Actualizacin de Nuevas Terapias de la Hepatitis C

1
Actualización de Nuevas Terapias de la Hepatitis C

• Dr Ricard Solá
• Hospital del Mar - Barcelona

III Jornadas de Hepatopatías Víricas 21 de Mayo
de 2008
2
The Hepatitis C Virus (HCV) Lifecycle Targets
for New Treatments
1) Virus Entry
2) Uncoating
3) Protein Synthesis
4) Cleavage
8) Re-infection
5) RNA Replication
7) Maturation
6) Packaging
Adapted from Pawlotsky JM, Gish RG. Future
therapies for Hepatitis C. Antivir Ther
200611397-408.
3
Objetivos Potenciales de los Antivíricos en la
Hepatitis C
Objetivos potenciales en los próximos 5 años
IFN
Proteínas Huésped
Inmunomoduladores
Vacuna Terapéutica
Objetivos antivirales
Receptor entrada
NS5A
IRES
Polimerasa
Proteasa
P7
Helicasa
4
Nuevos interferones
5
Albinterferón RBV en pacientes naïve y genotipo
1. Diseño del estudio fase 2b.
Aleatorización 12 sem. 24 sem.
48 sem.
PegIFN alfa 2-a 180 µg/s RBV 1000-1200 mg/día
(n114)
24 semanas seguimiento
AlbIFN 900 µg/2s RBV 1000-1200 mg/día (n118)
AlbIFN 900 µg/2s RBV 1000-1200 mg/día (n118)
AlbIFN 1200 µg/2s RBV 1000-1200 mg/día (n110)
RVS
AlbIFN 1200 µg/4s RBV 1000-1200 mg/día (n116)
PCR tiempo real 10 UI/mL Objetivo primario RVS
Zeuzem S, et al. AASLD 2007
6
Respuesta Virológica Análisis ITT
ETR, end-of-treatment response.
Zeuzem S, et al. AASLD 2007
7
Resumen de Tolerabilidad y Reducción de Dosis
Zeuzem S, et al. AASLD 2007
8
Specifically Targeted Antiviral Therapies for HCV
(STAT-C) Directly Target the Virus
Protease Inhibition
Polymerase Inhibition
Kwong A, et al. Beyond interferon and ribavirin
Antiviral therapies for hepatitis C virus. Drug
Discovery Today Therapeutic Strategies
20063211-220.
9
Specific Targets for HCV TreatmentProtease and
Polymerase Inhibition
C
E1
E2
p7
NS2
NS3
NS4A
NS4B
NS5A
NS5B
Kwong A, et al. Beyond interferon and ribavirin
Antiviral therapies for hepatitis C virus. Drug
Discovery Today Therapeutic Strategies
20063211-220.
10
HCV protease and co-factor NS4A
active site catalytic triad
NS4A
zinc finger
11
Características básicas de los inhibidores de la
proteasa del VHC

• Interactúan con la tríada catalítica
• Predominantemente activos frente al genotipo 1
  del VHC
• Rápida selección de cepas resistentes

12
Desarrollo de nuevas moléculas
Diana Fármaco Estado Proteasa BILN-2061
(Boheringer) Celuprevir Retirado
VX950 (Vertex/JJ)
Telaprevir Fase III SCH 503034
(Schering-Plough) Boceprevir Fase
II ITMN-191 (Intermune/Roche) Fase
I TCM435350 (Tibotec/Medivir) Fase
I Polimerasa MK-0608 (Merck) preclínica (Nucleós
ido) PSI-6130 R7128 (Pharmasset/Roche) Fase I
R1626 (Roche) Fase
II Valopicitabina (Idenix) Retirado Polimerasa A-
837093 (Abbott) preclínica (No-Nucles.) HCV-796
(ViroPharma/Wyeth) Fase II
13
PROVE 1 Telaprevir PegIFN/RBV en el
tratamiento de pacientes naive con genotipo 1

• Estudio fase II randomizado, controlado con
  placebo

Wk 12
Wk 24
Wk 48
Placebo PegIFN alfa-2a 180 ?g/wk RBV
1000/1200 mg QD (n 75)
End of Treatment
Telaprevir 750 mg every 8 hrs PegIFN alfa-2a
RBV (n 79)
PegIFN alfa-2a RBV
End of Treatment
Treatment-naive patients infected with HCV
genotype 1 (N 250)
24-Week Follow-up
Telaprevir PegIFN alfa-2a RBV (n 79)
PegIFN alfa-2a RBV

