NOVEDADES EN EL TRATAMIENTO ANTIRRETROVIRAL 2011

Transcripción

1 NOVEDADES EN EL TRATAMIENTO ANTIRRETROVIRAL 2011 Daniel Podzamczer Unitat VIH. Servei de Malalties Infeccioses Hospital Universitari de Bellvitge L Hospitalet. Barcelona

2 Agenda Cuando se inicia el TAR? Con que pautas se inicia? Nuevos fármacos Nuevas estrategias en el uso de TAR

3 FÁRMACOS ANTIRRETROVIRALES ANÁLOGOS DE NUCLEÓSIDOS/ NUCLEÓTIDOS (INH. TI) ZDV ddi 3TC FTC d4t ABC TDF ZDV/3TC ZDV/3TC/ABC ABC/3TC TDF/FTC INHIB. NO NUCLEÓS. DE LA TI EFAVIRENZ NEVIRAPINA ETRAVIRINA RILPIVIRINA INHIBIDORES DE PROTEASA ritonavir SAQUINAVIR INDINAVIR NELFINAVIR LOPINAVIR/rtv ATAZANAVIR FOSAMPRENAVIR TIPRANAVIR DARUNAVIR INHIBIDORES DE LA ENTRADA ENFUVIRTIDE MARAVIROC (CCR5) INHIB. DE LA INTEGRASA RALTEGRAVIR

4 Principales guías de TAR Disponible en : Consultado septiembre Hammer S. et al JAMA. 2008;300(5):

5

6 CUANDO INICIAR EL TAR?

7 Guidelines for Initiating ART in Asymptomatic Patients: Panel CD4+ Cell Count, cells/mm³ US DHHS June 1998 < 500 February 2001 < 350 April 2005 < 200 International AIDS Society-USA Panel July 1998 Any January 2000 < 500 July British HIV Association (BHIVA) June 1998 > 350 July July 2005 < 200

8 Mean CD4+ Cell Count (cells/mm 3 ) Likelihood of Achieving Normal CD4+ Cell Count Depends on BL Level Johns Hopkins HIV Clinical Cohort ATHENA National Cohort BL CD4+ Cell Count 1000 > < Years on HAART Moore RD, et al. Clin Infect Dis. 2007;44: Gras L, et al. J Acquir Immune Defic Syndr. 2007;45: BL CD4+ Cell Count > < Weeks From Starting HAART

9 Association Between Current CD4+ Cell Count & Non-AIDS Complications Study Lower Current CD4+ Cell Count Significantly Associated With Increased Risk? Non-AIDS malignanci es Renal disease/ death CVD events/ death Liver disease/ death FIRST Yes Yes Trend, NS No D:A:D Yes Yes Trend, NS Yes CASCADE Yes NA Yes Yes SMART Trend, NS Trend, NS Trend, NS Yes Phillips A, et al. CROI Abstract 8.

10 July 15, 2010 P.inclusión: CD4<350 CD4<200

11 Survival after ART initiated at different CD4 count levels between Muerte SIDA/Muerte The HIV-CAUSAL Collaboration, Ann Intern Med 2011

12 NA Accord. Effect of early versus deferred antiretroviral therapy for HIV on survival Kitahata M. N Eng J Med 2009; 360

13 START Design HIV-infected adults, ART-naive with CD4+ cell counts > 500 cells/mm 3 Early ART Group Immediately initiate ART N=2,000 Deferred ART Group Defer ART until CD4+ <350 cells/mm 3 or symptoms develop N=2,000 Primary endpoint: Serious AIDS & serious non-aids disease (375) Current Status: 1600 randomised; randomisation finished < 2012 and study < Substudies assessing various organ dysfunction incl. arteries, neuro-system & lungs. INSIGHT study group and collaborator

14 HIV/AIDS Highlights From Rome clinicaloptions.com/hiv HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Delayed Arm: 27 P <.001 Immediate Arm: 1 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression cortesía de JM Gatell Cohen MS, et al. N Engl J Med. 2011; 365:

15 RECOMENDACIONES DE INICIO DE TAR 2011 DHHS EACS GESIDA CD4<350 R R R CD R C(R) 1 R 2 CD4 >500 C 3 D(R/C) 4 D(C) 5 1 R = Nefropatía, TNC, L.Hodgkin, HPV cáncer; C = VHB, VHC 2 Excepto CD4 estable, carga viral baja, poca predisposición del paciente 3 50% del panel = recomendar; 50% = diferir 4 R/C = similar a C= en VHC; VHB en tratamiento; CV > ; CD4 < 14%; > 55 años ; RCV ; nefropatía VIH ; parejas discordantes con alto riesgo de transmisión DHHS octubre 2011; EACS octubre 2011; GESIDA enero 2011

