1. The 17th Conference on Retroviruses and Opportunistic Infections San Francisco, CA February 16-19, 2010

2. Studies in ARV-Naïve Patients When to Start Rick Elion, MD Associate Professor, George Washington University School of Medicine Washington, DC

3. Life Expectancy of HIV-Positive Patients Comparison of life expectancy of Athena cohort patients to general population (n=4174) Age at week 24, country of birth and stage B symptoms were associated with a higher risk of death Expected life years remaining at age 25 was 53.1 (44.9-59.5) for general population and 52.7 for asymptomatic HIV+ patients The modeled life expectancy of patient presenting at an older age and women were slightly lower that general population Years of Life Remaining General Population Asymptomatic HIV+ Patients Years of Life Remaining Age at time of death Remaining Life Years Age at 24 weeks (years) Years lived van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 526.

4. Increasing CD4 at First Presentation but Patients Still Present Late to Care NA-ACCORD analysis regarding median CD4 on first presentation from 1996-2007 (N=35,009) Median CD4 on presentation has increased from 234 to 327 cells/mm 3 (P<0.01) Proportion of CD4 ≥350 cells/mm 3 at first presentation has increased from 34% to 47% (P≤0.01) Althoff K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 982.

5. Linkage of Testing to Routine Care Leads to Earlier Diagnoses Washington DC has an estimated HIV seroprevalence of 3% 2006 DOH expanded HIV testing to be included in routine care with improved clinical linkages From 2004 to 2006, HIV tests increased from 19,000 to 73,000 Among newly diagnosed, median CD4 count increased 57% p<0.001 Castel A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 34.

6. CD4 at Initiation of ARV Therapy Predicts Extent of CD4 Recovery 1,378 patients at 10 US clinics followed from 1996-2007 Median Peak CD4 was progressively higher for specific CD4 strata (p<0.001) Multivariate analysis: Increased mortality with CD4 < 50 (HR=4.6) and CD4 50-199 (HR=2.6) compared to ≥200 cells/mm 3 Lower BL CD4 at initiation also associated with increased risk of death from non-AIDS-related causes. Median CD4+ cell count Palella F, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 983.

7. Correlation Between Nadir CD4+ T-cell Count and Cardiovascular Risk Cross-sectional study of 80 HIV+ men on ARV Tx with undetectable HIV RNA Median age 47 years, nadir CD4 + T cell count 180 cells/mm 3 CV risk assessed using arterial stiffness (AS) by pulse wave analysis and carotid-femoral pulse wave velocity (PWV) Nadir CD4 count <350 cell/mm 3 independently associated with significant increase in AS and PWV Other significant determinants of PWV in multivariate analysis included age, systolic and diastolic BP, and diabetes. AS was not affected by the duration of ARV therapy or exposure to PIs or ABC. Significant determinants of PWV on Multivariate Analysis Beta (95%)P-value Age 0.48 (0.26-0.70) <0.001 Systolic blood pressure 0.44 (0.12-0.76) 0.007 Diastolic blood pressure -0.29 (-0.53-0.04) 0.03 Diabetes mellitus 2.38 (1.38-3.38) <0.001 Nadir CD4 <350 0.58 (0.15-1.01) 0.008 Ho J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 707.

8. Neurocognitive Disorders Associated with Nadir CD4 Counts Multicenter cohort study (CHARTER) of 1526 pts evaluating HIV-associated Neurocognitive Disorders (HAND) Complex testing consistent with defined criteria used to determine HAND 603 had HAND (without a substantial confounder); 726 not impaired Most with HAND (n=428) were asymptomatic and only a few (n=27) had frank dementia Multivariate analysis: Higher CD4 nadir associated with lower risk of HAND NImpairedUnimpairedOR (95% CI) All1525799726 Nadir CD4 < 503872221651.00 (reference) Nadir CD4 50-1994812582230.86 [0.66, 1.13] Nadir CD4 200-3493701891810.78 [0.58, 1.03] Nadir CD4 ≥3502871301570.62 [0.45, 0.84] On ART, Plasma VL <50c/ml589320269 Nadir CD4 < 50185112 73 1.00 (reference) Nadir CD4 50-199214118 960.80 [0.54, 1.19] Nadir CD4 200-349133 64 690.60 [0.39, 0.95] Nadir CD4 ≥350 57 26 310.55 [0.30, 0.99] Odds Ratios for NP Impairment Odds Ratio for Cognitive Impairment by CD4 Nadir <5050-199200-349≥350 1.1 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Odds Ratio CD4 Nadir Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429.

