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and Hepatitis.com Coverage of the
18th Conference on Retroviruses and
Opportunistic Infections (CROI 2011)
February 27 - March 2, 2011, Boston, MA
Is Bone Loss Related to Immune Reconstitution in People on ART?
A growing body of evidence indicates that HIV positive people are prone to osteoporosis, or loss of bone mineral density, but it is not fully understood whether this is due to HIV infection itself, resulting inflammation, antiretroviral drugs, or some combination of these and possibly other factors.
Some studies find that bone loss occurs after starting HIV treatment, leading researchers to propose that it may be a side effect of ART in general or of specific drugs such as tenofovir (Viread, also in the Truvada and Atripla combination pills). Most research has looked at bone loss over time, however, and there is little data about changes immediately after starting therapy.
Ighovwerha Ofotokun from Emory University in Atlanta and colleagues conducted human and animal studies to evaluate when ART-related bone loss occurs and what might be contributing factors.
Since inflammation, T-cell activation, and altered cytokine production are known to contribute to bone loss in many diseases, the investigators prospectively analyzed changes in serum levels of RANKL (receptor activator of NF-kappa-B ligand), CTx (cross-linked C telopeptide of type I collagen), TNF-a (tumor necrosis factor-alpha), and osteocalcin at the start of treatment and after 2, 12, and 24 weeks on ART.
Activated T-cells produce RANKL, which stimulates osteoclasts, the cells that break down bone and promote resorption of its calcium and other minerals, the researchers noted as background; elevated levels are a marker of bone loss. A protein called osteoprotegerin binds to RANKL and thereby protects against bone loss. In contrast, osteocalcin is a protein produced by osteoblasts, the cells that build bone. CTx is a biomarker of collagen breakdown and bone resorption that is used to help diagnose osteoporosis.
The first analysis included 20 treatment-naive HIV positive men (average age 40 years) starting ART for the first time. After starting therapy they experienced an average CD4 T-cell gain of about 120 cells/mm3 and all but 1 achieved undetectable viral load by week 24.
The researchers then sought to evaluate the effects of T-cell reconstitution on bone loss in an animal model. They used TCRb knockout mice genetically engineered to lack specific T-cell receptors, and mimicked T-cell recovery on ART by introducing CD3 T-cells through adoptive transfer.
The researchers concluded that ART-related bone loss begins earlier than previously suspected after treatment initiation, driven at least in part by T-cell activation and reconstitution.
The dramatic and unexpected early surge in bone resorption immediately after ART initiation was similar to changes seen in women at menopause, Ofotokun said. Although the data are not yet fully analyzed, he noted that there appears to be a correlation between extent of bone resorption and magnitude of CD4 cell gains -- an interesting finding in light of other recent research showing a link between bone loss and low nadir CD4 cell count.
The researchers plan to conduct further analyses to see whether use of tenofovir is associated with greater bone loss. Understanding early bone loss after beginning ART might lead to pre-emptive therapies to prevent or ameliorate it, Ofotokun suggested.
Investigator affiliation: Emory University, Atlanta, GA.