CONDICIONES ESPECIALES PARA RESIDENTES

Presentación del tema: "CONDICIONES ESPECIALES PARA RESIDENTES"— Transcripción de la presentación:

1 CONDICIONES ESPECIALES PARA RESIDENTES
·Acceso a la zona privada de la página web de la AEEH que incluye. ·Versión on-line de la Revista Gatroenterología y Hepatología. ·Directorio de socios. ·Publicaciones de la AEEH. ·Foro de la AEEH. ·Canal Youtube con los vídeos y presentaciones de los cursos organizados por la AEEH. ·Participación en la Asamblea General de la AEEH. ·Y más…

2 Tratamiento actual de la Hepatitis C
Jose Luis Calleja Panero Profesor Titular de Medicina Servicio de Gastroenterologia y Hepatología 2012

3 Evolución del tratamiento en Hepatitis C
Direct-acting antivirals 100 2011 Peginterferon 80 Ribavirin 2001 Standard interferon 70+ 1998 60 55 1991 SVR (%) 42 39 40 34 20 16 6 IFN 6 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV mos PegIFN/ RBV/ DAA Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.

4 Respuesta Virológica Sostenida y Mortalidad
van der Meer AJ, et al. JAMA. 2012; 308(24):

5 Agenda Ensayos Clinicos: Cohortes de practica real Conclusiones
Eficacia Seguridad Esquemas de tratamiento Cohortes de practica real Conclusiones

6 SPRINT-2: Naives BOCEPREVIR
* * Key Point In the SPRINT-2 trial, the proportion of patients achieving an SVR was higher in the two boceprevir treatment groups than in the control group.1 Notes Higher SVR rates were observed with boceprevir versus control: 63% and 66% of patients in the BOC RGT and BOC44/PR48 arms versus 38% in the PR arm. For reference, and although comparisons across trials are inherently limited, an SVR rate of 74–79% was observed with the telaprevir T12PR regimen in the ADVANCE and ILLUMINATE trials.2 References VICRELIS (boceprevir) EU SmPC. INCIVO (telaprevir) EU SmPC. PR48 137/363 BOC RGT 233/368 BOC44/PR48 242/366 n/N = *p<0.001 for both boceprevir arms versus PR48 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward VICTRELIS (boceprevir) EU SmPC

7 ADVANCE and ILLUMINATE: TPV en Naives
74–79* PR48 166/361 T12/PR 683/903 n/N = *p< T12/PR vs PR48 (79% versus 46%) in ADVANCE SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used INCIVO (telaprevir) EU SmPC

8 ILLUMINATE: Telaprevir en Naives
Treatment duration according to eRVR status SVR rate  4% (2-sided 95% CI = –2% to +11%) <20 weeks 18% n=100 eRVR+* eRVR– 60%* 22% n=322 n=118 Eligible for 24 weeks and randomized to 24 or 48 weeks* 48 weeks <20 weeks (due to premature treatment discontinuation) eRVR+ T12PR24 149/162 eRVR+ T12PR48 140/160 eRVR– T12PR48 76/118 <20 weeks 23/100 *Patients who achieved eRVR (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone 65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20 Sherman KE, et al. N Engl J Med 2011;365:1014–24

9 Prior partial responders
REALIZE: TPV en No respondedores Prior relapsers Prior null responders Prior partial responders * * *p<0.001 vs PR48; post-hoc analysis * * SVR (%) * * PR48 16/68 LI T12/ PR /141 T12/ PR /145 PR48 4/27 LI T12/ PR48 26/48 T12/ PR48 29/49 PR48 2/37 LI T12/ PR48 25/75 T12/ PR48 21/72 n/N= Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14 9

10 Esquemas de Triple Terapia
TVR w4 BOC w12 Esteban R, Best Practice & Research Clinical Gastroenterology 2012

11 Agenda Ensayos Clinicos: Cohortes de practica real Conclusiones
Eficacia Seguridad Esquemas de tratamiento Cohortes de practica real Conclusiones

12 Telaprevir : Efectos adversos
Patients, % T12/PR (750 mg q8h) N=1346 Placebo/PR48 N=764 Leading to discontinuation of all study drugs*(%) Skin and subcutaneous tissue disorders Pruritus (SSC) 52 26 0.6% Rash (SSC) 55 33 2.6% Gastrointestinal disorders Nausea 39 29 <0.5 Diarrhea 19 Hemorrhoids 12 3 Anorectal discomfort 8 2 Anal pruritus 6 1 Blood and lymphatic system disorders Anemia (SSC) 32 15 0.9% *Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for rash and anemia) SSC: special search category Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

