1. Overcoming Treatment Challenges in the Treatment-Experienced Patient With HIV A Review of New Antiretroviral Agents Daniel S. Berger, MD Medical Director, NorthStar Healthcare Clinical Assistant Professor of Medicine University of Illinois at Chicago Chicago, IL

2. Case Discussion #1 JT is a 47-year-old man with HIV for the past 12 years He has been on a number of antiretroviral agents from all three of the main drug classes His current HIV RNA level is 36,442 copies/mL His current CD4 count is 144 cells/mm 3 Based on his current resistance profile, you believe you are able to construct an active antiretroviral regimen for him Because he is highly treatment-experienced, you talk to him about treatment goals

3. Case Discussion #1 What do you tell him about his treatment goals as a highly treatment-experienced patient? A.Since you can start an active regimen, you should aim to reduce his HIV RNA level to less than 50 copies/mL B.Since he is highly treatment-experienced, you can switch him to an active regimen and hope to reduce his HIV RNA level to <400 copies/mL C.Although you can switch him to an active regimen, you can only hope to reduce his HIV RNA level about one log (or ten-fold) down to <5,000 copies/mL, since he is highly treatment-experienced D.As long as you can reduce his HIV RNA about 0.5 log 10 copies/mL, you will be happy

4. Case Discussion #2 ME is a treatment-experienced patient with HIV who is failing his current antiretroviral regimen His CD4 count is 250 cells/mm 3 and has been relatively stable over the last year His most recent HIV RNA level is 15,000 copies/mL, which has been increasing over the past few months You believe that it will be possible to construct an active new antiretroviral regimen for him Given the stable CD4 count, you talk to him about the timing of the switch to this new regimen

5. Case Discussion #2 What do you tell him about the timing of the switch to the new regimen? A.Switch to the new antiretroviral regimen when the HIV RNA level exceeds 25,000 copies/mL B.Switch to the new antiretroviral regimen when the CD4 count falls below 200 cells/mm 3 C.Switch to the regimen now, since he has persistent viral replication D.Switch to the new antiretroviral regimen now only if repeat resistance testing shows additional viral mutations

6. Case Discussion #3 ME, from the last case, has failed his current regimen of zidovudine/lamivudine (Combivir ® ) + LPV/r His prior regimen was efavirenz (Sustiva ® ) + NRTI Results of resistance testing have indicated that he is resistant to all NNRTIs and PIs except tipranavir (TPV) and darunavir (DRV) –TDF is partially active

7. Case Discussion #3 What regimen would you recommend for him? A.TPV/r + TDF + ENF B.TPV/r + TDF C.TPV/r + MK-0518 through EAP D.DRV/r + TDF + ENF E.DRV/r + TDF + TMC125 through EAP F.DRV/r + TDF + MK-0518 through EAP EAP = Expanded Access Program

8. Overall Prevalence of HIV Drug Resistance HIV Cost and Services Utilization Study (HCSUS) Richman et al. AIDS. 2004 Jul 2;18(10):1393-1401. Drug Resistance Detected 76% 71% 41% 25% 48% 13% % with Drug Resistance Any drug NRTI PI NNRTI2 class 3 class Population with HIV RNA >500 copies/mL (n = 132,500)* *HIV drug susceptibility assays were performed on plasma virus from a random sample (n = 1,099) representative of the 132,500 patients who received care in 1996 yet were viremic with HIV RNA >500 copies/mL in 1998

9. DHHS Guidelines Treatment-Experienced Patients: ARV Treatment Failure Therapeutic options: –Clarify goals: in some, viral suppression may not be possible, but aim to reestablish maximal virologic suppression –Evaluate remaining ARV options –Base choices on expected tolerability, adherence, future treatment options, medication history, and resistance testing wwwaidsinfo.nih.gov: accessed December 27, 2006

10. Treatment-Experienced Patients Goals of Therapy (1) Limited prior treatment and drug resistance, with adequate treatment options: –Maximal viral suppression –Consider early change to prevent further resistance mutations Intermediate prior treatment and drug resistance, with some available treatment options: –Maximal viral suppression, if possible –Preservation of immune function and prevention of clinical progression wwwaidsinfo.nih.gov: accessed December 27, 2006

11. Treatment-Experienced Patients Goals of Therapy (2) Extensive prior treatment and drug resistance, with some or no adequate treatment options: –Viral suppression may be difficult to achieve –Preservation of immune function and prevention of clinical progression –Balance benefits of partial viral suppression with risk of additional resistance mutations wwwaidsinfo.nih.gov: accessed December 27, 2006

12. IAS-USA Guidelines Updated Goals of Therapy in Experienced Patients For heavily treatment-experienced patients, the goal of therapy should be to reduce HIV viral load to below 50 copies/mL If several potent drugs other than enfuvirtide are available, it may be best to defer enfuvirtide use until it becomes 1 of 2 available and fully active drugs –Since the goal of therapy is to achieve plasma HIV-1 RNA levels of less than 50 copies/mL, enfuvirtide often is required to achieve success among heavily antiretroviral–experienced patients Hammer SM, et al. JAMA. 2006 Aug 16;296(7):827-843

