Hepatitis C Genotype 3
Paris 2012
Graham R Foster
Professor of Hepatology
Queen Marys School of Medicine
Barts and The London
Hepatitis C – Genotype 3
• Classically ‘easy to treat’
• Common in Indian Sub-continent
• Increasing prevalence in Europe
SVR (%)
Treating HCV overall
Genotype non 1 – 40 KD PEG IFNα2a +
Ribavirin
90
80
70
60
50
40
30
20
10
0
78%
78%
n=106
n=162
PEG IFN
PEG IFN
RBV 800 RBV 1000/1200
24 weeks
Hadziyannis et al Ann Intern Med 2004:140;346-355
73%
77%
n=111
n=165
PEG IFN
PEG IFN
RBV 800 RBV 1000/1200
48 weeks
Hepatitis C – Genotype 3
Are these non-genotype 1 studies
representative of real world response
rates?
Genotype 3 HCV
Response to Peg+Riba
% S V R in As ia n V s No n As ia n P ts
100
90
80
% SVR
243/322
2 3 6 /3 1 7
60
50
40
30
20
10
N
on
A
.A
si
si
an
an
0
S
% SVR
70
Shoeb et al E J Gastro Hep 2011
Genotype 3
Audit of 639 patients treated with Peg+Riba
175/201
% SVR
yr
s
<4
0
yr
s
304/437
0
100
90
80
70
60
50
40
30
20
10
0
>4
% SVR
% SVR in in Different Age Groups
Shoeb et al E J Gastro Hep 2011
Genotype 3
% SVR
Audit of 639 patients treated with Peg+Riba
100
90
80
70
60
50
40
30
20
10
0
352/436
% SVR
92/161
is
s
ho
r
r
ci
no
c
is
s
ho
r
ir
Shoeb et al E J Gastro Hep 201
Genotype 3 and cirrhosis
Relapse is the commonest mode of treatment failure
25
% Patients
20
% patients
97/639
15
10
44/639
5 16/639
R
el
ap
se
rs
re
sp
on
de
rs
N
on
B
re
ak
th
ro
ug
h
0
Genotype 3 HCV
Can we shorten therapy?
Shortening treatment duration in
genotype 2/3 patients: ACCELERATE
Screening
132 centers; n=1469
PEGASYS
180 g/week
plus COPEGUS
800 mg/day
Follow-up
Treatment duration
blinded until week 16
PEGASYS
180 g/week
plus COPEGUS
800 mg/day
Follow-up
0 ------------------ 16 ---- 24 ----------------- 40 ----- 48
Weeks
Randomization to 16 or 24 weeks’ treatment
Shiffman M, et al. N Engl J Med 2007; 357: 124
ACCELERATE: 24 weeks is more effective
than 16 weeks in genotype 2/3 patients
PEGASYS 180 g/wk plus COPEGUS 800 mg/day
100
90
SVR (%)
80
70
76%
65%
60
50
40
30
20
10
n=679
n=630
16 weeks
24 weeks
0
Standard analysis
Shiffman M, et al. N Engl J Med 2007; 357: 124
Very high SVR rates with shorter duration
in G2/3 patients with an RVR and LVL
16 weeks PEGASYS plus COPEGUS
24 weeks PEGASYS plus COPEGUS
100
90%
95%
92%
88%
84%
78%
SVR (%)
80
60
40
20
n=123 n=101
n=43
n=49
n=295 n=260
0
≤400 000 IU/mL
Standard analysis
400–800 000 IU/mL
>800 000 IU/mL
Shiffman M, et al. 57th AASLD 2006; Abstract 340
Optimizing outcomes in genotype 3
• Most patients need 24 weeks
• A few patients may only need 16 weeks
• People with cirrhosis respond poorly,
should we extend therapy in such
patients?
STEPS
• Randomised controlled trial comparing 24
to 48 weeks therapy in patients with
Genotype 3 HCV and advanced fibrosis
• Fully recruited (140 patients)
• Results expected EASL 2013
Genotype 3 HCV
What about the future?
• New drugs are transforming therapy for
chronic HCV
• Cirrhotics with G3 who have failed to
respond to Peg + Riba are queuing up for
therapy
• What can we offer them?
Telaprevir in Genotype 3
Mean HCV RNA decline from baseline
Time (days)
0
3
6
9
12
15
Mean (SE) change in log10 HCV RNA
0
–0.5
–1
–2
–3
–4
–5
–6
T mono (n=8)
PR (n=9)
T/PR (n=9)
–4.5
–4.7
Foster et al Gastro 2011
Some G3 patients are more
equal than others
Some G3 patients are more
equal than others
Genotype 3 HCV
What about the future?
• Current protease inhibitors will not work for
most patients with G3
• Other drug classes may be more useful
• (NS5A, Cyclophilin, nucleosides)
Alisporivir + PegIFN may cure patients
after 4 weeks
Patient 5304 GT3
7
Peg-IFNα2a 180 ug/wk
Debio 025
200 mg 2x/day Day 1-7
200 mg 1x/day Day 8-29
6
5
Log10 IU/mL
Treatment period
4
3
2
Limit of detection
1
*
0
0
1
2
3
4
7
11
18
32
120
Weeks
Patient 5305 GT3
7
6
Peg-IFNα2a 180 ug/wk
Debio 025
600 mg 2x/day Day 1-7
600 mg 1x/day Day 8-29
5
Log10 IU/mL
Treatment period
4
Four similar patients presented at AASLD
(Heathcote et al)
3
2
Limit of detection
1
0
*
7977 and Genotype 3
 Treatment-naïve, non-cirrhotic
 Allowed concurrent methadone use
Wk 0
4
n=10
n=10
12
PSI-7977 + RBV + Peg-IFN
n=10
n=10
8
PSI-7977 + RBV + Peg-IFN
PSI-7977+
RBV + Peg-IFN
SVR12
PSI-7977 + RBV
PSI-7977 + RBV
PSI-7977 + RBV
24
SVR12
SVR12
SVR12
Gane EJ, et al. Hepatology 2011;54(Suppl. S1): Abstract 34
Proportion of patients with
undetectable HCV RNA (%)
7977 and Genotype 3
11
11
10
10
9
9
10
10
11
11
10
10
9
9
10
10
11
11
10
10
9
9
10
10
6
6
5
5
5
5
4
4
Hepatitis C – Genotype 3
• Easy to treat – provided your patient is
young with no fibrosis
• Tough to treat if your patient has cirrhosis
• Optimal duration of therapy remains
controversial
• New drugs are desperately needed