1. Current Clinical Controversies in the Treatment of HIV/AIDS Paul E. Sax, MD Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

2. 2 Faculty: Content Development and Training Calvin J. Cohen, MD, MS Research Director, CRI New England Clinical Instructor, Harvard Medical School Boston, Massachusetts Edwin DeJesus, MD, FACP Infectious Disease Consultants Medical Director, Orlando Immunology Center Orlando, Florida Paul E. Sax, MD Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women's Hospital Associate Professor of Medicine, Harvard Medical School Boston, Massachusetts

3. Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: — Describe and discuss current controversies regarding HIV treatment — Identify key studies that potentially can improve outcomes with HIV treatment — Summarize the clinical data supporting methods for improving the health and management of HIV-infected patients

4. 4 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co- Morbidities

5. 5 2009 DHHS Guidelines: Recommendations for Initiation of ART in Naïve Patients Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009. Strength of Recommendation: A = Strong; B = Moderate; C = Optional Quality of Evidence for Recommendation: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion Note: HIV RNA >100,000 c/mL and decline of CD4+ count > 100 cells/mm 3 per year favor starting ART Clinical Category CD4 Cell Count (cells/mm 3 ) 2009 DHHS GuidelinesStrength-Quality AIDS-defining illnessAny value Treat A-I Asymptomatic <350Treat 350 to 500Treat A/B-II: 55% A vs. 45% B >500 Treat/OptionalB/C-III: 50% B vs. 50% C Pregnancy, HIV-associated nephropathy, HIV/HBV when HBV treatment indicated Any value TreatA-III

6. 6 SMART: Influence of CD4+ Count and Treatment on Clinical Event Rate Last CD4+ Cell Count (cells/mL) <250250–349 350– 499 ≥500Overall Immediate ART Person- yrs (%)* 10 (2.6) 30 (7.9) 109 (28.8) 230 (60.7) 379 (100) Rate**10.46.71.80.01.3 Deferred ART Person- yrs (%)* 19 (6.4) 65 (21.7) 118 (39.5) 97 (32.4) 299 (100) Rate**16.09.27.63.17.0 Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018. Opportunistic Disease and Death Cum. Probability (X100) 25 Months Deferred ART Immediate ART HR = 4.38 (95%CI, 1.45–13.2); P =.009 5 20 10 15 0 08412162024283236 Serious Non-AIDS (CV, Renal, CA) HR = 7.05 (95% CI, 1.58–31.5); P =.01 36 Cum. Probability (X100) Deferred ART Immediate ART 5 20 10 25 15 0 084121620242832 Months *Time spent in the CD4+ cell count category censored at event **per 100 person years

7. 7 NA-ACCORD: Risk of Death with ART Deferral 351-500 CD4+>500 CD4+ RR95% CIPRR95% CIP Deferral of ART1.71.3, 2.3<0.0011.91.4, 2.8<0.001 Female Sex1.20.9, 1.60.241.91.3, 2.6<0.001 Older Age (per 10 years) 1.71.5, 1.9<0.0011.81.6, 2.1<0.001 Baseline CD4 count (per 100 cells/mm 3 ) 1.10.7, 1.80.590.90.9, 1.00.03 ●HIV RNA was not an independent predictor of mortality ●Exclusion of IDU or HCV did not affect overall relative risk ●Rate of virologic suppression (<500 c/ml) higher in pts who started ART earlier Kitahata M, et al. New Engl J Med 2009;360:1815-26.

8. 8 ART-CC: When Should ART be Started? Hazard ratios for AIDS or death, adjusted for lead time/unseen events Sterne J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 72LB. 4 Hazard Ratio for AIDS or Death 2.5 1 5004003002001000 CD4 Threshold (cells/mm 3 ) ComparisonHazard Ratio (95% CI) 276-375 vs 376-4751.19 (0.96 to 1.47) 251-350 vs 351-4501.28 (1.04 to 1.57) 226-325 vs 326-4251.21 (1.01 to 1.46)

9. 9 Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy 1. Moore R, et al. Clin Infect Dis. 2007;44(3):441-446; 2. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192. Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start 1000 800 600 400 200 0 0 4896 144 192 240 288336 ATHENA National Cohort 2 Weeks From Starting ART <50 50-200 200-350 350-500 ≥500 Years on ART Johns Hopkins HIV Clinical Cohort 1 Mean CD4 Cell Count (cells/mm 3 ) 0 12345 200 400 600 800 0 1000 <200 201-350 >350

10. 10 ●Patients initiating ART should be willing and able to commit to lifelong treatment and understand the benefits and risks of ART and the importance of adherence ●Patients and clinicians may defer therapy based on clinical or personal circumstances ●The decision to defer should depend on CD4 count and viral load ●Deferring therapy may be considered for: - Adherence barriers - Comorbidities that complicate or prohibit ART - Elite controllers/Long-term nonprogressors 2009 DHHS Guidelines: Conditions Where Deferral of Therapy Might be Considered Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.

