1. Long-Term Changes in Lipids and Glucose/Insulin among HIV-Infected Antiretroviral Naïve Persons Randomized to PI vs. NNRTI vs. PI+NNRTI-based strategies: Results of the CPCRA 061 Metabolic Study J. Shlay, G. Bartsch, G. Peng, J. Wang, C. Gibert, F. Visnegarwala, S. Raghavan, Y Xiang, M. Farrough, H. Perry, D. Kotler, C. Grunfeld, W. El-Sadr for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) XVI International AIDS Conference Abstract # ThABO101

2. CPCRA Background Morphologic changes (lipoatrophy and lipohypertrophy), insulin resistance, and dyslipidemia are important metabolic consequences of antiretroviral therapy in patients with HIV/AIDS However, long-term comparative data on the metabolic effects of initiating different ART strategies in ART-naïve patients are limited

3. CPCRA Objectives To assess long-term changes in metabolic parameters and body composition among antiretroviral-naïve patients randomized to three highly active antiretroviral therapy (ART) strategies

4. CPCRA Patient meets eligibility requirements Randomized to 3 strategy arms (1:1:1) N=1,397 PI + NRTIs N=470 NNRTI + NRTIs N=463 PI + NNRTI + NRTI(s) N=464 PI Strategy N=141 in Metabolic substudy NNRTI Strategy N=141 in Metabolic substudy PI + NNRTI Strategy N=140 in Metabolic substudy

5. CPCRA Baseline Characteristics – 1 * Age (years)373839 Female (%)262317 Race African American (%)616259 Prior AIDS (%)383932 CD4 (cells/mm 3 )235206 204 RNA (log 10 copies/mL)4.95.05.0 PI (N=141) NNRTI (N=141) PI + NNRTI (N=140) * No significant differences among treatment strategies

6. CPCRA Baseline Characteristics - 2 Triglycerides (mg/dL)122.9 129.3 146.4NS Total Cholesterol (mg/dL)160.0 157.1 168.7* HDL Cholesterol (mg/dL)39.0 36.8 35.3NS LDL Cholesterol (mg/dL)96.7 94.1 105.3* Glucose (mg/dL)86.1 88.6 86.4NS Insulin (µ/mL)8.5 9.9 10.4NS PI (N=141) NNRTI (N=141) PI + NNRTI (N=140) * Significant differences among treatment strategies: p < 0.05 P-Value

7. CPCRA ART Prescribed after Randomization PI (%) NFV 58064 IDV 12011 RTV-boosted 26022 Other 402 NNRTI (%) EFV 06350 NVP 13749 Other 001 NRTI (%) ZDV + 3TC 535338 d4T + 3TC 191910 ABC + 3TC 111216 ddI + d4T 121214 Single NRTI 0019 Other 642 PI (N=141) NNRTI (N=140) PI + NNRTI (N=140)

8. CPCRA Change in LDL Cholesterol * * If triglycerides ≥ 400, direct LDL, otherwise calculated LDL

9. CPCRA Change in HDL Cholesterol

10. CPCRA Change in Triglycerides

11. CPCRA Change in Insulin

12. CPCRA Conclusions - I PI+NNRTI strategy associated with a greater increase in LDL-C and triglycerides compared to the PI or NNRTI strategies; no significant differences noted between PI and NNRTI strategies LDL-C levels increased primarily within the first few months after initiation of ART, followed by a decline during the remainder of follow-up

13. CPCRA Conclusions - II Unlike LDL-C, triglyceride levels did not decline with continued therapy Significantly greater increases in mean HDL-C seen with the NNRTI strategy compared to the PI strategy PI+NNRTI strategy should be avoided unless no other options are available

14. CPCRA Conclusions - III Increases in insulin and glucose were noted during follow-up, with no differences by ART strategy Increases in insulin and glucose were gradual and continued throughout follow-up, unlike the pattern of changes noted with the lipids Findings support the need for ongoing monitoring of glucose levels as well as for the development of diabetes, irrespective of ART regimen used