FARMACOS DE RECIENTE APROBACIÓN

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2 FARMACOS DE RECIENTE APROBACIÓN Raltegravir Maraviroc Etravirina ASPECTOS NOVEDOSOS:. -Uso en naïve -Eficacia -Tolerancia y toxicidad -Resitencias 2

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4 STARTMRK Percent of Patients with HIV RNA <50 copies/ml (95% CI) 100 Non Completer = Failure 86% Percent of Patients with HIV RNA <50 Copies/mL Non inferiority p< % Number of Contributing Patients Raltegravir 400 mg b.i.d. a Weeks Efavirenz 600 mg q.h.s. a Lennox J, et al. ICAAC Abstract H 896a a In combination with TDF/FTC 4

5 STARTMRK Time to Virologic Response (HIV RNA <50 copies/ml) a In combination with TDF/FTC

6 STARTMRK Resistance by Week 48 in Patients with Virologic Failure a RAL Failures vrna >400 copies/ml N = 12 VL Failures N = 27 RAL N = 39 EFV EFV Failures vrna >400 copies/ml N = 8 No known RAL resistance mutation N = 5 4 Sens to TDF/FTC, 1 not tested IN gene could not be amplified N = 3 No known EFV resistance mutation N = 3 3 Sens to TDF/FTC RT gene no data N = 2 Known RAL resistance mutation N = 4 3 Res to FTC, 1 not tested IN Mutations: N = 2 G140S+Q148H/R N = 1 Y143H+L74M+E92Q+T97A N = 1 Y143R Lennox J, et al. ICAAC Abstract H 896a Known EFV resistance mutation N = 3 1 Res to FTC a Virologic failure, Nonresponder: (1) HIV RNA >50 copies/ml at the time of discontinuation or (2) HIV RNA >50 copies/ml at Week 24 Virologic rebound: HIV RNA >50 copies/ml (on 2 consecutive measurements at least 1 week apart) after 6 initial response

7 STARTMRK 48 Week Safety Summary RAL group had significantly fewer drug related clinical adverse experiences (AEs) compared to EFV a Clinical AEs RAL 90.0% vs EFV 96.5%

8 STARTMRK CNS Adverse Events Accumulated Up to Week 8 RAL a EFV a P-value % with CNS Adverse Events

9 STARTMRK Change from Baseline in Fasting Serum Lipids Week 48 a In combination with TDF/FTC

10 STARTMRK Conclusions In treatment naïve patients given 48 weeks of TDF/FTC, the integrase inhibitor raltegravir: Had potent, durable antiviral efficacy that was statistically non inferior to efavirenz 86% (RAL) versus 82% (EFV) <50 copies/ml at Week 48 Achieved faster vrna suppression <50 copies/ml Had greater immunological effect than efavirenz, measured by increases in CD4+ cell counts: DIFERENCIA N.S A LA 96 S 189 (RAL) versus 163 (EFV) cells/mm 3 at Week 48 Was better tolerated than efavirenz Significantly fewer overall and drug related clinical adverse events Significantly lower percentages of patients with CNS adverse experiences Had minimal effects on serum lipids Lennox J, et al. ICAAC Abstract H 896a 10

11 STARTMRK: Does the initial change in VL mean anything? Patients with HIV RNA <50 c/ml Through 96 Weeks (Non Completer = Failure) Immunologic:

12 RAL VS EFV: PARAMETROS METABÓLICOS Y LIPODISTROFIA EN NAÏVE STARTMRK Protocol

13 SUBESTUDIO METABOLICO DEL STARTMRK DEXA Lipidos y glucosa Lipodistofia (DX como E.A.) N: 76 13

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15 AUMENTO DE GRASA EN TODOS LOS COMPARTIMENTOS SOLO DOS CASO DE LD EB RAMA EFV DADO EL PEQUEÑO NUMERO DE CASOS, SOLO 48 SEMANAS Y AL DIVERSIDAD DE LA POBLACIÓN: IMPOSIBLE APRECIAR CAMBIOS SIGNIFICATIVOS OBJETIVOS EN LA R.G. 15

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18 -A hyperinsulinaemic euglycaemic clamp -Fasting lipids and adiponectin -Prior to and following each treatment period. 18

19 CONCLUSIONES In healthy, male, HIV negative volunteers: -2 weeks of LPVr resulted in a 16.10% reduction in insulinsensitivity. -There were statistically significant increases in total cholesterol, LDL cholesterol, triglycerides and adiponectin. 2 weeks of RALwas not associated with any significant change in I.S., adiponectin or selected lipid parameters. 19