11. 11 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co- Morbidities

12. 12 DHHS Guidelines: TDF/FTC a part of all Preferred Regimens for Treatment-Naïve Patients Preferred Regimens EFV/TDF/FTC ATV/r + TDF/FTC DRV/r (once daily) + TDF/FTC RAL + TDF/FTC [Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC] Alternative Regimens EFV + (ABC or ZDV)/3TC NVP + ZDV/3TC ATV/r + (ABC or ZDV)/3TC FPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC LPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC SQV/r + TDF/FTC Acceptable Regimens EFV + ddI + (3TC or FTC) ATV + (ABC or ZDV)/3TC Insufficient Data MVC + ZDV/3TC RAL + (ABC or ZDV)/3TC (DRV/r or SQV/r) + (ABC or ZDV)/3TC Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

13. 13 Studies Comparing ABC/3TC and TDF/FTC A5202HEATASSERT Sponsor NIAIDGSK Sample Size1858 (797 HIV RNA > 100,000 c/mL) 688385 BlindingDouble-Blind None 3 rd DrugEFV or ATV/rLPV/r QDEFV Primary EndpointTime to Virologic Failure* <50 c/mL at 48 wksChange in GFR at wk 48 by MDRD HLA-B*5701 TestingPermitted, not requiredNoRequired, only negative pts enrolled Key ResultsFor those with HIV RNA >100,000 c/mL, study stopped early due to higher rate of virologic failure with ABC/3TC ABC/3TC non- inferior No difference in eGFR; proportion <50 c/mL favored TDF/FTC (71% vs. 59%; difference 11.6%, 95% CI 2.2-21.1); Total hip and lumbar spine BMD decline more with TDF/FTC *Confirmed >1000 c/mL between wks 16-24, >200 c/mL wk 24 on)

14. 14 No. at Risk ABC-3TC398363313267222188137874920 TDF-FTC3993613212842362041601046523 A5202: Time to Virologic Failure in Patients with Baseline HIV RNA >100,000 c/mL Sax PE, et al. NEJM 2009;361:2230-2240. 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

15. 15 A5202: Virologic Failure According to Baseline Characteristics Sax PE, et al. NEJM 2009;361:2230-2240. ABC-3TC (N=398) TDF-FTC (N=399) Sub Group Events/person-yr at risk (Events per 100 person-yr) Hazard ratio (95%) P Value for interaction Overall57/398 (14.82)26/399 (6.34)2.33 (1.46-3.72)<0.001 Sex0.04 Male50/331 (15.41)18/345 (5.24)3.00 (1.74-5.17) Female7/67 (11.63)8/54 (11.97)0.85 (0.30-2.39) Age0.07 30yr3.24 (1.73-6.08) 40yr2.08 (1.28-3.39) Race or ethnic group0.55 White18/170 (10.33)8/202 (3.63)2.82 (1.22-6.53) Black26/112 (26.71)12/94 (13.93)1.94 (0.96-3.90) Hispanic9/103 (8.87)6/93 (6.59)1.35 (0.48-3.83) HIV-1 RNA0.20 5.5 log 10 copies/mL2.64 (1.58-4.40) 6.0 log 10 copies/mL3.39 (1.60-7.22) CD4 count0.007 50 cells/mm 3 3.54 (1.97-6.36) 200 cells/mm 3 1.68 (0.98-2.88) Genotype tested at screen0.02 Yes22/175 (14.05)3/166 (1.99)7.21 (2.15-24.20) No35/223 (15.35)23/233 (8.88)1.71 (1.00-2.91) 0.041.0025.00 ABC-3TC BetterTDF-FTC Better

16. 16 HEAT: Virologic Failure by Baseline HIV-1 RNA Using A5202 Efficacy Endpoint Percent without Virologic Failure n =n = 188155140205 Pappa K, et al. 17th IAC, Mexico City, 2008. Abst. THAB0304. Young B, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1233. 41% 63% 18% 19% 18% 4% 22% 15% 0% 20% 40% 60% 80% 100% ABC/3TCTDF/FTC Proportion of Subjects with VF ≥500,000 c/mL 250,000 - <500,000 c/mL 100,000 - <250,000 c/mL <100,000 c/mL ~59% ~37%

17. 17 ASSERT: Proportion of Subjects with HIV-1 RNA <400 and <50 copies/ml by Visit (TLOVR) Observed analysis: ≥90% in both arms achieved <50c/ml at Week 48 W48 difference for % <400 cps/ml was 9.5% (95% CI: 0.6,18.4) W48 difference for % <50 cps/ml was 11.6% (95% CI: 2.2, 21.1) ABC/3TC FDC QD: HIV-1 RNA <400 copies /mLTDF/FTC QD: HIV-1 RNA <400 copies /mL ABC/3TC FDC QD: HIV-1 RNA <50 copies /mLTDF/FTC QD: HIV-1 RNA <50 copies /mL Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1.

