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Mean Plasma Concentration (SD) at Steady State (ng/mL)

Virologic Determinants of 24-Week Efficacy of Atazanavir With or Without Ritonavir in Patients with Prior Failure on a Protease Inhibitor. C. Zala , A. Lazzarin, A. Casiro, B. Grinsztejn, L. Nieto, R. Salazar, E. Ledesma, T. Kelleher, R. McGovern, A. Rightmire, C. McLaren.

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Mean Plasma Concentration (SD) at Steady State (ng/mL)

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  1. Virologic Determinants of 24-Week Efficacy of Atazanavir With or Without Ritonavir in Patients with Prior Failure on a Protease Inhibitor C. Zala, A. Lazzarin, A. Casiro, B. Grinsztejn, L. Nieto, R. Salazar, E. Ledesma, T. Kelleher, R. McGovern, A. Rightmire, C. McLaren.

  2. Rationale for ATV 300 mg Boosted with RTV 100 mg 10,000 1000 Mean Plasma Concentration (SD)at Steady State (ng/mL) 100 75th percentile in vitro Estimated ProteinAdjusted EC90 Range Median  22.6 ng/mL 4.8–3132.3 ng/mL 25th percentile 10 400 mg ATV 300 mg ATV/100 mg RTV 1 0 4 8 12 16 20 24 Time (h)

  3. Objectives In patients with prior treatment failure: To determine the extent to which Baseline viral mutations correlate to antiviral effects of: • Unboosted atazanavir (ATV 400mg QD) • Boosted atazanavir (ATV 300mg QD plus RTV 100mg QD)

  4. BMS-045 Failed at least two regimens including: 1 PI 1 NRTI 1 NNRTI ATV 300mg QD RTV LPV 400mg BID RTV ATV 400mg QD SQV + TDF + TDF + TDF +1 NRTI +1 NRTI +1 NRTI N=120 N=123 N=115 Study Designs: BMS-043 and BMS-045 BMS-043 Currently failing PI-based regimen ATV 400mg QD LPV 400mg BID RTV +2 NRTIs +2 NRTIs N=150 N=150 NRTI use: Physician choice RTV 100mg per dose

  5. BMS-043 BMS-045 ATV 400mg QD LPV 400mg BID RTV ATV 300mg QD RTV LPV 400mg BID RTV Randomized, N 150 150 120 123 Age (median), yr 36 38 39 39 Female 23% 18% 20% 22% Race • Hispanic/Latino 51% 52% 23% 22% • White 43% 41% 63% 58% • Black 6% 7% 15% 17% AIDS 23% 27% 28% 29% CD4 (median), cells/mm3 288 261 317 283 Patient Characteristics: Baseline

  6. BMS-043 BMS-045 ATV 400mg QD LPV 400mg BID RTV ATV 300mg QD RTV LPV 400mg BID RTV HIV RNA (median), log10c/mL 4.18 4.14 4.44 4.47 • <30,000 c/mL 69% 59% 53% 50% • 30,000 to <100,000 c/mL 16% 23% 23% 27% • 100,000 c/mL 15% 17% 23% 23% Baseline susceptibility * • ATV, n (%) 108 (72) 88 (74) • LPV 129 (86) 91 (77) >4 mutations at Baseline • PI 39 (26) 35 (23) 39 (33) 45 (37) • NRTI 24 (16) 24 (16) 47 (39) 53 (43) Virologic Characteristics: Baseline * Baseline phenotypic susceptibility determined as <2.5 Fold Change (ViroLogic Phenosense)

  7. NRTI and PI Substitutions Evaluated Wild Type L K L V L M M G I I L A G V I L PI genotype 10 20 24 32 33 36 46 48 50 54 63 71 73 82 84 90 Substitutions F I I I F I I V M A P I A A V M I M I L L L A T S F V R V V V C V T I R T F L V G T H Q S T Wild Type M K D K L Q M L T K RT genotype 41 65 67 70 74 151 184 210 215 219 Substitutions L R A R V M I F E E G V S F G N W I Q T N R S A V N Y C H R Source: Stanford HIV RT and Protease Sequence Database

  8. BMS-043 BMS-045 Prior ARV use (median) ATV 400mg QD LPV 400mg BID RTV ATV 300mg QD RTV LPV 400mg BID RTV • Randomized, N 150 150 120 123 • Prior NRTI use, weeks (range) 159 (0.1-645) 167 (26.1-630) 269 (40-782) 265 (0.1-679) • Prior PI use, weeks (range) 133 (0.1-338) 136 (0.1-536) 133 (0.1-321) 136 (0.1-346) • Prior NNRTI use, weeks (range) 133 (1.6-210) 85 (1.6-158) 78 (0.1-227) 69 (0.1-304) Preceding regimen (PI or NNRTI) PI 36% PI 37% NNRTI 61% PI 100% PI 100% NNRTI 58% Treatment History