SVR
24-Week Follow-up
Telaprevir PegIFN alfa-2a RBV (n 17)

SVR
Patients received telaprevir 1250-mg loading
dose or placebo based on the arm to which they
were randomized. Patients must achieve
undetectable HCV RNA at Wk 4 (lt 10 IU/mL) and at
last test before stopping therapy at 12 or 24 wks.
McHutchison J, et al. EASL 2008. Abstract 4.
14
PROVE 1 Tasas de respuesta (ITT)

• One subject in the T12/PR24 arm did not meet RVR
  criterion, completed 48 weeks of treatment and
  had an SVR, but was not counted as a responder in
  this analysis

HCV RNA lt 10 IU/L Only subjects who met the
RVR criterion and stopped at 12 or 24 total weeks
of treatment
McHutchison J, et al. EASL 2008. Abstract 4.
15
PROVE 1 Efectos Adversos Asociados con Telaprevir

• Trastornos gastrointestinales, cutáneos (rash,
  prurito), y anemia más frecuentes en tratados con
  telaprevir
• Rash moderado y severo más frecuente en los
  tratados con telaprevir
• Incidencia y severidad de otros efectos adversos
  similar vs peginterferon alfa-2a y ribavirin
  solos
• Discontinuación acumulada por efectos adversos a
  semana 12
• Telaprevir 18
• Peginterferon alfa-2a y ribavirin solas 4
• Niveles de hemoglobina mas bajos en los tratados
  con telaprevir en las primeras 12 semanas

McHutchison J, et al. EASL 2008. Abstract 4.
16
PROVE 2 Telaprevir PegIFN RBV en el
tratamiento de pacientes naive con genotipo 1
Wk 12
Wk 24
Wk 48
Wk 36
Placebo PegIFN alfa-2a 180 µg/wk RBV
1000-1200 mg QD (n 82)
Treatment-naive patients infected with HCV
genotype 1 (n 323)
Telaprevir 750 mg every 8 hrs PegIFN alfa-2a
RBV (n 81)
PegIFN alfa-2a RBV (n 81)
Follow-up
Follow-up
Telaprevir 750 mg every 8 hrs PegIFN alfa-2a
RBV (n 82)
Follow-up
Telaprevir 750 mg every 8 hrs PegIFN
alfa-2a (n 78)
Patients received telaprevir 1250-mg loading
dose or placebo based on the arm to which they
were randomized. Patients received 12 or 24 weeks
regardless of whether RVR occurred.
Dusheiko G, et al. EASL 2008. Abstract. 58
17
PROVE 2 HCV RNA Undetectable Rates Week 4 and
12 (ITT)
PegIFN/RBV 48w (n82)
TPV 12w PegIFN/RBV 24w (n81)
TPV 12w PegIFN 12w (n78)
TPV 12w PegIFN/RBV 12w (n82)
100
P .001
P .001
P .001
P .001
80
79
80
73
69
62
60
51
Patients with undetectableHCV RNA ()
41
40
20
13
0
Week 4 (RVR)
Week 12
HCV RNA lt 10 IU/l
Dusheiko G, et al. EASL 2008. Abstract. 58
18
PROVE 2 SVR and Relapse Rates (ITT)
P .08
100
P .01
80
68
62
60
48
SVR ()
36
40
20
0
PegIFN/RBV 48w (n82)
TPV 12w PegIFN 12w (n78)
TPV 12w PegIFN/RBV 12w (n82)
TPV 12w PegIFN/RBV 24w (n81)
Relapse, (N)
PegIFN/RBV48w arm SVR12 (12-weeks follow-up
post-treatment)
Dusheiko G, et al. EASL 2008. Abstract. 58
19
PROVE 2 Efectos Adversos reportados en gt25 de
los Pacientes
Dusheiko G, et al. EASL 2008. Abstract. 58
20
Telaprevir PEGASYS ribavirin en el
tratamiento de pacientes naive con genotipo 1
TVR PEGASYS for 12 weeks total. No RBV
TVR SOC 12 weeks, then SOC for 36 weeks
Standard of care (SOC) (48 weeks)
significant vs SOC


