Avances en el tratamiento del VIH Mª

Presentación del tema: "Avances en el tratamiento del VIH Mª"— Transcripción de la presentación:

1 Avances en el tratamiento del VIH Mª
Avances en el tratamiento del VIH Mª. Paloma Geijo Martínez MI-Infecciosas. Hospital Virgen de la Luz. Cuenca XI Congreso de la Sociedad de Medicina Interna Madrid-Castilla la Mancha Albacete. 21 de Junio de 2007

2 Desarrollo Reciente en Antirretrovirales
Pacientes Naive. ¿Cuándo y cómo comenzar TARV?. Pacientes con TARV previo Pruebas de Resistencia Nuevos fármacos.

3 Caso Clinico (1) ¿Tratamiento AR ? ¿Profilaxis ?
Varón, 38 años. VIH B3 desde Via sexual. Naive a AR Fecha CD4 (%) C.Viral (log) Peso (Kg) E. Oportunistas 03/2004 1ª consulta 82 (6) (5,60) 67 Herpes simplex ¿Tratamiento AR ? ¿Profilaxis ?

4 A. Cuándo comenzar TARV. A. Pacientes Naive Pacientes Sintomáticos
(B y C de CDC): Tratar a todos. (A) Pacientes Asintomáticos (s. CD4 /mm3) < 200 Tratar a todos. 200–350 - mayoría TARV (B) - Diferir: CD4 estable pr. 350 y CVP < cop./mL > 350 Diferir inicio TARV. (B) Cuando el paciente esté listo para comenzar. IAS-USA International Panel. JAMA 2006 y Consenso GESIDA 07

5 B.¿Como comenzar?-HAART inicial) Gesida 2007
A. Pacientes Naive B.¿Como comenzar?-HAART inicial) Gesida 2007 N-NtRTI NNRTI ó IP Preferente EFV LPV/r fosAMP/r Preferente TDF ABC ZDV Alternativas d4T ddI FTC ó 3TC (+) (+) Alternativas NVP ATV/r SQV/r ATV NFV No IP ó NN: ABC + 3TC + ZDV

6 B. Pacientes con TARV previo (experimentados) y
Pruebas de Resistencia

7 Motivos habituales de cambio TARV
B. Pacientes con TARV previo. Motivos habituales de cambio TARV Fracaso terapéutico. Aparición de toxicidad o intolerancia. Falta de adherencia. Simplificación de régimen complejo a otro + sencillo.

8 Uso de Test de Resistencia TAR
Guía USA 06 Guía uso AR. GESIDA 07 RECOMENDADO Fallo virológico durante TAR. Supresión suboptima CV TAR. Infección HIV aguda, si TAR. CONSIDERAR Infección HIV Crónica antes de instaurar TAR. NO RECOMENDADO 4 semanas post-suspensión AR. CV < 1000 HIV RNA c/ml A. Pacientes sin TAR previo Mujeres embarazadas Infección aguda por VIH Profilaxis post-exposición Pacientes que inician TAR B. Pacientes pretratados En todos los fracasos. Use of Resistance Assays in Virologic Failure. Resistance assays are useful in guiding decisions for patients experiencing virologic failure while on antiretroviral therapy (Table 22). Prospective data supporting drug-resistance testing in clinical practice are derived from trials in which test utility was assessed for cases of virologic failure. These studies involved genotyping assays, phenotyping assays, or both [141, 145, ]. In general, these studies indicated that the virologic response to therapy was increased when results of resistance testing were available, compared to responses observed when changes in therapy were guided by clinical judgment only. Thus, resistance testing appears to be a useful tool in selecting active drugs when changing antiretroviral regimens in cases of virologic failure, as measured by the early virologic response to the salvage regimen (BII). (See Management of Treatment-experienced Patients.) Resistance testing can also help guide treatment decisions for patients with suboptimal viral load reduction (BIII). Virologic failure in the setting of combination antiretroviral therapy is, for certain patients, associated with resistance to one component of the regimen only [159, 160]. In that situation, substituting individual drugs in a failing regimen might be possible, although this concept will require clinical validation. (See Management of Treatment-experienced Patients.) Use of Resistance Assays in Determining Initial Treatment. Transmission of drug-resistant HIV strains has been documented and has been associated with suboptimal virologic response to initial antiretroviral therapy [161]. If the decision is made to initiate therapy in a person with acute HIV infection, it is likely that resistance testing at baseline will optimize virologic response, although this strategy has not been tested in prospective clinical trials (BIII). Because of its more rapid turnaround time, using a genotyping assay might be preferred in this situation. Since some resistance-associated mutations are known to persist in the absence of drug pressure, it may be reasonable to extend this strategy for 1-3 years post-seroconversion. (CIII) Using resistance testing before initiation of antiretroviral therapy in patients with chronic HIV infection is less straightforward. Available resistance assays might fail to detect drug-resistant species that were transmitted when infection occurred but, with the passage of time, have become a minor species in the absence of selective drug pressure. As with acute HIV infection, prospective evaluation of "baseline" resistance testing in this setting has not been performed. It may be reasonable to consider such testing, however, when there is a significant possibility that the patient was infected with a drug-resistance virus (i.e., if the patient is thought to have been infected by a person who was receiving antiretroviral drugs) (CIII). One study suggested that baseline testing may be cost-effective when the prevalence of drug resistance in the relevant drug-naïve population is >5% [162]. However, such population data are infrequently available. Genotipo / Fenotipo / Fenotipo virtual