13. Virologic Failure Changing an ARV Regimen (1) General principles (1): –Prefer at least 2 fully active agents to design a new regimen Determined by ARV history and resistance testing –If 2 active agents are not available, consider ritonavir-boosted PI plus optimized ARV background, and/or reusing prior ARVs to provide partial activity –Consider potent ritonavir-boosted PI and a drug with a new mechanism of action (e.g., entry inhibitor) plus an optimized ARV background: may have significant activity wwwaidsinfo.nih.gov: accessed December 27, 2006

14. Virologic Failure Changing an ARV Regimen (2) General principles (2): –In general, 1 active drug should not be added to a failing regimen because drug resistance is likely to develop quickly. In some patients with advanced HIV and few treatment options, this may be considered to reduce the risk of immediate clinical progression. –Consult with experts wwwaidsinfo.nih.gov: accessed December 27, 2006

15. Considerations for Choosing a Non-Suppressive “Holding Regimen” Never use an NNRTI –NNRTI mutations have no beneficial impact on fitness –Accumulation of additional mutations may result in cross- resistance to second-generation NNRTIs Strongly consider lamivudine or emtricitabine –Simple and well tolerated drugs –M184V decreases fitness –Presence of M184V mutation associated with increased activity of zidovudine, stavudine, and tenofovir DF Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations

16. NRTIs Retain Activity Even With Drug Resistance Observational study in clinically stable patients with limited treatment options (extensive resistance, drug toxicity): –Patients on NRTI + PI regimens discontinued either NRTIs or PIs Adapted from Deeks SG, et al. 10 th CROI, Boston 2003, #640 -100 -80 -60 -40 -20 0 Week 8 Week 12Week 16 Change in CD4 cells/mm 3 PI stopped, cont. NRTIs (n = 15) NRTI stopped, cont. PIs (n = 5) 0 0.5 1 Week 8 Week 12Week 16 Log 10 change in RNA

17. SCOPE Cohort: Risk of Delayed Switch on Stable Antiretroviral Therapy Treatment-experienced patients (n=106) –Stable ART for >120 days –HIV RNA >1000 c/mL –≥1 resistance mutation Emergence of new mutations at 1 year –Any mutation: 44% –NAM: 23% –PI: 18% 1.00 Number of available antiretrovirals from the following: ZDV, 3TC, ddI, ABC,TDF, EFV, IDV, NFV, SQV, RTV, APV, LPV 0 0.25 0.50 0.75 0 4 812162024 Months Time to loss of 1 drug equivalent No New Mutation (%) 1 new major PI mutation 1 new NAM Any new mutation No New Mutation (%) 04812162024 0 0.25 0.50 0.75 1.00 Time to new mutation Months Hatano H, et a. 13th CROI. Denver, 2006. Abstract 615.

18. Current Guidelines for Resistance Testing 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Oct. 10, 2006. 2. Hirsch MS, et al. Clin Infect Dis. 2003;37:113-128. 3. Vandamme AM, et al. Antivir Ther. 2004 Dec;9(6):829-848. Recommend **—— Pediatric Recommend * — Pregnancy Recommend Treatment Failure Recommend/ Consider RecommendConsider Chronic (< 2 years) Recommend—— PEP (Source Pt) Recommend Primary Infection EuroGuidelines [3] IAS-USA [2] DHHS [1] * Only if mother is viremic ** Only if mother was viremic and on treatment at time of birth

19. Treatment Strategies for Experienced Patients Options to Consider Darunavir Tipranavir ENF to minimize loss of drug sensitivity and improve viral suppression and durability in salvage Double boosting with specific PIs ? Consider EAPs to provide ≥ 2 active agents Maintain 184V with 3TC/FTC Options to Avoid Avoid sequential monotherapy Avoid double-boost with “specific” PI combinations Do not combine other PIs with TPV Avoid TDF + ddI in NNRTI regimens Avoid metabolically unfriendly antiretrovirals

20. Dual PI Boosting LPV + SQV Without NRTIs S. Staszewski et al All Patients n = 42 Females n, %8 (19%) Median age at start of LPV/r + SQV, years41 Median CD4 count at end of failing regimen, cells/mm 3 156.5 Median CD4 count at start of LPV/r + SQV, cells/mm 3 131 Median viral load at end of failing regimen, copies/mL 2,950 (3.5 log 10 ) Median viral load at start of LPV/r + SQV, copies/mL 165,500 (5.2 log 10 ) Reason for switch to LPV/r + SQV : –Toxicity, n (%) –Resistance, n (%) 16 (38%) 26 (62%)

