1. The Role of Protease Inhibitors in the Management of Treatment- Experienced Patients Joel E. Gallant, MD, MPH Professor of Medicine & Epidemiology Division of Infectious Diseases Johns Hopkins University School of Medicine Baltimore, Maryland

2. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Overview  Goals of therapy for treatment-experienced patients  Overview of TPV  Overview of DRV  Timing of use of new agents  Combination of novel agents with TPV and DRV

3. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals DHHS and IAS-USA Guidelines: Goals of Therapy  Evolving goal of antiretroviral therapy for all HIV-positive patients regardless of the extent of previous treatment experience –Achieve and maintain undetectable VL –Now applies to an increasing number of treatment- experienced patients Hammer SM, et al. JAMA. 2006;296:827-843. DHHS guidelines, May 2006. Available at: http://aidsinfo.nih.gov.

4. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Goals of Therapy in Patients With Access to < 2 Active Agents  Reduce VL by ≥ 1 log 10  Stabilize CD4+ count  Minimize drug toxicity  Prevent clinical progression and death  Avoid new resistance mutations that could reduce future options  Avoid “monotherapy” with new drugs  Increasing proportion of patients can access ≥ 2 active agents (approved ± investigational)

5. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals RESIST: Phase 3 Study of TPV/r 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 > 1000 Any CD4+ Best PI choice 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 Farthing C, et al. ICAAC 2006. Abstract H-1385. Hicks CB, et al. Lancet. 2006;368:466-475.

6. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals RESIST: Viral Load < 50 copies/mL at Week 96 0 081624324048 20 40 60 80 100 22.8% 10.2% Patients With HIV-1 RNA < 50 copies/mL (%) TPV/r (n = 746) CPI/r (n = 737) ITT: NC=F Farthing C, et al. ICAAC 2006. Abstract H-1385. 566472808896 20.4% 9.1% P <.0005

7. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals RESIST 1 and 2: 96-Week Results With TPV/RTV 80 0 20 40 All PatientsFirst-Time ENF Use Patients With VL < 50 copies/mL (%) TPV/RTVControl 34.7 14.4 n =746 60 100 80 0 20 40 All PatientsFirst-Time ENF Use Patients With VL < 400 copies/mL (%) TPV/RTVControl 44.4 14.4 n =746 60 100 P <.0005 P <.0001  TPV/RTV similar toxicity profile to comparator PIs at Wk 48, with 2 exceptions –Grade 3/4 ALT (10.1% vs 3.3%), AST (6.3% vs 2.9%) –Grade 3/4 TGs (30.8% vs 23.1%), TC (4.3% vs 0.7%) (P <.0001 for all comparisons) 20.4 9.1 26.9 10.9 Farthing C, et al. ICAAC 2006. Abstract H-1385. Hicks CB, et al. Lancet. 2006;368:466-475. P <.0002 P <.0001

8. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Cooper D, et al. CROI 2005. Abstract 560. TPV/RTV CPI/RTV Number of Sensitive Background ARVs 0 20 40 60 80 100 Patients With  1 log 10 Reduction in VL (%) Week 24 54.7 46.2 37.4 13.1 34.3 19.9 12.9 9.1 012  3 3 41.2 Overall 18.9 RESIST: Greater Response at Week 24 With More Active Agents in OBR

9. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Relationship of TPV Score to TPV Phenotype Results and Response TPV Score* Valdez H, et al. Resistance Workshop 2005. Abstract 27. -2 0 -3 Median Change in VL at Wk 24* (log 10 copies/mL) 0-12-34-56-78-9 -2.10 (n = 144) -0.89 (n = 242) -0.45 (n = 260) -0.49 (n = 68) -0.08 (n = 4) Median FC:0.7-0.91.1-1.42.0-3.13.3-3.9 14.7-52.5 Distribution of patients in RESIST-1 & -2 by BL TPV score *10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V

10. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals TPV Mutation Score vs IAS-USA Protease Gene Resistance Mutations  Many mutations (13, 35, 43, 58, 74, 83) have not been associated with resistance to other PIs  Major mutations (D30N, G48V, N88D, L90M) associated with other PIs do not contribute to TPV mutation score IAS- USA S C SAMV TTAVVIR SFSTLVALLFMI MDVAICVpVLLVVIIIINIRF 10 9088848277 7371 63 545350484746 36 3332302420 LNIVVCALIFIGIMMLVDLKL VV TMR VLPKEAVLTIGFMV 848382 74 69 5854 474643363533 2013 10 IVTHQIIMKMELKI TPV Score D N V L Kohlbrenner VM et al. HIV-DART 2004. Abstract 40.

11. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Adverse Effects of TPV/RTV: Black Box Warnings Aptivus [package insert]. Ridgefield, Conn: Boehringer Ingelheim; June 2006.  TPV/RTV associated with reports of –Fatal and nonfatal hepatitis and hepatic decompensation –More hepatotoxicity in patients on TPV/RTV in RESIST 1 and 2; patients with chronic HBV or HCV coinfection have increased risk –Fatal and nonfatal intracranial hemorrhage –13 patients receiving TPV/RTV experienced intracranial hemorrhage; use with caution in patients at risk of increased bleeding from trauma, surgery, or other medical conditions, or those receiving medications known to increase risk of bleeding

12. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Lazzarin A, et al. IAC 2006. Abstract TUAB0104. POWER 1 and 2: Study Design  DRV/RTV 600/100 mg BID provided greatest virologic response in Wk 24 analysis; FDA-approved dose for treatment-experienced pts VL, viral load; OBR, optimized background regimen (NRTIs ± enfuvirtide) Investigator- selected CPI(s) + OBR (without NNRTIs) Investigator-selected CPI(s) + OBR DRV/RTV 400/100 mg QD + OBR DRV/RTV 800/100 mg QD + OBR DRV/RTV 400/100 mg BID + OBR DRV/RTV 600/100 mg BID + OBR PI-, NRTI- and NNRTI- experienced  1 PI mutation (IAS-USA) PI-based regimen VL > 1000 copies/mL

13. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals DRV/RTV 600/100 mg BID *P <.001 vs comparator PI/RTV. 45* 12 46* 10 0 20 40 60 80 100 04812162024283236404448 Weeks 12 Control Patients With VL< 50 c/mL (%) 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. Lazzarin A, et al. IAC 2006. Abstract TUAB0104. POWER 1 and 2: VL < 50 copies/mL at Week 48 (ITT-TLOVR)

14. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals n = 120 POWER 1 and 2: VL < 50 copies/mL at Week 48 by Baseline Subgroups ENF Used (Naive) ENF Not Used ≥ 3 Primary PI Mut No Sensitive ARVs in OBR Overall Patients With VL < 50 copies/mL at Wk 48 (ITT, NC = F) (%) 020406080100 Lazzarin A, et al. IAC 2006. Abstract TUAB0104. 0 n = 25 n = 74 n = 55 n = 70 n = 61 n = 110 n = 35 n = 36 58 11 44 10 44 5 20 46 10 DRV/RTV 600/100 BID CPI/RTV n = 18 n = 11 n = 44 54 11 ≥ 1 Active Agent in OBR

15. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals POWER 3: VL < 50 copies/mL at Week 24 by ITT-TLOVR  POWER 3: ongoing phase III open-label study, DRV/RTV 600/100 mg [1]  Safety analysis similar to POWER 1 and 2 [2] 53 40 39 Patients With VL < 50 copies/mL (%) Weeks B/L 24812162420 0 10 20 30 40 50 60 70 POWER 1 (n = 65) POWER 2 (n = 66) POWER 3 (n = 327) 1. Molina JM, et al. IAC 2006. Abstract TUPE0060. 2. Madruga V, et al. IAC 2006. Abstract TUPE0062.

16. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals 50 25 13 n = 2556548 Effect of Baseline DRV Fold Change on Response to DRV  Baseline fold-change to DRV (by Antivirogram) was strong predictor of Week 24 response in POWER 1, 2, and 3 DeMeyer S, et al. Resistance Workshop 2006. Abstract 73. Patients With VL < 50 copies/mL at Wk 24 (%) 80 0 20 40 60 100 FC ≤ 10FC 11-40FC > 40 Baseline DRV FC Distribution of pts by baseline DRV FC

17. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals n = Effect of Baseline DRV-associated Mutations on Response to DRV  11 PI resistance mutations associated with reduced response –V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V Patients With VL < 50 copies/mL at Wk 24 (%) DeMeyer S, et al. Resistance Workshop 2006. Abstract 73. 12≥ 430 50 42 10 22 64 80 0 20 40 60 100 94113416758 Baseline No. of DRV Mutations Distribution of pts by baseline # of DRV mutations

18. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals 15% 59% n = 17 n = 33 12% 18% n = 11 n = 17 POWER 1, 2, and 3: Effect of ENF by Baseline FC to DRV (ITT-TLOVR) FC > 40 FC 10-40 FC  10 223 (74%) Adjusted estimate Controlling for # of active NRTIs in OBR, # of primary PI mutations, DRV FC, and ENF use (naive/not used) P =.32 49% 39% N (%)* *Patients reaching Wk 24 or D/C earlier, excluding those who had previously used ENF Response (< 50 c/mL) Subjects using ENF naivelySubjects not using ENF 52% 53% 020406080100 n = 64 n = 159 Data on file. Tibotec Therapeutics. 2006 50 (17%) 28 (9%)

19. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Relationship Between Activity of OBR and Response to DRV/RTV 600/100  Subgroup analyses of pooled POWER 1, 2, and 3 data  Highest rates of VL < 50 copies/mL in pts with ≥ 2 active agents in OBR [1]  No incremental benefit of active ENF if ≥ 1 active NRTI in OBR [1]  Phenotypic susceptibility score (PSS) of OBR also predicted VL < 50 at Wk 24 [2] –PSS ≤ 0.5: 34% –PSS 0.5-1.5: 49% –PSS > 1.5: 52% Characteristic of OBR VL < 50 at Wk 24, % # of active agents 0026 1146  ≥ 249 Type of active agent  Active ENF only43  ≥ 1 active NRTI, no ENF51  ≥ 1 active NRTI + active ENF 53 1. Pozniak A, et al. BHIVA, 2006. Abstract P3. 2. Vangeneugden T, et al. Resistance Workshop, 2006. Abstract 1138.

20. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals FDA Indications for New PIs TPV/RTV  “Adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors” DRV/RTV  “Antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor”

21. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Most Clinical Isolates Are Maximally Susceptible to Both TPV and DRV Minimal Reduced Maximal Susceptibility Picchio G, et al. ICAAC 2006. H-999.  Analysis of 56,018 samples submitted for routine resistance testing 0.2% 5.0% 94.8% 1.5% 8.7% 89.8% DRV TPV

22. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals TPV and DRV Mutations and Phenotypic Cutoffs Similarities and Differences in Key Mutations TPV10V13V20M/R/V33F35G36I43T46L47V DRV11I32I33F47V TPV54A/M/V58E69K74P82L/T83D84V DRV50V54L/M73S76V84V89V Assay/ Cutoff PhenoSense: FC for Reduced Activity PhenoSense: FC for No Response VircoTYPE: FC for Maximal Response VircoTYPE: FC for Minimal Response TPV [1,2] ≥ 2≥ 8< 1.2≥ 5.4 DRV [3,4] ≥ 10≥ 40< 3.4≥ 96.9 1. Oakley E, et al. Resistance Wkshp 2006. Abstract 71. 2. Bacheler L, et al. Euro Resistance Wkshp 2006. Abstract 40. 3. De Meyer S, et al. Resistance Wkshp 2006. Abstract 73. 4. Winters B, et al. Resistance Wkshp 2006. Abstract 160. Phenotypic Cutoffs

23. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Susceptibility to TPV or DRV After Failure of Each Other  Limited data suggest both agents may retain activity after failure of the other  Among 39 patients with virologic rebound on DRV/RTV [1] –Median 8.14 fold-change loss of DRV susceptibility from baseline –However, no decrease in susceptibility to TPV  In POWER 3, 51 patients (11%) were failing TPV/RTV at entry [2] –44% achieved VL < 50 copies/mL at Week 24, similar to overall response to DRV/RTV in POWER 1, 2, and 3 (42%) 1. De Meyer S, et al. CROI 2006. Abstract 157. 2. Lefebvre E, et al. ICAAC 2006. Abstract H-1387.

24. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Key Steps to Regaining Virologic Suppression  Aim for undetectable viral load  Use cumulative results from current and prior resistance tests along with treatment history to assess drug susceptibility  Select a new regimen containing at least 2 fully active agents

25. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals  Too soon –New drug used in combination with inactive or partially active drugs despite relatively preserved CD4+ cell count  Too late –New drug deferred until the patient’s virus is resistant to all other available drugs  Just right –New drug combined with other active agents or use deferred until other new agents available Use of New Agents: Too Soon, Too Late, or Just Right?

26. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals  NNRTIs: most patients have resistance to first-generation NNRTIs at this stage  NRTIs: assess NRTI resistance carefully, considering all resistance test results and treatment history  Other PIs: cannot be combined with TPV; limited data with DRV; minimal data supporting dual-boosted PIs  ENF: often the best choice in patients with extensive 3-class resistance  New agents What to Combine With the New PIs in Treatment-Experienced Patients

27. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Expanded Access Availability  Etravirine (TMC125): available since August 2006 –http://www.clinicaltrials.gov/ct/show/NCT00354627?order=2http://www.clinicaltrials.gov/ct/show/NCT00354627?order=2  MK-0518: available since September 2006 –http://www.benchmrk.com/secure/earmrk/earmrk.htmlhttp://www.benchmrk.com/secure/earmrk/earmrk.html  Maraviroc: expected to be available Q1 2007

28. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Combining New Agents With the New PIs  Etravirine (TMC125): second-generation NNRTI –DUET study in progress (DRV ± ETV) –EAP available

29. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals VL < 50 copies/mL at Wk 48 (%) 20 0 22 Control 23 ETV 400 mg BID Cohen C, et al. IAC 2006. Abstract TUPE0061.  199 HIV-infected patients with NNRTI resistance and ≥ 3 primary PI mutations –Median NNRTI FC –NVP: 61.3 –EFV: 41.4 –ETV: 1.6  Randomized to –ETV (400 mg BID or 800 mg BID) + NRTIs ± LPV/RTV ± ENF –Active control: best available regimen from approved agents (NNRTIs excluded) ETV 800 mg BID 0 40 60 80 100 TMC125-C223: Virologic Response to Etravirine at Week 48

30. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals TMC125-C223: B/L NNRTI Mutations and Virologic Response at Week 48  Each of the following mutations, always in combination with up to 4 other mutations was associated with a mean FC > 10 –K101P, V179E, V179F, Y181I, Y181V, G190S, M230L –For 179E, G190S, or M230L, the additional mutations always included Y181C when FC > 10 Cohen C, et al. IAC 2006. Abstract TUPE0061. ETV 800 BID Active Control Response to ETV 800 BID by # of B/L NNRTI mutations 0*12≥ 3 0 -0.5 -1.5 -2.0 n = 79n = 40n = 14n = 19n = 16n = 30 -1.01 -0.14 -1.67 -1.38 -0.9 -0.54 Mean Change in VL Log 10 *All patients had confirmed NNRTI mutations from prior genotypic resistance tests ITT, NC = no change from baseline

31. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Pilot Data on DRV/RTV Plus Etravirine  Combination of DRV + ETV associated with 30% reduction in ETV levels vs historical controls; not judged to be clinically significant [1]  3-class resistant patients treated with DRV/RTV 600/100 mg BID + ETV 200 mg BID + NRTIs ± ENF  Montaner et al. [2] –4/5 patients achieved VL < 50 copies/mL at Weeks 20-24  Boffito et al. [3] –10/12 patients completed 24 weeks of therapy –9/10 achieved VL < 50 copies/mL, 1/10 = 722 copies/mL –Median VL decline, -2.7 log 10 ; CD4 increase: 113 cells/mm 3 –No serious adverse events or changes in laboratory safety 1. Boffito M, et al. CROI 2006. Abstract 575c. 2. Montaner J, et al. IAC 2006. Abstract THPE0136. 3. Boffito M, et al. ICAAC 2006. Abstract H-1000.

32. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Combining New Agents With the New PIs  Etravirine (TMC125): second-generation NNRTI –DUET study in progress (DRV ± ETV) –EAP available  Integrase inhibitors –MK-0518: EAP available, BID, no RTV boosting effect

33. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals MK-0518 400 mg BID (n = 45) MK-0518 200 mg BID (n = 43) OBR alone (n = 45) MK-0518 600 mg BID (n = 45) MK-0518: Virologic Suppression Through Week 24 (NC = F) Grinsztejn B, et al. ICAAC 2006. Abstract H-1670b. Patients With VL < 400 copies/mL (%) 100 80 60 40 20 0 24812160 Week 24 Patients With VL < 50 copies/mL (%) 100 80 60 40 20 24812160 Week 24

34. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Combining New Agents With the New PIs  Etravirine (TMC125): second-generation NNRTI –DUET study in progress (DRV ± ETV) –EAP available  Integrase inhibitors –MK-0518: EAP available, BID, no RTV boosting effect  Entry inhibitors –Maraviroc (MVC): CCR5 inhibitor, EAP available soon

35. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Mayer H, et al. IAC 2006. Abstract THLB0215.  No difference in mean VL ↓ between MVC + OBR vs placebo + OBR –-0.97, -0.91, -1.20 log 10 for placebo, MVC QD, and MVC BID at Wk 24  No major AEs; no hepatotoxicity, lymphoma, or adenocarcinoma  Higher CD4+ cell counts at Week 24 with MVC vs placebo  Detection of only X4-tropic HIV more common at treatment failure with MVC vs placebo –However, similar CD4+ cell count increases in patients with detection of only X4 virus vs overall MVC-treated population, suggesting no impact on immunologic recovery Population Change in CD4+ Cell Count Placebo + OBR (n = 58) MVC QD + OBR (n = 57) MVC BID + OBR (n = 52) All treated patients +36 +60+62 Patients with only X4 virus detected at time of VF -104 (n = 2) +48 (n = 12)+33 (n = 12) MVC Safe in Experienced Patients With Detectable X4 HIV

36. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Other New Agents in Advanced Clinical Trials  Integrase inhibitor –GS-9137: QD, boosted by RTV  Maturation inhibitor –Bevirimat (PA-457)  Entry inhibitors –Vicriviroc: CCR5 inhibitor

37. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Guidelines for Choosing a Nonsuppressive “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  Always use 3TC or FTC –Simple and well-tolerated drugs –M184V decreases fitness, increases activity of ZDV, d4T, TDF  Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations

38. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Considering a Clinical Trial  What are the odds of receiving the study drug?  How many active drugs are available for the background regimen?  How active will the background regimen be if the patient is randomized to the control (placebo) arm?  How long will you have to wait for a suppressive regimen?  What are the clinical and resistance consequences of waiting?

39. clinicaloptions.com/hiv New Protease Inhibitors, New Treatment Goals Estimated Timeline for Availability of New Antiretrovirals Bevirimat PIs NNRTI NRTI Maturation inhibitors Maraviroc GS-9137 TMC278 Etravirine Apricitabine Brecanavir Integrase inhibitors Entry inhibitors (anti-gp120, CCR5) CXCR4 inhibitors MK-0518 TNX-355 20062007200820092010 Vicriviroc