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.
by
Ellen S. Chan;
Alan L. Landay;
Todd T. Brown;
Heather J. Ribaudo;
Paria Mirmonsef;
Ighoverha Ofotokun;
M. Neale Weitzmann;
Jeffrey Martinson;
Karin L. Klingman;
Joseph J. Eron;
Carl J. Fichtenbaum;
Jill Plants;
Babafemi O. Taiwo
Objective: Studies exploring the immunologic effects of maraviroc (MVC) have produced mixed results; hence, it remains unclear whether MVC has unique immunologic effects in comparison with other antiretroviral drugs. We sought to determine whether MVC has differential effects compared with tenofovir disoproxil fumarate (TDF) during initial antiretroviral therapy. Design: Prospective study in AIDS Clinical Trials Group A5303, a double-blind, placebo-controlled trial (N=262) of MVC vs. TDF, each combined with boosted darunavir and emtricitabine. Methods: A total of 31 cellular and soluble biomarkers were assayed at weeks 0 and 48. Polychromatic flow cytometry was performed on cryopreserved peripheral blood mononuclear cells. Soluble markers were assayed in plasma using ELISA kits. Analyses were as treated. Results: Analyses included 230 participants (119 in MVC arm and 111 in TDF arm). Over 48 weeks of treatment, no significant differences were detected in declines in markers of inflammation and activation with MVC vs. TDF. A greater CD4 + T-cell count increase (median + 234 vs. + 188 cells/μl, P=0.036), a smaller CD8 + T-cell count decrease (-6 vs. -109 cells/μl, P=0.008), and a smaller CD4 + :CD8 + ratio increase (0.26 vs. 0.39, P=0.003) occurred with MVC. Among participants with a baseline CD4 + :CD8 + ratio less than 1, a smaller proportion of MVC group normalized to a ratio greater than 1 at week 48 (15 and 36%, P < 0.001). Conclusion: MVC resulted in less improvement in the CD4 + :CD8 + ratio driven by greater increase in CD4 + cell count but smaller decline in CD8 + cell count. Changes in soluble or cellular biomarkers of inflammation and immune activation were not different between MVC and TDF.