9. Impact of Expanded HAART Availability on New HIV Diagnoses Evaluation of association between expansion of ART coverage, population level HIV viral load and new HIV diagnoses in British Columbia Expansion of ART access in 2004-2009 associated with a significant decline in new HIV diagnoses After 2007, ~50% decrease in new HIV diagnoses among IDU occurred and associated with a decline in proportion of HIV+ IDU with plasma HIV-1-RNA level >1500 copies/mL from ~50% (2000-2004) to ~20% (2009) (P<0.001) New HIV + Diagnoses (All) New HIV + Diagnoses (IDU) Active on HAART Montaner J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 88LB.

10. Studies in ARV-Naïve Patients What to Start Joseph Eron, MD Professor, University of North Carolina School of Medicine Chapel Hill, NC

11. Elvitegravir and Cobicistat (GS-9350): Design of the Two Phase 2 Studies Randomization stratified by HIV RNA (≤ or >100,000 copies/mL) Primary Endpoint: Proportions with HIV RNA <50 copies/mL at Week 24 48-week trials Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB. Treatment-naïve HIV RNA ≥5,000 copies/mL CD4 cells >50 cells/mm 3 No Resistance to NRTIs NNRTIs PIs HBV- and HCV-negative EVG/GS-9350 /TDF/FTC + placebo n=48 EFV /TDF/FTC + placebo n=23 2:1 GS-9350 + placebo ATV + FTC/TDF n=50 RTV + placebo ATV + FTC/TDF n=29 2:1

12. Baseline Characteristics Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

13. Primary Endpoint: Percentage with HIV RNA <50 copies/mL (ITT M=F) Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB. Week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%) EVG/GS-9350/TDF/FTC EFV/FTC/TDF EVG/GS-9350 vs. EFV 04812162024 0 20 40 60 80 100 83% 90% Week Percentage with HIV RNA <50 copies/mL RTV + ATV + TDF/FTC GS-9350 + ATV + TDF/FTC Week 24 stratum-weighted difference -1.9% (95% CI: -18.4% to 14.7%) RTV vs. GS-9350 04812162024 0 20 40 60 80 100 84% 86% Week Percentage with HIV RNA <50 copies/mL

14. Adverse Events >5% Related to Randomized Drug Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

15. HIV-1 RNA ≥1000 c/mL Any CD4+ count ≥16 years of age Stratified by screening HIV-1 RNA (< or ≥100,000 c/mL) HIV+, ART-naïve (N=1857) 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 ATV/r QD ATV/r QD EFV QD EFV QD A5202: Study Design Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

16. * Required for those with recent infection, otherwise optional A5202: Overall Baseline Characteristics EFV (n=465) ATV/r (n=463) EFV (n=464) ATV/r (n=465) ABC/3TCTDF/FTC Median Age (years)373839 Male79%84%85%83% Race/Ethnicity White non-Hispanic38%41%43%40% Black non-Hispanic35%33% 32% Hispanic23% 22%24% Median HIV RNA (log 10 c/mL)4.74.64.7 Median CD4 (cells/mm 3 )225236234224 History of AIDS19%15% Genotype at screening*43%47% 40% HCV positive6%9% 7% Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

17. A5202: Time to Virologic Failure in Patients with Baseline HIV RNA >100,000 c/mL TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank test Hazard ratio, 2.33 (95% CI, 1.46-3.72) Probability of No Virologic Failure Results similar between EFV and ATV/r arms Sax PE, et al. NEJM 2009;361:2230-2240; Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

18. Probability of No Virologic Failure and CD4+ Change at Week 96 Percent without Virologic Failure HR 1.26 (0.76,2.05) HR 1.23 (0.77,1.96) HR 1.13 (0.82,1.56) HR 1.01 (0.70,1.46) CD4 Change (cells/mm 3 ) P= 250251 221 252 0.890.002 HIV RNA <100,000 c/mL All Subjects Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB. ATV/r EFV ABC/3TC TDF/FTC Percent without Virologic Failure

19. A5202: Percent of Virologic Failures with Emergence of Major Resistance Mutations P-values: ATV/r vs. EFV (among failures) * Major mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB. ABC/3TC TDF/FTC P<0.0001 P=0.0003 P<0.0001 P=0.046 Percent Viral failures No baseline resistance (N) 76 63 54 48

20. ACTG 5208: Study Design Octane Trial II Only African sites; partner study to same comparison in women who had received sdNVP Open-label comparison of NVP and LPV/r, both combined with TDF/FTC Baseline CharacteristicsNVP (n=249)LPV/r (n=251) Age3534 CD4121 VL5.165.15 ZDV exp2%1% BL NVP Resistance1%0 Subtype C75%68% ART-naïve women with CD4+ <200 cells/mm 3 (N=500) LPV/r + TDF/FTC NVP + TDF/FTC Two primary endpoints: Time to VF/death Time to discontinuation Median F/U (weeks) 120 116 Boltz V, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 154.