18. 18 ASSERT: Adjusted Mean Change in eGFR (MDRD) Subjects at Visit TDF/FTC QD ABC/3TC QD192158144 193176167 Change from BL in GRF by MDRD (mL/min/1.73m2) -8 -6 -4 -2 0 2 4 6 8 02448 Week 36124 172 181 155 173 135 159 ABC/3TC QD TDF/FTC QD Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1. n Adjusted MeanS.E.Diff. 95% CI for DifferenceP-value ABC/3TC FDC QD1740.220.890 TDF/FTC FDC QD1841.180.8280.953(-1.445, 3.351)0.435

19. 19 ASSERT: % Change from Baseline in Hip and Spine Bone Mineral Density Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1. ABC/3TC: -1.90% TDF/FTC: -3.55%  = -1.68 ; 95% CI (-2.26, -1.09) ABC/3TC: -1.59% TDF/FTC: -2.41%  = -0.84 ; 95% CI (-1.61, -0.06) Subjects ABC/3TC: 176 134 117 182 141 125 TDF/FTC: 180 156 138 183 165 143 0 - 2 - 3 - 4 0 2448 Total Hip 0 - 2 - 3 - 4 0 24 P<0.001 Lumbar Spine 48 P=0.036 week % change in BMD

20. 20 D:A:D Study: NRTIs and Risk of MI Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abstract 44LB.; Sabin C, et al. Lancet. 2008;371:1417-26.. * Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddC) ZDV ddI ddC d4T 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 #MI: 523 331 148 405 554 221 139 1.9 1.5 1.2 1 0.8 0.6 Recent Exposure*: yes/no Cumulative Exposure: per year ** Relative Risk of MI (95% CI) Adjusting for eGFR does not change ABC MI finding: Adjusted RR 1.89; 95% CI (1.46 – 2.44; p=0.0001)

21. 21 VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MI Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202. Unadjusted HR of AMI for each PY of exposure to each one of the categories Adjusted for estimated GFR prior to regimen onset (by MDRD method) NRTI in last regimen during obs. period ABCTFVBoth ABC and TFV Hazard ratio 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2

22. 22 DHHS Guidelines: Criteria for Preferred PI ●The following criteria distinguish between preferred and alternative PIs: 1. Superior or noninferior virologic efficacy compared to another PI regimen, with at least 48-week data published; 2. No more than 100mg of ritonavir per day; 3. Once-daily dosing; 4. Low pill count; and 5. Good tolerability ●Using these criteria, ATV/r QD and DRV/r QD are preferred PIs Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

23. 23 DRV/r and ATV/r in ARV-Naïve Patients: Higher Response Rates than LPV/r Adapted from: 1. Mills A, et al. AIDS May 29, 2009 [Epub ahead of print]; 2. Molina J-M, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1250d *Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012) ARTEMIS 1 (ITT, TLOVR)* 96 weeks LPV/r QD or BID DRV/r 800/100 QD 79 71 n=343n=346 0 20 40 60 80 100 CASTLE 2 (ITT, NC=F) 96 weeks ATV/r 300/100 QD LPV/r 400/100 BID 68 74 0 20 40 60 80 100 n=443n=440 Patient Percent <50 copies/mL

24. 24 ARTEMIS: DRV/r Better Tolerated than LPV/r Grade 2–4 adverse events* ≥2% incidence, n (%) DRV/r (N=343) LPV/r (N=346) Mean exposure (weeks)95.091.4 Any grade 2–4 AE at least possibly related80 (23)119 (34) GI AEs (all AEs)23 (7)52 (15) Diarrhea14 (4) ‡ 38 (11) Nausea6 (2)10 (3) Rash (all types)9 (3)5 (1) *Excludes laboratory abnormalities reported as adverse events; ‡p<0.001 vs LPV/r; no other AEs showed a statistically significant difference between the two treatment arms Mills A, et al. AIDS May 29, 2009 [Epub ahead of print].

25. 25 CASTLE: ATV/r Better Tolerated than LPV/r a Through 96 weeks b Excluding lab abnormalities reported as AEs Molina J-M, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1250d. ATV/r n = 441 n (%) LPV/r n = 437 n (%) Serious Adverse Events (SAEs)63 (14)50 (11) Grade 2-4 treatment-related AEs a 133 (30)140 (32) Grade 2-4 treatment- related AEs  3% a,b Jaundice18 (4)0 Nausea18 (4)33 (8) Diarrhea11 (2)54 (12)

26. 26 Comparing PI Lipid Profiles *Significantly different from LPV/r: P<0.0001 ATV/r vs. LPV/r; p<0.001 DRV/r vs. LPV/r (TC+TG) Molina J, et al. 48th ICAAC/46th IDSA. Abst. H-1250d; Mills A, et al. Ibid. Abst. H-1250c; Walmsley S, et al. 11th EACS. Abst. PS1/4; Pulido F, et al. 47th ICAAC. Abst. H-361. Mean (CASTLE) or Median (ARTEMIS) Total Cholesterol and Triglyceride Level Increases at 96 Weeks * 100 mg RTV QD 200 mg RTV QD * * * 19 14 26 18 36 55 35 56 0 10 20 30 40 50 60 Total CholesterolTriglycerides CASTLE: ATV/r + TDF/FTC ARTEMIS: DRV/r + TDF/FTC CASTLE: LPV/r + TDF/FTC ARTEMIS: LPV/r + TDF/FTC Lipid Values mg/dl