13 Boceprevir : Efectos adversos
Patients, % BOC RGT BOC44/PR48 PR SPRINT-2 (naïve)1 N=368 N=366 N=363 Anemia* 49 29 Dysgeusia* 37 43 18 Grade 3-4 neutropenia (500 to <750/mm3 and <500/mm3) 33 RESPOND-2 (experienced)2 N=162 N=161 N=80 46 20 45 11 Dry skin** 21 22 8 25 27 13 Rash‡ 17 14 5 *p<0.001 for boceprevir arms versus PR **p=0.009 (BOC RGT) and p=0.004 (BOC44/PR48) versus PR ‡p=0.01 (BOC RGT) and p=0.05 (BOC44/PR48) versus PR 1. Poordad F, et al. N Engl J Med 2011;364:1195– Bacon BR, et al. N Engl J Med 2011;364:1207–17

14 Meta-analisis BOCEPREVIR
BOC/PR Adverse events, n (%) F0–2 N=436 F3 N=22 F4 N=32 F0–2 N=1638 F3 N=107 F4 N=180 Serious adverse event 36 (8) 3 (14) 2 (6) 189 (12) 13 (12) 33 (18) Death 4 (1) 5 (<1) 1 (1) Life-threatening treatment-emergent adverse event 4 (1) 25 (2) 3 (3) 7 (4) Dose modification due to anemia 55 (13) 1 (5) 5 (16) 414 (25) 29 (27) 58 (32) Discontinuation due to anemia 4 (4) 2 (1) Hemoglobin,* g/dL <10 8.5–<10 <8.5 N=432 127 (29) 110 (25) 17 (4) N=22 7 (32) N=32 7 (22) N=1629 870 (53) 741 (45) 129 (8) N=107 60 (56) 43 (40) 17 (16) N=178 113 (63) 85 (48) 27 (15) Platelets,* x109/L 25–<50 (Grade 3) <25 (Grade 4) N=430 5 (1) N=21 4 (13) N=1638 37 (2) 2 (<1) 6 (6) 2 (2) 35 (20) *Nadir values Anemia was defined as Hb <10 g/dL Vierling J, et al. EASL 2013: Abstract 1430

15 >90% of all rash = mild/moderate
Rash con Telaprevir >90% of all rash = mild/moderate Incidence of rash (%) Incidence of rash (%) (N=1346) (N=764) T12/PR arm Features: Typically pruritic and eczematous, and involving <30% BSA Progression was infrequent (<10% of cases) Time to onset: Approximately 50% of rashes started during the first 4 weeks But rash can occur at any time during telaprevir treatment INCIVO (telaprevir) EU SmPC Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf Reported within a special search category

16 Rash leve Mild rash is defined as localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body)

17 Rash Leve o moderado: Manejo
Monitor for progression or systemic symptoms until the rash is resolved For moderate rash, consider consultation with a specialist in dermatology. For moderate rash that progresses, permanent discontinuation of telaprevir should be considered If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted. Interruption of ribavirin may be required sooner if the rash worsens despite discontinuation of telaprevir Peginterferon alfa may be continued unless interruption is medically indicated For moderate rash that progresses to severe (≥50% body surface area), permanently discontinue telaprevir Mild Moderate Rash Treating patients with mild or moderate rash Use topical corticosteroids* or systemic antihistamines Permitted topical antihistaminic drugs may be tried for the treatment of associated pruritus Limit exposure to sun/heat and wear loose-fitting clothes *Concomitant use of systemic dexamethasone with telaprevir may result in loss of therapeutic effect of telaprevir. This combination should be used with caution or alternatives should be considered INCIVO (telaprevir) EU SmPC 17

18 Rash Severo Severe rash is defined as rash with extent of >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment

19 Anemia Hemolisis extravascular en relacion con stress oxidativo de la membrana Mielosupresion en relacion con PEG+ RIBA Toxicidad medular en relación con Inhibidores de la proteasa Factor esencial en el deterior de la calidad de vida