  9. BMS-045: ATV/r vs LPV/r Study week B/L 4 8 12 16 24 0 ATV/r LPV/r -1 ATV/SQV Mean HIV-1 RNA Change from Baseline -1.52 -1.86 -1.89 -2 Time Averaged Difference Estimate: ATV/r - LPV/r: 0.14 log10 c/mL. [97.5% CI: -0.09, 0.37] ATV/SQV - LPV/r: 0.31 log10 c/mL. [97.5% CI: 0.07, 0.55] Primary Endpoint: Virologic Efficacy Through 24 Weeks BMS-043: ATV vs LPV/r Study week B/L 4 8 12 16 24 0 unboosted ATV boosted LPV -1 Mean HIV-1 RNA Change from Baseline -1.67 -2.11 -2 Time Averaged Difference Estimate: ATV - LPV/r: 0.30 log10 c/mL. [97.5% CI: 0.09, 0.51]

  10. Effect of NRTI and PI Substitutions on Viral Load Reduction • BMS-043: ATV (unboosted) vs LPV/r • BMS-045: ATV/r vs LPV/r

  11. BMS-043: Baseline Genotypic Determinants of Viral Load Reduction at Week 24 Number of Baseline NRTI Mutations Number of Baseline PI Mutations none 1 2 3 4 5 none 1 2 3 4 5 Mean Change in Viral Load at Week 24 (log10 c/mL) ATV (unboosted) LPV/r ATV, n 26 33 8 15 8 5 15 22 18 20 9 11 LPV/r, n 20 43 13 11 9 6 8 22 27 22 7 16

  12. BMS-045: Baseline Genotypic Determinants of Viral Load Reduction at Week 24 Number of Baseline NRTI Mutations Number of Baseline PI Mutations none 1 2 3 4 5 none 1 2 3 4 5 Mean Change in Viral Load at Week 24 (log10 c/mL) ATV/r LPV/r ATV/r, n 16 22 9 21 18 26 17 28 22 11 10 24 LPV/r, n 13 15 18 19 13 32 10 24 26 10 15 25

  13. Effect of NRTI and PI Substitutions on Proportion of Subjects <400 copies/mL • BMS-043: ATV (unboosted) vs LPV/r • BMS-045: ATV/r vs LPV/r

  14. BMS-043: Baseline Genotypic Determinants of Virologic Response (<400 c/mL) at Week 24 Number of Baseline NRTI Mutations Number of Baseline PI Mutations ATV (unboosted) LPV/r Proportion <400 copies/mL, % none 1 2 3 4 5 none 1 2 3 4 5 ATV, n 32 37 13 16 10 6 16 28 20 22 10 18 LPV/r, n 26 46 14 13 9 7 9 27 29 23 8 19 ITT: Time to Loss Of Virologic Response

  15. BMS-045: Baseline Genotypic Determinants of Virologic Response (<400 c/mL) at Week 24 Number of Baseline NRTI Mutations Number of Baseline PI Mutations ATV/r LPV/r Proportion <400 copies/mL, % none 1 2 3 4 5 none 1 2 3 4 5 ATV/r, n 18 23 9 23 18 29 18 28 23 12 10 29 LPV/r, n 17 15 18 20 16 37 13 27 27 11 15 30 ITT: Time to Loss Of Virologic Response

  16. Effect of NRTI and PI Substitutions on Proportion of Subjects <50 copies/mL • BMS-043: ATV (unboosted) vs LPV/r • BMS-045: ATV/r vs LPV/r

  17. BMS-043: Baseline Genotypic Determinants of Virologic Response (<50 c/mL) at Week 24 Number of Baseline NRTI Mutations Number of Baseline PI Mutations ATV (unboosted) LPV/r Proportion <50 copies/mL, % none 1 2 3 4 5 none 1 2 3 4 5 ATV, n 32 37 13 16 10 6 18 23 9 23 18 29 LPV/r, n 26 46 14 13 9 7 17 15 18 20 16 37 ITT: Time to Loss Of Virologic Response

  18. BMS-045: Baseline Genotypic Determinants of Virologic Response (<50 c/mL) at Week 24 Number of Baseline NRTI Mutations Number of Baseline PI Mutations ATV/r LPV/r Proportion <50 copies/mL, % none 1 2 3 4 5 none 1 2 3 4 5 ATV/r, n 18 23 9 23 18 29 18 28 23 12 10 29 LPV/r, n 17 15 18 20 16 37 13 27 27 11 15 30 ITT: Time to Loss Of Virologic Response

