NUEVOS AGENTES DE NUEVAS CLASES. Parte 2

Presentación del tema: "NUEVOS AGENTES DE NUEVAS CLASES. Parte 2"— Transcripción de la presentación:

1 NUEVOS AGENTES DE NUEVAS CLASES. Parte 2
CARLOS ARTURO ALVAREZ. MD, DTMH

2 Repaso de Enfivurtide Primera droga del tipo inhibidor de entrada en ser aprobada por FDA Eficacia probada en los estudios TORO 1 y 2 Prueba de eficacia virológica probada cuando se administra en combinación con otros antirretrovirales demostrado en múltiples estudios clínicos Eficacia virológica en 48 semanas de estudio con ENF en TORO 1 y 2 100 TOB alone ENF + TOB 80 Todas las comparaciones P < .0001 60 Patients (%) 40 37.4 30.4 ENF, 20 17.1 18.3 12.0 7.8  1 log10 ↓ Desde linea de base HIV-1 RNA < 400 copias/mL HIV-1 RNA < 50 copias/mL Katlama C, et al. IAS Abstract LB2. 2

3 ENF + DRV/RTV en POWER 1 y 2 VIH-1 RNA < 50 copias/mL a 48 semanas por subgrupos de línea de base DRV/RTV 600/100 mg BID Control 70 58 60 50 45 44 40 Pacientes (%) 30 20 15 11 10 10 10 7 4/35 ENF Usado (primera vez) ENF usado (Exper) ENF No usado Todos los Pacientes Clotet B, et al. Lancet. 2007;369:

4 ENF + TPV/RTV en RESIST 1 y 2
VIH-1 RNA < 50 copias/mL y < 400 copias/m a semana 96 por subgrupo TPV/RTV Control TPV/RTV Control 100 100 80 80 P < .0001 Pacientes con VIH-1 RNA < 50 copias/mL (%) 60 P < .0002 Pacientes con VIH-1 RNA < 400 copias/mL (%) 60 P < .0001 44.4 P < .0001 34.7 40 40 26.9 20.4 14.4 14.4 9.1 10.9 20 20 Todos ENF primera vez Todos ENF primera vez Gazzard B, et al. Glasgow Abstract P23. Hicks CB, et al. Lancet. 2006;368: 4

5 VIH-1 RNA < 400 copias/mLa semana 16 por agentes específicos en TOB
ENF + RAL en BENCHMRK 1 y 2 VIH-1 RNA < 400 copias/mLa semana 16 por agentes específicos en TOB n Raltegravir + TOB Datos de eficacia total 447 79 230 43 Placebo + TOB Eficacia por agentes en TOB ENF Darunavir + + 44 98 23 87 + – 42 90 24 63 BENCHMARK, Blocking Integrase in Treatment Experienced Patients With a Novel Compound against HIV: MeRcK, MK-0518; c/mL, copies/mL; OBR, optimized background regimen; VL, viral load; Wk, week. A subset analysis of 677 patients in BENCHMRK 1 and 2 assessed rates of viral suppression at Week 16 based on the use of specific agents in the OBR, specifically enfuvirtide and darunavir. In contrast to the MOTIVATE studies, this analysis was completed among first-time users of either of these drugs. This was a virologic-failure-carried-forward analysis in which those who discontinued participation in the trial because of toxicity were censored from the analysis. Among patients who received both enfuvirtide and darunavir along with raltegravir, 98% achieved undetectable viral loads. It should be noted, however, that 87% of patients who received placebo along with both enfuvirtide and darunavir also achieved undetectable viral loads. This is probably related to the fact that these patients now had 2 active drugs in their OBR. However, among patients who received either enfuvirtide or darunavir in their background regimen, there was a clear advantage for the raltegravir treatment arm with approximately 90% of raltegravir-treated patients reaching < 400 copies/mL vs 63% or 55% of placebo-treated subjects who received enfuvirtide or darunavir, respectively. Moreover, a larger proportion of patients who received raltegravir and had neither enfuvirtide nor darunavir in their background regimen achieved viral loads < 400 copies/mL than those who received the placebo with neither drug in their OBR (74% vs 29%, respectively). The proportion of patients who achieved undetectable viral load was lower among both the raltegravir and placebo groups in those who did not receive either enfuvirtide or darunavir vs those who did receive one or both of these drugs. Thus, these data emphasize the importance of having at least 2 active drugs in any regimen. For more information about this study, see the Capsule Summary at: – + 80 90 47 55 – – 191 74 90 29 + : Primer uso en TOB – : No uso en TOB 20 40 60 80 100 Pacientes (%) Análiis estadistico: falla virológica, se llevó a cabo hacia adelante Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 5 5

6 MOTIVATE 1 y 2: Cambio de media en CV a sem 24 por uso de ENF en OBR
Placebo + OBR MVC QD + OBR MVC BID + OBR Enfuvirtide* -2.18 -1.20 -1.31 -1.97 -2.08 No Enfuvirtide 107 98 49 127 130 67 n = MOTIVATE 1 -2.5 -2.0 -1.5 -1.0 -0.5 Cambio en CV en log10 copias/mL -2.02 -1.12 -2.17 -2.45 -0.97 -2.22 -2.5 -2.0 -1.5 -1.0 -0.5 No Enfuvirtide Enfuvirtide* 73 67 41 112 113 50 n = MOTIVATE 2 BID, twice daily; ENF, enfuvirtide; MOTIVenE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Pacientes; MVC, maraviroc; OBR, optimized background regimen; QD, once daily; VL, viral load; Wk, semana. This slide shows a combined analysis of MOTIVenE 1 y2 detailing the decline in viral load en semana 24 based on the inclusion of enfuvirtide in the OBR. According to this analysis, use of enfuvirtide in the OBR was not associened with improved virologic suppression. However, this analysis did not distinguish between Pacientes who were already experienced with enfuvirtide vs those who were using enfuvirtide for the first time. It is possible then an analysis of only first‑time use of enfuvirtide would have yielded different results. This hypothesis is supported by the previous slide in which the number of active agents in the background regimen was found to correlene with response to maraviroc. For more informenion about this study, see the Capsule Summary en: Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB. 6

7 VIH-1 RNA < 400 copias/mL VIH-1 RNA < 50 copias/mL
ENF + MVC en MOTIVATE 1 y 2 Supresión viral a la semana 48 por uso de ENF Placebo + TOB MVC/día+ TOB MVC/2 día + TOB VIH-1 RNA < 400 copias/mL VIH-1 RNA < 50 copias/mL 60 100 Pacientes (%) 20 40 80 60 100 Pacientes (%) 20 40 80 71 71 64 61 43 ENF, enfuvirtide; MVC, maraviroc; OBR, optimized background regimen. 36 35 27 32 25 3 3 n = 59 91 108 30 75 72 59 91 108 30 75 72 ENF primera vez ENF Exp/Resistente ENF primera vez ENF Exp/Resistente Lalezari J, et al. ICAAC Abstract H-718a. 7 7

