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

Clinical Use of Clinical Use of CCR5 Antagonists CCR5 Antagonists

• Dr. Bj
• Dr. Bjö

örn Jensen rn Jensen

Klinik f Klinik fü ür Gastroenterologie, Hepatologie und Infektiologie r Gastroenterologie, Hepatologie und Infektiologie Universit Universitä ätsklinikum D tsklinikum Dü üsseldorf sseldorf

Bonn, 24.04.2009 Bonn, 24.04.2009

Conclusion Conclusion – – Clinical Use Clinical Use

1st-line: perhaps in the future, but current regimes are good (at least regarding efficacy), wait for long-term data 2nd-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 3rd/4th 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,

• nly useful if other substance available

Special Situations: Post-exposure prophylaxis (R5!), PHI

Tropism Assays Tropism Assays – – Clinicial Aspects Clinicial Aspects

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 Tropism Testing – – Present Situation Present Situation

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

• r 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 When to use CCR-

• 5 Antagonists

5 Antagonists 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 2nd-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 Clinical experience -

• Tolerability

Tolerability

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 Conclusion – – Clinical Use Clinical Use

1st-line: perhaps in the future, but current regimes are good (at least regarding efficacy), wait for long-term data 2nd-line (3rd/4th-line etc.): interesting, but be sure to use at least two

• ther 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 3rd/4th 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,

• nly useful if other substance available

Special Situations: Post-exposure prophylaxis (R5!), PHI

Thank you! Thank you!

Maraviroc Maraviroc – – Clinical Use 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)

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 & Westminster cohort[6] Naive 402 81 19 < 1 Demarest[7] Naive 299 88 12 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.

Chemokine Receptor Tropism

Association Between Tropism and Association Between Tropism and baseline CD4+ Cell Count baseline CD4+ Cell Count BL CD4+ cell count, cells/mm3 R5 virus, % D/M or X4 virus, % > 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.

Cross-sectional Canadian study of 979 patients beginning triple therapy

VICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced Patients with R5-Virus

NRTI-, NNRTI-, PI-experienced HIV-infected adults with ≥ 1 RT mutation, ≥ 1 primary PI mutation, CCR5 tropism, HIV-1 RNA > 1000 copies/mL, and

• n stable antiretroviral

therapy (N = 116) VCV 30 mg once daily + OBR including RTV-boosted PI Placebo + OBR including RTV-boosted PI Week 48

*Confirmation of tropism required before randomization.

Screening* (Weeks 4-6) VCV 20 mg once daily + OBR including RTV-boosted PI Zingman B, et al. CROI 2008. Abstract 39LB.

Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.

MOTIVATE 1 and 2: HIV-1 RNA < 50 c/mL at Wk 24 by Active Drugs in OBR

Number of Active Drugs in OBR 10 20 30 40 50 60 70 80 90 100 35 51 56 44 130 134 59 88 104 64 132 121 3 18 29 9 43 43 19 52 53 55 61 58 1 2 ≥ 3 Patients (%) n =

Combined Analysis: MOTIVATE 1 and 2

Placebo + OBR MVC QD + OBR MVC BID + OBR

MOTIVATE 1 and 2: Side effects MOTIVATE 1 and 2: Side effects

Hardy D, et al. CROI 2008. Poster 792.

Randomization 1:1 MERIT Study: Trial Design MERIT Study: Trial Design

Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)* Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*

Primary analysis 48 wk 96 wk Screening (6 weeks)

Patients stratified by:

• HIV-1

RNA < and ≥100,000 copies/mL at screening

• Geographic location: Northern Hemisphere and Southern Hemisphere

Patient eligibility criteria:

• ≥16 years of age
• Treatment naive
• R5

HIV-1 infection

First patient visit Nov 2004

• HIV-1

RNA ≥2,000 copies/mL

• No evidence of resistance to EFV, ZDV, or 3TC

*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 ( 48 (Primary Primary Endpoint Endpoint) ) 10 20 30 40 50 60 70 80 90 100 361 360 361 360 73.1 70.6 69.3 65.3 Patients (%) N=

MVC + CBV EFV + CBV

<400 copies/mL <50 copies/mL

–3.0* (–9.5†) –4.2* (–10.9†)

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

Heera J, et al. CROI 2008. Abstract 40LB.

MERIT Substudy: Viral Suppression at Week 48 by Baseline Tropism

20 30 70 10 40 50 60 80 90 100 69.3 54.6 7.1 n = 11 14 68.0 339 331 Patients With VL < 50 c/mL at Week 48 (%) EFV MVC 69.3 65.3 Overall 361 360 Tropism at Baseline (R5) Tropism at Baseline (D/M)

• Change in detected HIV-1 tropism

from R5 at screening to D/M at BL and potentially adherence may explain some treatment failures on MVC

3.5% of patients experienced

change in detected tropism between screening and BL

50.0% of patients with R5 virus

at BL and without confirmed X4 at failure had plasma MVC concentrations below limit of detection

• Tropism changes more common in

patients with lower mean CD4+ cell count at screening as well as with clade B or other/undetermined HIV-1 subtype vs clade C