67
70
70

60
60
48
50
50
41
40
40
36
Patients with an SVR ()
Patients with an SVR ()
30
30
20
20
10
10
0
0
PROVE-1 (USA)
PROVE-2 (Europe)
Dusheiko G, et al. 43rd EASL 2008 Abstract 58
McHutchison J, et al. 43rd EASL 2008 Abstract 4
21
Incidencia de resistencias con el uso de los
inhibidores de la proteasa en monoterapia
VX-950 dosing period
Post-dosing
Long-term follow-up
7
6
5
Long-term follow-up 37 months post-dosing
4
Median log HCV RNA
3
Follow-up 710 days post-dosing
2
EOD 14 days
1
Baseline
Time (days)
156
155
36/155
36
WT
WT
36
54
WT
155
155
155
WT
54
36
36/155
V36 M/A/L
R155 K/T/S/M
T54A
36/155
A156V/T
36/156
WT
IC50 fold change
1
4
7
12
46
466
781
EOD end of dosing
Sarrazin C, et al. Gastroenterology 2007 132
1767
22
Resistant virus is selected with Telaprevir alone
but declines with Peg-IFN Alfa-2a RBV
23
Como puede minimizarse el riesgo de aparición
de resistencias ?

• Escoger antivirales de acción directa que
  presenten una alta barrera genética.
• Combinación de varios antivirales de acción
  directa sin resistencia cruzada (p.e. inhibidores
  proteasa y polimerasa)
• Asegurar niveles séricos suficientes
• Utilizar un interferón óptimo
• Perfil farmacocinético inicio rápido de la
  acción y vida-media suficientemente larga
• Siempre optimizar la adherencia / cumplimiento

24
SCH 503034-Boceprevir
25
SPRINT-1 Boceprevir PegIFN/RBV en el
tratamiento de pacientes naive con genotipo 1
Week 40 Interim analysis
Week 72
Week 48
Week 4
Week 28
Baseline
PegIFN/RBV
PegIFN/RBV boceprevir
Lead in
48-week treatment arm
Follow-up
PegIFN/RBV boceprevir
No lead in
48-week treatment arm
PegIFN/RBV
PegIFN/Low-dose RBV arm
Only arms included in interim analysis
highlightedPegylated interferon alfa-2b 1.5
µg/kg/w and weight-based ribavirin 800-1400
mg/dayBoceprevir 800 mg TID
Kwo, et al. EASL 2008. Abstract .995
26
SPRINT-1 Undetectable HCV RNA at Weeks 4/12 of
Boceprevir Therapy (ITT)
PegIFN/RBV lead-in ? PegIFN/RBV boceprevir (n
103)
100
PegIFN/RBV boceprevir (n 107)
PegIFN/RBV (n 104)
78
80
73
60
60
Undetectable HCV RNA,
39
40
34
20
8
0
Duration 4 4 - Boceprevir
Rx 12 12 - (weeks) 8
4 4 Total RX 16 12
12
HCV RNA lt15 IU/mL
Kwo, et al. EASL 2008. Abstract .995
27
SPRINT-1 SVR 12 and Relapse Rates (ITT)
100
80
UndetectableHCV RNA,
57
55
60
40
20
0
or later SVR timepoint HCV RNA lt15 IU/mL
Kwo, et al. EASL 2008. Abstract .995
28
SPRINT-1 Highest WHO Grade Anemia During 28
Weeks of Treatment
PegIFN/RBV lead-in ? PegIFN/RBV boceprevir N
206
100
PegIFN/RBV boceprevir, N 226
PegIFN/RBV, N 104
80
60
54
50
45
46
of patients
40
27
25
23
21
20
10
1
0
0
0
0
0
0
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Anemia Severity

• Epoetin-alfa treatment
• PegIFN/RBV lead-in arm ? PegIFN/RBV boceprevir
  48
• PegIFN/RBV boceprevir 45
• PegIFN/RBV 25

Kwo, et al. EASL 2008. Abstract .995
29
NS5B RNA-dependent RNA polymerase
thumb
fingers
nucleoside analogues
palm
30
Características básicas de los inhibidores de la
polimerasa del VHC

• Análogos de sustratos naturales
• Igualmente activos frente a todos los genotipos
  del VHC
• Alta barrera genética a las resistencias