27. 27 D:A:D Exposure to PIs and Risk of MI D:A:D Study includes 33,308 patients, 580 with MI Lundgren J, et al. CROI 2009, abstract 44, 2/8/2009 1.9 1.13 1.1 1 0.9 MI RR Per Year (95%CI) IDVNFVLPV/rSQV 68,469 298 56,529 197 37,136 150 44,657 221 PYFU: MI: PI* * Approximate test for heterogeneity: P=0.02 Note: Insufficient number of pts on DRV/r and ATV/r to assess those agents

28. 28 Cumulative exposure (per additional year) No. exposed No. exposed cases OR[ 95% CI ]P value Saquinavir 324920.960.80 – 1.150.669 Indinavir 4971461.100.98 – 1.240.117 Nelfinavir 4531311.120.98 – 1.280.110 Lopinavir 290941.371.09 – 1.720.006 Amprenavir/Fosamprenavir117461.521.19 – 1.950.001 ANRS: Exposure to PIs and Risk of MI ●Nested, case-control study to evaluate association between risk of MI exposure to NRTIs and PIs ●Over 115,000 HIV-infected patients enrolled between 1989 and 2006 - Cases: 289 Patients with a first definite or probable MI prospectively reported between January, 2000 and December, 2006 - Matched Controls: For each MI case, up to 5 controls with no history of MI matched for age, sex and clinical center Lang S, et al.16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 43LB. Note: Insufficient number of pts on DRV/r and ATV/r to assess those agents

29. 29 RAL: Pros and Cons ●PROs - New class - No baseline resistance in ARV-naïve pts - Well Tolerated - Relatively few significant drug interactions - Established efficacy in experienced pts - No apparent teratogenicity - No lipoatrophy based on early (48 week) data ●CONs - BID - No long-term data - No randomized data with NRTIs other than TDF/FTC - PK/PD relationship unclear - Resistance data still emerging - No second generation agent available

30. 30 100 80 60 40 20 0 08162432404860728496 Immunologic: 240 vs. 225 cells/mm 3 (95% CI -13,+42) Study Week % Patients with HIV RNA Levels <50 Copies/mL 86% 82% 81% 79% Non-inferiority P-Value <0.001 STARTMRK: RAL and EFV Have Similar Virologic Efficacy Through 96 Weeks Patients with HIV RNA <50 c/mL Through 96 Weeks (Non-Completer = Failure) Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.  RAL + TDF/FTC  EFV + TDF/FTC

31. 31 STARTMRK: Adverse Events ●Overall adverse events similar between arms ●CNS events higher in EFV arm, but - were transient, mild and occurred within first 48 weeks - Led to few discontinuations - Rates of depression were similar between groups AEsRAL (%)EFV (%)P value Overall AE266 (94.7)275 (97.5)0.086 Drug Related AE132 (47)220 (78)<0.01 Serious Clinical AE40 (14)34 (12)0.457 Deaths3 (1)0 Malignancies3 (1)11 (4) CNS81 (29)171 (61)<0.001 Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.

32. 32 STARTMRK: Mean Change in Metabolic Parameters to Week 96 Change in TC/HDL ratio was RAL -0.18 and EFV -0.04 (p=0.192) P<0.001 Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.

33. 33 STARTMRK: Mean Change in DEXA Morphological Parameters to Week 48 DeJesus E, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1571.

34. 34 Recent Studies Comparing Non- Preferred to Preferred ARVs Overall virologic failures: NVP QD 11.2%, NVP BID 12.8%, ATV/r 14.0% Patients (%) with HIV RNA <50 c/mL ITT: 95% CI= -5.9% to 9.8%; p=0.63 6765 0 20 40 60 80 100 ATV/rNVP (QD/BID) 1. Soriano V, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924c; 2. Heera J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009. Abst. TUAB103. ARTEN: Comparison of NVP and ATV/r in ARV-naïve pts starting at CD4+ <400 (Men) and <250 (Women) (N=569) 1 MERIT-ES: Comparison of EFV and MVC in ARV-Naïve Patients with an R5 screening result by enhanced Trofile assay 2 62 59 0 20 40 60 80 100 MVCEFV Week 48 <50 c/mL Week 96 <50 c/mL D/C for AEs: 15.5% EFV vs. 6.1% MVC Virologic failures: 5.9% EFV vs. 12.5% MVC Patients (%) with HIV RNA <50 c/mL

35. 35 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co- Morbidities

36. 36 Potential Treatment Simplification Strategies ●Substitution of co-formulation for individual agents (e.g., EFV + TDF/FTC to EFV/TDF/FTC) ●Substitution for a single component of the regimen (e.g., ENF to RAL) to improve tolerability or decrease/prevent toxicity ●Dose or regimen de-escalation (e.g., Discontinuation of RTV or PI/r monotherapy) ●Maximizing the use of PK properties to achieve less drug exposure (e.g., FOTO)

