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Hépatite C chronique:
quoi de neuf?
Francesco Negro
Hôpitaux Universitaires de Genève
Colloque MPR18 juin 2014
HCV infects >185 million people worldwide
HAJARIZADEH et al. Nat Rev Gastroenterol Hepatol 2013;10:553-562
NEGRO and ALBERTI. Liver Int 2011;31 Suppl 2:1-3
HANAFIAH et al. Hepatology 2013;57:1333-1342
Hepatitis C: a chronic inflammatory
liver disease leading to cirrhosis and HCC
F1 F2
F3F4
Proportion of cirrhosis or HCC cases
attributable to HCV (Europe)
PERZ et al, J Hepatol 2006;45:529-38
%%
Chronic HCV increases mortality from hepatic and
non-hepatic diseases
� 23820 adults in Taiwan prospectively followed since 1991/2
� 1095 were anti-HCV positive; 69.4% had detectable HCV RNA
The REVEAL HCV Cohort Study
20 20
Hepatic diseases Extrahepatic diseases
Anti-HCV seropositives, HCV RNA detectable
Anti-HCV seropositives, HCV RNA undetectable
Anti-HCV seronegatives
Anti-HCV seropositives, HCV RNA detectable
Anti-HCV seropositives, HCV RNA undetectable
Anti-HCV seronegatives
p<0.001 for comparison among three groups
19.8%
18
16
14
12
10
8
6
4
2
0
18
16
14
12
10
8
6
4
2
00 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Follow-up (years) Follow-up (years)
Cu
mu
lati
ve
mo
rta
lity
(%
)
Cu
mu
lati
ve
mo
rta
lity
(%
)
p<0.001 for comparison among three groups
p<0.001 for HCV RNA detectable vs undetectable
p<0.001 for comparison among three groups
p=0.002 for HCV RNA detectable
vs undetectable
12.8%
1.6%0.7%
12.2%
11.0%
LEE et al, J Infect Dis 2012;206:469–477
The growing burden of mortality associated with
viral hepatitis in the US, 1999-2007 (CDC)
LY et al, Ann Intern Med 2012;156:271-8
How many die of …. ?
Deaths in 2010
HCV 57,000
HBV 31,000
HIV 8,000
Global Burden Disease Study 2010 (COWIE et al, EASL 2014, oral presentation #86)
Modeling the HCV epidemic in SwitzerlandModel inputs and 2013 estimates (BRUGGMANN et al, EASL 2014, poster 1285)
Historical Year 2013 (Est.)
HCV Infections 110,000 (57,000 - 128,000) 1998 104,000
Anti-HCV Prevalence 1.6% (0.8% - 1.8%) 1.3%
Total Viremic Infections 88,000 (45,400 - 102,000) 1998 82,700
Viremic Prevalence 1.2% (0.6% - 1.4%) 1.0%
Viremic Rate 79.7% 79.7%
HCV Diagnosed (Viremic) 32,900 2012 32,600HCV Diagnosed (Viremic) 32,900 2012 32,600
Viremic Diagnosis Rate 37.4% 39.4%
Annual Newly Diagnosed 1,050 2012 1,050
New Infections
New Infection Rate (per 100K) 13
Treated
Number Treated 1,100 2011 1,100
Annual Treatment Rate 1.3% 1.3%
SAGMEISTER et al, Eur J Gastroenterol Hepatol 2002; 14: 25-34
Swiss Federal Office of Public Health, http://www.bag.admin.ch/ (accessed June 3, 2013)
ARMSTRONG et al, Ann Intern Med 2006;144:705-14
IMS Health. IMS Health MIDAS Data. 2013
HCV
viremic
Acute
infections
= 350 py
Cured
Deaths
The input due to immigration is relevant and
underestimated: the Swiss situation
+250 viremic cases py
-700 cases py
viremic
pool
Immigration
Deaths
Emigration