  19. Conclusions • The efficacy of ATV- and LPV-containing regimens decreased with increasing numbers of PI and NRTI mutations • The relative magnitude of this effect was greatest in non-boosted ATV regimens • The effect of PI and NRTI mutations was similar in ATV/r and LPV/r regimens • These results indicate that RTV-boosted ATV may be a more appropriate regimen than unboosted ATV for patients with multiple PI and NRTI mutations

  20. Acknowledgments TO ALL THE PATIENTS AND STUDY CENTER PARTICIPANTS C. Zala 1, A. Lazzarin 2, A. Casiro 3, B. Grinsztejn 4, L. Nieto 5, R. Salazar 6, E. Ledesma 7, T. Kelleher 7, R. McGovern 7, A. Rightmire 7, C. McLaren 7. 1 Fundacion Huesped, Buenos Aires, Argentina. 2 Instituto di Ricovero e Cura a Carattere Scientifico S. Raffaele, Milan, Italy. 3 Hospital Teodoro Alvarez, Buenos Aires, Argentina. 4 Instituto de Pesquisa Clínica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil. 5 Hospital Gabriel Mancera, IMSS, Mexico, D.F. 6 Guillermo Almenara Hospital, Lima, Peru. 7 Bristol-Myers Squibb Company, Wallingford, CT, USA

  21. Investigators Jose Hernandez, DO. Miami Beach, FL Ross Hewitt, MD. Buffalo, NY Robert Houghton, MD. San Diego, CA Susan Jacobsen, MD. Berkely, CA Thomas Jefferson, MD. Little Rock, AR Joseph Jemsek, MD. Huntersville, NC Edwin deJesus, MD. Altamonte Springs, FL Sujata Lalla-Reddy, MD. Long Beach, CA Harry Lampiris, MD. San Francisco, CA Kenneth Lichtenstein, MD. Denver, CO George McKinley, MD. New York, NY Alexander McMeeking, MD. New Yok, NY Jane-Ellen Mobley, MD. Birmingham, AL Mary O’Hearn, MD. Portland, OR Samuel Pegram, MD. Winston-Salem, NC Peter Piliero, MD. Albany, NY Ronald Poblete, MD. Newark, NJ Arnaldo Quinones, MD. Ft Lauderdale, FL James Sampson, MD. Portland, OR Stefan Schneider, MD. Long Beach, CA Shannon Schrader, MD. Houston, TX David Stein, MD. Bronx, NY Charles Steinberg, MD. Denver, CO Donna Sweet, MD. Wichita, KS Rohit Talwani, MD. Columbia, SC Steven Zell, MD. Reno, NV Argentina Mexico Leopoldo Nieto, MD. Col. Del Valle Juan Sierra, MD. Tialpan Sergio Lupo, MD. Rosario Arnaldo Casiro, MD. Buenos Aires Claudia Rodriguez, MD. Buenos Aires Carlos Zala, MD. Buenos Aires Peru Juan Echevarria, MD. Lima Raul Salazar, MD. Lima Brazil Clovis Arns, MD. Curitiba Frederico Rangel, MD. Recife Tania Reuter, MD. Vitória Roberto Badaro, MD. Salvador Beatirz Grinsztejn, MD. Rio de Janeiro Erico Arruda, MD. Fortaleza Danilo Nunes, MD. São Paulo Breno Santos, MD. Trein Puerto Rico Javier Morales, MD. San Juan Gladys E. Sepulveda, MD. Ponce Gabriel A. Martinez, MD. Cotol Laurel United States Robert Baker, MD. Indianapolis, IN Nicholaos Bellos, MD. Dallas, TX David Brand, MD. Dallas, TX, Larry Bush, MD. Atlantis, FL Jerry Cade, MD. Las Vegas, NV Jeffrey Coco, MD. New Orleans, LA Calvin Cohen, MD. Boston, MA Timothy Cooley, MD. Boston, MA Robert Eng, MD. East Orange, NJ Jose Fernandez, DO. Miami Beach, FL Jeffrey Fessel, MD. San Francisco, CA Thomas File, MD. Akron, OH Richard Greenberg, MD. Lexington, KY Canada Christos Tsoukas, MD. Montreal, Quebec Chile Juan Ballesteros, MD. Santiago Luis Noriega, MD. Santiago Carlos Perez, MD. Santiago Marcelo Wolff, MD. Santiago Costa Rica Gisella Herrera, MD. San Jose

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