treating hcv genotype 2 & 3regist2.virology-education.com/2013/3hcvad/docs/06... ·...
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Christoph Sarrazin Klinikum der J. W. Goethe-Universität Frankfurt am Main, Germany
Treating HCV Genotype 2 & 3
3rd Workshop on HCV Therapy Advances, Rome 14.12.2013
HCV Genotypes 2 & 3
Laurel and Hardy
Geographical distribution and prevalence Genotype 2 and 3 in Europe
Cornberg et al. Liver International 2011; Suppl 2:30-60
Canada Norway Germany Sweden Czech Republic Poland
Russia
Hungary UK
France
Portugal
Spain Switzerland Italy Greece Israel Romania Turkey
<1% 1-1,9% 2-2,9% >3% unknown
HCV Prevalence
Geographical distribution and prevalence Genotype 2 and 3 Global
Sievert et al. Liver International 2011; Suppl 2:61-80
Syria Iraq Iran Pakistan China
Korea
Japan
Taiwan
Australia Vietnam
Thailand
India Saudi Arabia Jordan
Egypt
Lebanon
HCV Prävalenz
<1%
1-1,9%
2-2,9%
>3%
Nicht untersucht
Summary distribution and clinical features Genotype 2 and 3
Ferri et al., Autoimmun Rev 2007; Bochud et al., J Hepatol 2009, Probst et al., J Viral Hepatitis 2011
Genotype 2 Approx. 8% of HCV infections globally High prevalence in - Italy - Korea - Japan - Taiwan HCV associated NHL?
Genotype 3 Approx. 10% of HCV infections globally High prevalence in - Pakistan - India - Thailand - Europe - Australia Hepatic steatosis Faster fibrosis progression?
Treatment options Genotype 2 and 3
Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs
Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive)
PEG-IFN-α plus Ribavirin (24 weeks)
97
76 82
93 92
76 71 78
0
20
40
60
80
100
120
Dalgard etal.
Mangia etal.
Shiffman etal.
Zeuzem etal.
Genotype 2Genotype 3
Dalgard et al., Hepatology 2008; Mangia et al., NEJM 2005; Shiffman et al., NEJM 2007; Zeuzem et al., J Hepatol 2004
SVR
(%)
Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive)
Meta-Analysis of 8 studies with PEG-IFN-α plus Ribavirin (12-16 versus 24 weeks in RVR patients irresp. of baseline viral load)
83 84 84 86
0102030405060708090
100
Genotype 2 Genotype 3
12-16 weeks (RVR)24 weeks (RVR)
Andriulli et al., Alim Pharm Ther 2008
SVR
(%)
Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive)
Meta-Analysis of 8 studies with PEG-IFN-α plus Ribavirin (non-RVR patients with 24 weeks of treatment)
46
62
0102030405060708090
100
Genotype 2 Genotype 3
24 weeks (non-RVR)
Genotype 2Genotype 3
Andriulli et al., Alim Pharm Ther 2008
SVR
(%)
Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive)
Extension of treatment duration in non-RVR patients? N-Core Study design
CHC G2/3 patients on PegIFN alfa-
2a/ RBV
0 4 8 12 24 48 72
RVR: continue treatment outside the
study
Non-RVR: enrolled in the study
n=400 PegIFN alfa-2a/
RBV n=160
STOP n=160
48 week follow-up
24 week follow-up
Entry into study at week 8 if no RVR
Randomization of patients without RVR, but with undetectable HCV RNA or ≥2-log drop in HCV RNA from baseline at week 12
n=235
n=95
n=93
Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive)
Cheinquer H et al. AASLD 2012; #156 (S271A)
Odds ratio 0.68 0.63 0.44
95% CI 0.38–1.21 0.35–1.16 0.22–0.89
p value 0.1934 0.1461 0.0231
CI = confidence interval; ITT = intent-to-treat; PP = per protocol; SC = study completer; SVR24 = sustained virologic response ≥140 days after end of treatment.
