Transcript Slide 1

Treatment-experienced
HCV genotype 1 patients
Bill Sievert
Sally Bell
Learning objectives
• Review definitions of treatment failure and
characterisation of previous treatment
episodes
• Understand the impact of interferon sensitivity
on DAA treatment outcomes
• Review treatment outcomes in non-cirrhotic
and cirrhotic patients
• Understand the impact of viral resistance
• Review futility rules in DAA regimens
Ms CM
• 45-year-old woman with HCV genotype 1
referred for assessment in 2003
• Prior IDU
• Current medications: milk thistle,
glutamine, vitamins C/E, ‘liver detox’ and
‘liver gourd’ tablets
• No EtOH
• Past history – migraines
• Family history – eczema, alcoholism
Ms CM
• US – cholelithiasis, normal spleen and liver
• Liver biopsy – Metavir F3, steatohepatitis
Ms CM – 2004
• Peg-IFN 2a 180 µg + RBV 1000 mg x 48
weeks
• On-treatment adverse events
– Depression, treated with sertraline
– Diarrhoea, treated with loperamide
Ms CM – 2004
• Virological outcomes
– Pre-treatment
– Week 12
– Week 24
– Week 34
– End of treatment (Wk 48)
– Follow-up Wk 12
5.60 log IU/mL
3.58 log IU/mL
<2.78 log IU/mL
not detected
not detected
detected
• How would you characterise her virological
response?
Definitions
What’s in a name?
• Relapse
Undetectable HCV RNA at the end of
treatment but detectable HCV RNA during
follow-up
• Partial responder
≥2 log10 decline in HCV RNA at week 12 but
detectable at week 24 during therapy
• Null responder
<2 log10 decline in HCV RNA at week 12
Challenges in categorising previous
treatment response
• Lack of detailed records
• Lack of patient evaluation at key time
points on previous therapy
• Differentiation of previous partial
response vs null response
– May be unable to characterise decline in
HCV RNA levels at key times
Ms CM – 2008
• Liver tests
– Bilirubin
– ALT
– Albumin
– Hb
– Platelets
– INR
6 µmol/L
39 U/L
39 g/L
158 g/L
244 X 109/L
0.9
• Liver biopsy – F 3/4
• Genotype 1a
• What would you advise her to do now?
Boceprevir and Telaprevir
• Potent inhibitors of HCV NS3/4A protease
• Both tested in combination with standard-of-care peg-IFN
alfa/RBV in phase III studies in chronic HCV genotype 1 infection
Telaprevir
– ADVANCE:
Treatment-naïve patients
– ILLUMINATE: Response-guided therapy
(treatment naïve)
– REALIZE:
Treatment-experienced patients
(relapse, null and partial response)
Boceprevir
– SPRINT-2:
– RESPOND-2:
Treatment naïve patients
Treatment-experienced patients
(relapse and partial response)
RESPOND – BOC in relapse + partial responders
Control
48 P/R
(n=80)
Week 4
PR
lead-in
Week 36
PR + Placebo
(n=162)
PR
lead-in
Follow-up
Follow-up
PR + Boceprevir
TW 8 HCV-RNA Detectable
TW 12 Undetectable
PR +
placebo
BOC/
PR48
(n=161)
PR
lead-in
Week 72
TW 8 HCV-RNA Undetectable
Week 12
futility
BOC
RGT
Week 48
PR + Boceprevir
Follow-up
Follow-up
HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA
(LLD=9.3 IU/mL) at week 12 were considered treatment failures.
