Actualidad y tendencia de tratamiento ARV. Dr. Miguel A Arreola P HE CMN S XXI

Transcripción

1 Actualidad y tendencia de tratamiento ARV Dr. Miguel A Arreola P HE CMN S XXI

2 Terapia antirretroviral en 2006 Inhibidores de TR Nucleosidos AZT, DDI,DDC,D4T, 3TC, ABC TDF, FTC No nucleósidos Efavirenz, nevirapina Inhibidores de Proteasa Nelfinavir Indinavir Saquinavir FosAmprenavir Lopinavir/r Atazanavir Tipranavir Enfuvirtida Darunavir Inhibidores de Fusión

3 Retos y necesidades en el tratamiento antirretroviral. Retos Apego Toxicidad Potencia Resistencia Costo Curación Necesidades Simplificar mejorar tolerancia Bajar toxicidad mayor actividad virus resistentes Reservorios Nuevos blancos Vacunas

4 Selección de un tratamiento ARV y posibles puntos de falla Tasa de replicación (CV) Tasa de mutación (GT) Reservorios (?) Patogenicidad VIRUS ARVs Potencia Duración PK Interacciones Tolerancia Conveniencia Barrera genética PACIENTE Apego Acceso al medicamento Resistencia primaria Absorción y metabolismo Etapa de la enfermedad

5 Inicio del Tratamiento 2 ITRAN + IDV 2 ITRAN + SQV 2 ITRAN + RTV 2 ITRAN + LPV Secuencia? 2 ITRAN + IDV 2 ITRAN + SQV 2 ITRAN + LPV 2 ITRAN + ATV 2 ITRAN + TMC 2 ITRAN + FosAPV rtv Dr. Arreola.

6 Nuevas formulaciones/dosis Nucleósidos D4T liberación n prolongada DDI CE AZT/3TC/Abacavir Abacavir No nucleósidos Efavirenz 600 mg Inhibidores de proteasa Saquinavir gel suave/ SQV tabletas 500 mg Nelfinavir BID. Potenciación n farmacológica con RTV Atazanavir Prodroga de Amprenavir (FPV). LPV/r tabs 2x2. I. Fusión Enfuvirtida

7 Nuevos blancos para agentes antirretrovirales Inhibidores de proteinas reguladoras Inhibidores de desenvoltura Inhibidores de RNAsa II Inhibidores de dedos de zinc Inhibidores de ensamblaje y de formacion de capside.

8 Nuevas clases de antirretrovirales en desarrollo Inhibidores de entrada unión. n. CD4s,, otros inhibidores de co-receptores. Inhibidores de CXCR4 y de CCR5 inhibidores de fusión. T-1249T Inhibidores de integrasa. en fases clínicas en MéxicoM

9 Nuevos objetivos del Tx Unión, fusión y entrada Proteínas de la nucleocápside (zinc-finger) Proteasa Viral Transcriptasa viral RNA RT RNA DNA RT DNA RNA RNA Proteins Proteinas reguladoras virales DNA Provirus Integrasa viral

10 Nuevo Escenario ARV ITRAN/ITRANt Abacavir Alovudina Amdoxovir D-d4FC D-FDOC Didanosina-EC FTC Lamivudina SPD754 Reverset Stavudina-XR Tenofovir GS 7340 Zalcitabina Zidovudina ITRnAN Calanolida A Capravirina Delavirdina Efavirenz Nevirapina TMC 125 I. INTEGRASA L I. FUSION BMS Enfuvirtida GW T 1249 IPs Amprenavir Atazanavir Fosamprenavir Indinavir Lopinavir/r Nelfinavir /r Ro Saquinavir Tipranavir TMC 114 I. CCR5 SCH D AK 602 PRO 140 TAK 220 UK 427,857 I. CXCR4 AMD 070 I. DE CD4 BMS 806 PRO 542 TNX 355

11 PRIMERA LINEA

12 Circulación Sistémica Cómo actúa el refuerzo o booster? Vena Hepática Cmin > EC 50/90 SQV HGC SQV SGC Arteria hepática SQV Porta Intestino

