Boceprevir e Telaprevir nel
cirrotico e nel trapiantato
Bruno Cacopardo
Dipartimento di Biomedicina Clinica e Molecolare
Università di Catania
Paestum (Sa) 15- 16 -17 maggio
2014
Relatore
 May not need immediate
treatment
 BUT
• Easier to treat
• High likelihood of
response
Mild disease
 Greater need for treatment
 BUT
• Response to current IFNbased therapy may be
impaired
Cirrhosis
CAUTELA
GESTIONE DEL PAZIENTE CON CIRROSI (1)
1.
particolarmente complessa
a causa dei possibili effetti collaterali anche gravi (A1).
2. I pazienti con cirrosi epatica compensata costituiscono un gruppo di pazienti eterogeneo. Alcune
variabili clinico‐laboratoristiche (conta piastrinica <100.000/mmc e riduzione dei livelli di
albuminemia) possono essere utilizzate per identificare i pazienti con malattia piu avanzata e a
maggior rischio di sviluppare eventi avversi seri (B2).
3. Una fase iniziale di 4 settimane di duplice terapia con Peg‐IFN + RBV (inteso come test di
tollerabilita)
utile per identificare i soggetti con
ridotta tolleranza alla terapia Peg‐IFN + RBV e potenzialmente non in grado di sostenere la triplice
terapia (C1).
4. Il paziente cirrotico trattato con triplice terapia deve essere sottoposto a stretta sorveglianza clinica
per il pronto riconoscimento degli effetti collaterali e la loro tempestiva gestione (A1). Oltre agli
effetti collaterali tipici del trattamento con triplice (anemia, rash cutaneo, ecc.), particolare
attenzione va posta al rischio infettivo e a quello di scompenso funzionale della cirrosi (A1).
24 Aprile 2013
Outcome, %
Telaprevir
(N = 292)
Boceprevir
(N = 205)
Serious adverse event
45
33
Premature discontinuation
23
26
Hepatic decompensation
2
3
Death*
3
1
Infection (grade 3 or 4)
7
2
*Causes of death: septicemia, septic shock, pneumopathy (2), endocarditis, esophageal varices bleeding.

Why are the results different from phase III trials?
– Higher risk in cirrhotic patients?
– Study population healthier in phase III trials?
– Is the population truly compensated cirrhosis?
Hezode C, et al. AASLD 2012. Abstract 51.
 CUPIC enrolled treatment-experienced patients with compensated cirrhosis and
notable risk factors

Patients achieved high SVR rates with TVR or BOC plus pegIFN/RBV
 Patients with cirrhosis who present with significant risk factors require careful
monitoring when treated with pegIFN/RBV
Albumin
< 35 g/L
Albumin
≥ 35 g/L
Platelet Count
≤ 100,000/mm3
Platelet Count
> 100,000/mm3
37
31
Complications, n (%)
19 (51.4)
5 (16.1)
SVR12, n (%)
10 (25.0)
9 (29.0)
74
305
Complications, n (%)
9 (12.2)
19 (6.2)
SVR12, n (%)
27 (36.5)
168 (54.9)
N
N
Fontaine H, et al. AFEF 2013
Telaprevir
100
P < .001
81
Patients (%)
80
P < .001
60
< 65 yrs
≥ 65 yrs
Boceprevir
100
P = .088
80
68
60
53
48
40
P = .028
P ≤ .063
40
35
P = .032
21
20
12
10
0
22/
221
16/
78
26/ 27/
221 78
18
20
106/ 63/
221 78
Hezode C, et al. AASLD 2013. Abstract 1845.
7
0
8/
11/168 44
20
10
16/
168
9/
44
89/ 30/
168 44
Percentage of patients (%)
Colombo M et al AASLD 2013
Discontinuation for F3: n=3 (1%)
Discontinuation for F4: n=16 (5%)
Percentage of patients (%)
Colombo M et al AASLD 2013
Table TSFAE01b
Neutropenia
%
Anemia
%
Thrombocytopenia
%
PEG-IFNalfa + RBV
n. 28
22
32
28
BOC + PEG+ RBV
n.36
24
45*
46*
TEL + PEG + RBV
n.39
24
68*
52*
* P<0.01 vs PR
Suddle et al. Hep Int 2014