+800 anti-HCV+ py (+650 viremic cases py)
-1000 cases py
In Switzerland, HCV prevalence peaked in 2003, but HCV-associated
healthcare costs (excluding treatment costs) will peak in 2030
75
150
225
300
30
60
90
120
Tota
l Cos
ts (i
n m
illion
CH
F)
Tota
l Vire
mic
Infe
ctio
ns (
000)
00
Tota
l Cos
ts (i
n m
illion
CH
F)
Tota
l Vire
mic
Infe
ctio
ns (
000)
BRUGGMANN et al, EASL 2014, poster 1285
2013 2030
Viremic cases 82,700 (37,200 – 93,400) 63,200 (25,900 – 71,800)
HCV-related costs
(excluding treatment costs)89.6M (43.3M – 191.1M) 118.7M (43.9M – 282.9M)
20
40
60
80
100
10
20
30
40
50
60
Tota
l Vire
mic
Cas
es (i
n Th
ousa
nds)
Vire
mic
Cas
es
(by
Dis
ease
Sta
ge, i
n Th
ousa
nd)
As the infected population ages,
the number of advanced liver disease cases increases
-- Tota
l Vire
mic
Cas
es (i
n Th
ousa
nds)
(by
Dis
ease
Sta
ge, i
n Th
ousa
nd)
F0 F1 F2 F3
Cirrhosis Decomp Cirrhosis HCC Total Viremic
BRUGGMANN et al, EASL 2014, poster 1285
2030 *
Decompensated cirrhosis 1,800 (+55%)
HCC 760 (+85%)
HCV liver-related deaths 650 (+70%)
*Data compared to 2013, assuming constant treatment uptake
-
200
400
600
800
HCC
-
200
400
600
800
Liver related Deaths
Increasing SVR to 90-95% by 2016 will decrease HCV-related
HCC cases and liver-related mortality by 10% in 2030
380
650
580400
740
670
Base 90-95% SVR by 2016 Base 90-95% SVR by 2016
• Increasing SVR while maintaining an annual treatment uptake
of 1,100 patients will decrease HCC and liver-related mortality
by 10% by 2030
• Total viremic infections will decrease by 7% vs base case
BRUGGMANN et al, EASL 2014, poster 1285
-
200
400
600
800
HCC
Base Treat 3,940 (≥F2) by 2018 Treat 6,320 (≥F0) by 2018
-
200
400
600
800
Liver related Deaths
Base Treat 3,940 (≥F2) by 2018 Treat 6,320 (≥F0) by 2018
Increasing SVR to 90-95% by 2016 and treating 3,940 patients
by 2018 will decrease HCV liver-related mortality by 80%
650
400 380
130
740
160
150 120
Base Treat 3,940 (≥F2) by 2018 Treat 6,320 (≥F0) by 2018 Base Treat 3,940 (≥F2) by 2018 Treat 6,320 (≥F0) by 2018
• To reduce HCC and liver-related mortality by 80% by 2030, 3,940 patients will have to be treated
annually (≥F2) by 2018
• The proposed scenario would require the diagnosis of 4,740 new viremic infections annually by 2020 (as
compared to 1,050 in 2013)
• Expanding treatment access to ≥F0 patients would require treatment of 6,320 annually by 2018 to
achieve the same reduction in HCC cases and liver-related mortality
• An estimated CHF 735 M and CHF 742 M in healthcare cost savings (excluding scenario and treatment
costs) was projected for the scenario treating 3,940 ≥ F2 patients and 6,320 ≥ F0 patients, respectively
BRUGGMANN et al, EASL 2014, poster 1285
Indications au traitement (EASL 2014)
• Tous les patients atteint d’une hépatite C (jamais traités
ou ayant essuyé un échec thérapeutique) devraient être
évalués pour un traitement antiviral
• Priorité: fibrose avancée (Metavir F3 ou F4)
