1 / 25

Key Study Results in PI Monotherapy

Key Study Results in PI Monotherapy. Dr. Jose R Arribas HIV UNIT. OK04 trial design. Visits : Screening , Baseline , Week 4 and 12, then every 12 weeks up to Week 96. Arribas JR. et al ., JAIDS 2009 OK04. Time to HIV-1 RNA > 50 copies/mL (ITT M = F, Reinduction = F)*. 77.6%.

lalasa
Download Presentation

Key Study Results in PI Monotherapy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Key StudyResults in PI Monotherapy Dr. Jose R ArribasHIV UNIT

  2. OK04 trial design Visits: Screening, Baseline, Week 4 and 12, thenevery 12 weeksup toWeek 96 Arribas JR. et al., JAIDS 2009OK04

  3. Time to HIV-1 RNA > 50 copies/mL (ITT M = F, Reinduction = F)* 77.6% 77% % P=0.865; Log rank * Patients in the monotherapy arm who reached and maintained < 50 c/mL after resuming baseline nucleosides are considered as failures (n = 10) Arribas JR. et al., JAIDS 2009OK04

  4. Proportion without therapeutic failure at Week 96* - 9%; upper-limit 95%CI: 1.2%. * Patients in the monotherapy arm who reached and maintained < 50 c/mL after resuming baseline nucleosides are not considered as failures (n = 10) Arribas JR. et al., JAIDS 2009OK04

  5. Genotypic testing through Week 96 *All patients with HIV-1 RNA > 500 copies/mL analyzed (blips > 500 copies/mL included)

  6. MONET - Trial Design Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified) No prior use of darunavir (DRV) HIV RNA <50 copies/mL for at least 6 months, No history of virological failure DRV/r 800/100 mg OD + 2 NRTI (re-optimised at baseline) n = 129 Follow-up phase 96 weeks 256 subjects No run-in period DRV/r 800/100 mg OD n = 127 Follow-up phase 96 weeks 96 wks BL SC 30 days 4, 12, 24, 36, 48 weeks • Primary Endpoint:HIV RNA< 50 at week 48 (TLOVR). Per Protocol, Switch = Failure • 2 consecutive HIV RNA > 50 copies/mL (Roche Amplicor HIV-1 Monitor assay 1.5) • Stopping DRV/r • Starting NRTIs in the monotherapy arm • Stopping NRTIs in the triple therapy arm (switches in NRTIs were permitted at any time). J. Arribaset al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB

  7. MONET: Baseline Characteristics (ITT) Age, years (median, range) Male (%) Caucasian (%) 43 (24-72) 83% 90% 43 (25-67) 78% 92% 579 12% 6.4 (4.0) 57% 43% 48% 28% 0 15 (12%) 12 (9%) 571 14% 7.4 (4.2) 56% 44% 35% 23% 0 24 (19%) 20 (16%) Disease characteristics CD4 count (median (range), cells/uL) CD4 <350 cells/uL (%) Duration of prior ARVs, years (mean, sd) Use of PI at screening (%) Use of NNRTI at screening (%) On their first NRTI combination PI naïve Hep B Surface Antigen, positive, n (%) Hep C Antibody, positive, n (%) History of IV Drug use DRV/r +2NRTI (n=129) DRV/r (n=127) Multivariate analysis at Week 48 showed that HCV co-infection was highly predictive of response in the primary endpoint. Riegeret al. WAC July 2010, Vienna [abstr TBLBB209]

  8. MONET: statistical methods for HIV RNA analysis Main efficacy endpoint: TLOVR, switch equals failure analysis If a patient shows a confirmed elevation in HIV RNA >50 copies/mL at two visits, this is a failure, even if the HIV RNA is then suppressed <50 copies/mL at Week 96. Stoping DRV/r in either arm, or adding NRTIs in the monotherapy arm is also a failure. Missing data is failure. Secondary endpoint: Switch included analysis This analysis only includes the HIV RNA levels at Week 96. If HIV RNA is re-suppressed at Week 96 following an earlier elevation, this is counted as success. Changes in treatment are permitted. Missing data is failure. Riegeret al. WAC July 2010, Vienna [abstr TBLBB209]

  9. MONET: Primary Efficacy Analysis:HIV RNA <50 copies/mL at Week 48, TLOVR, S = F Per Protocol analysis (PP) Intent to Treat analysis (ITT) Primary analysis • 1.6%; lower limit 95%CI: -10.1% • 1%; lower limit 95%CI: -9.9% 100 87.8% 86.2% 85.3% 84.3% 90 80 HIV RNA <50 by Week 48 (%) 70 60 50 40 30 20 10 0 DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT) N=129 N=123 N=123 N=127 Table EFF 4-5 J. Arribas et al, AIDS 2010

  10. MONET Week 144 analysis: HIV RNA, TLOVR, ITT Population Switch=failure Switch NRTI d/c - other d/c - AE VF HIV RNA <50 HIV RNA <50 Percentage of patients difference=-5.9%, 95% C.I.-16.9%, +5.1%).