21. OCTANE 1: Results Among Women with Prior sdNVP Exposure Virologic Failure or Death Patient Percent NVPLPV/r Adjusted HR 3.6 (95% CI: 1.7-7.5) Boltz V, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 154. sdNVP=Single-dose NVP

22. ACTG 5208/OCTANE 2: Results at 168 Weeks Virologic Failure or Death Patient Percent NVP LPV/r HR 0.85 (95% CI: 0.56-1.29) VF: LPV/r 17% vs. NVP 15% Death: LPV/r 3% vs. NVP 2% HR 3.4 (95% CI: 2.2-5.5) Discontinuation Pts D/C due to AE: NVP 35 vs. LPV/r 0 − Hepatic events 20, rash 12, hepatic/rash 2 Boltz V, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 154. Patient Percent

23. Studies in Treatment-Experienced Patients And Investigational Compounds Calvin Cohen, MD Research Director, CRI New England Harvard Vanguard Medical Associates Boston MA

24. ODIN: Study Design Phase IIIb, randomized, open-label study DRV/r 800/100mg qd + OBT ‡ (n=294) DRV/r 600/100mg bid + OBT ‡ (n=296) ARV-experienced patients, aged  18 years HIV-1 RNA >1000 copies/mL CD4 cell count >50 cells/mm 3 No DRV RAMs at screening* Stable HAART for  12 weeks Treatment phase (up to 48 weeks) stratified by screening HIV-1 RNA (  50,000, >50,000 copies/mL) ARV = antiretroviral; HAART = highly-active antiretroviral therapy; OBT = optimized background therapy; qd = once-daily; bid = twice-daily; RAMs = resistance-associated mutations Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57 * DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V ‡ Individualized OBT included ≥2 N(t)RTIs based on ARV history and resistance testing Only restrictions on previous therapy: use of enfuvirtide, tipranavir, DRV, current use of investigational drugs

25. ‡Using Antivirogram ® Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57 ODIN: Key Features of Population including Prior and Concurrent ARVs

26. ODIN: Virologic Response Rates and Resistance Outcomes Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57 ‡ Not significant; §Also DRV RAMs Resistance Summary DRV/r 800/100mg qd Screening HIV-1 RNA (copies/mL) N= 222 22472 52.8% 76.8% 78.4% >50,000  50,000 0 20 40 60 80 100 % HIV-1 RNA <50 copies/mL (% [95% CI]) DRV/r 600/100mg BID DRV/r 800/100mg QD DRV/r 600/100mg bid Response by Screening HIV RNA Meets Noninferiority Difference in response qd vs. bid (ITT): 72.1–70.9 = 1.2% (95% CI = –6.1%, 8.5%)

27. ODIN: Summary of Safety and Lab Findings * Includes deaths (2 in qd group; 6 in bid group; none considered by investigator as related to DRV treatment Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57

28. VICTOR E3 & 4: DESIGN 2 randomized, identical, placebo-controlled, double-blind, phase 3 trials Documented resistance to ≥2 available drug classes (NRTI, NNRTI, or PI) or ART experience of at least 6 months Primary endpoint: % HIV RNA <50 copies/mL at 48 weeks Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB Treatment-experienced R5-HIV only (N=721)* Treatment-experienced R5-HIV only (N=721)* Vicriviroc 30 mg + OBT (n=486) Placebo + OBT (n=235) Week 24 Interim analysis Week 48 Final analysis Randomized 2:1 to VCV:Placebo *857 were enrolled but 721 R5 by Trofile ES; this is the MITT population and this subset was analyzed prior to any unblinding of results

29. VICTOR E3 & 4: Pooled Efficacy 70% n=176 55% n=85 ≤2 61% n=293 65% n=145 ≥3 % HIV RNA <50 c/mL Response by Overall Sensitivity Score 80% 60% 40% 20% 0% 100% VCVControl No. of Active Drugs in Background Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB Note: Subset with 0-1 active Drug: 47% VCV (n=19) vs. 12% (n=8) on Pbo responded

