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Vienne 2010 - PROGRESS - 48 semaines

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Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) Demonstrated Similar Antiviral Efficacy and Safety as LPV/r Combined with Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) in ...

Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) Demonstrated Similar Antiviral Efficacy and Safety as LPV/r Combined with Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) in Treatment-Naïve HIV-1-Infected Subjects:

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Vienne 2010 - PROGRESS - 48 semaines Vienne 2010 - PROGRESS - 48 semaines Presentation Transcript

  • Jacques Reynes 1 , Adebayo Lawal 2 , Federico Pulido 3 , Ruth Soto-Malave 4 , Joseph Gathe 5 , Min Tian 2 , Linda Fredrick 2 , Todd Correll 2 , Thomas Podsadecki 2 , Angela Nilius 2 XVIII International AIDS Conference ● Vienna, Austria ●18-23 July 2010 1. Department of Infectious and Tropical Diseases, Montpellier University Hospital, Montpellier, France 2. Abbott, Abbott Park, Illinois 3. Unidad VIH. Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid Spain 4. University of Puerto Rico, School of Medicine, Infectious Diseases Section, San Juan, Puerto Rico and Innovative Care PSC, Bayamon, Puerto Rico 5. Therapeutic Concepts, Houston, Texas MOAB0101 Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) Demonstrated Similar Antiviral Efficacy and Safety as LPV/r Combined with Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) in Treatment-Naïve HIV-1-Infected Subjects: PROGRESS 48 week results
  • Background
    • The standard ARV therapy of a PI or NNRTI + 2 NRTIs is effective, though 15-20% of patients on long-term therapy experience toxicity related to NRTI use 1-4
    • Combinations of drugs from other classes can be effective while avoiding NRTI-associated toxicity 5
    • LPV/r, a PI with durable antiviral activity, is approved for use in ARV-naïve and experienced patients in combination with NRTIs 6-8
    • RAL is an integrase inhibitor that quickly suppresses viral replication and is approved for use in ARV-naïve and experienced patients 9-10
    • The PROGRESS trial is the first phase III study designed to test the efficacy and safety of a novel NRTI-sparing strategy using RAL and LPV/r in naïve patients
    PROGRESS 48 week results – XVIII IAC 19-Jul-10 1. Hogg, RS et al . , Lancet , 1997; 349:1294; 2. Lewis, W et al . , Nat. Rev. Drug Discov ., 2003;2:812-22; 3. Shikuma, CM et al., AIDS , 2001;15:1801-9; 4. Nolan, D et al . , Sex Health , 2005;2:153-63; 5. Riddler, SA et al . , N. Engl. J. Med ., 2008;358:2095-106; 6. Gathe JR et al., JAIDS , 2009;50:474-481; 7. Zajdenverg, R., et al., JAIDS , 2010;54:143-51; 8 Kaletra US prescribing Information, 2010; 9. Lennox, J et al., Lancet , 2009; 374:796-806. 10. Isentress US prescribing Information, 2009.
  • LPV/r + RAL vs . LPV/r + TDF/FTC in Treatment-Naive Subjects: PROGRESS Study Design
    • Primary endpoint: plasma HIV-1 RNA <40 copies/mL at week 48 (FDA ITT TLOVR)
    • Non-inferiority assessed by 95% CI for the difference ([LPV/r + RAL] – [LPV/r + TDF/FTC]) using a -20% threshold
    • If non-inferiority with respect to the -20% margin was demonstrated, then non-inferiority with respect to a -12% margin was to be evaluated
    PROGRESS 48 week results – XVIII IAC 19-Jul-10 LPV/r 400/100 mg BID + TDF/FTC 300/200 mg QD (n=105)
    • Inclusion Criteria for PROGRESS (M10-336)
    • HIV-1 infection
