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-IFN2a
+ RBV
eRVR
N = 540
Peg-IFN2a
+ RBV
No eRVR
0
eRVR = undetectable HCV RNA at week 4
and week 12
*
3
6
4
8
6
0
Follow-up
Peg-IFN2a
+ RBV
Follow-up
Peg-IFN2a
+ 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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