30. VICTOR E3 & 4: Virologic Failure, Resistance and Discontinuations Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB

31. Victor E3 & 4: Key Adverse Events *Causes of Death (1 each): Intestinal obstruction & septicemia S/P prior abdominal surgery, Homicide; Myocardial infarction (recurrent while in OR for CABG); Chronic congestive heart failure with pericardial effusion; Acute cholecystitis with septicemia; Plasmablastic lymphoma; Multiorgan system failure accompanied by cholecystitis and pleural effusion

32. Potent Oral CCR5 and CCR2 receptor antagonist In vitro protein-adjusted EC50=0.29 nM for R5 Neither a CYP inducer nor inhibitor Additive / synergistic activity with other ART classes in vitro Oral bioavailability (current formulation) enhanced by food Once daily dosing (Plasma T ½=35-40 hours) Study Design: Ten day monotherapy, R5-tropic pts CCR2 receptors are associated with, and currently being studied in several inflammation-associated diseases (atherosclerosis, rheumatoid arthritis, insulin resistance) Thus far no significant safety signals are identified with CCR2 antagonists TBR-652: Characteristics and Potential for CCR2 Inhibition Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 53

33. TBR-652: Median and Nadir Antiviral Response with Ten Days Monotherapy Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 53 Median VL Response 10 day dosing Nadir Viral load Response Note: CCR2 inhibition observed using MCP-1 level increases

34. TBR-652: Summary of Adverse Events * AEs in 2 patients or more per cohort judged at least possibly related to study drug. Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 53

35. Studies in Resistance Issues Andrew Zolopa, MD Associate Professor, Stanford University School of Medicine Palo Alto, CA

36. Octane 1: Low Level NNRTI Resistant Variants Explain Virologic Failures Women prior SD NVP – For MTCT prevention Randomized clinical trial: NVP vs. LPV/r – TDF/FTC backbone NVP: Higher rate of VF (HR 3.5) Only 1/3 of NVP failures had resistance by standard GT Analyzed results by ASP Frequency of >0.8% associated with increased risk of VF (n=120) (n=119) (n=15) (n=18) (n=105) (n=101) P=0.001 P=0.006 P=0.038 8% 26% 13% 19% 6% 9% ASP=Allele specific PCR Boltz V, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 154.

37. OCTANE 1: Virologic Outcomes by Resistance at baseline by Allele Specific PCR (ASP*) Overall Baseline GT: no NNRTI R % Virologic Failure Boltz V, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 154. *ASP detects specific mutations; sensitivity to 0.1%

38. Transmitted Drug Resistance in US: Newly Diagnosed 2007 CDC surveillance for transmitted drug resistance (TDR) 10,496 with new HIV Dx 2,480 with genotype TDR detected in 16% of patients with new HIV diagnosis Most common: NNRTI 83% had single mutation No demographic risks factors identified HIV TDR Surveillance Areas (2007) Seattle-King County HIV TDR (2007) Percent with TDR 50% K103N Kim D, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 580.

39. Superinfection Leads to Viral Load Increases Report of HIV superinfection in MSM (M1 and M2) Source patient (M2) MDR HIV on partially suppressive LPV/r + ABC/3TC regimen Superinfected patient (M1) HIV RNA <50 c/mL on ABC/AZT/3TC Sudden increase in HIV RNA to >200 c/mL with further rebound Rebound associated with 3 class resistance that matched M1 Phylogenetically related viruses found in M1 and M2 M1 HIV displaced by M2 HIV Castro E, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 480.

40. BENCHMRK: Trial Design and Week 156 Results Week 240 HIV-1-infected Triple-class resistant HIV-1 RNA>1000 copies/mL; No CD4 cell cut-off RAL 400mg BID + OBT P018 (n=234) P019 (n=232) Placebo+ OBT P018 (n=118) P019 (n=119) RAL 400mg BID + OBT RAL 400mg BID + OBT Primary endpoints: Week 16 Current Analysis: Week 156 2:1 Raltegravir + OBT Placebo + OBT 462 237 461 237 462 237 460 237 459 237 Number of Contributing Patients Weeks 100 80 60 40 20 0 024156*96*48* Percent of Patients with HIV RNA <50 Copies/mL 22% 26% 33% 50% 57% 62% Percent of Patients (95% CI) with HIV RNA <50 Copies/mL (NC=F Approach) Raltegravir + OBT Placebo + OBT 462 237 435 230 397 208 418 219 439 228 Number of Contributing Patients 0 Change from Baseline CD4 Cell Count (cells/mm 3 ) Weeks 200 150 100 50 0 24156*96*48* 63 4945 124 109 164 Change from Baseline in CD4 Cell Count (cells/mm 3 ) (OF Approach) Eron J, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 515.