31
Desarrollo de nuevas moléculas
Diana Fármaco Estado Proteasa BILN-2061 Retirad
o ITMN-191 (Intermune/Roche) Fase I Telaprevir
(Vertex/JJ) Fase II SCH 503034
(Schering-Plough) Fase II Polimerasa
Valopicitabina (Idenix) Retirado (Nucleósido)
R1626 (Roche) Fase II MK-0608 (Merck) Fase
I PSI-6130 R7128 (Pharmasset/Roche) Fase I
Polimerasa A-837093 (Abbott) preclínica (No
-Nucles.) HCV-796 (ViroPharma/Wyeth) Fase II
32
R1626 presents a high barrier to resistance in
vitro
Nucleoside polymerase inhibitor
Non-nucleoside polymerase inhibitor
Protease inhibitor
HCV-796
R1626
Telaprevir
1X IC50
10X IC50
15X IC50
Untreated
1X IC50
10X IC50
15X IC50
1X IC50
10X IC50
15X IC50
3 weeks treatment

• Absence of colonies clearance of the replicon
• Presence of colonies selection of resistant
  colonies
• R1626 presents a higher barrier to resistance
  than protease and non-nucleoside polymerase
  inhibitors
• Lack of colonies after 3 weeks treatment with
  nucleoside inhibitors at 10X and 15X IC50

McCown M, et al. Antimicrob Agents Chemother Feb
19 2008 Epub ahead of print
33
R1626 Efecto antiviral
Tratamiento
Seguimiento
Placebo
1
500 mg/12h
1500 mg bid
0
3000 mg bid
4500 mg bid
-1
Descenso Medio de VHC RNA (Log10) Desde niveles
basales
-2
-3
-4
-5
0
5
10
15
20
25
30
Día del Estudio
8/9 debajo de límite cuantificable (lt600 IU/mL) y
5/9 PCR negativa (lt50 IU/mL) a dosis de 4500
mg/12h
34
Phase 2a study design in G1 treatment-naive
patients to evaluate 2 doses of R1626 with or
without RBV
DUAL LOW (R1626 1500 mg bid PEGASYS)
A
SOC (PEGASYS Ribavirin)
n20
DUAL HIGH (R1626 3000 mg bid PEGASYS)
B
SOC (PEGASYS Ribavirin)
Follow-up
n30
TRIPLE LOW (R1626 1500 mg bid PEGASYS
ribavirin)
C
SOC (PEGASYS Ribavirin)
Follow-up
n30
SOC (PEGASYS Ribavirin)
D
Follow-up
n20
72
0
4
48
Weeks
Patients randomised 1221 to treatments A, B, C
and D respectively
35
Synergistic antiviral effect of R1626 with
PEGASYS ribavirin Triple combination showing
the greatest drop in HCV RNA
Study week
0
1
2
3
4
5
0
1
SOC
2
Dual Low1500 mg R1626 PEGASYS
2.4
3
Mean HCV RNA (log10 IU/mL)
Decrease From Baseline
3.6
Dual High 3000 mg R1626 PEGASYS
4
4.5
5
5.2
Triple Low1500 mg R1626 SOC
6
SOCstandard of care PEGASYSRBV
Pockros P, et al. 58th AASLD 2007 Abstract 167
36
R1626 HCV Genotype 1 naive EOT (W48) virologic
response
4
48
PEG IFN 2a RBV R1626
PEG IFN 2a RBV
PEG IFN 2a RBV

GT1 Naive Patients
HCV RNAlt15 UI/mL

• Nelson et al. High end treatment response (84)
  after 4 weeks of R1626, peginterferon alfa-2A and
  ribavirin followed by a further 44 weeks of
• peginterferon alfa-2A and ribavirin. J
  Hepatology 2008 48 (suppl 2) S371

37
No resistance selection following treatment with
R1626 in Ph1 and Ph2a studies
11 patients with rebound from phase 1 and phase
2a

• No evidence for resistant virus variants after up
  to 4 weeks of treatment
• No phenotypic resistance vs baseline samples
• No S96T or N142T mutations (known to confer
  resistance in vitro)
• No other common amino acid substitutions
  (sequence analysis)

viral load decrease 0.5 log10 IU/mL followed by
0.5 log10 ? above nadir Le Pogam S, et al. 43rd
EASL 2008 Abstract 21
38
Dose-Escalating Trial of R7128 in Genotype 1
Previous Nonresponders

