Transcript Diapositiva 1
I SESSIONE
Moderatori: M. Colombo, G. Rizzardini
Malattia Virus C-correlata: l’inizio di una nuova era
•
Obiettivi e strategie di un futuro IFN-free
A. Mangia
•
Ottimizzare la gestione clinica della monoinfezione HCV oggi
S. Bruno
25 giugno 2014 Milano
Ottimizzare la gestione clinica della monoinfezione HCV oggi
SAVINO BRUNO, MD
Director
Internal Medicine and Hepatology Unit AO Fatebenefratelli e Oftalmico, Milano
Market whereTelaprevir has Non yet launched
2014 Treatment Options
Right drug - Right patient
HCV-related disease: a condition with a wide heterogeneity of clinical features
MILD TO MODERATE FIBROSIS stage
F1-2 Metavir, F1 to 3 Ishak, LSM: ≥ 6 KPa < 9.5 Kpa (possible overlap with either less or more severe stage), APRI: < 0.5 (possible overlap)
ADVANCED FIBROSIS stage
(F3 Metavir, F3 to 4 Ishak, LSM: ≥ 9.5 KPa < 12.5 Kpa (possible overlap wth either less or more severe stage), APRI: >0.5 <1.5 (possible overlap)
WELL COMPENSATED cirrhosis (early stage: 1)
F4 Metavir, F5 to 6 Ishak) or LSM: ≥ 12.5 KPa
#
, usually no clinically significant portal hypertension*: HVPG ≥ 6, mmHg < 10 mmHg, no esophageal varices, Child A5, MELD < 10.
MARGINALLY COMPENSATED (more severe stage: 2)
F4 Metavir, F5 to 6 Ishak or LSM: ≥ 12.5 KPa
#
, with moderate to severe portal hypertension § : HVPG ≥ 10/12 mmHg, ± esophageal varices , PLT ≤ 100000 /mm 3 , low albumin value, Child A5, A6 rarely B7, MELD ≥ 10,
in Child A5 severe portal hypertension with still preserved liver function may co-exist
DECOMPENSATED,
Child B7 or more, MELD >15 and/or waiting for OLT for ESLD
# *Garcia Tsao G. et al, Hepatology 2010
§
Castera L. Gastroenterology 2012 Qamar A. et al, Hepatology 2008 Boccaccio V, Bruno S. Liver International 2014 updated
2014 Treatment Options: Right drug - Right patient
Key Factors in Deciding to Treat or Wait
Patient factors
Urgency to treat
Likelihood of response
HCV genotype
Treatment experience
Degree of fibrosis
Patient motivation
Treatment factors
Efficacy of current options
Safety of current options
Duration of therapy
Pill burden, dosing frequency
Future options and their timelines
Affordability
Degree of liver fibrosis at baseline as a predictive factor affecting SVR with TVR-based triple therapy in treatment naïve patients* 100 80 60 80 78,8 40 20
n=630 n=580
0 F0 –1 F2
*Pooled analysis of TVR phase 3 trials in treatment naïve patients: ADVANCE, ILLUMINATE and OPTIMIZE
P
<0.0001, comparing F0 –2 vs F3–4;
P
<0.0001, chi-square for trend
68,4 53,5
n=247
F3
n=185
F4
Zeuzem S, et al. AASLD 2013: Abstract 1908
SVR according to fibrosis score and historical response in F0-F2 patients in REALIZE study
100 90 80 70 60 50 40 30 20 10 0 Relapsers 86 32 144/167 10/38 Partial responders Null responders 72 18 34/47 3/17 41 6 24/59 1/18
Zeuzem S, et al. J Hepatol 2011
SVR12 by TVR dose and fibrosis stage or cirrhosis status (OPTIMIZE) T12(bid)/PR T12(q8h)/PR All patients 100 80 60 40 20 0 80 79 80
213/ 267 208/ 262 421/ 529
213/ 267 F0 208/ –F2 421/ 529 60 57 59
61/ 102 62/ 108 123/ 210
61/ 102 62/ F3/F4 123/ 210 78 77 77 54 49 51
245/ 315 246/ 321 491/ 636
245/ 246/ 491/ No cirrhosis
29/ 54 24/ 49 53/ 103
29/ 54 24/ 53/ Cirrhosis
One patient did not have a baseline fibrosis assessment and was excluded from this analysis Horsmans Y, et al. EASL 2013. Abstract 826
CONCISE trial design (N=239)
IL28B CC non F4:
Naïves
Relapsers TVR (1125 mg bid) + PR RVR+ Follow-up PR Weeks 0 4 12 Randomisation 2:1 in patients with RVR who continued all study drugs through Week 12 24
Patients without RVR or not completing 12 weeks of TVR/PR were assigned to 24 or 48 weeks of PR depending on virologic response; RVR: Week 4 HCV RNA <25 IU/mL, target not detected PR: Peg-IFN alfa 2a (180 µg/week) and RBV (1000–1200 mg/day) Nelson DR, et al. HepDart 2013. Abstract 118
CONCISE: SVR24 in non-cirrhotic IL28B CC treatment naïve patients and relapsers achieving eRVR
