Transcript Incidence and predictors of Hepatocellular Carcinoma in

Massimo Puoti
Dept. of Infectious Diseases
AO Ospedale Niguarda Cà Granda
Milan, Italy
ELPA Symposium: COMPASSIONATE USE
IN HEPATITIS C
What patients populations have the
highest unmet needs ?
Patients population with the
highest unmet need
• Cirrhosis
• Patients without response to previous therapy
(triple & double)
• Patients intolerant to Interferon
Patients population with the
highest unmet need
• Cirrhosis
• Patients without response to previous therapy
(triple & double)
• Patients intolerant to Interferon
Cumulative Incidence of Liver-Related
Complications Following SVR in Cirrhosis
No SVR
Patients With Liver
Complications (%)
100
SVR
80
60
40
20
0
0
24
48
72
96
120
144
345
70
207
41
34
12
Mos
Pts at Risk, n 759
124
702
119
634
116
Bruno S, et al. Hepatology. 2007;45:579-587.
527
108
168
Cirrhosis: Efficacy of triple therapy in HCV G1
Study
Naïve
Relapsers
Partial
Responders
Null
Responders
Telaprevir
Phase III
Studies 1-2
71%
(F4)
59% (F3-F4)
84%
(F4)
34%
(F4)
14%
(F4)
Boceprevir
Phase III
Studies3-5
42%
83%
(F3-F4)
46%
(F3-F4)
1/2
CUPIC Real Life
Telaprevir6
_
71%
(SVR 12)
29%
(SVR12)
_
CUPIC Real Life
Boceprevir6
_
52%
(SVR 12)
31%
(SVR 12)
_
1.
Marcellin P, et al. J Hepatol 2011; 54 (Suppl 1): S183 2. Pol S, et al. Hepatology 2011;54(Suppl. S1):374A 3. Buti
M. AASLD 2012 3. Poordad F, et al. N Engl J Med 2011;364:1195–206 4. Bacon BR, et al. N Engl J Med
2011;364:1207–17 5. Vierling J et al AASLD 2011 6. Hezode C et al EASL 2013 Submitted
Safety in cirrhotics:
Clinical Trials vs Real World
Telaprevir
Boceprevir
PegIFN/RBV
Clinical trials
(including cirrhotics)
Treatment-naïve
n=727 n=361
(courtesy F. Poordad)
n=734 n=363
Real world
(cirrhotics only)
Treatment-experienced
n=530 n=132
n=323 n=80
Treatment-experienced
n=296
n=159
CUPIC: Risk of occurrence of death or severe
complications
Factors
Albumin > 3.5
g/dL
Albumin < 3.5
g/dL
Platelet
count >
100.000
3.3%
Platelet
Count <
100.000
4.8%
7.1%
40.6%
Hezode C et al EASL 2013 Submitted
Standard of Care (PEG IFN + RBV) in Decompensated Cirrhosis
HCV-RNA Neg
Author
N
Rx
EOT
SVR
Iacobellis
66
Peg/RBV
49%
20%
Forns
51
Peg/RBV
29%
20%
Tekin
20
Peg/RBV
45%
30%
Annichiarico
15
Peg/RBV
47%
20%
Everson
124
IFN/RBV
46%
24%
Forns
30
IFN/RBV
30%
20%
Thomas
20
IFN
60%
20%
Amarapukar
18
IFN/RBV
61%
38%
Crippin
15
IFN/RBV
33%
0%
TOTALS
359
44%
24%
Martinez-Camacho A, Fortune BE, Everson GT. Treating HCV Prior to Liver Transplantation.
In Chronic Hepatitis C: Advances in Treatment, Promise for the Future. ML Shiffman (ed).
2012. Springer Science-Business. NY.
Safety and tolerability
Deaths and AEs in the first 6 month of follow-up according to treatment or not
OR
2.4 (1.02 – 5.77)
OR
0.7
OR
0.6
OR
2.9
OR
0.6
OR
0.9
OR
1.2
OR
1.9
Iacobellis A, et al. J Hepatol 2007
DAA in PNC-HCV
G1 Cirrhosis awaiting LT
Verna EC1, Terry N2, Lukose T1, Mentore K2, Olsen SK1, Fox AN1, Laurin
J2, Satoskar R2, Dove LM1, Shetty K2, Brown RS1
High Early Response Rates with Protease Inhibitor Triple Therapy in a
Multicenter Cohort of HCV-Infected Patients Awaiting Liver
Transplantation.