• R7128 a prodrug of the oral cytidine nucleoside
  analogue polymerase inhibitor, PSI-6130

Mean HCV RNA Decrease at Day 15
Day 14
R7128 750 QD
R7128 750 BID
R7128 1500 QD
R7128 1500 BID
Placebo
0
Placebo (n 8)
-0.1
-1
-0.9
R7128 750 mg QD (n 8)
HCV GT 1 nonresponders to pegIFN RBV (N 40)
Log10 IU/mL
-1.48
-2
-2.11
R7128 1500 mg QD (n 8)
-3
-2.72
-4
R7128 750 mg BID (n 8)

• No serious AEs reported with R7128
• Placebo group had highest number of AEs
• No evidence of viral rebound

R7128 1500 mg BID (n 8)
Reddy R, et al. AASLD 2007. Abstract LB9.
39
Características básicas de los inhibidores no
nucleósidos de la polimerasa del VHC

• Identificados varios objetivos
• Dependientes del genotipo y del subtipo del VHC
• Su eficacia puede modificarse por polimorfismos
  naturales
• Rápida selección de cepas resistentes

40
Distinct non-nucleoside binding sites on HCV
polymerase
Benzothia- diazine
Indoles
A
C
A
B
C
D
Phe-Der. Thiophene
B
Benzofurans
D
Adapted from R. De Francesco, 1st International
Workshop on Hepatitis C Resistance and New
Compounds, Boston, 2006
41
Desarrollo de nuevas moléculas
Diana Fármaco Estado Proteasa BILN-2061 Retirad
o ITMN-191 (Intermune/Roche) Fase I Telaprevir
(Vertex/JJ) Fase II SCH 503034
(Schering-Plough) Fase II Polimerasa
Valopicitabina (Idenix) Retirado (Nucleósido)
R1626 (Roche) Fase II MK-0608 (Merck) Fase
I PSI-6130 R7128 (Pharmasset/Roche) Fase I
Polimerasa HCV-796 (ViroPharma/Wyeth) Disco
ntinuado (No-Nucles.) GS-9190 (Gilead) Fase
I PF-868554 (Pfizer) Fase I VCH-759
(Virochem) Fase I A-837093 (Abbott) preclínica
42
Nitazoxanida-Tratamiento de pacientes con
Hepatitis C Genotipo 4

• STEALTH C-1 Estudio fase II, randomizado,
  controlado
• Nitazoxanida Tiazolida con actividad in vitro
  frente a VHB y VHC
• Aprobada para el tratamiento de la diarrea
  causada por Giardia y Cryptosporidium

SVR12 Wk 60
s 48
s 12
PegIFN alfa-2a 180 ?g/wk RBV 1000-1200 mg QD (n
40 todos naive interferon)
Follow-up
VHC GT 4 pacientes de 2 centros de Egipto (N
120)
Nitazoxanida 500 mg BID (n 40)
Nitazoxanida 500 mg BID PegIFN alfa-2a 180
?g/wk
Follow-up
Nitazoxanida 500 mg BID (n 40)
Nitazoxanida 500 mg BID PegIFN alfa-2a 180
?g/wk RBV 1000-1200 mg QD
Follow-up
n 28 naive interferon 12 NR interferon.
Rossignol JF, et al. AASLD 2007. Abstract 178.
43
Nitazoxanida-Tratamiento de pacientes con
Hepatitis C Genotipo 4
ITT Análisis en pacientes naive a interferon
ARN-VHC Negativo durante tratamiento combinado

• SVR12 en pacientes NR
• Nitazoxanida pegIFN RBV 25
• Nitazoxanida pegIFN 8
• Discontinuationes durante tratamiento en
  pacientes naive
• Nitazoxanida pegIFN 18
• Nitazoxanida pegIFN RBV 14
• PegIFN RBV 18
• Nitazoxanida generalmente bien tolerada
• Neutropenia grado 3 más frecuente en brazos con
  nitazoxanida

Nitazoxanida/pegIFN
Nitazoxanida/pegIFN/RBV
PegIFN/RBV
P .006
100
86
79
79
80
73
71
71
68
64
58
54
60
Pacientes ()
43
38
40
20
0
Wk 4
Wk 12
ETR
RVS 12
ARN-VHC lt 10 IU/mL.
Rossignol JF, et al. AASLD 2007. Abstract 178.
44
Conclusiones

