Transcript Slide 1

Tratamiento de la hepatitis crónica C
Javier García-Samaniego
Unidad de Hepatología
Hospital Carlos III. CIBERehd
Madrid
III CURSO PARA RESIDENTES SOBRE DIAGNÓSTICO Y TRATAMIENTO
DE LAS ENFERMEDADES HEPÁTICAS
Barcelona, 11-12 de noviembre de 2011
Objetivos del tratamiento
• Objetivo primario =
curar
• Eliminar el virus1
• Detener la progresión
(necrosis/fibrosis)
• Aliviar los síntomas
Objetivos secundarios
•
•
•
•
Reducir la progresión de la fibrosis1
Reducir la evolución a cirrosis2
Evitar descompensaciones
Evitar el CHC2
1. Worman. Hepatitis C: Sourcebook 2002. 2. Peters et al. Medscape HIV/AIDS eJournal. 2002;8(1).
Hepatitis C differs from HIV and HBV
No long-term or latent reservoir
HBV
HIV
HCV
Viral RNA
cccDNA
Proviral DNA
Host DNA
TREATMENT
Long-term suppression of
viral replication
TREATMENT
TREATMENT
Long-term
Viral Eradication = Cure
suppression of viral replication
Evolución del tratamiento de la hepatitis C
Descubrimiento del genoma del VHC
Tratamiento con IFN alfa 3 veces/sem
durante 24 o 48 sem. Resultados pobres
La combinación IFN + RBV mejora la respuesta
Desarrollo de Peg-IFN en monoterapia
Peg-IFN alfa más RBV terapia de referencia
Terapia basada en la respuesta viral
Desarrollo de nuevos antivirales
1989
2011
Evolución de la tasa de respuesta
RVS (%)
Todos los genotipos
100
90
80
70
60
50
40
30
19%
20
6%
10
0
1997
24 s1
1998
48 sem2
IFN + RBV
IFN
Peg-IFN-2b
Peg-IFN-2b + RBV
Peg-IFN -2a
Peg-IFN-2 a + RBV
66%
41%
54%
56%
20015
20026
39%
23%
19981,2
20003
20014
20057
1. McHutchison J, et al. N Engl J Med 1998; 339: 1485 2. Poynard T, et al. Lancet 1998; 352: 1426
3. Zeuzem S, et al. N Engl J Med 2000; 343: 1666 4. Lindsay K, et al. Hepatology 2001; 34: 395 5. Manns M, et al. Lancet
2001; 358: 958 6. Fried M, et al. N Engl J Med 2002; 347: 975 7. Zeuzem S, et al. J Hepatol 2005; 43: 250
EASL 2011 HCV Guidelines:
PegIFN/RBV Regimens
Genotype 1/4
PegIFN alfa-2a
PegIFN alfa-2b
180 µg
1.5 µg/kg
RBV dose (daily)
15 mg/kg
15 mg/kg
Planned duration*
48 wks
48 wks
PegIFN alfa-2a
PegIFN alfa-2b
PegIFN dose (weekly)
180 µg
1.5 µg/kg
RBV dose (daily)
800 mg
800 mg
15 mg/kg
15 mg/kg
24 wks
24 wks
PegIFN dose (weekly)
Genotype 2/3
 If low responsiveness
anticipated
Planned duration†
*24 wks of therapy can be considered in patients with low HCV RNA (< 400,000-800,000
IU/mL) who achieve RVR.
†12-16 wks can be considered in patients who achieve RVR.
Craxi A, et al. J Hepatology. 2011;[Epub ahead of print].
