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  21st Conference on Retroviruses and
Opportunistic Infections
Boston, MA March 3 - 6, 2014
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Spine/Hip Bone Density Drops More in 96 Weeks With PIs Than With Raltegravir
  CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Hip and spine bone mineral density (BMD) dropped significantly more during 96 weeks of first-line boosted atazanavir or darunavir than with raltegravir, according to results of a randomized ACTG trial [1]. Total body BMD fell more with atazanavir than with darunavir or raltegravir.
BMD drops 2% to 6% in the first 48 to 96 weeks of antiretroviral therapy, ACTG researchers noted, depending on which antiretrovirals a person takes. Greater BMD declines have been linked to tenofovir and protease inhibitors (PIs), but the relative impact of PIs and integrase inhibitors remained unknown until this substudy of ACTG A5257.
This open-label trial recruited nearly 2000 antiretroviral-naive people in the United States and randomized them to once-daily atazanavir/ritonavir, once-daily darunavir/ritonavir, or twice-daily raltegravir, all with tenofovir/emtricitabine [2]. After 96 weeks the raltegravir combination proved superior to atazanavir/ritonavir or darunavir/ritonavir regimens in an endpoint combining virologic efficacy and tolerability. Atazanavir was inferior to raltegravir and darunavir in tolerability (largely because of hyperbilirubinemia), and darunavir was superior to atazanavir in the combined efficacy/tolerability endpoint.
With centrally read DXA scans, the ACTG team measured percentage change in BMD at the lumbar spine, total hip, and total body from baseline to week 96 [1].
Because the substudy also assessed cardiovascular endpoints, the researchers excluded people with cardiovascular disease, diabetes, or lipid-lowering treatment. They used multivariable linear regression to compare percentage change in BMD in the three treatment arms and in the combined PI arms.
The analysis included 109 people randomized to atazanavir, 113 to darunavir, and 106 to raltegravir. Median age across the three groups was about 36, and about 90% of participants in each arm were men. Whites made up 49% of the atazanavir group, 44% of the darunavir group, and 41% of the raltegravir group. Respective proportions of blacks and Hispanics were 31% and 18%, 33% and 22%, and 32% and 19%. Median body mass index was higher in the atazanavir arm (26 kg/m2) than in the other arms (24 kg/m2 in both). Similar proportions across the three arms--36% to 40%--were current smokers. Median pretreatment CD4 count stood around 350 and median viral load at about 35,000 copies.
Average BMD declines from baseline to 96 weeks were statistically significant in all study arms at all sites (P < 0.001). Change in total hip BMD did not differ significantly between the two PI arms (atazanavir -3.9% versus darunavir -3.4%, P = 0.36), but hip BMD fell significantly more in the combined PI arms than in the raltegravir arm (-3.7% versus -2.4%, P = 0.005). Lumbar spine BMD dropped by a similar percentage with atazanavir and darunavir (-4.0% and -3.6%, P = 0.42). And the spine BMD decline in the combined PI arms was greater than the decline with raltegravir (-3.8% versus -1.8%, P < 0.001).
Total body BMD fell significantly more with atazanavir than with darunavir (-2.9% versus -1.6%, P = 0.001) and more with atazanavir than with raltegravir (-2.9% versus -1.7%, P = 0.004). Total body BMD change through 96 weeks did not differ significantly between the darunavir and raltegravir arms (P = 0.72).
The bone analysis also found associations between baseline markers of inflammation and immune activation and more hip BMD loss, independently of CD4 count and viral load.
The ACTG team proposed that the greater 96-week loss in total body BMD with atazanavir/ritonavir than with darunavir/ritonavir "deserves further investigation." The smaller BMD drops seen with raltegravir than with the PIs suggested to the investigators that "raltegravir may have a more neutral effect on bone compared to PIs."
CROI: Bone Density Changes after Antiretroviral Initiation with Protease Inhibitors or Raltegravir - (03/10/14)
1. Brown T, Moser C, Currier J, et al. Bone density changes after antiretroviral initiation with protease inhibitors or raltegravir. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 779LB.
2. Landovitz RL, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 85. http://www.natap.org/2014/CROI/croi_30.htm