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Clinical Cases Hepatitis C Naïve Patients
Rafael Esteban Liver Unit.
Hospital General Universitari Vall Hebron. Barcelona.
• 27 year old woman, • Diagnosed with Chronic Hepatitis C 3 years ago • Never treated • Risk factor: occasional IVDU 10 years ago • Weight: 65 kg • No comorbidity, no medications • Genotype 1b, HCV RNA 1.000.000 UI/mL
• Fibroscan: 8 KPa
Case study 1
Case study 1
• Asymptomatic
• She wants to clear the viral infection quickly before being pregnant, so she wants to start a treatment rapidly
• No contraindication for the treatment
Would you treat her?
• No, because she has no significant fibrosis
• Yes, because she is really motivated
Would you perform an IL28B genotyping in this patient ?
• Yes, because the IL28B polymorphism can
influence the treatment strategy • No
Impact of IL28B polymorphisms on SVR in naïve patients
RVS
(%)
PR48
50/64 n/N=
CC TT
BOC44/ PR48
44/55
CT
BOC RGT
63/77
PR48
33/116
BOC44/ PR48
82/115
BOC RGT
67/103
PR48
10/37
BOC RGT
23/42
78 82 80
28
65 71
27
55 59
0
20
40
60
80
100
BOC44/ PR48
26/44
RVS
(%)
PR48
35/55 n/N=
CC TT
T12PR
45/50
PR48
6/26
T12PR
16/22
PR48
20/80
T12PR
48/68
CT
64
90
25
71
23
73
0
20
40
60
80
100
Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542
RVS
(%)
PR48
50/64 n/N=
CC TT
BOC44/ PR48
44/55
CT
BOC RGT
63/77
PR48
33/116
BOC44/ PR48
82/115
BOC RGT
67/103
PR48
10/37
BOC RGT
23/42
78 82 80
28
65 71
27
55 59
0
20
40
60
80
100
BOC44/ PR48
26/44
RVS
(%)
PR48
35/55 n/N=
CC TT
T12PR
45/50
PR48
6/26
T12PR
16/22
PR48
20/80
T12PR
48/68
CT
64
90
25
71
23
73
0
20
40
60
80
100
Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542
≈89 % of CC patients treated with BOC/PR
were eligible for shorter therapy
Impact of IL28B polymorphisms on SVR in naïve patient
≈80 % of CC patients treated with TVR/PR
were eligible for shorter therapy
Case study 1
• IL28B genotyping: CC
Are you going to treat her?
• PegInterferon +Ribavirin
• PegInterferon +Ribavirin+Telaprevir
• PegInterferon+Ribavirinin + Boceprevir
SVR Rates by First Time to PCR Negativity in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx.
PEG-IFN α-2b 1.5 µg/kg QW + ribavirin 800-1400 mg/day
89%
25%17%
0%
20%
40%
60%
80%
100%
% o
f Pat
ient
s
4, (n=110) 12, (n=61) 24, (n=24)
85%93%
67%
0%
20%
40%
60%
80%
100%
% o
f Pat
ient
s4, (n=13) 12, (n=15) 24, (n=3)
1. S. Zeuzem et al., Journal of Hepatology 44 (2006) 97–103. 2. Manns M. et al., Lancet 2001; 358: 958–65.
24 Weeks Tx.1, N=235 48 Weeks Historical Control2, N=38
47% HCV RNA PCR Negative (<29IU/mL at Week 4.
Standard of Care for Genotype 1 Treatment-Naive Patients
BOC + PegIFN + RBV
48 0 28 12 4
PegIFN + RBV PegIFN + RBV
8 36
BOC + PegIFN + RBV
24
Early response*; stop at Wk 28; f/u 24 wks
F/u 24 wks
Boceprevir[1,2]
TVR + PegIFN + RBV
48 0 24 12 4
eRVR†; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u
24 wks
Telaprevir[2,3]
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.
*Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy). †Undetectable HCV RNA at Wks 4 and 12 of triple therapy.
No eRVR; PegIFN + RBV
Case study 1
• IL28B genotyping: CC • Day 1: start of antiviral therapy
– Peginterferon α-2a 180 ug/week – Ribavirin: 400 mg BID – Telaprevir 750 mg every 8 hours
• Week 4:
– Side effect: fatigue Hb decline to 11 g/dl – Bad Tolerance to High fat- food every 8 h – HCV RNA undetectable
72,8 74,3
0
20
40
60
80
100
OPTIMIZE: Efficacy of Telaprevir BID vs
Telaprevir q8h in GT1 HCV Infection Primary endpoint: SVR12
SVR1
2 (%
)
270/371 274/369
T12(q8h)/PR T12(bid)/PR
T12(bid)/PR was non-inferior to T12(q8h)/PR for SVR12 Difference (95% CI): 1.5% (–4.9%, 12%)
Buti M, et al. AASLD 2012. Abstract LB-8.