41. BENCHMRK: Analysis by Early HIV RNA Response in RAL Treatment Group *For HIV RNA, only discontinuations due to lack of efficacy counted as failures Patients with low level viremia demonstrated: – Favorable wk 156 virologic and immunologic outcomes (CD4 increase from BL +226 cells/mm 3 ) – Significantly shorter time to loss of virologic response (TLOVR ≥400 cp/mL) compared to CS group Category Name Early Response Definition : Observed HIV RNA (copies /mL) Week 16-48 (5 time points) RAL N=462 Continuous SuppressionCSAll time points <50199 Low Level ViremiaLLVAll 50111 Not SuppressedNSIntermittent >400 (not consecutive)63 Not Included-Pts. who discontinued double blind treatment prior wk 48*89 Eron J, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 515.

42. Toxicities in Clinical Trials Paul Sax, MD Associate Professor, Harvard Medical School Boston, MA

43. A5202: ATV/r vs. EFV Median Change in Fasting Lipids (Week 48) In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r Median Change in Fasting Lipids (mg/dL) TCLDLHDLTG ABC/3TC ATV/r 2913824 EFV 40211215 p-value <0.001 0.07 TDF/FTC ATV/r 102514 EFV 2210813 p-value <0.0010.002<0.0010.26 Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

44. A5202: ATV/r vs. EFV Median Change in Creatinine Clearance Change in Calculated Creatinine Clearance (mL/min) Week 48Week 96 ABC/3TC ATV/r 3.16.1 EFV 4.37.8 p-value 0.170.33 TDF/FTC ATV/r -0.9-2.6 EFV 4.14.9 p-value 0.001<0.001 Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

45. A5202: Pre-Specified Clinical Adverse Events *Defined as coronary artery disease, infarct, ischemia, angina, cerebrovascular accident, transient ischemic attack or peripheral vascular disease. Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

46. 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 ATV/r QD ATV/r QD EFV QD EFV QD A5224s: Metabolic Sub-Study of A5202 N=69 N=70 N=65 Enrolled in Substudy Study Evaluations: -DXA at 0, 24, 48, 96 weeks, then yearly -CT abdomen at 0 and 96 weeks -Serum lipids and plasma Primary endpoints (TDF/FTC vs. ABC/3TC): 1) Percent change in hip and lumbar spine BMD 2) ≥ 10% loss of limb fat Secondary endpoints: 1) bone and fat loss between EFV and ATV/r 2) on-study fractures EFV N=139 ATV/r N=130 EFV vs. ATV/r TDF/FTC vs. ABC/3TC TDF/FTC N=139 ABC/3TC N=135 McComsey, G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

47. * linear regression No significant interaction of NRTI and NNRTI/PI components (P=0.63) A5224s: Mean % Change in Lumbar Spine BMD P=0.004 P=0.035 McComsey G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

48. A5224s: Limb Fat Changes No statistically significant differences incidence of 10% and ≥ 20% loss of limb fat between NRTI components and NNRTI/PI components Most study subjects gained limb fat; ATV/r increased limb/trunk fat more than EFV McComsey G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

49. STEAL: Switch to ABC/3TC or TDF/FTC Primary Results: Similar virologic results Increased risk of CV events in ABC/3TC group (8 ABC/3TC vs 1 TDF/FTC, p=0.048) not explained by lipid changes No difference in renal outcomes Loss of bone density in TDF/FTC vs gain in ABC/3TC group Inflammatory Marker Substudy 14 biomarkers (inflammatory/renal, thrombotic, endothelial function) measured at weeks 0, 12, 24, and 48 Primary analysis (change from week 0-12): No significant association between use of ABC/3TC and change in markers Alternative explanation for ABC/3TC association with CVD needed HIV+ Suppressed on 2 NRTI + PI or NNRTI (N=357) TDF/FTC FDC n=179 ABC/3TC FDC n=178 Martin Clin Infect Dis. 2009 Nov 15;49(10):1591-601; Humphries A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 718.