8 MOTIVATE 1 y 2: supresión virológica por uso de ENF, semana 48
Placebo + TOB MVC/día + TOB MVC 2 día + TOB VIH-1 RNA < 400 copias/mL VIH-1 RNA < 50 copias/mL 60 100 Pacientes (%) 20 40 80 60 100 Pacientes (%) 20 40 80 71 71 64 61 43 ENF, enfuvirtide; MVC, maraviroc; OBR, optimized background regimen. 36 35 32 27 25 3 3 n = 59 91 108 30 75 72 59 91 108 30 75 72 ENF primera vez ENF Exp/Resistente ENF primera vez ENF Exp/Resistente Lalezari J, et al. ICAAC Abstract H-718a. 8 8

9 Antagonistas CCR5 en investigación

10 PRO 140: efecto de una infusión IV de anticuerpos humanizados CCR5
Pacientes asintomáticos con virus R5 y CV VIH-1 RNA > 5000 copias/mL, Conteo de CD4+ > 250 cells/mm3 (con nadir > 200), y sin terapia antirretroviral por ≥ 3 meses (N = 39) PRO mg/kg una infusión IV (n = 10) PRO mg/kg una infusión IV (n = 10) Seguimiento 59 días PRO mg/kg una infusión IV (n = 10) Placebo (n = 9) 0.5 Placebo 0.5 mg/kg 2.0 mg/kg 5.0 mg/kg 0.0 Diferencia de media en VIH-1 RNA (log10 copias/mL) -0.5 -1.0 * ‡ † † ‡ *P ≤ .01 †P ≤ .001 ‡P ≤ .0001 ‡ -1.5 ‡ ‡ ‡ -2.0 10 20 30 40 50 60 Saag M, et al. IAS Abstract WESS201. Día de estudio 10

11 INCB009471: ensayo de 14 días de monoterapia con inhibidor de CCR5 en investigación
Pacientes con virus R5 y CV≥ 4.0 log10 copies/mL (N = 23) INCB mg oral /día (n = 19) Seguimiento 14 días Placebo (n = 4) Placebo INCB009471 0.5 10 Días 20 30 0.0 -0.5 Día Cambio en media de VIH-1 RNA (log10 copias/mL) (SEM) Día -1.0 Día -1.5 Día -2.0 Día -2.5 INCB suspendido al día 14 Cohen C, et al. IAS Abstract TUAB106.

12 Otros inhibidores de entrada en investigación

13 AMD11070: Antagonista X4 ACTG 5210[1]: Estudio etiqueta abierta escalando dosis con monoterapia para 10 Pacientes sin terapia por ≥ 14 dias con virus X4 or dual/mixto. 200 mg Q12h X 20 dosis (N = 6) 3/6 tuvieron reduccion ≥ 1 log10 en virus X4 para dia 10 5/6 pacientes tenian virus dual/mixto en Day 10; 1 tenia R5 No cambios en CV ≥ 1 log10 copias/mL XACT[2]: Estudio de monoterapia por 10-dias en pacientes NAIVE y experimentados con virus X4 detectado (N = 9 ) 4/9 Pacientes tenian ≥ 1 log10 reduccion virus X4 * para dia 10 3/4 tenian solamente virus R5 detectado en dia 10 No cambios en CV o conteo CD4+ entre los 4/9 Pacientes Desarrollo de este producto fue paralizado por toxicidad hepatica ACTG, AIDS Clinical Trials Group; Q12h, every 12 hours; R5, CCR5 tropic; X4, CXCR4 tropic.; There is significant interest in the development of CXCR4 inhibitors for Pacientes who have X4 or dual/mixed-tropic virus. AMD11070 is a candidene X4 antagonist. In the AIDS Clinical Trials Group 5210 study, Pacientes with X4 or dual/mixed-tropic virus received open‑label, dose‑escalening, 10‑day monotherapy with this compound after they had been off antiretroviral therapy for en least 14 days. Three of 6 Pacientes had en least a 1 log reduction in X4 virus by Day 10 as seen by a reduction in light units in the tropism assay. en Day 10, 5 of the 6 Pacientes had dual/mixed-tropic virus y1 had only R5-expressing virus, showing full suppression of the X4 virus. However, none of the Pacientes exhibited changes in viral load > 1 log10 copias/mL The XACT study was a 10‑day monotherapy study of AMD11070 in treenment‑naive ytreenment-experienced Pacientes who had detectable X4 virus. Four of 9 Pacientes had a reduction of X4 virus greener than 1 log10 light units by Day 10. However, there were no changes in viral load or CD4+ cell counts among these 4 Pacientes. Three of these 4 Pacientes had only R5 virus detected en Day 10, suggesting then AMD11070 had suppressed the X4 virus specifically. Development of this compound has been halted because of liver toxicity in animal models. There are other CXCR4 inhibitors being developed yinvestigened but all are in early stages of development.For more informenion about this study, see the Capsule Summary en: For more informenion about this study, see the Capsule Summary en: 1. Saag M, et al. CROI Abstract Boffito M, et al. CROI Abstract 511. 13

14 En falla virológica en cualquier brazo
TNX-355, Anticuerpo monoclonal inhibidor de entrada: estudio de fase II semana 24 semana 48 TNX mg/kg cada 2 semanas + TOB (n = 28) Pacientes VIH positivos con experiencia en multiples clases, CV VIH-1 RNA ≥ 10,000 copias/mL, y CD4+ ≥ 50 cels/mm3 (N = 82) TNX mg/kg cada 2 semanas + TOB (n = 27) OBR, optimized background regimen; PSGT, combined phenotype/genotype resistance assay; TNX-355, humanized monoclonal antibody. For more information, go to Placebo + TOB (n = 27) Etiqueta abierta TNX mg/kg cada 2 semanas + TOB nuevo En falla virológica en cualquier brazo Norris D, et al. IAC Abstract THLB0218. 14

15 TNX-355: análisis de eficacia las semanas 24 y 48
Desenlace primario: diferencia de medias en CVdesde línea de base a la semana 24 (LOCF) 15 mg/kg 10 mg/kg Placebo Wk 24 Wk 48 Wk 24 Wk 48 Wk 24 Wk 48 Aumento significativo en CD4+ a la semana (~ + 50 cels/mm3) TNX-355 bien tolerado; RAMs comparable con placebo -0.20 -0.14 -0.5 Diferencia de media de CV VIH-1 RNA a la semana 24 (log10 copias/mL) -0.71† -1.0 -0.95* -0.96‡ -1.16‡ -1.5 *P = .003 vs placebo. †P < .01 vs placebo. ‡P < .001 vs placebo. Norris D, et al. IAC Abstract THLB0218.