    • ARV-naïve
    • Plasma HIV-1 RNA >1000 copies/mL
    • Any CD4 + T-cell count
    Screening Week 96 LPV/r 400/100 mg BID + RAL 400 mg BID (n=101) Week 48 Primary Efficacy Endpoint
  • Baseline Demographics and HIV Disease Characteristics* PROGRESS 48 week results – XVIII IAC 19-Jul-10 * Excludes randomized but not dosed, n=3 † Plasma HIV-1 viral loads determined using automated, quantitative RT-PCR assay Variable LPV/r + RAL (N=101) LPV/ + TDF/FTC (N=105) Total (N=206) Males, n (%) 88 (87.1) 86 (81.9) 174 (84.5) White, n (%) 74 (73.3) 81 (77.1) 155 (75.2) Black, n (%) Other, n (%) 22 (21.8) 5 (4.9) 22 (21.0) 2 (1.9) 44 (21.4) 7 (3.4) Mean age ± SD, years 39.8 ± 9.9 39.4 ± 11.2 39.6 ± 10.6 Mean BL HIV-1 RNA, log 10 copies/mL (range) † 4.24 (2.0-6.0) 4.25 (2.7 – 6.0) 4.25 (2.0 – 6.0) Mean BL CD4, cells/ μ L (range) 289.3 (5 – 668) 297.6 (5 – 743) 293.5 (5 – 743)
  • Subject Disposition at Week 48 PROGRESS 48 week results – XVIII IAC 19-Jul-10 *P >0.100 for LPV/r + RAL vs . LPV/r + TDF/FTC comparison for each reason † 4 subjects discontinued prior to week 48 and 4 subjects discontinued after week 48 visit ** 9 subjects discontinued prior to week 48 and 2 subjects discontinued after week 48 visit ║ 1 LPV/r + RAL subject discontinued due to two reasons: Noncompliance and Other Reasons for Discontinuations LPV/r + RAL (N=101) n, (%) LPV/ + TDF/FTC (N=105) n, (%) Total (N=206) n, (%) All Reasons* 8 (7.9) † 11 (10.5) ** 19 (9.2) AE/HIV-related Event 2 (2.0) 2 (1.9) 4 (1.9) Withdrew Consent 1 (1.0) 3 (2.9) 4 (1.9) Lost to Follow-Up 3 (3.0) 3 (2.9) 6 (2.9) Noncompliance ║ 1 (1.0) 0 (0) 1 (0.5) Virologic Failure 1 (1.0) 2 (1.9) 3 (1.5) Other ║ 1 (1.0) 1 (1.0) 2 (1.0) On treatment beyond week 48 93 (92.1) 94 (89.5) 187 (90.8)
  • PROGRESS 48 week results – XVIII IAC 19-Jul-10 Primary Efficacy Endpoint at Week 48: Proportion of Subjects Responding (FDA ITT TLOVR) LPV/r + RAL was non-inferior to LPV/r + TDF/FTC in treatment-naïve subjects at 48 weeks
  • Mean CD4+ T-cell Count Change from Baseline to Week 48 (cells/mm 3 ) PROGRESS 48 week results – XVIII IAC 19-Jul-10
  • Emergence of Resistance Mutations *
    • 7 subjects (4 LPV/r + RAL and 3 LPV/r + TDF/FTC) met the protocol-defined criteria for resistance testing
      • N155H mutation detected in 1 LPV/r + RAL subject
      • M184V mutation detected in 1 LPV/r + TDF/FTC subject
    PROGRESS 48 week results – XVIII IAC 19-Jul-10 *LPV-associated mutations : Major: V32I, I47V/A, L76V, V82A/F/T/S. Minor: L10F/I/R/V, K20M/R, L24I, L33F, M46I/L, I50V, F53L, I54/V/L/A/M/T/S, L63P, A71V/T, G73S, I84V, or L90M RAL-associated mutations : Y143R/H/C, Q148H/K/R, or N155H TDF-associated mutations : K65R or K70E FTC-associated mutations : K65R or M184V/I † 1 RAL sample not available for testing after meeting protocol-defined criteria N/A-not applicable Study Drug Number of subjects with new mutations LPV/r + RAL LPV/r + TDF/FTC LPV 0/4 0/3 RAL † 1/3 N/A TDF 0/4 0/3 FTC 0/4 1/3
  • Percentages of Subjects with Moderate or Severe Drug-related Adverse Events* PROGRESS 48 week results – XVIII IAC 19-Jul-10 *Occurring in ≥2.0% in either treatment group P >0.100 for LPV/r + RAL vs . LPV/r + TDF/FTC comparison for each adverse event LPV/r + RAL (N=101) n (%) LPV/r + TDF/FTC (N=105) n (%) Any Adverse Event 28 (27.7) 29 (27.6) Diarrhea Hypercholesterolemia 8 (7.9) 8 (7.9) 14 (13.3) 5 (4.8) Hypertriglyceridemia 6 (5.9) 2 (1.9) Hyperlipidemia 3 (3.0) 1 (1.0) Blood triglycerides increased Alanine aminotransferase increased 3 (3.0) 2 (2.0) 1 (1.0) 1 (1.0)