9 Régimen posible trás 1º fracaso TARV
Cambio ARV. Si no añade ≥1 fármaco (a) a regimen fracasado (R), probable desarrollo R rápida a toda pauta ARV. Régimen posible trás 1º fracaso TARV Previo Nuevo R producidas 3 AN 2 AN + NN ó IP/r ó 1 ó 2 AN + NN + IP/r (frec.) M184V K65R. 2 AN + 1 NN 2 AN + IP/r 103N (todos NN) AN (M184V, LT4V o K65R). IP ó IP/r - 2 AN + 1 NN ó - 2 AN + IP/r ó - 1 ó 2 AN + 1 NN + IP/r 30N (NFV), 50L (ATV) No cruzadas 50V (FPV), (LPV/r y pos TMC114) I47A (LPV y AMP). V82A, I54V y M46I/L (nuevas LPV/r)

10 Pacientes (MR). Exposición múltiple
1. Fracaso TARV. Pacientes (MR). Exposición múltiple (Norma general), no suspender TAR, pueden evitar – corto/medio plazo - Deterioro inmunológico y progresión clínica. • Objetivo: máx. supresión CV. Actual NHS con nuevos fármacos: <50 copias/ml • Si situación inmun. estable: - esperar ≥ 2 AR nuevos, virus (S) o remitir Centro fármacos experim. Guía uso AR.GESIDA 07

11 2. Aparición de toxicidad o intolerancia.
Otros Motivos cambio TARV 2. Aparición de toxicidad o intolerancia. AN (20-40%) T. mitocondr. (Lipoatrofia/Hiperlip.) Acidosis l. NA (15-30%) Hipersensibilidad (Exantema) IP (25-50%) R insulina (DM) e Hiperlipemia (lipoac. abdom). Considerar Tto. Sintomático (antieméticos, antidiarreicos, etc.), si efecto adverso lo permite. Valorar cambio de fármacos = clase: AN (D4T/AZT – TNF/3TC) NN (EFV, si SNC – NVP). Valorar cambio de fármacos # clase: IP por NN o vv. ó nuevas familias AR.

12 Alteración de distribución de grasa corporal
Evaluación Tratamiento Diagnóstico clínico (deseable) medida objetiva Composición corporal (s/. dispone c/ centro) No medida satisfactoria. (eficacia parcial y no exentas de riesgos): Generales (dieta, ejercicio): evitar >5% peso. • Sustitución AR: IP o AN. • Fármacos: metformina ó H. crecimiento. pioglitazona, 30 mg/d, 1 ensayo c. • Cirugía plástica (relleno facial - lipoatrofia, cirugía reductora - lipoacum. (único tto. actual con resultados evidentes. Medida + sencilla, segura y barata).

