1. Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care This program is supported by an educational grant from

2. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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 Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Faculty Program Director Anton L. Pozniak, MD, FRCP Consultant Physician Director of HIV Services Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital NHS Trust London, United Kingdom Additional Faculty José R. Arribas, MD Associate Professor of Medicine Hospital La Paz Autónoma University School of Medicine Madrid, Spain Diego Ripamonti, MD Malattie Infettive Ospedali Riuniti di Bergamo Bergamo, Italy

4. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Faculty Disclosures José R. Arribas, MD, has disclosed that he has received consulting fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharpe and Dohme, and ViiV and funding for research support from Janssen. Anton L. Pozniak, MD, FRCP, has disclosed that he has received consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Roche, and ViiV and fees for non-CME services from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV. Diego Ripamonti, MD, has disclosed that he has received consulting fees and fees for non-CME services from Janssen.

5. Anton L. Pozniak, MD, FRCP Consultant Physician Director of HIV Services Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital NHS Trust London, United Kingdom Clinical Studies of Boosted PI Monotherapy: What Are the Data?

6. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care ConcernsResponses Less efficacious than HAART  Small difference in efficacy from HAART  May be PI dependent Increased risk of low-level viremia  Reversible after NRTI reintroduction Increased risk of resistance  May be PI dependent  Does not compromise other classes  Preserves other treatment options Higher level of adherence required  “Reversible” failure  Easy to identify patients needing to reintroduce NRTIs Durability uncertain  2-yr results encouraging  Ongoing trials collecting additional data Efficacy in reservoirs (CNS, genital) uncertain  More research needed (also true for triple-drug therapy) Benefits not proven  Clear cost benefit  Fewer metabolic disturbances Study size (< 1000 pts so far)  Additional trials ongoing Concerns About Boosted PI Monotherapy

7. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care SettingTrialPI NaiveIMANI I, II MONARK LPV/RTV Induction-maintenanceM0-613 SimplificationOK pilot OK04 KALMO IMANI III SARA* ACTG 5201 ATARITMO Karlström et al OREY ATV/RTV MONOI MONET DRV/RTV Studies of Boosted PI Monotherapy *Only 77% retrospectively determined to have HIV-1 RNA < 50 copies/mL at randomization.

8. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Studies of LPV/RTV Monotherapy as First-line or Maintenance Therapy StudyMONARK [1] M03-613 [2] OK04 [3] KALMO [4] Design  First-line monotherapy (n = 83)  Induction- maintenance monotherapy * (n = 104)  Simplification monotherapy (n = 21)  Simplification monotherapy (n = 30) Patient population  Naive  VL < 100,000  CD4+ > 100  Naive  VL > 1000  Any CD4+ count  Experienced w/o PI failure  VL 6 mos  LPV/RTV + 2 NRTIs for > 1 mo  VL 6 mos  No hx of VF  CD4+ > 200 Comparator  LPV/RTV + ZDV/3TC (n = 53)  EFV + ZDV/3TC (n = 51)  LPV/RTV + 2 NRTIs (n = 21)  Continued HAART (n = 30) Primary endpoint  VL < 400 at Wk 24 and < 50 at Wk 48  VL < 50 at Wk 96 (ITT, prior failure = failure)  VL < 500 at Wk 48 (ITT, M or change = F)  VL < 80 by Wk 96 (ITT, M = F) 1. Delfraissy JF, et al. AIDS. 2008;22:385-393. 2. Cameron DW, et al. J Infect Dis. 2008;198:234-240. 3. Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40:280-287. 4. Nunes EP, et al. HIV Clin Trials. 2009;10:368-374. *Subjects had suppressed VL for ~ 3 mos before simplification.

9. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Efficacy of LPV/RTV Monotherapy vs Comparator Arms Comparator arms LPV/RTV mono 75 87 80 61 48 81 95 0 25 50 75 100 64 Patients Meeting Primary Endpoint (%) Resistance 24 genotyped Mono arm:  3/21 PI mutations  No NRTI mutations LPV/RTV + ZDV/3TC arm:  M184V: 1  No PI Mutations 1. Delfraissy JF, et al. AIDS. 2008;22:385-393. 2. Cameron DW, et al. J Infect Dis. 2008;198:234-240. 3. Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40:280-287. 4. Nunes EP, et al. HIV Clin Trials. 2009;10:368-374. P =.19 P =.34 P =.17 83531045121 30 n = OK04 [3] Simplification KALMO [4] Simplification Resistance 16 genotyped LPV/RTV arms (both triple and mono)  PI mutations: 4  Multiclass:3 EFV arm:  K103N: 1 Resistance  4 genotyped  Mono arm: 2 patients developed primary PI mutations Resistance  2 VF, 1 in each arm, both genotyped  No evidence of resistance in either case ITTITT, Prior Failure = Failure ITT, M = F P =.48 ITT, M = F M03-613 [2] Induction/maintenance MONARK [1] Initial therapy

10. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Virologic Response to LPV/RTV Monotherapy Better With Simplification MONARK [1] Initial therapy M03-613 [2] Induction/Maintenance 0 20 40 60 80 100 01632 Wk 480163248648096 Wk 364812 OK04 [3] Simplification Discontinued On study, HIV-1 RNA > 400 On study, HIV-1 RNA 50-400 On study, HIV-1 RNA < 50 1. Delfraissy JF, et al. AIDS. 2008;22:385-393. 2. Cameron DW, et al. J Infect Dis. 2008;198:234-240.Published by University of Chicago. 3. Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40:280-287. 024 Patients (%)

11. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Bierman WF, et al. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. 2009;23:279-291. Systematic Review of LPV/RTV Monotherapy Therapy Failure, Intent to Treat Odds Ratio (95% CI) 4.71 (0.48-46.2) 1.70 (0.46-6.21) 2.17 (0.47-9.64) 1.03 (0.53-2.01) 1.67 (0.85-3.31) 1.48 (0.68-3.22) Favors HAART 1.48 (1.02-2.13) Studies OK04 2005 Singh et al, 2007 KALMO OK04 2008 MO6-613 MONARK Overall Favors monotherapy 0.1110100 Odds Ratio

12. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care StudyATARITMO [1] ACTG 5201 [2] Karlström [3] OREY [4] Design  Simplified maintenance monotherapy  24-wk pilot study  Simplified maintenance monotherapy  24-wk pilot-study, 48- wk data presented  Simplification monotherapy  Pilot trial planned for 72 wks  Simplification monotherapy  48-wk primary endpoint; continued through Wk 96 Patient population  30 experienced pts  HAART ≥ 6 mos or  Switching from IDV/RTV mono trial  VL < 50  36 experienced pts  VL < 50 for ≥ 48 wks on 2 NRTIs + PI  CD4+ count > 250  Pts switched to 2 NRTIs + ATV/RTV → ATV/RTV mono after 6 wks  30 experienced pts  VL < 20 for ≥ 1 yr on HAART  No PI experience  61 experienced pts  VL < 50 for ≥ 6 mos  No hx of VF  NRTIs + ATV/RTV ≥ 8 wks → ATV/RTV Comparator  Noncomparative Primary endpoint  2 x VL > 400 or  3 x VL > 200 or  4 x VL > 100  Risk of virologic failure (2 x VL > 200) at 24 wks  Number of pts w/o VF at 72 wks  VF: 2 x VL > 20  To be terminated if 5 cases of virologic failure occurred  VL > 400 at Wk 48  Tx discontinuation 1. Vernazza P, et al. AIDS. 2007;21:1309-1315. 2. Wilkin T, et al. J Infect Dis. 2009;199:866-871. 3. Karlström O, et al. J Acquir Immune Defic Syndr. 2007;44:417-422. 4. Pulido F, et al. EACS 2009. Abstract PS4/6. Studies of ATV/RTV Monotherapy

13. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Studies of ATV/RTV Monotherapy Study ATARITMO [1] ACTG 5201 [2] Karlström [3] OREY [4] Results  2 pts (7%) with VF at Wk 24 (1 d/c, 1 protocol violation)  5 pts with virologic “blips”  34 simplified to ATV/RTV monotherapy  88% (30) did not experience VF at Wk 48 after simplification  1 pt with VL = 508 at final visit  Stopped at 15 pts  5 VFs  No pts completing 72 wks on monotherapy without VF  9/14 (64%) with virologic success after median 36 wks  21% with tx failure  12% with virologic rebound Resistance  Not tested in plasma samples  5 pts genotyped  No major PI RAMs  No low frequency ATV resistance variants detected  3 pts genotyped  No PI resistance mutations  7 pts genotyped  1 pt with ATV resistance mutation N88S at Wk 48  1 additional pt with N88S + M46L after Wk 48 1. Vernazza P, et al. AIDS. 2007;21:1309-1315. 2. Wilkin T, et al. J Infect Dis. 2009;199:866-871. 3. Karlström O, et al. J Acquir Immune Defic Syndr. 2007;44:417-422. 4. Pulido F. et al. EACS 2009. Abstract PS4/6.

14. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care StudyMONET [1] MONOI [2] Design  Simplification monotherapy  DRV/RTV 800/100 QD (n = 127)  Wk 48 primary endpoint; 144-wk follow-up  Simplification monotherapy  DRV/RTV 600/100 mg BID (n = 112)  Wk 48 primary endpoint; 96-wk follow-up Patient population  256 experienced pts  HAART with 2 NRTIs + either NNRTI or PI at screening  No prior use of DRV  VL < 50 for ≥ 6 mos  No hx VF  226 experienced pts  DRV-naive HIV-infected pts on HAART  VL < 400 for ≥ 18 mos  VL < 50 at screening  No PI failure  CD4+ nadir > 50  All pts suppressed on DRV/RTV 600/100 mg BID + 2 NRTIs prior to comparative study ComparatorDRV/RTV 800/100 mg QD + 2 NRTIs (n = 129)DRV/RTV 600/100 mg BID + 2 NRTIs (n = 113) Primary endpoint  2 consecutive HIV RNA > 50 copies/mL  Discontinuation of randomized tx (TLOVR) Stopping DRV/RTV or starting NRTIs in mono arm Stopping NRTIs in the control arm (switches in NRTIs permitted)  Proportion with tx success at Wk 48  Tx failure: 2 x VL > 400 within 2 wks Tx modification Withdrawal 1. Arribas J, et al. AIDS. 2010;24:223-230. 2. Katlama C, et al. AIDS. 2010;24:2365-2374. Studies of DRV/RTV Monotherapy

15. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care DRV/RTV Monotherapy: Efficacy at Last Report 87.5 92.0 ITT Analysis 94.1 99 MONOI 48 Wks [2] 92.1 90.7 Switch (Intensification With NRTIs) Allowed DRV/RTV Mono 80.6 MONET 96 Wks [1] DRV/RTV Mono DRV/RTV + 2 NRTIs Lower limit of 90% CI: -9.1 TLOVR, S = F 74.8  = -5.8% (-16.0% to +4.4%) 129 127 DRV/RTV + 2 NRTIs  = +1.4% (-5.5% to +8.3%) 129 127 PP Analysis Lower limit of 90% CI: -11.2 DRV/RTV Mono DRV/RTV + 2 NRTIs DRV/RTV Mono DRV/RTV + 2 NRTIs 1. Rieger A, et al. AIDS 2010. Abstract THLBB209. 2. Katlama C, et al. AIDS. 2010;24:2365-2374. Mono not noninferior Mono noninferior Mono not noninferior 113 112 102 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 Patients Meeting Primary Endpoint /%)

16. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care MONET Trial: HIV-1 RNA at BL and Wk 96 Patients (%) > 400 50-400 5-50 < 5 HIV-1 RNA (c/mL) DRV/RTV Mono Arm* *Observed data analysis; patients with VF removed. Clumeck N, et al. Glasgow 2010. Abstract O-19. 100 90 80 70 60 50 40 30 20 10 0 BaselineWk 96BaselineWk 96 DRV/RTV + 2 NRTI Arm* 127104129115n =

17. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Adverse Events With DRV/RTV Monotherapy  MONET: greater percentage of patients in mono arm with certain lab abnormalities Parameter, % DRV/RTV Mono (n = 127) DRV/RTV + 2 NRTIs (n = 129) ALT6.32.4 AST3.92.4 LDL cholesterol9.47.8 Total cholesterol11.0 3.9 Triglycerides3.2 0.8 Rieger A, et al. AIDS 2010. Abstract THLBB209.

18. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care DRV Monotherapy: Resistance MONET [1]  Genotypes –20 in mono arm, 27 in triple-therapy arm –Only 1 pt per arm had any evidence of genotypic resistance –Mono arm: L33F at Wk 12 –Triple-therapy arm: M184V + I54V, V82T, L90M (BL geno had M184V, V82I, L90M) –Both pts regained suppression w/o change in tx –No evidence for evolution of resistance in pts with intermittent viremia in the monotherapy arm [3] MONOI [2]  Virologic failure in 3 pts on monotherapy vs 0 on standard therapy –Low DRV drug levels noted in 1 pt –1 pt had V11I which was also found in a BL sample; no DRV RAMs in other 2 –All 3 pts regained HIV-1 RNA < 50 c/mL on reintroduction of 2 NRTIs 1. Rieger A, et al. AIDS 2010. Abstract THLBB209. 2. Katlama C, et al. AIDS. 2010;24:2365-2374. 3. Pulido F, et al. Glasgow 2010. Abstract P131.

19. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Clinical Studies of Boosted PI Monotherapy: Conclusions  Boosted PI monotherapy appears most successful when pts are simplified from suppressive HAART regimens after at least 6 mos rather than started on monotherapy when either antiretroviral naive or as an induction/maintenance strategy  There are no studies comparing ATV/RTV monotherapy with HAART nor any data comparing LPV/RTV monotherapy with DRV/RTV monotherapy  Significant resistance in pts with virologic failure is rare but is a potential concern in patients with virologic failure on ATV/RTV monotherapy  Resuppression by intensifying the regimen with NRTIs usually possible in pts who have developed detectable HIV-1 RNA

20. Diego Ripamonti, MD Malattie Infettive Ospedali Riuniti di Bergamo Bergamo, Italy Unanswered Questions: Is Boosted PI Monotherapy Ready for Prime Time?

21. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care HIV Treatment Paradigm Since 1996  Start with and maintain a triple regimen (2 NRTIs + third drug) –Demonstrated virologic, immunologic, and clinical efficacy  Can boosted PI monotherapy compare with this standard of care?

22. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Guidelines EACS 2009 [1] PI/RTV monotherapy with BID LPV/RTV or QD DRV/RTV might represent an option in patients with intolerance to NRTI or for treatment simplification. IAS-USA 2010 [2] Therefore, PI/RTV monotherapy is not recommended except in exceptional circumstances when other drugs cannot be considered for reasons of toxicity/tolerability. DHHS 2009 [3] In aggregate, boosted PI monotherapy as initial or as simplification treatment has been somewhat less effective in achieving complete virologic suppression and avoiding resistance. Therefore, this strategy cannot be recommended currently. 1. EACS guidelines version 5.2, 2009. 2. Thompson MA, et al. JAMA. 2010;304;321-333. 3. DHHS guidelines, 2009. Guidelines Differ

23. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care What Data Are Needed to Change the Treatment Paradigm of HIV Therapy?  Well-designed noninferiority trials vs triple-combination therapy –With a clear definition of treatment success and failure  Sufficient number of patients in monotherapy  Robust risk assessment (for both the individual patient and for public health concerns)  Criteria for identification of patients who are likely to succeed/benefit from monotherapy  Assessment of the real benefit from switching  Assessment of response durability on monotherapy arm

24. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Noninferiority Margins for Monotherapy Trials Study (N)SettingDuration of Follow-up, Wks CIPrimary Analysis MONET (256) [1] Simplification96 Lower limit of 95% CI: -12% Per protocol, switch = failure MONOI (225) [2] Simplification48 Lower limit of 90% CI: -10% Per protocol, switch = failure OK04 (198) [3] Simplification96 Upper limit of 95% CI: 12% Per protocol, intensification allowed 1. Rieger A, et al. AIDS 2010. Abstract THLBB209. 2. Katlama C, et al. AIDS. 2010;24:2365-2374. 3. Arribas JR, et al. J Acquir Immune Defic Syndr. 2009; 51:147-152.

25. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care How Was Virologic Failure Defined?  “Confirmed detectable viremia”  Is this the same as in a routine clinical setting?  Is resuppression after intensification a true treatment “success”?

26. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Success or Failure? Patient in MONET trial on DRV/RTV monotherapy and confirmed 3 consecutive “double blips” meeting the definition of failure. He was kept on monotherapy arm with viral resuppression. Resistance tests failed to show any genotypic mutations. 96 140 133 < 50 Days 500 400 300 200 100 050100150200250300350400-50 < 50 HIV-1 RNA (copies/mL)

27. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Success or Failure? Patient in MONET trial on triple regimen and confirmed consecutive “double blips” meeting the definition of failure. He was kept on the same randomized triple arm with subsequent viral resuppression. < 50 59 989 < 50 Days 1200 1000 800 400 200 050100150200250300350-50 600 HIV-1 RNA (copies/mL) < 50 59< 50

28. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Monotherapy Trial Results: Per Protocol and Impact of NRTI Intensification StudyOutcomes MONET [1]  Monotherapy NOT noninferior in PP, S = F analysis at Wk 96 (Δ = -5.2%; 95% CI: -14.3% to +5.8%)  If resuppression with intensification included as success, then mono noninferior (Δ = +2.4%; 95% CI: -4.0% to +8.8%)  7/8 viremic pts resuppressed with reintensification MONOI [2]  Monotherapy noninferior in PP, S = F analysis at Wk 48 (Δ = -4.9%: 90% CI: -9.1% to -0.8%)  3/3 viremic pts in monotherapy arm resuppressed with intensification OK04 [3,4]  Monotherapy noninferior in PP (intensification allowed) analysis at Wk 96 (Δ = -9%; 95% CI: -20% to +1.2% for triple therapy vs monotherapy)  3/4 viremic pts on monotherapy resuppressed with intensification at 48 wks; 10/12 viremic pts on monotherapy resuppressed with intensification at 96 wks 1. Rieger A, et al. AIDS 2010. Abstract THLBB209. 2. Katlama C, et al. AIDS. 2010;24:2365-2374. 3. Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40:280-287. 4. Arribas JR, et al. J Acquir Immune Defic Syndr. 2009;51:147-152.

29. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Risk Assessment for Monotherapy  What are the downstream consequences of failing monotherapy? –Almost all patients resuppressed with NRTI reintroduction or same regimen  How can we quantify the “price” of failure? –PI-associated resistance mutations no more frequent in monotherapy vs triple regimen

30. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Which Patients Are Eligible for Monotherapy?  “No previous treatment failure” –Should we include patients with extensive RT mutations affecting NRTIs/NNRTIs? –Should we include patients with history of failure on a boosted PI without any primary PI mutations? –Does pretherapy HIV-1 RNA level matter? –Does nadir CD4+ cell count matter?

31. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care What Are the Potential Benefits of Switching to Monotherapy?  Simplification (for some patients only)  Sparing future options (using fewer drugs)  Reduction of NRTI-related toxicity (eg, lipoatrophy, renal disease, BMD loss)  Reduction of cost (vs dual or triple therapy)

32. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care M03-613 Trial: Changes in Limb Fat Over Time Cameron DW, et al. J Infect Dis. 2008;198:234-240. Published by the University of Chicago. LPV/RTV: n = 9790897974 EFV: n = 4541363232 Change in Limb Fat (%) 20 15 10 5 0 -5 -10 -15 -20 024487296 Wk LPV/RTV + ZDV/3TC → LPV/RTVEFV + ZDV/3TC P <.001 at Wk 96

33. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care MONOI: Median Change in Limb Fat From Baseline to Wk 48 Absolute Change% Change Valantin M, et al. CROI 2010. Abstract 721. *Between baseline and Wk 48 P =.001* P <.001* +340 g (IQR -40 to +1140) +8.3% (IQR -1 to +21) -20 g (IQR -530 to +520) -0.26% (IQR -10 to +9) 350 300 250 50 0 -50 200 150 100 9 6 5 1 0 4 3 2 8 7 NS* Change in Limb Fat, grrams Change in Limb Fat, % DRV/RTV + 2 NRTIs DRV/RTV mono

34. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care  DEXA scans: baseline, every 24 wks through Wk 96 (n = 106) Brown TT, et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen J Acquir Immune Defic Syndr. 2009;51:554-561. M03-613: Changes in Bone Mineral Density From Baseline to Wk 96 0 2 1 -2 -3 -5 0 -4 Wk 24487296 Mean (95% CI) Percent Change From BL in Total BMD LPV/RTV (n = 74) EFV (n = 32) Subjects in the LPV/RTV group discontinued ZDV/3TC between Wk 24 and Wk 48

35. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care HIV Replication in Sanctuary Sites  96% of patients with undetectable plasma HIV-1 RNA on triple regimen have suppressed CNS viral load [1]  Questions: –Do we really need 3 drugs to control HIV replication in sanctuary sites when plasma HIV-1 RNA is fully suppressed? –Do boosted PIs sufficiently penetrate into CNS for long-term control? –Can boosted PI monotherapy control HIV-1 RNA in the genital tract? 1. Letendre S, et al. CROI 2010. Abstract 172.

36. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care SubjectWks of LPV/RTV Pretreatment Plasma CD4+ cells/mm 3 Plasma CD4+ cells/mm 3 at Time of LP Plasma HIV-1 RNA copies/mL CSF HIV-1 RNA, copies/mL 00348228449< 75< 50 00448482546< 75< 50 01048204646< 75< 50 01648308471< 75< 50 01748257515< 75< 50 03132530599< 75< 50 032 (sample 9/06)36171348< 75251 032 (sample 1/07)48--399< 75747 03632272458< 75< 50 03732143265< 75< 50 04132516371< 75< 50 04424186769< 75< 50 IMANI: LPV/RTV Monotherapy and Viral Replication in CSF Yeh R, et al. CROI 2007. Abstract 381.  Significance of these data?  Few data comparing CSF VL on triple therapy vs monotherapy

37. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care MOST: LPV/RTV Monotherapy and Viral Replication in CSF  MOST: Randomized controlled open-label trial comparing LPV/RTV monotherapy with continued HAART tx for 48 weeks in patients with fully suppressed viral load  Trial prematurely ended when 6 pts on LPV/RTV mono arm demonstrated VF in plasma –At study termination, N = 60, with 29 pts randomized to mono arm and an additional 13 switched from HAART (delayed switch)  5/6 pts with plasma VF had lumbar puncture –All had elevated HIV-1 RNA in CSF (higher than plasma) –4/6 had neurological symptoms  HIV-1 RNA fully resuppressed in all failing patients after resumption of original HAART regimen –No drug resistant virus was found. –Only predictor of VF: low nadir CD4+ cell count (P <.02) Gutmann C, et al. AIDS. 2010;24:2347-2354.

38. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Yeh R, et al. EACS 2007. Abstract P7.7/02. IMANI: LPV/RTV Monotherapy and Viral Replication in the Female Genital Tract SubjectWk of LPV/RTV Baseline HIV-1 RNA, copies/mL CD4+ cells/mm 3 at FGT Sampling Vaginal HIV-1 RNA, copies/mL Cervical HIV-1 RNA, copies/mL 1544620790< 400-- 277131,862448< 400 38533,386682< 400 48112,308980< 400-- 5655827558< 400 685335,342560< 400-- 7885466405< 400--

39. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care KALMO: Resistance Patterns in Semen With PI/RTV Monotherapy  Randomized 96-wk study of LPV/RTV monotherapy compared with PI/RTV + NRTIs  15 male subjects on monotherapy provided semen samples at baseline and end of study  Only 1 had detectable seminal HIV-1 RNA –Semen HIV-1 RNA: 260 copies/mL (plasma HIV-1 RNA : 850 copies/mL) –Resistance pattern in semen and plasma were identical: 2 major PI mutations at PR loci 46 and 84 Nunes E, et al. IAC 2010. Abstract THPE0124. 900 800 700 600 500 400 300 200 100 0 Sep 04 Nov 04 Jan 05 Mar 05 May 05 Jul 05 Sep 05 Nov 05 Jan 06 Mar 06 May 06 Jul 06 Sep 06 Nov 06 NRTI Intensification (ZDV + 3TC) Serum and Semen Genotyping Serum Genotyping HIV-1 RNA (copies/mL) CD4+ cell count (cells/mm 3 )

40. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care What Do We Know So Far?  Long-term virologic control is possible with boosted PI monotherapy in a large proportion of patients  If NRTI reintensification is needed, full resuppression can be expected  Resistance rates low in all studies of boosted PI monotherapy  No clinical or immunologic detrimental effects occur Is it time for “routine use” then?

41. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Are the Current Data Sufficient to Justify Routine Use of Boosted PI Monotherapy?  Patient number: Relatively low number enrolled in trials  Risk of PI mutations: No higher risk vs triple therapy  Resuppression: Yes, with reintroduction of NRTIs  Are all boosted PIs the same? Not clear yet  Immune impairment: No effect on CD4+ count response  Clinical progression: No higher risk (and for CNS?)  Length of follow-up: 96 wks so far –How much follow-up is needed to assess equivalence in the long term?

42. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care TripleMono Efficacy Risk of failure Cost of failure Cost of therapy Durability Sanctuary site control Patient number Toxicity/tolerability Are Data Balanced Enough for “Prime Time”?

43. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care In Which Setting(s) Can Boosted PI Monotherapy Be Regarded as Safe?  In virologically suppressed patients (either on PI- or NNRTI-based regimens)  No history of PI failure  No previous HIV-related encephalopathy  Absence of HBV coinfection (or other conditions in which NRTIs are essential for therapy)  Patients able to tolerate low-dose RTV  Patients with history of optimal adherence  Nadir CD4+ cell count > 100 cells/mm³ [1-3] or HIV-1 RNA < 10 5 copies/mL [4] 1. Pulido F, et al. Antivir Ther. 2009;14:195-201. 2. Campo R, et al. CROI 2007. Abstract 514. 3. Gutmann C, et al. AIDS. 2010;24:2347-2354. 4. Katlama C, et al. AIDS. 2010;24:2365-2374.

44. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Conclusions  Data are encouraging for ranking monotherapy and triple regimens as equally effective in maintenance therapy  More patients and extended follow-up are needed before recommending boosted PI monotherapy as a routine option for long-term treatment  Ongoing studies –MONET trial: up to 144 wks –MONOI trial: up to 96 wks –PIVOT (PI Monotherapy Vs Ongoing Triple-therapy in the Long Term Management of HIV Infection) trial: planned for 5 years

45. José R. Arribas, MD Associate Professor of Medicine Hospital La Paz Autónoma University School of Medicine Madrid, Spain Case-Based Discussion: Applying Data to Patient Case Scenarios

46. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Case 1: HIV-Infected Man Started on ART  39-yr-old MSM  Diagnosed with HIV-1 infection in 1995  WHO category A2  CD4+ cell nadir: 246 cells/mm³ in June 2004  HAART started at that time with TDF + 3TC + EFV –Virologic suppression achieved quickly

47. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Date of Treatment Initiation Antiretroviral Therapy CD4+ Cell Count, cells/mm 3 HIV-1 RNA, copies/mL June 2004TDF + 3TC + EFV24683,000 March 2006TDF/FTC + EFV698< 50 May 2007TDF/FTC/EFV670< 50  However, the patient has become concerned about loss of limb fat and fat in this face  Total limb fat by DEXA: 3182 g Treatment History

48. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care What Are Potential Management Strategies for This Patient?  Continue with same regimen and counsel the patient? –Most patients with lipoatrophy are not content with “doing nothing”  Switch NRTIs and continue EFV? –TDF not generally associated with lipoatrophy when compared with other NRTIs [1]  Continue NRTIs and change EFV to a boosted PI? –Strategy supported by results of ACTG 5142 [1]  Switch to boosted PI monotherapy? –Potentially good strategy  Switch to RAL + boosted PI? –Potentially good strategy 1. Haubrich R, et al. AIDS. 2009;23:1109-1118.

49. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Lipoatrophy With LPV/RTV vs EFV and With NRTIs in ACTG 5142 Haubrich R, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. 2009;23:1109-1118. Pts With Lipoatrophy, % 100 30 20 10 0 4896 Wks on Study 21 10 7 32 17 9 188 191197 171 166173 9384 EFVLPV/RTVLPV/RTV +EFVd4TZDVTDF Pts With Lipoatrophy, % 50 40 20 10 0 4896 30 9 27 8 16 26 42 P Values at Wk 96 d4T vs ZDV.038 d4T vs TDF <.001 ZDV vs TDF <.001 P Values at Wk 96 EFV vs LPV/RTV.003 EFV vs LPV/RTV + EFV <.001 LPV/RTV vs LPV/RTV + EFV.023 Wks on Study 133153117136

50. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care  Patient was started on LPV/RTV monotherapy with maintenance of virologic suppression  The patient remained virologically suppressed for 7 mos  However, later the patient’s HIV-1 RNA increased to > 50 copies/mL at 2 separate times Initiation of LPV/RTV Monotherapy Duration of Treatment, mos Antiretroviral TherapyHIV-1 RNA, copies/mL 4LPV/RTV< 50 7LPV/RTV< 50 11LPV/RTV130 13LPV/RTV325

51. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Potential Management Strategies for This Patient  Assess adherence to regimen  Then, –Wait to see if the HIV-1 RNA resuppresses? –How long should one wait? –Intensify with NRTIs? –Data from boosted PI monotherapy trials have shown that this is an effective strategy –Add another non-NRTI agent? –No data to support this strategy –Switch to DRV/RTV QD monotherapy? –Potentially good strategy if adherence to twice-daily therapy a problem

52. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Arribas J, et al. AIDS. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. 2010;24:223-230. Resuppression of VL After Confirmed HIV-1 RNA Elevations in MONET PatientHIV-1 RNA in blips, copies/mLChange in TreatmentLast HIV-1 RNA, copies/mL 1140133None< 50 259214ZDV/3TC +NVP< 50 3132139LPV/RTV< 50 4539862TDF/FTC/EFV< 50 567810None810 640,500628None< 50 7158140ABC/3TC + DRV/RTV< 50 85180None< 50 9106268TDF/FTC + DRV/RTV< 50 10722157TDF/FTC + DRV/RTV< 50 11779267ABC/3TC+ DRV/RTV< 50

53. Case 2: Male Patient Fearful of CV Risk

54. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Case 2: Middle-Aged Man Fearful of CV Events  49-yr-old man with diagnosed with HIV-1 infection 3 yrs ago –CD4+ cell count at diagnosis 342 cells/mm³ –HIV-1 RNA 32,000 copies  No other medical concerns  Started on ABC/3TC + ATV/RTV immediately after diagnosis at his request –Wants to remain well; dislikes taking the meds but will do so to maintain health

55. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Virologic Suppression Throughout Treatment  Patient has been scrupulous about adherence to regimen  Has maintained HIV-1 RNA suppression throughout treatment  Has recently questioned you about dropping/changing ABC/3TC –Although he has no other CV risk factors, his father had MI at 60 yrs of age –He has heard information about potential association of ABC with CV risk –Also wants something “simpler”

56. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Potential Management Strategies for This Patient  Continue ABC/3TC + ATV/RTV? –Good strategy –Very low pill burden regimen (3/day) –Review CV risk with pt (low) to assuage anxiety about ABC  Consider ABC/3TC + ATV without RTV? –Supported by ARIES trial data –Lipids may decrease with dropping RTV  Switch to TDF/FTC/EFV? –Good strategy –Lowest pill burden (1/day)  Switch to ATV/RTV monotherapy? –Not recommended  Switch to DRV/RTV monotherapy? –Not lower pill burden

57. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Is This a Good Patient for Boosted PI Monotherapy?  Excellent adherence  Wants simpler regimen  Moderate baseline HIV-1 RNA and CD4+ cell count  No comorbidities

58. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care OREY: Efficacy at 48 Wks Outcome, % Maintained suppression < 400 c/mL 79 Maintained suppression < 50 c/mL67 Virologic rebound ≥ 400 c/mL12 Virologic rebound ≥ 50 c/mL27 Triple therapy resumed with HIV-1 RNA 50-400 c/mL 3  OREY: Simplification monotherapy trial (N = 60)  Patients on HAART ≥ 6 mos  HIV-1 RNA < 50 copies/mL ≥ 6 mos  No previous VF  On 2 NRTIs + ATV/RTV for ≥ 8 wks before simplifying to ATV/RTV Pulido F, et al. EACS 2009. Abstract PS4/6.

59. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care OREY: Resistance  7 patients with genotypes  2 subjects with ATV resistance mutation N88S –1 patient with N88S alone at Wk 48: resumed triple therapy at Wk 60 with TDF + FTC + DRV/RTV and resuppressed to < 50 c/mL –1 patient with N88S + M46L at Wk 68: resumed triple therapy with TDF + FTC + FPV/RTV but VL never decreased to < 50 c/mL during follow-up –New genotype at Wk 96: no N88S and M46L but I54L present –Antiretroviral therapy regimen maintained; last VL 85 c/mL Pulido F, et al. EACS 2009. Abstract PS4/6.

60. Case 3: MSM With Long History of HIV-1 Infection

61. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Case 3: MSM With Long History of HIV-1 Infection  39-yr-old MSM  Diagnosed with HIV-1 infection in 1995  WHO A2 category  CD4+ cell count nadir: 302 cells/mm³  Multiple HAART regimens with incomplete suppression  Presents to you for treatment for first time

62. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Treatment History  Patient treatment regimens included NNRTI-based therapy and triple- NRTI therapy –Patient repeatedly refused adding a PI to his regimen  Current genotype shows pan-NRTI resistance + major NNRTI mutation Date of Tx Initiation Regimen CD4+ Count, cells/mm³ HIV-1 RNA, copies/mL Resistance Development RTPR Jan 2000d4T + ddI520100-700No resistance tests Jan 2004ZDV/3TC/ABC65075-300No resistance tests April 2007 TDF/FTC + NVP 550< 50-800  NRTI: M41L, E44D, K70R, M184V, L210W, T215Y, K219E  NNRTI: G190A K20R, M36I (minor PI mutations)

63. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care  High CD4+ cell count  Low-level viremia  Completely resistant to NRTIs and major NNRTI mutation  Naive to PIs  You counsel the patient about current options and he agrees to consider a regimen that includes a PI Patient Characteristics

64. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Potential Treatment Options for This Patient  Boosted PI monotherapy? –Boosted PI monotherapy works best in pts with virologic suppression for > 6 months –No data supporting use in pts without virologic suppression  Boosted PI + ETR? –Option supported by data from DUET trial  Boosted PI + RAL? –Options supported by data from PROGRESS trial  Boosted PI + MVC? –Should be effective option if pt has CCR5 tropic virus only  Combinations of boosted PI and 2 other drugs?

65. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Boosted PI Plus ETR Plus RAL  The patient started a regimen of DRV/RTV 600/100 mg BID plus ETR plus RAL  Within 1 mo, his HIV-1 RNA became undetectable  However, the patient was unhappy with the number of pills he was taking and wanted to take fewer pills  In addition, he did not like the BID regimen and asked if a QD regimen was available

66. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care Potential Management Strategies for This Patient  Counsel him to continue this regimen a while longer? –Not a valuable strategy if pt is complaining that adherence to regimen is difficult  Change DRV/RTV BID to DRV/RTV QD and keep ETR and RAL? –Might not be enough of a change to satisfy pt  Stop ETR and continue DRV/RTV QD and RAL? –Worthwhile strategy; boosted PI + RAL effective in PROGRESS study  Stop RAL and continue DRV/RTV QD and ETR? –Worthwhile strategy; DRV/RTV + ETR effective in DUET  Consider monotherapy with DRV/RTV QD? –Concerns about duration of virologic suppression in this pt

67. clinicaloptions.com/hiv Can It Be Simpler? Assessing the Role of Boosted PI Monotherapy in HIV Care StudyInclusion Criteria OK04  HIV-1 RNA 6 mos KALMO  HIV-1 RNA 6 mos ATARITMO  HAART ≥ 6 mos or switching from IDV/RTV mono trial  HIV-RNA < 50 copies/mL ACTG 5201  HIV-RNA < 50 copies/mL for ≥ 48 wk on 2 NRTIs + PI Karlström et al  HIV-1 RNA < 20 copies/mL for ≥ 1 yr on HAART  No PI experience MONET  HIV-1 RNA < 50 copies/mL for ≥ 6 mos on HAART MONOI  HIV-1 RNA < 400 copies/mL for ≥ 18 mos on HAART  HIV-1 RNA < 50 copies/mL at entry HIV-1 RNA Inclusion Criteria for Boosted PI Studies

68. Go Online for More Information on Boosted PIs! Download a copy of this slideset with speaker notes to use in your own noncommercial talks clinicaloptions.com/monotherapy