Bone mineral density BMD changes until week 144 in a randomized trial of proteaseinhibitorsparing ve

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Bone mineral density (BMD) changes until week 144
in a randomized trial of protease-inhibitor-spari
ng versus nucleoside-analogue-sparing HAART

• Ann-Brit Eg Hansen, Court Pedersen, Henrik
  Nielsen, Niels Obel, Jan Gerstoft
• Rigshospitalet Copenhagen University Hospital
  Odense University Hospital Aalborg University
  Hospital, Denmark
• A BMD substudy of the SPAR study

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Background

• High prevalence of osteopenia and osteoporosis
  among HIV-infected persons
• Results of prospective studies
• Nolan AIDS 2001, Mondy CID 2003,
• Bolland Clin Endocrinol 2007 - no decline
• Gallant (Gilead 903) JAMA 2004,
• Duvivier AIDS 2009 - initial decline
• Grund (SMART) AIDS 2009 - ongoing decline

Brown et al AIDS 2006, 202165-2174
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• Only few long-term randomized studies with BMD
  measurements at hip and lumbar spine (Gilead 903,
  SMART)

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AIM

• Primary aim
• to compare changes in BMD during 144 weeks in
  HIV-infected patients initiating either
  NA-sparing or PI-sparing HAART
• Secondary aim
• to identify factors associated with changes in
  BMD and with low baseline BMD

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Methodology

• BMD substudy of the investigator-initiated SPAR
  trial
• 104 HAART naive patients randomized to
• lopinavir/ritonavir 533/133 mg BID and efavirenz
  600 mg QD
• or
• zidovudine/lamivudine 150/300 mg BID and
  efavirenz 600 mg QD
• Primary endpoint peripheral fat loss

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BMD substudy

• Patients at 3 of 5 centers had lumbar spine
• and femoral neck BMD evaluated by DEXA
• baseline, week 24, 48, 96 and 144
• All patients with baseline BMD measurements and
  at least one follow-up BMD measurement were
  included
• ITT and on class analyses

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Baseline characteristics
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Percentage change in spine BMD from baseline,
ITT
NA-sparing
PI-sparing
Week 24. NA-sparing -2.7


PI-sparing -3.2 P0.49
Week 144. NA-sparing -2.5


PI-sparing -1.9 P0.67
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Percentage change in hip BMD from baseline, ITT
NA-sparing
PI-sparing
Week 144. NA-sparing -4.5


PI-sparing -5.0 P0.73
Week 48. NA-sparing -5.1


PI-sparing -6.1 P0.49
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Percentage change in spine BMD from baseline,
on class
NA-sparing
PI-sparing
Week 24. NA-sparing -2.3


PI-sparing -3.2 P0.38
Week 144. NA-sparing -0.2


PI-sparing -2.4 P0.18
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Percentage change in hip BMD from baseline, on
class
NA-sparing
PI-sparing
Week 144. NA-sparing -4.8


PI-sparing -4.9 P0.49
Week 48. NA-sparing -5.7


PI-sparing -5.9 P0.87
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Predictors of change in spine BMD at week 24
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Predictors of change in hip BMD at week 24
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Predictors of baseline spine and hip BMD
Multivariable
Univariate
Hip
Multivariable
Univariate
Coef
.
Coef
Coef. (g/cm2)
.
Coef. (g/cm2)
P
-
value
P
-
value
P
-
value
P
-
value
CD4 cell count
CD4 cell count
-
0.003
0.30
-
0.004
0.42
-
-
(square
-
root)
(square
-
root)
BMI per unit
BMI per unit
0.22
0.006
0.55
0.0
0.
0.003
Multivariable analyses adjusted for CD4 cell
count/BMI, age, gender and current smoking
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Limitations

• No power calculations. Many drug discontinuations
• Results may not be valid for other NAs or PIs.
  Could not analyze the potential influence of
  NNRTIs

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Conclusion

• After initiation of HAART, BMD declined during
  the first 24 (spine) to 48 weeks (hip) but
  stabilized thereafter
• Our study provided no evidence for a drug class
  effect on BMD evolution, as decline was
  independent of randomization to NA-sparing or
  PI-sparing arm

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Interpretations

• The initial decline in BMD may be a result of
• delayed reversal of ongoing BMD loss in
  immuno-suppressed individuals
• a bone remodeling transient caused by HAART or
  by HAART induced immune alterations ?
  temporarily imbalance between bone resorption and
  bone formation

Heany RP J Bone Miner Res 1994 91515-23
Aloia JF Osteporos Int 2008 191001-9
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Interpretations

• The initial decline in BMD may be a result of
• delayed reversal of ongoing BMD loss in
  immuno-suppressed individuals
• a bone remodeling transient caused by HAART or
  by HAART induced immune alterations ?
  temporarily imbalance between bone resorption and
  bone formation

Heany RP J Bone Miner Res 1994 91515-23
Aloia JF Osteporos Int 2008 191001-9
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Acknowledgements

• Spar study investigators
• Jan Gerstoft
• Lars Mathiesen
• Court Pedersen
• Niels Obel
• Henrik Nielsen
• Alex Laursen
• Study participants
• Abbott, Denmark
• for an unconditional grant

• Study nurses
• Bente Baadegaard
• Lene Pors Jensen
• Kirsten Bødker
• Phillippa Collins
• Dorthe Pedersen
• Nete Bülow
• Lene Hergens
• Helle Møller
• Anita Nymark
• Iben Rose Loftheim

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Spine, ITT, only completers
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HIP, ITT, only completers
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Treatment discontinuations