50. Abacavir and CVD: Search for a Mechanism Increased platelet reactivity 1 Carbovir TP (ABC metabolite) inhibits soluble guanylyl cyclase, a known inhibitor of platelet function  increases platelet activation In vitro, ABC induces human leukocyte-endothelial cell interaction at clinically-relevant doses 2 1. Baum P, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 717; 2. de Pablo C, et al. ibid., 716. Abacavir Control

51. QUAD or GS-9350 Studies: Estimated GFR (Cockcroft-Gault) No treatment discontinuations due to renal adverse events Separate study in normal volunteers receiving GS-9350 or placebo for 7 days Creatinine increase occurs in days, rapidly reversible, due to inhibition of tubular secretion No effect on GFR as measured by iohexol clearance Effect similar to that seen with cimetidine or trimethoprim *Estimated GFR by Cockcroft-Gault Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

52. STARTMRK Metabolic Study: RAL vs. EFV Randomized, double-blind study comparing RAL vs EFV, both with TDF/FTC Week 96 lipids (all pts, n=563) EFV increased TC, HDL-C, LDL- C, TG, and glucose significantly more than RAL No significant difference in total/HDL chol ratio Dexa substudy (n=111) Limb fat increased over time Week 96, >20% loss of limb fat 3/37 (8%) on RAL 2/38 (5%) on EFV ‡ p <0.001 * P =0.025 ‡‡ ‡ ‡ * 18.2 17.0 18.1 17.7 Mean Percent Change in Appendicular Fat Lipid Changes DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720.

53. Metabolic Complications Ian Frank, MD Professor of Medicine Director, Clinical-Therapeutics Program University of Pennsylvania Center for AIDS Research Philadelphia, PA

54. DAD: Triglycerides and MI Risk Methods: Time from D:A:D enrollment to first MI by time-updated TG level Adjustments for associations of independence from other CAD risks TG without regard to fasting Subjects (n = 30,703): Age – 39; White – 54%; Current smoker – 37%; CD4+ 407; HIV RNA BLQ – 33% Incidence of MI according to TG group 580 MIs over 178,835 PY After adjustments for other CVD risks, doubling of TG associated with an 11% increased risk for MI Worm S, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 127. PY = Patient-Years

55. Markers Associated with CV Risk in NIH Studies Case controlled study of CVD events 52 of 1892 patients since 1995 Significant traditional risk factors for events: smoking, family hx, lipids Markers not associated with risk: hs- CRP, IL-6, IL-10, TNFa Conclusions: Biomarkers may help stratify CVD risk in HIV patients D-dimer and sVCAM associated with Increased Risk for CVD sVCAM-1 (ng/ml) Ford E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 713. CVD Cases Controls PTE=Prior to Event P value for all <0.05

56. Factors Associated with CVD Risk Visceral Adiposity 1 Observational study of 1325 HIV patients in metabolic clinic CVD in 51 Visceral adipose tissue was risk factor, but not waist size or BMI B-type natriuretic peptide (BNP) 2 SMART; 186 subjects with CVE and 329 controls Median BNP 48.1 in CVE group vs 25.7 in controls (p<0.0001) Adjusted OR 2.3 for CVE in highest vs. lowest quartile Incomplete Immune Recovery on ARVs 3 ATHENA cohort 3071 patients on ART >2 years; 58 CVE over 10 years of follow-up More CVE if CD4 <200 cells/mm 3 (overall log rank, p=0.02) Adjusted hazard ratio* (95% CI) for CVE by CD4: 1. Guaraldi G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 703; 2. Duprez D, et al. ibid., Abst. 712; 3. van Lelyveld S, et al. ibid., Abst. 714. CVD=cardiovascular disease; CVE=cardiovascular event <200200-350350-500>500 Referent0.45 (0.18-1.08)0.70 (0.33-1.47)0.54 (0.23-1.25) *Adjusted for age, gender, smoking, ARV regimen (PI vs. NNRTI) and family history of CVD

57. Increased Fracture Rate in HIV Outpatient Study Patients (HOPS) Comparison of HOPS cohort (n=8,456) vs National Hospital Discharge Survey and National Hospital Ambulatory Medical Care Survey (NHAMCS) Adjusted for age and gender HOPS: 276 Fractures during median 4.8 yrs follow-up Risk factors for fractures Age >47 Nadir CD4+ count <200 HCV co-infection Diabetes Substance use Conclusion: Fracture rates are higher in HIV infected population and rate is increasing with age Gender-adjusted rates of fracture among adults aged 25-54 years HOPS NHAMCS- OPD P value for trend = 0.01 P value for trend = 0.32 Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128.

