Effects of Testosterone Supplementation on Fat Mass and Distribution in HIV-Positive Men

1. Effects of Physiologic Testosterone Supplementation on Fat Mass and Distribution in HIV-Infected Men with Abdominal Obesity CM Shikuma1, RA Parker2, F Sattler3, B Alston4, R Haubrich5, T Umbleja2, S Bhasin6, for the AIDS Clinical Trials Group Protocol A5079 Study Team 1 University of Hawaii, Honolulu, HI; 2 Harvard School of Public Health, Boston, MA; 3 University of Southern California, Los Angeles, CA 4 Division of AIDS, NIAID, Bethesda MD; 5 University of California, San Diego, San Diego, CA; 6 Boston University, Boston MA

2. Background • Abdominal obesity is commonly seen in HIV+ men following use of potent antiretroviral therapy • In the general population, increases in visceral adipose tissue [VAT] have been linked to increased risk of cardiovascular disease and type 2 diabetes1 1Sowers JR, Am J of Med 115 (8A):37s-41s

3. Background • Testosterone replacement in hypogonadal HIV- middle-age men decrease visceral fat, increase insulin sensitivity and lower triglyceride and cholesterol levels 1,2,3 • Few studies have addressed the effects of testosterone therapy on body fat distribution in HIV+ men • Specifically, the effect of therapy on visceral fat in HIV+ men with abdominal obesity is unknown. 1Marin P et al 1992, Int J Obes Relat Metab Disord 16:991-997; 2Marin P et al Obes Res 1993, 1:245-251; 3Rebuffe-Scrive M Int J Obes 1991, 15:791-5

4. A5079 • Phase III, prospective, multicenter, randomized, placebo-controlled, double-blind study • Objective • to evaluate whether change in visceral fat cross-sectional area by CT is greater with testosterone replacement than with placebo in HIV+ men with abdominal obesity and mildly to moderately reduced serum testosterone levels

5. Methods • Study Population: HIV+ male subjects: • Abdominal obesity • waist-to-hip ratio >0.95 or mid-waist circumference > 100 cm • Mildly to moderately reduced testosterone (T) levels • serum total T 125-400 ng/dL, or • if serum total T > 400 ng/dL then bioavailable T < 115 ng/dLby ammonium sulfate precipitation method or free T < 50 pg/mLby equilibrium dialysis • Stable potent antiretroviral regimen for at least 3 months prior to entry, and plasma HIV RNA <10,000 copies/mL

6. A5079 Schema Double-Blind phase Open-Label phase 10 gm testosterone gel daily vs placebo 10 gm testosterone gel daily 24 wk 24 wk Wk 48 Wk 0 Wk 12 Wk 24 Wk 36 CT DEXA Body Cir CT DEXA Body Cir CT DEXA Body Cir Body Cir CT DEXA Body Cir

7. Statistical Methods • Intent-to-treat approach with last-value-carried-forward • Significance of changes over time within a treatment group was tested using a Wilcoxon Signed Rank test • Comparison between groups was tested using a Wilcoxon Rank Sum test

8. RESULTS: Baseline Demographic and HIV Related Variables aKruskal-Wallis; bExact Test for RxC Tables; cFisher’s Exact Test

9. Baseline Body Composition Entries are medians, unless otherwise indicated. *Wilcoxon Rank Sumtest

10. Changes in Safety Measures during Blinded Phase Table entries are median values of change *Change from baseline p=0.05; +Change from baseline p<0.001

11. Percent Change over 24 weeks in CT Measures (ITT) P<0.001 * P=0.04 P=0.76 8.1% 4.3% 3.1% -1.5% 0.3% -7.2% * VAT SAT Total Abd Fat Entries within bars are median values of change; *Change in within arm differences p<0.05

12. Percent Change over 24 Weeks in DEXA Measures (ITT) p=<0.001 p=<0.001 * * P<0.001 p=0.02 4.6% 4.5% * 3.8% 1.3% -0.3% -7.9% -10.1% -9.9% * * * Trunk Extremity Total Lean Fat Fat Fat Tissue Entries within bars are median values of change; *Change in within arm differences are p<0.05

13. Absolute Change over 24 weeks in DEXA Measures (ITT) Entries are median values

14. Change over 24 weeks in Waist and Waist/Hip Ratio Waist Circumference (cm) Waist to Hip Ratio P=0.03 P=0.04 -0.2 0.00 -2.1 -0.02 * * Entries are median values; *Change in within arm differences are p<0.05

15. Summary and Conclusions • Testosterone replacement over 24 weeks in HIV+ men with abdominal obesity and low testosterone levels did not result in any significant change in the primary endpoint of abdominal visceral fat content by CT • Testosterone replacement was however associated with a decrease in subcutaneous fat and increase in lean body mass

16. Summary and Conclusions • Ten grams of testosterone gel applied topically once daily was safe and associated with a low frequency of adverse events • Analyses of testosterone, other hormonal levels, insulin and lipid values are pending and may provide insight into the results of this study

17. Acknowledgements • A5079 Protocol Team • Pharmaceutical Co-sponsor: Solvay Pharmaceuticals, Inc • ACTG Participating Sites: Bellevue Hosp Cntr, Drew Med Cntr, UCSD, Pittsburgh, LAC/USC Med Cntr, U Minnesota, U Nebraska Med Cntr, Washington U, U Cincinnati, Indiana U, Wishard Mem Hsp, Northwestern, Rush Presbyterian/ St. Luke’s, U of Maryland, Univ. Hawaii, U Puerto Rico, U Colorado, U Pennsylvania • Quest Diagnostics • Division of AIDS, NIAID, NIH

18. Acknowledgements • Patient volunteers Thank you