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

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…

Tratamiento actual de la Hepatitis C

Jose Luis Calleja PaneroProfesor Titular de Medicina

Servicio de Gastroenterologia y Hepatología

2012

Evolución del tratamiento en Hepatitis C

Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.

SVR

(%)

IFN

6 mos

PegIFN/ RBV 12

mos

IFN

12 mos

IFN/RBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN/RBV/DAA

IFN/RBV

6 mos

6

16

3442 39

55

70+

0

20

40

60

80

100

Respuesta Virológica Sostenida y Mortalidad

van der Meer AJ, et al. JAMA. 2012; 308(24):2584-2593.

N=530 N=530

Agenda

• Ensayos Clinicos:– Eficacia– Seguridad– Esquemas de tratamiento

• Cohortes de practica real• Conclusiones

SPRINT-2: Naives BOCEPREVIR

BOC RGT

233/368

BOC44/PR48

242/366

PR48

137/363n/N =

VICTRELIS (boceprevir) EU SmPC

* *

*p<0.001 for both boceprevir arms versus PR48SVR 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

ADVANCE and ILLUMINATE: TPV en Naives

T12/PR

683/903

PR48

166/361n/N =

74–79*

INCIVO (telaprevir) EU SmPC

*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCESVR, 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

ILLUMINATE: Telaprevir en Naives

Sherman KE, et al. N Engl J Med 2011;365:1014–24

*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 alone65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20

Treatment duration according to eRVR status

60%*n=32222%

n=118

<20 weeks

23/100

SVR rate

18%n=100

Eligible for 24 weeks and randomized to 24 or 48 weeks*

48 weeks

<20 weeks (due to premature treatment discontinuation)

eRVR+*

eRVR–

<20 weeks

eRVR– T12PR48

76/118

eRVR+ T12PR48

140/160

eRVR+ T12PR24

149/162

4% (2-sided 95% CI = –2% to +11%)

REALIZE: TPV en No respondedores

PR48

4/27

T12/PR4829/49

SVR

(%)

Prior relapsers Prior partialresponders

LI T12/PR4826/48n/N=

PR48

2/37

T12/PR4821/72

LI T12/PR4825/75

PR48

16/68

T12/PR48

121/145

LI T12/PR48

124/141

Prior null responders*

*

**

* *

Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14

*p<0.001 vs PR48; post-hoc analysis

Esquemas de Triple Terapia

Esteban R, Best Practice & Research Clinical Gastroenterology 2012

w4

TVR

BOC

w12

Agenda



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 26 19 <0.5

Hemorrhoids 12 3 <0.5

Anorectal discomfort 8 2 <0.5

Anal pruritus 6 1 <0.5

Blood and lymphatic system disorders Anemia (SSC) 32 15 0.9%

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

*Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for rash and anemia) SSC: special search category

Boceprevir : Efectos adversos

Patients, % BOC RGT BOC44/PR48 PR

SPRINT-2 (naïve)1 N=368 N=366 N=363

Anemia* 49 49 29

Dysgeusia* 37 43 18

Grade 3-4 neutropenia (500 to <750/mm3

and <500/mm3) 29 33 18

RESPOND-2 (experienced)2 N=162 N=161 N=80

Anemia* 43 46 20

Dysgeusia* 43 45 11

Dry skin** 21 22 8

Grade 3-4 neutropenia (500 to <750/mm3

and <500/mm3) 25 27 13

Rash‡ 17 14 5

1. Poordad F, et al. N Engl J Med 2011;364:1195–2062. Bacon BR, et al. N Engl J Med 2011;364:1207–17

*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

Meta-analisis BOCEPREVIR

*Nadir valuesAnemia was defined as Hb <10 g/dL Vierling J, et al. EASL 2013: Abstract 1430

P/R BOC/PR

Adverse events, n (%)F0–2

N=436F3

N=22F4

N=32F0–2

N=1638F3

N=107F4

N=180

Serious adverse event 36 (8) 3 (14) 2 (6) 189 (12) 13 (12) 33 (18)

Death 4 (1) 0 0 5 (<1) 0 1 (1)

Life-threatening treatment-emergent adverse event 4 (1) 0 0 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 (1) 0 0 25 (2) 4 (4) 2 (1)

Hemoglobin,* g/dL<108.5–<10<8.5

N=432127 (29)110 (25)

17 (4)

N=227 (32)7 (32)

0

N=327 (22)5 (16)2 (6)