Case study 1
• Week 4 – Therapy adjusted – Peginterferon α-2a 180 ug/week – Ribavirin: 400 mg BID – Telaprevir bid
• Week 8
– Better tolerance and compliance – Minimal Rash in arms
Case study 1
• Week 10 – Rash increases arms and thorax (Moderate rash-
Grade 2) – HCV-RNA undetectable
Management of mild rash: which antihistamine?
OK to use with HCV PIs
Chlorpheniramine
Desloratidine
Levocetirizine
Promethazine
http://www.hep-druginteractions.org
In this patient, desloratidine was initiated
Case study 1
• Week 10 – Rash increased arms and thorax (Moderate rash-
Grade 2) – Topic steroids and desloratidine was initiated – Anemia stable – HCV-RNA undetectable
• Week 11
– No improvement in rash – Telaprevir was stopped
Drug considerations: mild and moderate rash
Treating patients with mild or moderate rash Use topical corticosteroids* Permitted systemic antihistaminic drugs may be tried for the treatment of associated
pruritus Limit exposure to sun/heat and wear loose-fitting clothes
Rash
Mild
Moderate
Telaprevir discontinuation is generally NOT required
Telaprevir discontinuation is generally NOT required
For moderate rash that progresses, permanent discontinuation (do not dose-reduce) of telaprevir should be considered
If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted.
Peginterferon alfa may be continued unless interruption is medically indicated
*Concomitant use of systemic dexamethasone with telaprevir may result in loss of therapeutic effect of telaprevir. This combination should be used with caution or alternatives should be considered Telaprevir EU SmPC
Case study 1 • Week 10
– Rash increased arms and thorax (Moderate rash-Grade 2) – Topic steroids and desloratidine was initiated – Anemia stable – HCV-RNA undetectable
• Week 11
– No improvement in rash – Telaprevir was stopped
• Week 12
– No Changes in rash – All the drugs were stopped – HCV RNA undetectable
What are the chances to get an SVR?
• 40%
• 60%
• > 90%
20
PROVE2 (telaprevir): study design
T12P12 (n=78) (no RBV)
PR48 (n=82)
T12PR12 (n=82)
0 Weeks
24 48 12 36
TVR + Peg-IFN
Peg-IFN + RBV Placebo
+ Peg-IFN + RBV
TVR + Peg-IFN +
RBV
Peg-IFN + RBV
TVR + Peg-IFN
+ RBV
T12PR24 (n=81)
Hézode C, et al. N Engl J Med 2009;360:1839–50
• Phase IIb, randomized, placebo-controlled, partially double-blind trial in 323 treatment-naïve patients with chronic HCV genotype 1 infection
PR: peginterferon/ribavirin; Peg-IFN: peginterferon alfa-2a; RBV: ribavirin; TVR: telaprevir; HCV: hepatitis C virus
46 36
60 69
PROVE2 (telaprevir): overall SVR Rates
PR48 T12P12 (no RBV)
T12PR12 T12PR24
100
80
60
40
20
0
Hézode C, et al. N Engl J Med 2009;360:1839–50
38/82 28/78 49/82 56/81
Patie
nts w
ith S
VR (%
)
SVR: sustained virologic response
SVR according to the treatment and IL28B genotype (telaprevir PROVE2 post-hoc analysis)
100 94
75 64
44
67
18
31 20
33 25
0
20
40
60
80
100
T12PR12 T12PR24 T12P12 PR48
CC CT TT
12 12
12 27
1 5
12 18
15 16
1 3
3 4
4 22
0 3
7 11
5 16
1 4
Prop
ortio
n of
pat
ient
s (%
)
Bronowicki J-P, et al. J Hepatol 2012;56 (Suppl 2):S430–1
Case study 1
• Follow-up 24-week • HCV RNA: undetectable.
24
Summary
• Naïve patients infected with HCV genotype 1 Easy to treat patients • IL28B CC, • Caucasian/White • Non-cirrhotic
• Can be cure with 12 weeks of triple combination
treatment with telaprevir, peginterferon, and ribavirin
Case Study 2
• 54 year old man, lawyer
• IVDU sporadically 20 years ago
• Chronic Hepatitis C diagnosed 6 years ago
• HCV genotype 1 b,
• F3
• Friends with HCV treated and non responders
• He was afraid about his disease
• He would like to be treated with DAAs but he was also afraid
about therapy!!!!!!