Hepatitis C: escenario en 2011
• Tratamiento con pegIFN + RBV en pacientes con genotipos
2, 3 y 4
• Aprobación de los primeros DAAs: telaprevir y boceprevir
• Incremento de la RVS hasta el 75% con terapia triple en
pacientes naïves G1
• Problemas potenciales con el uso de estos nuevos fármacos:
– Selección adecuada de los pacientes
– Control y monitorización inapropiados
– Manejo de los efectos adversos
– Resistencias
– Interacciones farmacológicas
HCV Treatment: A Lexicon of Acronyms
•
•
•
•
•
•
•
•
•
•
•
DAAs: direct acting antivirals
IL28B: IL28B polymorphism (rs12979860) genotype
test
NA: nucleoside analog polymerase inhibitors
NNI: nonnucleoside polymerase inhibitors
PI: protease inhibitors
MV: minority variants
UDPS: ultradeep pyrosequencing
vBT: viral breakthrough
RGT: response-guided therapy
eRVR: extended rapid virological response
DRM: drug-resistant mutations
New predictors: Genetic markers associated with
SVR to PEG plus RBV in genotype 1 HCV patients*
Whites (n = 871)
Blacks (n = 191)
Factor Associated With SVR
Hispanics (n = 75)
Odds Ratio (95% CI)
7.3
IL28B rs12979860
genotype (CC vs TT)
4.2
3.0
6.1
Baseline HCV RNA
(< vs ≥ 600,000 IU/mL)
5.1
1.1
5.6
Baseline fibrosis
(METAVIR F0-F2 vs F3F4)
2.4
4.1
0.1
*Ge D, et al. Nature.2009;461:399-401.
1.0
10.0
Genetics Predict Response: IL28B C/C
Associated With Higher SVR Rate in Gt 1
100
90
80
P = 1.06 x
10-25
P = 2.06 x
10-3
P = 4.39 x
10-3
P = 1.37 x
10-28
14
186
SVR (%)
70
60
50
40
30
20
10
n = 102 433 336
70
91
30
35
26
559 392
T/T T/C C/C
T/T T/C C/C
T/T T/C C/C
T/T T/C C/C
EuropeanAmericans
AfricanAmericans
Hispanics
Combined
0
Genotype of rs12979860 on chromosome 19. Ge D et al. Nature. 2009;461:399-401.
Select DAAs in Clinical Development
Phase I
Phase II
Phase III
Protease Inhibitors
ABT-450
ACH-1625
GS 9451
MK-5172
VX-985
BMS-650032-Asuprenavir
CTS-1027
Danoprevir
GS 9256
IDX320
Vaniprevir
BI 201335
Boceprevir (approved)
Telaprevir (approved)
TMC435
Nonnucleoside
polymerase inhibitors
BI 207127
IDX375
ABT-333
ABT-072
ANA598
BMS-791325
Filibuvir
Tegobuvir
VX-759
VX-222
Nucleoside polymerase
inhibitors
NS5A inhibitors
IDX184
PSI-7977
RG7128-Mericitabine
A-831
PPI-461
BMS-790052-Daclatasvir
BMS-824393
CF102
Anti-HCV drugs in development
Pre Clinic
Cyclo sporine analogue
SCY-635 (Scynexis)
Cyclo sporine analogue
Alisporivir (Novartis)
Cyclo sporine analogue
NIM-811 ( Novartis)
Entree inhibitor
PRO-206 (Progenics)
Cyclo sporine analogue
JTK-652 (Amsterdam)
TLR agonist
ANA 773 (Anadys)
Cyclo sporine analogue
EP-CyP282 (Enanta)
Phase I
Phase II
Phase III
Standard of care en 2012
Telaprevir
o
Boceprevir
PegIFN-α
Ribavirina
Boceprevir and Telaprevir
• Boceprevir, a potent inhibitor
of HCV NS3/4A protease
• Telaprevir, a potent inhibitor of
HCV NS3/4A protease
• Both being tested in
combination with standard-ofcare pegIFN alfa-2/RBV in
phase III studies in chronic
HCV infection
Boceprevir
– SPRINT-2: naive GT1
patients
– RESPOND-2: nonresponder
GT1 patients (partial
responders and relapsers)
Telaprevir
– ADVANCE: naive GT1
patients
– ILLUMINATE: responseguided therapy in naive GT1
paitents
– REALIZE: nonresponder
GT1 patients (null
responders, partial
responders, relapsers)
Phase III ADVANCE: Telaprevir + PegIFN/RBV in
GT 1 Tx-Naïve Patients
 Randomized, placebo-controlled trial
Wk 24
Wk 8 Wk 12
TVR + PR*
(n = 364)
Treatment-naive
patients with
GT 1 HCV
TVR + PR*
(n = 363)
Wk 48
eRVR†: PR*
Follow-up
PR*
eRVR†: PR*
Follow-up
Follow-up
PR*
Follow-up
(N = 1088)
PR*
(n = 361)
*TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.
†eRVR = undetectable HCV RNA at Wks 4 and 12.
Jacobson I, et al. N Engl J Med 2011;364:2405-2416.
