AREVIR 05.05.2011 CCR5 Antagonists In Clinical Practice Dr. Björn Jensen Klinik für Gastroenterologie, Hepatologie und Infektiologie Universitätsklinikum Düsseldorf Klinikdirektor: Univ.-Prof. Dr. Dieter Häussinger
Conclusion – Clinical Use 1 st -line: perhaps in the future, but current regimes are good (at least regarding efficacy), wait for long-term data 2 nd /3 rd /4 th …-line: interesting, but be sure to use at least two other fully active substances, esp. when substances with low genetic barrier involved Salvage: declining percentage of R5-viruses, but good option when R5-using virus, esp. as 3 rd /4 th substance in a regime Deep (Deep) Salvage: if there is a realistic chance of having a R5-virus (considering e.g. different false-positive rates of genotypic tests etc.) consider to give it a try, because low rate of side effects; only useful if other substance available AREVIR 2008
M.J. ♀ *1958 HIV-1 Subtype B, diagnosed in 1987 , CDC C3; IDU Chronic Hepatitis C 1995 Candida esophagitis 06/95 first ART multiple regimens containing: AZT, 3TC/FTC, d4T, ddI, ABC, TDF, IDV, SQV, RTV, EFV, NVP poor tolerance of ART → poor adherenz, 3 therapy interruptions (maximum 8 months)
M.J. ♀ *1958 02/08 (since 12/06) AZT 100 mg 1-1-1, FTC 200 mg 0-0-1, SQV 500 mg 0-0-3 (RTV 100 mg 0-0-1 – not taken since 11/07 because of GI- side effects) 02/08 CD4 854/µl (31%); HI-VL <40 c/ml; SQV-level not detectable long conversation about adherenz → will try to take RTV again (with loperamide) 08/08 Did not take RTV – again very long conversation about adherenz and alternative therapy options
M.J. ♀ *1958 Options?: ABC: HSR NVP: exanthema EFV: depression PI(r): GI-side effects – not tolerable Resistance: only M184V (at least as far as we knew) intensive fear concerning a therapy change 08/08 CD4 651/µl (21%); HI-VL 239 c/ml (66 c/ml one week later); Resistance testing: no resistance mutations; genotypic R5 (FPR 40,6%)
MOTIVATE 1 and 2: Side effects Hardy D, et al. CROI 2008. Poster 792.
M.J. ♀ *1958 09/08 TDF/FTC + MVC (first 3 days in hospital) 09/08 after 2 weeks: very good tolerability CD4 700/µl (28%); HI-VL 1130 c/ml! 10/08 CD4 567/µl (27%); HI-VL 153 c/ml 02/09 CD4 528 (22%); since 02/09 HI-VL <40 c/ml , still a difficult patient – sometimes control intervals > 6 months, but patient and doctor much „happier“ with ART
Thank You !!! Thank You !!!
K.S. ♀ *1970 HIV-1, subtype B, diagnosed in 11/95 , CDC B2; HET first contact in our department 09/00 CD 4 399/µl (28%), HI-VL 135 Eq/ml ? Crohn ´ s disease/ulcerative Colitis ´ 99, currently no symptoms 01/05 weaker, night sweat, vaginal candidiasis CD4 357/µl (26%), HI-VL 7346 Eq/ml 02/05 Monark (Kaletra mono) – no resistance mutations CD4 271/µl (30%), HI-VL 21900 c/ml GI-side effects (nausea/diarrhea) but tolerable, hypercholesterinemia ( → Loperamide, Statin) HI-VL <50c/ml
K.S. ♀ *1970 10/06 increasingly abdominal pain, hospital admission → upper/lower endoscopy: gastritis CD4 466/µl (35%), HI-VL <50 c/ml 01/07 severe abdominal pain, patient stopped LPV/r CD4 425/µl (37%), HI-VL 83700 c/ml 02/07 diffuse burning sensation whole body after eating, eats only baby food ; MRI: no pathological result
Chemokine Receptor Tropism Study/Source Population N R5, % D/M, % X4, % ACTG 5211 [1] Experienced 391 49 47 4 SCOPE [2] Experienced 186 60 39.5 0.5 MOTIVATE 1 & 2 [3] Experienced 2560 56 41 3 TORO [4] Experienced 627 50 48 2 HOMER cohort [5] Naive 979 82 18 < 1 Chelsea & Naive 402 81 19 < 1 Westminster cohort [6] Demarest [7] Naive 299 88 12 0 Pfizer 1026 [3] Naive 1428 85 15 < 1 1. Wilkin T, et al. CROI 2006. Abstract 655. 2. Hunt, et al. J Infect Dis. 2006;194:926-930. 3. Coakley E, et al. Second Viral Entry Wkshp. Abstract 8. 4. Melby T, et al. EI 2005. 5. Brumme ZL, et al. J Infect Dis. 2005;192:466-474. 6. Moyle GJ, et al. J Infect Dis. 2005;191:866-872. 7. Demarest J, et al. ICAAC 2004. Abstract H-1136.
Association Between Tropism and baseline CD4+ Cell Count Cross-sectional Canadian study of 979 patients beginning triple therapy BL CD4+ R5 virus, % D/M or X4 virus, % cell count, cells/mm 3 > 500 93 7 350-499 91 9 200-349 91 9 100-199 72 28 50-99 74 26 25-49 69 31 < 25 46 54 Brumme ZL, et al. J Infect Dis. 2005;192:466-474.