37. 37 Simplification Improves Adherence * Using the Mixed Effect Model DeJesus E, et al. ICAAC, San Francisco, 2009. # H1572 Analysis of Three Once-daily HAART Regimens by Daily Pill Burden* QD dose TDF + FTC + EFVTDF/FTC + EFVTDF/FTC/EFV 0 192 144 Week 9648 3 pills1 pill2 pills Extension phase Daily Pill Burden ComparisonP Value 1 vs. 20.2304 1 vs. 30.0005 2 vs. 30.0262 Once-Daily Regimens TDF + FTC + EFV (n=238) TDF/FTC + EFV (n=162) TDF/FTC/EFV (n=157) Daily Pill Burden321 Dose Duration (study wks) BL → 96 97 - 144145 – 240 Mean Adherance Rate (%)95.697.097.9

38. 38 EASIER: Quality of Life After Switch from Enfuvirtide to Raltegravir Boulet T, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PE 7.2/2. ENF + OBT HIV RNA <400 c/mL (Stable > 3 mos.) Screening Randomization 1:1 SWITCH  RAL + OBT MAINTENANCE  ENF +OBT RAL + OBT – W4 – W1 D0W24W48 Physical Summary Pain Social Functioning P=0.003 P=0.02 P=0.001 Mean score change from Baseline to Week 24 Better HRQoL Worse HRQoL

39. 39 SWITCHMRK 1 & 2: Study Design ●Identical, multicenter, double-blind, randomized, active-controlled studies ●Enrolled pts with HIV RNA <50 c/mL on LPV/r BID regimen in combination with at least 2 NRTIs - No limit on number of prior ART regimens - Prior virologic failure not an exclusion - No lipid lowering therapy for at least 12 weeks ●Randomized (1:1) to continue LPV/r or switch to RAL Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB. SWITCHMRK 1SWITCHMRK 2 RAL (N=174) LPV/r (N=174) RAL (N=176) LPV/r (N=178) HIV RNA ≤ 50 c/mL 94.3%92.5%96.0%95.5% Mean CD4 (cells/mm 3 ) 478508471482 LPV/r ≤ 1 yr 16.7%17.8%17.6%18.5% Median yrs prior ART (min, max) 3.3 (0.3, 22.3) 3.6 (0.5, 20.2) 3.7 (0.5,19.2) 4.6 (0.6,16.3) Median # prior ART (min, max) 5.0 (4.0, 16.0) 5.0 (2.0, 5.0) 5.5 (3.0,13.0) 6.0 (4.0,14.0)

40. 40 ●Statistically significant improvements in total cholesterol, non-HDL cholesterol and triglycerides were observed following switch to RAL ●Further Analysis underway to assess factors associated with failure after switch to RAL - Previous Resistance: 84% with confirmed HIV RNA >50 c/mL) in the RAL group were not on 1 st ART regimen; 66% with history of VF on prior regimen(s) - NRTI Backbone: Virologic failure rate higher on ABC/3TC than TDF/FTC SWITCHMRK 1 and 2: Virologic Outcomes (NC = F) Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB. SWITCHMRK 2

41. 41 SWITCHMRK 1 and 2: Lower Response with ABC than TDF http://www.emea.europa.eu/humandocs/PDFs/EPAR/isentress/Isentress-H-860-II-10-AR.pdf Study 032: <50 copies/mL (Observed Failure)* Difference in percent response % (95 CI) RaltegravirLopinavir/r Population n/N% (95 CI)n/N% (95 CI) Total 139/15490.3 (84.4, 94.4)152/16293.8 (88.9, 97.0)-3.6 (-10.0, 2.5) Concurrent background ART TDF** 72/7991.1 (82.6, 96.4)69/7592.0 (83.4, 97.0)-0.9 (-10.4, 8.8) ABC** 20/2580.0 (59.3, 93.2)22/2395.7 (78.1, 99.9)-15.7 (-35.9, 4.1)* *The difference in response was similar in study 033 (-12.9 % for ABC vs -4.6% for TDF) **plus FTC or 3TC

42. 42 MONET: Simplification to DRV/r QD Monotherapy Arribas J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUAB106. N=256 2NRTIs + PI/r or NNRTI HIV RNA<50 X 6 months No h/o VF; DRV naive DRV/r 800/100 mg QD + 2 NRTI * ( n = 129) DRV/r 800/100 mg QD ( n = 127) 96 wks DRV/r + 2NRTIsDRV/r HIV RNA < 50copies / mL, ITT, TLOVER,S=F85.3%84.3% HIV RNA < 50 at last visit97.7%97.6% Primary PI mutation11 Grade 2-4 GI AEs ≥ 2% incidence3.9%5.5% Grade 2-4 GI AEs ≥ 2% incidence ( all types )1.6% ALT > 5 x ULN1.6%4.8% Total Cholesterol > 300mg / dL, sustained1.6%4.8%

43. 43 IMANI III: Lopinavir/r QD Monotherapy ●48 week open-label pilot study ●Evaluated efficacy, safety and tolerability of LPV/r QD monotherapy in pts with undetectable VL while in active follow-up post IMANI I or after completion of IMANI II (LPV/r BID in ARV-naïve patients) LPV/r QD monotherapy for simplification: Caution warranted until results from larger ongoing studies evaluated Gathe J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 4/5. IMANI III 31 Subjects IMANI I 4 Subjects IMANI II 27 Subjects 2 protocol defined failures at Week 36 1 LFTU at Week 48 27 Subjects Week 48 Subject Baseline MutationsWeekVL On Treatment Mutations 007L63P364,145 M461, I54V, I62V, L63P, V82A 021 L63P, A71T 363,582 L10V, V32I, M46I/W, I47V, L63P, A71T

