1. Douglas Ward, MD Dupont Circle Physicians Group Washington, DC Evolving Options for First-line PI-Based Antiretroviral Regimens This program is supported by an educational grant from

2. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens About These Slides  Our thanks to the presenters who gave permission to include their original data  The full program is available on the Clinical Care Options HIV Web site: clinicaloptions.com/hiv/evolving  Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Overview of This Presentation  Boosted PI–Based vs NNRTI-Based Treatment Regimens  Differences Among Currently Available Boosted PIs  Current Treatment Guidelines  Options for Deintensification of PI-Based Regimens  Summary: Choosing an Initial PI Regimen

4. Boosted PI–Based vs NNRTI- Based Treatment Regimens

5. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens M97-720: Long-term Efficacy of HAART  Longest running study of LPV/RTV –1997-2005  100 treatment-naive patients received LPV/RTV + d4T/3TC –Randomized LPV/RTV dose ranging through Week 48 –Open-label LPV/RTV 400/100 mg BID after Week 48 Outcome (ITT), % Week 48 [1] 7-Year Follow-up [2] HIV-1 RNA < 50 copies/mL78 59 HIV-1 RNA < 400 copies/mL85 61 1. Murphy RL, et al. AIDS. 2001;15:F1-F9. 2. Murphy RL, et al. EACS 2005. Abstract PE7.9/3

6. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Advantages and Disadvantages of Boosted PIs for Initial Therapy  Potential advantages –QD dosing for 3 RTV-boosted PIs: ATV/RTV, DRV/RTV, LPV/RTV –Good virologic activity [1-3] –High genetic barrier to resistance –Lack of CNS AEs –Use in women of childbearing potential –PI resistance uncommon at failure –Preserve NNRTIs for future use  Potential disadvantages –All choices include RTV –Single coformulated NNRTI- based alternative –Marginally poorer outcomes at higher pretreatment HIV-1 RNA and low CD4+ cell count vs EFV-based therapy –Metabolic complications –Potential drug-drug interactions due to CYP450 metabolism, particularly with RTV 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Ortiz R, et al. AIDS. 2008;22:1389-1397. 3. Gathe J, et al. CROI 2008. Abstract 775.

7. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Advantages and Disadvantages of NNRTIs for Initial Therapy  Potential advantages –Convenient, simple dosing –Virologic superiority of EFV + 2 NRTIs vs LPV/RTV + 2 NRTIs [1] –Durable efficacy [2,3] –Fewer metabolic AEs (dyslipidemia, insulin resistance) than PIs –Consistent activity at high pretreatment HIV-1 RNA and low pretreatment CD4 [1,4] –Preserve PI options for future use  Potential disadvantages –Low genetic barrier to resistance –Use EFV with caution in women of childbearing potential –CNS AEs of EFV may limit use in small number of patients –Some providers avoid EFV in patients with psychiatric illness and substance abuse –Potential for rash, hepatotoxicity –Cross-resistance among first- generation agents 1. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. 2. Arribas JR, et al. J Acquir Immune Defic Syndr. 2008;47:74-78. 3. Pozniak AL, et al. J Acquir Immune Defic Syndr. 2006;43:535-540. 4. Ribaudo HJ, et al. J Infect Dis. 2008;197:1006-1010.

8. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ACTG 5142: First-line EFV + NRTIs vs LPV/RTV + NRTIs  Multicenter, prospective, open-label, randomized, phase III clinical trial  Primary endpoints: time to virologic failure and time to regimen completion Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. Antiretroviral-naive HIV-infected patients with HIV-1 RNA ≥ 2000 copies/mL (N = 753) EFV 600 mg QD + 2 NRTIs* (n = 250) LPV/RTV SGC 400/100 mg BID + 2 NRTIs* (n = 253) EFV 600 mg QD + LPV/RTV SGC 533/133 mg BID (n = 250) Week 96 Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL, presence or absence of chronic hepatitis infection (B, C, or both), and NRTI selection *NRTIs = 3TC 150 mg BID or 300 mg QD plus either ZDV 300 mg BID, d4T extended release 100 mg QD (participants < 60 kg received 75 mg QD), or TDF 300 mg QD.

9. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens P =.003 ACTG 5142: Week 96 Virologic Response  Percentage of patients with HIV-1 RNA < 200 copies/mL or < 50 copies/mL significantly higher with EFV + 2 NRTIs in ITT analysis (switches included, missing values censored) 93 89 86 77 92 83 0 20 40 60 80 100 EFV + 2 NRTIs (n = 250) LPV/RTV + 2 NRTIs (n = 253) EFV + LPV/RTV (n = 250) Patients (%) < 200 copies/mL< 50 copies/mL P =.04 Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

10. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ACTG 5142: Immunologic Response Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. EFV + 2 NRTIs (n = 250) LPV/RTV + 2 NRTIs (n = 253) EFV + LPV/RTV (n = 250) 230 287 273 0 50 100 150 200 250 300 350 P =.01 Median CD4+ Cell Count Increase at Week 96 (cells/mm 3 )

11. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ACTG 5142: AEs  Adherence similar between treatment arms [1]  Time to first treatment-limiting toxicity similar between arms [1]  More grade 3/4 laboratory events in EFV + LPV/RTV arm, resulting primarily from hypertriglyceridemia (P <.01 vs either NRTI-containing arm) [1]  Higher incidence of lipoatrophy (≥ 20% decline in extremity fat) in EFV + 2 NRTIs arm, regardless of specific NRTIs used [2] 1. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. 2. Haubrich R, et al. CROI 2007. Abstract 38.

12. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ACTG 5142: Genotypic Resistance Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. *EFV + LPV/RTV vs LPV/RTV + NRTIs: P <.001; EFV + NRTIs vs LPV/RTV + NRTIs: P =.002. † LPV/RTV + NRTIs vs EFV + NRTIs or EFV + LPV/RTV: P <.001. ‡ LPV/RTV + NRTIs vs EFV + NRTIs: P <.001; EFV + NRTIs vs EFV + LPV/RTV: P =.01.  Genotypic resistance data (180/227 patients with virologic failure) –Incidence of any drug-resistance mutation or 2-class resistance higher in patients with virologic failure on EFV-containing regimens –NNRTI mutations more common when failing on EFV + LPV/RTV vs EFV + 2 NRTIs CharacteristicEFV + NRTIs (n = 250) LPV/RTV + NRTIs (n = 253) EFV + LPV/RTV (n = 250) Virologic failures, n609473 Genotypic assays, n467856 Any mutation (except minor protease mutations),* % 482170 NRTI mutations, %301911 NNRTI mutations, † %43366 Mutations in 2 drug classes, ‡ %2617

13. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ACTG 5142: Dosing/Pill Burden  Because study designed several years ago, more recent drug formulations not included –Used original LPV/RTV SGC formulation BID, not current tablet formulation –FTC not permitted in NRTI backbone; did not evaluate fixed- dose EFV/TDF/FTC –3TC administered BID Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

14. Differences Among Currently Available Boosted PIs

15. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens LPV/RTV: Former Gold Standard With Which Other PIs Have Been Compared  Before 2006, DHHS guidelines recommended LPV/RTV as only preferred choice for first-line PI treatment  More recent DHHS guidelines include other PIs in preferred category  LPV/RTV has been the standard with which several newer PIs have been compared in determining efficacy 1. DHHS guidelines. Available at: http://www.aidsinfo.nih.gov. Accessed February 17, 2009.

16. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Study Primary Endpoint Patients With HIV-1 RNA < 50 copies/mL, % Estimated Difference, % KLEAN (48 weeks, ITT-E: TLOVR) [1] FPV/RTV 700/100 mg BID + ABC/3TC (n = 434) 66 N/A LPV/RTV SGC 400/100 mg BID + ABC/3TC (n = 444) 65 GEMINI (48 weeks, ITT) [2] SQV/RTV 1000/100 mg BID TDF/FTC (n = 167) 65 1.14 (95% CI: -9.60 to 11.90) LPV/RTV SGC 400/100 mg BID + TDF/FTC (n = 170) 64 CASTLE (48 weeks, ITT-CVR: NC = F) [3] ATV/RTV 300/100 mg QD + TDF/FTC (n = 440)781.7 (95% CI: -3.8 to 7.1) LPV/RTV SGC 400/100 mg BID + TDF/FTC (n = 443)76 ARTEMIS (48 weeks, ITT: TLOVR) [4] DRV/RTV 800/100 mg QD (n = 343) 84 5.5 (95% CI: -0.3 to 11.2) LPV/RTV 400/100 mg BID or 800/200 mg QD + TDF/FTC* (n = 346) 78 1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. EACS 2007. Abstract PS1.4. 3. Molina JM, et al. CROI 2008. Abstract 37. 4. Clumeck N, et al. EACS 2007. Abstract LBPS7.5. *77% of patients received BID dosing throughout study; 83% of patients switched from SGC to tablet formulation. Similar Efficacy of Boosted PIs in Treatment-Naive Patients

17. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens KLEAN: Study Design  Multicenter, randomized, open-label, phase IIIb noninferiority trial  Primary endpoint: HIV-1 RNA < 400 copies/mL at Week 48 Antiretroviral-naive patients with HIV-1 RNA > 1000 copies/mL; no CD4+ cell count restrictions (N = 878) FPV/RTV 700/100 mg BID + ABC/3TC FDC (n = 434) LPV/RTV SGC 400/100 mg BID + ABC/3TC FDC (n = 444) Week 48Stratified by baseline HIV-1 RNA < vs ≥ 100,000 copies/mL Eron J Jr, et al. Lancet. 2006;368:476-482.

18. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens KLEAN: Main Findings Patient Outcomes at Week 48FPV/RTV (n = 434) LPV/RTVSGC (n = 444) HIV-1 RNA < 400 copies/mL (ITT-E, TLOVR ), %7371 HIV-1 RNA < 50 copies/mL (ITT-E, TLOVR), %6665 Confirmed virologic failure, n (%)16 (4)24 (5) Median increase in CD4+ cell count, cells/mm 3 (IQR) 176 (106-281)191 (124-287) Median change in lipid levels, mg/dL (mmol/L)  TC+61.0 (+1.58)+52.5 (+1.36)  LDL cholesterol+28.0 (+0.73)+22.5 (+0.58)  HDL cholesterol+13.0 (+0.34)+14.0 (+0.36)  TG+67.0 (+0.76)+77.5 (+0.88) Eron J Jr, et al. Lancet. 2006;368:476-482.

19. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens KLEAN: Resistance and AEs  35 patients with virologic failure tested for resistance mutations –12 (34%) developed resistance mutations –None with major PI resistance mutations –5 with minor PI resistance mutations (I54I/L, K20K/R, and I62I/V) –7 with 3TC resistance mutations –No significant differences in mutational patterns between arms  Both regimens similarly well tolerated, with few discontinuations due to AEs –Suspected ABC hypersensitivity reaction occurred in 6% of patients –Individuals coinfected with hepatitis B/C experienced higher incidence of grade 3/4 ALT elevations vs noncoinfected individuals (12% vs 1%) Eron J Jr, et al. Lancet. 2006;368:476-482.

20. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens KLEAN: Key Conclusions  Patients treated with FPV/RTV or LPV/RTV SGC, both in combination with ABC/3TC, experienced comparable efficacy, safety, tolerability, and emergence of resistance mutations –Noninferiority of regimen established according to several sensitivity analyses –Similar responses observed in all subgroups assessed, including those with high HIV-1 RNA (≥ 100,000 copies/mL) and low CD4+ cell counts (< 50 cells/mm 3 ) –Confirmed virologic failure uncommon in both arms Eron J Jr, et al. Lancet. 2006;368:476-482.

21. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens GEMINI: SQV/RTV vs LPV/RTV in Treatment-Naive Patients  Prospective, phase IIIb, multicenter, open-label study  Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48 Week 48 SQV/RTV 1000/100 mg BID + TDF/FTC FDC (n = 167) LPV/RTV SGC 400/100 mg BID TDF/FTC FDC (n = 170) Walmsley SL, et al. EACS 2007. Abstract PS1.4. *Patients had fairly advanced HIV infection: mean baseline HIV-1 RNA > 100,000 copies/mL; two thirds of patients had HIV-1 RNA above that level. Treatment-naive patients with CD4+ cell count ≤ 350 cells/mm 3 and HIV-1 RNA > 10,000 copies/mL (N = 337)

22. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens GEMINI: Viral Suppression With SQV/RTV vs LPV/RTV at Week 48 (ITT)  No significant difference between SQV/RTV and LPV/RTV at any time point 100 80 60 40 20 0 0 HIV-1 RNA < 50 copies/mL (%) 4812162024283236404448 64.7% 63.5% LPV/RTV (n = 170) SQV/RTV (n = 167) Week Walmsley SL, et al. EACS 2007. Abstract PS1.4. Estimated difference in Week 48 response vs LPV/RTV for noninferiority*: PP = 3.5% (96% CI: 8.1-15.0; P <.0058) ITT = 1.14% (96% CI: -9.60 to 11.90; P <.0119) *Noninferiority defined as lower CI threshold of not crossing -12%. ITT, M = F

23. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens  Virologic failure in 11 (7%) and 5 (3%) patients in SQV/RTV and LPV/RTV arms, respectively (P =.1311) –1 SQV/RTV patient vs 0 LPV/RTV patients failed with new PI mutations –5 SQV/RTV patients vs 4 LPV/RTV patients failed with new M184V/I mutation  GI AEs more common with LPV/RTV –Incidence of non-GI AEs similar between treatment arms GEMINI: Virologic Failures and AEs Walmsley SL, et al. EACS 2007. Abstract PS1.4. GI AEs in ≥ 3% of Patients, n (%)SQV/RTV (n = 163) LPV/RTV (n = 168) Any 27 (17)45 (27) Nausea 10 (6)15 (9) Diarrhea 11 (7)24 (14) Vomiting 6 (2)10 (3) Abdominal pain 3 (2)5 (3)

24. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Walmsley SL, et al. EACS 2007. Abstract PS1.4. GEMINI: Change in Lipids From BL to Week 24 or 48 (On-Treatment Analysis)  Significantly higher triglyceride elevations with LPV/RTV vs SQV/RTV –Median increases: 55 mg/dL (0.62 mmol/L) vs 14 mg/dL (0.16 mmol/L), respectively, at Week 48 (P =.0022)  More patients in LPV/RTV group (39%) exceeded NCEP threshold for TC vs SQV/RTV arm (31%) 100 80 60 40 20 Median Increase From BL (mg/dL) 0 TG 14 55 P =.0022 LPV/RTV SQV/RTV n =9981 108 10 45 P =.0007 Week 4824 106

25. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens CASTLE: ATV/RTV vs LPV/RTV in Treatment-Naive Patients  Multicenter, randomized, open-label phase III study  Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48 Antiretroviral-naive HIV-infected patients with HIV-1 RNA ≥ 5000 copies/mL and no CD4+ cell count restriction (N = 883) LPT/RTV 400/100 mg BID* + TDF/FTC FDC (n = 443) ATV/RTV 300/100 mg QD + TDF/FTC FDC (n = 440) Week 48 Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL and by geographic region *LPV/RTV administered as SGC through Week 48; tablet formulation administered after Week 48 where available. Molina JM, et al. Lancet. 2008;372:646-655.

26. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens CASTLE: Week 48 Response to ATV/RTV vs LPV/RTV in Naive Patients  At 96 weeks, significantly more patients in the ATV/RTV arm achieved HIV-1 RNA < 50 copies/mL vs patients receiving LPV/RTV: 74% vs 68% (estimated difference 6.1% [95% CI: 0.3% to 12.0%; P <.05]) [2] 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. ICAAC/IDSA 2008. Abstract 1250d. Estimated difference: 1.7% (95% CI: -3.8% to 7.1%; P = NS) Weeks ATV/RTV (n = 440) LPV/RTV (n = 443) Primary endpoint [1] 0 20 40 60 80 100 0 436 1248 24 78% 76% HIV-1 RNA < 50 copies/mL (%) ITT-CVR, NC = F Reprinted from Molina JM, et al. Lancet. 2008;372:646-655. Copyright 2008, permission from Elsevier.

27. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens  Median change in creatinine clearance -1% in both arms CASTLE: AEs at Week 48 *Excluding laboratory abnormalities reported as AEs. Molina JM, et al. Lancet. 2008;72:646-655. AE, n (%) ATV/RTV (n = 441) LPV/RTV (n = 437) Serious AEs51 (12)42 (10) All grade 2-4 treatment-related AEs115 (26)129 (30) Grade 2-4 treatment-related AEs ≥ 2%*  Jaundice16 (4)0  Nausea17 (4)33 (8)  Diarrhea10 (2)50 (11)  Rash14 (3)9 (2)

28. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Molina JM, et al. Lancet. 2008;372:646-655. 0 10 20 30 40 50 60 70 80 90 100 ATV/RTVLPV/RTV P =.51P =.0085 80 75 76 78 80 78 69 63 n = 222 106 45 58 228 134 29 48 ≥ 200 cells/mm 3 100 - < 200 cells/mm 3 50 - < 100 cells/mm 3 < 50 cells/mm 3 Responder < 50 copies/mL (%) CASTLE: Week 48 Virologic Response by Baseline CD4+ Cell Count Reprinted from Molina JM, et al. Lancet. 2008;372:646-655. Copyright 2008, permission from Elsevier.

29. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens CASTLE: Mean Change in Fasting Lipids at Week 48 (LOCF)  2% of ATV/RTV vs 8% of LPV/RTV subjects initiated lipid- lowering therapy during study Lipid Measurement Mean Change From Baseline to Week 48, % P Value ATV + RTV (n = 440) LPV/RTV (n = 443) TC 1224<.0001 LDL cholesterol 1215NR HDL cholesterol 2732NR Non-HDL cholesterol 721<.0001 TG 1351<.0001 Molina JM, et al. Lancet. 2008;372:646-655.

30. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens  Randomized, open-label phase III study undertaken in 26 countries  Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48  83% of patients switched from capsule to tablet formulation of LPV/RTV during study, according to local regulatory approval and drug availability ARTEMIS: DRV/RTV vs LPV/RTV in Treatment-Naive Patients *Dosing based on regulatory approval; 77% of patients received BID dosing. DRV/RTV 800/100 mg QD + TDF/FTC (n = 343) LPV/RTV 400/100 mg BID or 800/200 mg QD* + TDF/FTC (n = 346) Antiretroviral-naive patients with any CD4+ cell count and HIV-1 RNA > 2000 copies/mL (N = 689) 1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. ICAAC/IDSA 2008. Abstract 1250c. Week 48 primary endpoint [1] Week 96 [2]

31. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Week 96 [2] : Estimated difference in response vs LPV/RTV for noninferiority: PP: 8.4% (95% CI: 1.9% to 14.8%; P <.001) Estimated difference in response vs LPV/RTV for superiority: ITT: 8.3% (95% CI: 1.8% to 14.7%; P <.012) ARTEMIS: Week 96 Response to DRV/RTV vs LPV/RTV in Naive Patients HIV-1 RNA < 50 copies/mL (% [±SE]) 84 6096 Weeks 83672 1648 24 79% 71% 84% 78% LPV/RTV (n = 346) DRV/RTV (n = 343) 0 20 40 60 80 100 0 Week 48 (Primary Endpoint) [1]: Estimated difference in response vs LPV/RTV for noninferiority: PP = 5.6% (95% CI: -0.1 to 11.3; P <.001) Estimated difference in response vs LPV/RTV for superiority: ITT = 5.5% (95% CI: -0.3 to 11.2; P =.062) 1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. ICAAC/IDSA 2008. Abstract 1250c.

32. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ARTEMIS: Week 48 Treatment- Associated AEs and Resistance Event DRV/RTV QD (n = 343) LPV/RTV* (n = 346) Grade 2-4 AEs in ≥ 2%, † n (%) Diarrhea 14 (4) ‡ 34 (10) Nausea 6 (2)10 (3) Rash 9 (3)4 (1) Grade 2-4 lipid abnormalities, † n (%) TC 44 (13) ‡ 78 (23) LDL 44 (13)36 (10) TG 10 (3) § 38 (11) Virologic failure and resistance HIV-1 RNA > 50 copies/mL, n (%) 34 (10)49 (14) Paired baseline and virologic failure genotype available, n 1018 IAS-USA PI RAMs, n 01 *27 patients receiving LPV/RTV BID + QD excluded. † Possibly related to study drug. ‡ P <.05 vs LPV/RTV. § P <.01 vs LPV/RTV. Ortiz R, et al. AIDS. 2008;22:1389-1397.

33. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ARTEMIS: Differences in Virologic Response by BL VL, CD4+ Cell Count HIV-1 RNA < 50 copies/mL at Week 48,* %DRV/RTV (n = 343) LPV/RTV (n = 346) Baseline HIV-1 RNA  < 100,000 copies/mL 8685  ≥ 100,000 copies/mL 79 † 67 Baseline CD4+ cell count  > 200 cells/mm 3 8784  50-200 cells/mm 3 8071  < 50 cells/mm 3 7767 *ITT, TLOVR. † P <.05 vs LPV/RTV by chi square analysis. Ortiz R, et al. AIDS. 2008;22:1389-1397.

34. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Differential Changes in Fasting Lipid Levels Between Boosted PIs  ARTEMIS: significantly higher 96-week TG, TC, and HDL elevations from baseline with LPV/RTV vs DRV/RTV [1] –TG: 50% vs 12% (P <.0001) –TC: 23% vs 15% (P <.0001) –HDL: 19% vs 15% (P <.0102)  CASTLE: significantly higher 96-week TG, TC, and non-HDL elevations with LPV/RTV vs ATV/RTV [2] –TG: 50% vs 13% (P <.0001) –TC: 25% vs 13% (P <.0001) –Non-HDL: 23% vs 11% (P <.0001 )  GEMINI: significantly higher TG elevations with LPV/RTV vs SQV/RTV [3] –Median increases: 55 mg/dL (0.62 mmol/L) vs 14 mg/dL (0.16 mmol/L), respectively, at Week 48 (P =.0022) 1. Mills A, et al. ICAAC/IDSA 2008. Abstract 1250c. 2. Molina JM, et al. ICAAC/IDSA 2008. Abstract 1250d. 3. Walmsley SL, et al. EACS 2007. Abstract PS1.4.

35. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Differing AEs at Week 48 CASTLE [1] : Grade 2-4 AEs, % ATV/RTV (n = 441) LPV/RTV SGC (n = 437)  Jaundice40  Nausea58  Diarrhea515 ARTEMIS [2] : Grade 2-4 AEs, % DRV/RTV (n = 343) LPV/RTV (n = 346)  Any GI related714  Diarrhea410 GEMINI [3] : Grade 2-4 AEs, % SQV/RTV (n = 163) LPV/RTV SGC (n = 168)  Any GI related1727  Diarrhea714 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Ortiz R, et al. AIDS. 2008;22: 1389-1397. 3. Walmsley SL, et al. EACS 2007. Abstract PS1.4.

36. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Failure of Initial Boosted PI Regimens  Boosted PI–based regimens associated with fewer emergent mutations at failure vs unboosted PI–based and NNRTI-based regimens  Overall risk of virologic failure low in KLEAN, [1] GEMINI, [2] ARTEMIS, [3] CASTLE [4]  Approximately 10% to 20% of patients in each trial failed with emergent M184V/I/M  Only 1 major PI mutation emerged in KLEAN, GEMINI, CASTLE, and ARTEMIS –1 patient failed in CASTLE with L10F, V32I, K43T, M46I, A71I, G73S, L90M (a second patient on ATV/RTV who failed with N88S and M46I subsequently resuppressed) 1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. EACS 2007. Abstract PS1.4. 3. Ortiz R, et al. AIDS. 2008;1389-1397. 4. Molina JM, et al. Lancet. 2008;646-655.

37. Current Treatment Guidelines

38. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Recommended Initial Regimens for Antiretroviral-Naive Patients: 2008 DHHS Guidelines “Preferred” Regimens, November 2008 [1] NNRTI-based regimenEFV* +TDF/FTC PI-based regimen ATV/RTV QD DRV/RTV QD FPV/RTV BID LPV/RTV BID LPV/RTV QD IAS-USA Guidelines “Recommended” Regimens, August 2008 [2] NNRTI-based regimenEFV* + ABC/3TC † TDF/FTC PI-based regimen ATV/RTV DRV/RTV FPV/RTV LPV/RTV SQV/RTV *Except during first trimester of pregnancy or in women with high pregnancy potential. † Contraindicated if HLA-B*5701 positive. Recent data suggest ABC should be used with caution in patients with a high cardiovascular risk or HIV-1 RNA > 100,000 copies/mL. 1. DHHS guidelines. Available at: http://www.aidsinfo.nih.gov. Accessed February 17, 2009. 2. Hammer SM, et al. JAMA. 2008;300:555-570.

39. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens General Considerations for Initiating Antiretroviral Therapy  Comorbidities (eg, liver, psychiatric, or cardiovascular disease; TB; pregnancy)  Adherence potential  Dosing convenience (eg, pill burden, dosing frequency)*  Potential AEs*  Potential drug interactions*  Pregnancy potential  Results of resistance testing  Patient sex and CD4+ cell count, if considering NVP  HLA B*5701 testing, if considering ABC *Patient-specific factors. Other factors are drug related.

40. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens QD PI Dosing Options  QD boosted PIs, DHHS preferred –ATV/RTV –DRV/RTV –LPV/RTV  QD boosted PIs, FDA approved but not DHHS preferred –FPV/RTV 1400/200 mg  QD boosted PIs, not FDA approved nor DHHS preferred –FPV/RTV 1400/100 mg –SQV/RTV 2000/100 mg

41. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens M05-730: LPV/RTV QD vs BID in Treatment-Naive Patients  Prospective, open-label, randomized phase III trial  Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48 LPV/RTV tablets 800/200 mg QD + TDF/FTC LPV/RTV SGC* 800/200 mg QD + TDF/FTC Antiretroviral-naive patients with HIV-1 RNA ≥ 1000 copies/mL (N = 664) LPV/RTV tablets 400/100 mg BID + TDF/FTC LPV/RTV SGC* 400/100 mg BID + TDF/FTC Week 8 LPV/RTV tablets 800/200 mg QD + TDF/FTC (n = 333) LPV/RTV tablets 400/100 mg BID + TDF/FTC (n = 331) Week 48 primary endpoint Gathe J, et al. CROI 2008. Abstract 775.

42. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens M05-730: Patients With HIV-1 RNA < 50 copies/mL at Week 48 (ITT, NC = F)  QD tablets noninferior to BID tablets: 77% vs 76% (95% Cl: -5% to 8%)  Similar increases in CD4+ cell count at Week 48 with LPV/RTV QD (+186 cells/mm 3 ) vs BID (+197 cells/mm 3 ) Patients (%) 60 40 0 100 70 20 80 90 50 30 10 LPV/RTV QD LPV/RTV BID BL VL < 100K P =.782 BL VL ≥ 100K P >.999 Overall P =.715 n = Gathe J, et al. CROI 2008. Abstract 775. Reproduced with permission. 333331173138160193

43. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens M05-730: No Significant Difference in AEs Between Treatment Arms at Wk 48  Similar incidence of AEs, including diarrhea  No significant differences in laboratory abnormalities between LPV/RTV arms except TC –Greater mean increases in TC with BID vs QD LPV/RTV (+34.5 mg/dL [+0.89 mmol/L] vs +29.0 mg/dL [+0.75 mmol/L]; P =.044) Grade 3/4 AEs, % LPV/RTV QD (n = 333) LPV/RTV BID (n = 331) Diarrhea17 15 Nausea7 5 Vomiting3 4 Elevated TG2 2 Gathe J, et al. CROI 2008. Abstract 775.

44. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens  Nonrandomized, post hoc analysis LPV/RTV Overall *27 patients receiving both LPV/RTV QD and BID excluded from analysis. P = NS P <.05 71 84 81 78 100 80 60 40 20 0 LPV/RTV BID * LPV/RTV QD * DRV/RTV QD Patients With HIV-1 RNA < 50 copies/mL (%) Clumeck N, et al. EACS 2007. Abstract LBPS7.5. P = NS n =34626752343 ARTEMIS: HIV-1 RNA < 50 copies/mL at Week 48 by LPV/RTV Dosing

45. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens PI-Based Regimens’ Pill Burden  Daily pill burden (PI component) and dietary requirements –ATV/RTV2 pills/capsuleswith food –DRV/RTV3 pills/capsuleswith food –FPV/RTV4 pills/capsuleswith or without food –LPV/RTV4 pills/capsuleswith or without food –SQV/RTV6 pills/capsuleswith food

46. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Lopinavir/Ritonavir  Advantages –Demonstrated long-term efficacy –Coformulation –Fewer pills –Fewer copays –No refrigeration –QD or BID dosing preferred in DHHS guidelines  Disadvantages –Increased GI AEs (vs ATV, DRV, SQV) –Increased lipids (vs ATV, DRV, SQV)

47. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Atazanavir  Advantages –QD dosing –Low pill burden –Dosed with only 100 mg/day RTV –Favorable GI and lipid profiles  Disadvantages –Hyperbilirubinemia/jaundice –Must be taken with food –Use caution when coadministering with a PPI –Uncommon AEs –Rash –Nephrolithiasis –PR interval prolongation

48. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Darunavir  Advantages –Demonstrated potency –QD dosing –Dosed with only 100 mg/day RTV –Comparatively low pill burden –Favorable GI and lipid profiles  Disadvantages –Must be taken with food –Rash –Hepatic toxicity (rare) –Use with caution in patients with sulfa allergy

49. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Saquinavir  Advantages –Long-term efficacy –Lower pill burden with current tablet formulation vs previous capsule  Disadvantages –Must be taken with food

50. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Fosamprenavir  Advantages –QD dosing  Disadvantages –GI AEs –Rash –Use with caution in patients with sulfa allergy –Less favorable lipid profile

51. Options for Deintensification of PI-Based Regimens

52. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Deintensification Strategies  For virologically suppressed patients receiving an RTV- boosted PI + 2 NRTIs, may be possible to deintensify regimen to simplify treatment or to reduce toxicity –Attempts at deintensification in 1990s failed, probably due to maintenance regimens that were too weak [1,2]  Discontinue NRTIs: boosted PI monotherapy  Discontinue RTV boosting: unboosted PI + NRTIs –Older unboosted PIs (IDV, SQV, NFV, etc) less potent, high rates of virologic failure –Newer PIs (ATV, FPV, etc) more potent with longer half-lives 1. Havlir DV, et al. N Engl J Med. 1998;339:1261-1268. 2. Reijers MHE, et al. Lancet. 1998;352:185-190.

53. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens OK04 Study: LPV/RTV Maintenance Monotherapy vs Continued HAART  Similar median time with HIV-1 RNA < 50 copies/mL at baseline in both groups (17-19 months) –100 patients randomized to LPV/RTV SGC 400/100 mg BID (reintroduction of NRTIs permitted for virologic rebound) –98 patients randomized to LPV/RTV SGC 400/100 mg BID + 2 NRTIs  Proportion without therapeutic failure: 94.0% vs 89.8% for monotherapy vs triple therapy  Time to virologic failure not significantly different  Sensitivity (ITT) analysis (reintensification = failure): 85.0% vs 89.8% for monotherapy vs triple therapy  Primary PI resistance mutations: 2 patients on monotherapy vs 1 patient on triple therapy Arribas J, et al. IAC 2006. Abstract THLB0203.

54. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens  HIV-1 RNA < 80 copies/mL at Week 48 (ITT: NC = F)  2 virologic failures, 1 in each arm  2 cases of low-level viremia, 1 in each arm (both resuppressed without further treatment) KALMO Study: LPV/RTV Maintenance Monotherapy vs Continued HAART Nunes EP, et al. IAC 2006. Abstract TUAB0103. Reproduced with permission. 86% 83% Patients With HIV-1 RNA < 80 copies/mL (%) 0 20 40 60 80 100 Baseline4 12243648 Monotherapy (n = 30) Maintain HAART (n = 30) Weeks

55. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Meta-Analysis of Boosted PI Monotherapy Trials AnalysisRR (95% CI)P Value ITT1.23 (0.75-2.01).42 Per protocol2.58 (1.07-6.20).03 Ena J, et al. ICAAC/IDSA 2008. Abstract H-1255.  Analysis of 13 studies (4 RCTs; 9 single-arm) with > 24 weeks of follow-up –Patients received boosted PI monotherapy after achieving HIV-1 RNA < 50 copies/mL with PI + 2 NRTIs  In single-arm studies, boosted PI monotherapy associated with relatively high virologic failure rates –Failure rate (ITT): 21.96/100 patient-years (95% CI: 16.63-28.24)  In RCTs, higher risk of virologic failure on boosted PI monotherapy vs continued HAART  No significant difference in discontinuations due to AEs

56. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Boosted vs Unboosted ATV: BMS-089  BMS-089: treatment-naive patients randomized 1:1 (both with d4T + 3TC) –ATV 400 mg QD (n = 105) –ATV/RTV 300/100 mg (n = 95)  Greater 48-week virologic efficacy with ATV/RTV: 75% vs 70% < 50 copies/mL* –Virologic failures lower with ATV/RTV vs ATV: 3 vs 10  More PI and NRTI resistance at failure with ATV vs ATV/RTV  More hyperbilirubinemia/ jaundice in ATV/RTV arm  Increased lipids on ATV/RTV *Not powered to determine whether ATV/RTV is superior to ATV. Malan N, et al. CROI 2006. Abstract 107LB.

57. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ATV Induction/Maintenance Therapy  Lower rate of virologic failure in treatment-naive patients with ATV/RTV in BMS-089, but for patients who have attained HIV-1 RNA < 50 copies/mL on RTV-boosted PI, unboosted ATV may be sufficient to maintain virologic suppression  Fewer AEs/toxicities with unboosted ATV –Jaundice, lipid abnormalities, GI disturbances  Retrospective review of 28 patients switched from ATV/RTV to ATV [1] –All patients maintained HIV-1 RNA < 50 copies/mL for up to 28 months –Cholesterol decreased 201 to 182 mg/dL (5.51 to 4.71 mmol/L) (mean) –TG decreased 270 to 187 mg/dL (3.05 to 2.11 mmol/L) (mean) –Bilirubin decreased 2.6 to 1.6 mg/dL (mean) Ward D, et al. Glasgow, 2006. Abstract P18.

58. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens ATV Deintensification: INDUMA Study  172 patients received ATV/RTV + 2 NRTIs for 26-30 weeks, with confirmed HIV-1 RNA < 50 copies/mL  Randomized to continue ATV/RTV or switch to unboosted ATV + 2 NRTIs (no TDF) Outcomes at Week 48 After DeintensificationATV (n = 87) ATV/RTV (n = 85) HIV-1 RNA < 50 copies/mL (ITT), %7875 Virologic failure (HIV-1 RNA ≥ 50 copies/mL), n117 Discontinuations (for AEs), n14 NRTI mutations in failures, n21 PI mutations in failures, n00 TC (change after switch), mg/dL (mmol/L)-10 (-0.26)+3 (+0.07) TG (change after switch), mg/dL (mmol/L)-56 (-0.63)+22 (+0.25) Delfraissy JF, et al. Glasgow 2008. Abstract O415.

59. Summary: Choosing an Initial PI Regimen

60. clinicaloptions.com/hiv Evolving Options for First-line PI-Based Regimens Conclusions: PI-Based Regimens in Treatment-Naive Patients  RTV-boosted PI-based regimens offer one reasonable, highly effective option for first-line therapy –Included among DHHS and IAS guidelines preferred options –Less resistance at treatment failure vs NNRTI-based regimens  All RTV-boosted PIs provide broadly similar efficacy, with differences primarily in –Pill burden, dosing frequency –AEs and toxicities

61. Go Online for More Information on First-line PI-Based Antiretroviral Regimens Interactive Virtual Presentation Downloadable PowerPoint Slideset clinicaloptions.com/evolving