58. Fracture Rate in HIV Infected Women in WIHS Cohort Retrospective analysis of 1728 HIV+ and 663 HIV- individuals Fractures at hip, spine, wrist or other site Ever or within past 6 months Demographics (HIV+) 56% black, median age = 40, BMI = 28 Medical History (HIV+) Smoking 45%, Vitamin D supplements 42%, Menopause 20%, HCV+ 25% CD4+ count = 482 On ARVs – 66%; Median years ART 5 +/- 10 HIV +HIV - No. Incident Fracture (%) Fracture/ 100 py No. Incident Fracture (%) Fracture/ 100 py P-value Any Site148 (9%)1.7947 (7%)1.410.13 Spine15 (1%)0.187 (1%)0.210.92 Hip15 (1%)0.184 (1%)0.120.32 Wrist25 (1%)0.2911 (1%)0.320.94 Other105 (6%)1.2535 (4%)1.040.29 Yin M, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 130.

59. High Prevalence of Vitamin D Deficiency in HIV Infection Retrospective seasonal analysis of Vitamin D deficiency and insufficiency within Swiss cohort Started ARV in: Fall (n=108); Spring (n=103) 75% men; age = 37; White = 87%; CD4+ 227; BMI = 22.9 ARVs: TDF – 17%; NNRTIs – 43%; PI -56% Conclusions Vitamin D deficiency and insufficiency are common, but seasonal Blacks are at increased risk NNRTI use a risk factor Vitamin D Deficiency is Not Influenced By ART Baseline before cART Fall (n=108) Spring (n=103) Vitamin D Deficiency (<30 nmol/L)14%42% Insufficiency (<75 nmol/L)62%53% Target Level (≥75 nmol/L)24% 5% 12 Months after cART Start Vitamin D Deficiency14%47% Insufficiency63%48% Target Level23% 5% 18 Months after cART Start Vitamin D Deficiency18%52% Insufficiency59%38% Target Level23%10% Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 752.

60. EuroSIDA Study: Risk for Chronic Kidney Disease Analysis of patients with ≥3 creatinine measurements + weight 6,842 patients with 21,482 person-years of follow-up Definition of CKD (eGFR by Cockcroft-Gault) If baseline eGFR ≥60 mL/min/1.73 m 2, fall to <60 If baseline eGFR <60 mL/min/1.73 m 2, fall by 25% 225 (3.3%) progressed to CKD Incidence of CDK: No TDF: 0.7/100 p-yrs (0.5 to 0.8) ≥4 years TDF: 2.4/100 p-yrs (1.7 to 3.0) Risk factors for CKD on TDF: age, HTN, HCV, lower eGFR, lower CD4+ count Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 107LB. Multivariable IRR/year95% CIP-value Tenofovir1.161.06-1.25<0.0001 Indinavir1.121.06-1.18<0.0001 Atazanavir1.211.09-1.340.0003 Lopinavir/r1.081.01-1.160.030 Cumulative Exposure to ARVs and Risk of CKD

61. Malignancies and Hepatitis Jürgen Rockstroh, MD Professor, University of Bonn Bonn, Germany

62. Cancer Incidence in AIDS Patients Study of cancer risk in AIDS patients from 1980-2006 (N=372,364) Predominantly male (79%), non-hispanic black (42%), MSM (42%) Median age of 36 years at the onset of AIDS Cancer risk in years 3 - 5 after AIDS onset increased for AIDS but also Non-AIDS defining cancers Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27. Cancer typeNo. casesSIR95% CI AIDS-defining cancers Kaposi sarcoma313653215137 - 5511 Non-Hodgkin lymphoma 33453231 - 33 Cervical cancer1015.65.5 - 6.8 Non-AIDS-defining cancers Anal cancer2192724 - 31 Liver cancer863.73.0 - 4.6 Lung cancer5313.02.8 - 3.3 Hodgkin lymphoma1849.17.7 - 11 All non-AIDS related cancers 21551.71.5 - 1.8 SIR=Standardized Incidence Ratios

63. Cancer Mortality in AIDS Patients Population attributable risk among people with AIDS in the US Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27. Cumulative Incidence (%)

64. HIV Infection and Lung Cancer VA-Cohort (3,707 HIV- positive patients) Predominantly male (98%), white (43%) Median age 47 years Lung cancer risk factors Smoking and drug abuse more often among HIV+ Similar rates of COPD After adjustment for smoking, risk of lung cancer higher in HIV+ patients Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 30. 26 cases per 10,000 pt-yrs 15 cases per 10,000 pt-yrs