16 Evolución del retraso diagnóstico en los nuevos diagnósticos de infección por VIH. Cataluña, Nous diagnòstics VIH N ,3 64,0 61,1 44,0 45,9 44, ,9 35, ,1 32, ,3 35, ,0 51,6 32,8 32, % <200(N) (N) <200(%) <350(%) Gallois A, Esteve A, y Grupo de estudio Piscis

17 CON QUÉ INICIAR EL TAR?

18 FÁRMACOS ANTIRRETROVIRALES ANÁLOGOS DE NUCLEÓSIDOS/ NUCLEÓTIDOS (INH. TI) ZDV ddi 3TC FTC d4t ABC TDF ZDV/3TC ZDV/3TC/ABC ABC/3TC TDF/FTC INHIB. NO NUCLEÓS. DE LA TI EFAVIRENZ NEVIRAPINA ETRAVIRINA RILPIVIRINA INHIBIDORES DE PROTEASA ritonavir SAQUINAVIR INDINAVIR NELFINAVIR LOPINAVIR/rtv ATAZANAVIR FOSAMPRENAVIR TIPRANAVIR DARUNAVIR INHIBIDORES DE LA ENTRADA ENFUVIRTIDE MARAVIROC (CCR5) INHIB. DE LA INTEGRASA RALTEGRAVIR

19 DHHS Guidelines (OCT 2011) Preferred antiretroviral regimens for antiretroviral therapy-naïve patients Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. October 14, 2011; 1 167

20 EACS Guidelines (Oct 2011).Initial combination regimen for antiretroviral-naïve adults patients Panel on EACS Guidelines. European AIDS Clinical Society (EACS) Guidelines. Version 6.0. October, 2011; 1 60

21

22 ARV THERAPY IN HIV-INFECTED NAIVE PATIENTS Education Willingness Viral load Social support Disease status Number of pills Other diseases

23 Evolución anual de la pauta de inicio de TAR en los pacientes de la Cohorte PISCIS ( ) 100% 80% 60% 40% Otros Basado en 3AN Basado en NN Basado en IP/boosted Basado en IP 20% 0% Any d'inici de tractament Gallois A, Esteve A, y Grupo de estudio Piscis

24 TAR inicial: temas en continuo debate Que análogos de nucleósidos? INNTI o IP/r? Que INNTI? Que IP/r? Otros fármacos? (Inhib. Integrasa, CCR5) Otras estrategias? (pautas sin AN)

25 RESISTÈNCIA TRANSMESA, PATRÓ DE MUTACIÓ Hospital Universitari de Bellvitge, Nº de pacients amb resistència (%) Patró de mutació (N) n= n= ITIAN 13 (4,58) 15 (4,20) TAMs=11 T69D=1 TAMs=13 T69D=1 M184V=1 M184V=1 ITINN 3 (1,05) 20 (5,60) K103N=2 Y181C=1 K103N=15 Altres=5 IP 0 3 (0,84) M46L=1 I54V, V82A=1 G48V, I54V, V82A, I84V, L90M=1 Total 16 (5,63) 34 (9,52)

26 Truvada o Kivexa producen aumento similar de la grasa en extremidades y tronco CROI LB (G McComsey)

27 RPV: menor toxicidad SNC mejor perfil lipídico, pero... Mayor fallo virológico y selección de resistencias en pts con CV > c/ml DHHS (oct 2011): alternativa a EFV Aprobado por FDA en mayo 2011 agosto 2011: TDF/FTC/RPV Cohen C, et al. Lancet 2011; 378:

28 Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/ emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection Cohen C, et al. AIDS 2011; 25: F7-F12 28

29 Proportion (%) <50 c/ml (TLOVR) DOLUTEGRAVIR: Rapid and Sustained Antiviral Activity.Week 48 Efficacy Analysis (%<50 c/ml) 91% 90% 88% 82% DTG 10mg DTG 25mg DTG 50mg EFV 600mg 95% confidence intervals are derived using the normal approximation 6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy

30 TDF/FTC impact on BMD HOPS Cohort 1 Increased rate of bone fractures in HIV+ compared to general population ACTG S sub-study ABC/3TC had less impact on BMD than TDF/FTC Differences in fracture outcomes cannot be causally related to choice of ARV regimen in this study 1. Young B et al. CID 2011; 52: McComsey GA et al. JID 2011; 203: McComsey GA et al. CROI Feb 16-20