16 Blanco Terapéutico y Grupo Farmacológico
Figura 1 Ciclo de Replicación del VIH Entrada Inhibidores de la unión gp120-CD4 Antagonistas de co-receptores Inhibidores de Fusión 1 ADN Celular ADN proviral no integrado CD4 Fusión ADN proviral Integrado gp120 Transcriptasa Reversa Síntesis Proteica Co-receptor RNA Genómico RNAm Transcripción Reversa Inhibidores de la Transcriptasa Reversa 2 Gemación Viral

17 Blanco Terapéutico y Grupo Farmacológico
Figura 1 Ciclo de Replicación del VIH Entrada Inhibidores de la unión gp120-CD4 Antagonistas de co-receptores Inhibidores de Fusión 1 ADN Celular ADN proviral no integrado CD4 Fusión ADN proviral Integrado gp120 Transcriptasa Reversa Síntesis Proteica Co-receptor RNA Genómico RNAm Transcripción Reversa Inhibidores de la Transcriptasa Reversa 2 Integración Inhibidores de la Integrasa 3 Gemación Viral

18 Inhibidores de la Integración del ADN viral
Inhibidores de la Integrasa MK-0518 Inhibición de la enzima Integrasa Fase III GS-9137 Fase II

19 RALTEGRAVIR. ISENTRESS
INVIMA mayo 2008

20 Protocolo 004: Raltegravir vs Efavirenz en el tratamiento de Pacientes - Naive
Tratamiento pacientes – naïve (n = 198) con VL > 5000 copias/mL y CD4+ > 100 cels/mm3 aleatorizado a una de 4 dosis de RAL (100, 200, 400, 600 mg dia) o EFV (600 mg dia) con TDF + 3TC[1] Desenlaces, % RAL 100 mg (n = 39) RAL 200 mg (n = 40) RAL 400 mg (n = 41) RAL 600 mg EFV 600 mg (n = 38) VL < 400 copias/mL Semana 24 95 85 98 Semana 48 97 90 87 VL < 50 copias/mL Semana 24 93 92 83 88 For more information about this study, see the Capsule Summary at: La dinámica viral, de la segunda fase del estudio puede decaer aceleradamente con RAL[2] 1. Markowitz M, et al. IAS Abstract TUAB Murray JM, et al. IAS Abstract TUAB103. 20

21 1.- Porque fue selecionda la dosis de 400 mg?
Raltegravir 400 mg dos veces al día fue muy eficaz y generalmente bien tolerado en los estudios de fase III (dosificado sin tener en cuenta a la alimentación en todos los estudios clínicos) Respecto a la interacción medicamentosa los estudios demuestran sólo impacto modesto sobre los parametros PK de raltegravir ante fuertes inductores de UGT1A1. En combinación con otros medicamentos antirretrovirales, la experiencia clínica indica que no es necesario ajustar la dosis (ritonavir, Efavirenz, etravirina

22 Protocolo 004: RAL Asociado con menores efectos sobre lipidos vs EFV
RAL bien tolerado sin toxicidad asociada a las dosis Vertigo, cefalea, y pesadillas mas frecuentes con EFV Colesterol total, LDL, trigliceridos no aumentados por RAL Cambio medio basal , mg/dL (mmol/L) RAL* mg dia (n = 160) Efavirenz 600 mg dia (n = 38) Valor p Total-HDL -0.59 -0.47 .52 Colesterol -2.3 (-0.06) +20.7 (+0.53) < .001 LDL-colesterol -7.5 (-0.19) +3.0 (+0.08) .016 Trigliceridos -1.0 (-0.01) +49.5 (+0.56) .068 For more information about this study, see the Capsule Summary at: *Todas las dosis RAL combinadas. Markowitz M, et al. IAS Abstract TUAB104. 22

23 Resistencia al inhibidor de la integrasa y resistencia cruzada
Protocolo 004: FV en 5 receptores RAL (3%)[1] 3 con mutaciones de integrasa no detectadas 1 N155H + M184M/I/V 1 N155H + otras mutaciones (V151I, D232D/N, G163G/R) Reportes separados de dos pacientes con FV a elvitegravir (EVG)/RTV, con respuesta durante las primeras semanas del cambio a RAL[2] Sugiere altos niveles de resistencia cruzada entre los primeros dos inhibidores de integrasa Paciente: 1= N155H y 3 = otras mutaciones de FV (VL: 840 copies/mL) en EVG/RTV Recuperó la supresión viral (< 50 copies/mL) tras la adicion de DRV/RTV a RAL Paciente: 2 tiene Q148R y 4 otras mutaciones de la integrasa como VF (VL: 10,700 copias/mL) en EVG/RTV No se ha podido recuperar la represión tras la adición de DRV / RTV a RAL For more information about this study, see the Capsule Summary at: 1. Markowitz M, et al. IAS Abstract TUAB DeJesus E , et al. IAS Abstract TUPEB032 .

24 Protocolo 005: Raltegravir + OBR en pacientes con tres clases de resistencia viral
Aleatorizado, doble enmascarado, placebo controlado, estudio fase IIb Semana 24 Semana 48 Doble enmascarado Fase abierta* Raltegravir 200 mg BID + OBR* (n = 43) Raltegravir 400 mg dia + OBR* (n = 100) Pacientes con tres clases de resistencia viral, VIH-1 RNA > 5000 copias/mL y CD4+ conteo celular > 50 cells/mm3 (N = 178) Raltegravir 400 mg BID + OBR* (n = 45) BID, twice daily; OBR, optimized background regimen; RAL, raltegravir *Pacientes recibiendo de manera abierta raltegravir 400 mg dia. Despues y hasta la semana 24 terapia de doble enmascaramiento . La duracion media de la fase doble enmascarada fue de 40 semanas para el grupo de raltegravir y 24 semanas para el grupo placebo. Raltegravir 600 mg BID + OBR* (n = 45) Placebo + OBR* (n = 45) *DRV/RTV no fue disponible para uso en OBR Grinsztejn B, et al. ICAAC Abstract H-713.

25 Protocolo 005: Resultados semana 48
Raltegravir 200 mg dia Raltegravir 400 mg dia Raltegravir 600 mg diaD Placebo ITT, NC = F Basales para VFs Enmascarado Enmascarado y abierto Enmascarado Enmascarado y abiertol 100 200 80 150 60 100 VIH-1 RNA < 50 copias/mL (%) Cambio en el conteo CD4+ (cells/mm3) 40 50 BID, twice daily; ITT, intent-to-treat; NC=F, non-completers = failure; VF, virologic failure 20 -50 2 4 8 12 16 24 32 40 48 2 4 8 12 16 24 32 40 48 Semanas Semanas No. de pacientes No. de pacientes 43 43 42 43 41 37 45 45 44 45 43 44 45 45 45 45 42 43 45 45 45 43 Grinsztejn B, et al. ICAAC Abstract H-713.

26 Protocolo 005: Resultados semana 48
Raltegravir 200 mg dia Raltegravir 400 mg dia Raltegravir 600 mg dia Placebo ITT, NC = F Basales para FVs Enmascarado Enmascarado y abiertol Enmascarado Enmascarado y abiertol 100 200 80 150 60 100 CD4+ Cell Count Change (cells/mm3) HIV-1 RNA < 50 copies/mL (%) 40 50 BID, twice daily; ITT, intent-to-treat; NC=F, non-completers = failure; VF, virologic failure 20 -50 2 4 8 12 16 24 32 40 48 2 4 8 12 16 24 32 40 48 Semanas Semanas No. de pacientes No. de pacientes 43 43 42 43 41 37 45 45 44 45 43 44 45 45 45 45 42 43 45 45 45 43 Grinsztejn B, et al. ICAAC Abstract H-713.