• Le traitement est *justifié* lors d’un score Metavir F2• Le traitement est *justifié* lors d’un score Metavir F2
• L’indication au traitement et le moment de son début
doivent être personnalisés si le score Metavir est F0-F1
But du traitement
• Le but du traitement est l’éradication du HCV, afin
d’arrêter l’évolution vers une cirrhose, le
développement d’une insuffisance hépatique, d’un
CHC, et de réduire la mortalité liée au foie
• Le patient est considéré comme étant guéri lorsque
son HCV RNA est négatif 12-24 semaines après la fin son HCV RNA est négatif 12-24 semaines après la fin
du traitement (réponse virologique soutenue = RVS)
• Chez 99% des cas, la RVS est définitive, et est
associée à une amélioration du pronostic
Like any dogma,
liver fibrosis is
reversiblereversible
D’AMBROSIO et al, Hepatology 2012;56:532-43
SVR is associated with a reduction
in liver-related mortality and risk of HCC
N=530 N=530
VAN DER MEER et al, JAMA 2012;308:2584-2593
1986 Interferon-αααα
1998 Interferon-αααα + Ribavirin
2001 Pegylated Interferon-αααα + Ribavirin
2011 Pegylated Interferon-αααα + Ribavirin +
First generation protease inhibitors
2014 Interferon-αααα-free regimens
...asvir
...previr...buvir
...asvir
CORNBERG & MANNS, Lancet Infect Dis 2013;13:378-9
Direct-acting antivirals against HCV: a rich pipeline
Interferon Free
Sofosbuvir
G2/3 +
Asunaprevir
Daclatasvir±
Sofosbuvir+
Ledipasvir
Ombitasvir
Dasabuvir
+
ABT-450/r
RBV
+
±
IFN
-fre
e
Protease inhibitor
NS5B nuc inhibitors
NS5A
NS5B non-nuc inhibitor
Sofosbuvir
Simeprevir +
RBV
±
G1/4
Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec
Telaprevir
Boceprevir
Triple therapy
Faldaprevir
(G1)
Sofosbuvir
(G1,4,5,6)
Sofosbuvir +
RBV
±
BMS-325
Daclatasvir
(G1, 2, 3, 4)
Ledipasvir
2011 2012 2013 2014 2015
IFN
-ba
sed Simeprevir
(G1, 4)
RBV
±
2014Sofosbuvir (Sovaldi TM)
Nucleotide polymerase inhibitor400 mg qd, all genotypesHigh barrier to resistance
Simeprevir (Olysio TM)NS3/NS4A serine protease inhibitor
150 mg qd, genotypes 1 and 4Low barrier to resistance
Daclatasvir (Daklinza TM)NS5A inhibitor
60 mg qd, all genotypesLow barrier to resistance
FaldaprevirNS3/NS4A serine protease inhibitor
120-240 mg qd, genotypes 1, 2, 4, 5 and 6Low barrier to resistance
HCV-1, jamais traitésHCV-1, jamais traités
IFN-based options for HCV genotype 1
treatment-naïve patients
7974
66
80
73 72
65 64
90
47
60
100
80
SV
R (%
)
OPTIMIZE2ADVANCE 1 SPRINT-23 NEUTRINO7Pooled QUEST1 & 24
COMMAND 16
STARTVerso1&2 5
47
20
40SV
R (%
)
0
295/327
285/363
274/369
242/366 9/19
419/521
382/521
378/524
95/147
94/146
1. Telaprevir EU SmPC; 2. Buti M, Gastroenterology 2014;146:744–53
3. Boceprevir SmPC; 4. Jacobson I, et al. AASLD 2013. Poster 1122
5. Jensen DM, et al. AASLD 2013. Abstract 1088
6. Hézode, et al. AASLD 2012: Abstract 755; 7. Lawitz E, et al. N Engl J Med 2013;368:1878–87
TVR/PR(q8h)
TVR/PR(bid)
BOC/PR SMV/PR FDV120mg/PR
FDV240mg/PR
DCV20mg/PR
DCV60mg/PR
SOF/PR SOF/RBV(24 weeks)
