Zeuzem S. et al. N Engl J Med 2011

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Future treatment of patients
with HCV cirrhosis
Marc Bourlière
Dept of Hepato-gastroenterology
Saint Joseph Hospital, Marseille
5th Paris Hepatitis Conference
Paris, January 30 th 2012
Agenda
• Where do we come from : HCV cirrhosis
treatment with PR
• Where are we now : HCV cirrhosis treatment
with PI + PR
• Vision of future
Agenda
• Where do we come from : HCV cirrhosis
treatment with PR
• Where are we now : HCV cirrhosis treatment
with PI + PR
• Vision of future
HCV cirrhosis treatment with PEG-IFN + RBV
• Clinical trials SVR in compensated cirrhosis ranged :
– 10 to 44% in HCV genotypes 1 /4
– 33 to 72% in HCV genotypes 2/3
• Real-life setting cohort : 306 cirrhotic / 2011 patients
SVR naive G1
SVR naive G2-G3
Vezali E et al. Clin Ther 2010; 32: 2117-38.
Bourlière M et al. Antivir Ther 2012; 17: 101-110.
HCV cirrhosis treatment with PEG-IFN + RBV
• Beneficial impact of SVR in cirrhosis :
– Improvement of fibrosis
– Regression of cirrhosis
– Reduction and prevention of cirrhosis-related complications
( portal hypertension or HCC )
• HCC surveillance programs should be maintained :
– HCC occur years after : 0.6 to 2.5% annually
Heathcote EJ et al. N Engl J Med 2000; 343: 1673-1680
Helbling B et al. J Viral Hepat 2006; 13: 762-69.
Abergel A et al. J Viral Hepat 2006; 13: 811-20.
Di Marco V et al. J Hepatol 2007; 47: 484-491.
Roffi L et al. Antivir Ther 2008; 13: 663-673.
Gianninni EG et al. J Intern Med 2009; 266: 537-46.
Aghemo A et al. Antivir Ther 2009; 14: 577-84.
Rumi MG et al. Gastroenterology 2010; 138: 108-115.
Cheng WS et al. J Hepatol 2010; 53: 616-623.
Bruno S et al. Hepatology 2010; 51: 388-397.
Hadziyannis SJ et al. Ann Intern Med 2004;140 :436-55.
Shiratori Y et al. Ann Intern Med 2005; 142: 105-114.
Hung CH et al. J Viral Hepat 2006; 13: 409-414.
Veldt BJ et al. Ann Intern Med 2007; 147: 677-684.
Kobayashi S et al. Liver Int 2007; 27: 186-191
HCV cirrhosis treatment with PEG-IFN + RBV
• Predictive factors of response:
– RVR is the strongest PFR
– Role of type of PEG-IFN remain controversial
• Safety and tolerance of PR in cirrhotic is not different :
– Dose modifications are more frequent ( hematological
toxicity)
– Rate of liver decompensation is low (0-3%)
caution in real-life practice
Vezali E et al. Clin Ther 2010; 32: 2117-38.
HCV decompensated cirrhosis treatment with
PEG-IFN + RBV
• The most in need of treatment ( 5years survival rate : 50%)
• SVR rates ranged :
– 7 to 16% in genotype 1-4
– 44 to 57% in genotype 2-3
• Treatment limitation:
– Higher risk of infection and deaths related to infection
– More frequent side effects in Child Pugh C (MELD >18)
• Treatment benefit :
– Lower rate of decompensation during follow-up
– Reduced mortality in responders
Fattovich G et al. Gastroenterology 1997; 112: 463-72.
Forns X et al. J Hepatol 2003; 39: 389-96.
Iacobellis A et al. J Hepatol 2007; 46: 206-212.
Iacobellis A et al. Aliment Pharmacol Ther 2009; 27: 1081-85.
Tekin F et al. Aliment Pharmacol Ther 2008; 27: 1081-85.
HCV decompensated cirrhosis treatment with
PEG-IFN + RBV
• 51 patients awaiting LT treated with PEG-IFN +RBV
15 SVR
(29%)
LT
10 no HCV recurrence
(20%)
• Independent predictive factors of response
– Adherence to treatment
– Higher dosage of drugs
• Risk / benefit ratio should be assessed in patients with ChildPugh class B on a case by case basis
Carrion JA et al. J Hepatol 2009; 50: 719-728.