91/106 T12/PR12 48/52 T12/PR24
Nelson DR, et al. HepDart 2013. Abstract 118
Boceprevir in treatment-naïve non-cirrhotic patients
Boceprevir in treatment-experienced non cirrhotic patients
14
SVR according to treatment week 8 virologic response* in F0-F2
100 90 80 70 60 50 40 30 20 10 0 86 54 6
5/78
F0-F2
*Treatment-naïve and previous treatment failures combined
Undetectable ≥3 log10 decline and detectable <3 log10 decline and detectable
Data on file
SVRs at a cutoff of 1,000 IU/mL at TW8 in the meta-analysis of 5 clinical studies
Fibrosis Score*
F0/F1
F2
F3/F4 F0-F4
SVR [n/m (%)] TW8 <1000 IU/ml TW8 ≥1000 IU/ml
869/1119 (78) 8/90 (9)
206/285 (72)
150/238 (63) 1264/1702 (74)
*Subjects in BOC arms from 5 clinical studies
5/41 (12)
0/31 (0) 13/177 (7)
Data on file
NEUTRINO: SVR12 by Sofosbuvir + P/R (12 weeks) According to Genotype and Fibrosis Level
100 80
89
60 40 20 0 n/N =
261/292 GT 1 SVR12 According to Genotype 96 27/28 GT 4 100 7/7 GT 5,6
100 80
SVR12 According to Fibrosis Level p=0.0096
92 80
60 40 20 0
252/273 43/54 No Cirrhosis Cirrhosis
Lawitz E, et al. NEJM 2013
Virologic Response Rates to Sofosbuvir-Containing Regimens Are Similar in Patients With and Without Traditional Negative Predictive Factors: A Retrospective Analysis of Phase 3 Data
In this large cohort of patients participating in SOF-containing Phase 3 studies with or without PEG-IFN and across genotypes 1-6,
traditional negative predictive factors did not have a consistent influence on response rates with the exception of cirrhosis and sex
.
Mangia A, et al. AASLD 2013
QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance
100
82
SMV + P/R P/R 100
90
80 80
71
60
53 58
60
49 52
40 20 0
29
40 20 n/N = 188/229 60/113 18/31 5/17 105/147 36/74 105/117 29/56 0
No Cirrhosis Cirrhosis GT 1a GT 1b Differences in SVR12 by Subgroup (95% CIs)
GT 1a/other HCV - With baseline Q80K vs Pbo
SMV (n) Pbo (n)
28.2 (13.4-42.9) 4.7 (-14.6 to 24.1) 147 60 74 74 - Without baseline Q80K vs Pbo GT 1b HCV 40.3 (25.8-54.8) 42.1 (26.5-57.6) 86 117 74 56 -100 -50
Favors Placebo
0 50
Favors SMV
100
Jacobson I, et al. EASL 2013
Simeprevir plus PegIFN and Ribavirin in treatment-experienced F0 F2 patients with HCV Genotype-1 infection (the ASPIRE trial) Partial responders Null responders
100 90 80 70 60 50 40 30 20 10 0 N=
56
16
Relapsers 92
48
95
52
8
12
76
38
79
48
23
13
53
30
66
29
Placebo+PR SMV 100 mg+PR* SMV 150 mg+PR* *duration groups pooled
Zeuzem S, et al. Gastroenterology 2013
Degree of liver fibrosis at baseline as a predictive factor affecting SVR with TVR-based triple therapy in treatment naïve patients* 100 80 60 80 78,8 40 20
n=630 n=580
0 F0 –1 F2
*Pooled analysis of TVR phase 3 trials in treatment naïve patients: ADVANCE, ILLUMINATE and OPTIMIZE
P
<0.0001, comparing F0 –2 vs F3–4;
P
<0.0001, chi-square for trend
68,4 53,5
n=247
F3
n=185
F4
Zeuzem S, et al. AASLD 2013: Abstract 1908
SVR according to fibrosis score and historical response in HCV G1 F3 patients in REALIZE study 100 90 80 70 60 50 40 30 20 10 0 Relapsers 85 13 53/62 2/15 Partial responders Null responders 55 10/18 0 0/5 39 15/38 0 0/9
Zeuzem S, et al. J Hepatol 2011
INTERNATIONAL EAP TELAPREVIR
Colombo M, et al J Hepatol 2014 in press
Colombo M, et al J Hepatol 2014 in press
100 80 60 40 20 0
Overall SVR by F3
54 26 58/107 F3 BOC PR 6/22 PR
Vierling JM, Bruno S, et al. J Hepatol, 2014
SVR according to treatment week 8 virologic response in F3 patients
*
90 80 70 60 50 40 30 20 10 0 85
40/47
34
16/47 F3
0
0/5 *Treatment naïve and previous treatment failures combined Undetectable ≥3 log HCV-RNA decline and detectable <3 log HCV-RNA decline and detectable
Vierling JM, Bruno S, et al. J Hepatol, 2014
The importance of TW 8 HCV-RNA decline in patients with advanced fibrosis/cirrhosis F3 and F4 pooled) during BOC-therapy
HCV-RNA detectable at wk 8 ≤ 1000 U.I.