P + R + sofosbuvir (NEUTRINO study)(HCV genotypes 1, 4-6; treatment-naive; 12-week triple treatment flat duration)
100
80
60
SV
R1
2 (
%)
89%
100%100
80
60
SV
R1
2 (
%)
92%
80%
96%
LAWITZ et al, N Eng J Med 2013
40
20
0
SV
R1
2
HCV-1 HCV-5, -6
261/292
40
20
0
SV
R1
2
No cirrhosis Cirrhosis
252/273 43/54
HCV-4
27/28 7/7
8087
80
100
Pooled QUEST 1 & 2:
SVR12 in all vs European patientsS
VR
12
(%
)
P <0.001 P <0.001
SMV + PR
Placebo + PR
50 53
0
20
40
60
FOSTER et al, EASL 2014, Poster P112725
All patients European patients
419/521 132/264 239/276 75/142
SV
R1
2 (
%) 88 88
100 100
SMV + PR: pooled QUEST 1&2Response-guided treatment*:
Early extended virological response allows a 24-week course of treatment
Met RGT criteria and were
eligible for 24 weeks of treatment Did not meet RGT criteria
88 88
0
20
40
60
80
RGT SVR12
SV
R12
(%
)
825
0
20
40
60
80
RGT not met SVR12
SV
R12
(%
)
JACOBSON et al, AASLD 2013, Poster 1122
405/ 459 11/44459/ 521 44/ 521
*Patients were eligible to stop therapy at Week 24 if HCV RNA <25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12
STARTVerso1&2SVR12 according to faldaprevir dose
50
73 72
60
80
100
SV
R1
2 (
%)
0
20
40
Pbo + PR FDV 120 mg + PR FDV 240 mg + PR
SV
R1
2 (
%)
131/264 382/521 378/524
JENSEN et al, AASLD 2013, Abstract 1088
STARTVerso1&2Patients who achieve ETS* can be treated 24 weeks
84 84
60
80
100
Pro
po
rtio
n o
f p
ati
en
ts w
ith
ET
S (
%)a 83 83
60
80
100
Pro
po
rtio
n o
f p
ati
en
ts w
ith
SV
R1
2 (
%)b
*ETS: HCV RNA <25 IU/mL (detected or undetected) at week 4 and <25 IU/mL (undetected) at week 8
0
20
40
FDV 120 mg
+ PR
FDV 240 mg
+ PR
Pro
po
rtio
n o
f p
ati
en
ts w
ith
ET
S (
%)
441/524436/5210
20
40
FDV 120 mg
+ PR
FDV 240 mg
+ PR
Pro
po
rtio
n o
f p
ati
en
ts w
ith
SV
R1
2 (
%)
368/441362/436
JENSEN et al, AASLD 2013, Abstract 1088
P + R + daclatasvir(treatment-naïve HCV-1: COMMAND-1, phase 2b study)
100
80
60(%)
58%
87%
P + R + placebo P + R + daclatasvir 60 mg
HEZODE et al, Hepatology 2012;56(suppl):553A
60
40
20
0
SV
R2
4 (
%)
38%
Subtype 1a
58%
Subtype 1b
n=56 n=113 n=31
31%
n=16
HCV-1, échecs thérapeutiquesHCV-1, échecs thérapeutiques
Overview of DAA + PR
in treatment-experienced patients
79
70
44
69
47
70
5860
80
100
SV
R1
2 (
%)
Relapsers Partialresponders
Nulls Relapsers Partialresponders
Nulls NullsPartialresponders
Nulls
1. Forns X et al Gastroenterology 2014;146:1669–1679
2. Reddy KR, et al. APASL 2014. Oral presentation
3. Jacobson I, et al. AASLD 2013. Abstract 1100
4. Gane EJ, et al. AASLD 2013. Abstract 73
33
10
0
20
40SV
R1
2
SMV + PR1 SMV + PR2 FDV 240 mg + PR3
12 week arm
206/260 69/99 33/57 48/145 1/10
SOF + RBV4TVR + PR2
101/145 102/234 110/238100/146
Benefits of the *second wave* PIs
Regimen Trial
HCV
genotype/
populationN
F4
(%)
Grade
3–4 AE
(%)SAEs
Disc. due
to AEs
(%)Notable AEs*
TVR + PR1 OPTIMIZE G1 TN 740 14 40 9% 17Nausea, pruritus,
rash and anaemia
BOC + PR2 SPRINT-2 G1 TN 1097 5 – 11% 12Increased anaemia
and dysgeusia
