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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 l.jpg

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 l.jpg
Background Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142

  • 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


Bone mineral density bmd objectives l.jpg
Bone Mineral Density (BMD) Objectives Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142

  • 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


A5142 study design l.jpg
A5142 Study Design Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142

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


Methods and statistical analysis l.jpg
Methods and Statistical Analysis Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142

  • 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


Baseline population l.jpg
Baseline population Transcriptase Inhibitor (NRTI) Selection on 96 Week Bone Mineral Density (BMD): Results from ACTG 5142

  • 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


Baseline characteristics population with dexa by use of nrti l.jpg
Baseline Characteristics: Population with DEXA by use of NRTI

* P > 0.05 for all comparisons except race/ethnicity (p=0.01)


Baseline factors significantly associated with baseline bmd l.jpg
Baseline Factors Significantly Associated with Baseline BMD NRTI

**

*

**

*

**

*

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


Baseline factors significantly associated with baseline bmd9 l.jpg
Baseline Factors Significantly Associated with Baseline BMD NRTI

  • 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


Mean percent change from baseline in bmd l.jpg
Mean Percent Change from Baseline in BMD NRTI

  • 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)


Mean percent change from baseline in bmd11 l.jpg
Mean Percent Change from Baseline in BMD NRTI

  • 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).


Mean percent change from baseline in bmd12 l.jpg
Mean Percent Change from Baseline in BMD NRTI

Observed Changes (irrespective of treatment changes)

EFV

LPV

% Change in BMD

from Baseline

NRTI Spare

EFV/ TDF

LPV/ TDF


Mean percent change from baseline in bmd13 l.jpg
Mean Percent Change from Baseline in BMD NRTI

Model- based Estimated Changes

LPV

EFV

% Change in BMD

from Baseline

NRTI Spare

EFV/ TDF

LPV/ TDF


Mean percent change from baseline in bmd repeated measures model l.jpg
Mean Percent Change from Baseline in BMD NRTIRepeated 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).


Mean percent change from baseline in bmd repeated measures model15 l.jpg
Mean Percent Change from Baseline in BMD NRTIRepeated 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


Summary l.jpg
SUMMARY NRTI

  • 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


Conclusions l.jpg
Conclusions NRTI

  • 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


With special thanks to l.jpg

Study volunteers NRTI

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:


Mean percent change from baseline in bmd20 l.jpg
Mean Percent Change from Baseline in BMD NRTI

Observed Changes (as treated)

LPV

EFV

% Change in BMD

from Baseline

NRTI Spare

EFV/ TDF

LPV/ TDF


Bmd loss with art initiation 2 6 at 48 96 weeks l.jpg
BMD Loss with ART-initiation: ~2-6% at 48-96 weeks NRTI

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


Follow up dexa availability l.jpg
Follow-up DEXA Availability NRTI

  • 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


Mean percent change from baseline in bmd23 l.jpg
Mean Percent Change from Baseline in BMD NRTI

Model- based Estimated Changes

LPV

EFV

% Change in BMD

from Baseline

NRTI Spare

EFV/ TDF

LPV/ TDF


Baseline metabolic characteristics by use of nrti l.jpg
Baseline Metabolic Characteristics NRTIby use of NRTI

* P = 0.025; other comparisons NS