26
Case study 2
• He started – Peginterferon α-2b 1.5 ug/kg/week – Ribavirin: 600 mg BID
• Week 4:
– Side effect: fatigue – Viral load: 4.2 log10 (vs 6.1 log10 at D1)
Lead-in Predicts SVR
28
SVR
(%)
187 228
121 234
178 218
BOC RGT BOC/PR48 PR48
21 73
3 62
31 79
16 24
12 26
22 36
BOC RGT BOC/PR48 PR48
6 24
0 21
5 16
Non-Black Patients Black Patients
≥1 log 10 HCV RNA decline from baseline <1 log 10 HCV RNA decline from baseline
Poordad F. N Engl J Med. 2011; 364:1195-1206.
Case study 2
• Started boceprevir 800 mg/8h at Week 4.
• Week 8. – Side effects: ↑ fatigue, dysgeusia, no rash. – Hb: 10.5 g/dL (vs 13 g/dL at Day 1). – HCV RNA: undetectable.
29
SVR for Early and Late Viral Responders With Boceprevir
30
ADVANCE
Poordad F. N Engl J Med. 2011; 364:1195-1206.
Undetectable HCV RNA at Week 8
Detectable HCV RNA at Week 8
SVR
(%)
51 60
184 208
184 204
46 129
52 131
81 271
SVR for Early and Late Viral Responders With Boceprevir
31
ADVANCE
Poordad F. N Engl J Med. 2011; 364:1195-1206.
Undetectable HCV RNA at Week 8
Detectable HCV RNA at Week 8
SVR
(%)
51 60
184 208
184 204
46 129
52 131
81 271
61 % 18 %
Case study 2
• Week 12. – Side effects: fatigue. – Hb: 9 g/dL. – HCV RNA undetectable.
• How to manage anemia?
32
SPRINT-2
PR48 BOC/PR48
SVR
(%)
Hgb ≥10 g/dL
Hgb <10 g/dL
Hgb ≥10 g/dL
Hgb <10 g/dL
RESPOND-2
SVR
(%)
Hgb ≥10 g/dL
Hgb <10 g/dL
Hgb ≥10 g/dL
Hgb <10 g/dL
Sulkowski M et al , EASL 2011
20
50
25
76
0
20
40
60
80
100
31
58 56
73
0
20
40
60
80
100
77 246
60 108
212 263
263 363
12 60
83 165
5 20
119 157
Impact of Anemia on SVR
n/N = n/N =
Efficacy endpoints: EPO vs RBV dose reduction for managing anemia with boceprevir
*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort CI: confidence interval; EOT: end of treatment
Patie
nts (
%)
Δ (95% CI) –0.7% (–8.6, 7.2)*
178/249 178/251
Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559
RBV DR EPO • Secondary anemia management intervention was used in 18% of RBV DR patients
and in 37% of EPO patients
Case study 2
• Week 12. – Side effects: fatigue. – Hb: 9 g/dL. – HCV RNA undetectable – Ribavirin was reduced to 800 mg/gay
• What are the chances to achieve an SVR?
35
Higher SVR Rates if Undetectable HCV RNA Levels at Start Time of Primary Anemia
Management
Case Report 2
• Week 24. – Side effects: fatigue.
– HCV RNA: undetectable.
– What will be the duration of therapy?
37
Triple therapy with Boceprevir for Genotype 1 Treatment-Naive Patients
BOC + PegIFN + RBV
48 0 28 12 4
PegIFN + RBV
PegIFN + RBV
8 36
BOC + PegIFN + RBV
24
Early response*; stop at Wk 28; f/u 24 wks
F/u 24 wks
Boceprevir[1,2]
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
SVR in Non-Black Patients with Undetectable HCV RNA Between Weeks 8-24
Column2
97 96
50
55
60
65
70
75
80
85
90
95
100
BOC RGT BOC/PR48
143 147
137 142
SVR
(%)
Case study 1
• Treatment stopped at Week 28.
• Follow-up 12-week and 24-week visits: HCV RNA: <25 IU undetectable.
40
Summary
• Anaemia is the main effect of Triple therapy with Boceprevir, peginterferon, and ribavirin
• Anaemia is associated with a higher SVR rates
• Anaemia can be managed by Ribavirin dose reduction without impacting SVR rates
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