13 Vena hepática Circulación sistémica Cmin > EC50/90 HGC SQV SGC Arteria hepática RTV SQV Porta Intestino

14 Terapia IP reforzado: Evitando toxicidad Concentración de fármaco Concentraciòn del fàrmaco arriba del umbral de toxicidad: Limitante por toxicidad Umbral de toxicidad Umbral de eficacia 0 0 Drug concentrations below inhibitory levels: viral rebound Tiempo (horas) 24 Refuerzo IP IP

15 Individualización de los tratamientos reforzados con IP s Tratamiento con IP s reforzados QD: Primer esquema, casos sin manejo previo con IP s, falla a IP s por toxicidad o mal apego. Tratamiento con IP s reforzados BID: Primer esquema, falla a IP s con resistencia mínima. Tratamiento con IP s doble refuerzo : Resistencia multiple a IP s y esquemas de rescate.

16 Antiviral efficacy of HAART HIV RNA < 50 copies/ml at week 24 (ITT) ATV/r + d4t + 3TC BMS-008 * 38% FPV/r + ABC + 3TC GSK SOLO * 55% LPV/r (od) + FTC + TDF Abbott % LPV/r + d4t + 3TC Abbott M * 65% NVP (bid) + d4t + 3TC Gilead 2NN * FTC % EFV + ddi + d4t Gilead FTC-301 EFV + TDF + 3TC Gilead 903 EFV + ddi + FTC SQV/r + 2 NRTIs *HIV RNA at 24 weeks estimated from graph Gilead FTC-301 Staccato 91% Subjects with HIV RNA < 50 copies/ml (%) ATV 400 mg results used 1. Murphy et al. AIDS 2003; 17: Gathe et al. AIDS 2004; 18: Podzamczer et al. 9th EACS Abstract F1/3 4. Walmsley et al. N Engl J M,ed 2002; 346: van Leth et al. Lancet. 2004; 363: Saag et al. JAMA 2004; 292: Staszewski et al. 10 th CROI Poster 564b 8. Ananworanich et al. XV IAC Poster TuPeB % 78% 81%

17 SQV/r: High percentage of patients with < 400 and < 50 copies/ml at 24 weeks (ITT) Patients (%) < 400 copies/ml < 50 copies/ml 95.2% 91.0% Time (weeks) Ananworanich et al. XV IAC 2004; Poster TuPeB4469

18 SQV/r: Change in median CD4 count from baseline over 24 weeks Median change in CD4 count from baseline (cells/mm 3 ) p < vs. baseline Time (weeks) Ananworanich et al. XV IAC 2004; Poster TuPeB4469

19 MaxCmin1: SQV/r is more potent than IDV/r (ITT) due to superior tolerability profile HIV RNA < 50 copies/ml at 48 weeks On treatment Intent-to-treat/exposed p = ns p = % 79% Patients (%) % 57% 0 IDV/r SQV/r ITT analysis includes all patients who received at least one dose of randomized medication; switch = failure Gerstoft et al. 42 nd ICAAC Abs H-172 Dragsted et al. J Infect Dis 2003; 188: IDV/r OT analysis includes all patients who remained on randomized medication at 48 weeks SQV/r

20 MaxCmin2: similar viral load response Patients (%) MaxCmin2 HIV RNA < 50 copies/ml at week 48 On treatment Intent-to-treat p = ns p = ns 75 % 70 % 60 % 53 % 20 0 LPV/r SQV/r ITT analysis includes all patients who received at least one dose of randomized medication; switch = failure Youle et al. 2 nd IAS Poster LB-23 LPV/r OT analysis includes all patients who remained on randomized medication at 48 weeks SQV/r

21 QUAD: SQV/r + NRTIs achieved median 4 log 10 reduction in HIV RNA (ITT) HIV RNA (copies/ml) SQV/r 1000/100 mg bid plus CBV TZV 10 BL Time (weeks) Adapted from Staszewski et al. 9 th EACS Oral F1/1

22 QUAD: impressive virological response after 48 weeks (OT) 100 Patients (%) SQV/r + CBV < 400 copies/ml SQV/r + TZV < 400 copies/ml SQV/r + CBV < 50 copies/ml SQV/r + TZV < 50 copies/ml 0 CBV n = TZV n = BL Adapted from Staszewski et al. 9 th EACS Oral F1/1 Time (weeks)