New Engl J Med 2011;364:1207-17
Boceprevir dose: 800 mg tds
REALIZE: TVR in HCV relapse, partial
response and null responders
Week 4
Week 12
Week 16
Week 48
PR
Week 72
Follow-Up
n=132
Follow-Up
n=264
Lead-in
PR
PR
PR + TVR
PR + TVR
PR
Follow-Up
N Engl J Med. 2011;364:2417-28.
n=266
Boceprevir and telaprevir improve SVR
rates in naïve and experienced patients
SVR (%)
80
63–75
38–44
40
20
80
60
Δ~40%
40
20
Current Standard
of Care
SOC, standard of care
SVR, sustained virologic response
Treatment-experienced
patients3,4
59–66
Δ~30%
60
0
100
SVR (%)
100
Treatment-naïve patients1,2
SOC + Protease
Inhibitor
0
17–21
Current Standard
of Care
SOC + Protease
Inhibitor
1. Poordad F, et al. NEJM 2011;364:1195-206; 2. Jacobson IM, et al. NEJM 2011;364:3405-16.
3. Bacon BR, et al. NEJM 2011;364:1207-17; 4. Zeuzem S, et al. NEJM 2011;364:2417-28.
Ms CM – 2008
• Enters REALIZE study: TPV 750 mg 8-hourly or
placebo + peg-IFN 180 µg/RBV 1200 mg
• Virological outcomes
– Pre-treatment
– Week 4
– Week 12
– Week 24
– FU Week 24
6.23 log IU/mL
4.81 log IU/mL
3.35 log IU/mL
1.66 log IU/mL
5.83 log IU/mL
• Virological response = ‘non-responder’
Ms CM – 2010
• Assigned to placebo arm in main study; enters
open-label roll-over study: TPV + peg-IFN/RBV
• Virological outcomes
– Pre-treatment
– Week 4
– Week 12
– Week 24
– Week 48
– FU Week 24
6.16 log IU/mL
not detected
not detected
not detected
not detected
not detected
• Virological response = SVR = cure
REALIZE: SVR rates according to
treatment arm and prior response
88%*
P/R 48
83%*
T12/PR 48
80
T12/PR 48, Lead-in
SVR (%)
60
59%*
41%* 41%*
54%*
40
33%*
29%*
24%
15%
20
5%
9%
0
Relapser
Nonresponder
Partial
responder
Null
responder
N Engl J Med. 2011;364:2417-28.
17
HCV Genotype 1a vs 1b
• GT nucleotide sequences differ by 30-35%
• Subtypes differ by 20-25%
• Genotype 1a less susceptible to NS3 protease,
NS5B polymerase, NS5a inhibitors than 1b
– Pre-existing mutations more frequent in 1a than 1b
– 1a requires only one mutation; 1b requires two
(1a has lower genetic barrier to resistance)
– Higher rate of virological failure with genotype 1a
Kuntzen, et al. Hepatology 2008;48:1769. Gao, et al. Nature 2010;465:96.
REALIZE (telaprevir): SVR by HCV subtype
and prior response to peg-IFN/RBV
Prior
relapsers
Prior partial
responders
Prior null
responders
Pbo/PR 48
SVR (%)
Pooled T12/PR 48
n/N=
HCV subtype
10/34
119/142
1a
6/31
123/140
1b
3/16
26/55
1a
1/10
27/40
1b
1/17
24/88
1a
1/20
22/59
1b
Zeuzem S, et al. J Hepatol 2011;54(Suppl 1):S3.
19
REALIZE (telaprevir): SVR rates by IL28B genotype
and prior response to peg-IFN/RBV
Prior relapsers
Prior partial
responders
Prior null
responders
Pooled T12/PR48 (n=79)
Pooled T12/PR48 (n=134)
Pbo/PR48 (n=52)
Pbo/PR48 (n=20)
Pbo/PR48 (n=33)
SVR (%)
Pooled T12/PR48 (n=209)
n/a
CC
n/N=
4/12
51/58
CT
CC
TT
6/30 100/117 3/10
29/34
1/5
CT
5/8
2/10
33/57
CC
TT
0/5
10/14
CT
4/10
1/18
27/92
TT
1/15
10/32
Pol S, et al. J Hepatol 2011;54(Suppl 1):S6.
