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HIV Treatment Interruption Associated with Reduced Bone Loss in SMART Trial

People who stopped antiretroviral therapy (ART) in the SMART trial had less bone loss and lower levels of bone metabolism biomarkers than people who remained on continuous treatment, according to a report in the January 8, 2013, advance edition of Journal of Bone Mineral Research.

Several studies have found reduced bone mineral density (BMD) in people with HIV, but whether this is due to the virus itself, associated metabolic and inflammatory abnormalities, toxicities of antiretroviral drugs, or other factors is not fully understood. Some research shows that a small reduction in bone density occurs soon after starting ART, which then stabilizes and does not worsen over time.

The SMART (Strategies for Management of Antiretroviral Therapy) trial tested the hypothesis that spending less time on ART might reduce non-AIDS conditions that, at the time, were suspected of being linked to drug toxicity. SMART included 5472 HIV positive participants who were randomly assigned to either start treatment immediately and stay on therapy with the aim of maintaining continuous viral suppression, or else to defer or stop treatment while CD4 counts were above 350 cells/mm³, resuming when they fell below 250 cells/mm³.

In brief, the study showed that people who interrupted treatment not only had a higher risk of progression to AIDS or death, but also higher rates of non-AIDS conditions including heart, liver, and kidney disease. Further analysis showed that people who interrupted therapy had higher levels of biomarkers associated with inflammation.

In the present analysis, Jennifer Hoy from Monash University in Melbourne and colleagues compared the effects of continuous versus intermittent ART on biomarkers of bone turnover in the SMART Body Composition Substudy, and looked at whether early changes in these markers predicted subsequent changes in bone density. (This data was previously presented in part at the 13th International Workshop on Adverse Drug Reactions and Comorbidities in HIV in July 2011.) 

The analysis included 202 participants randomized to receive continuous or intermittent ART. Most (83%) were men, 56% were white, 27% were black, and the average age was 44 years. In the continuous treatment group, 68% were on ART at baseline and 47% had HIV viral load < 400 cells/mm³; the rest started therapy and 91% were still on ART at month 12. In the intermittent treatment group, 80% were on ART at baseline and 62% had viral load < 400 cells/mm³; they interrupted ART, but 46% were advised to restart by month 12 due to declining CD4 T-cell counts or clinical events.

BMD was measured annually at the spine using dual X-ray absorptiometry (DXA) and computed tomography, and at the hip using DXA only. Plasma levels of biomarkers of inflammation and bone turnover were evaluated at baseline, month 4, and month 12:

• Markers of bone formation: bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP).
• Markers of bone resorption: cross-linked N-telopeptide of type 1 collagen (NTX), cross-linked C-telopeptide of type 1 collagen (CTX).
• Markers of bone remodeling: osteoprotegerin (OPG), receptor of nuclear factor-kappa-B ligand (RANKL).
• Inflammatory markers: interleukin 1 (IL-1), IL-6, tumor necrosis factor alfa (TNF-alfa).

Results

• People who interrupted treatment had significant decreases in mean levels of both bone formation and bone resorption markers including bALP, osteocalcin, P1NP, NTX, and CTX.
• These same biomarkers increased in the continuous ART group.
• The intermittent ART group had significant increases in RANKL level, RANKL-to-OPG ratio, TNF-alfa, and IL-6.
• These biomarkers decreased in the continuous ART group
• Biomarker changes were apparent by month 4, but thereafter remained stable through month 12.
• Adjustment for sex, ART use at study entry, and baseline CD4 cell count had minimal effect on between-group comparison.
• By month 12, bone density was significantly higher in the intermittent ART group (+0.33% increase at the hip; +1.64% at the spine).
• Conversely, bone density fell in the continuous ART group (-1.04% decrease at the hip; -0.13% at the spine).
• Increased levels of bALP, osteocalcin, P1NP, NTX, and CTX at month 4 predicted decreased hip BMD at month 12.
• Conversely, increases in RANKL and RANKL-to-OPG ratio at month 4 were associated with increased hip and spine bone density at month 12.

"This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months," the researchers concluded.

"Conditions associated with chronic immune activation and inflammation are well known to be associated with increased bone loss (e.g. rheumatoid arthritis and inflammatory bowel disease)," they explained in their discussion. "It is counterintuitive that the increases in RANKL and the [RANKL-to-OPG] ratio in the intermittent ART group occurred in association with reduction in markers of bone resorption and increased BMD."

"It is possible that ART increases bone turnover through a pathway that is not mediated by RANKL or osteoprotegerin, and that the increase in RANKL at cessation of ART occurred as a compensatory response to the reduction in markers of bone turnover," they continued. "Alternatively, the increase in RANKL may be a reflection of increased immune activation and subsequent expression and production of RANKL by activated T-cells associated with untreated HIV infection."

"In conclusion, this study has shown that interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine relative to continuous ART, and that early changes in markers of bone turnover predict BMD changes at 12 months," the authors summarized. "The stabilization of bone loss after ART interruption, despite increased inflammation, suggests a deleterious effect of ART on bone, either directly or indirectly."

"The clinical implication of these findings is unknown given the imperative need for ART to prevent major HIV-related outcomes; once started, ART needs to be used continuously," they cautioned. "The trend to initiate ART earlier in the course of HIV infection means that low BMD may become more prevalent as more patients use ART for longer, highlighting the need for prospective studies with longer follow-up."

1/15/13

Reference

J Hoy, B Grund, M Roediger, et al. Interruption or deferral of antiretroviral therapy (ART) reduces markers of bone turnover compared with continuous therapy: The SMART Body Composition substudy. Journal of Bone Mineral Research. January 8, 2013 (Epub ahead of print).