HCV protease inhibitors in the treatment of naive and experienced patients Pr Dominique Salmon Cochin Hospital, Paris Descartes University, Paris, France 2 nd Congress of Federation of Arab Societies of Clinical Microbiology and Infectious Diseases 22 nd Tunisian Congress of Infectious Diseases http://www.infectiologie.org.tn
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HCV protease inhibitors in the treatment of naive and … · SVR, considered virologic cure, was defined as HCV RNA
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HCV protease inhibitors in the treatmentof naive and experienced patients
Pr Dominique SalmonCochin Hospital, Paris Descartes University, Paris, France
2nd Congress of Federation of Arab Societies of ClinicalMicrobiology and Infectious Diseases
22nd Tunisian Congress of Infectious Diseases
http://www.infectiologie.org.tn
World prevalence of HCV
< 1%1 - 2,4%2,5 - 4,9%5 - 10%> 10%Data non available
WHO (97)http://www.infectiologie.org.tn
Distribution of HCV genotypes
North America
South America
South Africa
Central Africa
North EuropeRussia
ChinaJapan
AustraliaNew Zeland
Sout East Asia
1a 51b 2 3 4 6
Genotypes/sub-types
South Europa
Forns et Bukh (98)http://www.infectiologie.org.tn
Chronic hepatitis C progression
HCC3%/yr Decompensation
5%- 10%/anLiver mortality
2%- 5%/yr
5- 10 years 15- 30 years >30 years
Rapid Intermediate Slow
Progression speed
Cirrhosis
Fibrosis stage 0
1
2
3
4
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Therapeutic objectives for HIV, HBV and HCV
H
HBV
Host cell
cccDNAHost DNA
Integrated DNA
Nucleus
H
HIVHost cell
Host DNA
Proviral DNA
Nucleus
H
HCVHost cell
Host DNA
Nucleus
HCV RNA
Life long suppression of viral replication
Definitive viral clearanceand SVR
Long term suppression of viral replication
Kieffer et al. J Antimicrob Chemother 2010; Sorriano et al. J Antimicrob Chemother 2009; Clavel et al. New Engl J Med 2004; Zoulim &Locarnini Gastroenterology 2009; Sarrazin & Zeuzem Gastroenterology 2010
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Combinaison of peg interferon and ribavirin: first step towards cure …
PatientsachievingSVR (%)
100
80
60
40
20
024 48 78 Peg-IFN IFN +
ribavirinPeg-IFN +ribavirinWeeks
IFN monotherapy
All genotypesGenotype 1Genotypes 2 or 3
6-19 11-19 10-22
18-3935-43
61-79
33-36
76-82
42-46
*Range of values reported; lower bar represents lower value;
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0%
20%
40%
60%
80%
100%
IFN 24 wk IFN 48 wk
IFN 48 wk& Ribavirin
PEG-IFN 48 wk& Ribavirin
1990 1998 2000 2002 2012- 2015
Sustained VirologicalResponses Rates
Direct antivirals
2007
Future of anti HCV therapy
Optimization and individualization
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Better knowledge of HCV enzymes targeted by specific inhibitors
Di Bisceglie et al., Hepatology 2002http://www.infectiologie.org.tn
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Efficacy of with HCV protease inhibitors with peg interferon and ribavirin in NAIVE
SVR rate with telaprevir and peginterferon/RBV versus PR
ADVANCE and ILLUMINATE trials
46
0
20
40
60
80
100
SVR
(%)
T12/PR
683/903
PR48
166/361n/N =
74–79*
INCIVO (telaprevir) EU SmPC
*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCESVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was usedhttp://www.infectiologie.org.tn
*p<0.001 for both boceprevir arms versus PR48SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward
SVR rate with boceprevir and peginterferon/RBV versus PR
SPRINT 1 and SPRINT 2 trials
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Impact of rapid virologic response on SVR : leading to different durations of treatment
Exemple of telaprevir
Sherman KE, et al. N Engl J Med 2011;365:1014–24
*Patients who achieved eRVR (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20
Treatment duration according to eRVR status
60%*n=32222%
n=118
92 88
64
23
0
20
40
60
80
100
SVR
(%)
<20 weeks
23/100
SVR rate
18%n=100
Eligible for 24 weeks and randomized to 24 or 48 weeks*
48 weeks
<20 weeks (due to premature treatment discontinuation)