SMV + PR3 Pooled analysisG1 TN & TE 924 11 31 5.5% 4
Increased bilirubin,
Cross comparison of studies cannot be carried out
*Occurring more frequently vs PR alone
1. Buti. Gastroenterology 2014;146:744–53. 2. Poordad et al. N Engl J Med 2011;364:1195–
206. 3. Manns et al. Hep DART 2013. Poster 57. 4. Jensen et al. AASLD 2013. Poster 1088
SMV + PR3 Pooled analysis
Phase 2b/3G1 TN & TE 924 11 31 5.5% 4
Increased bilirubin,
rash, photosensitivity
FDV + PR4 STARTVerso G1 TN 524 10 – 8% 3Increased bilirubin,
rash, GI
Telaprevir and boceprevir led to increased
efficacy in HCV genotype 1 (63-75% SVR)
● Increased complexity, safety issues, pill burden
● Still associated with IFN-α and RBV
For physicians: lead-in, response-guided therapy
BOC = 12/day
RBV = 4-7/day
TVR = 6/day
RBV = 4-7/day
Pill burden Food requirementFor patients:
Platelet count
≤ 100 G/L
Platelet count
> 100 G/L
Albumin n
Complications, n (%)
37
19 (51.4%)
31
5 (16.1%)
CUPIC: SVR12 and risk of occurrence of
severe complications
< 35 g/LComplications, n (%)
SVR12, n (%)
19 (51.4%)
10 (27.0%)
5 (16.1%)
9 (29.0%)
Albumin
≥≥≥≥ 35 g/L
n
Complications, n (%)
SVR12, n (%)
74
9 (12.2%)
27 (36.5%)
305
19 (6.2%)
168 (54.9%)
HEZODE et al, J Hepatol 2013;59:434-441
FONTAINE et al, AFEF 2013
www.hcvguidelines.org (accessed April 6, 2014)
HCV-1, intolérants à l’IFN ou si HCV-1, intolérants à l’IFN ou si
l’IFN est contre-indiqué
SMV + SOF ± RBV in treatment-naive and prior null
responders, HCV-1 (COSMOS phase II study)
100
80
93 93
79
96100
93 93 93
COHORT 1
NR, F0-F2 (n=80)
SVR12
COHORT 2
Treatment-naive + NR, F3-F4 (n=84)
SVR12
60
40
20
0
SV
R (
%)
No ribavirin Ribavirin No ribavirin Ribavirin
Weeks
SULKOWSKI et al, EASL 2014; LAWITZ et al, EASL 2014
12 24 12 24 24 1212 24
Sofosbuvir + Daclatasvir ±±±± Ribavirin in HCV-1(126 naive + 41 PI-experienced; no cirrhotics; AI444040 phase II study)
100
80
60(%)
93*
100 10095* 93*
100**95**
Treatment-naive PI-experienced
SULKOWSKI et al, N Engl J Med 2014 Jan 16 [ePub ahead of print]
60
40
20
0
SV
R2
4 (
%)
S7 + SD23 SDR24 SDR12 SD24
n 15 14 15 41 2141 20
SD24 SD12 SDR24
*Considering 4 SVR36 and 1 reinfection, true SVR = 99% (125/126)
**SVR12 available only; considering 1 SVR24, true SVR = 100%
Les génotypes 2 à 4Les génotypes 2 à 4
2014: the different options for HCV-2
100
80
60
SV
R (
%)
89
100
87 91
9894
9296
60
100
7882
62
1. MANGIA et al, N Engl J Med 2005;352:2609-17; 2. FOSTER et al, Gastroenterology 2011;141:881-9
3. LAWITZ et al, N Engl J Med 2013;368:1878-87; 4. JACOBSON et al, N Engl J Med 2013;368:1867-77
40
20
0
SV
R (
%)
PR1
24
TPR2
2/24Weeks(RVR)
PR1
12
(RVR)
SOF + R4
12
SOF + R4
12
SOF + R4
16
SOF + R3
12
F4F4F4F4
(therapy-naive)
F4
PR3
24
PR3
24
(IFN-ineligible) (therapy-experienced)
2014: the different options for HCV-3
100
80
60
SV
R (
%)
100
77
6168
37
6361
71
87
60
94 92
1. MANGIA et al, N Engl J Med 2005;352:2609-17; 2. LAWITZ et al, N Engl J Med 2013;368:1878-87