80
70
60
50
40
30
20
10
0 ITT (n=188) PP (n=176) SC (n=153)
52
61
52
63
54
73
PegIFN 2a/RBV 24 weeks
PegIFN 2a/RBV 48 weeks
SVR2
4 (%
of p
atie
nts)
SC population: Significantly higher SVR24 rates with 48 weeks vs. 24 weeks of PegIFN 2a/RBV
Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (Relapser/NR)
Poynard et al., Gastroenterology 2009
EPIC-3 Study: relapser / non-responder to (PEG)IFN + ribavirin
48 weeks PEG-IFN plus Ribavirin
59 55 61
46
0102030405060708090
100
Genotype 2(n=75)
Genotype 3(n=292)
GT2/3 Relapser GT2/3 Non-Responder
SVR
(%)
Treatment options Genotype 2 and 3
Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs
Treatment options Genotype 2/3 Telaprevir
Foster et al. Gastroenterology 2011; 141: 881-889
-5,0
-6,0 -6,0
-4,0
-3,0
-2,0
-1,0
0,0
2 3 4 7 12 15 Time (days)
Baseline Med
ian
HC
V R
NA
decl
ine
(log 1
0 IU
/ml)
Telaprevir monotherapy Telaprevir plus Peg-IFN/RBV Peg-IFN/RBV
Genotype 2 A
-3,65
-4,83
-5,51 -5,0
-6,0 -6,0
-4,0
-3,0
-2,0
-1,0
0,0
2 3 4 7 12 15 Time (days)
Baseline
Genotype 3 B
-0,54
-4,72 -4,85
Genotype 2 Genotype 3
Telaprevir monotherapy Telaprevir monotherapy
Med
ian
HC
V R
NA
decl
ine
(log 1
0 IU
/ml)
Treatment options Genotype 2/3 Boceprevir
Antiviral activity of Boceprevir monotherapy in genotype 2/3
Silva et al. J Hepatol 2013
Treatment options Genotype 2/3 Telaprevir and Boceprevir
0
1
2
3
4
5
6
GT 1 GT 2 GT 3 GT 4 GT 5 GT 6
Mean maximum log10 HCV RNA decline during mono-therapies 7-14 days
Telaprevr 750mg TID; Reesink et al., Gastro 2006, Foster et al., Gastro 2011, Benhamou et al., EASL 2009
HC
V R
NA
log1
0 de
clin
e
4,4 3,9
0,5 0,9
Boceprevir 400mg TID (current dose 800mg TID); Sarrazin et al., Gastroenterology 2007; Silva et al., APASL 2011
2,1 1,4
1,7 no data
Treatment options Genotype 2/3 Telaprevir and Boceprevir
Rescue treatment in patients with incomplete virologic response
0
1
2
3
4
5
6
7
1 2 3 4 5 6 7 8
vira
l loa
d lo
g 10
dec
line
Treatment week
Case: 45 years female 80kg (BMI 26) Genotype 3 F4 (cirrhosis) treatment-naive PEG-2a 180
plus 1200 Riba
Treatment options Genotype 2/3 Telaprevir and Boceprevir
Rescue treatment in patients with incomplete virologic response
vira
l loa
d lo
g 10
dec
line
Treatment week
Case: 45 years female 80kg (BMI 26) Genotype 3 F-3 fibrosis treatment-naive PEG-2a 180
plus 1200 Riba 0
1
2
3
4
5
6
7
1 2 3 4 5 6 7 8
Add-on Boceprevir 3x800mg per die
Treatment options Genotype 2/3 Telaprevir and Boceprevir
Rescue treatment in patients with incomplete virologic response
HCV Genotype
Fibrosis Metavir IL28B*
Pre-Tx Status
Protease-Inhibitor
Viral load PI baseline
Virological response
2a 4 CT Relapse Telaprevir 6400 SVR 2a 2 CT Partial-NR Telaprevir 46300 Relapse 3a 4 CC Naive Boceprevir 20500 SVR 3a 2 CT Naive Boceprevir 320 SVR 3a 4 CT Naive Boceprevir 1120 BT 3a 4 CT Relapse Boceprevir 1250 Relapse 3a 4 CC Naive Boceprevir 125 SVR
*rs12979860
Treatment options Genotype 2 and 3
Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs
Treatment options Genotype 2/3 Sofosbuvir Monotherapy: antiviral activities
Lam et al., AAC 2012; Gane et al., AASLD 2011; Lawitz et al., EASL 2011
-5
-4
-3
-2
-1
0
0 1 2 3 4 5 6 7Days
Medi
an H
CV R
NA ch
ange
from
ba
selin
e (lo
g IU
/mL)
PSI-7977 400 mg QD In HCV GT2/3 (ELECTRON)
PSI-7977 400 mg QD In HCV GT1 (NUCLEAR)1
EC50 (µM)
GT1b con1
GT1a H77
GT2a JFH-1
GT1b/2a J6
GT1b/2b pt
GT1b/3a pt
SOF 0.048 0.044 0.037 0.0047 0.020 0.016
Treatment options Genotype 2/3 Sofosbuvir + Riba: IFN-intolerant tx-naive (Positron)
Jacobson et al., EASL 2013; #61 and NEJM 2013
92 94
68
21
0
20
40
60
80
100
GT 2 GT 3
SV
R12
(%)
85/92 16/17 57/84 3/14
No cirrhosis Cirrhosis
100% on tx response, no viral break-through, failure = relapse No resistance (deep and phenotypic)
