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Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Joseph Eron* 1, Jaime Andrade 2, Roberto Zajdenverg 3, Cassy Workman.

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Presentation on theme: "Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Joseph Eron* 1, Jaime Andrade 2, Roberto Zajdenverg 3, Cassy Workman."— Presentation transcript:

1 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Joseph Eron* 1, Jaime Andrade 2, Roberto Zajdenverg 3, Cassy Workman 4, David A. Cooper 5, Benjamin Young 6, Xia Xu 7, Bach-Yen Nguyen 7, Randi Leavitt 7, and Peter Sklar 7 1 University of North Carolina, Chapel Hill, NC, USA; 2 Antinguo Hospital Civil de Guadalajara, Guadalajara, Mexico; 3 Hospital Escola Sao Francisco de Assis, Rio de Janeiro, Brazil; 4 AIDS Research Initiative, Darlinghurst, Australia; 5 University of New South Wales, Sydney, Australia; 6 Denver Infectious Disease Consultants, Denver, CO, USA; and 7 Merck Research Laboratories, West Point, PA, USA

2 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd  Identical, multicenter, double-blind, randomized, active- controlled studies  Study population › Well controlled on a stable LPV/r regimen (b.i.d.) in combination with at least 2 NRTIs (and no other active PI) for ≥ 3 months  HIV RNA <50 copies/mL (US PCR) or <75 copies/mL (bDNA)  Patients were not required to be intolerant of LPV/r  Patients with prior virologic failure were not excluded  No limit on number of prior ART regimens › No lipid lowering therapy for at least 12 weeks  Randomized (1:1) to continue LPV/r or switch to RAL NRTI = nucleoside reverse transcriptase inhibitor PI = protease inhibitor

3 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd  Primary endpoints › Mean % change in lipids at week 12  Total-C, Triglycerides, non-HDL-C, and LDL-C › Proportion of patients with viral load <50 copies/mL at Week 24  Non-completer = Failure approach (NC=F)  Noninferiority hypothesis with 12% margin › Safety and tolerability

4 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd ‡ *In combination with background antiretroviral therapy ‡ Randomized and treated 174 ‡ Switched to RAL* 25 (14.4%) Discontinueddue to: Discontinued † due to: 3- Lack of efficacy 7- Adverse Experience 9 - Withdrew consent 4- Physician decision 2 - Other events ‡ Remained on LPV/r* 17 (9.8%) Discontinued due to: Discontinued † due to: 1 - Lack of efficacy 3 - Adverse Experience 6 - Withdrew consent 2 - Physician decision 5 - Other events 2 Protocol RAL: Deviation from protocol (1), Other (1) 2 LPV/r: Lost to follow-up (4), Deviation from protocol (1) 176 ‡ Switched to RAL* 10 (5.7%) Discontinued due to: Discontinued † due to: 4- Lack of efficacy 0- Adverse Experience 3 - Withdrew consent 2 - Physician decision 1 - Other events ‡ Remained on LPV/r* 6 (3.4%) Discontinueddue to: Discontinued † due to: 2- Lack of efficacy 0 - Adverse Experience 1 - Withdrew consent 1 - Physician decision 2 - Other events 4 Protocol RAL: Deviation from protocol (1) 4 LPV/r: Lost to follow-up (1), Deviation from protocol (1) † Reasons for discontinuation were investigator determined

5 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Protocol 032Protocol 033 RAL*LPV/r*RAL*LPV/r* # Patients TreatedN = 174 N = 176N = 178 Age (mean, years) % Male % Non-White Region EU/Australia † 117 (67.2)121 (69.5)20 (11.4)20 (11.2) North America57 (32.8)53 (30.5)32 (18.2)33 (18.5) Latin America75 (42.6)83 (46.6) Africa26 (14.8)20 (11.2) Southeast Asia23 (13.1)22 (12.4) *In combination with background antiretroviral therapy. † EU in Protocol 032 only