1Columbia University Medical Center, New York, 2Georgetown University
Hopsital, Washington, DC, United States
Triple therapy (PR + TPV or BOC)
Mean duration
Mean (range) initial UNOS MELD
HCC
History of ascites or HE
N. Completed (4w) - (12 w)
Time from PI to <LOD
Undetectable HCV-RNA
W4
W12
14 w
9 (7-31)
45%
20%
90 - 70%
28 days
61%
86%
DAA in PNC-HCV
G1 Cirrhosis awaiting LT
Verna EC1, Terry N2, Lukose T1, Mentore K2, Olsen SK1, Fox AN1, Laurin
J2, Satoskar R2, Dove LM1, Shetty K2, Brown RS1
High Early Response Rates with Protease Inhibitor Triple Therapy in a
Multicenter Cohort of HCV-Infected Patients Awaiting Liver
Transplantation.
1Columbia University Medical Center, New York, NY, United States.
2Georgetown University Hopsital, Washington, DC, United States
Triple therapy (PR + TPV or BOC)
Time from PI to <LOD
28 days
0
Breakthrough
1 NR
1 Rash
5 (25%)
Discontinuation
1 Neuritis
2 Decompensation (10%)
Patients populations with the highest
unmet needs
• Cirrhosis:
– Most urgent need  response = short term survival
– Lower rate of response to treatment
– Highest rate of side effects:
• Reasonable in compensated patients w/o advanced disease
• Chance of death or hospitalization > treatment response in
advanced disease
• Treatment not indicated in decompensated patients
SOUND-C2: Faldaprevir + BI-207127 ± R in
treatment-naїve patients
SVR12: cirrhosis vs. no cirrhosis
100
80
70
67
60
52
57
40
40
33
20
0
BI 207127 dosing
Duration (weeks)
RBV
11/21
124/217
6/9
48/69
Cirrhosis No cirrhosis
Cirrhosis No cirrhosis
TID
16, 28 & 40
+
BID
28
+
1/3
17/43
Cirrhosis No cirrhosis
TID
28
-
The presence of cirrhosis did not significantly influence the achievement of SVR12
in univariate regression analysis (odds ratio 0.84; p=0.66)
Soriano V et al. AASLD 2012:
http://www.natap.org/2012/AASLD/AASLD_19.htm
Ribavirin + Sofosbuvir + PEGIFN
Data in 153 cirrhosis
Summary of Fusion (68 HCVG2&3 experienced), Fission (100 HCV G2&3 naives) , Positron (31 HCV G2/3 IFN
intolerant) and Neutrino (54 G1&4-6 naives) Studies
Lawitz E NEJM 2013; Jacobson IM NEJM 2013
Patients population with the
highest unmet need
• Cirrhosis
• Patients without response after previous
therapy (double & triple)
• Patients intolerant to Interferon
PROPORTION OF NAÏVE HCV GENOTYPE 1 PATIENTS
WITHOUT RESPONSE TREATMENT
Setting
% without
Response
HCV G1 naive
100
80
SVR (%)
38-44
60
40
25-37%
20
0
PegIFN/RBV
BOC or TVR +
PegIFN/RBV
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
25-37
PROPORTION OF EXPERIENCED HCV GENOTYPE 1
PATIENTS WITHOUT RESPONSE AFTER TREATMENT
PegIFN + RBV
Setting
100
SVR (%)
80
60
BOC or TVR + PegIFN + RBV
85-93
71-76
HCV G1 naive
25-37
HCV G1 relapsers
17-31
HCV G1 partial
responders
41-60
95
62-71
41-60
HCV G1 null responders
40
% without
Response
63-71
17-31
20
5
0
Relapsers
Partial Responders
Null
Responders
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Vierling JM, et al. AASLD 2011. Abstract 931.
