Bonn, 24.04.2009 Bonn, 24.04.2009 Clinical Use of Clinical Use of - PowerPoint PPT Presentation

Bonn, 24.04.2009 Bonn, 24.04.2009 Clinical Use of Clinical Use of CCR5 Antagonists CCR5 Antagonists Dr. Bjö örn Jensen rn Jensen Dr. Bj Klinik f Klinik fü ür Gastroenterologie, Hepatologie und Infektiologie r Gastroenterologie, Hepatologie und Infektiologie Universitä Universit ätsklinikum D tsklinikum Dü üsseldorf sseldorf

Conclusion – – Clinical Use Clinical Use Conclusion � 1 st -line: perhaps in the future, but current regimes are good (at least regarding efficacy), wait for long-term data � 2 nd -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: when 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 � Special Situations: Post-exposure prophylaxis (R5!), PHI

Tropism Assays – – Clinicial Aspects Clinicial Aspects Tropism Assays � 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?

Tropism Testing – – Present Situation Present Situation Tropism Testing � Tropism Testing is used in routine clinical practice � Most therapeutic decisions are based on genotypic tropism assays (geno2pheno[ coreceptor ]), because - low viral loads/suppressed viral loads at the time of testing (switch/add-on because of persistent low-level viremia with or without detectable resistance mutations or side effects) - smaller time lag between sampling and receiving the result � Only rare cases with different results of the genotypic assay (geno2pheno[ coreceptor ]) and the phenotypic assay (Trofile) in our routine clinical use

When to test patients ? When to test patients ? � If you consider to use maraviroc – therefore What kind of patient is treated with Maraviroc ? What kind of patient is treated with Maraviroc ? � Salvage � 2nd/3rd-line situations with limited resistance (to bolster the following regimen) – higher proportion of R5 than in (deep) salvage � Intensifying non-suppressive regimens without detectable resistence (Double-PI, 2NRTI/PI) � Multiple intolerances � Problems with drug interactions („interaction-sparing“ regimens) � Suboptimal compliance – lower risk of resistance?

When to use CCR- -5 Antagonists 5 Antagonists When to use CCR Present Situation Present Situation � Over 40 patients are treated with Maraviroc in our Department � Most patients with viral load under the level of detection/good immunological effect � Some patients with intermittent low-level viremia/slow treatment response esp. in the patients with „multiple intolerances“ (compliance?) esp. if combined only with 2 NRTI´s � One clear therapy failure (switch) in 2 nd -line regime (Patient with NRTI/PI-primary resistance) � 1 Patient with switch to X4-using virus between testing and start of treatment (even with very good CD4-cells and subtype C) – but therapy did not fail

MOTIVATE 1 and 2: Side effects MOTIVATE 1 and 2: Side effects Hardy D, et al. CROI 2008. Poster 792.

Clinical experience - - Tolerability Tolerability Clinical experience � No major side effects/lab abnormalities � Some patients with obstipation � 1 patient with arthralgia (als RAL/ETR as new substances) – but transient � No treatment changes/interruptions because of side effects up to now

Conclusion – – Clinical Use Clinical Use Conclusion � 1 st -line: perhaps in the future, but current regimes are good (at least regarding efficacy), wait for long-term data � 2 nd -line (3 rd /4 th -line etc.): 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: when 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 � Special Situations: Post-exposure prophylaxis (R5!), PHI

Thank you! Thank you!

Maraviroc – – Clinical Use Maraviroc Clinical Use � Only with at least two other active substances, especially with substances with low genetic barrier � Substrate of CYP3A4/P-glycoprotein � 150 mg BID when combined with potent CYP3A inhibitors like boosted PI´s (other than Tipranavir/r and Fosamprenavir/r) � 300 mg BID with Tipranavir/r, Fosamprenavir/r, Nevirapine or no PI/NNRTI � 600 mg BID with potent CYP3A inducers like Efavirenz, Etravirine � 150 mg BID when dosed with both CYP3A4 inhibitor(s) and inducer(s)

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 Association Between Tropism and baseline CD4+ Cell Count 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.

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.

MOTIVATE 1 and 2: HIV-1 RNA < 50 c/mL at Wk 24 by Active Drugs in OBR Combined Analysis: MOTIVATE 1 and 2 100 90 Placebo + OBR MVC QD + OBR MVC BID + OBR 80 70 61 Patients (%) 58 55 60 53 52 50 43 43 40 29 30 19 18 20 9 10 3 0 n = 35 51 56 44 130 134 59 104 64 132 121 88 Number of Active Drugs in OBR 0 1 2 ≥ 3 Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.

MOTIVATE 1 and 2: Side effects MOTIVATE 1 and 2: Side effects Hardy D, et al. CROI 2008. Poster 792.

MERIT Study: Trial Design MERIT Study: Trial Design Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)* Randomization 1:1 Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)* 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, ZDV, or 3TC • R5 HIV-1 infection Patients stratified by: • HIV-1 RNA < and ≥ 100,000 copies/mL at screening • Geographic location: Northern Hemisphere and Southern Hemisphere *Patients 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 Percentage of Patients with Undetectable HIV HIV- -1 RNA 1 RNA at at Week Week 48 (Primary 48 ( Primary Endpoint) 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= 360 361 361 360 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