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MONOTERAPIA CON DARUNAVIR/RITONAVIR

MONOTERAPIA CON DARUNAVIR/RITONAVIR. Dr. Jose R Arribas UNIDAD VIH. Conflicto de intereses. He recibido becas de investigación y pagos como conferenciante y asesor de: Janssen Cilag Tibotec Abbott Bristol-Myers

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MONOTERAPIA CON DARUNAVIR/RITONAVIR

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  1. MONOTERAPIA CON DARUNAVIR/RITONAVIR Dr. Jose R Arribas UNIDAD VIH

  2. Conflicto de intereses • He recibido becas de investigación y pagos como conferenciante y asesor de: • Janssen Cilag • Tibotec • Abbott • Bristol-Myers • La presentación revisa la utilización de inhibidores de la proteasa potenciados con ritonavir (Lopinavir/r, Atazanavir/r, Darunavir/r) en pautas no recogidas en ficha técnica.

  3. Monoterapia con IPs

  4. 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% 12 12 24 24 36 36 48 48 0 16 32 48 64 80 96 0 0 16 16 32 32 48 48 Week Week Week Discontinued On study, HIV RNA >400 c/mL On study, HIV RNA 50–400 c/mL On study, HIV RNA <50 c/mL Monotherapy with LPV/r Study 613 – LPV/r Induction/maintenance OK – LPV/r Simplification MONARK – LPV/r Initial therapy

  5. A randomized multicenter study to compare the efficacy of a monotherapy of darunavir to a triple therapy with 2 nucleosides analogues combined to darunavir/r in HIV infected patients with full viral suppression. MONOI ANRS 136 C Katlama, MA Valantin, M Algarte-Genin, C Duvivier, S Lambert-Niclot, PM Girard, JM Molina, B Hosten, S Pakianather, G Peytavin, AG Marcelin, P Flandre. Abstract WELBB102

  6. MONOI Study Design 1 • Multicenter open label randomized study Randomisation 1:1 DRV/r (600/100 mg bid) Introduction DRV/r DRV/r (600/100 mg bid)+ 2 NRTIs W96 W-8 W48 W-10 W-4 Phase I Long-term follow-up Phase II Primary Endpoint • Main inclusion criteria • cART ≥ 18 months • CD4 count ≥ 200 cells/mm3 • HIV RNA <400 copies/ml in the last 18 months and <50 copies/ml at entry • No history of PI failure and naïve to darunavir

  7. MONOI Study Design 2 • Primary objective To demonstrate non-inferiority of DRV/r monotheray versus 2 NRTIs + DRV/r in patients with viral suppression ( per protocol population ) • Primary endpoint : virological success until W48 Virological failure is defined as • 2 consecutive HIV-1 RNA > 400 copies/ml within 2 weeks • Any ART modification or study withdrawal • Study power Power = 80% Non-inferiority margin of 10% ( 90% CI ) assuming success rates in both arms at W48 of 90% • ITT population All patients receiving drug at D0 (ITT exposed) • Per protocol (PP) populationexcluded Patients who withdrew (n=6) or discontinued Rx without VF or SAE (n=10) Patients who did not fulfill the inclusion criteria (n=5)

  8. DRV/r DRV/r + NRTIs MONOI Primary Endpoint W48

  9. MONOI Reasons for failure

  10. Virological Failures in DRV/r arm • HIV RNA and DRV PK data at time of failure pt # 1 : W8 2722 cp/mlLow C24h 1120 ng/ml pt # 2 : W24 411cp/ml Adequate C24h 3480 ng/ml pt # 3 : W32 484.569 cp/mlTreatment discontinuation • No new DRV resistance mutations in the 3 patients • In all 3 patients, intensification with 2 NRTIs added to DRV/r, led to HIV RNA <50 copies/ml

  11. Proportion of patients with HIV RNA < 50 copies /ml : ITT population 92.0% 86.6% % Patients with HIV RNA < 50 cp/ml

  12. 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. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB

  13. 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% 2 (1.6%) 14 (11.2%) 571 14% 7.4 (4.2) 56% 44% 35% 23% 1 (0.8%) 24 (19.0%) Disease characteristics CD4 count (median, 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 (%) DRV/r + 2NRTI (n=129) DRV/r (n=127)

  14. 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, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB

  15. MONET: Patient outcomes in DRV/r monotherapy (ITT) Baseline DRV/r monotherapy: n=127 Missing data n=0 HIV RNA>50 x2: n=11 (TLOVR) d/c or changed treatment, n=9 Treatment period HIV RNA<50: 107 HIV RNA<50: 10 HIV RNA>50: 1 HIV RNA<50: 7 HIV RNA>50: 2 Last visit HIV RNA<50: 97.6% 124/127

  16. Tamaño muestral Arribas JR. J Acquir Immune Defic Syndr 2005;40:280–287. Pulido F et al. AIDS. 2008 Jan 11;22(2):F1-9. Nunes EP. et al., XVI IAC,Toronto, Canada, 2006; #TUAB0102. Wilkin TJ et al. The Journal of Infectious Diseases 2009 Feb 1. Kalström O. J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):417-22. Pulido et al. GESIDA 2009 PO-69. Katlama et al. 5th IAS. #WELBB102. Arribas et al . AIDS (in press)

  17. Endpoints primarios

  18. Conclusiones

  19. 100 94 89.8 90 80 70 60 50 Percent without failure 40 30 OK 20 Triple 10 0 48 weeks OK04 Primary endpoint:Proportion without therapeutic failure at Week 48* Week 48 difference (Triple - OK) and 95% CI: - 4.2% (-11.8% to 3.4 %) * Patients in the monotherapy arm who reached and maintained < 50 c/mL after resuming baseline nucleosides are not considered as failures (n = 4) Pulido F et al. AIDS. 2008 Jan 11;22(2):F1-9.