21. Dual PI Boosting LPV + SQV Without NRTIs Baseline Characteristics: treatment history with a focus on PI exposure All Patients n = 42 Median cumulative time on ART (range)78 months (15-154) Median number of previous therapies9.5 Median number of PIs in past3 Previous exposure to LPV/r, n (%)11 (26%) Previous exposure to APV, n (%)9 (21%) Previous exposure to SQV, n (%)20 (48%) Previous exposure to IDV, n (%)33 (79%) Median number of drugs in last regimen4 Last regimen before LPV/r + SQV was PI-sparing, n (%)23 (55%) Number of PI-naïve patients, n (%)4 (9%) STI before starting LPV/r + SQV, n (%)27 (64%)

22. Dual PI Boosting LPV + SQV Without NRTIs Clinical Results All Patients n = 42 Median time on therapy (range)38 weeks (0.5-111) On therapy, n (%)33 (81%) Number of discontinuations9 (21%) Reasons for discontinuations –Virologic failure –Non-virologic reasons –Virologic failure and toxicity 531531 Median CD4 count at week 24, cells/mm 3 280 Median CD4 increase from start of LPV/r + SQV+149 Median viral load at week 24, copies/mL60 (1.7 log 10 ) Median viral load decrease from start of LPV/r + SQV- 3.5 log 10

23. Dual PI Boosting LPV + SQV Without NRTIs Median CD4 counts through week 24, n = 41

24. Dual PI Boosting LPV + SQV Without NRTIs Median viral load through week 24, n = 41

25. Patients With HIV-1 RNA < 400 Copies/mL (%) Study week 0163248648096 Arastéh K, et al. IAC 2004. Abstract MoOrB1058. ITT: DC or SW = F (n = 661) (n = 334) ENF + OBR OBR 34% 13% 0 10 20 30 40 50 60 70 80 90 100 26% TORO Studies Durability of Virologic Response

26. TORO Studies: 20% Achieve Undetectable Viral Load (<400 copies/mL) With 3 “Active ARVs” Miralles D, et al. AIDS. 2005 Dec 2; 19(18):2178-2179. Lalezani JP, et al. N Engl J Med. 2003 May 29; 348(22):2175-85. Lazzarin A, et al. N Engl J Med. 2003 May 29; 348(22):2186-95. 44% 32% 19%20% 9% 46% 8% 0% Patients on ARVs at Study Entry (%) With VL<400 copies/mL at wk48 Baseline “Active” Drugs in OBR (by GT) 52% 19% P <.05 DC + Switch = Failure

27. Genotype Susceptibility Loss Comparisons of Regimens With and Without ENF NNRTIs PIs Patients (%) Losing Sensitivity Between BL and VF n=91 n=67 n=71 n=103 n=68 n=141 n=115 n=68 n=78 n=34 n=65 n=36 n=35 n=28 n=47 n=49 n=55 n=64 n=94 n=102 n=115 n=64 n=47 n=52 n=33 n=50 n=26 NRTIs Cohen, et al. 44 th ICAAC 2004. ENF + OBROBR

28. 135561828917494121674928 Patients with HIV-1 RNA < 400 copies/ml (%) * P < 0.05 Number of positive prognostic factors (PPFs) 0123401234 n = Montaner, et al. XV IAC 2004, Bangkok, Thailand. TuPeB4483 BL CD4 count (> 100 cells/mm 3 ) BL plasma HIV-1 RNA (< 100,000) Number of prior ARVs ( ≤ 10) ≥ 2 active ARVs in background ENF + OBR OBR * * * * * TORO: Predictors of Viral Suppression

29. Tipranavir (TPV, Aptivus ® ) TPV is a novel non-peptidic PI with potent activity against multiple PI-resistant HIV-1 Administered as 2 x 250mg with ritonavir 200mg BID Resistance to TPV is associated with the development or presence of at least 3 baseline UPAMs TPV has an extensive & complex drug-drug interaction profile Close clinical and laboratory monitoring is advised RESIST 48-wk data recently presented

30. P. Cahn 1 and C. Hicks 2 for the RESIST-2 and RESIST-1 Study Teams 1. Fundación Huesped, Buenos Aires, Argentina; 2. Duke University, Durham, NC, USA RESIST-1 (R-1) and RESIST-2 (R-2) 48 week meta- analyses demonstrate superiority of protease inhibitor (PI) tipranavir + ritonavir (TPV/r) over an optimized comparator PI (CPI/r) regimen in antiretroviral (ARV) experienced patients

31. RESIST Entry Criteria ≥ 3 consecutive months of experience with 3 ARV classes (NRTIs, NNRTIs, PIs) ≥ 2 PI-based regimens for ≥ 3 months; one had to be the regimen at enrollment Any CD4 cell count; viral load (VL) ≥ 1,000 Viral isolate ≥ 1 primary PI mutation Viral isolate carrying ≤ 2 mutations at codons 33, 82, 84, and 90