20
Response-guided therapy – Telaprevir
Non-cirrhotic treatment-experienced patients
• RGT for previous relapse
• Full 48 weeks for partial or null response
Response-guided therapy – Boceprevir
Non-cirrhotic treatment-experienced patients
• RGT for previous relapse and partial response
• Full 48 weeks for null responders
Mr AB
•
•
•
•
•
46-year-old man
Office manager
HCV diagnosed during insurance examination
HCV genotype 1b
Blood transfusion at birth (Rh- mother); ‘blood
brother’ ritual at age 8 years
Mr AB – 2000
•
•
•
•
•
•
Bilirubin
ALT
Albumin
Hb
Platelets
INR
17 µmol/L
254 U/L
43 g/L
177 g/L
252 x 109/L
1.0
Mr AB – 2000
• Standard IFN 3 MU tiw + RBV 1200 mg/day
(December 2000 – August 2001)
• Virological outcomes
– Pre-treatment
– Week 12
– Week 24
– Week 36
9.51 MEq/mL *
detected
detected
detected (ceases Rx)
• Virological response = ‘non-responder’
* Mega equivalents/mL; Chiron bDNA assay
Mr AB – 2003
• EPIC3 study* – peg-IFN 1.5µg/kg/wk + RBV
1200 mg/day x 12 wk
• If response  complete 48 wk, if not,
maintenance peg-IFN or observation
• Virological outcomes
– Pre-treatment
– Week 12
5.61 log IU/mL
4.88 log IU/mL
• Virological response = null responder
• Randomised to observation arm (36 months)
*Gastroenterology 2009;136(5):1618-28.
Mr AB
• Poor response to IFN-based regimens in
two prior treatment episodes
• Will IFN responsiveness have an impact on
DAA treatment?
Concept of lead-in phase
• Identify interferon-responsive patients
• Decrease risk of resistance to direct-acting agents
• Avoid costs and side-effects of direct-acting agents
4 weeks
RVR
PEG IFN + RBV
No
RVR
PEG IFN + RBV + direct acting agent
PEG IFN + RBV
SVR (%)
SVR by Week 4 PR lead-in response
0
12
15
46
PR 48
BOC RGT
15
44
BOC/PR 48
17
67
80
110
PR 48
90
114
BOC RGT BOC/PR 48
Poorly responsive to IFN
Responsive to IFN
<1 log10 viral load decline at treatment
week 4
≥1 log10 viral load decline at treatment
week 4
Predictive value of response to lead-in
in treatment-experienced patients
Mr AB
Liver biopsy:
• Feb 2003
• Dec 2006
• Dec 2008
Metavir F2
Metavir F3
Metavir F3
“moderate fatty change”
“at least incomplete cirrhosis”
• What is the significance of cirrhosis in DAA
treatment regimens?
REALIZE: SVR by baseline fibrosis stage and
previous response
Cirrhosis in combination with prior null response has low SVR
N Engl J Med 2011;364:2417-28.