Follow-up
Wk 72
ADVANCE: SVR rates
T12PR
P<0.0001
100
Percent of patients with SVR
T8PR
90
P<0.0001
75
80
69
70
60
44
50
40
30
20
10
0
n/N =
271/363
250/364
SVR
Jacobson I, et al. N Engl J Med 2011; 364: 2405-16
158/361
PR
Telaprevir: Discontinuations
• Discontinuations due to adverse events in Phase
III ADVANCE:
Outcome, %
8-Wk TVR/PR +
16/40-Wk PR
(n = 364)
12-Wk TVR/PR
+ 12/36-Wk PR
(n = 363)
48-Wk PR
(n = 361)
Discontinuation of TVR/placebo due to
rash
7
11
1
Discontinuation of all drugs due to AEs
8
7
4
3.3
0.8
0.6
 Anemia
Jacobson I et al. N Engl J Med 2011: 364: 2405-18
Telaprevir Ph3 Trial: ILLUMINATE – GT1 Naïve
Non-inferiority trial requested by the FDA to specifically demonstrate that treating GT1 Naïve patients for 24 weeks was not a
disadvantage compared to treating them for 48 weeks
Weeks on therapy
2
4
1
2
Telaprevir
750 mg q8h
+ Peg-IFN2a
+ RBV
eRVR
N = 540
Peg-IFN2a
+ RBV
No eRVR
0
eRVR = undetectable HCV RNA at week 4
and week 12
*
3
6
4
8
6
0
Follow-up
Peg-IFN2a
+ RBV
Follow-up
Peg-IFN2a
+ RBV
Follow-up
7
2
ILLUMINATE:
Undetectable HCV RNA over time – ITT Population
Patients with Undetectable
HCV RNA levels (%)
100
87
80
72
72
65
60
40
20
0
n/N= 389/540
RVR
Sherman KE, et al. N Engl J Med 2011; 365: 1551 .
352/540
469/540
388/540
eRVR
EOT
SVR
ILLUMINATE
SVR Rates - Noninferiority of 24-week Regimen
Patients with SVR (%)
 4.5%
(2-sided 95% CI = -2.1% to +11.1%)
100
92
88
80
60
40
20
0
n/N=
149/162
T12PR24
Sherman KE, et al. N Engl J Med 2011; 365: 1551
140/160
T12PR48
REALIZE Telaprevir + PegIFN/RBV in GT 1 HCV
Pts Who Failed Previous PegIFN/RBV*
T12/PR48
n=266
T12(DS)/
PR48
n=264
Pbo +
Peg-IFN
+ RBV
TVR + Peg-IFN +
RBV
Pbo +
Peg-IFN
+ RBV
TVR+
Peg-IFN + RBV
Peg-IFN + RBV
Follow-up
Peg-IFN + RBV
Follow-up
Peg-IFN + RBV
Follow-up
Pbo/PR48
Pbo +
Peg-IFN + RBV
(control)
n=132
0
4
8
12
16
48
Weeks
72
SVR assessment
*Randomization stratified by viral load and prior response; stopping rules applied for TVR (Weeks 4, 6, and 8) and
Peg-IFN/RBV (Weeks 12, 24, and 36)
Peg-IFN = 180μg/week; RBV 1000–1200mg/day; TVR = 750mg every 8 hours ClinicalTrials.gov identifier: NCT00703118
Pbo = placebo; DS = delayed start
Zeuzem, et al. N Engl J Med 2011; 364: 2417-28
REALIZE: SVR According to Previous Response
SVR Based on Previous
Response, % (n/N)
T12/
PR48
LI-T12/
PR48
PR48
83* (121/145)
88* (124/141)
24 (16/68)
Partial responder
59* (29/49)
54* (26/48)
15 (4/27)
Null responder
29* (21/72)
33* (25/75)
5 (2/37)
Relapser
*P < .001 vs PR48.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Resumen de los estudios de telaprevir
• El tratamiento “guiado” por la respuesta viral
(RGT) durante 24 semanas es igual de eficaz
que el de 48 semanas de duración en
pacientes naïve con eRVR (semanas 4-12).