32. RESIST Phase III Study of TPV/r 1. Hicks C, et al. ICAAC 2004. Abstract 1137a. 2. Cahn P, et al. ICDT 2004. Abstract PL14.3. HIV resistance expert panel Preselection of regimen by investigator: CPI + OBR † (± enfuvirtide) Computerized randomization to OBR plus: Baseline genotypic resistance testing* CPI arm LPV/r, IDV/r, SQV/r, APV/r TPV/r arm Patients failing PI-containing HAART VL > 1,000 Any CD4 Best PI choice Wk 48 Interim analysis, Wk 24 Failures in CPI arm after Wk 8 eligible for TPV/r in rollover study * Entry criteria: ≥ 1 primary PI mutation: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M ≤ 2 mutations: 33, 82, 84, or 90 † CPI, comparator PI OBR, optimized background

33. RESIST 1 and 2 Baseline Characteristics TPV (n = 746) CPI/r (n = 737) Viral RNA log 10 4.73 CD4, cells/mm 3 196195 Hep B & C coinfection10.2 %15.3% Median # PIs44 Median # ARVs12 Previous ENF use10.2%10% Primary PI mutations33 Hicks C, et al. ICAAC 2004. Abstract 1137a. Cahn P, et al. ICDT 2004. Abstract PL14.3.

34. Pre-selected PI –LPV: 358 (48.6%) –IDV: 23 (3.1%) –SQV: 162 (21.9%) –APV: 194 (26.3%) Ongoing PI 519/1,483 (34.9%) ENF in regimen 304/1,483 (20.5%) ENF naïve –TPV123/746 (16.5%) –CPI97/737 (13.2%) GSS ≤ 1* 773/1,467 (52.7%) RESIST 1 and 2 Selected Regimens * Excludes ENF Hicks C, et al. ICAAC 2004. Abstract 1137a Cahn P, et al. ICDT 2004. Abstract PL14.3

35. RESIST Studies: 48-Week Virologic Response by Addition of Enfuvirtide *P<0.0001 vs CPI/r ITT: non-completer=failure. Cahn P, et al. 10 th EACS. Dublin, 2005. Abstract LBPS3/8. HIV RNA <400 copies/mL HIV RNA <50 copies/mL Patients (%) 52.0% 19.6% 30.4%* 13.8% Patients (%) 35.8% 22.8%* 14.4% 10.2% TPV/r CPI/r TPV/r CPI/r First-Time Enfuvirtide Use All PatientsFirst-Time Enfuvirtide Use All Patients n=123n=97n=123 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

36. RESIST: Greater Response With More Active Agents in Background Regimen Patients With  1 log 10 Reduction in HIV-1 RNA (%) 0 20 40 60 80 100 012 33 55 46 37 13 34 20 13 9 Number of Sensitive Background ARVs TPV/rCPI/r Cooper D. et al. CROI 2005. Abstract 560

37. Relationship of TPV Score to Antiviral Activity of a TPV-containing Regimen Valdez H, et al. Resistance Workshop 2005. Abstract 27. TPV Score MutationsVL Change 2 WksVL Change 24 Wks 0-1-1.25 log-2.1 log 2-3-1.37-0.89 4-5-1.40-0.45 6-7-1.27-0.49 8+-0.33-0.08 –Median viral load change at 2 weeks in patients with TPV score 1 log 10 –Median week 24 viral load change in patients with a TPV score 2 log 10 –Median week 24 viral load change in patients with a TPV score < 8 is between 0.5 and 1 log 10

38. TPV/r Reduces Amount of Virus and Suppresses Virus Longer with the Addition of NNRTI RESIST: Patients taking TPV/r in combination with a further active NNRTI achieved greater viral load decreases and immune cell increases than patients who received TPV/r without a NNRTI More patients receiving an NNRTI in their OBR achieved virologic suppression at 24 weeks Kohlbrenner V, et al. EACS 2005. Abstract PE7.7/2. Patients With HIV-1 RNA < 50 copies/mL at Week 24 (ITT) TPV/r + NNRTITPV/r 33%22.1%

39. 1. King NM, et al. J Virol 2004 Nov;78(21):12012–12021. 2. Tie Y, et al. J Mol Biol 2004 Apr 23;338(2):341–52. 3. Dierynck I, et al. 14th IHDRW 2005. Abstract 64. Darunavir (DRV, TMC114, Prezista ® ) Unique chemical structure induces tight binding with protease and a close fit within the substrate envelope –Competitively inhibits but does not disturb protease –Close conformation within substrate volume and structural flexibility lowers susceptibility to resistance [1] –Increased H-bonding with protease forms a more stable complex [2] –Enhanced bis-THF stereochemistry allows variations in the dissociation rate [3] –Quick binding to and very slow dissociation from protease results in a stronger affinity compared with other PIs [3] 3-4 orders of magnitude stronger in wild-type HIV 1.5 orders of magnitude stronger in multidrug–resistant strains Stronger affinity for protease predicts high virological efficacy and a high genetic barrier against resistance