20 Incidencia de anemia N= 140 % % % Llop et al. EASL 2013

21 Factores predictivos de anemia en semana 12
<10 g/dL≥8.5 g/dL p <8.5 g/dL Edad (>50) Sexo Femenino Hemoglobina basal No F4 vs F4 Disminución Hb sem 4 0.02 0.03 <0.001 0.04 0.004 Sexo femenino Hemog Basal Llop et al. EASL 2013

22 Tratamiento de la anemia
Primary Efficacy Results* Efficacy Results in Cirrhotics and Non-Cirrhotics Poordad F et al. Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients with Chronic HCV Genotype 1 Infection—a Randomized Trial: Gastroenterology (2013), doi: /j.gastro

23 Consejos prácticos Identificar pacientes de alto riesgo
Usar lead in como prueba de tolerancia Monitorización frecuente de Hemoglobina Mejor reducir que suspender Usar EPO precozmente Trasfundir en un grupo seleccionado de pacientes 23

24 Cohortes de practica real Conclusiones
Agenda Ensayos Clinicos: Eficacia Seguridad Esquemas de tratamiento Cohortes de practica real Conclusiones

25 Cohortes de practica real
62% other 84% other Real world CUPIC1 100% 44% 55% EAP2 38% TARGET3 16% German cohort4 36% F0 F1 F2 F3 F4 Liver cancer 86% Clinical trials 22% 6% ADVANCE5 73% 42% 15% 26% REALIZE6 29% 22% 6% SPRINT 27 5% 12% RESPOND 28 7% 1. Hézode C, et al. Hepatology 2012;56(Suppl.):217A; 2. Colombo M, et al. AASLD: LB Fried M, et al. EASL 2013: Abstract 818; 4. Berg T, et al. EASL 2013: Abstract 793 5. Jacobson I, et al. N Eng J Med 2011;364:2405–16; 6. Zeuzem S, et al. N Eng J Med 2011;364:2417–28 7. Poordad F, et al. N Eng J Med 2011;364:1195–206; 8. Bacon BR, et al. N Eng J Med 2011;164:1207–17

26 Cohortes de practica real
N=1079 for TVR, N=342 for BOC Treatment naïve and treatment experienced1 38% F4 German non-interventional study N=400 (all TVR)4 Treatment naïve and treatment experienced 16% F4 PAN cohort 5–8 N=776 for TVR N=176 for BOC 10–21% F4 TVR EAP in 16 European countries2 N=609 F3–F4 treatment naïve and treatment experienced Spanish national cohort3 N=102 (all BOC) Bridging fibrosis or cirrhosis treatment naïve and treatment experienced CUPIC9 Compassionate Use of Protease Inhibitors in viral hepatitis C Cirrhosis N=497 (TVR and BOC) F4 treatment experienced Other national cohorts from Europe and North America 1. Fried M, et al. EASL 2013:818; 2. Colombo M, et al. AASLD; 2012:LB-15; 3. Calleja J, et al. EASL 2013:799 4. Berg T, et al. EASL 2013:793; 5. Mauss S, et al. EASL 2013:871; 6. Christensen S, et al. EASL 2013: Moog G, et al. EASL 2013:875; 8. Spengler U, et al. EASL 2013:908; 9. Hézode C, et al. Hepatology 2012;56(Suppl.):217A

27 Características basales EAP-TEL/NPP-BOC
Valor (n=609) Nivel basal ARN- VHC < UI/mL ≥ UI/mL 30.9% 65.5% Índice de fibrosis F3 Cirrosis (F4) 44.5% 55.0% Genotipo VHC 1a 1b 28.2% 67.5% Perfil por respuesta Naïve Recaída R. Parcial R. Nula 20% 28% 15% 29% Características Valor (n=102) ARN-VHC medio basal (log 10 UI/mL) 6,2 log Índice de fibrosis F3 Cirrosis (F4) 14% 86% Genotipo VHC 1a 1b 18% 82% Perfil por respuesta Naïve Recaída R. Parcial R. Nula 19% 31% 36% 33% 1 M. Colombo et al. Hepatology AASLD 2012 2 JL Calleja et al. J Hepatol EASL 2013

28 Eficacia semana 12 EAP- TEL & NPP-BOC
ARN VHC INDETECTABLE Semana 12 NPP2 ARN VHC INDETECTABLE Semana 12 14/23 22/32 37/41 14/23 24/41 22/32 22/32 18/42 18/42 22/23 1 M. Colombo et al. Hepatology AASLD 2012 2 JL Calleja et al. J Hepatol EASL 2013

