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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
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Reported by Jules Levin
CROI 2012 March 5-8 Seattle, WA
Study Authors Summarized:
- in virologically suppressed patients on ART, a switch to TDF/FTC is associated with increases in bone turnover.
- Changes in bone turnover correlate with reductions in lumbar spine (but not femoral neck) BMD.
- The impact of these changes on future risk for fracture is unknown.
Longitudinal studies are required toanswer this question.
- whether this is a direct effect of TDF on bone or an indirect effect via tubulr function is unanswered.
In the Q&A Todd Brown commented that if we could correlate early changes in markers with BMD after starting TDf we could perhaps identify those who might not do well on TDf or those who might not have a bone problem. Mike Yinn in a question I think suggested the changes observed are similar to that seen after starting HAART.
STUDY AIMS: compare bone markers in virologically suppressed patients on AZT/3TC to continue or switch to TDF/FTC, hypothesizing that the switch to TDF/FTC will result in altered bone metabolism.
BACKGROUND: Initiation of ART is associated with an early 2-6% reduction in bone mineral density. [from Jules: There is a study at this CROI suggesting that BMD loss after early decline may not stabilize as we had thought as continued abnormal bone metabolism continues this report says.]
ART switch is also associated with further declines in BMD. Greater reductions in BMD are observed with regimens containing TDF.
Wilst the exact underlying pathogenesis remain to be elucidated, postulated mechanisms include immune-mediated, direct effect of ART.
24 patients continued on AZT/3TC & 30 switched to TDF/FTC; average age 46.
CTX-1 is a marker for resorption, osteocalcin & PiNP are markers for formation. CTX-1 for TDF/FTC was significantly higher at baseline vs for AZT/FTC, over the 48 weeks of the study there was a significant increase in CTX-1 for those on TDF/FTC but not for those on AZT/3TC as measured by AUC. Osteocalcin increased significantly for those who switched to TDF/FTC but not for those remaining on AZT/3TC there was no baseline difference between the 2 ART groups. For PiNP there was no baseline difference, again with TDF/FTC there was a significant increase for those switched but for those on AZT/3TC there appeared to be a small increase but for those who switched to TDF/FTC there were increases in both markers over the 48 weeks with a significant difference between the 2 ART groups for this marker.. Of note for both markers there did not appear to be any change for those remaining on AZT/3Tc, 48 week followup also.
BMD: there was a median reduction at the Femoral Neck in BMD for those switched to TDF/FTC of -1.52% and a small nonsignificant gain of 0.14% for those staying on AZT/3TC. The within group and between group changes were not statistically signicant. For the lumbar spine there was a -2.4% median reduction for those switching to TDF/FTC and there was a significant median decline of -0.18% for those staying on AZT/3TC and the difference in change between the 2 ART groups was significant, and the change within group was significant as well. .
All 3 bone markers correlated with change in BMD. The realtionships were statistically significant for osteocalcin & PiNP but not for CTX-1.
They performed a mutivariate analysis adjusting for baseline values, gender & ethnicity & found TDF/FTC was independently associated with the change in all 3 bone markers.
They said their limitations included only a 48 week followup, the relatively small study size may have limited some analyses, there was an absence of data on some classical risk factors including smoking histrory, and significant use of steroids.
link to webcast:
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16637&mediaType=podiumVideo
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
Aoife Cotter*1,2, S Vrouenraets3,4, J Brady2, F Wit3, C Fux5, H Furrer5, K Brinkman6, C Sabin7, P Reiss3, and P Mallon1,2
1Univ Coll Dublin Sch of Med & Med Sci, Ireland; 2Mater Misericordiae Univ Hosp, Dublin, Ireland; 3Academic Med Ctr, Amsterdam, The Netherlands; 4Slotervaart Hosp, Amsterdam, The Netherlands; 5Bern Univ Hosp and Univ of Bern, Switzerland; 6Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands; and 7Univ Coll London, UK
Background: Although initiation of tenofovir (TDF)-containing ART is associated with reduced bone mineral density (BMD) and increased bone turnover, the effect of switching to TDF on markers of bone turnover in virologically suppressed, ART-treated patients is unknown.
Methods: We examined changes in markers of bone turnover and BMD by DXA over 48 weeks in a sub-study of virologically suppressed patients (HIV RNA <50 copies/mL) on first-line zidovudine/lamivudine (AZT/3TC)-containing ART, randomized to switch to TDF/emtricitabine (FTC) or remain on AZT/3TC, with available samples stored at 0, 4, 12, 24, 36, and 48 weeks and DXA at 0 and 48 weeks. Markers of bone formation (osteocalcin [OC], procollagen type 1 amino-terminal propeptide [P1NP]) and bone resorption (type 1 collagen cross-linked C-telopeptide [CTX]) were measured by immunoassay from which area under-the-curve (AUC) change from baseline to 48 weeks was determined.
Between-group differences in bone biomarkers were assessed by Wilcoxon tests. Associations between change in bone biomarkers and BMD measures were determined by Spearman's correlation and multivariable linear regression, before and after adjustment for potential confounders. All data are median [IQR] unless specified.
Results: Of 54 subjects (median age 46 years, 85.2% male, 75.9% Caucasian), 30 switched to TDF/FTC. There were slightly more males in the TDF/FTC group (93% vs 75%, p = 0.07). All 3 biomarkers significantly increased from week 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (see the table). There was significantly greater decline in lumbar spine (LS) BMD in those switching to TDF/FTC (-2.04%, -3.28 to -0.40, vs -0.18%, -2.35 to 1.85, p = 0.03). Greater declines in LS BMD correlated with greater increases in OC and P1NP (OC r = -0.37, P1NP r = -0.32, both p <0.02), with a borderline association between CTX and LS BMD (r = -0.21, p = 0.11). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender and ethnicity.
Conclusions: This is the first randomized study to show that in virologically suppressed patients on ART, a switch to TDF/FTC is associated with increases in bone turnover that correlate with reductions in BMD. These data suggest that TDF exposure directly affects bone metabolism in vivo. Whether this is due to direct TDF toxicity on bone or indirect effects of TDF-induced renal dysfunction remains to be determined.
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