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46th ICAAC2006

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Information about 46th ICAAC2006
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Published on October 29, 2007

Author: Coralie

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Slide1:  46th Interscience Conference on Antimicrobial Agents and Chemotherapy Program Overview:  Program Overview Provide comprehensive information on the latest clinical data from recent major HIV/AIDS conferences as it relates to the selection of initial and/or subsequent antiretroviral therapy Efficacy and/or durability of response Management approaches and adherence Resistance Potential new therapeutic options Slide3:  Efficacy and/or Durability of Response Recommended Regimens for Treatment-Naïve Patients: DHHS 2006:  Recommended Regimens for Treatment-Naïve Patients: DHHS 2006 Available at: http://aidsinfo.nih.gov/Default.aspx. Revision October 10, 2006. Choose a PI or NNRTI from column A and NRTIs from column B. Study 121: NRTI-Sparing Regimen in Treatment-Naïve Patients:  Study 121: NRTI-Sparing Regimen in Treatment-Naïve Patients Treatment-naïve patients (n=65) Open-label, 48-week trial Regimens Atazanavir + RTV 300/100 mg or 400/100 mg All patients received efavirenz 600 mg qd Primary analysis Week 8 changes in triglyceride levels for pooled arms Secondary analyses Week 48 changes in lipid profile, virologic and immunologic outcomes Safety and tolerability Ward D, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1057. Study 121: NRTI-Sparing Regimen in Treatment-Naïve Patients (cont’d):  Study 121: NRTI-Sparing Regimen in Treatment-Naïve Patients (cont’d) Primary outcome (week 8) Triglyceride levels increased 61% (range: 51.9% to 70.5%) in both atazanavir arms* Secondary outcome (week 8) Triglyceride increase in the atazanavir + ritonavir arms 300/100 mg : 52% 400/100: 70% Week 48 Both regimens had comparable antiretroviral activity and immunologic improvement Ward D, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1057. *Both groups received efavirenz 600 mg qd. ALERT Study: Boosted Fosamprenavir Versus Atazanavir:  ALERT Study: Boosted Fosamprenavir Versus Atazanavir Treatment-naïve patients (n=106) Open-label, 48-week exploratory trial, not powered for non-inferiority Planned 24-week analysis Regimens Fosamprenavir + RTV (1400/100 mg qd) Atazanavir + RTV (300/100 mg qd) All patients received FTC/TDF qd Primary analysis HIV RNA <50 copies/mL at 48 weeks Secondary analyses Week 24 HIV RNA <50 copies/mL Week 24 and 48 HIV RNA <50 and 400 copies/mL, CD4, resistance, adverse events Smith K, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1670a. ALERT Study: Boosted Fosamprenavir Versus Atazanavir:  ALERT Study: Boosted Fosamprenavir Versus Atazanavir Planned 24-week analysis showed comparable antiretroviral activity and immunologic improvement between both regimens Awaiting final week 48 analysis *Both groups received FTC/TDF qd. Smith K, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1670a. ACTION Study: Triple NRTI Versus Unboosted Atazanavir:  ACTION Study: Triple NRTI Versus Unboosted Atazanavir Treatment-naïve patients (n=279) Open-label, non-inferiority trial Baseline HIV RNA: 4.55 log10 copies/mL CD4: 270 cells/mm3 Regimens Zidovudine/lamivudine/abacavir bid Atazanavir 400 mg qd + ZDV/3TC bid Week 48 results met criteria for non-inferiority Use of either regimen as a first-line choice in treatment-naïve patients is questionable given current treatment options Kumar PN, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1058. POWER 1, 2, and 3 Pooled Analysis: 24-Week Outcomes With Darunavir + Ritonavir:  POWER 1, 2, and 3 Pooled Analysis: 24-Week Outcomes With Darunavir + Ritonavir Phase IIb studies in patients with 3-class failure receiving darunavir + ritonavir (600/100 mg bid) and an optimized background regimen with or without enfuvirtide POWER 1 and 2 (n=131) POWER 3 (n=327) Failed PI-based regimens at screening Tipranavir + ritonavir (11%) Lopinavir/ritonavir (42%) Fosamprenavir + ritonavir (16%) Lefebvre E, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1387. POWER 1, 2, and 3: 24-Week Outcomes:  POWER 1, 2, and 3: 24-Week Outcomes Lefebvre E, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1387. The PI-based regimen used at baseline did not affect 24-week outcomes Slide12:  Management Approaches and Adherence COOL Study: Lamivudine-Sparing