40. De Meyer S, et al. Antimicrob Agents Chemother 2005 Jun;49(6):2314–2321. n = 2,202 PI-resistant, recombinant isolates from 5,601 patients 98% of PI-resistant clinical isolates were susceptible to DRV at <100nM Darunavir : Active Against PI-resistant Clinical HIV Isolates Clinical isolates (%) 0 20 40 60 80 100 IDVRTVNFVSQVAPVLPVATVDRV EC 50 <10nM EC 50 10–100nM EC 50 >100nM

41. POWER 1 and 2 Major Inclusion Criteria Documented HIV-1 infection [1,2] PI-, NRTI- and NNRTI-experienced patients currently on a PI-containing regimen [1,2] At least one primary PI mutation (IAS-USA March 2003) [1,2] –Patients with ≥3 primary PI mutations were allowed to enter the trial (limited to 30% of total) –IAS-USA list of mutations was revised during the trial –Number of PI mutations updated based on October 2004 list Plasma HIV RNA >1,000 copies/mL [1,2] No CD4 cell count restrictions [1,2] Coinfection with hepatitis B or C allowed in POWER 1 [1] 1. Katlama C, et al. 3rd IAS 2005. Abstract WeOaLB0102. 2. Wilkin T, et al. 45th ICAAC 2005. Abstract 2860.

42. POWER 1 and 2 Study Design *Based on IAS-USA March 2003 at start of study; updated to October 2004 list during study. † OBR = optimized background regimen (NRTIs ± ENF). Randomization PI-, NRTI- and NNRTI-experienced  1 PI mutation * PI-based regimen VL >1,000 copies/mL No NNRTI in OBR † DRV/r 800/100mg QD + OBR DRV/r 400/100mg BID + OBR DRV /r 600/100mg BID + OBR Investigator-selected CPI(s) + OBR DRV/r 400/100mg QD + OBR Screening 6 weeks Treatment period 96 weeks Follow-up 4 weeks CPI(s) Screening 4 weeks Treatment continuation from screening 2 weeks Investigator-selected CPI(s) + OBR 96 weeks DRV/r Functional monotherapy 2 weeks DRV/r + OBR 94 weeks POWER 1 [1] POWER 2 [2]

43. POWER 1, 2, and 3 Trials Study Design * Based on IAS-USA October 2004 1 Katlama C, et al. 3 rd IAS Conference July 2005, presentation WeOaLB0102. 2 Wilkin T, et al. 45th Annual ICAAC, December 2005. Abstract H-413. 3 Molina, J, et al. 12 th BHIVA, Brighton, UK, Mar 29-Apr 1, 2006. Poster P4. PI-, NRTI- and NNRTI- experienced  1 PI mutation * PI-based regimen VL >1,000 copies/mL No NNRTI in OBR DRV/r 800/100mg QD + OBR DRV/r 400/100mg BID + OBR DRV/r 600/100mg BID + OBR † Investigator-selected PI(s) + OBR DRV/r 400/100mg QD + OBR DRV/r 600/100mg BID + OBR n = 327 n = 303 de novo DRV/r n = 24 Rolled-over POWER 1 + 2 [1-2] POWER 3 [3] Screening Treatment 4 weeks144 weeks ** Primary Objective: – Proportion of patients with ≥ 1 log 10 reduction in HIV RNA from baseline to Week 24 Secondary Objectives: –Safety, tolerability, durability of response, PK/PD, resistance, immunologic response, body changes

44. POWER 1, 2 and 3 BL Characteristics of Patients Treated With DRV/r 600/100mg BID de novo Parameter POWER 1 (n = 65) POWER 2 (n = 66) POWER 3 (n = 327) Disease characteristics Mean HIV duration (years)11.112.912.8 Mean HIV RNA (log 10 copies/mL)4.594.62 Median CD4 count (cells/mm 3 )176115 Mean previous treatment duration (months) NRTI10793112 NNRTI292827 PI676269 BL phenotype and genotype Median primary PI mutations * (n)233 Median PI resistance-associated mutations * (n)889 ≥1 sensitive PIs available (%)393320 ≥1 sensitive NRTIs in OBR (%)776761 *IAS-USA Oct 2004 Molina JM, et al. 12th BHIVA 2006. Abstract P4.

45. POWER 2 PI Regimens for Control Patients Wilkin T, et al. 45th ICAAC 2005. Abstract 2860. 83% 17% Single PI-boosted Double PI-boosted BL: 33% of control patients were sensitive to ≥1 PI PIControl, n (%) APV22 (42) SQV16 (30) LPV15 (28) ATV6 (11) IDV2 (4) NFV1 (2)

46. POWER 1 and 2 Patient Disposition n (%)DRV/r 600/100mg BID (n = 131)CPI(s) (n = 124) Total discontinued28 (21)100 (81) Virologic failure11 (8)83 (67) Adverse event12 (9)6 (5) Withdrew consent1 (1)6 (5) Lost to follow-up3 (2)2 (2) Non-compliant1 (1)2 (2) Ineligible to continue01 (1) Patients who had not yet reached Week 48 were censored at their last available visit; responses of patients who had discontinued were imputed as ‘none’ in the time-to-loss of virologic response (TLOVR) analyses Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104. BL48362412 Weeks 0.2 0 1.0 0.8 0.6 0.4 Proportion remaining in the study DRV/r 600/100mg BID CPI(s)

47. POWER 1, 2 and 3 DRV/r 600/100mg BID Patients With Plasma VL <50 copies/mL at Week 24 (ITT-TLOVR) POWER 1 POWER 2 POWER 3 Response rate (%) BL24812162024 52% 40% 38% 100 90 80 70 60 50 40 30 20 10 0 Molina JM, et al. 12th BHIVA 2006. Abstract P4.