13 3.Fracaso TARV por falta de Adherencia
Otros Motivos cambio TARV 3.Fracaso TARV por falta de Adherencia • Identificar causas accesibilidad a fármacos, depresión, consumo de drogas, falta de apoyo sociofamiliar, etc.). corregirlas antes de nuevo TARV • Considerar simplificar el tratamiento (reducir nº pastillas o intervalo dosis).

14 Otros Motivos cambio TARV
4. Simplificación* TARV LPV/rtv: 4 tabletas/ día, estables al calor. SQV: tableta 500 mg. T-20: Apar. Biojector® con aguja libre de gas. Estrategias STI. (interrupción programada ARV) No se recomienda (gral). Malos resultados (varios ensayos cl.) Inducción y mantenimiento: - Nº ARV vs potencia + barrera genética.

15 Simplification TARV. Avances
3 TARV (2 comprimidos): 1. ZDV + 3TC (CombivirR), 2. ABC + 3TC (KivexaR) (+) 3. TDF + FTC (TruvadaR) EFV (SustivaR) 600 mg. TARV 1 vez/día (régimen QD): (ABC, 3TC ó TDF) (FTC) (EFV o ATVr) (ddI + TDF: no utilizar hasta resultados concluyentes). Monoterapia con LPV/rtv: tras supresión virológica con triple terapia.

16 Caso Clinico (2). Evolución
Varón, 38 años. VIH B3. Naive a AR Fecha Tratamiento CD4 (%) C.Viral (log) Adher. Basal 3TC, ddI, EFV 82 (6) (5,60) 3 meses 580 (34) (4,55) 100% 6 meses 116 (9) (4,96) Profilaxis 03/ / P. CARINII (1ª): Septrin forteR 1c, L,X,V 04/ / HONGOS: Fluconazol c/semanal

17 Caso Clinico (3). Resolución
Fecha / AR 3TC,ddI,EFV CD4 (%) C.Viral (log) GENOTIPO RTI – AN RTI – NN IP 6 meses AZT, 3TC, TDF, ATV/r 116 (9) (4,96) 74V (ddI,ABC ) 184V (3TC/FTC) 100I (EFV) 103N (NN) 71V (Polim) 12 meses 278 (12) < 50 24 meses FTC,TDF, ATVr 434 (17) 36 meses 545 (22)

18 D. Nuevos fármacos en Pacientes experimentados

19 Nuevos Fármacos ARV - INVESTIGACIÓN
PIs Darunavir TMC 114 PPL-100 (I) SPI-256 (I) NRTIs Racivir (I/II) Apricitabine (II) Elvucitabine (II) (VM lar) GS-9131 (prodr GS 9148) KP1461 (I) MIV-210 (II) (+ VHB) Entry Is CXCR4 Is AMD070 (I) KRH 3955 (I) KRH 3140 (I) CCR5 Is Maraviroc Nifeviroc (II) China Fusion Is TRI-1144 (I) TRI-999 (I) WS Attachment/CD4+ binding Is (Monoclonal) PRO 140 (I) TNX 355 (II) Maturation Is PA-457 (Bevirimat) (II) Integrase Is MK-0518 (Raltegravir) GS-9137 (Elvitegravir) (II) NNRTIs Etravirine-TMC 125 Rilpivirine- TMC 278 (II) Yellow=drugs addressed within deck (*) Acceso expandido

20 Tipranavir/Rtv: RESIST 1 y 2
Nuevos IP comercializados Tipranavir/Rtv: RESIST 1 y 2 Ant. Genotipo 21 mutac Fenotipo Cohen IAC 06. Parkin CROI 06. (%) + T20 TPV/r 22.8% > IP compar-CPI 10.2% T20 (ptes. factores mal pronóstico) Cooper D, et al. 12th CROI 2005, Boston, abstract 560

