Embed Size (px)
Citation preview
Hepatitis C Genotype 3Paris 2012
Graham R FosterProfessor of Hepatology
Queen Marys School of MedicineBarts and The London
Hepatitis C – Genotype 3
• Classically ‘easy to treat’
• Common in Indian Sub-continent
• Increasing prevalence in Europe
Treating HCV overallGenotype non 1 – 40 KD PEG IFNα2a +
Ribavirin
SV
R (
%)
0
10
20
30
40
50
60
70
80
90
24 weeks 48 weeks
78% 78% 73% 77%
n=106 n=162 n=111 n=165
PEG IFNRBV 800
PEG IFN RBV 1000/1200
PEG IFNRBV 800
PEG IFNRBV 1000/1200
Hadziyannis et al Ann Intern Med 2004:140;346-355
Hepatitis C – Genotype 3
Are these non-genotype 1 studies representative of real world response rates?
Genotype 3 HCVResponse to Peg+Riba
% SVR in Asian Vs Non Asian Pts
S.Asi
an
Non Asi
an
0102030405060708090
100% SVR
236/317 243/322
% S
VR
Shoeb et al E J Gastro Hep 2011
Genotype 3Audit of 639 patients treated with Peg+Riba
Shoeb et al E J Gastro Hep 2011
% SVR in in Different Age Groups
>40
yrs
<40
yrs
0102030405060708090
100% SVR
% S
VR
304/437
175/201
Genotype 3Audit of 639 patients treated with Peg+Riba
Shoeb et al E J Gastro Hep 2011
cirrh
osis
no cirr
hosis
0102030405060708090
100% SVR
92/161
352/436
% S
VR
Genotype 3 and cirrhosis
Break
thro
ugh
Non resp
onders
Relap
sers
0
5
10
15
20
25% Patients
97/639
44/639
16/639
% p
atie
nts
Relapse is the commonest mode of treatment failure
Genotype 3 HCV Can we shorten therapy?
Scr
ee
nin
g
Weeks
0 ------------------ 16 ---- 24 ----------------- 40 ----- 48
PEGASYS 180 g/week
plus COPEGUS800 mg/day
Follow-up
PEGASYS 180 g/week
plus COPEGUS 800 mg/day
Follow-up
Treatment duration blinded until week 16
132 centers; n=1469
Shortening treatment duration in genotype 2/3 patients: ACCELERATE
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
Standard analysis
SV
R (
%)
n=679 n=630
65%
76%
0
20
40
60
80
100
10
30
50
70
90
16 weeks 24 weeks
PEGASYS 180 g/wk plus COPEGUS 800 mg/day
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 COPEGUS24 weeks PEGASYS plus COPEGUS
n=123 n=101 n=295 n=260 n=49n=43
≤400 000 IU/mL 400–800 000 IU/mL >800 000 IU/mL
90%84%
78%
95%92% 88%
SV
R (
%)
0
20
40
60
80
100
Standard analysis 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 HCVWhat 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?
0 3 6 9 12 15
Telaprevir in Genotype 3 Mean HCV RNA decline from baseline
Mea
n (
SE
) ch
ang
e in
log
10 H
CV
RN
A
0
–1
–2
–3
–4
–5
–6
Time (days)
–0.5
T mono (n=8)–4.5
PR (n=9)PR (n=9)–4.7
T/PR (n=9)T/PR (n=9)
Foster et al Gastro 2011
Some G3 patients are more equal than others
Some G3 patients are more equal than others
Genotype 3 HCVWhat 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 5310 GT1b
0
1
2
3
4
5
6
7
0 1 2 3 4 7 33 120
Weeks
Lo
g10
IU
/mL
Patient 5305 GT3
0
1
2
3
4
5
6
7
0 1 2 3 4 7 33 92 120
Weeks
Lo
g10
IU/m
L
Patient 5304 GT3
0
1
2
3
4
5
6
7
0 1 2 3 4 7 11 18 32 120
Weeks
Lo
g10
IU/m
L
Peg-IFNα2a 180 ug/wk
Debio 025 200 mg 2x/day Day 1-7200 mg 1x/day Day 8-29
Treatment period
Limit of detection
Peg-IFNα2a 180 ug/wk
Debio 025 600 mg 2x/day Day 1-7600 mg 1x/day Day 8-29
Treatment period
Limit of detection
Peg-IFNα2a 180 ug/wk
Debio 025 1000 mg 2x/day Day 1-71000 mg 1x/day Day 8-29
Treatment period
Limit of detection
Patient 1207 GT3
0
1
2
3
4
5
6
7
0 1 2 3 4 7 40 120
Weeks
Lo
g10
IU
/mL
Debio 025 200 mg 2x/day Day 1-7200 mg 1x/day Day 8-29
Treatment period
Limit of detection
*
*
*
Patient 5310 GT1b
0
1
2
3
4
5
6
7
0 1 2 3 4 7 33 120
Weeks
Lo
g10
IU
/mL
Patient 5305 GT3
0
1
2
3
4
5
6
7
0 1 2 3 4 7 33 92 120
Weeks
Lo
g10
IU/m
L
Patient 5304 GT3
0
1
2
3
4
5
6
7
0 1 2 3 4 7 11 18 32 120
Weeks
Lo
g10
IU/m
L
Peg-IFNα2a 180 ug/wk
Debio 025 200 mg 2x/day Day 1-7200 mg 1x/day Day 8-29
Treatment period
Limit of detectionLimit of detection
Peg-IFNα2a 180 ug/wk
Debio 025 600 mg 2x/day Day 1-7600 mg 1x/day Day 8-29
Treatment period
Limit of detectionLimit of detection
Peg-IFNα2a 180 ug/wk
Debio 025 1000 mg 2x/day Day 1-71000 mg 1x/day Day 8-29
Treatment period
Limit of detectionLimit of detection
Patient 1207 GT3
0
1
2
3
4
5
6
7
0 1 2 3 4 7 40 120
Weeks
Lo
g10
IU
/mL
Debio 025 200 mg 2x/day Day 1-7200 mg 1x/day Day 8-29
Treatment period
Limit of detectionLimit of detection
*
*
*
Four similar patients presented at AASLD (Heathcote et al)
7977 and Genotype 3 Treatment-naïve, non-cirrhotic Allowed concurrent methadone use
PSI-7977+RBV + Peg-IFN
PSI-7977 + RBV
PSI-7977 + RBV + Peg-IFN
PSI-7977 + RBV + Peg-IFN
84Wk 0 12 24
PSI-7977 + RBV
PSI-7977 + RBV
SVR12
SVR12
SVR12
SVR12
n=10
n=10
n=10
n=10
Gane EJ, et al. Hepatology 2011;54(Suppl. S1): Abstract 34
7977 and Genotype 3P
rop
ort
ion
of
pat
ien
ts w
ith
u
nd
etec
tab
le H
CV
RN
A (
%)
1111
1010
99
1010
1111
1010
99
1010
1111
1010
99
1010
66
55
55
44
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