48. 140 120 100 80 60 40 20 0 –10 POWER 1, 2 and 3 Mean Change From BL in CD4 Count Up to Week 20 (LOCF) n (POWER 1) = 66666666 n (POWER 2) = 65656565 n (POWER 3) = 323 321 320308 POWER 1 POWER 2 POWER 3 Mean (±SE) change in CD4 count (cells/mm 3 ) 481220 122 80 61 Weeks Molina JM, et al. 12th BHIVA 2006. Abstract P4.

49. POWER 1 and 2 Patients With  1.0 log 10 VL Reduction From BL Over Time to Week 48 (ITT-TLOVR) Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104. DRV/r n = 131 131 131 130 120 110 CPI(s) n = 124 124 124 124 121 120 *P <.001 vs CPI(s) ITT = intent-to-treat, TLOVR = time-to-loss of virologic response Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit 70%* (n = 92/131) 21% (n = 26/124) 61%* (n = 67/110) 15% (n = 18/120) 0 20 40 60 80 100 04812162024283236404448 Weeks Patients (%) 21 DRV/r 600/100mg BID CPI(s)

50. POWER 1 and 2 Patients With VL <50 copies/mL From BL Over Time to Week 48 (ITT-TLOVR) DRV/r 600/100mg BID CPI(s) 45%* (n = 59/131) 12% (n = 15/124) 46%* (n = 50/110) 10% (n = 12/120) 0 20 40 60 80 100 04812162024283236404448 Weeks Patients (%) 12 *P <.001 vs CPI(s) ITT = intent-to-treat, TLOVR = time-to-loss of virologic response Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit DRV/r n = 131 131 131 130 120 110 CPI(s)n = 124 124 124 124 121 120 Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104.

51. POWER 1, 2 and 3 Summary of Efficacy for DRV/r 600/100mg BID 1 Bellos N, et al. 44 th IDSA 2006. 2 Saag M, et al. 44 th IDSA 2006. All DRV/r 600/100 mg BID

52. POWER 1 and 2 Mean Change in CD4 Count From BL Over Time to Week 48 (LOCF) 92* 102* 17 19 *P <.001 vs CPI(s) LOCF = last observation carried forward 2 20 40 60 80 100 120 140 04812162024283236404448 Weeks Mean change in CD4 count (cells/mm 3 ) 0 DRV/r n = 131 131 131 130 120 110 CPI(s) n = 124 124 124 124 121 120 DRV/r 600/100mg BID CPI(s) Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104.

53. Combined POWER 1 and 2 Week 24 Virologic Response Efficacy parameter (Intent-to-treat analysis) DRV/r 600/100mg BID n = 131 CPI Susceptible 1 n = 34 Resistant 1 n = 86 Overall n = 124 HIV RNA log 10 change (copies/mL) (Non-completer = failure)−1.89***−0.58−0.43−0.48 Patients with ≥1 log 10 VL reduction (%) (TLOVR) 2 70***321621 Patients with HIV RNA <50 copies/mL (%) (TLOVR)45***24 712 ***P <.001 (multivariate analysis) Updated data (all patients reached Week 24) 1 Defined by Antivirogram ® 2 TLOVR = time-to-loss of virological response DRV/r 600/100mg BID vs CPI De Meyer S, et al. 13th CROI 2006. Abstract 157.

54. Katlama C, et al. 3rd IAS 2005. Abstract WeOaLB0102. POWER 1 Subgroup Analysis of Patients With HIV RNA <50 copies/mL DRV/r 600/100mg BID vs CPI(s) 1020 30 40 50 60 7080 2 sensitive NRTIs in OBR 1 sensitive NRTI in OBR No sensitive NRTI in OBR Patients with HIV RNA <50 copies/mL (%) 0 27% (n = 15) 57% (n = 23) 0 (n = 16) 65% (n = 20) 0 (n = 9) 17% (n = 12) 37% (n = 19) 75% (n = 4) ≥ 3 sensitive NRTIs in OBR CPI(s)DRV/r 600/100mg BID

55. POWER 2 Most Common Treatment-Emergent AEs (Any Grade) at Week 24 (Observed Incidence) * Berger D, et al. 45th ICAAC 2005. Abstract H-1094. *AEs reported in ≥10% of patients in any treatment arm 0102030405060 Insomnia Fatigue Diarrhea Nausea Headache Patients (%) DRV/r 400/100mg QD DRV/r 800/100mg QD DRV/r 400/100mg BID DRV/r 600/100mg BID CPI(s)

56. POWER 2 Most Common Treatment-Emergent AEs (Any Grade) at Week 24 (Events/100 Patient Years of Exposure) 0102030405060 Insomnia Fatigue Diarrhea Nausea Headache Events/100 Patient Years of Exposure DRV/r 400/100mg QD DRV/r 800/100mg QD DRV/r 400/100mg BID DRV/r 600/100mg BID CPI(s) Berger D, et al. 45th ICAAC 2005. Abstract H-1094.