23 QUAD: rapid CD4 recovery reducing risk of opportunistic infection 200 Median CD4 count* (cells/mm³) *ITT LOCF SQV/r 1000/100 mg bid plus CBV TZV BL Time (weeks) Staszewski et al. 9th EACS Oral F1/1

24 Enfuvirtida TM Fuzeon TM

25 Mecanismo de Acción Aproximación de la partícula viral a los receptores CD4 Adhesión de la gp 120 a los receptores CD4 Unión de la proteína gp 120 a los co-receptores CD4+ Desprendimiento de la proteína gp 120 Inserción de la gp 41 Retracción de la partícula viral hacia la célula Aparece FUZEON Inhibe la fusión

26 Enfuvirtida + TO cambio promedio de CV y CD4 desde el inicio (On-Treatment) 166 CD4 mean change from BL CD4 0 RNA mean change from BL Viral load CD4 VL Study Week

27 Conclusiones La carga viral disminuye considerablemente desde el inicio de la terapia La respuesta de CD4s y CV se mantiene durante 96 semanas FUZEON fue bien tolerado y en general no se relaciono con toxicidad sistémica No se presentaron eventos adversos adicionales entre la semana 48 y la 96. La reacción n en el sitio de la inyección n fue el evento adverso presente.

28 Otros estudios con nuevos fármacos

29 2006 Update of IAS-USA Guidelines for Initial Therapy Recommended Components of Initial Antiretroviral Therapy* NRTIs TDF/FTC ZDV/3TC ABC/3TC NNRTIs EFV (NVP) PIs LPV/RTV ATV/RTV FPV/RTV SQV/RTV Hammer S, et al. JAMA. 2006;296: *Therapy should consist of 2 NRTIs + either an NNRTI or PI. Or 3TC. Or FTC.

30 ACTG 5142: Change in CD4+ Cell Count at Week 96 P =.96 Median CD4+ Change, cells/mm P = P = LPV/RTV + 2 NRTI EFV + 2 NRTIs LPV/RTV + EFV Riddler S, et al. IAC Abstract THLB0204.

31 KLEAN: FPV/RTV vs LPV/RTV as Initial Therapy Phase IIIb, randomized, open-label, 48-week study FPV/RTV 700/100 mg BID (n = 434) vs LPV/RTV SGC (400/100 mg BID) (n = 444) + ABC/3TC (600/300 mg) QD No difference in virologic outcome overall or stratified by baseline VL or CD4+ count CD4+ gain: +176 (FPV/RTV) vs +191 (LPV/RTV) (ITT-E) VL Suppression at Wk 48 (%) TLOVR Analysis < 400 c/ml < 50 c/ml 73% FPV/ RTV 71% LPV/ RTV 66% FPV/ RTV 65% LPV/ RTV Eron JJ Jr, et al. Lancet. 2006;368:

32 GS934: HIV RNA < 400 and < 50 copies/ml at Week 96 (TLOVR) 100 Responders (%) FTC/TDF < 400: 75% FTC/TDF < 50: 67% ZDV/3TC < 400: 62% ZDV/3TC < 50: 61% P (< 400) =.004 P (< 50) = BL Gallant J, et al. IAC Abstract TUPE0064. Weeks

33 MONARK: LPV/RTV Monotherapy vs LPV/RTV + 2 NRTIs in Naive Patients Week 24 Week 48 Week 96 Antiretroviral naive; VL < 100,000; CD4+ > 100 (N = 138) LPV/RTV monotherapy SGC 400/100 mg BID (n = 83) LPV/RTV SGC 400/100 mg BID + ZDV/3TC 300/150 mg BID (n = 53) Primary efficacy analysis Proportion of subjects with HIV-1 RNA < 400 copies/ml at Week 24 AND < 50 copies/ml at Week 48 Delfraissy JF, et al. IAC Abstract THLB0202.

