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J. Huang M. Hughes S. Riddler R. Haubrich For the ACTG 5142 Team

Effects of Randomized Regimen and Nucleoside Reverse Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142. J. Huang M. Hughes S. Riddler R. Haubrich For the ACTG 5142 Team. Background.

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J. Huang M. Hughes S. Riddler R. Haubrich For the ACTG 5142 Team

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  1. Effects of Randomized Regimen and Nucleoside Reverse Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142 J. Huang M. Hughes S. Riddler R. Haubrich For the ACTG 5142 Team

  2. Background • Effects of HIV disease and treatment for HIV may effect bone density • Bone loss 2- 6% seen in first 48-96 weeks upon ART initiation for most regimens. • The exact contribution of particular classes of ARV on changes in BMD remains unclear

  3. Bone Mineral Density (BMD) Objectives • PRIMARY • To determine the effects of ARV regimen on change in bone density • Evaluate specific effects of NNRTI, PI and NRTI exposure • SECONDARY • To determine associations between baseline characteristics and baseline BMD • To determine associations between baseline and change from baseline in factors on change in BMD

  4. A5142 Study Design LPV/r SGC 533/133 mg BID + EFV 600 mg QD Design Multicenter Open label Randomized LPV/r SGC 400/100 mg BID + 2 NRTI 96 weeks EFV 600 mg QD+ 2 NRTI Population: ARV-naïve HIV RNA >2,000 c/mL Any CD4 count Stratification: HIV RNA > 100,000 c/mL Hepatitis infection Selection of NRTI Investigator Selection of ZDV or d4T XR or TDF + 3TC

  5. Methods and Statistical Analysis • BMD Measurements • Whole body DEXA at baseline and weeks 48 and 96 • Scans read centrally (Tufts University); reviewers masked to treatment assignment • Whole body BMD expressed as total density (g/ cm2); specific lumbar/ hip t and z scores not captured. • Analyses • 6 subjects with extreme baseline or follow-up data by DEXA excluded; sensitivity analyses including subjects did not yield different results • Baseline clinical and laboratory factors assessed for association with baseline BMD in univariate (t-test or regression) and multivariate regression models • The mean percentage change in BMD with time was evaluated by regimen / NRTI selection using repeated measures models

  6. Baseline population • Subjects at baseline, N = 753 • DEXA present: 687 (91%) • Subjects with versus without baseline DEXA similar except: • Fewer women (19% vs 35%, p = 0.002) • No difference in race/ ethnicity, age, randomized regimen, NRTI selection, CD4 or HIV RNA

  7. Baseline Characteristics: Population with DEXA by use of NRTI * P > 0.05 for all comparisons except race/ethnicity (p=0.01)

  8. Baseline Factors Significantly Associated with Baseline BMD ** * ** * ** * Difference in BMD from Reference (gm/cm2) <50 <30 25-30 30-39 40-49 < 18.5 White 50-199 18.5-25 Hispanic 200-299 * P < 0.05; ** P < 0.001

  9. Baseline Factors Significantly Associated with Baseline BMD • Multivariate model significant associations with lower BMD (P < 0.001) • Female sex • Post-menopause • White, non-Hispanic and Hispanic race/ethnicities • Lower BMI • Higher CD4 • Age not significant, but BMD tended to increase until age 34 and decline thereafter

  10. Mean Percent Change from Baseline in BMD • All regimens had significant decline at week 48 and 96 • No overall difference in mean percent change in BMD by randomized regimen (P = 0.17), but trend for greater decline for two NRTI regimens with LPV vs EFV (P = 0.06, after adjustment for NRTI) • Fractures were rare (8 total; study not designed to capture this data)

  11. Mean Percent Change from Baseline in BMD • Significant difference in BMD at week 48 by NRTI used (p<0.001), maintained at week 96 • Little difference between d4T vs ZDV (p=0.97) • TDF subjects had larger declines (1.54% greater mean decline vs ZDV, p<0.001, repeated measures model).

  12. Mean Percent Change from Baseline in BMD Observed Changes (irrespective of treatment changes) EFV LPV % Change in BMD from Baseline NRTI Spare EFV/ TDF LPV/ TDF

  13. Mean Percent Change from Baseline in BMD Model- based Estimated Changes LPV EFV % Change in BMD from Baseline NRTI Spare EFV/ TDF LPV/ TDF

  14. Mean Percent Change from Baseline in BMDRepeated Measures Model • Week 48 • Compared to the NRTI sparing arm (-1.9%) • EFV + ZDV or d4T had smaller BMD declines (-1.1% and -0.9% respectively; P < 0.03 for both) • LPV +TDF had greater BMD declines (-3.1%, P = 0.004) • ZDV and d4T had very similar changes • trend toward greater mean declines among subjects taking NRTI with LPV/r versus EFV (difference: -0.5%, P = 0.08).

  15. Mean Percent Change from Baseline in BMDRepeated Measures Model • Week 96 • All regimens decreased by similar amounts between 48 and 96 weeks: -0.48 • Baseline adjustments did not change overall findings (highlighted factors also significant in multivariate models) • Age, race/ethnicity, menopausal, BMD, BMI, extremity fat percentage, truncal fat percentage, lean body mass percentage, CD4 count, HIV RNA, lactate level, glucose level and hepatitis

  16. SUMMARY • Expected associations with baseline BMD and sex, menopause, race/ ethnicity, age and BMI. Lower CD4 associated with higher BMD • BMD decreased significantly in all regimens at week 48 • Relative order: TDF (with LPV or EFV) > NRTI-sparing > ZDV or d4T (with LPV or EFV) • LPV regimens tended to have greater declines than EFV across all NRTIs used (did not reach significance). • BMD further decreased between week 48 and 96 to similar extents for all treatments, maintaining the same relative order of decline according to regimen/ NRTI use

  17. Conclusions • ART therapy was associated with reductions in BMD, especially in the first year after initiation. • Among the NRTI-containing arms, NRTI selection, especially use of TDF, had a greater effect on BMD change with a non-significant trend for greater declines in the LPV arm. • The long term clinical significance of these BMD changes remains to be determined

  18. Study volunteers Investigators and study staff from 55 participating ACTG Sites Pharmaceutical Sponsors: Abbott: Kevin Garren BMS: Kristy Grimm Gilead: Jim Rooney NIH/ NIAID Additional team members John Mellors Diane Havlir Karin Klingman Michael Dorosh Joelle Touw David Rusin With Special Thanks to:

  19. Mean Percent Change from Baseline in BMD Observed Changes (as treated) LPV EFV % Change in BMD from Baseline NRTI Spare EFV/ TDF LPV/ TDF

  20. BMD Loss with ART-initiation: ~2-6% at 48-96 weeks No head to head comparison for BMD changes between ATV/r and EFV or for body composition changes between ABC and TDF or ATV/r and EFV in ART-naïve subjects

  21. Follow-up DEXA Availability • Subjects with baseline DEXA, N = 687 • DEXA at week 48: 575 (84%) • DEXA at week 96: 509 (73%) • No week 96 DEXA (178): 16 died, 122 lost and 40 on study but no DEXA

  22. Mean Percent Change from Baseline in BMD Model- based Estimated Changes LPV EFV % Change in BMD from Baseline NRTI Spare EFV/ TDF LPV/ TDF

  23. Baseline Metabolic Characteristicsby use of NRTI * P = 0.025; other comparisons NS

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