Erste Erfahrungen mit neuen Substanzen -Raltegravir-

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2 Erste Erfahrungen mit neuen Substanzen -Raltegravir- HIV im Dialog Berlin, Stephan Dupke Praxis Carganico/Baumgarten/Dupke

3 Integrase Essentielles virales Enzym zur Vermehrung von HIV-1und HIV-2 Integration Folgt auf die reverse Transcription, bei der virale RNA in eine DNA umgeschrieben wird Integriert die virale DNA in den Zellkern der befallenen Zelle

4 Neue antiretrovirale Substanzen Entry inhibitors Mature virus PIs Darunavir Tipranavir Maraviroc Reverse transcriptase inhibitors Etravirine Integrase inhibitors Raltegravir

5 Studien zu Integrase-Inhibitoren Inhibitoren

6 Protocol 004 Phase IIa: Raltegravir Monotherapie Proof-of-Concept Study Stratification by baseline HIV-1 RNA or > 50,000 copies/ml Day 10 Antiretroviral-naive patients with HIV-1 RNA 5000 copies/ml and CD4+ cell count 100 cells/mm 3 (N = 35) Raltegravir 100 mg BID (n = 7) Raltegravir 200 mg BID (n = 7) Raltegravir 400 mg BID (n = 6) Raltegravir 600 mg BID (n = 8) Placebo (n = 7) 14-day follow-up Markowitz M, et al. J Acquir Immune Defic Syndr. 2006;43:

7 Protocol 004 Phase IIa: Day 10 Virologic Efficacy VL-Senkung log 10 c/ml (95% CI) HIV-1 RNA < 400 c/ml, n (%) HIV-1 RNA < 50 c/ml, n (%) RAL 100 mg (n = 7) (-2.44 to )* RAL 200 mg (n = 7) (-2.49 to )* RAL 400 mg (n = 6) (-1.99 to )* RAL 600 mg (n = 8) (-2.55 to )* Placebo (n = 7) (-0.42 to 0.07)* 4 (57) 4 (57) 3 (50) 4 (50) 0 1 (14) 2 (29) 1 (17) 1 (13) 0 Markowitz M, et al. J Acquir Immune Defic Syndr. 2006;43:

8 Protocol 004 Phase IIb: Raltegravir bei nicht Vorbehandelten Stratification by baseline HIV-1 RNA or > 50,000 copies/ml Week 48 Raltegravir 600 mg BID (n = 40)* HIV-1 RNA 5000 copies/ml, CD4+ cell count 100 cells/mm 3 (N = 203)* Raltegravir 400 mg BID (n = 41)* Raltegravir 200 mg BID (n = 40)* Raltegravir 100 mg BID (n = 41)* Efavirenz 600 mg QD (n = 41) Each combined with TDF + 3TC *8 patients in each raltegravir arm previously treated with same dose of raltegravir monotherapy for 10 days. Markowitz M, et al. J Acquir Immune Defic Syndr. 2007;46:

9 Protocol 004: 96-Wochen Wochen-Ergebnisse RAL vs EFV bei Unvorbehandelten Pts (NC = F) Patients With HIV-1 RNA < 50 copies/ml (%) * 83% 84% Using observed failure approach: RAL 92% and EFV 91% Number of Contributing Patients Week RAL 100 mg BID RAL 200 mg BID RAL 400 mg BID RAL 600 mg BID EFV 600 mg QD *After Week 48, patients in all RAL groups continued at 400 mg BID. All patients received TDF/3TC Markowitz M, et al. IAC Abstract TUAB0102.

10 Protocol 004 Phase IIb: Raltegravir-Nebenwirkungen ~ 85% leicht bis mässig Häufigkeit der NW unabhängig von der Dosierung NW unter Raltegravir (48%) seltener als unter Efavirenz (71%) Häufigste NW: Übelkeit, Schwindel, Kopfschmerzen Neuropsychiatrische Ereignisse seltener unter Raltegravir seltener als bei Efavirenz Woche 8: 8% vs 21% Woche 48: 13% vs 29% Markowitz M, et al. J Acquir Immune Defic Syndr. 2007;46:

11 Protocol 004 Phase IIb: Cholesterinwerte nach 48 Wochen Gesamtcholesterin Raltegravir: -2.3 mg/dl (-0.06 mmol/l) Efavirenz: 20.7 mg/dl (+0.54 mmol/l) (P <.001) Low density lipoprotein cholesterin( böses Cholesterin ) und Triglyceride Raltegravir: unverändert (P =.07) Efavirenz: erhöht (P =.016) High density lipoprotein cholesterin ( gutes Cholesterin ) Leichte Erhöhung unter beiden Substanzen, unter Raltegravir weniger ausgeprägt Markowitz M, et al. J Acquir Immune Defic Syndr. 2007;46:

12 BENCHMRK-1 1 & -2: RAL bei vorbehandelten Patienten Week 16 primary analysis Week 48 current analysis Week 156 planned follow-up HIV-infected patients mit 3-Klassen-Resistenz und HIV-1 RNA > 1000 copies/ml (BENCHMRK-1: N = 352; BENCHMRK-2: N = 351) RAL 400 mg BID + OBR* (BENCHMRK-1: n = 232; BENCHMRK-2: n = 230) Placebo + OBR* (BENCHMRK-1: n = 118; BENCHMRK-2: n = 119) *Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted. Cooper DA, et al. CROI Abstract 788. Steigbigel R, et al. CROI Abstract 789.

13 BENCHMRK-1 1 & -2: Patienten mit HIV-1 1 RNA < 50 c/ml bei Woche 48 RAL + OBR BENCHMRK-1 [1] BENCHMRK-2 [2] Placebo + OBR Patients (%) %* 65%* 33% 31% Weeks Patients (%) %* 36% 60%* 34% Weeks n = n = *P <.001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log 10 ), first ENF use in OBR, first DRV use in OBR, active PI in OBR. 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright 2008 Merck & Co., Inc. All Rights Reserved

14 BENCHMRK 1 & 2: Efficacy by BL HIV-1 1 RNA and CD4+ Cell Count HIV-1 RNA < 50 copies/ml at Week 48* Patient Group, % Raltegravir + OBR (n = 443) Placebo + OBR (n = 228) All patients HIV-1 RNA at BL, copies/ml > 100, (n = 156) 16 (n = 76) 100, (n = 287) 43 (n = 152) CD4+ cell count at BL, cells/mm (n = 139) 20 (n = 75) > 50 to ( n = 167) 39 (n = 82) > (n = 136) 44 (n = 71) *Virologic failures carried forward. 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

15 BENCHMRK-1 1 & -2: HIV-1 1 RNA < 50 c/ml at Week 48, Overall, and by GSS Subgroup n Patients (%) Total RAL + OBR Placebo + OBR GSS GSS=genotypic susceptibility score Cooper DA, et al. CROI Abstract 788. Steigbigel R, et al. CROI Abstract 789. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright 2008 Merck & Co., Inc. All Rights Reserved.

16 BENCHMRK-1 1 and -2: Drug-Related* Any Grade AEs at Week 48 Rates of all-cause, serious, and drug-related AEs, death, and laboratory abnormalities did not differ significantly between treatment arms Malignancy rate: RAL 3.5/100 person-years vs placebo 2.3/100 person-years RR: 1.5 (95% CI: ) AEs at Week 48, % RAL + OBR (n = 232) BENCHMRK-1 [1] BENCHMRK-2 [2] Placebo + OBR (n = 118) RAL + OBR (n = 230) Placebo + OBR (n = 119) Diarrhea Nausea Fatigue Headache Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789. *

17 BENCHMRK 1 & 2: Risk of Myopathy and Rhabdomyolysis Creatine phosphokinase Grad 4 Erhöhung (> 20- fach) Raltegravir: 2.2% Placebo: 0.7% Vorsicht bei der Kombination von Raltegravir mit Medikamenten, die eine Erhöhung der CK verursachen können (z.b.cse-hemmer). Raltegravir package insert.

18 Resistenz-Entwicklung unter Raltegravir: BENCHMRK 1 49 Patients mit virologischem Versagen in Wo (57%) Mutationen an Position 148 und/oder (27%) mit Q148H/K/R 19 (39%) mit N155H Zusammen mit anderen Mutationen 21 (43%): keine Mutationen an Position 148 oder (10%) andere bekannte raltegravir Resistenz-Mutationen 7 (14%) andere Mutationen mit unbekanntem Einfluss auf Resistenz 9 (18%) keine wesentlichen genotypischen Veränderungen zu Baseline Cooper D, et al. CROI Abstract 788.

19 Switching ENF(Fuzeon ) RAL bei Patienten mit negativer Viruslast CHEER (N = 52): multicenter, open-label US study of switching ENF RAL in heavily treated patients on stable ENF-based therapy [1] 49 (94%) der Pat. Blieben zu Woche 24 unter der Nachweisgrenze CD4+ -Anstieg von durchschnittl. 32 /mm 3 Alle NW Grade 1/2 Montreal cohort (N = 25): multicenter, retrospective study of switching ENF RAL in heavily treated patients on stable ENF-based therapy [2] 24/25 Patienten (96%) blieben unter der Nachweisgrenze zu Woche 12 Keine wesentlichen Veränderungen CD4; keine wesentlichen NW 3 Fälle von massiver Leberwerterhöhung nachdem von ENF RAL geswitcht wurde, die vorher TPV/RTV + ENF erhalten hatten 1 subject had higher TPV level after switch 1. Towner W, et al. IAC Abstract TUPE Talbot A, et al. IAC Abstract TUPE Khanlou H, et al. IAC Abstract TUPE0087.