20 VENTAJAS: Eficacia al menos igual Descenso mas veloz CV Mejor tolerancia Escaso efectos en SNC Mejor perfil metabolíco No metabolizado por CYP 3A4 INCOVENIENTES Barrera genética baja (vs IP) Resitencias cruzadas(familia) Dosificación BID: EC III: QDMRK en marcha Sin experiencia a largo plazo: STARMRK 96s Precio IIb Protocolo 004: 144s 20

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22 The MERIT Study of Maraviroc in Antiretroviral-Naive Patients With R5 HIV-1: 96-Week Results Heera J, Ive P, Botes M, DeJesus E, Mayer H, Goodrich J, Clumeck N, Cooper D, Walmsley S, Craig C, Reeves J, van der Ryst E and Saag M 22

23 Time (weeks) EFV n= MVC n=

24 RAMA CON MVC: Significantly Greater Increases in Mean CD4+ at Weeks 48 and 96 MERIT ES CD4+ Cell Changes From Baseline (per mm 3 ) cells/mm 3 (95% CI 17, 65) 30 cells/mm 3 (95% CI 10, 51) 212* * 171* 144* Week 48 Week 96 EFV + CBV MVC + CBV MAYOR QUE CON OTRAS PAUTAS * Week 48 or 96 mean value adjusted for randomization strata Last observation carried forward; blinded therapy values only. Includes all patients with R5 virus at screening by enhanced 24 Trofile assay who received at least one dose of study medication

25 Malignancies at Week 96 Analysis includes all patients who received at least one dose of study medication Patients, n (%) EFV + CBV N=361 MERIT

26 Patients (%) Patients at Week 96 Whose Lipid Values On Treatment* Exceeded Cutpoints for Considering Lipid-Lowering Therapy 100 N = P < P < Total cholesterol 200 mg/dl ( 5.2 mmol/l) mg/dl ( 3.4 mmol/l) LDL cholesterol P < mg/dl ( 4.1 mmol/l) P > LDL, low density lipoprotein EFV + CBV MVC + CBV 16.0 Triglycerides 200 mg/dl ( 2.3 mmol/l) MERIT * At one or more on study assessments (fasting lipoprotein profiles were obtained for each patient at week 24 and week 48, or at early termination) As defined by NCEP guidelines 26 P values are for comparisons of proportions (Pearson s chi square test)

27 MERIT Study 96-Week Summary A similar percentage of patients on MVC and EFV achieved HIV 1 RNA < 50 copies/ml at Week 96 The lower bound of the one sided 97.5% CI for the 96 week treatment difference between MVC and EFV was above 10% for the < 50 copies/ml time to loss of virologic response analysis Analysis of percentage of patients with undetectable viremia over time continues to show only small differences between EFV and MVC through week 96 without further separation between the two treatment groups The difference in CD4+ cell count increases favoring MVC was maintained through week 96 In the MERIT ES reanalysis the percentage of patients discontinuing from the study through week 96 was similar in the MVC (33.1%) and EFV (34.0%) arms Fewer patients experienced malignancies in the MVC arm than in the EFV arm Maraviroc had a more favorable impact on lipids than EFV MERIT MERIT ES 27

28 MOTIVATE 1 and 2: Change in CD4+ Count at Time of Failure Mean Change in CD4+ Cell Count in Patients With Treatment Failure Placebo + OBR MVC QD + OBR MVC BID + OBR All treatment failures +14 (n = 97) In Patients With Tropism Results at Baseline and Failure R5 R5 R5 D/M or X4 +15 (n = 80) +67 (n = 4) +49 (n = 68) +61 (n = 18) +37 (n = 31) +71 (n = 77) +138 (n = 17) +56 (n = 32) ~ 8% of patients experienced shift in detected tropism between screening and baseline Among patients with treatment failure, shift in detected tropism more common among maraviroc vs placebo recipients Among maraviroc recipients with tropism results at time of failure, approximately 2/3 had dual/mixed or X4 virus detected Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.