Agenda
• Where do we come from : HCV cirrhosis
treatment with PR
• Where are we now : HCV cirrhosis treatment
with PI + PR
• Vision of future
Virological efficacy of
Boceprevir or Telaprevir
Naive genotype 1 patients
Increased SVR compared to Peg-IFN/RBV
Boceprevir
SVR increases from
+ 38%
30%to 63/66%
Telaprevir
SVR increases from 44% to 72/75%
+ 30%
Treatment-experienced patients
Relapsers
SVR increases from 29% to 75%
Relapsers
SVR increases from 24% to 83/88%
Partial-Responders
SVR increases from 7% to 52%
Partial-responders
SVR increases from 15% to 54-59%
Null-responders
SVR : 38 %
Null-responders
SVR increases from 5% to 29/33%
+ 46%
+ 45%
Poordad F et al. N Engl J Med 2011: 364: 1195-1206
Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.
Vierling J. et al. Hepatology 2011: 54: 796A .
+ 60%
+ 40%
+ 25%
Sherman KE et al. N Engl J Med 2011; 365: 1014-1024.
Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16.
Zeuzem S. et al. N Engl J Med 2011;364:2417–28
TREATMENT EFFICACY WITH PI
IN GENOTYPE 1 PATIENTS WITH
SEVERE FIBROSIS OR CIRRHOSIS
Treatment response with Boceprevir in genotype 1
patients with severe fibrosis or cirrhosis
Naive patients ( Sprint 2 study)
% patients with SVR
 100/ 1097 patients had F3 (47) or F4 (53)
 SVR rates in patients with advanced fibrosis : 52% BOC/PR48,
41% BOC RGT, 38% PR
Sustained virological response
328 319 313
Bruno S et al. J Hepatol 2011: 54: S4
11
18
18
13
16
24
Poordad F et al. N Engl J Med 2011: 364: 1195-1206
Treatment response with Boceprevir in genotype 1
patients with severe fibrosis or cirrhosis
Treatment-experienced patients ( Respond 2 study)
% patients with SVR
 78/ 403 patients had F3 (29) or F4 (49)
 SVR rates in patients with advanced fibrosis : 68% BOC/PR48,
44% BOC RGT, 13% PR
Sustained virological response
61 117 119
Bruno S et al. J Hepatol 2011: 54: S4
5
15
9
10 17
22
Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.
Treatment response with Boceprevir in genotype 1
patients with severe fibrosis or cirrhosis
Naive patients ( Sprint 2 study)
• SVR with Boceprevir is increased by 14% compared with PR
• Relapse rate is more frequent (12-18% vs 9%)
• RVR during triple therapy is less frequent (25% vs 46%)
• SVR in RVR patients is higher in patients receiving 48 weeks of
treatment ( 92%) compared with those receiving RGT (75%)
Naive genotype 1 patients with severe fibrosis or cirrhosis
Benefit from triple therapy with Boceprevir but should
received 48 weeks of treatment
Bruno S et al. J Hepatol 2011: 54: S4
Poordad F et al. N Engl J Med 2011: 364: 1195-1206
Treatment response with Boceprevir in genotype 1
patients with severe fibrosis or cirrhosis
RESPOND-2
SVR by Fibrosis Score and Historical Response
F 0/1/2
Bruno S et al. J Hepatol 2011: 54: S4
F 3/4
Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.
Treatment response with Boceprevir in genotype 1
patients with severe fibrosis or cirrhosis
Treatment-experienced patients ( Respond 2 study)
• SVR with Boceprevir is increased by 42% compared with PR
• Relapse rate is more frequent (21% vs 11%)
• RVR during triple therapy is less frequent (25% vs 53%)
• SVR in RVR patients is higher in patients receiving 48 weeks of
treatment ( 90%) compared with those receiving RGT (80%)
Treatment-experienced genotype 1 patients with severe
fibrosis or cirrhosis
Benefit from triple therapy with Boceprevir but should
received 48 weeks of treatment
Bruno S et al. J Hepatol 2011: 54: S4
Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.