20 Pharmacology of Raltegravir: Dosierung, Interaktionen Raltegravir wird 2xtgl.400mg unabhängig von Mahlzeiten genommen Atazanavir(Reyataz ): erhöht Raltegravir-Spiegel, wahrscheinlich ohne klinische Relevanz [1] Tipranavir(Aptivus ) : reduziert of Raltegravir-Spiegel [2] bei 100 Patients wurde kein Wirksamkeitsunterschied bei der Kombination von Raltegravir mit Tipranavir/ritonavir im Vergleich mit einem Kontroll-PI gesehen [1] Vorsicht bei der Kombination von Raltegravir mit Substanzen, die die CK erhöhen können 1. Raltegravir package insert. 2. Wenning LA, et al. ICAAC Abstract A-0374.

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22 Raltegravir in Experienced Patients With Virologic Failure High rate of integrase resistance at virologic failure highlights risk of prescribing raltegravir for experienced patients without other active agents in OBR Principles for use of raltegravir in this population Combine with other new active agents Regimen containing raltegravir plus 2 other active agents appears more effective than regimen containing raltegravir plus 1 other active agent [1,2] Likelihood of achieving virologic suppression greater if raltegravir introduced earlier rather than later while [1,2] HIV-1 RNA is relatively low and Patient still susceptible to at least some other antiretrovirals 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

23 Mutations Resistant to 3 Types of InIs Surround Metal Ions in Active Site Highly conserved residues; low potential for preexisting resistance S153 Q148 N155 G140 E138 Catalytic residues Diketoacid Naphthyridine Pyrimidine T66 Mg F121 V72 T125 Adapted with permission of Merck & Co., Inc., Whitehouse Station, NJ. Copyright Merck & Co., Inc. Whitehouse Station, NJ. All rights reserved.

24 Protocol 005 Phase IIb: Raltegravir bei Vorbehandelten Randomized, double-blind, placebocontrolled, dose-ranging, phase IIb study Week 24 Double-Blind Phase Open-label phase Week 48 Patients with triple class resistant virus, HIV-1 RNA > 5000 copies/ml and CD4+ cell count > 50 cells/mm 3 (N = 178) Raltegravir 200 mg BID + OBR* (n = 43) Raltegravir 400 mg BID + OBR* (n = 45) Raltegravir 600 mg BID + OBR* (n = 45) Placebo + OBR* (n = 45) Raltegravir 400 mg BID + OBR* (n = 100) Patients allowed to receive openlabel raltegravir 400 mg BID after at least 24 weeks of double-blind therapy; median duration of double-blind phase was 40 weeks for the raltegravir groups and 24 weeks for the placebo group *DRV/RTV was not available for use in OBR Grinsztejn B, et al. ICAAC Abstract H-713.

25 Protocol 005: 48-Week Results HIV-1 RNA < 50 copies/ml (%) Raltegravir 200 mg BID Double-Blind Only ITT, NC = F Double-Blind Plus Open Label Week No. of Contributing Patients Raltegravir 400 mg BID CD4+ Cell Count Change (cells/mm 3 ) Adapted with permission of Merck & Co., Inc., Whitehouse Station, NJ. Copyright Merck & Co., Inc. Whitehouse Station, NJ. All rights reserved Raltegravir 600 mg BID BL Carried Forward for VFs Double-Blind Only Week No. of Contributing Patients Placebo Double-Blind Plus Open Label

26 TRIO Study: RAL + ETR(TMC 125) + DRV/RTV (Prezista ) Highly Effective as 3 Active Agents Multicenter, phase II study of DRV/RTV plus ETR plus RAL (N = 103); addition of NRTIs, ENF Inclusion criteria included susceptibility to DRV and ETR based on 3 DRV and 3 ETR RAMs, respectively 59% of patients had < 1 active agent in OBR, as assessed by GSS 90% of patients attained HIV-1 RNA < 50 copies/ml at Week 24 (95% CI: 85% to 96%) Median increase in CD4+ cell count from BL to Week 24: 99 cells/mm 3 (IQR: ) Of 10 patients with detectable HIV-1 RNA at Week 24, only 3 had confirmed HIV-1 RNA > 400 copies/ml 2 possibly drug-related clinical grade 4 adverse events; only 1 led to treatment discontinuation Yazdanpanah Y, et al. IAC Abstract THAB0406.

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