27 Protocolo 005: Resistencia Raltegravir
38 (29%) de 133 receptores RAL en fase doble enmascarada VF (rechazo o falla para alcanzar VIH-1 RNA < 400 copias/mL) Datos de genotipos disponibles para todas las 38 fallas Mayoría (35/38) tenían mutaciones de la integrasa confiriendo resistencia a raltegravir Vías de mutación N155 o Q148 presentadas en 34/35 ≥ 2 mutaciones presentes en 31/35 pacientes Q148H/G140S combinación mas común (n = 13) Factores asociados con probabilidad de mutación reducida al fracaso. VIH-1 RNA ≤ 100,000 copias/mL Primera vez de uso de ENF en OBR Puntaje de susceptibilidada fenotipica > 0 OBR, optimized background regimen; RAL, raltegravir; VL, viral load Grinsztejn B, et al. ICAAC Abstract H-713.

28 Desenlace primario: Semana 16 Duracion Planeada: Semana 48
BENCHMRK 1 y 2: Raltegravir (MK-0518) en pacientes experimentados a TARV Estudios fase III aleatorizados, doble enmascaramiento con placebo controlado. Desenlace primario: RNA HIV-1, conteo células CD4+, y eventos adversos en semana 16 Desenlace primario: Semana 16 Duracion Planeada: Semana 48 VIH-infectados, resistente triple-clase, HIV-1 RNA > 1000 copias/mL BENCHMRK-1 (N = 350) (Europa, Asia/Pacifico, Peru) BENCHMRK-2 (N = 349) (Norte, Sur America) Raltegravir 400 mg twice daily + OBR* BENCHMRK-1 (n = 232) BENCHMRK-2 (n = 230) BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; OBR, optimized background regimen; Pts, Pacientes. Another highlight of this conference was the presentenion of the results of the Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518 (BENCHMRK) trials. These were 2 parallel, phase III multinenional studies of raltegravir, previously known as MK‑0518, in treenment‑experienced Pacientes. These trials had a similar design to other studies involving treenment‑experienced Pacientes: Triple class–experienced Pacientes with viral loads > 1000 copias/mL were randomized to either treenment with raltegravir or a placebo, each combined with an OBR. For more informenion about this study, see the Capsule Summary en: Placebo + OBR* BENCHMRK-1 (n = 118) BENCHMRK-2 (n = 119) *antiretrovirales permitidos en OBR. Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 28

29 BENCHMRK-1 y 2: Raltegravir Tratamiento pacientes experimentados
Análisis actual: Semana 48 Seguimiento planeado: Semana 156 Raltegravir 400 mg dos veces dia + OBR* (BENCHMRK-1: n = 232; BENCHMRK-2: n = 230) Pacientes infectados con VIH con tres clases de resistencia y VIH-1 RNA > 1000 copias/mL (BENCHMRK-1: N = 352; BENCHMRK-2: N = 351) Placebo + OBR* (BENCHMRK-1: n = 118; BENCHMRK-2: n = 119) Inclusion de darunavir y tipranavir permitidas. 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

30 BENCHMRK-1 y 2: Desenlaces virológicos e immunológicos a la semana 48
BENCHMRK-1 Semana 48[1] RAL + OBR (n = 232) Placebo + OBR (n = 118) Valor p VIH-1 RNA < 50 copias/mL (NC = F), % 65 31 < .001 VIH-1 RNA < 400 copias/mL (NC = F), % 74 36 Cambios medios en conteo CD4+ vs valores de base, cels/mm3 120 49 BENCHMRK-2 Semana 48[2] RAL + OBR (n = 230) Placebo + OBR (n = 119) Valor p VIH-1 RNA < 50 copias/mL (NC = F), % 60 34 < .001 VIH-1 RNA < 400 copias/mL (NC = F), % 71 38 Cambio medio en valor de CD4+ cell vs valores basales, cells/mm3 98 40 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

31 BENCHMRK-1: Pacientes con VIH-1 RNA < 50 c/mL a la semana 48
100 80 65% 62% 60 Pacientes (%) P < .001 P < .001 40 20 33% 31% 2 4 8 12 16 24 32 40 48 Semanas Raltegravir* n = 232 231 231 230 229 232 229 230 231 Placebo* n = 118 118 118 118 117 118 118 118 118 Cooper DA, et al. CROI Abstract 788. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright © 2008 Merck & Co., Inc., All Rights Reserved.

32 BENCHMRK-2: Pacientes con VIH-1 RNA < 50 c/mL a la semana 48
100 80 62% 60% 60 Pacientes (%) P < .001 P < .001 40 20 36% 34% 2 4 8 12 16 24 32 40 48 Semanas Raltegravir* n = 230 228 227 230 229 229 224 228 228 Placebo* n = 119 119 118 119 119 119 119 119 119 Steigbigel R, et al. CROI Abstract 789. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright © 2008 Merck & Co., Inc., All Rights Reserved.

33 BENCHMRK-1 y 2: CV < 50 c/mL a la semana 48, total y por PSG, PSF
Grupo de pacientes Pacientes con VL < 50 c/mL, % RAL + OBR Placebo + OBR Todos los pacientes 64 (n = 443) 34 (n = 228) GSS y basales 45 (n = 112) 3 (n = 65) 1 67 (n = 166) 37 (n = 92) ≥ 2 75 (n = 158) 59 (n = 68) PSS y basales (número de agentes con actividad plena, FC < menor a punto de corte) 51 (n = 65) 2 (n = 44) 61 (n = 137) 29 (n = 69) 71 (n = 221) 48 (n = 108) PSS at basales (numero de agentes con actividad completa o parcial , FC < mayor a punto de corte) 52 (n = 33) 8 (n = 12) 48 (n = 71) 13 (n = 54) 70 (n = 313) 43 (n = 153) Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

34 BENCHMRK-1 y 2: VIH-1 RNA < 50 c/mL a la semana 48, en conjunto y por PSG
Subgrupo n Porcentaje de pacientes Raltegravir 443 64 Total 228 34 Placebo GSS: 112 45 65 3 Virologic failures carried forward. For patients with GSS=1, 4 ART agents represented at least 80% of the active agents in OBT: darunavir (52%, 52% in raltegravir and placebo groups, respectively), enfuvirtide (8%, 16%), tenofovir (12%, 6%), and tipranavir (11%, 11%). Rates of virologic suppression also greater with RAL vs placebo when analyzed by baseline PSS Similar results when assessing PSS by number of fully active drugs and by number of fully or partially active drugs 166 67 1 92 37 158 ≥ 2 75 68 59 20 40 60 80 100 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright © 2008 Merck & Co., Inc., All Rights Reserved. 34