> 1000 U.I
88% 12% SVR 63 % 150/238 P<0.0001
SVR 0 0/31
Vierling JM, Bruno S, et al. J Hepatol 2014
Patients characteristics*
Baseline characteristics of 416 patients at study entry
All patients N (col %) 416 No 35 Received Boceprevir Yes (row %) 381 (91.6) Total patients Sex
Men Women
Age
<50 years 50-59 years ≥60 years
Metavir F3
F4
CHILD class
A5 A6
Varices
No Yes
Fibroscan
<12.5 kPa ≥12.5 kPa
Albumin
Low (≤3.5 g/dL) >3.5 g/dL
Platelets
Low (≤100,000/μL) >100,000/μL
Genotype
1b 1a
Previous response
Relapser Partial responder Null responder
IL28
CC CT TT * some information are missing for few patients 291 (70.0) 125 (30.0) 116 (28.4) 151 (37.0) 141 (34.6)
127 (30.5)
289 (69.5) 240 (85.4) 41 (14.6) 209 (74.9) 70 (25.1) 131 (36.9) 224 (63.1) 34 ( 8.7) 357 (91.3) 55 (13.2) 361 (86.8) 323 (77.6) 93 (22.4) 145 (35.0) 96 (23.2) 173 (41.8) 28 (10.5) 173 (64.5) 67 (25.0) 21 14 13 7 14 29 20 8 25 5 8 23 6 28 10 25 27 8 8 7 20 2 9 6
6
270 (92.8) 111 (88.8) 103 (88.8) 144 (95.4) 127 (90.1)
121 (95.3)
260 (90.0) 220 (91.7) 33 (80.5) 184 (88.0) 65 (92.9) 123 (93.9) 201 (89.7) 28 (82.4) 329 (92.2) 45 (81.8) 336 (93.1) 296 (91.6) 85 (91.4) 137 (94.5) 89 (92.7) 153 (88.4) 26 (92.9) 164 (94.8) 61 (91.0)
P-value
0.18
0.10
0.08
0.04
0.37
0.24
0.10
0.02
1.00
0.15
0.51
Bruno S, et al. submitted
80 30 20 10 0 70 60 50 40 EoTR, SVR12 and relapse rate overall and in F3 patients All patients who received at least one dose of BOC included Overall F3 62% 65% 237/381 79/121 EoTR 49% 58% 188/381 70/121 SVR12 20% 49/237 11% 9/79 Relapse
Bruno S, et al. submitted
30 20 10 0 70 60 50 40 SVR12 overall and according to prior response in F3 patients All patients who received at least one dose of BOC included 61,3% 61,7% Overall F3 61,3% 50,6% 50% 84/137 29/47
Relapser
45/89 19/31
Partial responder
37,9% 58/153 21/42
Null responder
Bruno S, et al. submitted
SVR12 in F3 according to treatment week 8 virologic response All patients who received at least one dose of BOC included 90 80 70 60 50 40 30 20 10 0 HCV-RNA Undetectable HCV-RNA Detectable 80,0% 39,7% 20,0% 60,3% 44 55 23 58 11 55 35 58 SVR No SVR
PPV=80,0% NPV=60.3%
100 90 80 70 60 50 40 30 20 10 0 HCV-RNA < 1000 UI/mL 67% 67 98 0% SVR HCV-RNA > 1000 UI/mL 33% 33 98 100% 13 13 No SVR
PPV=67% NPV=100%
Bruno S, et al. submitted
ITT SVR12 and NNT dose according to at-entry characteristics, historical response and HCV-RNA value at treatment week 8 in F3 patients All patients who received at least one BOC included
Variable