eRVR+*
eRVR–
<20 weeks
eRVR–T12PR48
76/118
eRVR+ T12PR48140/160
eRVR+ T12PR24149/162
∆ 4% (2-sided 95% CI = –2% to +11%)
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Efficacy of with HCV protease inhibitors with peg interferon and ribavirin in
patients infected with genotype 1, non responders to peg IFN/RBV
Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22http://www.infectiologie.org.tn
SVR to telaprevir with PR in relapsers, partial responders and null responders to PR
22
88 84
15
5661
5
33 31
0
20
40
60
80
100
PR48
4/27
T12/PR48
30/49
SVR
(%)
Prior relapsers Prior partialresponders
LI T12/PR48
27/48n/N=
PR48
2/37
T12/PR48
22/72
LI T12/PR48
25/75
PR48
15/68
T12/PR48
122/145
LI T12/PR48
124/141
Prior null responders
**
**
* *
INCIVO (telaprevir) EU SmPC
*p<0.001 vs PR48SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was usedhttp://www.infectiologie.org.tn
29
6975
7
40
52
0
20
40
60
80
100
PR48
2/29
BOC44/PR48
30/58
SVR
(%)
Prior relapsers Prior partialresponders
BOCRGT
23/57n/N=
PR48
15/51
BOC44/PR48
77/103
BOC RGT
72/105
Prior null responders were excluded from RESPOND-2
SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward VICTRELIS (boceprevir) EU SmPC
SVR to boceprevir with PR in relapsers and partial responders to PR
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Three main baseline predictors of SVR under tritherapy with PI
HCV viral load
HCV G1 subtype: 1b > 1a
Fibrosis stage
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HCV G1 subtype as a Predictor of SVR (BOC Arms Combined)
20
54
27
43
25
47
0
20
40
60
80
100
% S
VR
1154
1935
33124
44178
2661
4596
1a 1b 1a 1b 1a 1b
RESPOND-2 SPRINT-2 CombinedStudies
p = 0.001 p = 0.028 p < 0.001
Bacon, AASLD, 2011http://www.infectiologie.org.tn
Fibrosis Score as a Predictor of SVR (BOC Arms Combined)
41
21
37
15
38
17
0
20
40
60
80
100
% S
VR
2663
419
58157
842204
278
46
F0/1/2 F3/4RESPOND-2 SPRINT-2 Combined
Studies
p = 0.11 p = 0.025 p = 0.007
F0/1/2 F3/4 F0/1/2 F3/4
Bacon, AASLD, 2011http://www.infectiologie.org.tn
HCV Viral Load as a Predictor of SVR (BOC Arms Combined)
SAFETY OF TELAPREVIR OR BOCEPREVIR IN COMBINATION WITH PEGINTERFERON
ALFA/RIBAVIRIN, IN CIRRHOTIC NON RESPONDERS FIRST RESULTS OF THE FRENCH EARLY ACCESS
PROGRAM (ANRS CO20-CUPIC)
C Hézode1, C Dorival2, F Zoulim3, T Poynard4, P Mathurin5, S Pol6, D Larrey7, P Cacoub4, V de Ledinghen8, M Bourlière9, PH Bernard10, G Riachi11, Y Barthe2, H Fontaine6, F Carrat2, JP Bronowicki12
for the CUPIC study group (ANRS CO 20)
Hôpital Henri Mondor, Créteil1, UMR-S 707, Paris2, INSERM U871, Lyon3, Hôpital de la Pitié-Salpêtrière, Paris4, Hôpital Claude Huriez, Lille5, Hôpital Cochin, Paris6, Hôpital Saint-
Eloi, Montpellier7, Hôpital Haut-Lévèque, Pessac8, Fondation Hôpital Saint Joseph, Marseille9, Hôpital Saint André, Bordeaux10, Hôpital Charles Nicolle, Rouen11, Hôpital de Brabois, Nancy12, France
Patients, (% patients with >1 event) Telaprevirn=296
BoceprevirN=159
Serious adverse events (SAEs)* 48.6% 38.4%
Premature discontinuation 26.0% 23.9%
Death 2.0% 1.3%
Infection (Grade 3/4) 8.8% 2.5%
Anemia (Grade 3/4) 19.6% 22.6%
EPO use 56.8% 66.0%
Transfusion 15,2% 10.7%
Rash Grade 3Grade 4
6.8%0.7%
0%0%
Pruritus (Grade 3/4) 3.7%*407 SAEs in 144 patients; SCAR: severe cutaneous adverse reaction
Preliminary safety findings
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Telaprevir: preliminary efficacy data
0
20
40
60
80
100
Week 4 Week 8 Week 12 Week 16
53
85 86 86
% o
f pat
ient
s w
ith u
ndet
ecta
ble
HC
V R
NA
145/276 224/265 219/254 177/205
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Boceprevir: preliminary efficacy data
0
20
40
60
80
Week 4 Week 8 Week 12 Week 16
% o
f pat
ient
s w
ith u
ndet
ecta
ble
HC
V R
NA
1
37
61
71
2/155 55/149 88/144 89/126
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Practical use of boceprevir and telaprevir in France
• Indications : treatment of hepatitis C, genotype 1, in association with PR, in patients with compensated liver disease, naive or non responders to previous anti HCV treatment.