Treatment response with Telaprevir in genotype 1
patients with severe fibrosis or cirrhosis
Naive patients ( ADVANCE study)
 231/ 1088 patients had advanced fibrosis F3 (163) or F4 (68)
 SVR rates in patients with advanced fibrosis : 62% T12PR48,
53% T8PR48, 33% PR
Sustained virological response
288 290 279
52
52
59
21
21
26
Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16.
Treatment response with Telaprevir in genotype 1
patients with severe fibrosis or cirrhosis
Naive patients ( ILLUMINATE study)
 149/ 540 patients had advanced fibrosis F3 (88) or F4 (61)
 SVR rates in patients with advanced fibrosis : 63% vs 75% F0/1/2
Sustained virological response
124 127 76
20 21
18 12
42
Sherman KE et al. N Engl J Med 2011; 365: 1014-1024.
Treatment response with Telaprevir in genotype 1
patients with severe fibrosis or cirrhosis
Naive patients ( Advance and Illuminate studies)
• SVR with Telaprevir (T12) is increased by 30% compared with PR
• eRVR during triple therapy is less frequent (46 - 49% vs 58 - 60%)
• SVR in RVR patients is higher in patients receiving 48 weeks of
treatment ( 88%) compared with those receiving 24 weeks (82%)
Naive genotype 1 patients with severe fibrosis or cirrhosis
Benefit from triple therapy with Telaprevir but should
received 48 weeks of treatment in case of cirrhosis
Sherman KE et al. N Engl J Med 2011; 365: 1014-1024.
Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16.
Treatment response with Telaprevir in genotype 1
patients with severe fibrosis or cirrhosis
Treatment-experienced patients ( Realize study)
% patients with SVR
 316/ 663 patients had advanced fibrosis F3 (147) or F4 (169)
 SVR rates in patients with advanced fibrosis : 67% T12PR48 vs 7% PR (F3)
47% T12 PR 48 vs10% PR (F4)
Sustained virological response
73
273
29
118
30
139
Zeuzem S. et al. N Engl J Med 2011;364:2417–28
Treatment response with Telaprevir in genotype 1
patients with severe fibrosis or cirrhosis
Treatment-experienced patients ( Realize study)
Sustained virological response
Prior
relapsers
38 167
15 62
Prior
Partial responders
15 57
17 47
5 18
5 32
Prior
Null responders
18 59
9 38
10 50
Pol.S et al. Hepatology 2011: 54: 374A
Treatment response with Telaprevir in genotype 1
patients with severe fibrosis or cirrhosis
Treatment-experienced patients ( Realize study)
• SVR with Telaprevir (T12) is increased compared with PR
irrespective of fibrosis stage.
• SVR rates are lower in patients with cirrhosis except in relapsers .
• Relapse rate is higher in cirrhotic patients with previous partial or
null response (10% vs 4%).
• No relation between advanced fibrosis and RAVs occurrence
• Predictive factors of response :
– Previous PR response
– High baseline ALT or AST
Treatment –experienced genotype 1 patients with
severe fibrosis or cirrhosis benefit from triple therapy
with Telaprevir
Zeuzem S. et al. N Engl J Med 2011;364:2417–28
Pol.S et al. Hepatology 2011: 54: 374A
TREATMENT SAFETY WITH PI
IN GENOTYPE 1 PATIENTS WITH
SEVERE FIBROSIS OR CIRRHOSIS
Safety issue in phase III trials
• In Phase III trial safety issue were reported :
– Rash, pruritus and anemia with Telaprevir (TVR)
– Anemia and dysgeusia with Boceprevir (BOC)
• Few patients with cirrhosis were included :