HCV Genotype 2 and 3: good results with PEGIFN
+ RBV but 30-40% without response
Setting
% without
Response
Primary analysis population
HCV G1 naive
25-37
HCV G1 relapsers
17-31
Virological response (%)
Genotype 2 (n=1025)
HCV G1 partial
responders
94.9
100
84.7
80
80
60
HCV G3
40
100
HCV G1 null
responders
71.4
HCV G2
60
Genotype 3 (n=1259)
41-60
92.2
63-71
74.0
29
60.6
28
40
25.5
19.9
20
20
0
0
n=
261
Week 2
868
Week 4
(RVR)
973
Week 12
732
SVR24
251
Week 2
932
Week 4
(RVR)
1161
Week 12
763
SVR24
The error bars correspond to the 95% confidence intervals
Virological response defined as: HCV RNA <50 IU/mL by week 2, 4 (RVR)
18
or 12, or ≥24 weeks after end of treatment (SVR)
Marcellin PM, et al. Hepatology 2012 [Epub ahead of print]
Virological response : G1 and G4 two genotypes
same pitfall of the
Standard of
Care
Setting
% without
Response
HCV G1 naive
25-37
HCV G1 relapsers
17-31
HCV G1 partial
Genotype 1 (n=4520)
41-60
Genotype 4 (n=317)
Virological response (%)
responders
100
100
HCV G1 null responders
63-71
70.3
80
HCV G2
80
29
HCV G341.8
60
28
HCV G4
40
59
61.3
60
40
26.5
20
20
6.3
0
41.0
40.4
10.1
0
n=
287
Week 2
1200
Week 4
(RVR)
2769
Week 12
1891
SVR24
32
Week 2
128
223
130
Week 4
(RVR)
Week 12
SVR24
The error bars correspond to the 95% confidence intervals
Virological response defined as: HCV RNA <50 IU/mL by week 2, 4 (RVR)
19
or 12, or ≥24 weeks after end of treatment (SVR)
Marcellin PM, et al. Hepatology 2012 [Epub ahead of print]
Patients populations with the highest
unmet needs
• Cirrhosis:
– Most urgent need  response = short term survival
– Lower rate of response to treatment
– Highest rate of side effects:
• Reasonable in compensated patients w/o advanced disease
• Chance of death or hospitalization > treatment response in advanced
disease
• Treatment not indicated in decompensated patients
• With actual treatment options > 40% of patients without
response (60% HCV genotype 4 – 30% HCV genotype 2)
Previous Null Responders: Quad Therapy
Daclatasvir (NS5A) + Asunaprevir (PI)
+ PegIFN/RBV x 24 wks (Quad)
90[1]
88% GT1a
93*[2]
61% GT1a
100
84
80
80
SVR12 (%)
SVR12 or 24 (%)
100
Danoprevir/r (PI) + Mericitabine (Nuc)
+ PegIFN/RBV x 24 wks (Quad)[3]
60
40
60
40
20
20
n/N =
9/10
38/41
0
n/N =
62/74
0
*Asunaprevir QD and BID combined.


Quad therapy may be a good option for null responders
Well tolerated BUT cirrhotics excluded
1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Lok AS, et al. AASLD 2012. Abstract 79.
3. Feld JJ, et al. AASLD 2012. Abstract 81.
SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION:
RESULTS FROM THE AVIATOR STUDY
Kowdley KV EASL 2013
Simeprevir + Sofosbuvir + RBV
Genotype 1 F0-F2 non responders
Simeprevir
Sofosbuvir
RBV
Simeprevir
Sofosbuvir
Simeprevir
Sofosbuvir
RBV
Simeprevir
Sofosbuvir
24 weeks
24 weeks
12 weeks
12 weeks
Number
24
15
27
14
RVR %
81
66
85
57
UND EOTR
83
88
100
100
4/6 66%
5/5 100%
26/27 96%
13/14 (92%)
Anemia %
25
0
11
0
Bilirubin
increase
2
0
2
0
SVR8
CAVEAT SVR w8 mild fibrosis
Lawitz CROI 2013
SVR Daclatasvir + Sofosbuvir + RBV
G1 Telaprevir /Boceprevir failure
N
EOT
UNDETECTABLE
SVR 4
SVR 12
DCV +SOF
21
21/21 (100%)
DCV + SOF + RBV
20
19/20 (95%)
21/21 (100%)
20 (100%)
Non cirhosis, breakthrough, relapsers and non responders
1a 80% IL28b; nonCC 98%; > F2 83%
Sulkowski EASL 2013
• HCV genotype 2 or 3
patients who failed prior
interferon-based therapy
were randomized (1:1) to
receive either a 12-week
(n=103) or 16-week
(n=98) course of
sofosbuvir 400 mg once
daily plus RBV (1,000 or
1,200 mg/day).
