1. THE BODY PRO The HIV Resource for Health Professionals The Body PRO Covers the XVII International AIDS Conference (AIDS 2008) Mexico City; August 3-8, 2008 This activity is supported by educational grants from Faculty: David Wohl, M.D. Associate Professor of Medicine at the University of North Carolina at Chapel Hill Copyright © 2008 Body Health Resources Corporation. All rights reserved. This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO. David Wohl, M.D.

2. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 1 Faculty for This Activity David Wohl, M.D. Dr. Wohl is an associate professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections. Dr. Wohl is an investigator in the NIAID-sponsored AIDS Clinical Trials Group (ACTG) and a member of the ACTG Complications of HIV Disease Research Agenda Committee. His research focuses on metabolic and infectious complications of HIV and its therapies, as well as issues related to medication adherence and access to care -- particularly among incarcerated inmates with HIV infection. Disclosures Dr. Wohl has been a consultant for Abbott Laboratories, Tibotec and Merck & Co. He has served on speakers bureaus for Abbott, Gilead, Roche Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec and Merck. In addition, he has received research support from Abbott, Roche and Merck.

3. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 2 ACTG 5202: Study Design 96-Week, Randomized, Partially Blinded Study Comparing efficacy, safety and tolerability of regimens shown below as initial therapy for HIV-1 infection Any CD4+ Count HIV-1 RNA ≥ 1,000 Copies/mL ≥ 16 Years of Age Stratified by HIV-1 RNA (< or ≥ 100,000 Copies/mL) ART-naïve N=1858 Randomized 1:1:1:1 EFV QD ATV/r QD ATV/r QD ART-Naïve N = 1,858 Randomized 1:1:1:1 QD TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.

4. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 3 ACTG 5202: NIAID Therapeutic DSMB Findings and Recommendations Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. January 29, 2008: First Efficacy Review ABC/3TC showed excess virologic failures Data Combined and Analyzed as Two Arms (ABC/3TC vs. TDF/FTC) Per DSMB Request Found highly significant differences ABC/3TC: Excess virologic failures occurred in patients with viral load ≥ 100,000 copies/mL

5. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 4 ACTG 5202: Primary Study End Points Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. Efficacy Time to Virologic Failure Early Failure Weeks 16 to 24 Confirmed Viral Load ≥ 1,000 Copies/mL Later Failure Week 24 On Confirmed Viral Load ≥ 200 Copies/mL Safety Lab Abnormality at Least One Grade Higher Than Baseline OR Time to First Grade 3 or 4 Sign/Symptom TolerabilityTime to Modification of Originally Randomized Regimen

6. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 5 ACTG 5202: Timing and Type of Virologic Failure Tenofovir/Emtricitabine (N = 399) Abacavir/Lamivudine (N = 398) Total With VF* 26 (7%)57 (14%) ≥ 200 Copies/mL ≥ 24 Weeks Prior < 200 Copies/mL 1529 ≥ 200 Copies/mL ≥ 24 Weeks No Prior < 200 Copies/mL 29 ≥ 1,000 Copies/mL < 24 Weeks No Prior < 200 Copies/mL 919 Post hoc analysis: There was no significant difference in the risk of virologic rebound (P = 0.247) for subjects achieving two < 50 copies/mL on therapy. Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. *VF = virologic failure

7. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 6 ACTG 5202: Proportion < 50 Copies/mL (95% CI) Secondary, ITT: Regimen Change/Prior Virologic Failure Included Proportion < 50 Copies/mL Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. Number with RNA Value Abacavir/Lamivudine388 357 324 293 245 212 163 114 59 Tenofovir/Emtricitabine393 352 325 285 244 211 169 109 69 Week 48: Abacavir/Lamivudine: 0.75 (0.69 – 0.80) Tenofovir/Emtricitabine 0.80 (0.74 – 0.85); P = 0.20

8. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 7 ACTG 5202: Selected Grade 3 or 4 Safety Events Among Those Reported in ≥ 5% Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. Safety EventsTenofovir/EmtricitabineAbacavir/Lamivudine Total (All Events) 78 (19%)130 (33%) Metabolic (Lipids) 11 (3%)41 (10%) General Body 38 (10%)58 (14%) Aches and/or Pains 1424 Asthenia 106 Headache 68 Itchy and/or Pruritis 29 Gastrointestinal 17 (5%)26 (7%) ALT 57 AST 412 Diarrhea and/or Loose Stool 77 Nausea and/or Vomiting 33

9. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 8 ACTG 5202: Conclusions Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. Patients With HIV RNA ≥ 100,000 Copies/mL Significantly shorter time to virologic failure associated with ABC/3TC  No obvious relationship between virologic failure and suspected hypersensitivity reactions Shorter time to first adverse event with ABC/3TC Resistance and Other Analyses Ongoing ACTG 5202 Continues Until November 2009 Blinded NRTIs with HIV RNA < 100,000 copies/mL ATV/r vs. EFV

10. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 9 Responding to ACTG 5202: Clinical Trials With Third Drugs (N ≥ 100) Keith Pappa et al. AIDS 2008; abstract THAB0304. Copyright GlaxoSmithKline. Used with permission 2008.

11. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 10 Responding to ACTG 5202: 48-Week Protocol-Defined Virologic Survival by Baseline VL Using A5202 Efficacy End Point 1 Keith Pappa et al. AIDS 2008; abstract THAB0304. Copyright GlaxoSmithKline. Used with permission, 2008.

12. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 11 ACTG 5202: Why Might These Results Differ From Other Studies? Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303. Studies Differ in Follow-Up, Design, Endpoints and Conduct ACTG 5202 vs. HEAT 1 Sample size: ACTG 5202 = 1,858 vs. HEAT = 688  HIV RNA ≥ 5.0 log: ACTG 5202 = 797 vs. HEAT = 296 Third drug: ACTG 5202 = ATV/r or EFV vs. HEAT = LPV/r QD capsules Others Compared Different NRTI Strategies ABC/3TC BID + EFV vs. ABC/3TC QD, N = 770 2 ABC/3TC BID + EFV vs. ZDV/3TC BID + EFV, N = 649 3 1 K Smith. CROI 2008; abstract 774. 2 G Moyle et al. JAIDS. 2005:38:417-25. 3 E DeJesus. Clin Infect Dis. 2004;39:1038-46.

13. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 12 Responding to D:A:D/SMART: Methods Jaime Hernandez et al. AIDS 2008; abstract WEAB0106. Copyright GlaxoSmithKline. Used with permission, 2008. GSK-sponsored clinical trials with > 24 weeks of follow up with data from 1995-2006 were analyzed –Data from 54 clinical trials analyzed: 12/54 adult trials were randomized for ABC vs. control 33/54 trials included ABC in background ART 8/54 trials did not include ABC Includes data from 14,683 subjects (14,174 adults and 509 children) Descriptive statistics were summarized for naïve and experienced subjects treated with and without ABC

14. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 13 Responding to D:A:D/SMART: CV Outcomes - Exposure to ABC or No ABC (12 Adult Randomized Trials) Jaime Hernandez et al. AIDS 2008; abstract WEAB0106. Copyright GlaxoSmithKline. Used with permission, 2008. Exposure to ABC Events /Patients Frequency Events /Person-Years Rate/1,000 Person-Years Relative Rate (95% CI) Any Myocardial Infarction or Acute Myocardial Infarction None6/16920.355%7/17064.10 ABC CART2/15700.127%4/18632.15 0.523 (0.15 – 1.79) Any Ischemic Coronary Artery Disease or Disorder None13/16920.768%13/17027.64 ABC CART5/15700.318%8/18604.30 0.563 (0.23-1.36)

15. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 14 SMART*: Primary and Major Secondary End Points Adapted from Wafaa El-Sadr et al. N Engl J Med. 2006;355(22):2283-2296.

16. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 15 SMART: Comparison of Hazard Ratios* for “ABC (No ddI)” and for “ddI (w/wo ABC)” vs. “Other NRTIs” Jens Lundgren et al. AIDS 2008; abstract THAB0305. Reprinted with permission.

17. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 16 SMART: Hazard Ratios* for Using “ABC (No ddI)” vs. Using “Other NRTIs” According to CV Risk Status at Study Entry Jens Lundgren et al. AIDS 2008; abstract THAB0305. Reprinted with permission.

18. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 17 SMART: Adjusted Mean Differences in Biomarker Levels At Study Entry for Using “ABC (No ddI)” or “ddI (w/wo ABC)” vs. Using “Other NRTIs” Jens Lundgren et al. AIDS 2008; abstract THAB0305. Reprinted with permission.

19. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 18 Protocol 004: Part II Design Hypotheses - RAL + TDF/3TC will have similar antiretroviral activity versus EFV + TDF/3TC - RAL + TDF/3TC will be generally well tolerated Key Inclusion Criteria - Antiretroviral-naïve - Susceptible to 3TC, EFV, TDF - CD4+ ≥ 100 cells/mm 3 ; HIV RNA ≥ 5,000 copies/mL Timepoints - Primary -- 24 weeks; Secondary -- 48 weeks and 96 weeks - 48-week data presented at AIDS 2007 Current Presentation is 96-Week Update - RAL doses of 100 mg, 200 mg, 400 mg or 600 mg BID (0 to 48 weeks) - Doses could not be differentiated at 48 weeks - All RAL groups received 400mg BID after 48 weeks - All RAL data after 48 weeks is shown as a single group (N = 160) Endpoints - Adverse events, CD4+ counts, HIV RNA - Exploratory: Central nervous system and lipids Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102.

20. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 19 Protocol 004: 96 Weeks Percent of Patients (95% CI) With HIV RNA < 50 Copies/mL [Non-Completer = Failure] Week 96 Raltegravir: 83% Efavirenz: 84% * After Week 48 patients in all RAL groups continued at 400 mg BID. All patients received TDF/3TC. Week:02448*60728496 RAL 100 mg BID39 RAL 200 mg BID 40 RAL 400 mg BID41 160 159160 RAL 600 mg BID40 EFV 600 mg QD383738 Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102. Percent of Patients With HIV RNA < 50 Copies/mL

21. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 20 Protocol 004: Treatment-Emergent Mutations Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102. GroupVF* Type3TCEFVRALTDF RAL 100NR † M184M/I/V K65K/R V151I, N155H D232D/N, G163R/G K65K/R RAL 100REL¹M184M/I/VY143C ‡ RAL 200NR † M184M/I/VN155H RAL 200NR † M184V RAL 200REL¹ RAL 200/400REL¹, ² EFVNR † K65RG190ES230S/N ∞ K65R EFVREL¹, ²M184V Y188L K103K/N NOTE: Percentage of virologic failures in RAL 6/160 (3.8%) and in EFV 2/38 (5.3%). *VF = virologic failure † NR = non-response; > 400 copies/mL at week 24 or early discontinuation; All achieved > log 10 decrease in HIV RNA at nadir. ¹REL = virologic relapse; > 400 copies/mL after initial response of < 400 copies/mL or 1.0 log 10 increase above nadir level. 2 Failure occurred after week 48. ‡ Mutation developed after patient was a virologic failure. ∞A common polymorphism that does not affect raltegravir sensitivity in phenotypic assays. All other mutations listed were associated with reduced drug sensitivity.

22. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 21 Protocol 004: Percent of Patients With Grade 3 / 4* Laboratory Abnormalities Laboratory TestToxicity Criteria* EFV (N = 38) N (%) RAL (N = 160) N (%) Absolute Neutrophil Count< 750 cells/µL 0 (0.0)1 (0.6) Alanine Aminotransferase> 5 x ULN 2 (5.3)2 (1.3) Alkaline Phosphatase> 5 x ULN 0 (0.0)1 (0.6) Aspartate Aminotransferase> 5 x ULN 1 (2.6)4 (2.5) Creatine Kinase≥ 10 x ULN 1 (2.6)10 (6.3) Fasting LDL Cholesterol≥ 190 mg/dL 2 (5.3)1 (0.6) Fasting Total Cholesterol> 300 mg/dL 2 (5.3)0 (0.0) Fasting Triglycerides> 750 mg/dL 3 (7.9)0 (0.0) Lipase> 3 x ULN 0 (0.0)2 (1.3) Pancreatic Amylase> 2 x ULN 0 (0.0)4 (2.5) Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102. *No grade 3 or 4 abnormalities were reported in either treatment group for the following parameters: hemoglobin, platelet count, fasting glucose, creatinine, and total bilirubin.

23. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 22 EFV vs. LPV/r: Study Design Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission. Screened (N = 264) ZDV/ 3TC 300/150 mg BID Substitution of AZT for ABC allowed (N = 14; EFV 6 and LPV/r 8) (1:1) National Multicenter, Open-Label, Randomized, 48-Week Study to Compare the Virological Success of EFV vs. LPV/r in Treatment-Naïve HIV-1 Infected Subjects EFV 600 mg QD (N = 95) LPV/r 400/100 mg BID (N = 94) Screening Failure (N = 75) 189 ARV naïve; > 18 years; HIV RNA  1,000 copies/mL, CD4 + < 200 Randomization stratified by CD4 + (> and < 100 cells/mL)

24. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 23 EFV vs. LPV/r: Patient Disposition At Week 48 Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission. Efavirenz N = 95 Lopinavir/r N = 94 P Value Completed 48 Weeks68 (71)55 (58)0.05 Viral Load < 50 Copies/mL67 (70)50 (53)0.01 Discontinuation Virological Failure7 (7)17 (18)0.02 Lost to Follow Up15 (16)11 (12)0.4 Adverse Events5 (5)11 (12)0.1 Death2 (2)5 (5) Tuberculosis1 (1)2 (2)

25. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 24 EFV vs. LPV/r: Proportion of Patients With HIV RNA < 400 Copies/mL Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission.

26. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 25 EFV vs. LPV/r: Change of Median CD4+ Cell Counts Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission.

27. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 26 TMC278–C204: Study Design Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission. Ongoing (extended to 5 years), randomized, active-controlled, dose-ranging Phase IIb study in ARV-naïve patients. Primary objective to evaluate the TMC278 efficacy (ITT-TLOVR) and safety dose-response relationship at Week 48. EFV = efavirenz; ITT = intent to treat; TLOVR = time to loss of virologic response NRTI backbone chosen by investigator and is either AZT/3TC or TDF/FTC administered as fixed-dose combinations where available Screening and Randomization 1:1:1:1 ARV-Naïve Patients (N = 368) HIV RNA  5,000 Copies/mL Primary Analysis at 48 Weeks Analysis at 96 Weeks 96 weeks TMC278 25 mg QD + 2 NRTIsN = 93 TMC278 75 mg QD + 2 NRTIsN = 95 TMC278 150 mg QD + 2 NRTIsN = 91 EFV 600 mg QD + 2 NRTIsN = 89

28. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 27 TMC278–C204: High Response Rate and Sustained Virologic Response Over 96 Weeks Similar to EFV Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission. HIV-1 RNA < 50 Copies/mL to Week 96 (ITT-TLOVR Algorithm) CI = confidence interval

29. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 28 TMC278–C204: Potent Antiviral Efficacy at Week 48 Sustained to Week 96 Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission.

30. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 29 TMC278–C204: Doses Were Safe and Well Tolerated With No Consistent Association Between Safety Assessments and TMC278 Dose Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission. AE (%) TMC278 groups 25 mg QD (N = 93) 75 mg QD (N = 95) 150 mg QD (N = 91) All TMC278 (N = 279) EFV 600 mg QD (N = 89) Any AE90979293 AEs Leading to Discontinuation91214129 Any Serious AEs1314101215 Any Grade 3/4 AEs3025262721 Investigations Reported as Grade 3/4 AEs* 16812 9 Grade 3/4 Laboratory Abnormalities 3322242724 Summary of Treatment-Emergent AEs, Regardless of Severity and Causality *Investigations included laboratory assessments and electrocardiograms

31. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 30 TMC278–C204: Additional Investigations Endocrine No clinically relevant changes in adrenal and thyroid parameters were observed ECG Increases in QTc interval were seen with all TMC278 doses and EFV up to 48 weeks, which then stabilized up to Week 96 –increases were primarily seen with the AZT/3TC backbone –mean increase was lowest with TMC278 25 mg Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission.

32. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 31 GRACE: Study Design and Baseline Characteristics Judith Currier et al. AIDS 2008; abstract THPDB202. Reprinted with permission.

33. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 32 GRACE: 24-Week Interim Analysis: Efficacy and Safety Virologic Response (VL < 50 Copies/mL) At Week 24, mean increase in CD4 cell count in women was 86 cells/mm3 (ITT-NC=F) At Week 24, discontinuation rate for women was 24.4% -- Discontinuations were generally unrelated to VF (0.6%) or AEs (7.8%) Safety and Tolerability in Women Most common grade 2-4 adverse events at least possibly related to study drug: —Nausea (6.1%) — Diarrhea (5.6%) — Rash (2.8%) — Weight gain (2.8%) Serious AEs were reported in 16.7% (N = 30) of women — Most common was pneumonia, reported in 4.4% (N = 8) of women No major issues with Grade 2-4 laboratory abnormalities were noted ITT, intention-to-treat; TLOVR, time to loss of virologic response algorithm; TLOVR-non-VF, algorithm excluded patients who discontinued for reasons other than virologic failure; NC=F, non-completer=failure Judith Currier et al. AIDS 2008; abstract THPDB202. Reprinted with permission.

34. The Body PRO Antiretroviral Strategy Update: Highlights From AIDS 2008 33 Visit The Body PRO for comprehensive coverage of AIDS 2008. This presentation was created to accompany The Body PRO's summaries of key research presented at AIDS 2008, by David Wohl, M.D. Learn more at: TheBodyPRO.com/AIDS2008 In addition, be sure to browse through The Body PRO's extensive coverage of AIDS 2008, which includes: –Summaries and analyses of research on a wide array of clinical subjects. –Interviews with top researchers discussing the results of noteworthy studies. –Audio podcasts you can play online or download to your computer or MP3 player. –Narrated, online slide presentations highlighting major study results. Visit TheBodyPRO.com/AIDS2008 today for a full listing of our conference materials!