Patients randomized 2:1 to either placebo or eltrombopag + pegIFN alfa-2a (ENABLE-1) or
placebo or eltrombopag + pegIFN alfa-2b (ENABLE-2)

Higher platelet counts in eltrombopag arms vs placebo by Wk 2 of treatment,
enabling full dose of pegIFN to be maintained

ENABLE-1: 11,000/µL vs 79,000/µL
–
ENABLE-2: 124,000/µL vs 89,500/µL
100
Placebo
Eltrombopag
SVR (%)
80
60
40
P = .0064
P = .0202
23
14
20
n/N =
0
32/
232
13
103/
449
ENABLE-1
Afdhal NH, et al. Gastroenterology. 2014;146:442-452.
33/
252
19
96/
506
ENABLE-2
 Observational study of 1185 patients with GFR data at baseline
 Results emphasize that renal function must be assessed during treatment
Renal Impairment at Wk 12 in
Pts With Normal Renal
Function at Baseline (%)
100
Risk Factor for Renal
Insufficiency
P = .0188
80
60
P = .0753
40
20
0.9
(1/109)
4.7
(10/211)
6.6
(38/575)
BOC PR
TVR PR
0
PR
Mauss S, et al. EASL 2013. Abstract 872.
P Value
Age
< .001
Hypertension
< .001
Diabetes
< .05
Cirrhosis > 7 CP
< .05
Glomerular filtration rate assessed by MDRD after 12
weeks of therapy was significantly increased
(p<0.001) for both protease Inhibitors: cautious
clinical monitoring should focus also on renal
function
Virlogeux V et al J Vir Hep 2014
Saxena et al Aliment Pharmacol Ther 2014
EFFICACIA
F0-2
100
80
80
67
SVR (%)
SVR (%)
67
60
38
40
20
0
F3/4
100
60
52
38
40
41
20
n/
N=
123/
328
213/
319
211/
313
48 PR
BOC
RGT
BOC
48
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
0
n/
N=
9/
24
14/
34
22/
42
48 PR
BOC
RGT
BOC
48
ADVANCE1
Bridging fibrosis
or cirrhosis
18n/N=
No,
minimal
or portal
fibrosis
Bridging
fibrosis
or cirrhosis
SVR (%)
SVR (%)
No, minimal
or portal fibrosis
ILLUMINATE2
PR48
T12PR
PR48
T12PR
T12PR
ITT
T12PR
ITT
134/288
226/290
24/73
45/73
294/391
94/149
1. Jacobson IM, et al. N Engl J Med 2011;364:2405-16; 2. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A
REALIZE: TVR + PegIFN/RBV in GT1 Previous Relapsers and Nonresponders
Previous Relapsers
100
86
85
Previous Partial
Responders
SVR (%)
Pooled T12/PR48
Pbo/PR48
84
80
72
56
60
40
41
32
0
53/
62
2/
15
No,
Bridging
Minimal, or Fibrosis
Portal Fibrosis
48/
57
2/
15
Cirrhosis
20
18
13
13
144/ 12/
167 38
39
34
20
n/N =
Previous Null
Responders
34/
47
3/
17
10/
18
0/5
No,
Bridging
Minimal, or
Fibrosis
Portal Fibrosis
Stage
Zeuzem S, et al. EASL 2011. Abstract 5.
0
11/
32
1/
5
Cirrhosis
10
6
24/
59
1/
18
14
15/
38
0
0/9
No,
Bridging
Minimal, or Fibrosis
Portal Fibrosis
7/
50
1/
10
Cirrhosis
80
74
70
60
53
50
40
40
TEL. SVR12
38
BOC SVR12
30
19
20
10
0
0
Relapsers
Partial
Null
Hezode C et al. Gastroenterol 2014
F0-4
100
F4
83
F0-4
F4
F4
F3/4
84
80
69
SVR (%)
F3/4
53
Telaprevir
Boceprevir
74
60
F4
54
41
40
29
29
28
20
19
0
0
Relapsers
*Cross-comparison of studies cannot be carried out
Null Responders
1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Fontaine
H, et al. EASL 2013. Abstract 60. 4. Fontaine H, et al. AFEF 2013. Abstract 26. 5. Vierling JM, et al. DDW 2013. Abstract 869c.
Saxena et al Aliment Pharmacol Ther 2014
70
62
60
51
50
40
41
44
42
BOC
%
30
TEL
19
20
14 14
10
0
Naive
Null
Partial
Relapse
Backus et al Aliment Pharmacol Ther 2014
Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155
Everson et al. Hepatology 2013
Everson et al. Hepatology 2013
Berenguer M. J Hepatol 2008;49:274-87
120
100
80
%60
40
20
0
SVR 24
RBV dose red.
EPO
Eltrombopag
Kwo et al. Clin Transplant 2014
 Prospective multicenter cohort
study of 79 pts from 17 European
transplant centers
Active, chronic GT1 HCV
 HCV recurrence: ≥ F1 or
cholestatic hepatitis