All Italy Spain TW8 Undetectable TW8 <1000 IU/mL TW8 ≥1000 IU/mL Prior relapser Prior partial Prior null Fibroscan <12.5 kPa Fibroscan ≥12.5 kPa Albumin >3.5 g/dL Albumin ≤3.5 g/dL PLT >100,000 /μL PLT ≤100,000 /μL
Total Patients SVR (%)
381 188 (49.3) 267 128 (47.9) 114 60 (52.6) 159 115 (72.3) 143 56 (39.2) 48 4 ( 8.3) 137 84 (61.3) 89 45 (50.6) 153 58 (37.9) 123 71 (57.7) 201 91 (45.3) 329 168 (51.1) 28 5 (17.9) 336 177 (52.7) 45 11 (24.4)
NNT
2.0
2.1
1.9
1.4
2.6
12.0
1.6
2.0
2.6
1.7
2.2
2.0
5.6
1.9
4.1
None of the 7 patients with both low albumin and low platelet counts had SVR
METAVIR F3 Patients SVR (%) NNT
121 70 (57.9) 100 57 (57.0) 1.7
1.8
21 13 (61.9) 55 44 (80.0) 43 22 (51.2) 15 1 ( 6.7) 47 29 (61.7) 31 19 (61.3) 42 21 (50.0) 1.6
1.3
2.0
15.0
1.6
1.6
2.0
1.6
107 65 (60.7) 99 56 (56.6) 1.8
121 70 (57.9) 1.7
Bruno S, et al. submitted
Simeprevir plus PegIFN and Ribavirin in treatment-experienced F3 patients with HCV Genotype-1 infection (the ASPIRE trial)
100 90 80 70 60 50 40 30 20 10 0 N= 4
0
Relapsers
79
19
55
11 Partial responders
13
8
50
16
50
10 Null responders
0
1
22
9
38
8 Placebo+PR SMV 100 mg+PR* SMV 150 mg+PR* *duration groups pooled
Zeuzem S, et al. Gastroenterology 2013
Degree of liver fibrosis at baseline as a predictive factor affecting SVR with TVR-based triple therapy in treatment naïve patients* 100 80 60 80 78,8 40 20
n=630 n=580
0 F0 –1 F2
*Pooled analysis of TVR phase 3 trials in treatment naïve patients: ADVANCE, ILLUMINATE and OPTIMIZE
P
<0.0001, comparing F0 –2 vs F3–4;
P
<0.0001, chi-square for trend
68,4 53,5
n=247
F3
n=185
F4
Zeuzem S, et al. AASLD 2013: Abstract 1908
SVR according to fibrosis score in F4 patients in REALIZE study
100 90 80 30 20 10 0 70 60 50 40 Relapsers 84 13
48/57 2/15
Partial responders 34 20
11/32 1/5
Null responders 14
7/50
10
1/10
Zeuzem S, et al. J Hepatol 2011
Colombo M, et al J Hepatol 2014 in press
Colombo M, et al J Hepatol 2014 in press
Colombo M, et al J Hepatol 2014 in press
100 80 60 40 20 0
Overall SVR by F4
55 99/180 F4 BOC PR 17 6/32 PR
Vierling JM, Bruno S, et al. J Hepatol, 2014
100 90 80 70 60 50 40 30 20 10 0
SVR according to treatment week 8 virologic response* in F4
40/47
89 35
65/73 28/79 0 0/17 Undetectable ≥3 log HCV-RNA decline and detectable <3 log HCV-RNA decline and detectable *Treatment naïve and previous treatment failures combined
Vierling JM, Bruno S, et al. J Hepatol 2014
The importance of TW 8 HCV-RNA decline in patients with advanced fibrosis/cirrhosis F3 and F4 pooled) during BOC-therapy
HCV-RNA detectable at wk 8 ≤ 1000 U.I.