  20. Sensitivity analysis of virological outcomes at 48 weeks. OK04. Response rate MT vs T Difference between treatment arms 95% confidence intervals Analysis -12% +12% 0% -5.7% +3.9% -15.3% < 50 HIV RNA copies/mL (TLOVR) 82.5% vs 88.2% -1.8% +7.3% -10.9% < 500 HIV RNA copies/mL (TLOVR) 86.4% vs 88.2% -8.2% -15.5% -0.8% < 50 HIV RNA copies/mL (OT) 88.5% vs 96.7% -4% +1.4% -10.4% < 500 HIV RNA copies/mL (OT) 92.7% vs 96.7% Lopinavir + 2 nucs better LPV/r Monotherapy better Pulido F et al. AIDS. 2008 Jan 11;22(2):F1-9.

  21. MONET trial: sensitivity analyses Difference in 48 week HIV RNA response rate between DRV/r mono and DRV/r + 2NRTI arms (95% confidence intervals) Analysis -12% 0% -1.8% -7.0% +3.5% PP, HIV RNA <200, TLOVR, switch equals failure 94.8% vs 96.6% -1.6% +4.2% -7.4% ITT, HIV RNA <50, TLOVR, switch included(S  F) 93.5% vs 95.1% -9.5% -3.2% +3.1% Observed HIV RNA <50 91.3% vs 94.6% -0.8% +2.6% -4.2% Observed HIV RNA <200 97.6% vs 98.4% DRV/r + 2NRTI better DRV/r + 2NRTI better

  22. Conclusiones • Darunavir/ritonavir es el primer IP potenciado que usado como monoterapia muetra una eficacia no inferior comparado a la triple terapia para el mantenimiento de la supresión virológica.

  23. Pulido F et al. Antivir Ther. 2009;14(2):195-201.

  24. Pharmacokinetic Considerations for Approved and Investigational Once-daily NRTIs Investigational Approved Approved Approved Approved QD as QD or BID as QD or BID as QD as QD 50 45 40 35 30 Hours 25 24 hours 20 ** * 15 12 hours 10 ** 5 0 ZDV d4T ABC 3TC ddI FTC TDF Indicates range where available Serum half-life Intracellular half-life * Piliero, et al. 43rd ICAAC, Chicago, 2003. ** Anderson, et al. AIDS 2003; 17(15):2159-2168. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64

  25. ARTEMIS: percentage of patients with HIV-1 RNA <50 copies/mL at Week 96 by adherence p=0.3312 p<0.0001 82%(n=269) 78%(n=252) 76%(n=55) 53%(n=70) Patients with <50 copies/mL at Week 96 Adherent Sub-optimally Adherent Sub-optimally adherent adherent Darunavir/r LPV/r Note: adherence based on average % adherence Week 4 through Week 96 Nelson M, et al. 16th CROI 2009. Abstract 575

  26. *Over 12-hour dosing interval; ‡HIV-infected patients and healthy volunteers following light meal, mean; §Healthy volunteers following light meal, mean; ¶HIV-infected patients following light meal, mean

  27. Potencial Inhibitorio Instantáneo Shen L et al. Nat Med. 2008 Jul;14(7):762-6.

  28. MONET: Drug resistance Genotypic results DRV/r + 2NRTI N=129 DRV/r mono N=127 Patients with at least 1 successful genotype 13 22 No primary PI, DRV or NRTI mutations 21/22 (96%) 12/13 (92%) M184V 1 0 Primary IAS-USA PI mutations 1 1 DRV mutations 0 1 1 patient per arm had any evidence of genotypic resistance No patients had phenotypic resistance to DRV J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB

  29. Darunavir en LCR Yilmaz A. AIDS Research And Human Retroviruses. Volume 25, Number 4, 2009 Letendre S. ICAAC 2009. Poster #45

  30. Grade 1-4 Nervous System Adverse Events MONET DRV/r + 2NRTI N=129 DRV/r N=127 Total Areflexia Burning sensation Carotid artery stenosis Disturbance in attention 21 (16.3%) 1 1 0 1 20 (15.7%) 0 0 1 0 Dizziness Dysgeusia Headache Hypoasthaesia 3 1 9 1 1 1 10 2 Intracranial hypotension Nervous system disorder Parasthaesia Post herpetic neuralgia 0 1 0 0 1 0 2 1 Radiculitis Sciatica 2 1 0 0 Syncope Tremor 0 1 2 0 Trigeminal neuralgia 0 1 Data on file.

  31. Grade 1-4 Psychiatric Adverse Events DRV/r + 2NRTI N=129 DRV/r N=127 Total Anxiety disorder Apathy Depression Drug dependence 12 (9.3%) 1 0 3 2 12 (9.4%) 0 1 7 0 Insomnia Libido decreased Nightmare Obsessive-compulsive disorder 3 1 1 0 0 1 0 1 Psychotic disorder Sleep disorder Stress 0 5 1 1 4 0 Data on file.

  32. SAVE $1000 a month!! Arribas et al. TUAB106-LB

  33. Annual French Costs of ARV’s Annual French cost per person €12900 €12820 €10431 €6400

  34. MONOTERAPIA CON DARUNAVIR/RITONAVIR • En pacientes con supresión virológica mantenida, una pauta simple QD con Darunavir/ritonavir (800/100) usada en monoterapia ha demostrado en dos estudios la no inferioridad frente a la continuacion de una pauta triple basada en IPs o NNRTIs • El beneficio económico de esta pauta es importante • Otro tipo de beneficios (metabólicos, distribución grasa, preservación de opicones futuras de tratamiento) están aún por demostrar.

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