Back HIV-Related Conditions Bone Loss CROI 2012: Switching to Tenofovir Increases Bone Turnover, Raltegravir Can Improve Bone Density

CROI 2012: Switching to Tenofovir Increases Bone Turnover, Raltegravir Can Improve Bone Density

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HIV positive people who substituted tenofovir (Viread) for zidovudine (AZT; Retrovir) in their antiretroviral regimen showed elevated levels of biomarkers associated with bone turnover and decreased bone mineral density (BMD), researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last month in Seattle. A related study found that switching from tenofovir to raltegravir (Isentress) led to increases in bone density.

People with HIV are more likely to have low bone density -- osteopenia or more severe osteoporosis -- compared with the general HIV negative population. The reasons for bone loss in this group are not fully understood, but may include chronic viral infection itself, HIV-related inflammation or metabolic changes, immune dysfunction, and/or side effects of antiretroviral therapy (ART).

Switch to Tenofovir

Aoife Cotter from University College Dublin School of Medicine and fellow investigators with the PREPARE trial evaluated the impact on bone metabolism when people switched from zidovudine to tenofovir. Tenofovir has been linked to bone loss in some studies, but data have been inconsistent.

Zidovudine is an older antiretroviral drug associated with side effects including anemia, peripheral neuropathy, and mitochondrial toxicity. Tenofovir, now one of the most widely used antiretroviral agents, is generally well-tolerated and is a component of the once-daily single-tablet regimens Atripla (tenofovir/emtricitabine/efavirenz) and Complera (tenofovir/emtricitabine/rilpivirine).

The PREPARE bone biomarker sub-study included 54 HIV positive individuals who had been on a first-line ART regimen containing zidovudine and lamivudine (3TC; Epivir) for more than 2 years and had fully suppressed viral load for more than 6 months. Within this group, 24 people stayed on zidovudine/lamivudine and 30 switched to tenofovir/emtricitabine.

Most participants (about 85%) were men, 75% were white, and the median age was approximately 46 years. They had been on zidovudine/lamivudine for about 5 years on average. At baseline all had HIV RNA < 50 copies/mL and the median CD4 T-cell count was nearly 500 cells/mm3.

Over 48 weeks, the researchers used an electrochemiluminescence immunoassay (ECLIA) to assess serum levels of CTX-1 (type 1 collagen cross-linked C-telopeptide), a biomarker of bone resorption, and osteocalcin and P1NP (pro-collagen type 1 N-terminal propeptide), 2 markers of bone formation. A subset of participants also underwent dual-energy X-ray absorptiometry (DEXA) scans of the femoral neck (hip joint) and lumbar spine.

Normally bone formation and resorption are tightly coupled leading to stable BMD, Cotter explained, but formation or resorption may get out of balance for various reasons. Increased bone metabolism, or turnover, is associated with reduced bone density.

Results

  • CTX-1 levels were significantly higher at baseline in the tenofovir/emtricitabine group, and the difference increased over time; CTX-1 levels rose significantly in the tenofovir/emtricitabine group but remained stable in zidovudine/lamivudine group.
  • Osteocalcin levels were similar at baseline and increased significantly in the tenofovir/emtricitabine group, while remaining stable in the zidovudine/lamivudine group.
  • P1NP levels also became significantly higher in tenofovir/emtricitabine switch group and again remained stable in the zidovudine/lamivudine group.
  • At 48 weeks, BMD of the femoral neck stayed about the same in the zidovudine/lamivudine group (+0.14%) while falling in the tenofovir/emtricitabine group (-1.52%), but the difference was not statistically significant.
  • BMD of the lumbar spine decreased more in the zidovudine/lamivudine group than in the tenofovir/emtricitabine group (-0.18 vs -2.04, respectively), which was a significant difference.
  • Bone biomarker levels were correlated with changes in BMD, significantly so for osteocalcin and P1NP (but not for CTX-1). 
  • In a multivariate analysis, switching to tenofovir/emtricitabine was independently associated with larger increases in all 3 biomarkers after adjusting for demographic factors.

Based on these findings, the researchers concluded, "In virologically suppressed patients on ART a switch to [tenofovir/emtricitabine] is associated with increases in bone turnover," which "correlated with reduction in lumbar spine (but not femoral neck) BMD."

Cotter noted that it is not yet known whether these changes in bone biomarkers and BMD will impact the overall risk of fractures in this population. Furthermore, it is not clear whether these changes reflect a direct effect of tenofovir on the bone or perhaps an indirect effect related to kidney dysfunction.

During the discussion following the presentation, it was suggested that early changes in bone biomarkers might help determine which patients are likely to experience clinically relevant bone loss after starting tenofovir.

Switch to Raltegravir

Mark Bloch and fellow investigators with the Australian TROP study looked at bone outcomes among people who switched from tenofovir to the HIV integrase inhibitor raltegravir, which has not been linked to bone problems in studies to date.

This open-label, non-randomized study included 37 participants with osteopenia or osteoporosis (spine or femoral neck T-scores of -1.0 or less) who had undetectable viral load for at least 3 months on a stable ART regimen that included tenofovir and a ritonavir-boosted protease inhibitor.

Almost all (97%) were men, 84% were white, the average age was 49 years, and they had been HIV positive for nearly 15 years on average. About one-third were current smokers and another third were ex-smokers. The average time on tenofovir was 3 years.

Participants switched from tenofovir to raltegravir while remaining on the same boosted protease inhibitor. The primary endpoint was change in BMD, assessed by DEXA, from baseline to 48 weeks after the switch. The researchers also measured biomarkers including osteocalcin, N-telopeptide (another bone resorption marker), bone alkaline phosphatase, and 25OH vitamin D.

Results

  • BMD showed significant increases at 48 weeks:
    • Spine: +1.5%;
    • Femoral neck: +2.1% (left hip) to +2.3% (right hip);
    • Total hip: +2.5% (left) to +2.7% (right).
  • Levels of osteocalcin, N-telopeptide, and bone alkaline phosphataseall decreased significantly at weeks 24 and 48.
  • No participants sustained fractures during the study.
  • Week 48 "FRAX" prediction scores indicated a modest decrease in the 10-year probability of hip fractures, though no significant decrease in probability of major osteoporotic fractures.
  • No serious adverse events were reported during the study period.
  • 2 participants discontinued treatment, 1 due to increased pill burden with raltegravir and 1 due to an adverse event; both experienced HIV rebound.

These findings led the researchers to conclude, "Switching to raltegravir from [tenofovir] in virologically suppressed HIV-infected adults stable on [ritonavir-boosted protease inhibitors] with low BMD results in significant improvements in BMD in both hip and spine at 48 weeks."

"There is additionally a significant reduction in bone turnover markers by 24 weeks as measured by N-telopeptide, osteocalcin, and bone alkaline phosphatase levels," they continued.

They cautioned, however, that this study was limited by the absence of randomization and the short duration of treatment after the switch.

4/10/12

References

A Cotter, S Vrouenraets, J Brady, et al. Impact of Switching from Zidovudine/Lamivudine to Tenofovir/Emtricitabine on Bone Mineral Density and Bone Metabolism in Virologically Suppressed HIV-1+ Patients: A Sub-study of the PREPARE Study. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 125LB.

M Bloch, W Tong, J Hoy, et al. Improved Low BMD and Bone Turnover Markers with Switch from Tenofovir to Raltegravir in Virologically Suppressed HIV-1+ Adults at 48 Weeks: The TROP Study. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 878.