44. 44 DHHS Guidelines: Regimen Simplification ●Switching patients with an extensive treatment history from LPV/r to RAL should be done with caution ●RAL can safely substitute for ENF in patients not previously treated with integrase inhibitors ●Any drug substitution may introduce unanticipated adverse effects or drug-drug interactions ●PI/r monotherapy studies have reported mixed results and should not be regarded as a clinical strategy until further data are available Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

45. 45 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co- Morbidities

46. 46 Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm 2009 DHHS Guidelines: Opt-out Testing ●Patients must be identified early in the course of HIV infection, making earlier initiation of therapy an option ●Most HIV-infected patients are not diagnosed until they are at much later stages of disease ●For the current treatment guidelines to have maximum impact, opt-out testing per current CDC recommendations is essential

47. 47 CDC Recommendation for HIV Testing in Adults and Adolescents ●Routine, voluntary, HIV screening for all persons aged 13–64 years, not based on risk ●Opt-out HIV screening Opportunity to ask questions and option to decline ●Consent for HIV test is part of general consent for care Separate consent not recommended Prevention counseling not required in conjunction with HIV screening ●Low-prevalence setting If yield from screening <0.1%, continued routine screening not warranted Branson BM et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

48. 48 Removing Written Consent Increases HIV Testing Rates ●After HIV testing opt-out policy change, rate of HIV tests per 1000 patient-visits increased 4.38 (CI, 2.17–6.60, p<0.001) ●No increase in ordering of other tests (hematocrit or creatinine) or of HIV testing in control setting without policy change ●Increase occurred across all patient populations and led to a rise in newly-diagnosed HIV Zetola PLoS One. 2008;3(7):e2591 20 15 10 5 0 HIV Tests per 1,000 patient -vts 061218243036 Months July 2004June 2007 Before PolicyAfter Policy SFGH HIV Tests 50 40 30 10 0 Tests per 1,000 visits 061218243036 Months July 2004June 2007 Before PolicyAfter Policy Creatinine Tests 20 15 10 5 0 HIV Tests per 10,000 Laboratory t 061218243036 Months July 2004June 2007 Before PolicyAfter Policy Control University-based Medical Center HIV Tests Hematocrit Tests 50 40 30 10 0 Tests per 1,000 visits 061218243036 Months July 2004June 2007 Before PolicyAfter Policy 20

49. 49 Changing HIV Testing Laws: Impact on Survival ●Comparison of diagnosis rates in states with opt-out vs. opt-in testing ●In states with opt-out testing, HIV is diagnosed at a higher CD4 cell count  better treatment outcomes ●Computer-based simulation model of HIV disease applied to these data ●If all remaining states switched to opt-out, potential national survival gain would be > 600,000 life years April M, et al. 47th IDSA Meeting, Philadelphia, 2009. Abst. 1254

50. 50 HIV Testing Expansion: Earlier Diagnosis, Higher CD4 Counts ●Program to expand testing in medical and jail settings in Washington, DC began in 2006 ●Since program began, patients diagnosed with higher CD4 counts at initial testing ●During first 18 months of program, increase in median CD4+ count at diagnosis to 332 cells/mm 3 Median CD4+ Count at Time of Testing 215 187 198 220 262 332 183 0 50 100 150 200 250 300 350 2001200220032004200520062007 Year of HIV Diagnosis Median CD4 Count Hader S, et al. 16th CROI; 2009; Montreal. Abstract 57.

51. 51 Adoption of Opt-out Testing Opt inOpt out Written consent required: n= 8 (MA, MI, NE, OR, NY, PA, WI, RI) Mahajan AP, et al. Ann Intern Med 2009;150:263-9.

52. 52 Why is Opt-out Screening Not Being Implemented in All States? ●Need to reduce stigma and discrimination before universal testing ●Before universal testing there must be universal prevention counseling for HIV-negative and treatment and care for HIV-positive ●Broad testing leading to increase in numbers of HIV- positive patients entering into care could potentially have grave consequences due to a lack of funding and healthcare resources ●While it is everyone’s human right to know their HIV status, they also have the right to decide when and where they will be HIV tested The Global Network of People living with HIV, Scaling up HIV Testing: Different perspectives; http://www.gnpplus.net/component/option,com_docman/task,cat_view/gid,245/Itemid,53/?mosmsg= You+are+trying+to+access+from+a+non-authorized+domain.+%28search.yahoo.com%29; Accessed 12/10/09

53. 53 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co- Morbidities

54. 54 First Positive HIV Vaccine Trial ●16,401 patients enrolled from 2003-2005 in Thailand in placebo-controlled trial ●Intervention: Canarypox ALVAC-HIV and glycoprotein 120 AIDSVAX B/E (“boost) ●Intervention reduced infection by 30% Rerks-Ngarm S et al. N Engl J Med 2009. Placebo Vaccine Intention-to-analysis Modified Intention-to-analysis P<0.05

