1. Body Composition and Metabolic Changes in Antiretroviral-Naïve HIV-Infected Patients Randomized to Didanosine and Stavudine (ddI+d4T) vs. Abacavir and Lamivudine (ABC+3TC) J. Shlay, F. Visnegarwala, G. Bartsch, J. Wang, G. Peng, W. El-Sadr, C. Gibert, D. Kotler, C. Grunfeld, S. Raghavan for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) XV International AIDS Conference Abstract # ThOrB1360

2. CPCRA Objectives To compare the rates of change in body composition and various metabolic parameters in antiretroviral naïve patients randomized to ddI+d4T vs. ABC+3TC containing regimens in the presence of highly active antiretroviral therapy

3. CPCRA Background Lipodystrophy has been associated with the use of thymidine analogue nucleoside reverse transcriptase inhibitors, particularly d4T Few prospective studies have compared body composition changes in thymidine analogue- sparing regimens to thymidine analogue- containing regimens

4. Patient meets eligibility requirements Randomized to 3 strategy arms (1:1:1) N=1,397 (422 in Metabolic Substudy) PI + NRTI N=470 NNRTI + NRTI N=463 PI + NNRTI + NRTI N=464 Allowed additional randomization to NRTI Substudy (1:1) N=182 ddI+d4T N = 89 (46 in Metabolic Substudy) ABC+3TC N = 93 (50 in Metabolic Substudy) CPCRA

5. Methods At baseline and every 4 months, the following measurements were obtained: –Anthropometric measurements: centralized and standardized training; re-certification annually height, weight, body mass index (BMI), body circumferences: arm, waist, hip, thigh skinfolds: triceps, suprascapular, subscapular, abdomen, thigh –body cell mass (BCM), total body fat (TBF) using BIA –Metabolic parameters: triglycerides, total cholesterol, HDL, LDL, VLDL, glucose, insulin (all also done at 1 month)

6. CPCRA Baseline Characteristics - 1 Age (yrs)3835 Female (%)3026 Race (%) Non-white7676 Mean CD4 cells/mm 3 268234 Mean logRNA copies/ml4.855.03 Initial PI (%)7070 * No significant differences between treatment arms ddI+d4T* N = 46 ABC+3TC* N = 50

7. CPCRA Baseline Characteristics - 2 Body composition BMI (kg/m 2 )25.024.7 BCM (kg)26.526.6 TBF (kg)17.416.6 Circumferences (cm) Waist86.185.1 Hip99.697.6 Skinfold fat area (cm 2 ) Mid-arm20.721.6 Waist77.474.7 * No significant differences between treatment arms ddI+d4T* N = 46 ABC+3TC* N = 50

8. CPCRA Triglycerides (mg/dL) 129.3124.6 Total cholesterol (mg/dL)177.3 161.4 HDL cholesterol (mg/dL)41.336.7 LDL cholesterol (mg/dL)111.899.8 Glucose (mg/dL)82.483.0 Insulin (µ/mL)9.411.6 Insulin resistance (HOMA) † :2.12.5 ddI+d4T* N = 46 ABC+3TC* N = 50 Baseline Characteristics - 3 *No significant differences between treatment arms † Insulin resistance = (0.0555 x glucose x insulin / 22.5)

9. CPCRA Rates of Change of Body Mass Index Months Change (kg/m 2 /month) SEP-value ddI+d4T-0.020.020.01 ABC+3TC0.040.02 Mean Change from Baseline Body Mass Index (kg/m 2 ) 464541442635363120 504947452739393422 No. of Patients ddI+d4T ABC+3TC 048121620242832 -2-101234 CPCRA

10. 048121620242832 Months Change (kg/month) SEP-value ddI+d4T0.020.010.30 ABC+3TC0.040.01 *As measured by BIA Mean Change from Baseline -2024 -50510 Body Cell Mass* (kg)Total Body Fat* (kg) 048121620242832 Months Change (kg/month) SEP-value ddI+d4T-0.080.04<0.01 ABC+3TC0.080.04 Rates of Change of Body Composition CPCRA

11. Rates of Change of Circumferences 048121620242832 Months Change (cm/month) SEP-value ddI+d4T-0.020.050.14 ABC+3TC0.070.04 Mean Change from Baseline 0510 -15-10-5051015 Waist (cm)Hip (cm) 048121620242832 Months Change (cm/month) SEP-value ddI+d4T-0.180.06<0.01 ABC+3TC0.100.06 CPCRA

12. 048121620242832 Months Change (cm 2 /month) SEP-value ddI+d4T-0.210.06<0.01 ABC+3TC0.050.06 Mean Change from Baseline -50510 -40-20020406080 Waist (cm 2 ) 048121620242832 Months Change (cm 2 /month) SEP-value ddI+d4T-0.620.29<0.01 ABC+3TC0.620.27 Rates of Change of Skinfold Fat Areas Mid-(cm 2 )arm CPCRA

13. 048121620242832 Months Change (cm 2 /month) SEP-value ddI+d4T0.010.060.81 ABC+3TC0.030.06 Mean Change from Baseline -5051015 050100 Waist (cm 2 ) 048121620242832 Months Change (cm 2 /month) SEP-value ddI+d4T0.320.560.91 ABC+3TC0.410.53 Rates of Change of Fat Free Areas Mid-(cm 2 )arm CPCRA

14. 048121620242832 Months Change (mg/dL/month) SEP-value ddI+d4T-0.660.160.08 ABC+3TC-0.260.16 *If triglycerides ≥400, direct LDL, otherwise calculated LDL Mean Change from Baseline -2002040 -505101520 LDL Cholesterol* (mg/dL) HDL Cholesterol (mg/dL) 048121620242832 Months SEP-value ddI+d4T--0.110.080.03 ABC+3TC0.130.08 Rates of Change of Metabolic Parameters CPCRA Change (mg/dL/month)

15. 048121620242832 Months SEP-value ddI+d4T2.140.870.08 ABC+3TC0.070.83 Mean Change from Baseline --50050100150 -1001020 Triglycerides (mg/dL) Insulin (µ/mL) 048121620242832 Months SEP-value ddI+d4T0.120.090.57 ABC+3TC0.050.09 Rates of Change of Metabolic Parameters CPCRA Change (mg/dL/month) Change (µ/month)

16. CPCRA Conclusions - I After initiation of HAART, an initial increase was seen in all body composition parameters (i.e., BMI, BCM, total and subcutaneous fat), regardless of the treatment arms Progressive loss of total and regional fat was observed in the ddI+d4T arm compared to the ABC+3TC arm after the initial period, indicating a differential treatment effect Significant early and sustained increases in insulin and insulin resistance was seen in the ddI+d4T arm compared to ABC+3TC, despite a similar proportion of PI use for each arm

17. CPCRA Conclusions - II The differential effects on lipid metabolism and insulin by treatment assignment necessitate close clinical monitoring and ongoing longitudinal assessment Our study, using anthropometric measurements, yielded data consistent with the other studies that have utilized DEXA scans, supporting the use of these simple measures