Interim analysis of Compassionate Use of
Protease Inhibitors in Viral C Cirrhosis (CUPIC)
• National, multicentre, prospective, observational study of French
early-access program
• Inclusion criteria:
– Genotype 1 HCV with compensated cirrhosis (Child-Pugh A)
– Previous relapse or partial response to peg-IFN/RBV
• Patients with null response theoretically excluded (<2 log10
decrease in HCV RNA at Week 12), although some
mistakenly included
• Primary endpoint: SVR
Hezode C, et al. EASL 2012
Treatment regimen
Interim analysis
peg-IFN +
RBV
BOC + peg-IFN α-2b + RBV
Follow-up
BOC: 800 mg/8h; peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day
TVR + peg-IFN α-2a +
RBV
Follow-up
peg-IFN α-2a + RBV
TVR: 750 mg/8h; peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day
0
4
8
12
36
16
Weeks
72
48
SVR assessment
http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf
http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf
Telaprevir: Preliminary efficacy data
% of patients with undetectable HCV RNA
100
85
80
79
86
86
Per Protocol
ITT
78
71
60
53
51
40
20
145/276 145/285
145/285
224/265 224/282
219/254 219/281
177/205 177/251
Week 12
Week 16
0
Week 4
Week 8
% of patients with undetectable HCV RNA
Boceprevir: preliminary efficacy data
80
71
Per Protocol
ITT
61
60
40
37
37
55/149
55/150
58
61
20
1
0
2/155
1
2/155
Week 4
Week 8
88/144 88/151
Week 12
89/126 89/146
Week 16
Main findings
• Telaprevir- and boceprevir-based regimens: high rates of SAEs in real-world setting
• 6 deaths in telaprevir group: sepsis (n=2), pneumopathy (n=1), bleeding of
oesophageal varices (n=1), encephalopathy (n=1), and lung carcinoma (n=1)
• 2 deaths in boceprevir group: bronchopulmonary infection (n=1) and sepsis (n=1)
• SAE in 38% (BOC) and 49% (TPV) :
– High rates of discontinuation because of AEs (7% to 15%)
– Grade 3/4 anaemia common with both regimens and responds poorly to
erythropoietin
• Treat cirrhosis patients cautiously; carefully monitor because of a high incidence of
anaemia with poor response to EPO and risk of sepsis
Hezode C, et al. EASL 2012
Mr AB – 2008
•
•
•
•
•
•
Bilirubin
ALT
Albumin
Hb
Platelets
INR
17 µmol/L
232 U/L
38 g/L
180 g/L
184 x 109/L
1.1
Mr AB – 2008
• Enters REALIZE study: TPV 750 mg 8-hourly
or placebo + peg-IFN 180 µg/RBV 1200 mg
• Widespread rash
– Day 3: Mild (Rx promethazine)
– Week 4: Rash improving (promethazine, Kerri
Oil baths, betamethasone cream)
– Week 10: “Patchy discoid rash on legs”
– Week 12: “Macular rash both legs, lower back”
– Week 20: “Discoid erythematous areas of rash”
Adverse events associated with
NS3 protease inhibitors in clinical trials
Boceprevir1
Adverse Event (%)*
Boceprevir + alfa-2b/RBV
(n=1225)
Alfa-2b/RBV
(n=467)
Anaemia
50
30
Dysgeusia
35
16
*
Events occurring at ≥10% with boceprevir+alfa-2b vs alfa-2b/RBV alone in treatment-naïve patients
Telaprevir2
Adverse Event (%)†
Telaprevir + alfa-2a/RBV
(n=1797)
Alfa-2a/RBV
(n=493)
Rash
56
34
Pruritus
47
28
Nausea
39
28
Anaemia
36
17
†
Alfa=peg-IFN alfa
RBV=ribavirin
Events occurring at ≥10% with telaprevir+alfa-2a/RBV vs alfa/RBV alone in treatment-naïve and -experienced patients
1. Victrelis™ (boceprevir) US prescribing information. May 2011. 2. Incivek™ (telaprevir) US prescribing information. May 2011.
Mr AB – 2008
• Virological outcomes
– Pre-treatment
– Week 4
– Week 12
– Week 24
6.95 log IU/mL
<25 IU/mL
<25 IU/mL
2.33 log IU/mL (216 IU/mL)
What is happening?
– FU Week 4
– FU Week 24
6.17 log IU/mL
6.47 log IU/mL
Mr AB
• Converted a null response to peg-IFN/RBV
to a breakthrough response to triple
therapy
• Could antiviral resistance to telaprevir
contribute to his non-response?