57. POWER 1, 2 and 3 Factors Influencing Outcome at Week 24 24-week efficacy data from POWER trial patients who initiated treatment with DRV/r 600/100mg BID were analyzed according to: –BL phenotypic DRV FC –Number of susceptible ARVs in OBR –BL genotype (number of BL primary PI mutations) –BL VL Efficacy measurements –≥1.0 log 10 VL reduction –HIV RNA <50 copies/mL –Mean log 10 VL reduction Pozniak A, et al. 12th BHIVA 2006. Abstract P3.

58. POWER 1, 2 and 3 Effect of BL DRV FC on Virologic Response at Week 24 BL DRV FC was the strongest predictor of response Patients with FC ≤10 had the greatest response for all efficacy parameters –2.08 log 10 VL reduction –50% achieved HIV RNA <50 copies/mL –79% had ≥1 log 10 VL reduction DRV/r responses were consistently higher than those of CPI regardless of DRV FC Pozniak A, et al. 12th BHIVA 2006. Abstract P3.

59. POWER 1, 2 and 3 Effect of Background Therapy on Virologic Response at Week 24 BL 24 8 1216 2024 Mean (±SE) change in log 10 VL (NC = F) −0.78 −0.09 −0.18 −1.27 −1.67 −2.15 Time (weeks) 0 –1 –2 –3 DRV/r: 0 susc. ARV = 0 DRV/r: 1 susc. ARV = 1 DRV/r:  2 susc. ARVs CPI: 0 susc. ARV CPI: 1 susc. ARV CPI:  2 susc. ARVs Pozniak A, et al. 12th BHIVA 2006. Abstract P3.

60. POWER 1, 2 and 3 Effect of BL and On-Treatment Mutations on DRV Susceptibility and Efficacy Number of BL mutations associated with diminished response –  10 PI resistance-associated mutations –DRV/r response still higher than that of CPI Specific types of BL mutations associated with diminished response –V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V –Presence associated with a higher overall number of PI mutations –DRV/r response still higher than that of CPI De Meyer S, et al. 13th CROI 2006. Abstract 157.

61. Mutations developing in  10% of virologic failures – V32I, L33F, I47V, I54L and L89V In vitro: mutations V32I, L33F, I47V and I54L alone or in combination with 1 or 2 mutations –no decreased susceptibility to DRV (FC <10) –may need higher number of mutations to decrease DRV susceptibility DRV rebounders have no increase in TPV FC De Meyer S, et al. 13th CROI 2006. Abstract 157. POWER 1, 2 and 3 Effect of BL and On-Treatment Mutations on DRV Susceptibility and Efficacy

62. POWER 1, 2 and 3 Virologic Response (<50 copies/mL) by Number of BL PI Resistance-Associated Mutations % With HIV-1 RNA <50 copies/mL (Week 24) 60 0 10 20 30 40 50 (72)(215) CPI Overall DRV (Number of isolates) Number of BL PI resistance-associated mutations (IAS–USA March 2005) 55 67891011  12 (28) (16) (36) (44) (50) (27) (9) (3) De Meyer S, et al. 13th CROI 2006. Abstract 157.

63. POWER 1, 2 and 3 Virologic Response (<50 copies/mL) by Specific Protease Mutations at BL BL protease mutations V11IV32IL33FI47VI50VI54LI54MG73SL76VI84VL89V (21) (17) (90) (28) (11) (15) (15) (40) (20) (84) (20) (72)(215) CPI Overall DRV (Number of isolates) 0 10 20 30 40 50 % With HIV-1 RNA <50 copies/mL (Week 24) 60

64. Observed change in VL at Week 24 (NC = F) FC  1010< FC  40 FC >40 n = 2556546 50% 25%13% VL <50 copies/mL Change in VL Darunavir FC (All Patients) Virologic Response at Week 24 vs BL

65. 0 10 20 30 40 0 (67) 1 (94) 2 (113) 3 (58)  4 (41) Number of DRV mutations (Number of patients) Percentage of patients Distribution of Number of Mutations Associated With Diminished Response to Darunavir Present at BL (All Patients)

66. 0 5 10 15 20 25 01234567891011121314151617181921 Number of IAS PI mutations Percentage of isolates 0 (n = 5,401)1 (n = 1,423) Johnson VA, et al. Top HIV Med 2005;13:125–31. Number of IAS PI Resistance-Associated Mutations for One Mutation Associated With a Diminished Response to DRV/r