29 Seguridad & Tolerabilidad EAP-TEL & NPP-BOC
Efecto Adverso TVR1 (n=609) BOC2 (n=102) Acontecimientos Adversos Graves (SAEs) 85 (14%) Acontecimientos Adversos Graves (SAEs) 33 (32,4%) Interrupción de Telaprevir por SAEs Interrupción de Boceprevir 10 (10%) Anemia SSC Grado 1 Grado 2 Grado 3 y grado 4 67 (11%) 97 (16%) 189 (31%) Anemia Hg <10.0 g/dL Hb <8.0 g/dL 29 (28,4%) 3 (3,2%) Reducción dosis RBV EPO Transfusión hematíes 207 (34%) 148 (24%) 70 (11 %) Reducción dosis RBV 27 (26,4%) 26 (25,5%) 9 (8,8%) Muertes 3 (0,5%) 2 (1,9%) 1 M. Colombo et al. Hepatology AASLD 2012 2 JL Calleja et al. J Hepatol EASL 2013

30 EAP Telaprevir: Anemia y reacciones cutáneas
59% 42% Interrupción por anemia: n=19 (3%) Interrupción por reacción cutánea: n=30 (5%) Grade 1: Hb 10.0 – 10.9 g/dl o cualquier caída de 2.5 – 3.4 g/dL Grade 2: Hb 9.0 – 9.9 g/dL o cualquier caída de 3.5 – 4.4 g/dL Grade 3: Hb 7.0 – 8.9 g/dL o cualquier caída de >4.5 g/dL Grade 4 : Hb <7.0 g/dL M. Colombo et al. Hepatology AASLD 2012

31 CUPIC: Baseline patient characteristics
The primary objective of CUPIC is to determine the SVR24 rates in HCV patients with cirrhosis. The interim analysis determined the SVR12 rates Characteristic TVR N=295 BOC N=190 Male, % 201 (68) 133 (70) Mean age, years (range) 57 (27–83) 57 (34–79) Mean BMI, SD (kg/m2) 26.5 (18.2–40.4) 26.2 (18.1–39.4) HCV genotype 1 subtype, n (%) 1a 1b Other 98 (33) 162 (55) 33 (11) 77 (41) 96 (51) 16 (8) HCV RNA ≥800,000 IU/mL, n (%) 182 (62) 122 (64) Treatment history, n (%) Prior relapse Prior partial response Prior null response Others 116 (39) 135 (46) 28 (10) 15 (5) 85 (45) 80 (42) 9 (5) Exclusion criteria, n (%) REALIZE RESPOND-2 99 (34) 137 (46) 52 (27) 73 (38) Fontaine H, et al. EASL 2013: Oral 60

32 CUPIC: SVR rates – ITT analysis
100 80 60 Patients with undetectable HCV RNA (%) 40 20 171/ 299 249/ 299 81/ 212 243/ 299 119/ 212 231/ 299 128/ 212 205/ 299 131/ 212 180/ 299 114/ 212 147/ 299 87/ 212 6/212 Week 4 Week 8 Week 12 Week 16 Week 24 Week 48 (EOT) Week 60 (SVR12) Patients received HCV treatment for 48 weeks. SVR12 rates were measured during the Week 60 follow-up visit EOT: End of treatment Hézode C, et al. Unpublished data

33 CUPIC: Telaprevir SVR rates based in prior response
100 80 60 Patients with undetectable HCV RNA (%) 40 20 83/ 117 107/ 95/ 91/ 82/ 70/ 134 107/ 88/ 73/ 54/ 11/ 32 17/ 6/ 5/ Relapse Partial response Null response Hézode C, et al. Unpublished data 33

34 CUPIC: Boceprevir SVR rates based in prior response
100 80 Patients with undetectable HCV RNA (%) 60 40 20 240/ 259 3/92 64/ 92 68/ 60/ 47/ 3/94 44/ 94 53/ 46/ 35/ 2/ 10 Relapse Partial response Null response Hézode C, et al. Unpublished data 34