> 1000 U.I
88% 12% SVR 63 % 150/238 P<0.0001
SVR 0 0/31
Vierling JM, Bruno S, et al. J Hepatol 2014
Patients characteristics*
Baseline characteristics of 416 patients at study entry
All patients N (col %) 416 No 35 Received Boceprevir Yes (row %) 381 (91.6) Total patients Sex
Men Women
Age
<50 years 50-59 years ≥60 years
Metavir
F3
F4 CHILD class
A5
A6 Varices
No
Yes Fibroscan
<12.5 kPa ≥12.5 kPa
Albumin Low (≤3.5 g/dL)
>3.5 g/dL
Platelets Low (≤100,000/μL)
>100,000/μL
Genotype
1b 1a
Previous response
Relapser Partial responder Null responder
IL28
CC CT TT * some information are missing for few patients 291 (70.0) 125 (30.0) 116 (28.4) 151 (37.0) 141 (34.6) 127 (30.5)
289 (69.5)
240 (85.4)
41 (14.6)
209 (74.9)
70 (25.1)
131 (36.9) 224 (63.1)
34 ( 8.7)
357 (91.3)
55 (13.2)
361 (86.8) 323 (77.6) 93 (22.4) 145 (35.0) 96 (23.2) 173 (41.8) 28 (10.5) 173 (64.5) 67 (25.0) 21 14 13 7 14 6
29
20 8 25 5 8 23 6 28 10 25 27 8 8 7 20 2 9 6 270 (92.8) 111 (88.8) 103 (88.8) 144 (95.4) 127 (90.1) 121 (95.3)
260 (90.0)
220 (91.7) 33 (80.5) 184 (88.0) 65 (92.9) 123 (93.9) 201 (89.7) 28 (82.4) 329 (92.2) 45 (81.8) 336 (93.1) 296 (91.6) 85 (91.4) 137 (94.5) 89 (92.7) 153 (88.4) 26 (92.9) 164 (94.8) 61 (91.0)
P-value
0.18
0.10
0.08
0.04
0.37
0.24
0.10
0.02
1.00
0.15
0.51
Bruno S, et al. submitted
80 30 20 10 0 70 60 50 40 EoTR, SVR12 and relapse rate overall and in cirrhotic patients All patients who received at least one dose of BOC included Overall F4 62% 65% 237/381 158/260 EoTR 49% 58% 188/381 118/260 SVR12 20% 11% 49/237 40/158 Relapse
Bruno S, et al. submitted
30 20 10 0 70 60 50 40 SVR12 overall and according to prior response in cirrhotic patients All patients who received at least one dose of BOC included Overall F4 61,3% 61,1% 84/137 55/90
Relapser
50,6% 44,8% 45/89 26/58
Partial responder
37,9% 33.3% 58/153 37/111
Null responder
Bruno S, et al. submitted
SVR12 in F4 according to treatment week 8 virologic response All patients who received at least one dose of BOC included 80 70 60 50 40 30 20 10 0 HCV-RNA Undetectable HCV-RNA Detectable 71,9% 68,3% 28,1% 71 104 38 135 SVR 31,7% 33 104 97 135 No SVR
PPV=68,3% - NPV=71,9%
100 90 80 70 60 50 40 30 20 10 0 HCV-RNA < 1000 UI/mL 51,7% 106 204 9,1% 3 33 SVR HCV-RNA > 1000 UI/mL 48,3% 99 204 90,9% 30 33 No SVR
PPV=51,7%-NPV=90,9%
Bruno S, et al. submitted
Univariate and Multivariate analysis for SVR12 in cirrhotic patients
Variable
TW8 <1000 IU/mL TW8 ≥1000 ≥3 log decline TW8 ≥1000 <3 log decline TW4 <1 log decline Male Age ≥60 years Child A6 Fibroscan (≥12.5 kPa) Fibroscan (continuous) Varices HCV genotype 1b Prior null Prior partial Albumin ≤3.5 g/dL PLT ≤100,000 /μL Baseline viral load >800,000
Reference
Undetectable Undetectable Undetectable ≥1 log decline Female <60 years Child A5 <12.5 kPa Per 1 kPa F4 - No varices 1a Prior relapser Prior relapser >3.5 g/dL >100,000 /μL ≤800,000
METAVIR-F4 Univariate RR (95% CI) 4.06 (2.27-7.26) 34.4 (4.38-270.) 15.1 (3.24-70.1) 3.77 (1.91-7.42)
0.57 (0.33-1.00) 1.23 (0.71-1.48)
3.55 (1.48-8.52)
0.73 (0.25-2.07) 1.04 (1.00-1.07) 1.03 (0.57-1.86) 0.85 (0.48-1.53)
3.14 (1.76-5.61)
1.93 (0.99-3.78) 4.37 (1.60-11.9)