Antiviral resistance
• Barriers to resistance
– Genetic: number of amino acid substitutions needed for mutant to
acquire full resistance
• 1 substitution = low barrier
• 3+ substitutions = high barrier
– In vivo fitness and drug exposure
• Low Barrier DAA
– First-generation protease inhibitors (telaprevir, boceprevir)
– NS5A inhibitors
– Non-nucleoside polymerase inhibitors
• High barrier DAA
– Nucleoside polymerase inhibitors
– Cyclophilin inhibitors
– ? Second-generation protease inhibitors
J-M Pawlotsky. J Hepatol 2012;56:11
REALIZE: TVR-resistant variants associated with
virologic failure in the TVR/placebo treatment phase
Genotype 1a
25
20
Number of patients
Number of patients
25
15
10
5
0
Genotype 1b
20
Lower-level
15
V36A/M
T54A/S
R155I/K/M/T
A156S
Combinations
Higher-level
V36M+R155K
A156T/V
Combinations
10
5
0
T12/PR 48
LI T12/PR 48
T12/PR 48
LI T12/PR 48
(n=136)
(n=149)
(n=126)
(n=113)
Not available
Wild-type (no TVR-resistant variants)
Analysis used population-based sequencing. On-treatment virologic failure: patients
who discontinued due to a virologic stopping rule and/or patients with viral
breakthrough
De Meyer, et al. J Hepatol 2011;54:S475
CONFIDENTIAL. FOR ADVISORY BOARD USE ONLY. Not for further distribution.
Viral kinetics in patients meeting the >1000 IU/mL HCV RNA Week 4
stopping rule with telaprevir
Treatment-naïve patients
107
107
106
106
105
104
103
105
104
103
102
102
10
10
0
2
4
6
Weeks
8
10
Treatment-experienced patients
108
HCV RNA (IU/mL)
HCV RNA (IU/mL)
108
12
0
2
4
6
8
10
Weeks
Jacobson I, et al. EASL 2012. Abstract 45
12
Futility rules – Boceprevir
• Treatment-naïve and treatment-experienced
Jacobson I, et al Hepatology 2012; Accepted Article, doi: 10.1002/hep.25865
Futility rules – Telaprevir
• Treatment-naïve and treatment-experienced
Mr AB – 2012
What can you offer this patient with:
• Cirrhosis and persistent ALT elevation?
• Null response to peg-IFN/RBV
• Breakthrough/partial response to TPV + pegIFN/RBV
• Re-treat with boceprevir?
• Refer for clinical trial?
Future treatment options for HCV
Alfa/Lambda + RBV
• Improved tolerability
• Favourable IL28B genotypes
TRIPLE: IFN/RBV + DAA
• Shortened duration
• Improved tolerability
Simple, all-oral,
pan-genotypic
regimens?
QUAD: IFN/RBV + 2 x DAAs
• Difficult-to-treat
• Null/non-responders
• Cirrhotics
DUAL: 1-2 x DAAs (±RBV)
•IFN ineligible/intolerant
•Genotype 1b, 2/3
Alfa, peg-IFN alfa; DAA, direct-acting antiviral; IFN, interferon; Lambda, peg-IFN lambda-1a; RBV, ribavirin
Modeling first-line DAAs vs Quad therapy for
null responders
• Treat F3/4 with DAA now vs quad therapy in 5 yrs
• Assumptions:
– SVR TPR 42% F3, 14% F4; Quad 90% SVR
– Quad rescue AFTER TPR –> PI resistance 80%: SVR reduced
by 70%
F3
F4
TPR
Wait
TPR
Wait
SVR
55%
78%
34%
60%
QALY
8.5
8.6
6.55
7.24
Ewan et al # 991 EASL 2012
Using DAAs in treatment-experienced patients
• Assess prior response, histology, subtype
– Relapsers likely to do well on either DAA, even if
cirrhotic
– Null or partial responders who are cirrhotic, G1a
are likely to do poorly
• SVR low, resistance high 1a >1b (-> need 2 DAAs)
• Risk of sepsis and SAE significant: Check CP score, MELD
• Consider trials using quad therapy
– Null or partial responders, non cirrhotic, G1b
• DAAs (SVR 40-55%), trials (new trials 80-90%) or wait