65. Clearance Chronic HCV Predictive value pRVC223PPV 88% No pRVC423NPV 85% cEVC324PPV 89% No cEVC223NPV 92% Natural Course AHC in HIV-positive Multicenter observational cohort study HIV+ patients with acute hepatitis C (AHC) and 24 week follow-up after diagnosis or presumed date of infection (N=92) HCV-RNA level 4 weeks after AHC diagnosis may identify patients unlikely to spontaneously clear HCV pRVC (partial rapid virological control)=2 log drop of HCV-RNA at week 4 cRVC (complete rapid virological control)=HCV-RNA <600 IU/ml at week 4 cEVC (complete early virological control)=HCV-RNA <600 IU/ml at week 12 Clearance=HCV-RNA <600 IU/ml week 24 Vogel M, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 640.

66. Adherence and Pharmacokinetics Edwin DeJesus, MD, FACP Medical Director, Orlando Immunology Center Orlando, FL

67. HIV REACH cohort Difficult to treat population: marginally housed, substance abuse, psychiatric illness, etc. Started ART within 6 months PI (n=11) PI/r (n=57) NNRTI (n=14) TDF/FTC/EFV (n=40) Adherence and virologic outcomes evaluated among different treatment regimens Controlled for confounders: Age, gender, race, education, IVDA, homeless, depression, CD4 nadir Adherence with a Once-daily Pill (EFV/TDF/FTC) PIPI/rNNRTIEFV/TDF/FTC ADHERENCE >90% BY TREATMENT GROUP 36.4%37.5%23.1%67.5% HIV RNA ≤50 c/mL BY TREATMENT GROUP 54.6%47.4%42.9%70% Bangsberg D, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 510.

68. Adherence and Virologic Success with Once-Daily Pill (EFV/TDF/FTC) In comparison to other commonly prescribed regimens, EFV/TDF/FTC exhibited higher rates of adherence and virologic suppression Virological suppression was better with EFV/TDF/FTC even when comparing patients with lower adherence rates Bangsberg D, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 510.

69. Raltegravir Concentrations in Cervicovaginal Fluid PK study of RAL levels in cervicovaginal fluid (CVF) in 14 HIV+ women Virologically controlled on a stable RAL containing regimen Evaluated with paired sample of blood plasma and CVF Samples collected between 13-14.5 hours post last dose intake Results: RAL levels in CVF > plasma All patients had undetectable CVF HIV RNA Similar study in men found Semen to blood plasma concentration ratio was higher at the end of dosing interval suggesting accumulation and persistence of RAL in semen RAL concentrations in CVF were about 2.3 fold those in plasma, and 16 fold higher than the IC50 of wild type HIV-1 Distribution of RAL concentrations in Blood Plasma and Cervicovaginal fluid (n=14) 100 Cervicovaginal Fluid Plasma 93 ng/mL 235 ng/mL IV :127% IV :176% 10 IC 95 ~15 ng/mL for WT-HIV-1 with 50% Human Serum Log RAL Concentration (ng/mL) Interindividual Variability (IV) IQR 75% Median IQR 25% Legend Cyril C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 608; Bonora S, et al. ibid., Abst. 609.

70. Darunavir Penetration in Seminal Plasma of HIV Positive Patients 47 men participating in the MONOI study receiving DRV 600/100 BID Darunavir Concentrations From Paired Samples: Blood And Seminal Plasma Seminal plasma DRV level: Average of 6-fold above the DRV EC 50 for wild type HIV-1; however, some close to or below EC 50 Log RAL Concentration (ng/mL) 100000 10000 1000 100 10 Blood Plasma Total Fraction Blood Plasma Free Fraction Seminal Plasma DRV EC 50 Corrected for protein binding of WT HIV-1 DRV Concentration (ng/ml) 95% 75% Median 25% 5% Legend: 344 ng/mL 3200 ng/mL 212 ng/mL Lambert-Niclot S, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 610.

71. Limitations of Current Therapies in Developed Countries HIV persists despite suppressive therapy Full life expectancy is not restored Immune recovery may be incomplete Immune activation and inflammation persist in many treated patients Long term toxicity; known and undiscovered Adherence to therapy remains a challenge Antiretroviral drug resistance Failure, as yet, to decrease transmission Access to care Eron J. 17th CROI; San Francisco, CA; February 16-19, 2010. Symposium 183 (Modified).

72. The 17th Conference on Retroviruses and Opportunistic Infections San Francisco, CA February 16-19, 2010