N=1629870 (53)741 (45)129 (8)

N=10760 (56)43 (40)17 (16)

N=178113 (63)85 (48)27 (15)

Platelets,* x109/L25–<50 (Grade 3)<25 (Grade 4)

N=4305 (1)

0

N=2100

N=324 (13)

0

N=163837 (2)2 (<1)

N=1076 (6)2 (2)

N=17835 (20)

2 (1)

Rash con Telaprevir

>90% of all rash = mild/moderate

Inci

denc

e of

rash

(%)

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

Inci

denc

e of

rash

(%)

INCIVO (telaprevir) EU SmPChttp://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting

Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

(N=1346) (N=764)

Reported within a special search category

T12/PR arm

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)

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

Rash Leve o moderado: Manejo

Rash

Mild

Moderate

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

*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

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

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

Incidencia de anemia

%

%

%

Llop et al. EASL 2013

N= 140

Factores predictivos de anemia en semana 12

<10 g/dL≥8.5 g/dL p <8.5 g/dL p

Edad (>50)Sexo Femenino

Hemoglobina basal No F4 vs F4

Disminución Hb sem 4

0.020.03

<0.0010.04

0.004

Edad (>50)Sexo femeninoHemog Basal

0.040.04

0.004

Llop et al. EASL 2013

Primary Efficacy Results* Efficacy Results in Cirrhotics and Non-Cirrhotics

Tratamiento de la anemia

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: 10.1053/j.gastro.2013.07.051

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

Agenda



Cohortes de practica real

1. Hézode C, et al. Hepatology 2012;56(Suppl.):217A; 2. Colombo M, et al. AASLD: 2012. LB-15 3. 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

CUPIC1

TARGET3

EAP2

Livercancer

100%

Real world

Clinical trials

REALIZE6

ADVANCE5

SPRINT 27

RESPOND 28

F0 F1 F2 F3 F4

62% other 38%

55%44%

7%73% 12%

5%86% 6%

29% 22%22% 26%

42% 15%36% 6%

84% other 16%German cohort4

Cohortes de practica real

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 2013:805 7. 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

TVR EAP in 16 European countries2

N=609F3–F4 treatment naïve and treatment experienced

Spanish national cohort3

N=102 (all BOC)Bridging fibrosis or cirrhosis treatment naïve and treatment experienced

German non-interventional study N=400 (all TVR)4

Treatment naïve and treatment experienced16% F4

PAN cohort 5–8

N=776 for TVRN=176 for BOCTreatment naïve and treatment experienced10–21% F4

Other national cohorts from Europe and North America

N=1079 for TVR, N=342 for BOCTreatment naïve and treatment experienced1

38% F4

CUPIC9

Compassionate Use of Protease Inhibitors in viral hepatitis C Cirrhosis N=497 (TVR and BOC)F4 treatment experienced

Características basales EAP-TEL/NPP-BOC

Características Valor (n=609)

Nivel basal ARN- VHC

< 800.000 UI/mL≥ 800.000 UI/mL

30.9%65.5%

Índice de fibrosis F3

Cirrosis (F4)44.5%55.0%

Genotipo VHC 1a1b

28.2%67.5%

Perfil por respuesta

NaïveRecaída

R. ParcialR. Nula

20%28%15%29%

EAP 1 NPP 2

Características Valor (n=102)

ARN-VHC medio basal (log 10 UI/mL)

6,2 log

Índice de fibrosis

F3Cirrosis (F4)

14%86%

Genotipo VHC 1a1b

18%82%

Perfil por respuesta

NaïveRecaída

R. ParcialR. Nula

19%31%36%33%

1 M. Colombo et al. Hepatology 2012. AASLD 2012

2 JL Calleja et al. J Hepatol 2013. EASL 2013

18/4222/32

14/23

14/23

22/32

24/41

37/41

22/32 18/42

22/23

EAP1

ARN VHC INDETECTABLESemana 12

68%

79% 81%77%

37%

0,0%

10,0%

20,0%

30,0%

40,0%

50,0%

60,0%

70,0%

80,0%

90,0%

100,0%

Global Naive Recaedores Respondedoresparciales

Respondedoresnulos

NPP2

ARN VHC INDETECTABLESemana 12

Eficacia semana 12 EAP- TEL & NPP-BOC


68%

82% 85% 85%77%

0

10

20

30

40

50

60

70

80

90

100

Global Naive Recaedores Respondedoresparciales

Respondedoresnulos

Pacie

ntes c

on AR

N-VH

C ind

etecta

ble (%

)