31 PI monotherapy has been investigated in a number of studies MONET Study 1 DRV/r OD + 2 NRTI vs. DRV/r OD N = 256 OK04 Study 2 LPV/r BID + 2 NRTI vs. LPV/r OD N = 200 ACTG 5201 Study 3 ATZ/r OD N = 36 Patients and methods Taking 2 NRTI + either NNRTI or boosted PI at screening HIV RNA <50 cp/ml for 6 months Taking LPV/r + 2 NRTI for >2 months HIV RNA <50 cp/ml for >6 months Taking a PI + 2 NRTI for >48 weeks HIV RNA <50 cp/ml for >6 months Study findings At 96 weeks: Discontinuations were slightly higher in the DRV/r monotherapy arm, compared with DRV/r + 2NRTI Most elevations in HIV RNA were low level ( copies/ml). Patients were resuppressed either on the original randomised treatment or with intensified treatment At 96 weeks: Discontinuation due to adverse events was a more frequent cause of treatment failure in the LPV/r + 2 NRTI group In the monotherapy group low level viremia was the main cause for a treatment change. The majority of these patients resuppressed after restarting nucleosides At 24 weeks: Virologic success occurred in 91% of patients No treatment discontinuations due to adverse effects No significant changes in CD4 cell count or plasma lipid levels 1. Rieger et al, IAS 2010; 2. Arribas et al, EACS 2007; 3. Swindells et al, JAMA 2006

32 Proportion of Subjects Responding at Week 96 (FDA-TLOVR)

33 MVC + ATV/r is active and well-tolerated in a 24-week interim analysis 9/121 subjects discontinued therapy prior to week 24 (5 MVC arm; 4 TDF/FTC arm) 2 subjects in MVC arm due to AEs (vomiting, jaundice) 1 subject in MVC arm due to insufficient clinical response No resistance observed in 5 evaluable patients 3 patients on MVC 2 patients on TDF/FTC 121 CCR5-tropic treatment-naïve patient (CD4+ counts 100 cells/µl) were randomized to receive ATV/r with either MVC 150mg QD or TDF/FTC; * 1 patient accidentally dosed with MVC prior to 24-hr sample draw Mills A et al, IAS 2010

34 Probability of not having a VF Probability of not having a VF ACTG 5262: DRV/r+RAL Time to Virologic Failure (ITT approach) 1.0 Time to Virologic Failure (VF) 1.0 Time to VF by Baseline HIV-1 RNA Log Rank Test p= HIV-1 RNA 100,000 copies/ml HIV-1 RNA > 100,000 copies/ml Time (weeks) n with VF: n at risk: Taiwo B, et al. CROI Boston. # Time (weeks) HIV-1 RNA 100,000 copies/ml n with VF: n at risk: HIV-1 RNA > 100,000 copies/ml n with VF: n at risk:

35 N Engl J Med 2010; 363:

36 DISEÑO Participantes: 2499 VIH (-) HSH ó transexuales (varones de nacimiento) con prácticas de riesgo. Período: 10 julio 2007 a 17 diciembre Centros: 11 centros en seis países (EEUU, Perú, Ecuador, Brasil, Tailandia y Sudáfrica) Intervención: - TVD ó placebo (1 c/dia). - Visitas a semanas 0, 4, 8, 12, 18, 24 y cada 12 meses. Counselling sobre protección sexual, adherencia al tratamiento, diagnóstico y tratamiento de ETS. Seguimiento 1,2 años (máximo 2,8 años).

37 36 infectados en TVD vs 64 en placebo: 44% reducción (IC 95% 15-63; p<0.005).

38 Oral Preexposure prophylaxis for HIV Another arrow in the quiver? VIH+; 7000 nuevas infecciones/d ( /año!!) Medidas de prevención: métodos barrera, < prev. sangre, modif. conductas, prof. postexposición, saber sero-status, ARV embarazo/lactancia, tto ETS. Más recientes: circuncisión varones, vacunas, microbicidas vaginales. PROF. PREEXPOSICION: eficacia 44% (IC95% 15-63) (> si niveles fármacos) Limitaciones/dudas: -baja correlación adherencia auto-referida/niveles fármacos -toxicidad (renal) a largo plazo (> con > adherencia!) -resistencia a FTC (en 2 pts con infeción aguda) (y a HBV?) -adherencia en mundo real fuera de un estudio? (fatiga...) -efecto sobre otras medidas de prevención (preservativos), sobre el conoc. de status VIH? sobre frecuencia sexo casual? Michael, NL. N Engl J Med 2010; 363:

39 Efficacy of Daily Oral FTC/TDF PrEP Trial Pop. Efficacy 95% CI iprex MSM 42% 18 to 60% Partners PrEP Men 83% 49 to 94% Women 62% 19 to 82% TDF2 Men 80% 25 to 97% Women 49% -22 to 81% FemPREP Women Discontinued for futility Grant R, NEJM 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, cortesía de JM Gatell

40 Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes: a cohort study. Lancet Infectious Diseases 2011 (published online October 10, 2011) Fármacos nuevos: más eficaces, menos tóxicos, menos comprimidos y tomas Combos: facilitan la adherencia y la supresión viral a largo plazo Inicio más precoz del TAR: Mayor eficacia y menor toxicidad

41 TAR. Conclusiones Inicio cada vez más precoz del TAR ( ) Pautas individualizadas Siguen apareciendo nuevos ARV (RPV, DTG...) Biterapia (útil en algunos escenarios?, faltan datos, diferencias según pautas) Papel de profilaxis pre-exposición en la vida real?