6 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Protocol 032Protocol 033 RAL*LPV/r*RAL*LPV/r* # Patients TreatedN = 174 N = 176N = 178 % with vRNA ≤ 50 copies/mL Mean CD4 count (cells/μl) % on LPV/r ≤ 1 yr Median yrs of prior ART (min, max) 3.3 (0.3, 22.3) 3.6 (0.5, 20.2) 3.7 (0.5,19.2) 4.6 (0.6,16.3) Median # of prior ART (min, max) 5.0 (4.0, 16.0) 5.0 (2.0,15.0) 5.5 (3.0,13.0) 6.0 (4.0,14.0) *In combination with background antiretroviral therapy.

7 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd PROTOCOL 032 ARTRAL (n)LPV/r (n) abacavir4958 didanosine3840 emtricitabine8983 lamivudine112 stavudine3840 tenofovir zalcitabine119 zidovudine8084 efavirenz26 etravirine21 nevirapine19 amprenavir2. atazanavir53 fosamprenavir.3 indinavir1916 lopinavir174 nelfinavir2223 ritonavir174 saquinavir1519 tipranavir.1 enfuvirtide22 PROTOCOL 033 ARTRAL (n)LPV/r (n) abacavir46 didanosine5865 emtricitabine4839 lamivudine stavudine6559 tenofovir8573 zalcitabine67 zidovudine delavirdine.2 efavirenz3050 emivirine1. etravirine46 loviride1. nevirapine2631 amprenavir24 atazanavir75 darunavir.1 fosamprenavir11 indinavir3542 lopinavir nelfinavir28 ritonavir saquinavir1315 tipranavir21 enfuvirtide. 1 NRTIs NNRTIs PIs Fusion Inhibitor

8 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd ART Protocol 032 Protocol 033 RALLPV/rRALLPV/r (N=176)(N=178)(N=173)(N=171) n (%) TDF + FTC/3TC87 (50.3)80 (46.8)58 (33.0)44 (24.7) ABC + FTC /3TC30 (17.3)27 (15.8)23 (13.0)19 (10.7) AZT + 3TC25 (14.5)28 (16.4)58 (33.0)60 (33.7) other combination of 2 ARTs (RTI) 16 (9.3)20 (11.7)21 (12.0)38 (21.3) 1 ART † 1 (0.6) 4 (2.3)1 (0.6) 3 or more ARTs14 (8.1)16 (9.4)12 (6.8 )16 (9.0) † protocol violators TDF=tenofovir, FTC=emtricitabine, 3TC=lamivudine, ABC=abacavir, AZT=zidovudine RTI = reverse transcriptase inhibitor

9 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Fasting Cholesterol Non HDL-C Fasting Triglycerides* Fasting LDL-C Fasting HDL-C %1%2% -15% -2% 4% -41% 1% -1% -13% P<0.001 P=0.704 nps** RAL + ARTs LPV/r + ARTs % 3% -15% 4% 8% -43% -3% -1% -12% P<0.001 P=0.269 nps** Fasting Cholesterol Non HDL-C Fasting Triglycerides* Fasting LDL-C Fasting HDL-C *Median Percent Change **Not prespecified for test Mean mg/dL: At Baseline Change from baseline at week 12, mean% At Week 12 Protocol 032Protocol 033

10 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd In P032,  149 patients on RAL had HIV RNA < 50 copies/mL at Week 12; 134/149 (90%) remained suppressed (< 50 copies/mL) at Week 24.  152 patients on LPV/r had HIV RNA < 50 copies/mL at Week 12; 145/152 (95%) remained suppressed (< 50 copies/mL) at Week 24. In P033,  157 patients on RAL had HIV RNA < 50 copies/mL at Week 12; 148/157 (94%) remained suppressed (< 50 copies/mL) at Week 24.  167 patients on LPV/r had HIV RNA < 50 copies/mL at Week 12; 161/167 (96%) remained suppressed (< 50 copies/mL) at Week Weeks 94% 88% Protocol 033  (95% CI) : -5.8 (-12.2, 0.2) Number of Contributing Patients Percent of Patients with HIV RNA <50 Copies/mL Protocol Weeks 81% 87%  (95% CI) : -6.6 (-14.4, 1.2) RAL + ARTs LPV/r + ARTs