3. JACOBSON et al, N Engl J Med 2013;368:1867-77; 4. ZEUZEM et al, N Engl J Med 2014
40
20
0
SV
R (
%)
PR1
24Weeks(RVR)
PR1
12
(RVR)
SOF + R3
12
SOF + R3
12
SOF + R3
16
34
21
37
19
SOF + R2
12
F4F4F4F4
(therapy-naive)
F4
30
PR2
24
PR2
24
(IFN-ineligible) (therapy-experienced)
SOF + R4
24
F4
SOF + R4
24
F4
(therapy-naive)
In 2014, all SOF-based options for treatment-naive
HCV-4 to 6 will still contain PR
100
80
60
SV
R (
%)
96
G-4 G-5 G-6
43-70
60
60-85
100 100
1. ANTAKI et al, Liver Int 2010;30:342-55
2. LAWITZ et al, N Engl J Med 2013;368:1878-87
60
40
20
0
SV
R (
%)
PR1
48
SOF + PR2
12Weeks
SOF + PR2
12
SOF + PR2
12
PR1
48
PR1
48
P + R + Simeprevir(treatment-naive or -experienced HCV-4: Phase III RESTORE trial)
100
80
60(%)
83%86%
60%
MORENO et al, EASL 2014, late breaking poster 1319
60
40
20
0
SV
R2
4 (
%)
Naive
40%
NR
n=35 n=22 n=40n=10
PRRR
20152015
IFN-free combination options*NI PI NS5A NNI RBV Genotype
Nucleotide analogue-based
Gilead Sofosbuvir GS-9451 Ledipasvir ± 1-4
Roche Mericitabine Danoprevir/r Setrobuvir ± 1, 4
Nucleos(t)ide-free triple combo
AbbVie ABT-450/r ABT-267 ABT-333 ± 1
BMS Asunaprevir Daclatasvir BMS791325 ± 1, 4
Janssen/GSK Simeprevir GSK2336805 TMC647055 ± 1
Nucleos(t)ide-free second generation double combo
Merck MK-5172 MK-8742 ± 1, 2, 4-6
Achillion ACH-2684 ACH-3102 ± 1
Off-label options
(na) Sofosbuvir Simeprevir - 1
(na) Sofosbuvir Daclatasvir - 1-3
*VX-135 and deleobuvir are not shown since currently on hold
Sofosbuvir/ledipasvir (single pill, once a day) ± RBV Results of phase III studies
Study Population Treatment Duration SVR12
ION-1
HCV-1
treatment-naive
(incl. 136/865 or 15.7%
with cirrhosis)
SOF/LDV 12 weeks 99%
SOF/LDV + RBV 12 weeks 97%
SOF/LDV 24 weeks 98%
SOF/LDV + RBV 24 weeks 99%
HCV-1 SOF/LDV 12 weeks 94%
ION-2
HCV-1
treatment-experienced
(including 88/440 or
20% with cirrhosis)*
SOF/LDV 12 weeks 94%
SOF/LDV + RBV 12 weeks 96%
SOF/LDV 24 weeks 99%
SOF/LDV + RBV 24 weeks 99%
ION-3HCV-1
treatment-naive
(all non-cirrhotics)
SOF/LDV 8 weeks 94%
SOF/LDV + RBV 8 weeks 93%
SOF/LDV 12 weeks 95%
*Includes patients treated with PI-containing regimens
AFDAHL et al, N Engl J Med 2014; AFDAHL et al, N Engl J Med 2014KOWDLEY et al, EASL 2014
ABT-450/r/ombitasvir qd + dasabuvir bid + R bid, 12 weeks (SAPPHIRE-1 phase 3 study, HCV-1, n = 631 treatment-naive)
All non-cirrhotics
8-9 pills a day…
FELD et al, EASL 2014
ABT-450/r/ombitasvir qd + dasabuvir bid + R bid, 12 weeks (SAPPHIRE-2 phase 3 study, HCV-1, n = 394 treatment-experienced)
ZEUZEM et al, EASL 2014
Les traitements sans interféron, en peu de mots
• Très efficaces (RVS >90%)
• Presque pas d’effets secondaires
• Schémas thérapeutiques simplifiés
– Courte durée, peu de comprimés– Courte durée, peu de comprimés
– Pas besoin de surveiller la réponse pendant
traitement
– Peu d’influence de la part des
caractéristiques au basal (cirrhose, HCV-3)
• Presque pas de résistance
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