3.06 (1.48-6.36)
1.00 (0.58-1.71)
Multivariate* RR (95% CI) 4.49 (2.32-8.71)
TW8 >1000 -
21.4 (5.11-89.4) 2.75 (1.23-6.14)
1.07 (1.02-1.11) Prior null/partial 2.86 (1.50-5.48)
6.37 (1.96-20.7) 4.05 (1.65-9.90)
-
p-value <0.0001
<0.0001
0.01
0.003
0.001
0.002
0.002
* Only variables for which the association remained statistically significant were included in the final multivariable logistic regression model (Backwise variables selection)
Bruno S, et al. submitted
Predictors of treatment failure among 159 patients with undetectable HCV-RNA at treatment week 8 or of treatment success among 222 patients with detectable HCV-RNA at treatment week 8*
Patients characteristics SVR Undetectable HCV RNA at TW8 No SVR P-value Detectable HCV RNA at TW8 No SVR SVR P-value 44 (27.7%) 132 61 (31.6%) Overall Sex 115
Men Women 89 26
Age
<50 years 50-59 years ≥60 years 35 40 39
METAVIR
F3 F4 44 71
CHILD class (F4)
A5 A6 64 4
Varices (F4)
No Yes 32 18
Fibroscan
<12.5 kPa ≥12.5 kPa 45 55
Albumin
>3.5 g/dL Low (≤3.5 g/dL) 104 3
Platelets
>100,000 /μL Low (≤100,000 /μL) 106 9
Genotype
1b 1a 88 27
Previous response
Relapser Partial responder Null responder 52 26 37
IL28
CC CT TT * HCV-RNA status is missing for 29 patients 13 46 14 25 (21.9%) 19 (42.2%) 12 (25.5%) 16 (28.6%) 16 (29.1%) 11 (20.0%) 33 (31.7%) 27 (29.7%) 6 (60.0%) 16 (33.3%) 12 (40.0%) 13 (22.4%) 27 (32.9%) 35 (25.2%) 6 (66.7%) 34 (24.3%) 10 (53.6%) 34 (27.9%) 10 (27.0%) 14 (21.2%) 14 (35.0%) 16 (30.2%) 1 ( 7.1%) 18 (28.1%) 7 (33.3%)
0.02
0.93
0.14
0.08
0.63
0.19
0.01
0.01
1.00
0.27
0.21
94 38 37 50 44 35 97 77 17 54 23 36 76 112 15 113 19 101 31 38 25 68 4 58 28 46 (32.9%) 15 (28.3%) 14 (27.5%) 27 (35.1%) 16 (26.7%) 23 (39.7%) 38 (28.2%) 36 (31.9%) 2 (10.5%) 20 (27.0%) 9 (28.1%) 23 (39.0%) 29 (27.6%) 53 (32.1%) 1 ( 6.3) 59 (34.3%) 2 ( 9.5%) 49 (32.7%) 12 (27.9%) 24 (38.7%) 16 (39.0%) 20 (22.7%) 6 (60.0%) 31 (34.8%) 6 (17.7%) 0.61
0.53
0.13
0.10
1.00
0.16
0.04
0.02
0.71
0.054
0.03
Bruno S, et al. submitted
Predictor of serious or hematological adverse events during treatment with BOC (TW5-TW48)
SERIOUS EVENTS Events/patients (%) OR (95% CI) HEMATOLOGICAL EVENTS Events/patients (%) OR (95% CI) Sex
Men Women
Age
<50 years 50-59 years ≥60 years
METAVIR
F3 F4
CHILD class (F4)
A5 A6
Fibroscan
<12.5 kPa ≥12.5 kPa Per 1 kPa increase
Varices (F4)
No Yes
Genotype
1b 1a
Albumin
>3.5 g/dL Low (≤3.5 g/dL)
Platelets
>100,000 /μL Low (≤100,000 /μL)
Previous response
Relapser 33/270 (12.2%) 1.00
18/111 (16.2%) 1.39 (0.75-2.59) 10/103 ( 9.7%) 1.00
21/144 (14.6%) 1.59 (0.71-6.53) 19/127 (15.0%) 1.64 (0.73-3.69) 5/121 ( 4.1%) 1.00
46/260 (17.7%) 35/220 (15.9%) 1.00
11/ 33 (33.3%) 7/123 ( 5.7%) 1.00
37/201 (18.4%)
4.99 (1.93-12.9) 2.74 (1.22-6.16) 3.74 (1.61-8.67)
1.03 (0.99-1.06) 26/135 (19.3%) 1.00
14/ 65 (21.5%) 1.15 (0.56-2.39) 40/296 (13.5%) 1.00
11/ 85 (12.9%) 0.95 (0.47-1.95) 40/329 (12.2%) 1.00
11/ 52 (21.2%) 41/340 (12.1%) 1.00
10/ 41 (24.4%)
3.42 (1.45-8.08) 2.39 (1.12-5.10)
22/137 (16.1%) 1.00
176/270 (65.2%) 1.00
89/111 (80.2%) 101/127 (79.5%)
2.16 (1.27-3.67)
60/103 (58.3%) 1.00
98/144 (68.1%) 1.53 (0.90-2.58)
2.78 (1.56-4.98)
81/121 (66.9%) 1.00
