Transcript Slide 1

Non-genotype 1 HCV
Treatment naïve, relapse, partial
response and null responders
Geoff McCaughan
Amany Zekry
Objectives
• Discuss current treatment with peg-IFN and
RBV (SOC)
• Controversies re. initiating treatment
• Predictors of response
• Role of IL-28
• Emerging new therapies for non-genotype 1
Ms J Smith
• Ms J Smith, 36 yo, Caucasian, social worker
• Single mother, 2 children aged 12 and 14 yo
• IDU at the age of 18 (experimenting)
• HCV genotype 3a
• Has deferred treatment in the past
• Now new relationship – “wants to get rid of the virus”
Ms J Smith
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•
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•
•
Alcohol intake: 20 g/day (more on weekends)
Non-smoker
Mild depression in the past; no treatment
BMI 24 kg/m2
Physical examination unremarkable
Ms J Smith – Investigations
LFTs:
• Bili
• ALP:
• AST:
• ALT:
• GGT:
• Alb:
13 umol/L
50 g/L
54 U/L
60 U/L
68 U/L
36 g/L
Other results:
• FBC: normal
• VL: 800,000 IU/mL
• HCV genotype 3a
• Fibroscan: 8kDa
Ms J Smith
Question
To treat or not to treat?
Reasons to consider immediate
treatment
• Response rates more favourable in patients with
milder vs more advanced disease
• Chronic HCV infection may impair quality of life
• New regimens in development might encounter
unexpected problems
– Some promising drugs fail in phase III clinical trials
due to unexpected AEs
Reasons to consider deferring therapy
• Disease progression is slow in many patients
• Current regimens are complex with many AEs
• If patient is hesitant, may be less adherent
– Could lead to outgrowth of resistant variants
• New experimental therapies are being developed
– IFN-free regimens are an active focus of research
Impact of genotype on SVR to peg-IFN/RBV
peg-IFN alfa-2b 1.5 µg/kg/wk +
RBV 800 mg/day for 48 Wks[1]
peg-IFN alfa-2a 180 µg/wk + weight-based RBV
(1000 or 1200 mg/day) for 48 Wks[2]
100
100
82
SVR (%)
80
60
60
54
76
80
56
46
42
40
40
20
20
n = 511
0
Overall
348
163
Genotype
1
Genotype
2/3
n = 453
0
Overall
298
140
Genotype
1
Genotype
2/3
1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002
Factors that influence response in patients
with genotype 3
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•
•
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Extent of hepatic injury
RVR
Baseline viral load
Metabolic factors
IL-28B genotype mutation
Others
Shoeb D, et al. Eur J Gastroenterol Hepatol. 2011.
Rates of SVR in G2/3 patients depending on baseline
viral load, liver fibrosis and RVR
Fig 1
%
100
82%
%
%
100
100
16 weeks
81%
85%
24 weeks
79%
74%
67%
Sustained virological
response
75
75
75
67%
58%
55%
50
45%
48%
50
50
26%
25
25
132/161
122/150
208/506
367/547
334/501
0
25
420/566
88/185
0
Viral load
< 400.000
IU/mL
Viral load
> 800.000
IU/mL
387/489
95/165
400/470
58/220
110/247
0
Mild fibrosis
Bridging fibrosis
/ cirrhosis
RVR
Non RVR
IL-28B polymorphisms and response to
peg-IFN/RBV by HCV genotype
100
Genotype 1
Genotype 2/3
Genotype 4
88
85
CC
79 78
80
CT
SVR (%)
TT
60
45
40
50
41
32
25
20
0
Stättermayer AF, et al. Clin Gastroenterol Hepatol. 2011;9:344-350.
IL-28B polymorphism in genotype 2/3
patients who do not achieve a RVR
Mangia A, et al, Gastroeneterology 2010
Ms J Smith – Baseline parameters
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•
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•
•
Young
Female
White
Normal body weight
Favorable genotype: 3a
Not consuming alcohol
Not diabetic
Ms J Smith
• Commenced peg-IFN + weight-based RBV
• Viral load at 4 weeks – detectable
• Viral load at 12 weeks – 80,000 IU/mL
Question
Duration of treatment in genotype 3:
Standard or shorter?