35 Safety findings (week 60) for TVR and BOC
Patients, n (%) with at least one event TVR (n=295) BOC (n=190) Serious adverse events 160 (54.2) 97 (51.0) Premature discontinuation Due to serious adverse events 139 (47.1) 63 (21.3) 80 (42.1) 27 (14.2) Death 7 (2.4) 3 (1.6) Infection (Grade 3/4) 27 (9.1) 8 (4.2) Hepatic decompensation (Grade 3/4) 15 (5.1) 9 (4.7) Rash Grade 3/SCAR 18 (6.1) 2 (1.0) Anemia (Grade 3/4: Hb <8 g/dL) 38 (12.9) 19 (10.0) EPO use Blood transfusion 168 (56.9) 53 (18.0) 119 (62.6) 26 (13.7) GCSF use 8 (2.7) 13 (6.8) TPO use 6 (2.0) SCAR: severe cutaneous adverse reaction; GCSF: granulocyte colony-stimulating factor TPO: thrombopoeitin Hézode C, et al,.APASL 2013

36 SVR12 and severe complications rates according to baseline platelet count and serum albumin*
≤100,000/mm3 >100,000/mm3 Albumin <35 g/L N Complications, n (%) SVR12, n (%) 37 19 (51.3) 8 (21.6) 31 5 (16.1) 9 (29.0) 35 g/L 74 9 (12.2) 26 (35.1) 305 16 (5.2) 160 (52.5) *Missing data in 69 patients Hézode C, et al. Unpublished data

37 Infecciones Graves con Telaprevir
SAEs Fibrosis Semana Evolución Endocarditis /Sepsis Enterocc. Faecc. F4 34 Vivo Sepsis Staph. Aureus 8 Sepsis (SDRA) - 7 Muerto Cándida Neumonía 20 Bronquiolitis 18 ITU Influenza Múltiples abcesos F2 Gastroenteritis F1 30 Diverticulitis Rutter K, et al. J Hepatol EASL 2013 ABS 65

38 Infección en tratamiento con PEG+ RIBA
Infecciones severas Todas las infecciones 70/321 13/321 La mayor parte de las infecciones graves fueron neumonias 96 infections occurred in 70 patients,13 patients had 13 severe infections *p=0.08 vs F0–F3 for all infections Roomer R, et al. Hepatology 2010;52:1225–31

39 Incidencia de infecciones con la edad en PEG+ RIBA
Incicencia acumulada de infecciones 0.7 >60 years 0.6 Adjusted HR: 7.69 (95% CI:1.83–32.51; p<0.01) 0.5 31–60 years 0.4 Cumulative hazard 0.3 Adjusted HR: 5.07 (95% CI:1.22–20.97; p=0.02) 0.2 0.1 18–30 years 4 8 12 16 20 24 28 32 36 40 44 48 Weeks after starting Peg-IFN and RBV treatment Incidence of infection: 41 per 100 person-years 5% of infections were severe 40% of all infections reported in this study were respiratory Antonini MG, et al. Infection 2008;36:250–5

40 Complications of liver diseases 66 Medical comorbidities 63
50.5% CONTRAINDICATIONS (200 patients analyzed) n Complications of liver diseases 66 Medical comorbidities 63 Significant prior side effects 26 Psychiatric Disease 25 Advanced age 11 Other 9 287 patients Will Initiate treatment 91 patients (18,7 % of the cohort) No treatment initiation 196 Patient refusal 89 45.4 % Mild disease 69 35.2 % Awaiting new treatments 38 19.3 % 1. Chen et al. Clin Gastrol Hepatol 2013;11:1014–1020.

41 Tasa de discontinuación elevada
40 487 GT1 Patients Evaluated[1] 30 50 21 20 40 21 10 30 Patients (%) 22 15 17 18 20 D/C Before Wk 12 11 AE, adverse event; D/C, discontinued; GT, genotype; TVR, telaprevir. 10 n/N = Mild Disease Patient Choice Wait for Better Therapies Started Therapy D/C < 12 wks Due to AEs Did Not Start 1. Chen et al. Clin Gastrol Hepatol 2013;11:1014–1020.

42 Conclusiones El tratamiento con triple terapia es el tratamiento de elección en pacientes infectados por VHC Consigue tasas de curación muy altas y , en un porcentaje significativo de pacientes, en menor tiempo de tratamiento El tratamiento actual se asocia a un porcentaje de efectos adversos relevantes, que ocurren especialmente en cirróticos Las cohortes de practica real demuestran una eficacia comparable a los ensayos clinicos aunque un porcentaje de efectos adversos mayor Es esencial una adecuada selección de pacientes para conseguir los mejores resultados