184/260 (70.8%) 1.20 (0.75-1.90) 155/220 (70.5%) 1.00
25/ 33 (75.8%) 1.34 (0.57-3.11) 79/123 (64.2%) 1.00
145/201 (72.1%) 1.44 (0.89-2.33) 1.03 (0.99-1.06) 94/135 (69.6%) 1.00
49/ 65 (75.4%) 1.34 (0.68-2.62) 209/296 (70.6%) 1.00
56/ 85 (65.9%) 0.80 (0.48-1.34) 225/329 (68.4%) 1.00
40/ 52 (76.9%) 1.39 (0.57-3.37) 228/340 (67.1%) 1.00
37/ 41 (90.2%)
5.13 (1.79-14.7)
105/137 (76.6%) 1.00
Partial responder Null responder 12/ 89 (13.5%) 0.82 (0.38-1.74) 17/153 (11.1%) 0.65 (0.33-1.29) 66/ 89 (74.2%) 0.88 (0.47-1.62) 94/153 (61.4%)
0.49 (0.29-0.81)
In Multivariate analysis, only child class A6 is independent predictor of serious adverse event In Multivariate analysis, older age and low platelets count are associated with increased risk of hematological adverse event, while previous null response is associated with reduced risk.
Bruno S, et al. submitted
ITT SVR12 and NNT dose according to at-entry characteristics, historical response and HCV-RNA value at treatment week 8 in cirrhotic patients All patients who received at least one BOC included
Variable Total Patients SVR (%) NNT METAVIR F4 Patients SVR (%) NNT
All Italy 381 188 (49.3) 267 128 (47.9) 2.0
2.1
260 118 (45.4) 167 71 (42.5) 2.2
2.4
Spain TW8 Undetectable TW8 <1000 IU/mL TW8 ≥1000 IU/mL Prior relapser Prior partial Prior null Fibroscan <12.5 kPa Fibroscan ≥12.5 kPa Albumin >3.5 g/dL Albumin ≤3.5 g/dL PLT >100,000 /μL PLT ≤100,000 /μL 114 60 (52.6) 159 115 (72.3) 143 56 (39.2) 48 4 ( 8.3) 137 84 (61.3) 89 45 (50.6) 153 58 (37.9) 123 71 (57.7) 201 91 (45.3) 329 168 (51.1) 28 5 (17.9) 336 177 (52.7) 45 11 (24.4) 1.9
1.4
2.6
12.0
1.6
2.0
2.6
1.7
2.2
2.0
5.6
1.9
4.1
93 47 (50.5) 104 71 (68.3) 100 34 (34.0) 33 3 ( 9.1) 90 55 (61.1) 58 26 (44.8) 111 37 (33.3) 16 6 (37.5) 201 91 (45.3) 230 112 (48.7) 28 5 (17.9) 215 107 (49.8) 45 11 (24.4) 2.0
1.5
2.9
11.0
1.6
2.2
3.0
2.7
2.2
2.1
5.6
2.0
4.1
None of the 7 patients with both low albumin and low platelet counts had SVR
Bruno S, et al. submitted
Simeprevir plus PegIFN and Ribavirin in treatment-experienced cirrhotic (F4) patients with HCV Genotype-1 infection (the ASPIRE trial)
Relapsers Partial responders Null responders 100 90 80 70 60 50 40 30 20 10 0 N=
0
6
70
10
73
15
0
2
15
13
82
11
0
2
46
11
31
13 Placebo+PR SMV 100 mg+PR* SMV 150 mg+PR* *duration groups pooled
Zeuzem S, et al. Gastroenterology 2013
NEUTRINO: SVR12 by Sofosbuvir + P/R (12 weeks) According to Genotype and Fibrosis Level
SVR12 According to Genotype
100
100 80 60
89
40 20 0 n/N = 261/292
GT 1 96
27/28
GT 4
7/7
GT 5,6
*(
95% CI, 67 to 89: based on HCV-RNA HVL vs LVL, IL28B not CC vs CC , advanced fibrosis
) 100 80 SVR12 According to Fibrosis Level p=0.0096
92 80
60 40 20 0 252/273 43/54
No Cirrhosis Cirrhosis*
Lawitz E, et al. NEJM 2013
CUPIC SVR12 rates and safety (ANRS CO20-CUPIC)
Undetectable HCV RNA (ITT) n (%) SVR 12 (Total) SVR 12 in relapsers SVR 12 in partial responders BOC n = 212 91(43) TVR n = 299 155 (52) 55/102 (54) 92/124 (74) 36/94 (38) 54/135 (40) SVR 12 in null responders SAE Death Infections Hepatic decompensation Anemia <8g/dl or blood tx 0/10 (0) 44.3% 1.4% 3.8% 4.2% 9%/11.8% 6/31 (19) 53.8% 2.7% 9.7% 4.7% 12.7%/18%