Maintenance Regimen:  COOL Study: Lamivudine-Sparing Maintenance Regimen Treatment-experienced (n=143) Open-label, 48-week trial Stable HAART for 3 months HIV RNA <50 copies/mL Switched to either Tenofovir DF + efavirenz Tenofovir DF + lamivudine + efavirenz Primary outcome Maintain HIV RNA <50 copies/mL Girard PM, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1383. COOL Study: Lamivudine-Sparing Maintenance Regimen (cont’d):  COOL Study: Lamivudine-Sparing Maintenance Regimen (cont’d) Tenofovir DF + efavirenz with lamivudine More efficacious as a maintenance regimen versus without lamivudine Tenofovir DF + efavirenz without lamivudine demonstrated lower efficacy due to: Virologic failure Higher discontinuation rate Girard PM, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1383. Study 720: Estimating CD4 Cell Count Plateau:  Study 720: Estimating CD4 Cell Count Plateau Treatment-naïve patients 100 enrolled Baseline CD4 (cells/mm3) >200 (n=64) 50-199 (n=19) <50 (n=17) Regimen Lopinavir/r 400/100 mg bid with lamivudine + stavudine Mean 7-year CD4 cell gain by baseline CD4 strata >200: +532 cells/mm3 50-199: +476 cells/mm3 <50: +495 cells/mm3 King M, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1401. CD4 count (cells/mm3) Weeks Estimated CD4 Time to Plateau 0 50 100 150 200 250 300 350 400 Comparison of CD4 Cell Plateau in Patients Receiving HAART:  Comparison of CD4 Cell Plateau in Patients Receiving HAART King M, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1401. Lower Adherence to HAART Observed Prior to Transient HIV Viremia:  Lower Adherence to HAART Observed Prior to Transient HIV Viremia Assessment of correct dosing adherence with occurrence of blip and non-blip episodes in treatment-naïve patients (n=273) Data from 2 randomized trials Lopinavir/ritonavir: 800/200 mg qd or 400/100 mg bid MEMS® monitored dosing Blip: HIV RNA >50 and <1000 copies/mL Results Incidence of blips: 26.9% Median HIV RNA: 82 copies/mL Median time to first blip: 282 days Blips not related to: Baseline viral load or CD4 count Virologic failure Development of resistance Blips associated with decreased adherence during prior week of therapy Podsadecki TJ, et al. 46th ICAAC. San Francisco, 2006. Abstract H-992. Slide18:  Resistance PREPARE Study: Drug Resistance in Treatment-Naïve Patients:  PREPARE Study: Drug Resistance in Treatment-Naïve Patients Cohort (n=2035) from clinical trials (2000-2005) sponsored by one pharmaceutical company Primary resistance at baseline (2005 IAS-USA, Stanford) Cohort demographics Median HIV RNA: 4.86 log10 copies/mL Median CD4: 252 cells/mm3 Overall primary resistance 2000-2003: 5% to 10% 2004: 13% to 15% 2005: 17% to 18% Increase in primary resistance in 2005 Seen in all geographic regions in US Due primarily to increased incidence of NNRTI mutations (10% to 11%) Ross L, et al. 46th ICAAC. San Francisco, 2006. Abstract H-993. PREPARE Study: Drug Resistance in Treatment-Naïve Patients (cont’d):  PREPARE Study: Drug Resistance in Treatment-Naïve Patients (cont’d) Primary Resistance Mutations (%) Any Drug NRTI NNRTI PI 2000 (n=251) 2003 (n=405) 2001 (n=411) 2004 (n=522) 2002 (n=206) 2005 (n=240) Ross L, et al. 46th ICAAC. San Francisco, 2006. Abstract H-993. IAS-USA Defined Resistance Mutations Study 934: 96-Week Resistance Results:  Study 934: 96-Week Resistance Results Resistance analysis excludes patients with baseline NNRTI resistance mutations 11 in each group All emtricitabine + tenofovir patients in the resistance analysis (n=14) remained phenotypically susceptible to TDF, ZDV, ABC, ddI, and d4T At week 96, patients in the emtricitabine + tenofovir DF group had: Significantly less M184V/I than those in the zidovudine/ lamivudine group No emergence of K65R *P=0.035; †P=0.036 versus zidovudine/lamivudine. McColl DJ, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1004. KLEAN Study: 48-Week Resistance Results:  KLEAN Study: 48-Week Resistance Results Treatment-naïve patients (n=878) Open-label, non-inferiority trial Median CD4: 192 cells/mm3 Median HIV RNA: 5.1 log10 copies/mL Regimens Lopinavir/ritonavir (soft-gel capsules; 400/100 mg bid) Fosamprenavir + RTV (700/100 mg bid) All patients received fixed-dose abacavir/lamivudine (600/300 mg qd) At week 48, efficacy data met the criteria for non-inferiority. In addition, both groups had similar rates of virologic failure, treatment discontinuations, and primary and secondary PI mutations