ACCELERATE: Treatment duration in
genotype 2 and 3 patients
1:1 Randomisation
(blinded until Wk 16)
Genotype 2 or 3
HCV-infected patients
(n=1469)
Wk 16
peg-IFN alfa-2a 180 µg/wk +
RBV 800 mg/day
(n=732)
peg-IFN alfa-2a 180 µg/wk +
RBV 800 mg/day
(n=732)
Wk 24
24 wks of
follow-up
24 wks of
follow-up
Shiffman M, et al. N Engl J Med. 2007;357:124-134.
ACCELERATE: Higher SVR with 24 wks vs
16 wks in genotype 2/3 patients
100
PegIFN alfa-2a 180 g/wk + RBV 800 mg/day
p<0.001
76
80
SVR (%)
65
60
40
20
0
n=667
n=652
16 Wks
24 Wks
Shiffman M, et al. N Engl J Med. 2007;357:124 -134.
Very high SVR rates with shorter duration in
GT 2/3 patients with RVR and LVL
peg-IFN alfa-2a 180 µg/wk + RBV 800 mg/day
SVR in Patients With RVR (%)
100
80
p=0.02
85
79
p=0.21 95
90
16 wks
p=0.34
92
84
24 wks
p=0.002
88
78
60
40
20
0
n = 487
466
All Patients
123
101
≤ 400,000 IU/mL
Shiffman M, et al. N Engl J Med. 2007;357:124 -134.
43
49
400,000-800,000 IU/mL
295
260
> 800,000 IU/mL
High SVR rates in GT 2/3 patients achieving
RVR with weight-based RBV
• Small scale trials using weight-based RBV support shorter
duration of treatment in GT 2/3 patients who achieve RVR
Study
SVR in Patients Achieving RVR, %
Shorter duration (Wks)
24 Wks
Von Wagner[1]
82 (16)
80
Mangia[2]
85 (12)
91
Yu[3]
100 (16)
98
Manns[4]
75 (16)
72
1. Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Mangia A, et al. N Engl J Med. 2005;352:2609-2617.
3. Yu ML, et al. Gut. 2007;56:553-559. 4. Manns MP, et al. J Hepatol. 2011. 5. Dalgard O, et al. Hepatology. 2008;47:35-43.
5. Craxi A, et al. J Hepatol. 2011.
Relapse rate: Short vs standard duration in
subset of patients infected with genotype 2/ 3
Optimal treatment duration for
non-RVR patients
• In non RVR patients, the SVR rate varied with
treatment duration:
– 26% after short therapy
– 46% after standard therapy
Role for longer treatment duration?
1. Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Mangia A, et al. N Engl J Med. 2005;352:26092617. 3. Yu ML, et al. Gut. 2007;56:553-559. 4. Manns MP, et al. J Hepatol. 2011. 5. Dalgard O, et al. Hepatology.
2008;47:35-43. 5. Craxi A, et al. J Hepatol. 2011.
Longer treatment duration for genotype
2/3 without RVR
• 1 prospective study: 24 wks vs 36 wks – no difference*
• 1 retrospective analysis: 5 trials of patients without RVR**
Pegasys + weight based RBV - ITT analysis
SVR (%)
Relapse (%)
22/34 (65)
7/29 (24)
28/37 (76)
1/27 (4)
*Mangia A. J Hepatol 2010
**Willems B, et al. J Hepatol 2007;46 (Suppl 1)
EASL: Response-guided therapy in patients
with genotype 2/3 infection
Wk
0
4
Neg
(RVR)
12
Pos
HCV RNA
Risk factors
(fibrosis, IR)
12-16 Wks
of therapy*
24 Wks
of therapy
Pos < 2 log
drop or
pos at
Wk 24
Pos > 2 log
drop but neg
thereafter
(DVR)
Stop Tx
Neg
(EVR)
48 Wks
of therapy
*Marginally less effective due to higher relapse rates, especially for G3 with high HCV RNA.