– Telaprevir :
• ADVANCE1 = 47
• ILLUMINATE2 = 61
• REALIZE3 = 139
247
– Boceprevir :
• SPRINT-24 = 40
• RESPOND-25 = 39
79
1. Jacobson IM, et al, N Engl J Med 2011;364:2405-16
2. Sherman KE, et al, N Engl J Med 2011;365:1014-24
3. Zeuzem S, et al, N Engl J Med 2011;364:2417-28
4. Poordad F, et al, N Engl J Med 2011;364:1195-206
5. Bacon BR, et al, N Engl J Med 2011;364:1207-17
From February 2011 to September 1th 2011
430 patients were included in 51 sites
310 patients were included in this analysis
•
•
HCV genotype 1 patients
Compensated cirrhosis (Child
Pugh A) genotype 1
•
Non-responders
– Relapsers
– Partial responders
( >2 log10 HCV RNA
decline at Week 12)
– Null responders
theoretically excluded
•
Treated in the French ATU
Interim safety analysis
PegIFN +
RBV
BOC + Peg-IFN α-2b + RBV
Follow-up
BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 à 1400 mg/d
TVR + Peg-IFN α2a + RBV
Follow-up
Peg-IFN α-2a + RBV
TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200
mg/d
0
4
8
12
16
Weeks
36
48
72
SVR assessment
http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf
http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf
Hezode C et al. Hepdart 2011
Adverse Experience (AE) Summary in Combined SPRINT-2
and RESPOND-2 BOC/PR Groups by Fibrosis Score
Median Treatment Duration 201 days
SPRINT-2 and RESPOND-2 BOC/PR
Treatment-emergent AE
Serious AE
Discontinuation due to AE
Dose modification due to AEb
Death
F0/1/2
N=868
n (%)
F3/4
N=139
n (%)
862 (99)
99 (11)
116 (13)
301 (35)
3c (<1)
138 (99)
21 (15)
17 (12)a
57 (41)
0
a 11/79
(14%) discontinuations due to AE in F4 group; 6/60 (10%) in F3.
Any study drug
c All deaths were in F0/1/2 group and were suicides.
b
Bruno S et al. J Hepatol 2011: 54: S4
Safety: Most Common (>20%) AEs by Fibrosis Score, %
Adverse Events
Fatigue
Anemia
Dysgeusia
Headache
Nausea
Chills
Pyrexia
Insomnia
Myalgia
Diarrhea
Influenza-like illness
Rash
Decreased appetite
Dry Skin
Vomiting
Irritability
PR
F0/1/2
N=389
98
58
28
16
44
41
28
32
31
25
21
26
20
23
18
15
21
PR
F3/4
N=39
100
56
26
18
33
46
26
31
28
18
18
23
13
23
3
8
28
BOC/PR BOC/PR
F0/1/2
F3/4
N=868
N=139
99
99
55
56
47
53
41
44
44
42
46
38
34
37
31
34
32
30
23
29
24
28
24
25
22
23
25
22
21
22
18
21
22
21
Bruno S et al. J Hepatol 2011: 54: S4
CUPIC: Boceprevir – preliminary safety findings
Patients, n (%)
Boceprevir (n=134)
Phase III study (79)
39 (29)*
21 (15)
Discontinuation due to serious AE
8 (6)
14%
Death
1(1)
0
Serious AEs
Rash
Grade 3
SCAR
23%
0
0
Infection (Grade 3/4)
2 (1,4)
Other AEs (Grade 3/4)
Anemia
Grade 2 (8.0 – <10.0 g/dL)
Grade 3/4 (<8.0 g/dL)
EPO use
Transfusion
41 (31)
Neutropenia
Grade 3 (500 – <1000/mm3)
Grade 4 (<500/mm3)
G-CSF use
Thrombopenia
Grade 3 (25,000 – <50,000)
Grade 4 (<25,000)
53%
41 (31)
8 (6)
70 (52)
8 (6)
10 (7)
5 (4)
7 (5)
8 (6)
3 (2)
*86serious AEs in 39 patients; SCAR: severe cutaneous adverse reaction; EPO: erythropoetin; G-CSF: granulocyte-colony stimulating factor
Hezode C et al. Hepdart 2011
REALIZE: AEs Leading to Study Drug
Discontinuation (FAS, Pooled TVR arms, N=530)
Cirrhotics (F4)
N=139
Non-cirrhotics
(F0–3) N=391
Total
N=530
Discontinuation of all study drugs during TVR treatment phase, n (%)
Any AE
10 (7)
17 (4)
27 (5)