Consequences for the clinician Demand for a tropism test which should be readily available and should produce reliable results as soon as possible in almost all patients Problems: patients with low viremia (esp. phenotypic tests) time lag between sampling and receiving the result/starting therapy minorities (clinical relevance?) Non-B-Subtypes?
MERIT Study: Trial Design Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC Randomization 1:1 Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3T Screening 0 96 wk 48 wk (6 weeks) First Primary patient visit analysis Nov 2004 Patient eligibility criteria: • ≥ 16 years of age • HIV-1 RNA ≥ 2,000 copies/mL • Treatment naive • No evidence of resistance to EFV, • R5 HIV-1 infection ZDV, or 3TC Patients stratified by: • HIV-1 RNA < and ≥ 100,000 copies/mL at screening • Geographic location: Northern Hemisphere and Southern Hemisphere experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative NRTI Saag M, et al. IAS 2007. Abstract WESS104.
Percentage of Patients with Undetectable HIV-1 RNA at Week 48 (Primary Endpoint) <400 copies/mL <50 copies/mL 100 –3.0* (–9.5 † ) –4.2* (–10.9 † ) 90 EFV + CBV 80 73.1 70.6 69.3 MVC + CBV 70 65.3 Patients (%) 60 50 40 30 20 10 0 N= 36 36 36 36 0 1 1 0 Includes all patients who received at least one dose of study medication, ITT *Difference (adjusted for randomization strata) † Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10% Saag M, et al. IAS 2007. Abstract WESS104.
MERIT: Maraviroc vs Efavirenz in Treatment-Naive Pts MVC failed to meet primary endpoint of noninferiority in HIV-1 RNA <50 copies/mL at Week 48 (lower 97.5% CI: -10.9%) MVC noninferior in HIV-1 RNA < 400 copies/mL MVC associated with higher CD4+ cell count increases Superior safety profile for MVC vs EFV
MERIT Substudy: Viral Suppression at Week 48 by Baseline Tropism Change in detected HIV-1 tropism from R5 at screening to D/M at BL and potentially adherence may Patients With VL < 50 c/mL at Week 48 (%) 100 explain some treatment failures on EFV 90 MVC MVC 80 69.3 3.5% of patients experienced 69.3 68.0 70 65.3 change in detected tropism 60 between screening and BL 54.6 50 50.0% of patients with R5 virus 40 at BL and without confirmed X4 30 at failure had plasma MVC concentrations below limit of 20 7.1 detection 10 n = 361 360 339 331 11 14 Tropism changes more common in 0 Overall Tropism at Tropism at patients with lower mean CD4+ cell Baseline Baseline count at screening as well as with (R5) (D/M) clade B or other/undetermined HIV-1 subtype vs clade C Heera J, et al. CROI 2008. Abstract 40LB.
VICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced Patients with R5-Virus Screening* Week 48 (Weeks 4-6) VCV 20 mg once daily + NRTI-, NNRTI-, OBR including RTV-boosted PI PI-experienced HIV-infected adults with ≥ 1 RT mutation, ≥ 1 primary PI mutation, VCV 30 mg once daily + CCR5 tropism, HIV-1 RNA OBR including RTV-boosted PI > 1000 copies/mL, and on stable antiretroviral therapy (N = 116) Placebo + OBR including RTV-boosted PI *Confirmation of tropism required before randomization. Zingman B, et al. CROI 2008. Abstract 39LB.
VICTOR-E1: Virological Efficacy at Week 48 VCV 30 mg VCV 20 mg Placebo 100 n = 39 n = 40 n = 35 0 90 Mean Change in HIV-1 RNA from BL -0.2 80 Patients With HIV-RNA-1 -0.4 < 50 copies/mL (%) 70 (log 10 copies/mL) -0.6 56 60 53 -0.8 50 -0.79 -1.0 40 -1.2 30 -1.4 20 14 -1.6 10 -1.8 -1.77 -1.75 0 Difference: Difference: -2.0 -0.96 VCV 30 mg VCV 20 mg Placebo -0.98 n = 26 n = 24 n = 9 P = .0017 P = .0028 No clinically significant differences in adverse events between VCV arms and placebo Zingman B, et al. CROI 2008. Abstract 39LB.
MOTIVATE: Maraviroc in Treatment-Experienced Patients with R5 Virus Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies Primary endpoint: mean change in HIV-1 RNA at Week 24 2:2:1 randomization; Planned interim analysis stratified by ENF use Week 24 Week 48 and VL < or � 100,000 c/mL Maraviroc 150 mg or 300 mg twice daily + OBR* (n = 426) Triple-class–resistant or triple-class– experienced patients with R5 virus and HIV-1 RNA ≥ 5000 copies/mL Maraviroc 150 mg or 300 mg once daily + OBR* (n = 414) ( MOTIVATE 1 : N = 601; Canada, US) ( MOTIVATE 2 : N = 475; Europe, Australia, US) Placebo + OBR (n = 209) *Patients receiving PI (except TPV) or delavirdine received 150 mg; all others received 300 mg. Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.
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