VICTOR-E1: Virological Efficacy at Week 48

Zingman B, et al. CROI 2008. Abstract 39LB. Mean Change in HIV-1 RNA from BL (log10 copies/mL)

• 1.77
• 0.79
• 2.0
• 1.8
• 1.0
• 0.8

VCV 30 mg n = 39 VCV 20 mg n = 40 Placebo n = 35

• 1.75

Difference:

• 0.96

P = .0028 Difference:

• 0.98

P = .0017

• 1.6
• 1.4
• 1.2
• 0.6
• 0.4
• 0.2

20 30 70 10 40 50 60 80 90 100

56 53 14

Patients With HIV-RNA-1 < 50 copies/mL (%) No clinically significant differences in adverse events between VCV arms and placebo VCV 30 mg n = 26 VCV 20 mg n = 24 Placebo n = 9

Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB. Triple-class–resistant or triple-class– experienced patients with R5 virus and HIV-1 RNA ≥ 5000 copies/mL (MOTIVATE 1: N = 601; Canada, US) (MOTIVATE 2: N = 475; Europe, Australia, US) Placebo + OBR (n = 209) Maraviroc 150 mg or 300 mg once daily + OBR* (n = 414) Maraviroc 150 mg or 300 mg twice daily + OBR* (n = 426) 2:2:1 randomization; stratified by ENF use and VL < or ≥ 100,000 c/mL Planned interim analysis Week 24 Week 48

• Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies
• Primary endpoint: mean change in HIV-1 RNA at Week 24

MOTIVATE: Maraviroc in Treatment-Experienced Patients with R5 Virus

*Patients receiving PI (except TPV) or delavirdine received 150 mg; all others received 300 mg.

• MVC + OBR associated with significantly greater viral suppression than

placebo + OBR in treatment-experienced patients

MOTIVATE 1 and 2: Combined Virologic and Immunologic Efficacy

Patient Outcome at Week 48 Placebo + OBR (n = 209) MVC QD + OBR (n = 414) MVC BID + OBR (n = 426) Median HIV-1 RNA change from BL, log10 copies/mL*

• 0.78
• 1.68*
• 1.84†

Mean CD4+ cell count change from baseline, cells/mm3 61 116 124

*Difference vs placebo: -0.89 (95% CI: -1.17 to -0.62).

†Difference vs placebo: -1.05 (95% CI: -1.33 to -0.78).

Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48

4 20 28 Patients with VL < 50 c/mL (%) 40 30 20 Time (Weeks) Placebo + OBR (n = 209) MVC BID + OBR (n = 426) MVC QD + OBR (n = 414) 16.7% 43.2%* 45.5%* 100 90 80 70 60 50 10 8 12 16 24 32 36 40 44 48 *P < .0001 vs placebo

Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1 and 2: MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48 Combined Virologic Efficacy at Week 48

26 59 58 10 32 35 10 20 30 40 50 60 70 80 90 100 Placebo MVC QD + OBR MVC BID + OBR Patients <50 c/mL (%) <100.000 copies/mL >100.000 copies/mL

Hardy D, et al. CROI 2008. Abstract 792.

Immunological Efficacy of CCR5 Immunological Efficacy of CCR5-

• Coreceptor

Coreceptor-

• Antagonists

Antagonists

• Meta-analysis of 37 arms from 16 clinical trials in treatment-

experienced patients (9 arms from 4 trials used CCR5 inhibitors): CCR5 inhibitor-use associated with greater increase in CD4+ cell count after controlling for baseline viral load and virologic response (+32 cells/mm3; 95% CI: 19-54)

• Redistribution of CD4 cells to the periphery by blocking CCR5 receptors

which serve as a homing receptor to lymphatic tissues ?

Wilkin T, et al. CROI 2008. Abstract 800.

CCR5 Antagonists: Safety issues CCR5 Antagonists: Safety issues Development of Aplaviroc discontinued due to severe liver toxicity ACTG 5211 (Phase-II Vicriviroc) with a higher incidence of cancer in patients treated with the active drug, though relationship with drug doubtful1 Postural hypotension was the dose-limiting AE for Maraviroc in Phase I-Study – only seen at rates higher than placebo for doses

• f ≥600 mg2
• 1. Gulick R, et al. IAS 2007. Abstract TUAB102.
• 2. McHale M, et al. IAS 2005. Oral TuOa0204.

MOTIVATE 1 and 2: Maraviroc Safe and Well Tolerated at Week 48 MOTIVATE 1 and 2: Maraviroc Safe and Well Tolerated at Week 48

Similar frequency of serious all-grade AEs, toxicity-driven discontinuations, laboratory abnormalities, AIDS-defining infections, and AIDS- or non-AIDS–defining malignancies among MVC vs placebo arms at Week 48 Most common AEs across study arms: diarrhea, nausea, fatigue, headache No deaths reported during the study or up to 28 days of stopping study drug were considered to be related to study medication.

Hardy D, et al. CROI 2008. Poster 792.