1 (<1)
1 (<1)
2 (<1)
Anemia
0
3 (<1)
3 (<1)
Pruritus
1 (<1)
0
1 (<1)
0
2 (<1)
2 (<1)
21 (15)
46 (12)
67 (13)
Rash
4 (3)
6 (2)
10 (2)
Anemia
3 (2)
9 (2)
12 (2)
Pruritus
2 (1)
2 (<1)
4 (<1)
1 (<1)
2 (<1)
3 (<1)
Rash
Anorectal signs and symptoms*
Discontinuation of TVR or Pbo during TVR treatment phase, n (%)
Any AE
Anorectal signs and symptoms*
*Grouped term including several different AEs in the anorectal area; Pbo = placebo
Pol.S et al. Hepatology 2011: 54: 374A
REALIZE: Laboratory Abnormalities
Cirrhotics (F4)
N=139
Non-cirrhotics (F0–3)
N=391
≤10g/dL
63 (46)
156 (40)
≤8.5g/dL
19 (14)
49 (13)
Grade 3 (500 to <750/mm3)
35 (25)
68 (17)
Grade 4 (<500/mm3)
10 (7)
9 (2)
Grade 3/4
45 (32)
77 (19)
16 (12)
12 (3)
2 (1)
1 (<1)
18 (13)
13 (3)
n (%)
Hemoglobin
Neutrophils
Platelets
Grade 3 (25,000 to <50,000/mm3)
Grade 4 (<25,000/mm3)
Grade 3/4
Pol.S et al. Hepatology 2011: 54: 374A
CUPIC: telaprevir – preliminary safety findings
Patients, n (%)
Telaprevir (n=176)
Phase III studies (n=139)
Serious AEs
90 (51)*
Discontinuation due to serious AE
21 (12)
10 (7) 21 (15)
Death
3 (1.7)
0
Rash
Grade 3
SCAR
58 (42)
12 (6.8)
0
Infection (Grade 3/4)
8(4.5)
Other AEs (Grade 3/4)
Anemia
Grade 2 (8.0 – <10.0 g/dL)
Grade 3/4 (<8.0 g/dL)
EPO use
Transfusion
84 (48)
Neutropenia
Grade 3 (500 – <1000/mm3)
Grade 4 (<500/mm3)
G-CSF use
Thrombopenia
Grade 3 (25,000 – <50,000)
Grade 4 (<25,000)
58 (33)
23 (13)
96 (55)
32 (18)
54 (39)
46%
14%
20 (11)
2 (1)
5 (3)
25%
7%
26 (15)
12 (7)
12%
1%
*228serious AEs in 90 patients; SCAR: severe cutaneous adverse reaction; EPO: erythropoetin; G-CSF: granulocyte-colony
stimulating factor
Hezode C et al. Hepdart 2011
Conclusion
• Triple therapy with first generation PI is a major step forward
in treatment of both naïve and treatment-experienced
genotype 1 compensated cirrhotic patients.
• Cirrhotic patients with prior relapse or partial response have
the greatest benefit in SVR rate with both PI.
• Triple therapy with PI appears to be less beneficial in cirrhotic
patients with prior null-response and this should be weighed
against the increase of side effects.
Conclusion
• The safety profile of PI among compensated cirrhotic patients
treated in the CUPIC cohort is poor , however , it is compatible
with use in real-life practice.
• Patients with cirrhosis should treated with cautious and
should be carefully monitored due to High incidence of
anemia with poor response to EPO.
• There is no data on the efficacy and safety of triple therapy
with PI in decompensated cirrhosis
Agenda
• Where do we come from : HCV cirrhosis
treatment with PR
• Where are we now : HCV cirrhosis treatment
with PI + PR
• Vision of future
HCV treatment: future
perspectives
2014/2015?
2016/2017?
Protocols for HCV cirrhotic patients are expected
NS5B
Polymerase
inhibitor +
PR
PI + PR
83%
BI 201335 + PR
SVR G1
TMC435 + PR
86%
SVR G1
PSI-7977 + PR
91%
SVR G1
100%
SVR G2/3
PI: protease inhibitor; PR: peginterferon + ribavirin; DAA: direct-acting antiviral
QUAD therapy
Interferon
free/sparing
regimens
BMS-650032 +
BMS-790052 +
PR
BMS-650032 +
BMS-790052
100%
SVR G1
PSI-7977 +
RBV
100%
SVR G2/3
Lok AS et al. N Engl J Med 2012; 366: 216-224.
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