Craxi A, et al. J Hepatol. 2011.
Summary: Response-guided therapy for
genotype 2/3 patients
• Peg-IFN/RBV is recommended for patients with
genotype 2/3 infection
• Shorter duration of therapy may be considered in a
highly selected groups of patients
• Patients with cirrhosis are not suitable for short
duration therapy
Ms J Smith
• Struggles during therapy – fatigue, bone aches, lack
of energy, insomnia
• Mood swings:
– Problems with new partner, due to her mood changes
– Unable to cope with children problems
– Commenced antidepressant therapy
• No dose reduction was required during treatment
Ms J Smith
• Completed 24 weeks of therapy
• HCV PCR-negative at end of therapy
• Relieved – Wants to resume “normal life”
Ms J Smith
• Returns after 6 months
• HCV PCR-positive
• Devastated!
• Repeat Fibroscan – 6 kDa
Ms J Smith
Options:
• Do nothing for now
• Repeat course of therapy
• Await new treatments
Progression of fibrosis in re-biopsied patients
Patients
(%)
• 282 patients with Ishak stage 0 or 1 on initial biopsy – re-biopsied
• Progression of fibrosis occurred in 42% of patients over median of 52.5 mths
60
50
40
30
20
10
0
-1
0
1
2
3
Change in Fibrosis Score
4
5
Factors associated with fibrosis progression of ≥2 Ishak stages:
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•
Age at first biopsy (p=0.001) and median ALT level (p=0.007)
Fibrosis progression more rapid in patients coinfected with HIV
Williams MJ, et al. J Viral Hepat. 2011;18:17-22. Deng LP, et al. World J Gastroenterol. 2009;15:996-1003.
EPIC3 Non-responders study: Predictors of SVR
• HCV genotype
– GT2/3 vs GT1: OR=4.9 (p<0.0001)
• Baseline METAVIR fibrosis score
– F2 vs F4: OR=2.2 (p<0.0001)
– F3 vs F4: OR=1.4 (p=0.0183)
• Baseline viral load
– ≤600,000 IU/mL vs > 600,000 IU/mL: OR=1.9 (p<0.0001)
• Previous treatment
– IFN α + RBV vs peg-IFN α + RBV: OR=2.0 (p<0.0001)
• Previous treatment response
– Relapser vs non-responder: OR=3.8 (p<0.0001)
EPIC Non-responders study:
SVR by Week 12 HCV RNA decrease
HCV RNA level in patients with HCV RNA ≥2 log10
at week 12 of treatment, IU/mL
SVR rate, %
(n/N)
> 750
0 (0/53)
501-750
6 (1/17)
251-500
9 (2/21)
125-250
16 (5/32)
Low positive (unquantifiable)
23 (15/65)
Undetectable (< 125 IU/mL)
56 (463/821)
Poynard T, et al., Gastroenterology 2009 May.
SVR by previous treatment and response
Peg-IFN alfa-2b 1.5 µg/kg/wk + weight-based RBV 800-1400 mg/day for 48 Wks
60
Patients (%)
All
38
40
Prior nonresponders
43
Prior relapsers
34
32
25
22
20
14
18
18
17
7
0
All
(n=2293)
Poynard T, et al. Gastroenterology 2009 May.
IFN/RBV
(n=1423)
6
Peg-IFN a-2b + PegIFN a-2a +
RBV (n=488)
RBV (n=375)
Previous regimen
Summary of re-treatment
• Selected patients
• Re-treatment responses of ~30%-50%
• EVR is predictive of SVR (? stop if RNA +, ?
longer therapy )
• Can new treatments offer more?
Future therapies for genotype 3:
Towards interferon-free regimens?