  • Number and % of Subjects with Grade 3+ Laboratory Values* PROGRESS 48 week results – XVIII IAC 19-Jul-10 *Occurring in ≥2.0% in either treatment group † P =0.023 for LPV/r + RAL vs . LPV/r + TDF/FTC comparison LPV/r + RAL (N=101) n (%) LPV/r + TDF/FTC (N=105) n (%) SGPT/ALT >5X ULN, n (%) SGOT/AST >5X ULN Creatine phosphokinase >4X ULN † Calcium <1.75 mmol/L Cholesterol >7.77 mmol/L Triglycerides >8.475 mmol/L Calculated creatinine clearance <50 mL/min Lipase >2X ULN 3 (3.0) 5 (5.0) 13 (12.9) 2 (2.0) 16 (15.8) 10 (9.9) 1 (1.0) 4 (4.0) 1 (1.0) 1 (1.0) 4 (3.8) 0 14 (13.5) 5 (4.8) 4 (3.8) 7 (6.7)
  • PROGRESS 48 week results – XVIII IAC 19-Jul-10 Lipid Changes From Baseline to Week 48 # P-values based on one-way ANOVA Variable LPV/r + RAL N=97 LPV/r + TDF/FTC N=97 P-value #
  • Study Conclusions 1 PROGRESS 48 week results – XVIII IAC 19-Jul-10
    • Through 48 weeks, LPV/r + RAL and LPV/r + TDF/FTC had similar efficacy in treatment-naïve subjects
      • LPV/r + RAL was non-inferior to LPV/r + TDF/FTC at week 48
        • Proportion of subjects responding [FDA ITT TLOVR, P =0.850]
          • LPV/r + RAL: 83.2%
          • LPV/r + TDF/FTC: 84.8%
      • Similar mean increases in CD4+ T-cell counts at week 48 ( P =0.237)
        • LPV/r + RAL: 214.9 cells/mm 3
        • LPV/r + TDF/FTC: 245.0 cells/mm 3
    • No new protease mutations associated with lopinavir resistance developed on study in either treatment arm
      • A RAL associated resistance mutation was observed in one subject receiving LPV/r + RAL
      • A FTC associated resistance mutation was observed in one subject receiving LPV/r + TDF/FTC
    • Both regimens were generally well tolerated with few study drug-related discontinuations
      • Discontinuations for AEs or HIV-related events: LPV/r + RAL=2.0% and LPV/r + TDF/FTC=1.9%
      • AE profile and laboratory abnormalities were generally similar with statistically greater mean increases in TC, TG, and HDL and more reports of at least moderate lipid elevations in the LPV/r + RAL group
    • Outcomes that will be available after 96 weeks include:
      • Adherence
      • DEXA scans
      • Anthropometric measurements
      • Patient reported outcomes
    Study Conclusions 2 PROGRESS 48 week results – XVIII IAC 19-Jul-10
  • PROGRESS: Acknowledgements
    • The authors express their gratitude
    • To the patients and their families for their participation and support during the study
    • To the PROGRESS (M10-336) Study Team at Abbott and the clinical research personnel who worked on this study
    • To Merck for providing raltegravir
    • To the PROGRESS investigators:
      • USA
        • Larry M. Bush
        • Frederick A. Cruickshank
        • Edwin DeJesus
        • Robin Henry Dretler
        • Joseph Gathe
        • Cynthia Mayer
        • Igho Ofotokun
        • Moti Ramgopal
        • Louis Marshall Sloan
        • Lawrence F. Waldman
    PROGRESS 48 week results – XVIII IAC 19-Jul-10
      • Canada
        • Jonathan B. Angel
        • Mona Loutfy
        • Anita Rachlis
      • France
        • Laurent Cotte
        • Pierre-Marie Girard
        • Jacques Reynes
        • Dominique Salmon
      • Italy
        • Fiorella DiSora
        • Adriano Lazzarin
        • Andrea Antinori
      • Poland
        • Marcin Czarnecki
      • Puerto Rico
        • Ivan Melendez-Rivera
        • Ruth Soto-Malave
      • Spain
        • Bonaventura Clotet
        • Daniel Podzamczer
        • Federico Pulido
        • Jesus Sanz
        • Pompeyo Viciana