35 BENCHMRK 1 y 2: Eventos Adversos y Resistencia Análisis Parcial
Eventos adversos y de laboratorio en grupos raltegravir + OBR Vs placebo + OBR Fracaso virologico: raltegravir vs placebo: 76 (16%) vs 121 (51%) 41 Pacientes raltegravir con análisis de genotipo: 9 no mutaciones en integrasas; 32 tenían ≥ 1 mutacion en integrasa Fracaso Raltegravir fue asociado con 1 de 2 vías geneticas : N155H or Q148K/R/H Mutaciones adicionales en las dos vías N155H + (E92Q,V151I, T97A, G163R, L74M) Q148K/R/H + (G140S/A, E138K) Puede existir otras vías eg, Y143R/C + (L74A/I, E92Q, T97A, I203M, S230R) BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; OBR, optimized background regimen. In terms of adverse events ylaborenory abnormalities, in the BENCHMRK studies raltegravir yplacebo appeared to be comparable regarding clinical adverse effects and/or laborenory abnormalities. Earlier studies with raltegravir demonstrened similar findings. In fact, there have not been any obvious drug‑specific adverse effects or toxicities entributed to raltegravir to dene, according to the limited follow-up dena available. Virologic failure was obviously higher among Pacientes receiving the placebo than among those on raltegravir. Among 41 Pacientes who took raltegravir ywho had genotypic analysis en failure, 9 had no integrase mutenions, y32 had 1 or more mutenions in the integrase gene. Two different genetic penhways to raltegravir resistance have been observed—one associened with the mutenion N155H ythe other with Q148K/R/H. In addition, there were other mutenions observed with both penhways then are shown on this slide. The mutenions appear to be proximal to the cenalytic center ysimilar to those then had been selected in in vitro experiments. Our knowledge concerning resistance to integrase inhibitors is growing as there are more studies in progress. Lener in this presentenion, issues concerning cross-resistance between this drug ythe other integrase inhibitor in development, elvitegravir, will be discussed. For more informenion about this study, see the Capsule Summary en: Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 35

36 BENCHMRK-1 y 2: Fracaso virológico y resistencia en la semana 48
Falla virológica generalmente asociada con mutaciones como Q148 o N155, en combinación con al menos alguna otra mutación. Falla virológica*: BENCHMRK-1: n = 50; BENCHMRK-2: n = 48 Falla virológica definida como < 1 log10 ↓ VIH-1 RNA de BL y > 400 c/mL a la semana 16 o falla > 1 log10 ↑ VIH-1 RNA a través de nadir o > 400 c/mL de nadir después de respuesta de < 400 c/mL (en 2 mediciones consecutivas ≥ 1 semana) 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

37 Desenlace primario: Semana 16 Duracion Planeada: Semana 48
BENCHMRK 1 y 2: Raltegravir (MK-0518) en pacientes experimentados a TARV Estudios fase III aleatorizados, doble enmascaramiento con placebo controlado. Desenlace primario: RNA HIV-1, conteo células CD4+, y eventos adversos en semana 16 Desenlace primario: Semana 16 Duracion Planeada: Semana 48 VIH-infectados, resistente triple-clase, HIV-1 RNA > 1000 copias/mL BENCHMRK-1 (N = 350) (Europa, Asia/Pacifico, Peru) BENCHMRK-2 (N = 349) (Norte, Sur America) Raltegravir 400 mg twice daily + OBR* BENCHMRK-1 (n = 232) BENCHMRK-2 (n = 230) BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; OBR, optimized background regimen; Pts, Pacientes. Another highlight of this conference was the presentenion of the results of the Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518 (BENCHMRK) trials. These were 2 parallel, phase III multinenional studies of raltegravir, previously known as MK‑0518, in treenment‑experienced Pacientes. These trials had a similar design to other studies involving treenment‑experienced Pacientes: Triple class–experienced Pacientes with viral loads > 1000 copias/mL were randomized to either treenment with raltegravir or a placebo, each combined with an OBR. For more informenion about this study, see the Capsule Summary en: Placebo + OBR* BENCHMRK-1 (n = 118) BENCHMRK-2 (n = 119) *antiretrovirales permitidos en OBR. Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 37

38 BENCHMRK 1 y 2: VL < 400 copias/mL (ITT, NC = F)
Raltegravir + OBR Placebo + OBR Semanas Pacientes con RNA VIH-1 < 400 copias/mL (%) P < .001 en semana 16 2 4 8 12 16 24 20 40 60 80 100 BENCHMRK-1 77% 41% 230 81 158 118 232 n = P < .001 en semana 16 Semanas 2 4 8 12 16 24 20 40 60 80 100 BENCHMRK-2 77% 43% 229 69 128 119 230 n = BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; ITT, intent to treen; NC = F, noncompleter equals failure; OBR, optimized background regimen; VL, viral load. An intent-to-treen analysis of Pacientes who achieved viral loads < 400 copias/mL was conducted. Pacientes who did not complete the trial were considered to have failed. Among the raltegravir arm, excellent results were obtained. A total of 77% of Pacientes receiving raltegravir achieved a viral load < 400 copias/mL en semana 24 in comparison to between 41% to 43% of those receiving placebo. For more informenion about this study, see the Capsule Summary en: Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 38

39 BENCHMRK 1 y 2: VL < 50 copias/mL (ITT, NC = F)
Raltegravir + OBR Placebo + OBR P < .001 en semana 16 61% 33% Semanas 2 4 8 12 16 24 230 81 158 118 232 n = 20 40 60 80 100 Pacientes con RNA VIH-1 < 50 copis/mL (%) BENCHMRK-1 P < .001 en semana 16 62% 36% Semanas 2 4 8 12 16 24 BENCHMRK-2 229 69 128 119 230 n = 20 40 60 80 100 BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; ITT, intent to treen; NC = F, noncompleter equals failure; OBR, optimized background regimen; VL, viral load. Similar results were found in the analysis of Pacientes who achieved viral loads < 50 copias/mL. Notably, 61% to 62% of Pacientes receiving raltegravir vs 33% to 36% of those receiving placebo achieved a viral load < 50 copias/mL. This is certainly an impressive result for this heavily treenment–experienced populenion. For more informenion about this study, see the Capsule Summary en: Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 39

40 BENCHMRK 1 y 2: CV < 400 c/mL y Semana 16 por Agentes Especificos en TOB
Raltegravir + TOB n Placebo + TOB Denos Eficacia Total 447 98 90 74 79 230 87 63 55 29 43 Efficacia por Agentes en OBR Enfuvirtide Darunavir + + 44 23 + – 42 24 BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; c/mL, copias/mL; OBR, optimized background regimen; VL, viral load; Wk, semana. A subset analysis of 677 Pacientes in BENCHMRK 1 y2 assessed renes of viral suppression en semana 16 based on the use of specific agents in the OBR, specifically enfuvirtide ydarunavir. In contrast to the MOTIVenE studies, this analysis was completed among first-time users of either of these drugs. This was a virologic-failure-carried-forward analysis in which those who discontinued participenion in the trial because of toxicity were censored from the analysis. Among Pacientes who received both enfuvirtide ydarunavir along with raltegravir, 98% achieved undetectable viral loads. It should be noted, however, then 87% of Pacientes who received placebo along with both enfuvirtide ydarunavir also achieved undetectable viral loads. This is probably relened to the fact then these Pacientes now had 2 active drugs in their OBR. However, among Pacientes who received either enfuvirtide or darunavir in their background regimen, there was a clear advantage for the raltegravir treenment arm with approximenely 90% of raltegravir-treened Pacientes reaching < 400 copias/mL vs 63% or 55% of placebo-treened subjects who received enfuvirtide or darunavir, respectively. Moreover, a larger proportion of Pacientes who received raltegravir yhad neither enfuvirtide nor darunavir in their background regimen achieved viral loads < 400 copias/mL than those who received the placebo with neither drug in their OBR (74% vs 29%, respectively). The proportion of Pacientes who achieved undetectable viral load was lower among both the raltegravir yplacebo groups in those who did not receive either enfuvirtide or darunavir vs those who did receive one or both of these drugs. Thus, these dena emphasize the importance of having en least 2 active drugs in any regimen. For more informenion about this study, see the Capsule Summary en: – + 80 47 – – 191 90 + : Primer uso in OBR – : No uso en OBR 20 40 60 80 100 Pacientes (%) Analisis estadistico : Fracaso virologico continuó. Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 40