11 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd

12 Protocol 032Protocol 033 RAL † LPV/r † RAL † LPV/r † >400 copies/mL * 3292 >50 copies/mL * Based upon post-hoc data collection: 84% (27/32) of patients with confirmed VF (>50 c/mL) in the RAL group reported that their regimen at study entry was not their 1 st ART regimen 66% (18/27) reported a history of VF on prior regimen(s) † In combination with background antiretroviral therapy *Virologic failure required confirmed viral rebound at least 1-week apart

13 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd PN032 Confirmed Failures Study Drug Virologic Failures (>400/ml) Study drug mutations (InSTI or PI * ) RTI mutations † RAL3 N155HK103N NoneV118I, M184V; V179D NoneV179E LPV/r2 L10I/V, G16G/E, L63S, A71A/T, V77I None Not done * Data derived by population sequencing. All amino acid changes from baseline observed in any of multiple independent PCR reactions are listed without regard to linkage. † RTI mutations do not necessarily reflect concurrent OBT

14 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd PN033 Confirmed Failures Study Drug Virologic Failures (>400/ml) Study drug mutations (InSTI or PI * ) RTI mutations † RAL9 G140G/S, Q148R, Q148Q/H, N155N/H D67D/G, M184V, T215T/I; Y181C N155HM184M/V; K103R N155H, Q148Q/R, Y143Y/CD67D/N, K70K/R, M184V, K219Q Q148H, G140SM184V; K103N, P225H G140G/S, Q148R, Q148Q/H, N155N/H, Q148Q/R None N155HNone Y143Y/S, Q148Q/RNone Not done LPV/r2 L10I, K20R, M36I, M46L, I54V, L63P, A71V, V82A, L90M K65R, D67N, K219E; K103R, Y181C V11V/I, L63P, V77INone * Data derived by population sequencing. All amino acid changes from baseline observed in any of multiple independent PCR reactions are listed without regard to linkage. † RTI mutations do not necessarily reflect concurrent OBT

15 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd  Analysis of efficacy by age, race/ethnicity demonstrated similar trends as the overall study results Response (% with HIV RNA < 50 copies/mL) Difference in Percent Response † % (95% CI) RALLPV/r Subpopulationn/N% (95% CI)n/N% (95% CI) Total 293/ (85.8, 92.7)319/ (91.4, 96.6)-4.8 (-9.1, -0.7) Gender Male 233/ (83.4, 91.6)245/ (91.5, 97.3)-7.0 (-12.1, -2.3) Female 60/ (88.8, 99.6)74/ (84.4, 97.2)4.3 (-4.4, 12.8) Region EU/Australia 115/ (84.9, 95.6)125/ (90.3, 98.3)-4.2 (-11.0, 2.1) North America 68/ (76.5, 92.8)77/ (84.9, 97.3)-6.7 (-17.0, 3.0) Latin America 65/ (78.2, 94.3)76/ (84.8, 97.3)-4.8 (-15.2, 4.7) Africa 24/ (79.6, 99.9)19/ (75.1, 99.9)1.0 (-15.6, 20.5) Southeast Asia 21/ (72.0, 98.9)22/ (84.6, 100.0)-8.7 (-27.1, 7.1) † The 95% CIs were calculated using Miettinen and Nurminen's method. N = Number of patients in each treatment group; n = Number of patients in each subcategory.