• 63% HCV genotype 3.
• 34% Cirrhosis
• Historical control group:
25% SVR
Jacobson IM NEJM 2013
% SVR
Sofosbuvir + Ribavirin in HCV G2 &3 Non
responders: Fusion Study
Patients population with the
highest unmet need
• Cirrhosis
• Patients without response after triple therapy
• Patients intolerant to Interferon
Gaps in Care Resulting in Low Overall Effectiveness
of HCV Treatment in Veterans with Chronic HCV
SVR
Completed HCV treatment
Received Peg-IFN and ribavirin
No controindications to HCV treatment
Tested for genotype
4%
6%
12%
36%
60%
Patients with Chronic HCV
100%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
% of HCV infected Veterans (n = 99,166)
Kramer JR et al, J Hepatol 2011
Patients populations with the highest
unmet needs
• Cirrhosis:
– Most urgent need  response = short term survival
– Lower rate of response to treatment
– Highest rate of side effects:
• Reasonable in compensated patients w/o advanced disease
• Chance of death or hospitalization > treatment response in advanced disease
• Treatment not indicated in decompensated patients
• Patients w/o response to the most advanced treatment options & patients
with genotype 4 with poor response to PEGIFN + RBV
• HIV+ response  reduced all cause mortality but uncommon with PEGIFN
+ RIBA, few data with triple therapy
• Intolerant to interferon  the missed target that could change the
landscape
Dual oral therapy with daclatasvir and asunaprevir for patients
with HCV genotype 1b infection and limited treatment options
Suzuki J Hepatol 2013
Asunaprevir and Daclatasvir in 22 Japanese HCV
G1b ineligible/intolerant to Interferon
HCV RNA levels, individual patients
Suzuki J Hepatol 2013
Daclatasvir and asunaprevir
trough plasma concentrations
59/97
• Study population: HCV G2 or G3 were
interferon intolerant, interferon
ineligible or unwilling to take
interferon
• randomized (3:1) to receive 12 weeks
of either sofosbuvir 400 mg once daily
plus weight-based RBV twice daily
(n=207) or matching placebo (n=71).
• 207 patients randomized to the
sofosbuvir/RBV arm,
102/110
POSITRON Efficacy of a 12-Week of Sofosbuvir Plus
Ribavirin for Chronic Hepatitis C Patients HCV G2 or 3 who
are Unable or Unwilling to Take Interferon
0/71
– 15 percent had compensated cirrhosis
(more advanced liver disease)
– 53 percent were infected with
genotype 2.
Jacobson IM NEJM
Patients populations with the highest
unmet needs
• Cirrhosis:
– Most urgent need  response = short term survival
– Lower rate of response to treatment
– Highest rate of side effects:
• Reasonable in compensated patients w/o advanced disease
• Chance of death or hospitalization > treatment response in advanced disease
• Treatment not indicated in decompensated patients
• Patients w/o response to the most advanced treatment options & patients
with genotype 4 with poor response to PEGIFN + RBV
• HIV+ response  reduced all cause mortality but uncommon with PEGIFN
+ RIBA, few data with triple therapy
• Intolerant to interferon  the missed target that could change the
landscape
The paradox of new anti HCV drugs
development
• Studies mainly in easy to treat populations with the lower urgent
need:
–
–
–
–
HCV G1b
Naives
Non cirrhotics
HIV-
• Few studies in difficult to treat populations with the most urgent need:
–
–
–
–
–
Transplanted patients
Decompensated and compensated cirrhosis
Null responders
HCV G1a
HIV+
• Marketing of new anti HCV drugs with high prices  cost
effectiveness only in sickest patients without enough data from
phase III studies