  11. MONET Week 144 analysis:Major IAS-USA Genotypic mutations when HIV RNA >50 copies/mL Only 1 patient per arm had any evidence of genotypic resistance

  12. MONET Week 144 analysis:Outcome of HIV RNA elevations in DRV/r arm (21 patients)

  13. MONET Week 144 analysis:Outcome of HIV RNA elevations in DRV/r arm (21 patients) 11

  14. MONET Week 144 analysis:Outcome of HIV RNA elevations in DRV/r arm (21 patients) 7 3

  15. MONET Week 144 analysis:Outcome of discontinuations in DRV/r arm (18 patients)

  16. MONET Week 144 analysis:Outcome of discontinuations in DRV/r arm (18 patients)

  17. Patient PL0000520Treatment arm: DRV/r Week 96 Endpoint ARV treatment started: 2002 Prior antiretrovirals taken: ABC/3TC, EFV Nadir CD4 count: 125 Hepatitis C: Antibody positive HCV RNA PCR: no data • Resistance when HIV RNA above 50 copies/mL: • Week 24: fully sensitive to NRTI, NNRTI and PI • Week 26: not amplifiable • Week 36: not amplifiable • Week 40: fully sensitive to NRTI, NNRTI and PI • DRV plasma PK levels (ng/mL): • Week 4: 4430 • Week 12: 2140 • Week 24: 1570 • Week 36: 3470 • Week 48: 2800 • Week 96: 3370 • NRTI intensification: Yes - with ABC/3TC after Week 36 Intensified onto ABC/3TC/DRV/r FAILURE by TLOVR, switch equals failure analysis NOT FAILURE by Switch included analysis HIV RNA (copies/mL) Double HIV RNA blip Time in MONET trial - weeks

  18. MONET Week 144 analysis: HIV RNA <50 copies/mL, Switch included analysis, and observed failure (OF) Switch included analysis (PP) Observed Failure analysis (PP) TLOVR HIV RNA <50 by Week 144 (%) n=121 n=122 n=121 n=122

  19. MONET Week 144 analysis: delta and 95% c.i.*(full multivariate analysis) HIV RNA <50 at Wk 144 DRV/r vs DRV/r +2NRTI Difference between arms Lower and upper 95% C.I. Analysis -14.6% +7.3% PP, HIV RNA <50, TLOVR, switch=failure 74.5% vs 78.2% +7.1% -15.1% Which is more clinically relevant? ITT, HIV RNA <50, TLOVR, switch=failure 71.3% vs 75.3% -7.19% +10.28% PP, HIV RNA <50 Switch included 86.72% vs 85.18% -12.9% +3.4% Observed failure TLOVR HIV RNA <50 85.5% vs 90.3% + + + DRV/r + 2NRTI better DRV/r mono better * Multivariate logistic regression, adjusting for previous PI use and factors from exploratory multivariate analysis

  20. MONET 144 weeks: laboratory abnormalities • Differences in lipid parameters likely reflect the fact that some patients in the DRV/r + 2 NRTIs arm were taking TDF, which may have a direct lipid-lowering effect *Of the 16 patients with elevated total cholesterol in the DRV/r arm, 10 were at a single visit Arribas JR, et al. IAS 2011. Abstract MOPE216.

  21. MONET: DRV/r MT does not increase IL-6 or hs-CRP levels • Levels of the inflammatory markers, interleukin-6 (IL-6) and C-reactive protein (CRP), are elevated in HIV-infection. • High levels of IL-6 (>3 pg/mL) and CRP (>5 mg/L) have been associated with more rapid progression to AIDS and death1 p=n.s. for both comparisons, chi-square test • There was no difference between the treatment arms in IL-6 or hs-CRP levels at the Week 144 visit • Rodger A, et al. JID 2009, 200: 973-983. Arribas JR, et al .EACS, Belgrade, Serbia, October 2011. Abstract PS 10/2.

  22. MONOI Design Valantin MA et al. Poster 534 CROI

  23. MONOI: Predictors of Response Marcelin AG, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.

  24. A PI/r switching strategy is suggested as an option in the EACS guidelines ‘PI/r monotherapy with bid LPV/r or qd DRV/r might represent an option in patients with intolerance to NRTI or for treatment simplification. Such a strategy only applies to patients without history of failure on prior PI-based therapy and who have had viral loads <50 copies/mL in at least the past 6 months’ European AIDS Clinical Society (EACS) guidelines, 2011. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/eacsguidelines-6.pdf.

More Related