41 BENCHMRK 1 y 2: CV < 400 c/mL en Sem 16 por FSS/GSS de TOB
Raltegravir + TOB n Datos Eficacia Total Placebo + TOB 447 87 61 76 57 85 89 79 230 5 41 57 10 43 71 (FSS) 62 44 141 1 68 222 2 o más 110 (GSS) 111 BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; c/mL, copias/mL; GSS, genotype susceptibility score; OBR, optimized background regimen; PSS, phenotype susceptibility score; VL, viral load; Wk, semana. A similar analysis of virologic responses was conducted based on either the phenotypic susceptibility score or the genotypic susceptibility score of the OBR. This slide illustrenes the number of active drugs in the OBR as defined either by genotype or phenotype ythe corresponding viral activity of the entire regimen. As demonstrened by the dena, there was clearly an advantage to having a higher number of active drugs in the background regimen. This was true for both the raltegravir yplacebo groups, although the Pacientes receiving raltegravir did better in each case in comparison with the corresponding group in the placebo-treened arm, presumably due to the addition of the active drug raltegravir. It is important to note, however, then darunavir was assumed to be a fully active drug in all darunavir-naive Pacientes because phenotypic susceptibility testing for darunavir was not available en the study outset (although it is now routinely provided by commercial assays). Studies have suggested then darunavir does retain activity against most PI-resistant viral variants; however, some such variants do have reduced susceptibility to darunavir. When trying to extrapolene these findings to one’s own Pacientes, it is important to remember then darunavir may not necessarily be a fully active drug in all PI-experienced Pacientes even if they are darunavir naive ythen, as with any other antiretroviral, it is important to assess susceptibility by genotypic or phenotypic testing. For more informenion about this study, see the Capsule Summary en: 63 170 1 93 159 2 or mas 70 20 40 60 80 100 Analisis estadistico : Fracaso virologico continuó. Pacientes (%) Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 41

42 BENCHMRK 1 y 2: Eventos Adversos y Resistencia Análisis Parcial
Eventos adversos y de laboratorio en grupos raltegravir + TOB Vs placebo + TOB Fracaso virologico: raltegravir vs placebo: 76 (16%) vs 121 (51%) 41 Pacientes raltegravir con análisis de genotipo: 9 no mutaciones en integrasas; 32 Tenían ≥ 1 mutacion en integrasa Fracaso Raltegravir fue asociado con 1 de 2 vías geneticas : N155H or Q148K/R/H Mutaciones adicionales en las dos vías N155H + (E92Q,V151I, T97A, G163R, L74M) Q148K/R/H + (G140S/A, E138K) Puede existir otras vías eg, Y143R/C + (L74A/I, E92Q, T97A, I203M, S230R) BENCHMARK, Blocking Integrase in Treenment Experienced Pacientes With a Novel Compound against HIV: MeRcK, MK-0518; OBR, optimized background regimen. In terms of adverse events ylaborenory abnormalities, in the BENCHMRK studies raltegravir yplacebo appeared to be comparable regarding clinical adverse effects and/or laborenory abnormalities. Earlier studies with raltegravir demonstrened similar findings. In fact, there have not been any obvious drug‑specific adverse effects or toxicities entributed to raltegravir to dene, according to the limited follow-up dena available. Virologic failure was obviously higher among Pacientes receiving the placebo than among those on raltegravir. Among 41 Pacientes who took raltegravir ywho had genotypic analysis en failure, 9 had no integrase mutenions, y32 had 1 or more mutenions in the integrase gene. Two different genetic penhways to raltegravir resistance have been observed—one associened with the mutenion N155H ythe other with Q148K/R/H. In addition, there were other mutenions observed with both penhways then are shown on this slide. The mutenions appear to be proximal to the cenalytic center ysimilar to those then had been selected in in vitro experiments. Our knowledge concerning resistance to integrase inhibitors is growing as there are more studies in progress. Lener in this presentenion, issues concerning cross-resistance between this drug ythe other integrase inhibitor in development, elvitegravir, will be discussed. For more informenion about this study, see the Capsule Summary en: Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. 42

43 Fase etiqueta abierta*
Protocolo 005: Raltegravir + TOB en pacientes con virus resistentes a tres clases de medicamentos Estudio aleatorizado, doble ciego, controlado por placebo, de rango de dosis, fase IIb semana 24 Semana 48 Fase doble ciego Fase etiqueta abierta* Raltegravir 200 mg 2 día + TOB* (n = 43) Raltegravir 400mg 2 día + TOB* (n = 100) Pacientes con resistencia a tres clases, VIH-1 RNA > 5000 copias/mL y conteo de CD4+ > 50 cells/mm3 (N = 178) Raltegravir 400 mg 2 día + TOB* (n = 45) BID, twice daily; OBR, optimized background regimen; RAL, raltegravir *Pacientes que recibieron raltegravir 400 mg 2 veces día, etiqueta abierta después de por lo menos 24 semanas de terapia doble ciego. La duración media de la fase doble ciego fue de 40 semanas para los grupos raltegravir y 24 para placebo. Raltegravir día + TOB* (n = 45) Placebo + TOB* (n = 45) *DRV/RTV no estaba disponible para su uso en TOB Grinsztejn B, et al. ICAAC Abstract H-713.

44 Protocolo 005: resultados semana 48
Raltegravir 200 mg 2 día Raltegravir 400 mg 2 día Raltegravir 600 mg 2 día Placebo L[inea de base prospectiva para FV ITT, NC = F Doble-ciego solo Doble-ciego + etiqueta abierta Doble-ciego solo Doble ciego + etiqueta abiertal 100 200 80 150 60 100 VIH-1 RNA < 50 copias/mL (%) Cambio en el conteo de CD4+ (cells/mm3) 40 50 BID, twice daily; ITT, intent-to-treat; NC=F, non-completers = failure; VF, virologic failure 20 -50 2 4 8 12 16 24 32 40 48 2 4 8 12 16 24 32 40 48 semana semana No. de pacientes contribuyentes No. de pacientes contribuyentes 43 43 42 43 41 37 45 45 44 45 43 44 45 45 45 45 42 43 45 45 45 43 Grinsztejn B, et al. ICAAC Abstract H-713.