21 Nº of Primary PI Baseline Mutations
Nuevos IP. Acceso Expandido Darunavir (DRV). Estudio POWER. Effect of Baseline Resistance on Response 11 mutations associated with reduced response V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V TMC-114 vs IP/r HIV-1 RNA < 50 c/mL en sem 24 (%) Global: % vs 9% T-20 (Naive): 67% vs 16% No ARVa OBR: 31% vs 0% 100 80 64 60 50 Patients With HIV RNA < 50 c/mL at Wk 24 (%) 42 Turning to the resistance profile of darunavir/ritonavir, what we have depicted on this slide is what we know about the effect of baseline resistance in terms of the likelihood of a patient to respond to darunavir/ritonavir. What is depicted on this slide is the baseline effect of either genotypic resistance or phenotypic resistance on the efficacy of darunavir/ritonavir. These are analyses from the POWER 1, 2, and 3 trials. The first thing that we are going to look at is the bar chart on the left-hand side of the slide, which looks at the effect of genotypic resistance—in other words, the number of primary PI mutations that the virus harbored at the time that the patient went onto darunavir. As you might expect, as the number of primary PI mutations increased, the proportion of patients who were able to achieve viral loads of less than 50 copies per mL declined substantially, so that by the time the baseline virus had more than 4 primary PI mutations, the proportion of patients who were achieving viral loads of less than 50 copies per mL was 10%. Turning now to the graph on the right-hand side of the slide, looking at darunavir phenotypic sensitivity, viruses that were relatively sensitive, meaning that there was a fold change of less than 10 to darunavir, were able to achieve virologic suppression. Once the fold change is greater than 40, one sees a decrease in the number achieving suppression. So, this is just a snapshot of what we know about the resistance profile in an attempt to help as one thinks about how to use darunavir/ritonavir in one’s patient population. 40 22 20 10 n = 67 94 113 58 41 1 2 3 ≥ 4 Nº of Primary PI Baseline Mutations DeMeyer S, et al. Antivir Ther. 2006;11:S83.

22 Papel de IPs de 2-Generation : Darunavir y Tipranavir
Elegirlos en funcion de test resistancia: Genotype: “Scoring systems” en evolucion Phenotype: ventaja potencial en ptes. con IPs Preferido DRV por < toxicidad, cuando no hay clara diferencia en R. Resultados de ensayo DRV/r vs LPV/r, despues 1º fallo, este verano. Gallant. 9 HIV Management Update. John Hopckins. June 2007

23 Etravirine (TMC 125) NNRTIs. Acceso Expandido
ETV efectivo c/. muchas cepas NNRTI-(R). < Eficacia si > mutaciones NNRTI : No continuar EFV o NVP en 1 regimen no-supresivo. Resistencia Cruzada: Genotype: No “scoring system” actual. Phenotype: No valido hasta aprobar AR. No usar fenotipos antiguos. Resultados ensayo DUET: este verano.

24 Rilpivirine (TMC 278) NNRTIs. Investigacion
Activo c/. virus NNRTI-resistente. Puede no ser activo c/. virus ETV-resistente (y viceversa) Atractivo NNRTI 1 linea, QD. Potencia y PK. Potencial para coformulacion. Parece tener ventajas en EA s. EFV (↓CNS, rash, lipidos) Pozniak A, et al. CROI Abst 143LB.

25 MOTIVATE 1 & 2: VL <400 (ITT, NC = F)
Inhibidor correceptores CCR5. Acceso Expandido Maraviroc MOTIVATE 1 & 2: VL <400 (ITT, NC = F) Placebo + OBR (n = 118) MVC QD + OBR (n = 232) MVC BID + OBR (n = 235) 100 MOTIVATE 1 100 MOTIVATE 2 90 90 80 80 P < .0001* P < .0001* 70 70 60.4% 61.3% 60 60 54.7% 55.5% 50 50 Patients, % Patients, % P < .0001* P < .0001* 40 40 31.4% 30 30 23.1% 20 20 10 10 2 4 8 12 16 20 24 2 4 8 12 16 20 24 Time (Wks) Time (Wks) * P values vs placebo at Week 24 Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abst 104bLB.