34 MONARK: HIV RNA < 400 and < 50 copies/ml at Week 48 (ITT Analysis) 100 % Patients (ITT, 95% CI) LPV/RTV < % Triple < % Triple < 50 75% LPV/RTV < 50 71%* < 400 copies/ml < 50 copies/ml 0 Sample Size LPV/r Arm: 83 Triple Arm: Week Delfraissy JF, et al. IAC Abstract THLB0202. *3 intensified with ZDV/3TC

35 OK04 Study: LPV/r Maintenance Monotherapy vs Continued HAART Randomized 1:1 Primary endpoint Week 48 Monotherapy Strategy HIV-infected patients with VL < 50 copies/ml for 6 months on LPV/RTV + 2 NRTIs for 1 month; no history of virologic failure on a PI (N = 198) LPV/RTV SGC 400/100 mg BID Reintroduction of NRTIs permitted for virologic rebound (n = 100) Triple Therapy Strategy LPV/RTV SGC 400/100 mg BID + 2 NRTIs (n = 98) Arribas J, et al. IAC Abstract THLB0203.

36 OK04 Study: LPV/RTV Maintenance Monotherapy vs Continued HAART Similar median time < 50 copies/ml at baseline in both groups ( mos) Proportion without therapeutic failure 94.0% vs 89.8% for monotherapy vs triple therapy Time to virologic failure not significantly different 4 LPV/RTV monotherapy pts required intensification with NRTIs for virologic rebound > 500 copies/ml Sensitivity (ITT) analysis (reintensification( = failure) 85.0% vs 89.8% for monotherapy vs triple therapy Primary PI resistance mutations 2 pts on monotherapy vs 1 on triple therapy Arribas J et al. IAC Abstract THLB0203.

37 RESIST 1 TPV/r vs Otros IP/r En presencia de mutaciones a IP En ausencia de mutaciones a IP (1-2) Análisis a 24 semanas Porcentaje de pacientes con eficacia (> 1 log) TPV/r IP/r Schapiro

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40 RESIST 2 TPV/r vs LPV/r Terapia optimizada por genotipo Dos medicamentos activos Pacientes pretratados 2 Carga viral (log promedio) LPV/r TPV/r semanas Cooper

41 Booster de TMC (power( power) Estudio en pacientes con experiencia triple clase 50 TMC 114/r IP/r 2 Seguimiento a 24 semanas (multicéntrico) TO+ENF+TMC 114/r (600/100mg BID) vs Otro IP/r La dosis ya fue seleccionada Tolerancia adecuada y comparable a otros esquemas booster % pts CV < 50 copias TMC IP/r <50 copias CV Log (-) 1 0 RNA CV log (-) Haubrich

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43 Qué pasa con las resistencias en la actualidad?

44 SPREAD: Transmitted Drug Resistance in Europe, nation study in Europe and Israel 1083 newly diagnosed patients in Overall prevalence of any resistance: 9% 71% of pts with drug resistance had single mutation Implies little loss of susceptibility to boosted PIs Prevalence of Mutations, , % Any NRTI NNRTI PI 2 Classes Wensing AMJ, et al. IAC Abstract TUAB00101.

45 Transmitted Drug Resistance Over Time: SPREAD and CATCH Comparison of data from SPREAD (Europe and Israel) with earlier retrospective data from CATCH (Europe) Prevalence of Mutations, % NRTI NNRTI PI Wensing AMJ, et al. IAC Abstract TUAB CATCH SPREAD

46 Nuevo enfoque SEGURIDAD Lo más m nuevo A los médicos m nos interesan los pacientes!!!

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48 Why do patients stop therapy? Reasons for discontinuation of a first HAART regimen by 45 weeks in ICONA cohort (n = 862) Toxicity 58.3% Virological failure 14.1% Other 8.0% Non-adherence 19.6% d Arminio Monforte et al. AIDS 2000; 14:

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51 Tolerability and convenience drive adherence, which drives efficacy Tolerability and convenience

52 Tolerability and convenience drive adherence, which drives efficacy Adherence Tolerability and convenience

53 Tolerability and convenience drive adherence, which drives efficacy Adherence Tolerability and convenience Efficacy

54 Hyperlipidaemia Prevalence (%) 15 Incidence of coronary events in 8 years of follow-up (%) Total Cholesterol to HDL-Cholesterol Ratio Munster heart study

55 D:A:D Prolonged Antiretroviral Exposure and Myocardial Infarction 10 Incidence of MI Per 1000 PY Events PYFU None All subjects < > 6 Exposure to HAART (Yrs) El-Sadr W, et al. Abstract 42.