16 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd  RAL in combination with background RTI was generally well tolerated compared with LPV/r in combination with background RTI based on statistical comparisons for clinical and laboratory AE categories › No serious drug-related AE or deaths in any treatment group in either Protocol  Grade 3 or 4 laboratory abnormalities (excluding lipids) were uncommon (<5%) and similar between treatment groups in either protocol

17 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd  The patient population enrolled was heterogeneous with regard to prior ART therapy and included patients who previously experienced virologic failure  Raltegravir was superior to LPV/r as measured by % change from baseline in fasting triglycerides, total, and non-HDL cholesterol at Week 12; changes in LDL and HDL from baseline were comparable between the 2 treatment groups  Raltegravir did not demonstrate non-inferiority, as measured by proportion of patients with HIV RNA < 50 copies/mL at Week 24 (NC=F)  Both raltegravir and LPV/r were generally well tolerated In these studies where virologically suppressed patients on a LPV/r containing regimen were randomized to continue LPV/r or switch to RAL each in combination with background RTIs:

18 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd InvestigatorsMerck Research Laboratories K. A. IbargurenF. MazzottaP. Sklar A. AntinoriA. MillsR. Leavitt F. AntunesR. A. MyersB.-Y. Nguyen K. ArastehM. NelsonX. Xu N. BellosC. OrkinA. Rodgers D. S. BergerG. PieroneM. Walker T. BrancoD. M. PoretzM. Shaughnessy P. L.W. ChurchA. RachlisR. Isaacs E. DeJesusR. R. RedfieldK. Gottesdiener G. FaetkenheuerG. RiegG. Gallagher M. FisherG. RizzardiniT. Finn J. GerstoftP. J. RuaneM. Miller J. G. GarcíaM. S. SaagR. Barnard M. GottliebR. SarmentoD. Hazuda J. Hernández-QueroA. ScarsellaK. Strohmaier H. JaegerJ. Slim M. A. JohnsonG. H. R. Smith R. LalondeK. E. Squires A. LazzarinE. Teófilo R. L. LiporaceJ. v. Lunzen J. L. AldeguerS. Walmsley F. MaltezC. Workman R. MarquesB. Young O. L. Mathiesen

19 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd InvestigatorsMerck Research Laboratories C. A. AlvarezA. K. PatelP. Sklar J. AndradeG. PerezR. Leavitt S. M. AndrewsP. J. RuaneB.-Y. Nguyen T. AnekthananonS. SantiagoX. Xu A. I. ArangoD. G. SapleA. Rodgers E. BaraldiS. R. SchraderM. Walker T. B. CampbellK. Y. SmithM. Shaughnessy D. A. CooperT. N. L. SouzaR. Isaacs I. FrankS. SungkanuparphK. Gottesdiener J. Garcia-DiazS. SwaminathanG. Gallagher J. GatheM. A. ThompsonT. Finn J. GoldI. TorresM. Miller D. W. JohnsonJ. D. VelezR. Barnard P. N. KumarD. WohlD. Hazuda P. E. L. LeivaC. WorkmanK. Strohmaier O. M., LeiteD. P. Wright F. C. M. UrbinaR. Zajdenverg S. Miller

20 Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd Switching from Stable Lopinavir/Ritonavir (LPV/r)- Based to Raltegravir (RAL)-Based Combination Antiretroviral Therapy (ART) Resulted In a Superior Lipid Profile at Week 12 but Did Not Demonstrate Non-Inferior Virologic Efficacy at Week 24 Joseph Eron* 1, Jaime Andrade 2, Roberto Zajdenverg 3, Cassy Workman 4, David A. Cooper 5, Benjamin Young 6, Xia Xu 7, Bach-Yen Nguyen 7, Randi Leavitt 7, and Peter Sklar 7 1 University of North Carolina, Chapel Hill, NC, USA; 2 Antinguo Hospital Civil de Guadalajara, Guadalajara, Mexico; 3 Hospital Escola Sao Francisco de Assis, Rio de Janeiro, Brazil; 4 AIDS Research Initiative, Darlinghurst, Australia; 5 University of New South Wales, Sydney, Australia; 6 Denver Infectious Disease Consultants, Denver, CO, USA; and 7 Merck Research Laboratories, West Point, PA, USA


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