29 EFECTO DEL MVC SOBRE LA R.I EN VOLUNTARIOS SANOS N: 16 voluntarios años. Estudio randomizado (1:1), cruzado, en que se administraba MVC o placebo durante dos semanas en cada grupo. Clamp hiperinsulinemico euglucémico se realizó, con las otras evaluaciones al inicio y final de cada periodo. ElE2ca MVno tuvo impacto significativico ela 29

30 VENTAJAS: Eficacia al menos igual Aumento significtivamente mayor de CD4 Mejor tolerancia Mejor perfil metabolíco INCOVENIENTES Necesidad de tropismo Dosificación BID Sin experiencia a largo plazo Precio Sustrato pero no modifica otros metab- del CY3A4 30

31 INTELENCE: USO CLÍNICO La barrera genética y otros datos del NN de segunda generación

32 RESCATE TRS PRIMER TAR CON NNITI

33 RESISTENCIAS TRAS EL PRIMER FRACASO GRUPTA ET AL, CLIN INFEC DIS. 2008;47:

34 Prevalencia de mutaciones a NN entre pacientes con resistencia a NN de primera generación ( ) La mutación K103N sigue siendo la más prevalente Seguida de la Y181C, G190A, V108I, K100I, Y188I. Llibre JM, et al. J Antimicrob Chemother

35 IMPORTANCIA DEL CAMBIO PRECOZ AIDS 2008

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37 Mutaciones para etravirina Factor de ponderación 2008 Factor de ponderación Mutaciones G190A, V179T, A98G, K101H, K101E, V179D, V90I V179F, G190S, V106I, E138A M230L, Y181C, L100I, K101P Y181I, Y181V

38 RESCATE TRAS MULTIPLES FRACASOS

39 DUET 1 Y 2 NUEVA GENERACIÓN DE NNITI: ETRAVIRINA SIMILAR EN BARERA GENETICA A LOS IP 39

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41 INTELENCE : un valor diferencial para la indetectabilidad CV <50 copias/ml semana 48 (ITT-TLOVR)

42 TRIO: DISEÑO DEL ESTUDIO +/- NRTIs and/or enfuvirtide (based on the physician s discretion) Primary endpoint: 24 week viral 42

43 TRIO : Proportion of patients with HIV RNA < 50 copies/ml at 24 weeks (missing = failure) 43

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46 COHORTE FRANCESA: PREVALENCIA DE RESISTENCIAS PRIMARIAS NAIVE Descamps D. 16TH CROI, # N=530: entre es del 10,6%, mayor que en 2001 (3,9%), y significativamente mayor para IP y NAN. Las cepas con mutaciones a dos familias han aumentado hasta el 2,6% en (0,6% en 2001).

47 16. Lalezari J, DeJesus E, Osiyemi O, et al. Pharmacokinetics of once daily etravirine without and with once daily darunavir/ritonavir in antiretroviralnaive HIV 1 infected adults. Program and abstracts of the 9th International Congress on Drug Therapy in HIV Infection; November 9 13, 2008; Glasgow, United Kingdom. Abstract O413 LA POSIBILIDAD DE QD: DATOS EN NAÏVE

48 INTELENCE: NUEVAS PERSPECTIVAS DE USO CLINICO: CONCLUSIONES

49 PRIMER NNITI DE 2º GENERACIÓN BARRERA GENÉTICA MAS SIMILAR A IPS RESCATE PRECOCES DE FRACASOS CON NNITI GRAN EFICACIA EN FRACASOS MULTIPLES ACOMPAÑADO DE DRV CON UN FÁRMACO DE NUEVA DIANA FUTUROS NUEVAS INDICACIONES: TOXICIDAD NN RESITENCIA PRIMARIA EN NAIVE

50 AUNQUE LA ESPERANZA DE VIDA SE HA INCREMENTADO, TODAVIA ES MENOR QUE LA DE LA POBLACIÓN N DE REFERENCIA 50

51 MRC, RAL, ETV EN LA CLÍNICA DIARIA: CONCLUSIONES RAL Y MVC: POSIBLE USO EN NAÏVE SELECCIONADOS: VENTAJAS ADICIONALES? Control rápido de CV Aumento de CD4 Perfil metabolico No afectan el SNC No afectan metadona CAMBIOS: ETV: CAMBIO PRECOZ, K103N CAMBIO POR TOXICIDAD PREVENCION DEL RCV PREVENCIÓN DE LA LIPODISTROFIA INTERACCIONES BIEN ESTUDIADAS

52 Factores a tener en cuenta en TAR eficaz a medio y largo plazo EFICACIA CONVENIENCIA RECUPERACIÓN INMUNE TOXICIDAD INTERACCIONES RCV LIPODISTOFIA OTRAS COMORBILIDADES 52

53 FUTURO: TAR A MEDIDA 53

54 INDIVIDUALIZACIÓN 54

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56 GRACIAS POR VUESTRA ATENCIÓN 56