Fontaine H, et al. AFEF 2013
Risk-benefit (SAE / SVR 12)
( number of patients ) Risk factors for SAE Platelets count Platelets count > 100,000/mm 3 SAE : 6.2 % ≤ 100,000/mm 3 SAE: 12.2 % Albumin
35 g/L (306) SAE: 16.1 % (74) SAE: 51.4 % Albumin <35 g/L
Missing data in 63 patients
(31) (37) 9%
Hezode C, et al. Gastroenterology 2014
SVR12 according to on-treatment response
TELAPREVIR BOCEPREVIR
100 90 80 70 60 50 40 30 20 10 0
63% 125/198 RVR P < 0.001
40% 30/101 NO RVR
100 90 80 70 60 50 40 30 20 10 0
P < 0.001
63% 62/99 26% 29/113 HCV RNA HCV RNA Decline ≥ 1log W4 Decline < 1log W4 P < 0.001
72% 25% 58/81 33/131 RVR W8 NO RVR W8 6% 4/63 HCV RNA Decline < 3log W8
Fontaine H , France, AFEF 2013,
Treating with IFN-based vs Deferring Therapy waiting for all oral drugs in patients with HCV G1 (moderate to advanced fibrosis stage including nulls) Progression to more severe disease and complications not predictable in the single individual Safety profile manageable, especially in less severe stages With first generation PIs, short period of treatment (12 to 36 weeks), high overall SVR rates, risk-Cost/Benefit ratio and NNT favorable also in F3 while using baseline predictors and new approved futility rules With second generation PIs or NUC safety, duration of therapy shorter (12 to 24 weeks), pill burden and dosing frequency, better
Treating with IFN-based vs Deferring Therapy waiting for all oral drugs in patients with HCV G1 (cirrhosis early stage, nulls excluded) Short-term prognosis to quite favorable but difficult to assess in the single individual Safety profile acceptable With first generation PIs, overall SVR rates satisfactory in relapsers, risk Cost/Benefit ratio and NNT favorable while using new approved futility rules With second generation PIs or NUC safety, duration of therapy shorter (12 to 24 weeks), pill burden and dosing frequency, better No way to obtain IFN FREE by compassionate use
2014 Treatment Options
Right drug - Right patient
HCV-related disease: a condition with a wide heterogeneity of clinical features
MILD TO MODERATE FIBROSIS stage TREAT NOW
F1-2 Metavir, F1 to 3 Ishak, LSM: ≥ 6 KPa < 9.5 Kpa (possible overlap with either less or more severe stage), APRI: < 0.5 (possible overlap)
ADVANCED FIBROSIS stage TREAT NOW
(F3 Metavir, F3 to 4 Ishak, LSM: ≥ 9.5 KPa < 12.5 Kpa (possible overlap wth either less or more severe stage), APRI: >0.5 <1.5 (possible overlap)
WELL COMPENSATED cirrhosis (early stage: 1) TREAT NOW
F4 Metavir, F5 to 6 Ishak) or LSM: ≥ 12.5 KPa
#
, usually no clinically significant portal hypertension*: HVPG ≥ 6, mmHg < 10 mmHg, no esophageal varices, Child A5, MELD < 10.
MARGINALLY COMPENSATED (more severe stage: 2) DEFER
F4 Metavir, F5 to 6 Ishak or LSM: ≥ 12.5 KPa
#
, with moderate to severe portal hypertension § : HVPG ≥ 10/12 mmHg, ± esophageal varices , PLT ≤ 100000 /mm 3 , low albumin value, Child A5, A6 rarely B7, MELD ≥ 10,
DECOMPENSATED
Child B7 or more, MELD >15 and/or waiting for OLT for ESLD
# *Garcia Tsao G. et al, Hepatology 2010
§
Castera L. Gastroenterology 2012 Qamar A. et al, Hepatology 2008
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