 Pts treated with 1 of 3 regimens
(planned duration, 48 wks)
P/R lead-in for 4 wks, followed by
BOC 800 mg TID + P/R (n = 35)
 P/R lead-in for 4 wks, followed by
TVR 750 mg TID + P/R (n = 19)
 TVR 750 mg TID + P/R (n = 25)

Coilly A, et al. AASLD 2013. Abstract 216.
Characteristic
BOC + P/R
(n = 35)
TVR + P/R
(n = 44)
11.0 (4.5)
11.2 (6.8)
 ≥ F3
39
48
 F4
24
23
FCH, %
6
16
GT1b HCV, %
63
72
IL28B CC genotype, %
23
6
Mean HCV RNA, log10
IU/mL (SD)
6.69 (0.68)
6.54 (0.73)
 Naive
40
51
 Nonresponse
54
58
 Relapse
21
23
 Breakthrough
25
19
5.5 (6.0)
4.3 (4.0)
Mean MELD score (SD)
METAVIR stage, %
Previous P/R post-LT, %
Mean time from LT, yrs
(SD)


Virologic Outcomes

TVR + P/R
BOC + P/R
100
Patients (%)
Required transfusion: 49%
Required GCSF: 19%
SAEs, %
80
Rehospitalization
 Acute kidney injury
60
60
51
43
40
20
N=
0
RBV dose reduction + EPO: 94%
41
BOC + P/R
(n = 35)
TVR + P/R
(n = 44)
26
59
3
14
Biopsy-proven acute
17
rejection
 FCH only factor independently
Infections
33
9
21
Death
8
7
BOC + P/R
(n = 35)
TVR + P/R
(n = 44)
Tacrolimus
5.5
20.2
Cyclosporine
1.1
2.4
associated with infection (P = .04)
44 35
44 35
EOT
SVR12
Coilly A, et al. AASLD 2013. Abstract 216.
Reproduced with permission.
Fold Increase in CNI
at PI Completion
 Ongoing multicenter, single-arm study
Virologic Response Rates
 Median time since LT: 4.3 yr
 CTP ≤ 7 and MELD ≤ 17
 40% with cirrhosis
 52% severe adverse events (60%
anemia, 25% infections,15% rejection
Response (%)
75
75
75
54
60
45
30
15
0
Week 4
EOT*
SVR12
Charlton MR, et al. EASL 2014.
.
Twice-Daily Telaprevir in Combination with Peginterferon Alfa2a/Ribavirin in Genotype 1 HCV post-transplant patients :
Interim Week 12 Safety and Efficacy Results REFRESH STUDY
AEs are manageable when T/PR is used with TAC or CsA
• Anemia was more common than in non-liver transplant patients
•No moderate, severe, or serious rash reported
• No rejections, autoimmune hepatitis, or deaths have been reported to date
•Grade 2 or 3 creatinine toxicity was observed in 12/46 patients.
Brown KA et al AASLD 2013

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