1. THE BODY PRO The HIV Resource for Health Professionals Faculty: David Wohl, M.D. Associate Professor of Medicine at the University of North Carolina at Chapel Hill The Body PRO Covers ICAAC/IDSA 2008 Washington, D.C.; October 25-28, 2008 Copyright © 2008 The HealthCentral Network, Inc. All rights reserved. This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO. David Wohl, M.D. Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008

2. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 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 speaker 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. This activity is supported by an educational grant from

3. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 2 STARTMRK: Patient Disposition Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. 281 Treated with RAL* 24 (8.5%) Discontinued due to: 8- Adverse events 4- Lack of efficacy 3- Lost to follow-up 9- Other events Randomized 1:1 to RAL or EFV arms 282 Treated with EFV* 257 (91.5%) Completed 48 weeks 247 (87.6%) Completed 48 weeks 35 (12.4%) Discontinued due to: 17- Adverse events 2- Lack of efficacy 7- Lost to follow-up 9- Other events *In combination with TDF/FTC

4. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 3 STARTMRK: Baseline Characteristics Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. RAL*EFV* # Patients Treatedn = 281n = 282 Age (Mean, Years)3837 % Male8182 % Non-White5956 vRNA Copies/mL (Geometric Mean)103,205106,215 % With vRNA > 10 5 Copies/mL5551 Mean CD4+ Count (Cells/μl)219217 % With CD4+ ≤ 200 Cells/μl4748 % Hepatitis B or C77 % Non-Clade B2117 *In combination with TDF/FTC

5. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 4 STARTMRK: Percent of Patients With HIV RNA < 50 Copies/mL (95% CI) (Non-Completer = Failure) Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. 281279281279281279278280 282 281282280281 Raltegravir 400 mg BID* Efavirenz 600 mg QHS* Number of Contributing Patients *In combination with TDF/FTC

6. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 5 STARTMRK: Time to Virologic Response (HIV RNA < 50 Copies/mL) Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. Number of Patients at Risk 2822672291589544171186 28121413471422313832 Efavirenz 600 mg QHS* Raltegravir 400 mg BID* Log-Rank P Value < 0.001 024812162432404856 Weeks 0 20 40 60 80 100 Cumulative Virologic Response Rate (%) *In combination with TDF/FTC

7. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 6 STARTMRK: Change From Baseline in CD4+ Cell Count (95%) (Observed Failure) Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. 281274277272270266260259258 281272 268269266260254251 Raltegravir 400 mg BID* Efavirenz 600 mg QHS* Number of Contributing Patients *In combination with TDF/FTC

8. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 7 STARTMRK: Resistance by Week 48 In Patients With Virologic Failure* Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. *Virologic failure: Non-responder: (1) HIV RNA > 50 copies/mL at the time of discontinuation or (2) HIV RNA > 50 copies/mL at Week 24 Virologic rebound: HIV RNA > 50 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response No known RAL resistance mutation n = 5 4 Sens to TDF/FTC, 1 not tested Known RAL resistance mutation n = 4 3 Res to FTC, 1 not tested IN gene could not be amplified n = 3 IN Mutations: n = 2 G140S+Q148H/R n = 1 Y143H+L74M+E92Q+T97A n = 1 Y143R RAL Failures vRNA > 400c/mL n = 12 No known EFV resistance mutation n = 3 3 Sens to TDF/FTC Known EFV resistance mutation n = 3 1 Res to FTC RT gene no data n = 2 EFV Failures vRNA > 400c/mL n = 8 VL Failures n = 27 RAL n = 39 EFV

9. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 8 STARTMRK: Most Common ‡ Drug-Related ¥ Clinical Adverse Events Of Moderate or Severe Intensity Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. ‡ Present in ≥ 2% of either treatment group ¥ Determined by investigator to be possibly, probably or definitely related to any drug in the treatment regimen *In combination with TDF/FTC 8 (2.8) 0 (0.0) Rash 7 (2.5) 0 (0.0) Rash Maculo-Papular 8 (2.8) 3 (1.1) Diarrhea 8 (2.8) 4 (1.4) Fatigue 10 (3.5) 8 (2.8) Nausea 9 (3.2)10 (3.6) Insomnia 18 (6.4) 4 (1.4) Dizziness 13 (4.6)11 (3.9) Headache n (%) EFV* n = 282 RAL* n = 281

10. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 9 STARTMRK: Grade 3/4 ‡ Laboratory Abnormalities Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. Laboratory Blood TestToxicity Criteria ‡ RAL* n = 281 EFV* n = 282 n (%) Absolute Neutrophil Count < 750 cells/µL5 (1.8) 3 (1.1) Hemoglobin < 7.5 gm/dL2 (0.7) Platelet Count < 50 k/µL0 (0.0) 1 (0.4) Fasting LDL Cholesterol ≥ 190 mg/dL3 (1.1)10 (3.6) Fasting Total Cholesterol > 300 mg/dL0 (0.0) 7 (2.5) Fasting Triglycerides > 750 mg/dL1 (0.4) 3 (1.1) Fasting Glucose > 250 mg/dL1 (0.4) 0 (0.0) Total Bilirubin > 2.5 x ULN2 (0.7) 0 (0.0) Alkaline Phosphatase > 5 x ULN0 (0.0) 2 (0.8) Aspartate Aminotransferase > 5 x ULN6 (2.1) 5 (1.8) Alanine Aminotransferase > 5 x ULN5 (1.8) 6 (2.1) ‡ Grades 3/4 by DAIDS criteria *In combination with TDF/FTC

11. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 10 STARTMRK: Change From Baseline In Fasting Serum Lipids Week 48 Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. Lipid-Lowering RxRAL* # (%)EFV *# (%) Added Rx3 (1)11 (4) Increased Rx4 (1) ‡ P < 0.001 ‡ * * *In combination with TDF/FTC ‡ ‡ ‡ T CHOL/HDL Mean Change (Ratio) RAL EFV P = 0.292

12. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 11 ARTEMIS: Phase III Study Design Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

13. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 12 ARTEMIS: Viral Load < 50 Copies/mL To Week 48 (ITT-TLOVR) Estimated difference in response vs LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) p<0.001 Estimated difference in response vs. LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) P < 0.001 Estimated difference in response vs. LPV/r for superiority: ITT = 5.5% (95% CI –0.3;11.2) P = 0.062 50 40 30 20 10 0 100 90 80 70 60 84% 78% 481216243648 Time (weeks) Patients With VL < 50 Copies/mL (% [±SE]) LPV/r QD or BID (n = 346) DRV/r QD (n = 343) 2 Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.

14. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 13 ARTEMIS: Viral Load < 50 Copies/mL To Week 96 (ITT-TLOVR)* Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

15. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 14 ARTEMIS: Virologic Response at Week 96 in the TLOVR Non-VF Censored Population ‡ Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

16. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 15 ARTEMIS: VF Analysis Over 96 Weeks Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

17. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 16 ARTEMIS: Median Lipid Levels at Baseline and Week 96 Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

18. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 17 CASTLE: Study Design Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

19. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 18 CASTLE: HIV RNA < 50 Copies/mL (CVR, NC = F) Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

20. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 19 CASTLE: Selected Grade 3-4 Laboratory Abnormalities Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

21. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 20 CASTLE: CVR (HIV RNA < 50 Copies/mL) Treatment Outcomes at Week 96 Among Subjects With Advanced Disease Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

22. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 21 HEAT: Methods Ben Young et al. ICAAC/IDSA 2008; abstract H-1233. Copyright GlaxoSmithKline. Used with permission, 2008.

23. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 22 HEAT: Virologic Failure by Baseline HIV-1 RNA Strata and Failure Criterion Ben Young et al. ICAAC/IDSA 2008; abstract H-1233. Copyright GlaxoSmithKline. Used with permission, 2008.

24. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 23 HEAT: Summary of Treatment Emergent Resistance in Subjects With Protocol-Defined Virologic Failure Ben Young et al. ICAAC/IDSA 2008; abstract H-1233. Copyright GlaxoSmithKline. Used with permission, 2008.

25. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 24 ARIES: Study Design Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a. Copyright GlaxoSmithKline. Used with permission, 2008.

26. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 25 ARIES: Proportion of Subjects With vRNA < 50 Copies/mL and < 400 Copies/mL Through Week 36, ITT-E Population Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a. Copyright GlaxoSmithKline. Used with permission, 2008.

27. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 26 ARIES: Overall and Stratified Results by Baseline Viral Load Through Week 36, ITT-E Population Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a. Copyright GlaxoSmithKline. Used with permission, 2008.

28. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 27 MERIT: Phase III Trial Design Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

29. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 28 MERIT: Percentage of Patients With Undetectable HIV-1 RNA at Week 48 (Primary Endpoint) Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

30. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 29 MERIT: Patients With a D/M Tropism Result Using the Enhanced Sensitivity Trofile Assay Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

31. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 30 MERIT: Re-analysis With Enhanced Trofile At Screening Identified ~50% of Patients Who Displayed D/M Virus on Study Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

32. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 31 MERIT: Percentage of Patients With HIV-1 RNA < 400 and < 50 Copies/mL At Week 48 Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

33. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 32 ACTG 5211: Coreceptor Tropism by The Original and Enhanced Trofile Zhaohui Su et al. ICAAC/IDSA 2008; abstract H-895. Reprinted with permission. 25/114 Enhanced Trofile reclassified 25 individuals with R5 virus at screen 15/25 were VCV recipients 12/15 had early detection of X4 virus on study (before week 8) by original Trofile Original TrofileEnhanced Trofile ScreenEntryOn studyDM at Screen (n, %) R5DMDM/X47/12, 58% R5 DM/X49/18, 50% R5 9/84, 11%

34. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 33 ACTG 5211: Viral Load Reduction in Subjects With R5 Virus at Screen by the Original & Enhanced Trofile Assays Zhaohui Su et al. ICAAC/IDSA 2008; abstract H-895. Reprinted with permission. -2 -1.5 -0.5 0 0.5 Placebo 5 10 15Placebo 5 1015 Day 14Week 24 Change in Viral Load (Log10 HIV-1 RNA) Original Enhanced

35. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 34 NA-ACCORD: Distribution of 8,374 Study Patients First CD4+ Count Between 351 – 500 Measured 1996 – 2006 No Prior AIDS Diagnosis or ARVs (n = 8,374) Defer HAART n = 5,901 Initiate HAART n = 2,473 Transit to CD4+ < 350 Defer HAART n = 2,229 Initiate HAART n = 1,220 No Transit n = 2,452 Deaths (Person-Years) in Cohort Analysis 100 (5,815)137 (5,526)209 (5,295)221 (8,358) Percent Censored in IPW Analysis 57%0%10%0% Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

36. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 35 NA-ACCORD: Baseline Characteristics In Study Patients Defer HAART n = 5,901 Initiate HAART n = 2,473 Follow Up Person-Years16,6368,358 Hepatitis C Virus Infection (%)*3427 History of Injection Drug Use (%)*2116 Males (%)7583 Median Age Years (IQR)38 (32, 45)40 (34, 48) Median CD4+ Count Cells/mm 3 (IQR)432 (391, 468)421 (386, 459) Median log 10 HIV RNA Copies/mL (IQR)*4.1 (3.3, 4.6)4.3 (3.1, 4.9) White (%)3839 *Among patients with known status Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

37. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 36 NA-ACCORD: Results of Subset Analysis Both a history of IDU and HCV infection were significantly associated with increased risk of mortality RH95% CIP Value When Restricting the Analysis to Patients With Data Regarding History of Injection Drug Use (IDU) and Adjusting for IDU 1.71.2, 2.30.003 When Restricting the Analysis to Patients With Data Regarding Hepatitis C Virus (HCV) Infection and Adjusting for HCV 1.71.3, 2.1< 0.0001 RH = relative hazard of death for deferral of HAART; CI = confidence interval Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

38. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 37 NA-ACCORD: Inverse Probability Weighted Cox Regression Multivariate Analysis RH*95% CIP Value Deferral of HAART at 351 – 5001.71.4, 2.1< 0.001 Older Age (Per 10 Years)1.61.5, 1.8< 0.001 Female Sex1.10.9, 1.50.290 Baseline CD4 Count (Per 100 Cells/mm 3 ) 0.90.7, 1.00.083 Results were similar when restricting the analysis to the 77% of participants with baseline HIV RNA data Adjusted RH for deferral vs. immediate treatment was also 1.7; 95% C.I. was 1.4, 2.2; and P value was < 0.0001 HIV RNA was not an independent predictor of mortality RH = relative hazard; CI = confidence interval *Stratified by cohort and year Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

39. The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008 38 This presentation was created to accompany The Body PRO's summaries of key research presented at ICAAC/IDSA 2008, by David Wohl, M.D. The Body PRO's extensive coverage of ICAAC/IDSA 2008 also 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/ICAAC2008 today for a full listing of our conference coverage! Disclaimer: The Body PRO is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body PRO should not be used for diagnosing or treating a health problem or a disease.