Seguridad & Tolerabilidad EAP-TEL & NPP-BOC

Efecto Adverso TVR1 (n=609) Efecto Adverso BOC2 (n=102)

Acontecimientos Adversos Graves (SAEs) 85 (14%) Acontecimientos

Adversos Graves (SAEs) 33 (32,4%)

Interrupción de Telaprevir por SAEs 85 (14%)

Interrupción de Boceprevirpor SAEs

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 RBVEPOTransfusión hematíes

207 (34%)148 (24%)70 (11 %)

Reducción dosis RBVEPO Transfusión hematíes

27 (26,4%)26 (25,5%)

9 (8,8%)

Muertes 3 (0,5%) Muertes 2 (1,9%)



M. Colombo et al. Hepatology 2012. AASLD 2012

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

CUPIC: Baseline patient characteristics

Fontaine H, et al. EASL 2013: Oral 60

The primary objective of CUPIC is to determine the SVR24 rates in HCV patients with cirrhosis. The interim analysis determined the SVR12 rates

CharacteristicTVR

N=295BOC

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 (%) 1a1bOther

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 relapsePrior partial responsePrior null responseOthers

116 (39)135 (46)28 (10)15 (5)

85 (45)80 (42)

9 (5)16 (8)

Exclusion criteria, n (%)REALIZERESPOND-2

99 (34)137 (46)

52 (27)73 (38)

CUPIC: SVR rates – ITT analysis

Patients received HCV treatment for 48 weeks. SVR12 rates were measured during the Week 60 follow-up visitEOT: End of treatment Hézode C, et al. Unpublished data

Week 4

100

80

60

40

20

0

Pat

ien

ts w

ith

un

det

ecta

ble

HC

V R

NA

(%

)

Week 8 Week 12 Week 16 Week 24 Week 48(EOT)

Week 60(SVR12)

171/299

6/212

249/299

81/212

243/299

119/212

231/299

128/212

205/299

131/212

180/299

114/212

147/299

87/212

Patients, n (%) with at least one eventTVR

(n=295)BOC

(n=190)

Serious adverse events 160 (54.2) 97 (51.0)

Premature discontinuationDue 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 useBlood 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) 3 (1.6)

Safety findings (week 60) for TVR and BOC

SCAR: severe cutaneous adverse reaction; GCSF: granulocyte colony-stimulating factorTPO: thrombopoeitin Hézode C, et al,.APASL 2013

Platelet count ≤100,000/mm3

Platelet count >100,000/mm3

Albumin <35 g/L

NComplications, n (%)SVR12, n (%)

3719 (51.3)8 (21.6)

31 5 (16.1)9 (29.0)

Albumin 35 g/L

NComplications, n (%)SVR12, n (%)

749 (12.2)

26 (35.1)

30516 (5.2)

160 (52.5)

SVR12 and severe complications rates according to baseline platelet count and serum albumin*

*Missing data in 69 patients Hézode C, et al. Unpublished data

Infecciones Graves con Telaprevir

SAEs Fibrosis Semana Evolución

Endocarditis /Sepsis Enterocc. Faecc. F4 34 Vivo

Sepsis Staph. Aureus F4 8 Vivo

Sepsis (SDRA) - F4 7 Muerto

Sepsis (SDRA) Cándida F4 7 Vivo

Neumonía F4 20 Vivo

Bronquiolitis F4 18 Vivo

ITU F4 8 Vivo

Influenza F4 20 Vivo

Múltiples abcesos Staph. Aureus F2 8 Vivo

Gastroenteritis F1 30 Vivo

Diverticulitis F1 8 Vivo

Rutter K, et al. J Hepatol 2013. EASL 2013 ABS 65

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

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 %

287 patients

50.5%

1. Chen et al. Clin Gastrol Hepatol 2013;11:1014–1020.

1. Chen et al. Clin Gastrol Hepatol 2013;11:1014–1020.

50

40

30

20

10

0

Pat

ien

ts (

%)

n/N =

18

487 GT1 Patients Evaluated[1]

Started Therapy

2217

11

Did Not Start

PatientChoice

Wait forBetter

Therapies

MildDisease

Tasa de discontinuación elevada

D/CBeforeWk 12

21

40

30

20

10

0

D/C < 12 wks

21

15

Due to AEs

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

42

Documents

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