• Continuaremos utilizando el IFN y la RBV como
  espina dorsal del tratamiento durante un tiempo
  ........
• Mayor eficacia, menor duración del tratamiento
• Menos efectos secundarios ?
• La eficacia de las nuevas moléculas depende del
  uso conjunto de IFN

45
Posibilidades terapéuticas de la hepatitis C
Mejora de los fármacos actuales
Inhibidores proteasas polimerasa
Inhibidores de la fibrogénesis
Adaptación del tratamiento actual
Albuferón
2006 2008 2010 2011
46
Polymerase Inhibitor R7128 PegIFN/RBV Efficacy

• Significant antiviral effect of R7128 in
  combination with Peg-IFN alfa-2a/RBV over 4 weeks
• 5.1 log10 mean decrease in HCV RNA with R7128
  1500mg BID
• R7128 safe and well tolerated over 4 weeks
• No substantial differences from PegIFN
  alfa-2a/RBV
• No hematologic or other toxicity identified

Lalezari, et al. EASL 2008. Abstract .66
47
Debio 025 PegIFN alfa-2a in Treatment-Naive
Patients

• Double-blind, placebo-controlled study of Debio
  025 PegIFN alfa-2a 180 mg/wk
• 90 patients randomized, stratified by genotype

Plt.05 vs PegIFN placebo and Debio 025
100mg/day monotherapy arms
Flisiak, et al. EASL 2008. Abstract . 143
48
PegIFN Weight-based Taribavirin or RBV in
Treatment-Naive HCV GT 1

• No significant differences in Week 12 viral
  response (EVR)

100
Undetectable HCV RNA
2 log10 decrease in HCV RNA
80
60
EVR,
64.2
57.1
40
54.4
51.4
41.8
20
41.4
25.0
31.4
0
20 mg/kg N67
25 mg/kg N70
30 mg/kg N68
Ribavirin N70
Taribavirin
Undetectable HCV RNA (lt39 IU/mL) or 2 log10
decrease from baseline
Poordad F, et al. EASL 2008. Abstract . 996
49
PegIFN Weight-based Taribavirin or RBV in
Treatment-Naive HCV GT 1

• Significantly less anemia in 20 mg/kg/d and 25
  mg/kg/d taribavirin arms vs RBV

100
80
60
Patients with Anemia, (Hgb lt 10g/dL)
P .022
40
P .009
24.3
14.7
20
9.0
7.1
0
20 mg/kg/d N67
25 mg/kg/d N70
30 mg/kg/d N68
Ribavirin N70
Taribavirin
Poordad F, et al. EASL 2008. Abstract . 996
50
Silibinin PegIFN/RBV in PegIFN/RBV Nonresponders

• Silibinin Major active isomer of silymarin
  (milk thistle)

Week 1
Week 2
Week 13

• PegIFN/RBV
• Silymarin 280 mg TID

• Silibinin 5 mg/kg/d
• PegIFN/RBV

Silibinin 5 mg/kg/d
Previous PegIFN/RBV nonresponders (N20)
Silibinin 10 mg/kg/d

• Silibinin 10 mg/kg/d
• PegIFN/RBV

Silibinin 15 mg/kg/d

• Silibinin 15 mg/kg/d
• PegIFN/RBV

Silibinin 20 mg/kg/d

• Silibinin 20 mg/kg/d
• PegIFN/RBV

All patients had detectable HCV RNA at Week 24
Ferenci P, et al. EASL 2008. Abstract .63
51
Silibinin PegIFN/RBV in PegIFN/RBV Non
responders

• Silibinin monotherapy for 7 days followed by 7
  days of silibinin therapy PegIFN/RBV was well
  tolerated

Week 2 ( 14 days silibinin 7 days PegIFN/RBV)
Week 1 (Silibinin monotherapy)
6
P .0027

5
P lt.0001

4
Log10 HCV-RNA decrease from baseline (IU/mL)
3
2
1
0
5 mg/kg/d (N3)
10 mg/kg/d (N3)
15 mg/kg/d (N5)
20 mg/kg/d (N9)
Silibinin dose (iv)
Patients with undetectable HCV RNA 15mg/k/d
(n2) / 20 mg/kg/d (n4)
Ferenci P, et al. EASL 2008. Abstract .63