Yeni P, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1056. KLEAN Study: 48-Week Resistance Results (cont’d):  KLEAN Study: 48-Week Resistance Results (cont’d) Yeni P, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1056. In Vitro Drug Susceptibility Cut-Off Values for PIs:  In Vitro Drug Susceptibility Cut-Off Values for PIs Clinical cut-off Maximal response to PI: fold-change < clinical cut-off 1. Reduced response to PI: fold-change between clinical cut-off values Minimal response to PI: fold-change > clinical cut-off 2. Biological cut-off PI susceptible: fold-change < biological clinical cut-off PI resistant: fold-change > biological cut-off. Picchio G, et al. 46th ICAAC. San Francisco, 2006. Abstract H-999. vircoTYPE clinical cut-offs: predicted fold change by multiple linear regression to 56,017 sequences submitted for routine resistance analysis from 2004-2005. RESIST Trials: Defining Lower and Upper Phenotypic Clinical Cut-Off Values:  RESIST Trials: Defining Lower and Upper Phenotypic Clinical Cut-Off Values Coakley EP, et al. 46th ICAAC. San Francisco, 2006. Abstract H-995. LCCO: lower clinical cut-off (baseline fold-change where HIV RNA response first begins to decline relative to wild type. UCCO: upper clinical cut-off (fold-change above which the attributable HIV RNA response <0.3 log10 copies/mL. NRTI Mutations: Correlation With Replicative Capacity and Reduced Drug Susceptibility:  NRTI Mutations: Correlation With Replicative Capacity and Reduced Drug Susceptibility Ross L, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1001. Samples collected analyzed between January 2003 and December 2005 (n=35,222). Data from emtricitabine, tipranavir, and zalcitabine not available. Reduced susceptibility: fold-change in IC50 above the PhenoSense GT specific drug cut-off value. Slide27:  Potential New Therapeutic Options Week 24 Results: Etravirine (TMC125) Plus Darunavir + Ritonavir:  Week 24 Results: Etravirine (TMC125) Plus Darunavir + Ritonavir Open-label single-arm study 12 treatment-experienced patients (2 withdrawals unrelated to therapy) Baseline HIV RNA: 4.6 log10 copies/mL CD4: 75 cells/mm3 Number of mutations NRTI (7), NNRTI (2), primary PI (4), all PIs (11) Etravirine (200 mg bid) + darunavir + RTV (600/100 mg bid) No serious adverse events or AIDS-defining events Boffito M, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1000. Integrase Inhibitor (MK-0518): Lipid Effects :  Integrase Inhibitor (MK-0518): Lipid Effects Randomized, double-blind, dose-ranging study (Study 004) Treatment-naïve patients Baseline HIV RNA: ~4.8 log10 copies/mL CD4: 271-338 cells/mm3 AIDS: 29%-43% Total cholesterol: 161-170 mg/dL Triglycerides: 110-155 mg/dL All groups received tenofovir DF + lamivudine Week 24 MK-0518 was not associated with increases in total cholesterol, triglycerides, or LDL-C *P<0.05 versus efavirenz. Teppler H, et al. 46th ICAAC. San Francisco, 2006. Abstract H-256a. Integrase Inhibitor (MK-0518): Study 005:  Integrase Inhibitor (MK-0518): Study 005 Treatment-experienced patients (n=167) Baseline HIV RNA: 4.7 log10 copies/mL CD4: 220-274 cells/mm3 3-class resistance Duration on antiretrovirals: 10 years Regimens Placebo MK-0518: 200, 400, or 600 mg bid oral administration All patients received an optimized background regimen (OBR) Mean of 4 antiretroviral agents Enfuvirtide included in 20%-28% of OBR Grinsztejn B, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1670b. Integrase Inhibitor (MK-0518): Study 005 Week 24 Results:  Integrase Inhibitor (MK-0518): Study 005 Week 24 Results Grinsztejn B, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1670b. Monoclonal Antibody (HGS004): Phase I Study:  Monoclonal Antibody (HGS004): Phase I Study Treatment-naïve and treatment - experienced patients (n=63) Treatment-experienced patients off HAART for >8 weeks Baseline HIV RNA: 4.0-4.8 log10 copies/mL CD4: 336-639 cells/mm3 CCR5-only virus 56-day follow-up Regimens 50%-58% in the 8.0-40 mg/kg dose arms achieved an HIV RNA reduction of >1 log10 copies/mL by day 14 4-day delay in onset of efficacy, then efficacy continues for 28 days Moderately severe infusion-related urticarial rash in 2.0 mg/kg arm (n=2) No rash in higher dose groups Shift in tropism (CCR5 to dual/mixed) observed in 5 patients Minimal antiviral response in these patients Lalezari J, et al. 46th ICAAC. San Francisco, 2006. Abstract H-1668.

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