55. 55 Many PrEP Trials Pending Study/ Location Sponsor/ Funder Population (mode of exposure)Intervention arms (s) Status/Expected Completion US Extended Safety Trial (CDC 4323) United States CDC400 gay/men and other men who have sex with men (penile/rectal) Daily oral TDFFully enrolled/2009 Fully enrolled July 2007 Final data analysis Q1/10 Bangkok Tenofovir Study (CDC 4370) Thailand CDC2,400 injecting drug users (parenteral) Daily oral TDFEnrolling/2010 1 st interim analysis Q4/09 CAPRISA 004 South Africa CAPRISA, FHI, CONRAD, USAID, LIFElab 1,200 heterosexual women (vaginal) Coitally dependent topical tenofovir gel Fully enrolled/2010 1 st interim analysis in Q4/08 2 nd interim analysis in Q3/09 iPrEx Brazil, Ecuador, Peru, South Africa, Thailand, US NH, BMGF3,000 gay men and other men who have sex with men (penile/rectal) Daily oral TDF/FTCEnrolling/2011 1 st interim analysis in Q4/09 TDF2 (CDC 4940) Botswana CDC2,000 heterosexual men and women (penile and vaginal) Daily oral TDF/FTC (switched from TDF Q1 2007) Enrolling 2012 Partners PrEP Kenya, Uganda BMGF3,900 serodiscordant heterosexual couples (penile and vaginal) Daily oral TDF & daily oral TDF/FTC Enrolling 2012 FEM-PrEP Kenay, Malawi, South Africa, Tanzania, Zambia FHI, USAID, BMGF 3,900 heterosexual women (vaginal) Daily oral TDF/FTCEnrolling 2012 VOICE (MTN 003) South Africa, Uganda, Zambia, Zimbabwe, additional sites to be determined MTN, NIH5,000 heterosexual women (vaginal) Daily oral TDF; daily oral TDF/FTC; daily topical tenofovir gel Enrolling 2013 IAVI E001 and E002 Kenya, Uganda IAVI150 serodiscordant couples and at-risk men and women (vaginal and penile/rectal) Daily oral TDF/FTC; intermittent oral TDF/FTC (twice weekly – coital dosing) Planning/2010 Anticipated start Q3/2009 Ongoing ARV based Prevention (Oral PrEP and Topical Microbicide) Trials (September 2009) BMGF-BI & Melinda Gates Foundation; CAPRISA – Centre for the AIDS Programme of Research in South Africa; CDC – US Centers for Disease Control and Prevention; FHI – Family Health International; FTC – emtricitabine; IAVI – International AIDS Vaccine Initiative; MTN – Microbicide Trials Network; NIH – US National Institute of Health; Q1-4 – quarters 1-4; TDF – tenofovir disoproxil fumarate; USAID – United States Agency for International Development

56. 56 A Major PrEP Issue: Is it Cost-Effective in the US? ●Computer simulation of HIV acquisition, detection, and care to model PrEP among MSM at high risk of HIV in US ●Model assumed 50% PrEP efficacy and TDF/FTC $753/month ●Base-case: $298,000/Quality-adjusted life year (QALY) – not generally considered cost-effective by US standards Paltiel AD, et al. Clin Infect Dis 2009;48:806-815.. $0 $100,000 $200,000 $300,000 $400,000 $500,000+ TDF Resistance (0%-100%) ART Efficency Reduction (0%-15%) PrEP Toxicity (None Extreme scenario) Cohort age (30-34) HIV Testing Frequency (Never-Annual) PrEP Cost Multiplier (0.1-1.0) HIV Injection Incidence Multiplier (0.3-2.0) PrEP Efficiency (90%-20%) Incremental Cost per QALY

57. 57 2009 DHHS Guidelines: Preventing Secondary Transmission of HIV ●Essential tools for prevention of sexual and blood-borne transmission of HIV include: - Consistent and effective use of ARV therapy, resulting in a sustained reduction in viral load; - Consistent condom usage; - Safer sexual and drug use practices; and - Detection and treatment of STIs ●Medical visits provide an opportunity to: - Reinforce HIV prevention messages; - Discuss sexual- and drug-related risk behaviors; - Diagnose and treat intercurrent STIs; and - Develop open communication between provider and patient Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

58. 58 HIIV Treatment Reduces the Risk of Transmission ARV Status CY Observation No. Linked Infections Infection Rate (C-Y) Infection Rate Ratio (95% CI) Not on ARV5,0621713.4/100--- On ARV54740.7/1000.21 (0.08, 0.59) On ARV – conservative* 54761.0/1000.32 (0.14, 0.73) ●Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05) ●Both ART and change in behavior independently reduced HIV transmission *Includes 2 partners who seroconverted in the same 3-month interval when the HIV- infected partner initiated ARVs 2,993 couples were followed for a median of 512 days HIV-free Survival of HIV-negative partners, by ARV status of HIV+ Partner 0 2073 920 500 1035 475 1000 598 256 1500 252 69 2000 80 6 2500 0 0.0 0.2 0.4 0.6 0.8 1.0 Survival Probability Days Off ARV On ARV Censored Logrank P<.0001 Sullivan P, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 52bLB.

