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ARTs Cause Bone Loss
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Bone mineral density (BMD) changes until week 144 in a randomized trial of protease-inhibitor-sparing versus nucleoside-analogue-sparing HAART
"Both HIV and antiretroviral therapy have been associated with bone loss. In Hansen's study from Demark, HIV positive individuals were randomized to receive lopinavir/ritonavir and efavirenz or zidovidune/lamivudine and efavirenz . There were significant bone losses (particularly during the first 24 to 48 weeks of the study) independently of what the patients were receiving for treatment." And at baseline in these trestment-naÏve patients there was 40-50% osteopenia & 14% osteoporosis.
Reported by Jules Levin
5th IAS Capetown July 19-22 2009
from Jules: This study in Denmark looked performed bone dexas in 60 HIV+ treatment naives who were randomized to a nuke-sparing regimen (EFV/kaletra) or PI sparing (azt/3TC/EFV). Of note at baseline average age was ONLY 41-44 yrs old but already 40-50% had osteopenia and 14% had osteoporosis showing high rates of osteopenia/osteoporosis in HIV+ individuals before starting HAART and this could be due to HIV itself causing bone loss and high rates of traditional risk factors among HIV+ individuals. After starting HAART there was an immediate decline in bone mineral density from baseline in both spine and hip. At week 24 there was a -2.7% reduction in BMD in the nuke=sparing regimen and a -3.2% reduction in the PI-sparing regimen. After 144 weeks the nuke=sparing regimen showed a -2.5% reduction in spine BMD so the initial reduction at week 24 remained the same. In the PI-sparing regimen the week 144 reduction was -1.9%. So the reductions appeared to worse at week 144 then they were at week 24. A similar trend occurred regarding bone mineral density loss in the hip. At week 48 there was a -5.1% BMD loss in the nuke-sparing regimen & a -6.1% loss in the PI-sparing regimen. And at week 144 the losses were -4.5% in the nuke sparing & -5.0% in the PI-sparing so after week 48 the loss in BMD at the hip also appeared to stay the same. THERE WAS NO difference in bone loss between the 2 regimens EFV/Kaletra or AZT/3TC/EFV so THIS study did not sort out bone loss by ART class, for example, bone loss due to PIs, NRTIs, or NNRTIs. At this meeting there was a study reporting that EFV can lower Vitamin D levels and there were 2 case reports recently in AIDS journal. The mechanism of action may be the p450 affect of EFV, and the PI affect on p450 may be different than NNRTIs but this has not been studied yet. So it appears reasonable at this time to presume both PIs and NNRTIs may affect Vitamin D levels and this may drive bone loss until disproven. The affect of nukes are by a different mechanism. TDF is associated with bone loss but AZT has been found to also be associated with bone loss. d4T and ddI may cause bone loss through other mechanisms, I recall in the Gilead 903 study that bone loss occurred equally for patients whether they recd d4T or TDF. I don't think we have data yet on abacavir which perhaps won't cause bone loss. But the mechanism for nukes d4T, AZT & ddI could be lactic acidosis and mitochondrial toxicity. Studies on all these questions have not adequately been performed so we need better research and evidence to understand these issues. I have repeatedly spoken with the ACTG & NIAID to get them to do these studies but we still don't have clear answers. Perhaps studies in HIV-negatives in specific drugs could help.
Presented by Ann-Brit Eg Hansen (Denmark).
A.-B.E. Hansen1, C. Pedersen2, H. Nielsen3, N. Obel1, J. Gerstoft1
1Rigshospitalet, Copenhagen University Hospital, Department of Infectious Diseases, Copenhagen, Denmark, 2Odense University Hospital, Department of Infectious Diseases, Odense, Denmark, 3Aalborg University Hospital, Department of Infectious Diseases, Aalborg, Denmark
Background: Studies have shown BMD loss following HAART initiation; however data on long-term consequences of ongoing HAART treatment on BMD are not consistent.
Methods: We performed DEXA-scans to evaluate lumbar spine and femoral neck (hip) BMD changes compared with baseline at week 24, 48, 96, and 144 in 60 HAART-naÏve patients randomized to lopinavir/ritonavir and efavirenz (nucleoside-analogue-sparing arm) or zidovidune/lamivudine and efavirenz (protease-inhibitor-sparing arm). We used univariate and multivariate linear regression to evaluate predictors of BMD loss during the first 24 weeks.
Results:
At baseline, median spine BMD was 1.08 and hip BMD was 0.91 g/cm2. 55% had DEXA-defined osteopenia or osteoporosis. Baseline median CD4 count was 185 cell/µl, age was 42, and BMI was 21.9, 88% were men.
Median (interquartile range) changes in spine BMD were -0.034 (-0.054 to -0.007) at week 24, -0.023 (-0.053 to -0.006) at week 48, -0.020 (-0.040 to 0.004) at week 96, and -0.024 (-0.047 to 0.005) at week 144.
Median changes in hip BMD were -0.028 (-0.048 to -0.020) at week 24, -0.049 (-0.086 to -0.024) at week 48, -0.039 (-0.065 to -0.014) at week 96, and -0.033 (-0.067 to -0.0150) at week 144.
Low baseline CD4 count was a predictor of spine (p=0.01) and hip BMD loss (p=0.02) and low BMI was associated with hip BMD loss (p=0.01) at week 24.
Treatment arm did not influence lumbar spine (p= 0.70) or hip BMD loss (p=0.55). Age and smoking were not associated with changes in BMD. P-values reported for multivariate analyses.
Conclusions: After initiation of HAART, spine and hip BMD declined during the first 24 to 48 weeks independently of randomization to nucleoside-analogue-sparing versus protease-inhibitor-sparing arm, but BMD stabilized thereafter. The initial decline in BMD may be a result of delayed reversal of ongoing BMD loss in immuno-suppressed individuals.
Patients in the study were mainly white males with a median Cd4 cell count 190 cells/ml and a median age of 42 years. More than half of the patients had'osteopenia or osteopororsis as defined by a'te score (42%) had DEXA-defined osteopenia and 8 (14%) had osteoporosis. There were no significant differences between groups
Consistent with the patters seen in Gilead 0903. Data on the influende of Pis on BMD have been conflicting, the Hippocamoe found larger decrease in the PI containing arn arm while the ACTG 5125 trial did not. Decline was independent of randomization to NA-sparing or PI-sparing arm.
Results regarding the influence Pis on BMD have been conflicting but our study provide no evidence for a gereral drug class effect on BMD loss. If it was simply a deleyed reversal of ongoing loss a association between low baseline BMD and greater BMD loss during the first 24 to 48 weeks should be expected but was not seen
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