Treatment options Genotype 2/3 Sofosbuvir plus Riba vs. PEG/R tx-naive (Fission)
Gane et al., EASL 2013; #5 and NEJM 2013
98 82
91
62
61 71
34 30
0
20
40
60
80
100
SOF + RBV Peg-IFN + RBV
GT 2 GT 3
SVR
12 (%
)
No cirrhosis No cirrhosis Cirrhosis Cirrhosis
58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37
Treatment options Genotype 2/3 Sofosbuvir plus Ribavirin in tx-experienced (Fusion)
Gane et al., EASL 2013 and NEJM 2013
96 100
60 78
0
20
40
60
80
100
37
63
19
61
0
20
40
60
80
100
6/10 5/26
SV
R12
(%)
25/26 7/9 23/23 14/38 14/23 25/40
No cirrhosis
SOF + RBV 12 weeks SOF + RBV 16 weeks
No cirrhosis Cirrhosis Cirrhosis
GT 2 GT 3
Treatment options Genotype 2/3 Sofosbuvir plus Ribavirin 12 vs. 24 wks. (Valence)
Zeuzem et al., AASLD 2013; 1085
Genotype 2/3, tx-naive and Non-Responder: Extension of treatment
duration in GT3 patients
Treatment options Genotype 2/3 Sofosbuvir plus Ribavirin 12 vs. 24 wks. (Valence)
Zeuzem et al., AASLD 2013; 1085 Zeuzem et al., AASLD 2013; 1085
Genotyp 2/3, Tx-naive and Non-Responder: Extension of treatment duration in genotype 3 patients
Treatment options Genotype 2/3 Sofosbuvir+ PEG + Riba: tx-experienced (Lonestar 2)
Lawitz et al., AASLD 2013; LB4
Genotyp 2/3, Re-treatment (85% BT or Relapse), 50% F4, n=47 Sofosbuvir 400mg QD plus PEG-2a + Riba for 12 weeks
96 83
100
83 93
83
0
20
40
60
80
100
120
Genotype 2 Genotype 3
SVR
12 (%
)
allno cirrhosiscirrhosis
Relapse 2 1 1
22/23 20/24
Treatment options Genotype 2/3 Sofosbuvir + Riba +/- PEG: Adverse events
Preferred term, n (%) SOF + RBV
n=207 Placebo
n=71
p-value* Fatigue 91 (44) 17 (24) 0.003 Nausea 46 (22) 13 (18) 0.614 Headache 43 (21) 14 (20) 1.00 Insomnia 39 (19) 3 (4) 0.002 Pruritus 23 (11) 6 (9) 0.655 Anemia 27 (13) 0 <0.001
Jacobson et al., EASL 2013; #61
Patients, n (%) SOF + RBV n=207 Placebo n=71
Overall safety
AEs 185 (89) 55 (78) Serious AEs 11 (5) 2 (3) Treatment disc. due to AEs 4 (2) 3 (4)
Hematologic abnormalities
Hemoglobin <10 g/dL 15 (7) 0 Hemoglobin <8.5 g/dL 2 (1) 0 Absolute neutrophil count <750/mm3 0 1 (1) Platelets <50,000/mm3 0 2 (3)
Treatment options Genotype 2/3 Simeprevir
Moreno et al., J Hepatol 2012
-2.19 log
-2.73 log
-3.52 log
-0 log
Genotype 1: -3.8 log decline
Treatment options Genotype 2/3 Faldaprevir Potentcy of BI 201335 (Faldaprevir), telaprevir, and boceprevir against NS3-NS4A proteins of differnt HCV genotypes
White et al., AAC 2010
Treatment options Genotype 2/3 Sofosbuvir: FDA approval Dec. 13
Treatment options Genotype 2 and 3
Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs
Treatment options Genotype 2/3 Future drugs
NS3 Protease-Inhibitors − MK-5172 (activity against genotype 3 at toxic doses only) NS5A-Inhibitors: − Daclatasvir (lower activity against GT3 versus GT1) − Ledipasvir (in vitro low activity against GT3) − ABT-267 (in vitro lower activity against GT3 versus GT1) − GS-5816 (improved activity against GT3) Non-nucleoside Polymerase-Inhibitors − no clinical data Nucleoside Polymerase-Inhibitors − several compounds in phase 1/2 (VX-135, IDX-20963, ACH3422)
Summary
Different geographical distribution of genotypes (GT) 2 and 3
Countries with high prevalence of GT 2 or 3 (>30%) PEG-Interferon plus ribavirin for 12-16 weeks in
patients with RVR (without cirrhosis, <45 years and BMI <30)
PEG-Interferon plus ribavirin for 48 weeks in non-RVR and previous Rel/NR patients?
Rescue treatment with Boceprevir / Telaprevir? Sofosbuvir plus Ribavirin for 12 weeks in genotype 2 Sofosbuvir plus Ribavirin for 24 weeks in genotype 3
(Sofosbuvir + Riba + PEG for 12 weeks?) No efficacy / data for Simeprevir and Faldaprevir
HCV Genotypes 2 & 3
Laurel and Hardy