59. 59 Potential Impact of “Test and Treat” Strategy on HIV Epidemic and Use of ART Granich R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPL101. Strategy: Universal ART ART if CD4+ <350 cells/mm 3 No ART 0.000 0.005 0.010 0.015 0.020 Incidence/year 0.00 0.05 0.10 0.15 Prevalence 0.00 0.05 0.10 0.15 1980200020202040 0.000 0.005 0.010 Mortality/year 0.000 0.005 0.010 1980200020202040 HIV ART Proportion of adolescents and adults 15 years or older 0.000 0.001 0.002 0.003 0.004 0.005

60. 60 Concerns Regarding Using “Test and Treat” Strategy 1. Crepaz N et al. JAMA 2004;292:224-236; 2. Vernazza PL, et al. AIDS 2000;14:117-21; 3. Marcelin, A-G, et al. AIDS 2008;22:1673-81. HIV RNA detected in semen of 7/145 (5%) of men with VL <40 c/mL # HIV RNA in seminal plasma (c/mL)ARV combination 1940ZDV, 3TC, IDV, RTV 22573TC, EFV, LPV/r 31230ZDV, 3TC, LPV/r 4255TDF, FTC, AZT 5802ZDV, 3TC, IDV, RTV 6267FTC, ATV, RTV 7620TDF, FTC, EFV HIV in semen in ARV naïve and ARV treated men with VL <400 P<0.0001 P<0.01 ●Patients who believe that ART or an undetectable viral load protects against transmitting HIV have higher rates of unprotected sex (OR 1.82; 95% CI, 1.52-2.17) 1 ●While HIV RNA significantly lower in semen of pts on ART with an undetectable plasma HIV RNA, still detectable in some 2,3

61. 61 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co- Morbidities

62. 62 Life Expectancy of ARV-treated Patients by CD4 Nadir Depending on when HAART is started, life expectancy during modern HAART era is 10 to 30 years less than that in uninfected patients CD4+ Nadir (cells/mm 3 )< 100100-200>200 Life expectancy at age 20 (years) 324250 ART-Cohort Collaboration. Lancet. 2008;372:293-299 (see also Lohse N, et al. Ann Intern Med. 2007;146:87-95 and Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-77.) Life Expectancy by CD4+ Nadir When HAART Started

63. 63 Kaplan RC, et al. Clin Infect Dis. 2007; 5:074-1081. Traditional Health Related Risk Factors More Prevalent Among HIV-positive Patients 01020304050607080 01020304050607080 Prevalence, % (95% CI) High LDL Level Low HDL Level High Triglycerides Level Hypertension Smoking Overweight or Obese Diabetes HIV+ Men HIV- Men HIV- Women HIV+ Women

64. 64 Many Non-AIDS Events Appear to be Higher in Treated HIV Disease than Controls ●Cardiovascular disease 1-4 ●Cancer (non-AIDS) ●Bone fractures/osteopenia 5,6 ●Left ventricular dysfunction ●Liver failure 7 ●Kidney failure ●Cognitive decline (controversial) 8 ●Frailty 9 1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2. Hsue P, et al. Circulation. 2004;109:316-319. 3. Mary-Kraus M, et al. AIDS. 2003;17:2479-2486. 4. Grinspoon SK, et al. Circulation. 2008;118:198-210. 5. Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8. McCutchan JA, et a. AIDS. 2007; 21:1109-1117. 9. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286

65. 65 Many Factors Contribute to Non-AIDS Events Being More Common In HIV Behavior Pre- HAART Harm HAART Toxicity Persistent Immune Defects Premature Aging Deeks and Phillips, BMJ 2009

66. 66 Association Between Current CD4 Cell Count and Non-AIDS Complications Study Non-AIDS malignanciesRenal disease/deathCVD events/death Liver disease/ death FIRSTYes Trend, NSNo D:A:DYes Trend, NSYes CASCADEYesNAYes SMARTTrend, NS Yes Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8. Is Lower Current CD4 Cell Count Significantly Associated With Increased Risk of non-AIDS Events?

67. 67 DHHS Guidelines: T-cell Activation and Inflammation ●Early untreated HIV infection associated with sustained high-level inflammation and T-cell activation which are associated with disease progression ●ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation - Persistent inflammation, as represented by levels of IL-6, may be associated with risk of death ●These observations support earlier use of ART: - Treatment decreases the level of inflammation and T-cell activation; and - Degree of residual inflammation and/or T-cell dysfunction during ART is higher in patients with lower CD4 cell nadirs and earlier treatment may result in less residual immunological perturbations Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

68. 68 Current Clinical Controversies in the Treatment of HIV/AIDS 1.When to Start: 2009 DHHS Guidelines 2.What to Start: 2009 DHHS Guidelines 3.Benefits and Limits of Simplification 4.Adoption of Opt-out Testing 5.Potential Strategies for HIV Prevention 6.The Importance of Non-AIDS Co-Morbidities