45 Protocol 005: resultados semana 48
Raltegravir 200 mg 2 día Raltegravir 400 mg 2 día Raltegravir 600 mg 2 día Placebo ITT, NC = F Línea de base prospectiva para FV Doble ciego solo Doble ciego + etiqueta abierta Doble-ciego solo Doble ciego +etiqueta abiertal 100 200 80 150 60 100 Cambio en el conteode CD4+ (cells/mm3) VIH-1 RNA < 50 copias/mL (%) 40 50 BID, twice daily; ITT, intent-to-treat; NC=F, non-completers = failure; VF, virologic failure 20 -50 2 4 8 12 16 24 32 40 48 2 4 8 12 16 24 32 40 48 semana semana No. de pacientes contribuyentes No. de pacientes contribuyentes 43 43 42 43 41 37 45 45 44 45 43 44 45 45 45 45 42 43 45 45 45 43 Grinsztejn B, et al. ICAAC Abstract H-713.

46 Protocol 005: resistencia a Raltegravir
38 (29%) de los 133 recibiendo RAL en La fase doble ciego, tuvieron falla virológica (rebote o falla en alcanzar CV VIH-1 RNA < 400 copies/mL) Datos de genotipificación disponibles para los 38 casos La mayoría (35/38) tenían mutaciones de la integrasa que les conferían resistencia a raltegravir Vía de mutación N155 o Q148 presente en 34/35 ≥ 2 mutaciones presentes in 31/35 pacientes Q148H/G140S fué la combinación más frecuente (n = 13) Factores asociados con probabilidad reducida de mutaciones en el fracaso VIH-1 RNA ≤ 100,000 copias/mL Uso por primera vez de ENF en el TOB Clasificación de susceptibilidad fenotípica > 0 OBR, optimized background regimen; RAL, raltegravir; VL, viral load Grinsztejn B, et al. ICAAC Abstract H-713.

47 Inhibidor de Integrasa Elvitegravir (GS-9137) en Pacientes Experimentados
Estudio fase II (determinado dosis), aleatorizado, parcialmente enmascarado (dosis de elitegravir) Desenlace primario: Tiempo promedio ponderado de cambio en ARN VIH de línea basal a semana 24 (DAVG24). Sem 16 Sem 24 Estratificado por ENF en OBR Elvitegravir/RTV 20/100 mg + OBR*†‡ (n = 71) Pacientes HIV-infectados; CV ≥ 1000 copias/mL; Conteo células CD4+; ≥ 1 mutación IP (N = 278) Elvitegravir/RTV 50/100 mg + OBR*† (n = 71) CPI, comparenor PI; DAVG24, timed-average difference en semana 24; DRV, darunavir; DSMB, dena ysafety monitoring board; ENF, enfuvirtide; OBR, optimized background regimen; RTV, ritonavir; TPV, tipranavir; VL, viral load. Elvitegravir, previously known as GS-9137, is another integrase inhibitor in development. A phase II dose‑finding study of ritonavir‑boosted elvitegravir was conducted in treenment‑experienced Pacientes with viral loads > 1000 copias/mL ywith en least 1 PI mutenion. This was a randomized, active‑controlled, partially blinded (to the dose of elvitegravir) study. Pacientes were randomized to one of 3 different doses of elvitegravir/ritonavir (20/100 mg, 50/100 mg, or 125/100 mg) plus OBR vs a comparenor PI plus OBR. It is important to note then PIs were initially excluded from the OBR because of lack of informenion on drug interactions between elvitegravir yPIs. In addition, NNRTIs were excluded from the OBRs in the elvitegravir arms. Thus, the background regimens in this study were not truly optimized as they only consisted of NRTIs with or without enfuvirtide. This informenion becomes important lener as we analyze the results of the study. For more informenion about this study, see the Capsule Summary en: Elvitegravir/RTV 125/100 mg + OBR*† (n = 73) CPI/RTV + OBR* (n = 63) *OBR = NRTIs ± ENF (NNRTI fue excluido †TPV yDRV permitido despúes semana 16. ‡Descontinuado en semana 16 por DMSB. Zolopa A, et al. CROI Abstract 143LB. 47

48 Elvitegravir: Análisis desenlace primario
Promedio ponderado en el tiempo Δ de línea basal a semana 24 (DAVG24) en HIV-1 RNA GSS = 0 para NRTIs por 50% de Pacientes; media 11 mutaciones de proteasa Primer uso de ENF en 17% a 26% de Pacientes En brazo CPI, 49% incluído DRV; 27% incluído TPV Brazos Elvitegravir 50-mg y125-mg reunieron criterios de no inferioridad DAVG24 vs CPI Brazo Elvitegravir 125-mg demostró disminución significativa en media de RNA HIV-1 en Semanas 16 y 24 vs CPI Elvitegravir 50 mg (n = 71) Elvitegravir 125 mg (n = 73) CPI (n = 63) -0.4 Δ VL en Wk 24 (DAVG24) -0.8 -1.2 -1.2 CPI, comparenor PI; DAVG24, timed-average difference en semana 24; DRV, darunavir; ENF, enfuvirtide; GSS, genotype susceptibility score; RTV, ritonavir; TPV, tipranavir; VL, viral load; Wk, semana. Before discussing the primary endpoint analysis, it is important to discuss when we know about the activity of the OBR for each group. First, the genotypic susceptibility score for NRTIs was 0 for one half of the Pacientes in this study. In addition, there was a mean of 11 protease mutenions seen in the subjects. These genotypic susceptibility scores as presented in the dena in this slide did not count enfuvirtide when assessing the number of active agents. Nevertheless, the genotype susceptibility score does give an indicenion of the large proportion of Pacientes in this study who were receiving relenively few active drugs. In the comparenor PI arm, 49% of the subjects received darunavir y27% received tipranavir. The 2 highest-dose arms of elvitegravir/ritonavir (50/100 mg y125/100 mg) met the noninferiority criteria for viral load reduction compared with the comparenor PI. The highest‑dose arm of 125/100 mg showed significantly greener mean decrease in viral load en semana 16 ysemana 24 compared with the comparenor PI arm. This is represented graphically on the figure; the table below shows the percentage of Pacientes with viral loads < 50 copias/mL en semana 16. The differences among the arms for this endpoint are not stenistically significant. Differences in CD4+ cell count increase en semana 16 among the arms (dena not shown) were also not stenistically significant. For more informenion about this study, see the Capsule Summary en: -1.6 -1.4 P = .27* -1.7 -2.0 P = .02* *Pairwise comparison vs CPI/RTV. semana 16 HIV-1 RNA < 50 copias/mL,% CPI 30 Elvitegravir 50 mg 38 Elvitegravir 125 mg 40 Zolopa A, et al. CROI Abstract 143LB. 48

49 Elvitegravir: Eventos Adversos y Resistencia
Eventos adversos similares al IP comparador[1] Resistencia en loci 66 y 92 2] Potencial resistencia cruzada con raltegravir in vitro; Significancia clínica? Adverse events among the elvitegravir/ritonavir arms were similar to those seen in the comparenor PI arm. There appeared to be 2 resistance penhways with mutenions en loci 66 y92 then were accompanied by additional mutenions. Additionally, another presentenion en the conference indicened then there does appear to be some potential for cross‑resistance with raltegravir in vitro. The clinical significance of these findings has yet to be determined. For more informenion about this study, see the Capsule Summary en: 1. Zolopa A, et al. CROI Abstract 143LB. 2. Jones G, et al. CROI Abstract 627. 49

