H.-J. Stellbrink, Hamburg 1/ 2
Mega-/Giga-HAART Interruption Lopinavir/r „simple salvage“ Doppel-PI Fitness disadvantage Enfuvirtide 3TC/NRTI mono Tipranavir Darunavir Etravirine always undetectable Accept replication
TORO 1 & 2 POWER 1 & 2 RESIST 1 & 2 64% 60% 54% 46% Patients (%) Patients (%) Patients (%) 30% 30% <400 copies/ml <400 copies/ml <50 copies/ml Week 24 Week 24 Week 24 LPV/r TPV/r TMC114/r LPV/r + ENF TPV/r + ENF TMC114/r + ENF Haubrich et al . IDSA 2005. Abstract 785; Hill and Moyle. BHIVA 2006. Abstract P1.
7 Patienten <400 Kopien/ml in Woche 16 nach ausgewählten Substanzen im OBT Subgruppe n % Patienten 79 447 Wirksamkeit insgesamt 43 230 Wirksamkeit nach ART im OBT Enfuvirtid Darunavir 44 98 + + 23 87 42 90 + - 63 24 80 90 - + 55 47 191 - - 74 29 90 100 0 20 40 60 80 + : Erstmalig im OBT - : Kein Einsatz im OBT Raltegravir + OBT Placebo + OBT * Virological failures carried forward
9 Mean Change from Baseline in HIV-1 RNA at Week 24 According to Baseline HIV-1-RNA and Enfuvirtide Use in OBT* Placebo + OBT MVC QD + OBT MVC BID + OBT Screening HIV-1 RNA copies/mL <100,000 ? 100,000 No Enfuvirtide Enfuvirtide N= 70 135 139 46 93 95 N= 67 130 127 107 49 98 from baseline (log 10 copies/mL) 0 0 Mean change in HIV-1 RNA -0.5 -0.5 -1.0 -1.0 -0.94 -1.20 -1.31 -1.5 -1.5 -1.45 -2.0 -2.0 -1.97 -2.02 -2.02 -2.08 -2.08 -2.10 -2.18 -2.18 -2.5 -2.5 * Protocol-defined randomization strata; MOTIVATE 1-Week 24 Includes all patients who received at least one dose of study medication; LOCF
19 Mean Change from Baseline in HIV-1 RNA at Week 24 According to Baseline HIV-1-RNA and Enfuvirtide Use in OBT* Placebo + OBT MVC QD + OBT MVC BID + OBT Screening HIV-1 RNA <100,000 >=100,000 No enfuvirtide Enfuvirtide 113 73 N= 50 67 53 103 104 38 77 81 112 41 N= from baseline (log 10 copies/ml) 0 0 Mean change in HIV-1 RNA -0.5 -0.5 -1.0 -1.0 -0.98 -0.97 -1.12 -1.14 -1.5 -1.5 -2.0 -2.0 -2.02 -2.13 -2.16 -2.17 -2.22 -2.22 -2.26 -2.5 -2.5 -2.45 * Protocol-defined randomization strata; MOTIVATE 2-Week 24 Includes all patients who received at least one dose of study medication; LOCF
24 Percentage of Patients with HIV-1 RNA < 50 copies/mL at Week 24 by Number of Active Drugs in OBT* Placebo + OBT MVC QD + OBT 100 MVC BID + OBT 90 80 70 61 Patients (%) 58 60 55 53 52 50 43 43 40 29 30 19 18 20 9 10 3 0 N= 35 51 56 44 130 134 59 88 104 64 132 121 Number of active 0 1 2 ? 3 drugs in OBT* * Based on Overall Susceptibility Score MOTIVATE 1 & 2-Week 24 Includes all patients who received at least one dose of study medication; LOCF
TORO 1 & 2: Positive prognostic factors Disease stage Baseline CD4 cell count ( ≥ 100 cells/mm 3 ) Baseline plasma HIV-1 RNA (< 5 log 10 copies/ml) Treatment history Number of prior ARVs ( ≤ 10) Activity of background regimen Number of active ARVs in OB regimen ( ≥ 2 active ARVs*) * Based on phenotypic sensitivity score (PSS) at baseline, defined as the total number of drugs in a patient’s assigned OB regimen to which that patient’s pre-study virus sample showed phenotypic sensitivity. Montaner, et al . XV IAC 2004, Bangkok, Thailand. TuPeB4483
