AREVIR 05.05.2011 CCR5 Antagonists In Clinical Practice Dr. Bjrn - - PowerPoint PPT Presentation

▶
arevir 05 05 2011
SMART_READER_LITE
LIVE PREVIEW

AREVIR 05.05.2011 CCR5 Antagonists In Clinical Practice Dr. Bjrn - - PowerPoint PPT Presentation

Apr 13, 2023 238 likes •525 views

AREVIR 05.05.2011 CCR5 Antagonists In Clinical Practice Dr. Bjrn Jensen Klinik fr Gastroenterologie, Hepatologie und Infektiologie Universittsklinikum Dsseldorf Klinikdirektor: Univ.-Prof. Dr. Dieter Hussinger Conclusion

slide-1
SLIDE 1

CCR5 Antagonists In Clinical Practice

  • Dr. Björn Jensen

Klinik für Gastroenterologie, Hepatologie und Infektiologie Universitätsklinikum Düsseldorf Klinikdirektor: Univ.-Prof. Dr. Dieter Häussinger

AREVIR 05.05.2011

slide-2
SLIDE 2

Conclusion – Clinical Use

  • 1st-line:

perhaps in the future, but current regimes are good (at least regarding efficacy), wait for long-term data

  • 2nd/3rd/4th…-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:

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

slide-3
SLIDE 3

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

  • f ART →

poor adherenz, 3 therapy interruptions (maximum 8 months)

slide-4
SLIDE 4

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

  • f 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

  • ptions
slide-5
SLIDE 5

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%)

slide-6
SLIDE 6

MOTIVATE 1 and 2: Side effects

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

slide-7
SLIDE 7

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

slide-8
SLIDE 8

Thank Thank You You !!! !!!

slide-9
SLIDE 9

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

slide-10
SLIDE 10

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

  • nly

baby food ; MRI: no pathological result

slide-11
SLIDE 11

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

slide-12
SLIDE 12

Association Between Tropism and 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

slide-13
SLIDE 13

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?
slide-14
SLIDE 14

Randomization 1:1

MERIT Study: Trial Design

Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3T 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

experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative NRTI Saag M, et al. IAS 2007. Abstract WESS104.

slide-15
SLIDE 15

Percentage of Patients with Undetectable HIV-1 RNA at Week 48 (Primary Endpoint)

10 20 30 40 50 60 70 80 90 100 36 1 36 36 1 36 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.

slide-16
SLIDE 16

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
slide-17
SLIDE 17

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

slide-18
SLIDE 18

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.

slide-19
SLIDE 19

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

slide-20
SLIDE 20

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.

slide-21
SLIDE 21
  • 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.

slide-22
SLIDE 22

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.

slide-23
SLIDE 23

MOTIVATE 1 and 2: 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.

slide-24
SLIDE 24

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

slide-25
SLIDE 25

Immunological Efficacy of CCR5-Coreceptor- 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.

slide-26
SLIDE 26

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 –

  • nly 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.
slide-27
SLIDE 27

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-

  • r 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.

slide-28
SLIDE 28

Maraviroc – Clinical Use

  • Only with at least two other active substances, especially with

substances with low genetic barrier

  • Substrate
  • f 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)