ELECTRON: PSI-7977 ± RBV ± peg-IFN in GT2/3
treatment-naive patients
SVR12 Outcomes
• Nucleotide analogue PSI7977 400 mg QD + RBV for
12 wks
• All patients in all arms had
undetectable HCV RNA by
Wk 4
• 100% SVR12 in all RBVcontaining arms
100
100
100
10/10
9/9
10/10
PSI-7977/
RBV
+ 0 Wks
Peg-IFN
(IFN-free)
PSI-7977/
RBV
+ 4 Wks
Peg-IFN
PSI-7977/
RBV
+ 8 Wks
Peg-IFN
100
80
Patients (%)
– peg-IFN included for 0, 4,
8, or 12 wks
100
60
40
20
n/N =
0
Gane EJ, et al. AASLD 2011. Abstract 34.
11/11
PSI-7977/
RBV
+ 12 Wks
Peg-IFN
Daclatasvir + GS-7977 ± RBV in Tx-naive GT 2/3
Wk 1
D
Tx -naive
patients with
GT2/3
E
Wk 24
GS-7977
(n=16)
Daclatasvir + GS-7977
Daclatasvir + GS-7977
Wk 48
Follow-up
Follow-up
(n=14)
(n=44)
F
Daclatasvir + GS-7977 + RBV
(n=14)
Follow-up
Doses: GS-7977 400 mg QD; daclatasvir 60 mg QD; RBV; 800 mg/day
Sulkowski M, et al. EASL 2012. Abstract 1422.
Daclatasvir + GS-7977 ± RBV:
Efficacy analysis according to genotype
Genotype 2/3
Patients (%)
100
80
100 100 100
88
94
100
93 93
79
60
86
86
64
100
88 100 86
88
79
Group D
Group E
Group F
40
20
n=
0
16 14 14
16 14 14
16 14 14
Wk 4
Wk 24
(EOT)
SVR4
Sulkowski M, et al. EASL 2012. Abstract 1422.
Daclatasvir + GS-7977 ± RBV
• Anaemia most common grade 3 or 4
laboratory abnormality, occurring only with
RBV
• No grade 3 or 4 ALT, AST, total/direct bilirubin
elevations
More on non-genotype 1
Chronic HCV genotype 4:
Some clinical issues
HCV genotype 4
• HCV GT4 comprises ~ 20% of the world’s HCVinfected population
• Under-represented in the large multicentre
clinical trials
• Is it a "difficult to treat” genotype?
Khattab et al J Hep 2011;54:1250
Meta-analysis:
HCV genotype 4 treatment responses
RVR and EVR as predictors of SVR in patients
with chronic genotype 4
Leandro G, et al. Gastroenterology 2006
Impact of ethnicity on SVR rates in
chronic genotype 4
• SVR rates in patients from Middle East are higher than
SVR in patients from Europe/sub-Saharan Africa:
– SVRs of 63% vs 51% vs 39%
• In multivariate analysis, two factors were
independently associated with SVR:
– Egyptian origin
– Absence of severe fibrosis
Roulot D, et al. J Viral Hepatitis 2007; Elefsiniotis I, et al. Intervirology 2005
Khattab et al J Hep 2011;54:1250
Asselah et al J Hep 2012;56:527
Asselah et al J Hep 2012;56:527
Treatment of thalassaemia major patients
with genotype 4
2 studies evaluating the efficacy of peg-IFN ± RBV
• Peg-IFN monotherapy
SVR 30%–46%
• Peg-IFN/RBV
SVR 62%–64%
• Combination therapy was associated with
increase in transfusion requirements, up to 30%
Kamal S, et al. Hepatology 2006; Inati A, et al. Br J Haematol 2005.
New drugs for genotype 4
• Cyclophilin inhibitors
• NS5A inhibitors
Data are limited
Summary
• SVR in GT4 have improved
• Ethnicity, RVR and IL28 genotype have an
impact response to therapy
• New drugs – trials have not yet exploded for
GT4