56 D:A:D Prolonged Antiretroviral Exposure and Myocardial Infarction Updated analysis shows continuing increase in risk with longer duration [1] Increased risk partially but not completely explained by dyslipidemia HAART per add l year Age per 5 yrs older Male sex Previous CVD Adjusted RR, 1.17 (95% Cl, ) However, trend for decreasing MI incidence from after adjusting for smoking, lipid-lowering lowering therapy [2] 0 Smoking Family history [2] 1 10 Relative rate of MI (95% Cl) Multivariate model; adjusted for family history, BMI, HIV risk, cohort, year and race 1. El-Sadr W, et al. Abstract Sabin C, et al. Abstract 866.

57 MaxCmin1 & 2: SQV/r exhibited a superior lipid profile MaxCmin1 MaxCmin2 Median change in fasting lipids from baseline to week 48 (%) n = p < 0.05 n = 121 Total cholesterol p < 0.05 n = 73 n = 60 LDL cholesterol p < 0.05 n = 132 n = 129 Triglycerides n = 145 p = ns n = 135 Total cholesterol p = n = 148 n = 139 Triglycerides IDV/r SQV/r SQV/r LPV/r Gerstoft et al. 42 nd ICAAC Abstract H-172 Walmsley et al. 11th CROI Poster N-90

58 FOCUS trial: saquinavir/r* and efavirenz have similar impact on lipids 6 Mean serum lipid levels (mmol/l) Total cholesterol Triglycerides Time (weeks) Saquinavir/r n = Efavirenz n = *Investigational saquinavir/r 1600/100 mg od dosage. The licensed dosage of saquinavir/r is 1000/100 mg bid. Montaner, et al. 42nd ICAAC. San Diego, USA, H-167

59 FOCUS trial: saquinavir/r* and efavirenz have similar impact on triglycerides Mean change in triglyceride levels to week 48 (mmol/l) n = p = ns No d4t vs d4t p = Saquinavir/r Efavirenz Saquinavir/r Efavirenz without d4t without d4t with d4t with d4t Walmsley et al. 4 th Int Wkshop ADE & Lipo Abstract 52. p = ns *Investigational saquinavir/r 1600/100 mg od dosage. The licensed dosage of saquinavir/r is 1000/100 mg bid.

60 Table 2. Adverse Events in the Study Groups

61 Inhibición e inducción enzimática Influencia en interacciones medicamentosas y eventos adversos Drug Atazanavir Delavirdine Efavirenz Fosamprenavir Indinavir Lopinavir/ritonavir [1] Tipranavir/ritonavir [1] Nelfinavir Nevirapine Ritonavir Saquinavir [2] Enzyme Inhibition Enzyme Induction Assessment also reflects the effects of ritonavir. 2. Saquinavir can inhibit P450 3A4 in vitro, but this is not generally manifested clinically. Modified from: Flexner CW.

62 SQV/r Sin toxicidad característica Class toxicities Gastrointestinal Lipodystrophy ATV FPV LPV/r NFV SQV Signature toxicities Hyperbilirubinaemia Scleral icterus, Jaundice Rash Hyperlipidaemia Diarrhoea = Toxicidad principal

63 Efectos metabólicos de los IP s RTV (full dose) LPV/r IDV/(r) NFV APV/(r) or FPV/(r) TPV/r TMC-114/r SQV/(r) ATV/(r) Lipids TC/TG TC/TG TC/TG LDL/TG, HDL(?) TC/TG TC/TG TC/TG little Δ little Δ Glucose insulin resistance insulin resistance insulin resistance no Δ insulin sensitivity no Δ insulin sensitivity?? no Δ insulin sensitivity no Δ insulin sensitivity

64 Conclusión: Perfil Metabólico de saquinavir/r en pacientes VIH+: Saquinavir/r muestran un ligero y limitado efecto en lípidos comparado con los demás IP reforzados. Particularmente si se usan RTV 100 mg QD Combinación garantizada: : saquinavir/r y ATV/r (EsAs) Benéfico cuando es usado en combinación con ITRN con poco o nulo efecto esperado en tejido adiposo periférico rico y sensibiidad a la insulina (evitando d4t) Efecto en la distribución de tejido adiposo motivará investigación futura.

65 Pueden vivir? Cuántas tabletas están dispuestos a tomar y por cuánto tiempo para mantener su nivel de vida?