50 Cambio medio de línea basal en log10 HIV-1 RNA, copias/mL
Elvitegravir 125 mg: Cambio de CV en línea basal por actividad de OBR Elvitegravir 125 mg sin drogas activas en OBR (n = 26) Elvitegravir 125 mg con ≥ 1 NRTI activa o primer uso de ENF (n = 47)* semana 2 4 8 12 16 20 24 -0.7 -1 Cambio medio de línea basal en log10 HIV-1 RNA, copias/mL BL, baseline; ENF, enfuvirtide; OBR, optimized background regimen; VL, viral load. This graph demonstrenes the importance of having active drugs in the background regimen. It includes the dena for the highest‑dose arm—elvitegravir/ritonavir 125/100 mg—yexamines the change from baseline in viral load based on the number of active drugs in the OBR. The green line represents those Pacientes who did not receive any active drugs, then is, neither an active NRTI nor enfuvirtide. Among these Pacientes, there was an initial viral load response, which quickly started to return toward baseline; as a result, the overall durability of response was limited throughout the 24 Semanas. The orange line represents the results of Pacientes who had en least 1 active drug in their OBR—either an NRTI or first use of enfuvirtide. These Pacientes had a 2 log10 copias/mL reduction in viral load then was sustained throughout the 24 Semanas. In fact, although these dena are not shown on the slide, Pacientes who received enfuvirtide exhibited better suppression of viral load than those who had not. It is important to stress then the orange line represented in this slide combines dena from those with both first-time use of enfuvirtide those who had who received an active NRTI. The active NRTI was likely to have been recycled in many of the Pacientes. For more informenion about this study, see the Capsule Summary en: P < .001 -2 -2.1 -3 *Datos de Pacientes con elvitegravir 125 mg después de la adición de un IP se excluyerón. Zolopa A, et al. CROI Abstract 143LB. 50

51 Elvitegravir en pacientes experimentados
Estudio aleatorizado, con control activo, parcialmente ciego (dosis de elvitegravir), de fase II, para búsqueda de dosis Desenlace primario: cambio en el tiempo promedio desde línea de base en VIH RNA durante 24 semanas (DAVG24) Semana 16 Estratificado por ENF en TOB Semana24 Elvitegravir/RTV 20/100 mg + OBR*†‡ (n = 71) Pacientes VIH positivos con VIH-1 RNA ≥ 1000 copias/mL, cualquier conteo de CD4+ y ≥ 1 mutación para IP (N = 278) Elvitegravir/RTV 50/100 mg + OBR*† (n = 71) CPI, comparator PI; DAVG24, timed-average difference at Week 24; DRV, darunavir; DSMB, data and safety monitoring board; ENF, enfuvirtide; OBR, optimized background regimen; RTV, ritonavir; TPV, tipranavir; VL, viral load. Elvitegravir/RTV 125/100 mg + OBR*† (n = 73) CPI/RTV + OBR* (n = 63) *TBO = INTRs ± ENF (INNTRs excluidos). †TPV y DRV permitidos después de semana 16. ‡Descontinuado a la semana 16 por DMSB. Zolopa A, et al. ICAAC Abstract H-714. 51

52 Elvitegravir 125/100 mg: DAVG total y con ENF primera vez
2.0 CPI/RTV EVG/RTV 125/100 mg DAVG tras 24 semanas total 1.0 DAVG tras 16 semanas Primera vez ENF DAVG tras 24 semanas Primera vez ENF Cambio promedio en VIH-1 RNA (log10 copias/mL) -1.0 CPI, comparator PI; ENF, enfuvirtide; EVG, elvitegravir; RTV, ritonavir; VL, viral load. -1.2 -1.5 -1.6 -2.0 -1.7 P = .02 -2.5 -2.6 -3.0 P = .02 P = .03 Zolopa A, et al. ICAAC Abstract H-714.

53 Elvitegravir 125/100 mg: respuesta virológica por agentes activos en TOB
semana 100 P = .0001 4 8 12 16 20 24 75 P = .04 74 -1 desde línea base (log10 copias/mL) Cambio promedio en VIH-1 RNA -0.7 VIH-1 RNA < 50 copias/mL a la semana 16 (%) P < .03 50 -2 P < .0001 44 -1.7 P < .02 30 ENF, enfuvirtide; OBR, optimized background regimen; VL, viral load -3 25 15 -2.9 No agentes activos en TOB (n = 26) ³ 1 INTR activo sin primera vez de ENF (n = 28) Primera vez de ENF ± INTRI activo (n = 19) No TOB activo 1 INTR activo* ≥2 INTR activos* primeraVez ENF† *sin primera vez de ENF. †Con o sin INTR activo. Datos de pacientes despúes de adicionar IP fueron excluidos Zolopa A, et al. ICAAC Abstract 714.

54 Blanco Terapéutico y Grupo Farmacológico
Ciclo de Replicación del VIH Entrada Inhibidores de la unión gp120-CD4 Antagonistas de co-receptores Inhibidores de Fusión 1 ADN Celular ADN proviral no integrado CD4 Fusión ADN proviral Integrado gp120 Transcriptasa Reversa Síntesis Proteica Co-receptor RNA Genómico RNAm Transcripción Reversa Inhibidores de la Transcriptasa Reversa 2 Integración Inhibidores de la Integrasa 3 Maduración y Ensamblaje Inhibidores de la proteasa Inhibidores de maduración 4 Gemación Viral

55 Inhibidores de la Integración del ADN viral
Inhibidores de maduración PA-457 Impide la formación del precursor p24 a partir de p25 Fase II

56 INTERSTART: Interleucina-2 previo a HAART en pacientes no tratados
Ensayo fase II/III etiqueta abierta, aleatorizado, controlado, con análisis primario a la semana 96 Interleucina-2 3 ciclos de 4.5 MIU 2 veces día por 5 días a las semanas 0, 8 y 16* (n = 65) Pacientes (or ≤ 6 sin HAART), conteo de CD4+ entre cels/mm3 (N = 128) Seguimiento hasta la semana 96 Observacion (n = 63) *cuarto ciclo opcional a la semana 24 si el conteo de CD4+ era dos veces menor que el valor de la línea de base; 1 o 2 ciclos adicionale desde semanas si los CD4+ eran 1.2 veces menores a la línea de base. Molina J, et al. ICAAC Abstract H-718.

57 INTERSTART: Tasa de fracaso menor en el brazo de interleucina-2
Desenlace hasta semana 96 Interleucina-2 (n = 65) Observación (n = 63) Fracaso,* % 36† 61 Causa de fracaso, n Conteo CD4+ < 300 cels/mm3 18 28 Inicio de HAART 4 6 Evento definitorio de SIDA 2 Muerte 1 La interleucina 2 aumenta el conteo de CD4+ (+51 vs -64 cels/mm3; P < .0001) sin afectar la carga viral en plasma (VIH-1 RNA) La interleucina retrasa significativamente el tiempo hasta el inicio de HAART *Fracaso definido como conteo CD4+ < 300 cels/mm3, inicio de HAART, evento definitorio de SIDA o muerte. †P = .006 vs observación. Molina J, et al. ICAAC Abstract H-718.