• La RGT es posible en 2/3 de los pacientes
• La duración óptima del tratamiento con TVR
es de 12 semanas
1. Jacobson IM, McHutchison JG,Dusheiko GM, et al. AASLD 2010: Abstract 211.
2. Sherman KE, Flamm SL, Afdhal NH, et al. AASLD 2010:LB-2.
Telaprevir Regimens
• Treatment-naive patients and previous relapsers
– Triple therapy with TVR 750 mg TID + pegIFN/RBV for
12 wks, followed by 12-36 wks of pegIFN/RBV alone
• Duration of pegIFN/RBV dependent on treatment response (cirrhotics
may benefit from full 48-wk course)
• Previous partial and null responders
– Triple therapy with TVR 750 mg TID + pegIFN/RBV for
12 wks, followed by 36 wks of pegIFN/RBV alone
*
Telaprevir [package insert]. 2011.
SPRINT 2: Study Design
Week 4
Control
PR
48 P/R lead-in
N = 363
Week 28
Week 48
PR + Placebo
Week 72
Follow-up
TW 8-24 HCV-RNA Undetectable
Follow-up
BOC
PR
RGT
lead-in
N = 368
PR + Boceprevir
TW 8-24 HCV-RNA Detectable
PR + Placebo
BOC/
PR
PR48 lead-in
N = 366
PR + Boceprevir
Follow-up
Follow-up
Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using
weight based dosing of 600-1400 mg/day in a divided daily dose. BOC 800 mg 3 times daily
Poordad F, et al. N Engl J Med 2011; 364: 1195-206.
SPRINT 2: SVR and Relapse Rates (ITT)
SVR*
Relapse Rate
p <0.0001
p =0.004
p < 0.0001
100
80
67
68
60
211
316
213
311
40
20
40
125
311
23
37
162
0
48 P/R
9
21/232
p = 0.044
80
% Patients
% Patients
100
8
18/230
53
60
40
20
0
BOC RGT BOC/PR48
Non-Black Patients
42
23
12
52
14
2/14
48 P/R
22
52
29
55
12
3/25
17
6
35
BOC RGT BOC/PR48
Black Patients
*SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week posttreatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA
documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (207/316) and 68% (210/311),
respectively and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively.
Poordad et al. NEJM 2011
Boceprevir: Adverse Events and
Discontinuations
• Anemia and dysgeusia reported more frequently in BOC
arms vs control in SPRINT-2[1-2]
Outcome
4-Wk PR + ResponseGuided BOC/PR
(n = 368)
4-Wk PR + 44-Wk
BOC/PR
(n = 366)
48-Wk PR
(n = 363)
49
49
29
• EPO use
41
46
21
 Dysgeusia[2]
37
43
18
Discontinuations due to
adverse events, %[1]
12
16
16
 Anemia[1]
2
2
1
Adverse event, %
 Anemia[1]
1. Poordad F, et al. NEJM 2011.
RESPOND-2 Study Arms and Dosing Regimen
Week 36
Week 4
Control
48 P/R
N = 80
PR
PR + Placebo
lead-in
PR
lead-in
Follow-up
Follow-up
PR + Boceprevir
TW 8 HCV-RNA Detectable/
TW 12 Undetectable
PR +
placebo
BOC/
PR48
N = 161
PR
lead-in
Week 72
TW 8 HCV-RNA Undetectable
Week 12
futility
BOC
RGT
N = 162
Week 48
PR + Boceprevir
Follow-up
Follow-up
HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 IU/mL) at week 12
were considered treatment failures.
(
Peginterferon P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R)
using weight based dosing of 600-1400 mg/day in a divided daily dose
Boceprevir dose of 800 mg thrice daily
Bacon et al. N Engl J
Med 2011; 364: 1217-17.
RESPOND-2 SVR and Relapse Rates
Intention to treat population
p <0.0001
100
SVR
% of Patients
p < 0.0001
80
59
60
32
40
21
20
0
Relapse Rate
66
17
80
8
25
15
12
95 17
162 111
107 14
161 121
PR 48 BOC RGT BOC/PR48
SVR rates in BOC RGT and BOC/PR48 arm not statistically
different (OR, 1.4; 95% CI [0.9, 2.2])
12-week HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where
missing data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/80), 58%
(94/162) and 66% (106/161), respectively.
Resumen de los estudios Sprint-21 y Respond-22
• Las pautas de tratamiento con BOC requieren un
periodo de 4 semanas de lead-in (LI) con
PEGIFN+RBV
• La RGT (viremia C indetectable en las semanas 8 y
24) es posible en aproximadamente la mitad de los
pacientes naïve
• Se requiere un mínimo de 24 semanas de BOC
para la respuesta viral óptima en pacientes naïve
• Se requiere LI + un periodo mínimo de 32 semanas
de tratamiento con BOC/PEGIFN/RBV para los
pacientes con fallo a un tratamiento previo con
PEGIFN/RBV
1.