67. Weighing the Mutations Associated With a Diminished Response to DRV/r V11IV32I L33F I47V I50V I54L I54M G73S L76V I84V L89V > 43 to 42 to 3< 2 Determined by multiple regression analyses of the 1,405 screening. samples from the POWER 1, 2 and 3 studies. Mutations Estimated increase in FC

68. Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104. POWER 1 and 2 Virologic Response Defined as VL <50 copies/mL by BL Subgroups at Week 48 (ITT-TLOVR) 70 Patients (%) 60 50 40 30 20 10 0 2 primary PI mutations* ≥3 primary PI mutations* 6/9 3/16 24/55 4/74 20/46 DRV FC  10 DRV 10 < FC ≤ 40 DRV FC > 40 39/70 11/76 10/29 0/24 0/10 0/16  1 primary PI mutation* FC = fold change in EC 50 *Based on IAS-USA guidelines 2004 (Johnson VA, et al. Top HIV Med 2004 Oct-Nov;12(4):119–124) 5/30 DRV/r 600/100mg BID CPI(s)

69. POWER 1 and 2 Virologic Response Defined as VL <50 copies/mL by BL Subgroups at Week 48 (ITT-TLOVR) Patients (%) 70 60 50 40 30 20 10 0 ENF used (naïve) ENF used (non-naïve) ENF not used 21/36 1/15 7/70 0 sensitive ARVs in OBR ≥1 sensitive ARVs in OBR 5/25 0/18 44/82 11/100 4/35 2/13 27/61 ARV = antiretroviral drug; OBR = optimized background regimen; ENF = enfuvirtide. Use of ENF was not randomized in POWER 1 and 2. DRV/r 600/100mg BID CPI(s) Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104.

70. POWER 1, 2 and 3: Effect of Baseline DRV FC on Change in Viral Load at Week 48 (NC = F) All DRV/r 600/100 mg BID

71. Relative Efficacy of DRV/r and TPV/r vs CPI in the POWER and RESIST Trials Meta-analysis compared efficacy of DRV/r, TPV/r and CPIs in RESIST and POWER trials –RESIST 1 and 2: TPV/r vs CPI (plus OBR) –POWER 1 and 2: DRV/r vs CPI (plus OBR) Similar background for POWER and RESIST –BL patient characteristics Treatment-experienced HIV RNA >1,000 copies/mL ≥1 primary PI mutation –Primary endpoint Proportion of patients with ≥1 log 10 VL reduction (ITT- TLOVR) at Week 24 Hill A, et al. 12th BHIVA 2006. Abstract P1.

72. ≥1 log 10 HIV RNA reduction Relative Efficacy DRV/r and TPV/r vs CPI DRV (n = 99) Patients achieving response (%) 18% CPI (n = 102) TPV/r (n = 582) CPI (n = 577) POWERRESIST +50% [95% CI 39–61] +22% [95% CI 17–27] 40% 21% 71% 20 40 60 80 Hill A, et al. 12th BHIVA 2006. Abstract P1.

73. Relative Efficacy DRV/r and TPV/r vs CPI DRV (n = 99) Patients achieving response (%) CPI (n = 102) TPV/r (n = 582) CPI (n = 577) POWERRESIST +34% [95% CI 22–42] +14% [95% CI 10–18] 48% 14% 9% 23% 20 40 60 80 HIV RNA < 50 copies/mL Hill A, et al. 12th BHIVA 2006. Abstract P1.

74. Distribution of Antiviral Activity LPV, TPV or DRV n = 2,682 Isolates Isolates (%) 7% 93% 0 25 50 75 100 LPV 65% 35% TPV 78% 22% DRV Decreased susceptibility Susceptible De Meyer S, et al. 4th EHDRW 2006. Abstract 42.

75. In-Vitro Antiviral Activity of DRV, LPV and TPV Against 9,968 Recent HIV-1 Clinical Isolates Decreased Susceptibility to LPV Decreased Susceptibility to TPV Decreased Susceptibility to DRV Number of PI resistance- associated mutations* ≥6≥10≥11 Isolates** Total (%)933522 Susceptible to LPV (%)00.5 Susceptible to TPV (%)053 Susceptible to DRV (%)77700 *Analysis on 5,546 / 9,968 isolates with available genotype **Analysis on 2,682 / 9,968 isolates with decreased susceptibility to LPV, TPV or DRV De Meyer S, et al. 4th EHDRW 2006. Abstract 42.

76. Darunavir Drug-Drug Interaction Results No dose adjustment: AtazanavirClarithromycin IndinavirKetoconazole EfavirenzParoxetine NevirapineSertraline Etravirine (TMC125)Ranitidine TenofovirOmeprazole Modify dose: Atorvastatin, Rifabutin, Sildenafil Not recommended: Lopinavir, SQV, Pravastatin Levels likely to decrease: Methadone, oral contraceptives