1. Keeping It Simple: Treatment Simplification in HIV Management This program is supported by an educational grant from

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3. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Faculty Santiago Moreno, MD, PhD Professor Department of Medicine University of Alcalá Head Division of Infectious Diseases Hospital Ramón y Cajal Madrid, Spain Stefano Vella, MD Director, Department of Pharmacology and Therapeutic Research Research Group on HIV, Hepatitis, Global Health Istituto Superiore di Sanità Rome, Italy

4. What Is Treatment Simplification and Who Are Optimal Candidates?

5. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Definition: Treatment Simplification  US Department of Health and Human Services [1] –Defined broadly as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirement [1]  GeSIDA [2] –A switch from a suppressive therapy regimen to a more simple one that can maintain virological suppression [2] 1. DHHS Guidelines, October 2011. 2. GeSIDA Guidelines, January 2012.

6. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Reasons to Consider Treatment Simplification  Improve adherence, convenience, and quality of life –Reduce number of doses –Reduce number of pills –Reduce number of drugs –Reduce costs  Many physicians fear simplification out of perceived risk of tolerability issues and loss of virologic suppression  However, if simplification is not effective, reverting back to the previous regimen is an option if carefully managed

7. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Claxton AJ, et al. Clin Ther. 2001;23:1296-1310. Adherence Inversely Related to Number of Doses per Day Studies of Electronic Monitoring of Adherence Mean Dose-Taking Adherence (%) 71 0 20 40 80 100 Overall 79 QD 69 BID 65 TID 51 QID 60 P =.008 P <.001 P =.001

8. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Stone VE, et al. J Acquir Immune Defic Syndr. 2004;36:808-816.  HIV-positive patients on ART including ≥ 3 antiretrovirals (N = 299)  6 US cities  Self-report questionnaire with aid of facilitator Not Helpful at All Pills/Day Dosing Frequency Food RulesBiggest Pill 2 pills 5 pills 8 pills 12 pills None With food Empty stomach Extremely Helpful QD mix times QD/BID All QD, same time All BID Small Medium Large 0 20 40 60 80 100 Mean Relative Impact of Regimen Features on Adherence

9. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management ARV Agents Approved for Once-Daily Dosing and Fixed-Dose Combinations Agents Approved for Once-Daily Dosing ClassUSEU NRTIs ABC 3TC ddI FTC TDF ABC 3TC ddI FTC TDF NNRTIs EFV NVP-XR EFV NVP-XR PIs ATV/RTV FPV/RTV (for tx-naive patients only) DRV/RTV (for tx-naive patients or tx-exp patients without DRV resistance mutations) LPV/RTV (for tx-naive patients only) ATV/RTV DRV/RTV (for tx-naive patients or tx-exp patients without DRV resistance mutations) LPV/RTV (if necessary) Approved Once-Daily Fixed-Dose Combinations ClassUSEU NRTIs TDF/FTC ABC/3TC TDF/FTC ABC/3TC PIsLPV/RTV Two drug classes EFV/TDF/FTC RPV/TDF/FTC EFV/TDF/FTC RPV/TDF/FTC

10. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management DHHS Guidelines, October 2011.  Patients without a history of treatment failure or drug- resistant virus  Patients receiving complex regimens –However, for some forms of treatment simplification (eg, boosted PI monotherapy), good adherence is a prerequisite Optimal Candidates for Treatment Simplification

11. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management  In patients with controlled viremia and no tolerability issues, simplifying treatment to improve quality of life should be considered [1-4]  When switching treatment, for whatever reason, maintenance of virologic suppression remains the main concern  Efficacy and likely adherence to the new regimen should be considered  Numerous clinical trials have studied the efficacy, safety, and tolerability of a switch in patients with stable virologic suppression 1. DHHS Guidelines, October 2011. 2. GeSIDA Guidelines, January 2012. 3. EACS Guidelines, 2011. 4. Thompson MA, et al. JAMA. 2010;304;321-333. Summary and Additional Considerations