2.
Poordad F, et al. NEJM 2011; 364: 1195-206.
Bacon B et al. NEJM 2011; 364: 1207-17
Recommended Treatment Duration With BOC in TxNaive Patients
 All patients start with pegIFN/RBV for 4 wks
 At Wk 4, BOC added to pegIFN/RBV for a duration
determined by response at Wks 8 and 24
HCV RNA
at Wk 8
HCV RNA
at Wk 24
Recommendation
Undetectable
Undetectable
Complete BOC + pegIFN/RBV at Wk 28
Detectable
Undetectable
 Continue BOC + pegIFN/RBV
through Wk 36, then
 PegIFN/RBV through Wk 48
 Stop all therapy if HCV RNA > 100 IU/mL at Wk 12 or
detectable at Wk 24
Boceprevir [package insert]. 2011.
Similarities and Differences in Phase III
Studies of TVR and BOC in GT1 Naive Pts
Parameter
TVR[1]
BOC[2]
PR lead-in?
No
Yes: 4 wks
PegIFN alfa formulation
2a
2b
PI dosing requirements
TID; administer with fatty
meal
TID
8-12 wks followed by 12-40
wks PR
24-44 wks after
4 wks PR lead-in
Undetectable HCV RNA until
Wk 12 of triple therapy
Undetectable HCV RNA
until Wk 24 of triple
therapy
65 (24 wks)
44 (28 wks)
69-75
63-66
9
9
Rash, anemia, pruritus,
nausea
Anemia, dysgeusia
Duration of PI triple therapy
Qualification for shortened therapy
(response guided)
Qualified for shortened therapy, %
SVR, %
Relapse, %
Adverse events more frequent in PI
arms
Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. N Engl J Med 2011; 364: 1195-206 .
Summary of telaprevir and boceprevir in
treatment-experienced patients
Telaprevir1
 Significantly improved SVR
rates in prior relapsers, partial
responders, and null
responders
 Phase III trial included null
responders
 Telaprevir taken for 12 weeks
 PR lead-in phase not required
 Treatment duration is 48
weeks, or 24 weeks for eligible
prior relapsers
Boceprevir2
 Significantly improved SVR
rates in prior relapsers and
partial responders
 Phase III trial excluded null
responders
 Boceprevir taken for:
 32 weeks in non-cirrhotic
relapsers and partial responders
 44 weeks in those with
compensated cirrhosis and in all
null responders
 PR lead-in phase is required
 Treatment duration is 48 weeks
1. Telaprevir EU SmPC
2. Boceprevir SmPC
Resistencia a los inhibidores de la proteasa
• Las mutaciones de resistencia se desarrollan muy
rápidamente (1-2 semanas en monoterapia).
• Es esencial que los pacientes reciban adecuadamente
tratamiento con pegIFN/RBV junto con los IPs (estimular
cumplimiento).
• No se debe reducir la dosis del IP.
• Interrumpir el IP si se produce un breaktrough virológico
(aumento de HCV RNA)
Stopping Rules for Telaprevir and Boceprevir
Time Point
Wk 4
Wk 12
Wk 24
Any
TVR +
PegIFN/RBV
Discontinue all therapy if
HCV RNA > 1000 IU/mL
BOC +
PegIFN/RBV
N/A
Discontinue all therapy if
HCV RNA > 100 IU/mL
Discontinue all therapy if detectable HCV RNA
Discontinue protease inhibitor if pegIFN/RBV
discontinued for any reason
Telaprevir [package insert]. 2011. Boceprevir [package insert]. 2011.
IFN-Free Combination Therapies
with 2 or More DAAs
DRUG
COMBOS
CLASS
COMPANY
PHASE
BMS-650032
(Asuprenavir)+
BMS-790052
(Daclatasvir)
PI+NS5a
BMS
2a
Danoprevir +
Mericitabine+/RBV
PI+NI
Roche/
2b
Tegobuvir+ GS9256
NNI+PI
Gilead
2a
BI-201335+ BI207127 +/- RBV
PI+NNI
Boehringer
Ingelheim
2a
Genetech
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RBV
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