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

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.

Tenofovir exposure in utero and linear growth in HIV-exposed, uninfected infants

“…[26, 27] Although severe immune reconstitution inflammatory syndrome (IRIS) is not common in pregnancy, the fetal effects of maternal immune reconstitution during pregnancy (particularly among women with advanced disease initiating potent ART) are not clear. The risk of ART-related bone resorption in HIV-infected adults appears to be highest among those initiating treatment at advanced disease stages,[6, 28] and a similar relationship may exist between disease severity at ART initiation in pregnancy and subsequent infant health outcomes. HIV disease severity is also associated with increased risk of maternal cytomegalovirus (CMV) reactivation, which increases the risk for congenital CMV and in turn, growth restriction.…”

The protease inhibitors and HIV-associated bone loss

“…Recently, our group examined bone turnover in treatment naïve HIV-infected patients initiating cART. We observed a surge in bone resorption, starting as early as 2 weeks after cART initiation and lasting through 24 weeks [68**]. Because T-cell recovery with cART reaches a significant magnitude by 12 weeks [69], the time point at which we observed a peak in bone resorption, we speculated that there was a link between immune reconstitution and cART-induced bone loss [68**].…”

“…We observed a surge in bone resorption, starting as early as 2 weeks after cART initiation and lasting through 24 weeks [68**]. Because T-cell recovery with cART reaches a significant magnitude by 12 weeks [69], the time point at which we observed a peak in bone resorption, we speculated that there was a link between immune reconstitution and cART-induced bone loss [68**]. Using an animal model of immune reconstitution created by adoptive transfer of T-cells into T-cell knock-out mice, we demonstrated that immune reconstitution did indeed result in a profound loss in BMD via activation of T-cells and/or other immune cells leading to RANKL and/or tumor necrosis factor-alpha (TNF-α) production [70*].…”

A Single-dose Zoledronic Acid Infusion Prevents Antiretroviral Therapy–induced Bone Loss in Treatment-naive HIV-infected Patients: A Phase IIb Trial

“…Pilot data from a study of treatment-naive HIV-infected patients on therapy for 24 weeks with lopinavir/ritonavir + TDF/ FTC [14] form the basis for estimating sample size. Assuming an increase on average of 1.2 µg/L for CTx in the active placebo arm and on average no change in the ZOL arm and an estimated standard deviation in each group of 1.4 µg/L, a sample size of 30 patients per treatment arm achieves 90% power to detect a treatment difference of 1.2 µg/L in CTx between active placebo and ZOL at 24 weeks if the true difference between treatments is 1.2 µg/L (2-sided, 2-sample equal-variance t test and α = .05).…”

“…To better understand the mechanism underlying this phenomenon, we previously examined bone turnover in HIVinfected patients initiating ART, and observed a surge in bone resorption, starting as early as 2 weeks and lasting through 24 weeks [14]. Because T-cell recovery with ART reaches a significant magnitude by 12 weeks [15], the time point at which we observed a peak in bone resorption, we speculated that there was a link between immune reconstitution and ART-induced bone loss.…”