26 Tropism at Screening in MVC Trials MOTIVATE 1, 2, and A4001026
Trial 1026 Antiretroviral-naive (n=1428) MOTIVATE Antiretroviral-experienced (n=2560) X4 (0.3%) DM (14.7%) DM (41.4%) The ARV-naïve samples came from individuals located in Europe (n=378), Australia (n=86), South Africa (n=319), North America and Central and South America (n=536 and n=109, respectively). • The ARV-experienced samples came from individuals located in Europe (n=608), Australia (n=92) and North America (n=1860). • Observed tropism profiles were R5 (85%, 56.1%), DM (14.7%, 41.3%) and X4 (0.3%, 2.6%), for ARV-naïve and ARV-experienced individuals, respectively R5 (85%) R5 (56%) Europe, Australia, South Africa, America X4 (2.6%) Europe, Australia, North America Coakley E, et al. International Workshop Targeting HIV Entry, Abst 8.

27 Papel de los Inhibidores CCR5
Requiere screening: test comercial tropismo. Sensibilidad test: riesgo no detectar virus X4 Virus R5: + prob. Ptes. con > nadir CD4 Implicación: momento inicio TARV. Limitación: uso in cambio TARV tardío. Tolerancia a largo plazo (ptes. con otras opciones) No se debería usar como substituto de otros agentes (ej,T-20) en un régimen supresivo. Gallant. 9 HIV Management Update. John Hopckins. June 2007

28 BENCHMRK 1 & 2: VL <400 ITT, NC = F)
Inhibidores de la Integrasa. Acceso Expandido MK-0518 (Raltegravir) BENCHMRK 1 & 2: VL <400 ITT, NC = F) RAL + OBR RAL + OBR 2 4 8 12 16 24 20 40 60 80 100 BENCHMRK-1 2 4 8 12 16 24 20 40 60 80 100 BENCHMRK-2 77% 77% P < .001 at Wk 16 P < .001 at Wk 16 % with VL <400 43% 41% P < .001 Wks Wks Cooper D, et al. CROI Abs 105aLB. Steigbigel R, et al. CROI Abs 105bLB.

29 ¿Cómo se usará Enfuvirtide -T-20?
Muchos pacientes CV< 50 y T-20, substituir por nuevo AR: Raltegravir > Etravirine > Maraviroc Pacientes con virus R5-tropic y/o virus (S) a DRV, TPV, or ETV pueden no necesitar T-20. T-20 mejora resultados en TORO[1] , RESIST[2] POWER[3] , MOTIVATE[4,5] y BENCHMRK[6,7] T-20 todavía necesario en pts muy experim. (v. D/M-tropic, (R) cruzada a DRV, TPV, ETV) 1. Trottier. J Acq Imm Defic Syndr Farthing. ICAAC Abs H Clotet. Lancet Nelson. CROI Abs 104aLB. 5. Lalezari .CROI Abs 104bLB. 6. Cooper. CROI Abs 105aLB. 7. Steigbigel. CROI Abs 105bLB.

30 Estimated Timeline for New Antiretrovirals
Entry inhibitors (anti-gp120, CCR5) Elvitegravir Maturation inhibitors Raltegravir TNX-355 Integrase inhibitors Maraviroc Bevirimat CXCR4 inhibitors 2006 2007 2008 2009 2010 This slide is an estimated timeline of when the drugs discussed here may become available. It compares the novel agents on the top of the slide with new agents in existing classes on the bottom of the slide. This timeline is based on best estimates, but it seems likely that etravirine (TMC125) will be the next newly available agent. CCR5 inhibitors may be available next year, and integrase inhibitors might be available in late 2007 or early 2008 if all goes well. Rilpivirine Etravirine Apri-citabine PIs NNRTI NRTI

31 Gracias por la atención
Daulaguiri-8000 m Gracias por la atención