Ofotokun and M. Neale Weitzmann have contributed equally to this work as lead investigators.

I.O. and M.N.W were involved in the study conception, design, and implementation, and writing of the manuscript.

K.T, A.V, S.R.P, T.V performed all the experiments and were involved in data analysis.

F.V., K.R., A.N.S, C.D.L, J.L.L were involved in study conception, design, and significant editing of the manuscript.

The authors thank Dr. Max Cooper (Emory University) for critical reading of the manuscript and helpful suggestions.

The authors gratefully acknowledge services provided by the Emory Center for AIDS Research (CFAR) funded though NIAID (P30AI050409) and the Atlanta Clinical and Translational Science Institute (ACTSI), funded though the National Center for Advancing Translational Sciences (UL1TR000454).

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Infectious Diseases
  • Virology
  • antiretroviral therapy
  • bone loss
  • immune reconstitution osteoporosis
  • RANKL
  • TNF alpha
  • osteoporosis
  • ART
  • HAART
  • cART
  • osteoclasts
  • T cells
  • B cells
  • HIV

Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection

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Journal Title:

AIDS

Volume:

Volume 30, Number 3

Publisher:

, Pages 405-414

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Objective: Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV-infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4+ T cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNFα by immune cells, driving enhanced bone resorption and loss in bone mineral density. Design: To confirm these findings in humans, we investigated the early kinetics of CD4+ T cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study. Methods: Clinical data and blood sampling for HIV-RNA PCR, CD 4+ T cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naïve HIV-infected subjects initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART. Results: C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (α<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators (RANKL and TNFα). Importantly, the magnitude of CD4+ T cell recovery correlated significantly with CTx (Rs=0.387, α=0.01). Conclusions: Our data suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain the skeletal decline common to all ART.

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