12. Simplification Strategies: Within-Class Simplifications

13. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Within-Class Simplifications  Preserves unused drug classes for potential future use  Types of simplifications –PI substitutions –Simplification from twice-daily PI to once-daily PI –Simplification from boosted PI to unboosted PI –NNRTI substitutions –Simplification to agents with reduced dosing frequency or coformulated agents –NRTI substitutions –Simplification to agents with reduced dosing frequency or coformulated agents

14. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Medical History  27-yr-old white MSM  Diagnosed HIV positive in January 2004  Otherwise healthy; no past medical history of interest  Blood cell count and chemistry: no significant abnormalities  CD4+ count: 325 cells/mm 3 ; HIV-1 RNA: 4.7 log 10 c/mL  Baseline HIV genotype: K103N  HLA-B*5701: negative  HAV, HBV immune; HCV antibody negative

15. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Treatment History  Antiretroviral therapy initiated in March 2004 –TDF (QD) + 3TC (QD) + LPV/RTV (BID)  Medication generally well tolerated –Loose stools twice daily  After 2 yrs of therapy DateHAARTCD4VLCreat, mg/dL HDL, mmol/L LDL, mmol/L TC, mmol/L TG, mmol/L March 2004 Naive2974.70.70.8283.5434.8361.468 June 2006 TDF + 3TC + LPV/RTV 412< 1.70.90.9574.4746.0253.782

16. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Considerations for Treatment Simplification  Suppressive regimen  No previous failures  Regimen well tolerated (although persistent loose stools)  Mild to moderate rise in lipids  BID regimen, 6 pills/day  Patient asks if he could be switched to a regimen with fewer pills

17. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Rubio R, et al. HIV Med. 2010;11:545-553. SIMPATAZ: Simplification From PI-Based Therapy to ATV/RTV  183 virologically suppressed patients enrolled in multicenter, prospective, noninterventional study –Physician recommended treatment simplification  At Mo 12, 95% of patients on treatment maintained undetectable HIV-1 RNA  Overall AE rate low –3.8% of patients experienced moderate to severe AEs, judged related to ATV/RTV –Only 1 discontinuation judged related to ATV/RTV AE  Total cholesterol, triglycerides, and LDL cholesterol all improved significantly  Proportion of patients classifying themselves as highly satisfied with their antiretroviral therapy regimen increased significantly from baseline to Month 12 after switch (47% vs 91%; P <.001)

18. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Outcome  Patient was switched to fixed-dose TDF/FTC (QD) and to ATV 300 mg QD + RTV 100 mg QD (QD regimen, 3 pills/day)  After 18 mos of therapy with the new regimen, loose stools disappeared  After more than 5 yrs on this therapy: DateHAARTCD4VLCreat, mg/dL HDL, mmol/L LDL, mmol/L TC, mmol/L TG, mmol/L March 2004 Naive2974.70.70.8283.5434.8361.468 June 2006 TDF + 3TC + LPV/RTV 412< 1.70.90.9574.4746.0253.782 August 2011 TDF/FTC + ATV/RTV 596< 1.70.90.9313.8795.4312.314

19. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Gatell J, et al. Clin Infect Dis. 2007;44:1484-1492. P =.004 P =.53 P <.001 0 5 10 15 20 25 All PatientsPatients on Boosted PI at BL Patients on Unboosted PI at BL Patients With HIV-1 RNA ≥ 50 copies/mL at Wk 48 (%) ATV (n = 278)Control PI (n = 141) 7 16 8 11 5 22  Switched patients experienced significantly fewer fasting triglyceride, total cholesterol, and non-HDL cholesterol elevations vs control patients (P <.001)  Comparable rates of AE-related discontinuations and serious AEs between arms SWAN: Switching PI-Based Therapy to ATV + NRTIs for Tx Simplification

20. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Squires K, et al. IAS 2011. Abstract MOPE215. ARIES: Switch From a RTV-Boosted PI to Unboosted ATV P =.390 0 20 40 60 80 100 ATV HIV-1 RNA < 50 c/mL at Wk 144 (%) 77 73 ATV/RTV  515 virologically suppressed treatment-naive patients with no evidence of virologic failure during 36-wk induction phase of ATV/RTV + ABC/3TC randomized to switch to unboosted ATV or no change for 48 wks Tx-Related Grade 2-4 AEs, % ATV (n = 189) ATV/RTV ( n = 180) BL to Wk 362630  Hyperbilirubinemia13  Diarrhea43  Nausea32 Wk 36 to Wk 1441323  Hyperbilirubinemia*614 *P =.0232  Changes in median lipid levels from randomization to Wk 144 more favorable with ATV vs ATV/RTV therapy

21. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Final Outcome  Patient was switched to fixed-dose ABC/3TC (QD) and to unboosted ATV 400 mg QD (QD regimen, 3 pills/day) –TDF decreases unboosted ATV concentrations by 20% to 40% and, therefore, should only be coadministered with RTV-boosted ATV [1]  After 6 mos of therapy with the new regimen: DateHAARTCD4VLCreat, mg/dL HDL, mmol/L LDL, mmol/L TC, mmol/L TG, mmol/L March 2004 Naive2974.70.70.8283.5434.8361.468 June 2006 TDF + 3TC + LPV/RTV 412< 1.70.90.9574.4746.0253.782 August 2011 TDF/FTC + ATV/RTV 596< 1.70.90.9313.8795.4312.314 February 2012 ABC/3TC + ATV 622< 1.70.81.1383.4914.5261.524 1. Atazanavir PI.

22. Simplification Strategies: Out-of-Class Simplifications

23. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Out-of-Class Simplifications  Can be useful option for patients with tolerability issues  Strategies –Simplification from PI-based regimen to NNRTI-based regimen –NVP-based regimens –EFV/FTC/TDF –RPV/FTC/TDF –No data but ongoing clinical trial [1] –Simplification from PI-based regimen to RAL –Simplification from RAL + FTC/TDF to EVG/COBI/FTC/TDF –No data but ongoing clinical trial [2] 1. ClinicalTrials.gov. NCT01252940. 2. ClinicalTrials.gov. NCT01533259.

24. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Medical History  33-yr-old white man  Injection drug user until 1995 when he initiated a methadone-maintenance program  Known HIV positive in 1994 when he presented with pulmonary tuberculosis –At that time, CD4+ cell count: 390 cells/mm 3, HIV-1 RNA: 4.4 log 10 copies/mL  Lost to follow-up; never attended clinic appointments

25. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Medical History  Seen at the clinic in January 2003  Receiving methadone but no other medications  No complications after TB (treatment was completed in a DOT program)  At this time –CD4+ cell count: 215 cells/mm 3 ; HIV-1 RNA: 4.9 log 10 copies/mL –LFT results: AST 102 IU/L, ALT 97 IU/L; no other significant findings –Hepatitis B immune, hepatitis C antibody positive –HIV resistance test: wild type

26. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Treatment History  ART initiated in February 2003: ABC (BID) + 3TC (BID) + FPV/RTV (BID)  Medication well tolerated  The patient remained on same therapy until current presentation –HIV-1 RNA persistently < 1.7 log 10 IU/mL –CD4+ cell count rose to 541 cells/mm 3 –Significant elevation in triglycerides (from 0.926 to 4.968 mmol/L) –LFT similar (refused treatment for chronic hepatitis C at this time)

27. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Considerations for Treatment Simplification  Suppressive regimen  No previous failures  Regimen well tolerated  Moderate increase in lipids  BID regimen, 8 pills/day ... but the patient feels well

28. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management DeJesus E, et al. J Acquir Immune Defic Syndr. 2009;51:163-174. Simplification of PI- or NNRTI-Based Regimens to EFV/FTC/TDF  Patients with HIV-1 RNA < 200 copies/mL for ≥ 3 mos randomized 2:1 to EFV/FTC/TDF or no change –87% vs 85% of patients who switched or maintained current regimen maintained HIV-1 RNA < 50 copies/mL at Wk 48 –Higher rate of discontinuation for AEs in switch vs no change arm: 5% vs 1% –Mainly due to increase in CNS AEs –Self-reported adherence high at baseline and during study (≥ 96%) –Patients randomized to EFV/FTC/TDF preferred switch at all postbaseline study visits (P <.001)

29. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Outcome  Patient switched to EFV/FTC/TDF (1 pill/day) and regimen was well tolerated  Drug-drug interaction with methadone needed minor adjustments of methadone dose  Patient feels his quality of life has really improved  Latest evaluations –HIV-1 RNA: < 1.7 log 10 IU/mL –CD4+ cell count: 578 cells/mm 3 –Triglycerides lower, but still high (3.274 mmol/L) –LFT similar (transient elastography shows only mild fibrosis [F1])

30. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Case Discussion  Which other out-of-class regimens may have been appropriate for this patient? –RPV/FTC/TDF? –Nevirapine-based regimen? –Raltegravir-based regimen?

31. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management 1. Ena J, et al. HIV Med. 2008;9:747-756. 2. EMEA Nevirapine PI. Simplification From Suppressive PI-Based Therapy to NVP-Based Regimens  Meta-analysis of 6 randomized clinical trials (N = 550) switching suppressive PI-based therapy to NVP-based therapy or no change [1]  Overall discontinuation rate due to AEs similar among arms –However, NVP-based regimens led to more discontinuations because of liver toxicity compared with PI-based therapies (7.4% vs 0%)  Although treatment-naive women and men with CD4+ counts > 250 cells/mm 3 and > 400 cells/mm 3, respectively, should not initiate NVP, EMEA endorses switching patients with suppressed HIV-1 RNA to NVP regardless of CD4+ count [2] -0.5-0.2500.250.5 Favors PI-based therapyFavors NVP-based therapy StudyRisk Difference (Fixed), 95% CI Ruiz Total (95% CI) Arranz Negredo Calza Barreiro

32. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management SPIRAL: Switch to RAL Noninferior to Maintaining PI/RTV Regimens 0 20 40 60 80 100 Patients (%) Switch to RAL Continue PI/RTV 86.6 89.2 Free of Treatment Failure at Wk 48 (ITT, S = F) Patients With VFRAL (n = 4) PI/RTV (n = 6) Previous VF13 Previous suboptimal ART23 Resistance test at VF14  Mutations03 (PR, RT) Martinez E, et al. AIDS. 2010;24:1697-1707. Mean Change From Baseline to Wk 48, % Switch to RAL Continue PI/RTV P Value TG-22.1+4.7<.0001 TC-11.2+1.8<.0001 LDL-C-6.5+3.0<.001 HDL-C-3.2+5.8<.0001 Total to HDL-C ratio -4.9-1.3<.05

33. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Eron J, et al. Lancet. 2010;375:396-407. SWITCHMRK-1 and -2: Switch From Stable LPV/RTV to RAL-Based HAART  Predefined criteria for noninferiority: lower limit of the 95% CI for treatment difference > -12% RAL + ARVs, n 174 166 169 173 172 176 176 176 176 175 LPV/RTV + ARVs, n 174 171 171 171 174 178 178 177 177 178 50 60 70 80 90 100 04 Wks HIV-1 RNA < 50 c/mL (%) 81224 87% 81% ∆: -6.6 (95% CI: -14.4 to 1.2) Protocol 032Protocol 033 50 60 70 80 90 100 04 Wks 81224 ∆: -5.8 (95% CI: -12.2 to 0.2) 94% 88% HIV-1 RNA < 50 c/mL (%)

34. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Eron J, et al. Lancet. 2010;375:396-407. SWITCHMRK -1 and -2: Significant Decrease in Lipids With Switch to RAL Mean Change From Baseline at Wk 12 (%) -50 -40 -30 -20 -10 0 10 20 RAL + ARVs LPV/RTV + ARVs Protocol 032 Protocol 033 * NS nps -12.8 0.7 -15.2 2.3 -41.5 3.6 -2.4 2.1 -0.9 0.8 NS nps -12.4 1.3 2.9 8.2 4.0 0.6 -0.6 -2.5 -14.8 -42.8 Fasting Cholesterol Fasting Non- HDL-C Fasting TG † Fasting LDL-C Fasting HDL-C Fasting Cholesterol Fasting Non- HDL-C Fasting TG † Fasting LDL-C Fasting HDL-C *P <.0001; † median change from BL at Wk 12, %. * * * * *

35. Simplification Strategies: Reducing the Number of Active Drugs in a Regimen

36. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Switches That Reduce the Number of Active Drugs in a Regimen  Reduces drug exposure and may improve tolerability of regimen  Strategies –Boosted PI monotherapy –Avoids NRTI toxicities; reduces costs –Ongoing clinical trials of switches to boosted PI + 3TC only –Simplification from 2 NRTIs plus a third agent to ATV/RTV + 3TC as maintenance therapy (SALT) [1] –Simplification from LPV/RTV plus 2 NRTIs to LPV/RTV + 3TC [2] 1. ClinicalTrials.gov. NCT01307488. 2. ClinicalTrials.gov. NCT01471821.

37. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Medical History  39-yr-old white woman  Known HIV positive in September 2008 (infected presumably by unprotected heterosexual contact)  Asymptomatic  Past medical history: nothing significant  CD4+ count: 220 cells/mm 3 ; HIV-1 RNA: 5.2 log 10 c/mL  Baseline HIV genotype: wild type  HLA-B*5701 positive

38. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Treatment History  Antiretroviral therapy initiated in December 2008: EFV/FTC/TDF  Transient dizziness and abnormal dreams that resolved spontaneously  After 1 yr of therapy: DateHAARTCD4+VLCreat, mg/dL eGFR, mL/min/1.73 m 2 December 2008 Naive2205.20.797 January 2010 EFV/FTC/TDF526< 1.71.557

39. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Considerations for Treatment Simplification  Suppressive regimen  No previous failures  Regimen well tolerated  Impairment of renal function  QD, 1 pill

40. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Patient Case: Outcome  Patient was switched to DRV/RTV monotherapy  Regimen has been very well tolerated  After 2 yrs of monotherapy: –HIV-1 RNA remains < 1.7 log 10 copies/mL –CD4+ cell count: 670 cells/mm 3 –Improvement in renal function—serum creatinine: 0.9 mg/dL; eGFR: 89 mL/min/1.73 m 2

41. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management 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 patients  HAART with 2 NRTIs + either NNRTI or PI at screening  No previous use of DRV  VL < 50 for ≥ 6 mos  No hx VF  225 experienced patients  DRV-naive HIV-infected patients on HAART  VL < 400 for ≥ 18 mos  VL < 50 at screening  No PI failure  CD4+ nadir > 50  All patients 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 Switch

42. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management DRV/RTV Monotherapy: Efficacy at Last Report 93.4 91.9 Switch (Intensification With NRTIs) Allowed DRV/RTV Mono 80.6 MONET 96 Wks [1] DRV/RTV Mono DRV/RTV + 2 NRTIs TLOVR, S = F 74.8  = -5.8% (-16.0% to +4.4%) 129 127 DRV/RTV + 2 NRTIs  = +1.6% (-5.0% to +8.1%) 129 127 1. Clumeck N, et al. J Antimicrob Chemother. 2011;66:1878-1885. 2. Katlama C, et al. AIDS. 2010;24:2365-2374. Mono not noninferior Mono noninferior 100 80 60 40 20 0 100 80 60 40 20 0 MONOI 48 Wks [2] 94.1 99.0 Lower limit of 90% CI: -9.1 PP Analysis DRV/RTV Mono DRV/RTV + 2 NRTIs Mono noninferior 102 100 80 60 40 20 0 87.5 92.0 ITT Analysis Lower limit of 90% CI: -11.2 DRV/RTV Mono DRV/RTV + 2 NRTIs Mono not noninferior 112 113 100 80 60 40 20 0 Patients Meeting Primary Endpoint (%)

43. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management DRV Monotherapy: Resistance  MONET [1] –Only 1 patient per arm had any evidence of genotypic resistance –Both patients regained suppression without change in treatment  MONOI [2] –Virologic failure in 3 patients on monotherapy vs 0 on standard therapy –1 patient had DRV resistance associated mutation that was also found in prestudy sample; no DRV resistance associated mutations in other 2 –All 3 patients regained HIV-1 RNA < 50 copies/mL on reintroduction of 2 NRTIs 1. Clumeck N, et al. J Antimicrob Chemother. 2011;66:1878-1885. 2. Katlama C, et al. AIDS. 2010;24:2365-2374.

44. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Case Discussion  Could other boosted PIs have been considered for this patient as monotherapy? –LPV/RTV –ATV/RTV

45. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Bierman WF, et al. 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 (0.49-9.64) 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 MO3-613 MONARK Overall Favors monotherapy 0.1110100 Odds Ratio

46. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management 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

47. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Studies of ATV/RTV Monotherapy StudyATARITMO [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.

48. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management EACS 2011 [1] IAS-USA 2010 [2] DHHS 2011 [3] 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 Therefore, PI/RTV monotherapy is not recommended except in exceptional circumstances when other drugs cannot be considered for reasons of toxicity/tolerability 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 outside of a clinical trial 1. EACS Guidelines version 6, 2011. 2. Thompson MA, et al. JAMA. 2010;304;321-333. 3. DHHS Guidelines, 2011. Guidelines Differ Regarding PI Monotherapy

49. Conclusions

50. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Reasons to Consider Treatment Simplification  Improve adherence, convenience, and quality of life: active simplification –Reduce number of doses –Reduce number of pills –Reduce number of drugs –Reduce costs  In patients with controlled viremia and no tolerability issues, simplifying treatment to improve quality of life should be considered  Many physicians fear simplification out of perceived risk of tolerability issues and loss of virologic suppression  However, if simplification is not effective, reverting back to the previous regimen is an option if carefully managed

51. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Potential Benefits of Treatment Simplification  Several highly convenient regimens available, including newer agents and reformulations/coformulations of older drugs with less frequent dosing and less toxicity –Regimens with lower pill burdens and less frequent daily dosing are associated with better adherence  When switching treatment, for whatever reason, maintenance of virologic suppression remains the main concern –Studies have identified simplification strategies that usually maintain virologic suppression and often reduce adverse events –Previous use of suboptimal therapy may reduce likelihood of effective treatment response

52. clinicaloptions.com/hiv Keeping It Simple: Treatment Simplification in HIV Management Recommendations for Treatment Simplification  A boosted PI may be switched for simplification to unboosted ATV, an NNRTI, or RAL only if full activity of the 2 NRTIs remaining in the regimen can be guaranteed  Complex multidrug regimens should be changed to simpler, well-tolerated, active regimens  BID NRTIs can be switched to QD NRTIs  Intraclass switches preferred for drug-specific AE  Boosted PI monotherapy may represent an option for treatment simplification in suppressed patients without history of failure on previous PI-based therapy EACS guidelines version 6, 2011.

53. Go Online for More Educational Programming on HIV Treatment Simplification! Downloadable slideset for personal study or use in your own noncommercial talks clinicaloptions.com/simple