Baseline-Charakteristika TORO 1 & 2 (n=995) n=44 (40 männl., 4 weibl.) + ENF - ENF • Stadium: – CDC A: 3 (6,8 %) – CDC B: 14 (31,8 %) CDD C3 79 % 86 % – CDC C: 27 (61,4 %) • HIV-Infektion im Mittel 14,3 +/- 4,7 Jahre bekannt # ARVs 12 12 • Mit im Mittel 9,4 -/- 4,0 ARV vorbehandelt • Umstellung wegen VF (n=40) oder Intoleranz (n=3) • ENF-unvorbehandelt: 42, vorbehandelt: 2 CD4 88 97 • CD4-Zellzahl – Mittelwert 175 +/- 147 Zellen/µL • RNA 5,2 5,1 HIV-RNA – Mittelwert 4,7 +/- 1,1 log10 (1,7-7) • Aktuelles Regime mit ENF + im Mittel 3,7 +/- 1,0 ARVs • Neue Pis – TPV: 15 Pat. – DRV: 19 Pat. • Therapiepause vor ENF: n=2 (2/8 Monate)
First interim analysis: RNA Overall antiviral effect (p=,000001, n=27) vertical bars represent 0.95 CI 6,0 5,5 5,0 4,5 HIV RNA (log10) 4,0 3,5 3,0 - 2.13 log 2,5 (74% >-1 log 10 ) 2,0 1,5 log BL log W4 log W12 study visit
Early = good response to enfuvirtide Week 12 : decrease from BL of HIV RNA Ja (n = 395) Nein (n = 225) 100 100 90 90 80 80 70 70 % Patienten 60 % Patienten 60 50 50 40 40 30 30 20 20 10 10 0 0 <400 copies/mL N=164 Week 24 <400 copies/mL N=389 Week 24 N=125 Week 48 <50 copies/mL N=366 Week 48 <50 copies/mL N=65 Week 96 N=291 Week 96 Raffi et al. CID 2006; 42:870-872
Strategies for Regaining Control of HIV Replication Needle-Free Injection System for Administration of Enfuvirtide Use of needle-free gas-powered � injection system – Compared with standard needles and syringes � No significant differences in ENF plasma levels � ISR-related signs and symptoms significantly reduced � 24 pts evaluated reported that needle-free injector was similar or easier to use than needles Needle Biojection gas-powered device Montaner J, et al. IAS 2005. Abstract WeFo0205. clinicaloptions.com/hiv
ENF induces a specific CD8 response PBL response to single T20-peptides KN EQ 0,2 QE LE 0,15 % of total CD8+ T cells 0,1 0,05 0 #1 #2 #3 #4 #5 #6 patient #
Cost month year Kaletra 757,85 9220,51 Aptivus/r 1186,18 14431,86 Prezista/r 975,02 11862,48 Truvada 753,69 9169,90 Kivexa 707,53 8608,28 Fuzeon 2032,04 24723,15
Frequency of 3-class failure ("extensive triple class failure", ETCF) - Analysis of UK CHIC ART started with ≥ 3 Medikamenten - 10.603 patients • median CD4: 184/µl • 58% NNRTI • 10% PI/r ETCF in 170 subjects; risk of ETCF • 2% at 5 years; 8% at 10 years • subjects with CD4>200/µl at BL: 4% at 10 years Risk factors for ETCF • low CD4, high age, transmission risk other than MSM A Phillips et al. CROI 2007 #532
Enfuvirtide: a clinician‘s perspective 1. Valuable due to extracellular mode of action without an intracellular activation step 2. Effective in salvage therapy 3. In vivo synergy with NRTI, NNRTI, PI 4. In vitro synergy with maraviroc, in vivo not shown (bias ?) 5. Clinical use limited by route of administration and ISR. 6. High cost 7. Small target population
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