HCV Treatment around the world: Patients in...
Transcript of HCV Treatment around the world: Patients in...
-
1
Heiner Wedemeyer Hannover Medical School
Germany
HCV Treatment around the world: Patients in Germany
-
H. Wedemeyer: 12-2015 HCV Treatment
Disclosures
Honoraria for consulting or speaking (last 5 years): Abbott, AbbVie, Biolex, BMS, Boehringer Ingelheim, Eiger,
Gilead, ITS, JJ/Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV
Research grants: Abbott, Abbvie, BMS, Gilead, Merck, Novartis, Roche,
Roche Diagnostics, Siemens
-
H. Wedemeyer: 12-2015 HCV Treatment
HCC, decompensated cirrhosis and transplant: Germany, England, France and Spain
Razavi H, et al. J Viral Hepat 2014; 21(suppl. 1):3435.
Liver transplant Decompensated cirrhosis HCC
Germany England
France Spain
-
H. Wedemeyer: 12-2015 HCV Treatment
Age distribution, 2013 Germany, England, France and Spain
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
% o
f Tot
al H
CV
Infe
ctio
ns (2
013)
Germany England France Spain
Bruggmann et al., J Viral Hepatitis 2014
-
H. Wedemeyer: 12-2015 HCV Treatment
Non-nucs
NS5A-inhibitors asvirs
Sofosbuvir Ledipasvir
Sofosbuvir Daclatasvir
Sofosbuvir Simeprevir
Protease- inhibitors previrs
Polymerase-inhibitors buvirs
Nucleos(t)ide
Paritaprevir/r Ombitasvir Dasabuvir
Sofosbuvir + RBV
Approved IFN-free combination therapies for hepatitis C
-
H. Wedemeyer: 12-2015 HCV Treatment
When to start? Which treatment when? How long? Ribavirin yes/no? Resistance?
Child B/C-cirrhosis? Impaired renal function? Optimal treatment for HCV Genotype 3?
How to manage DAA failures?
-
H. Wedemeyer: 12-2015 HCV Treatment
Alexander
52 years
Born in Siberia Cirrhosis
HCV GT1b Ascites controlled
PegIFN/RBV relapser
Petra
42 years
OST since 10y F2 fibrosis HCV GT1a
never treated HCV RNA 4.2 x106 IU/ml
Horst
62 years Cirrhosis HCV GT3a
Treatment-nave 7.6 x106 IU/ml
-
H. Wedemeyer: 12-2015 HCV Treatment
ALT 84 IU/L; AST 50 IU/L Bilirubin, albumin, INR normal Platelets 205.000
Sofosbuvir Ledipasvir
Possible treatment options in Germany
Paritaprevir/r Ombitasvir Dasabuvir
Sofosbuvir Simeprevir
Sofosbuvir Daclatasvir
Petra
42 years
OST since 10y F2 fibrosis HCV GT1a
never treated HCV RNA 4.2 x106 IU/ml
-
H. Wedemeyer: 12-2015 HCV Treatment
ALT 84 IU/L; AST 50 IU/L Bilirubin, albumin, INR normal Platelets 205.000
Petra
42 years
OST since 10y F2 fibrosis HCV GT1a
never treated HCV RNA 4.2 x106 IU/ml
Treatment for 8 weeks No ribavirin! SVR!
Jan 2015
Sofosbuvir Ledipasvir
-
H. Wedemeyer: 12-2015 HCV Treatment
ALT 84 IU/L; AST 50 IU/L Bilirubin, albumin, INR normal Platelets 205.000
Petra
42 years
OST since 10y F2 fibrosis HCV GT1a
never treated HCV RNA 5.8 x106 IU/ml
Still 8 weeks?
Sofosbuvir Ledipasvir
Assay: Abbott ART
-
H. Wedemeyer: 12-2015 HCV Treatment
ALT 84 IU/L; AST 50 IU/L Bilirubin, albumin, INR normal Platelets 205.000
Petra
42 years
OST since 10y F2 fibrosis HCV GT1a
never treated HCV RNA 4.2 x106 IU/ml
Sofosbuvir Ledipasvir
How long to treat?
Paritaprevir/r Ombitasvir Dasabuvir
Sofosbuvir Simeprevir
Are 8 weeks possible? SOF/LDV label allows 8 weeks SIM-SOF 8 weeks? 3D 8 weeks in G1b?
-
H. Wedemeyer: 12-2015 HCV Treatment
Viral load cut-offs to guide treatment duration Consider differences between HCV RNA assays
Roche CAP/CTM gives higher values than Abbott ART!
Vermehren. et al. EASL 2015
Percentage of patients Qualifying for shorter therapy
-
H. Wedemeyer: 12-2015 HCV Treatment
Alexander
52 years
Born in Siberia Cirrhosis
HCV GT1b PegIFN/RBV relapser
ALT 74 IU/L; AST 120 IU/L Bilirubin 1.1, albumin 36 Platelets 105.000 HCV RNA 900.000 IU/mL
Sofosbuvir Ledipasvir
Possible treatment options in Germany
Paritaprevir/r Ombitasvir Dasabuvir
Sofosbuvir Simeprevir
Sofosbuvir Daclatasvir
-
H. Wedemeyer: 12-2015 HCV Treatment
Alexander
52 years
Born in Siberia Cirrhosis
HCV GT1b PegIFN/RBV relapser
ALT 74 IU/L; AST 120 IU/L Bilirubin 1.1, albumin 36 Platelets 105.000 HCV RNA 900.000 IU/mL
Paritaprevir/r Ombitasvir Dasabuvir
-
H. Wedemeyer: 12-2015 HCV Treatment
Ombitasvir/Paritaprevir/r + Dasabuvir without ribavirin in patients with compensated cirrhosis
Turquoise III
Feld et al. J Hepatol 2015; epub
-
H. Wedemeyer: 12-2015 HCV Treatment
Alexander
52 years
Born in Siberia Cirrhosis
HCV GT1b PegIFN/RBV relapser
Treatment for 12 weeks SVR
June 2014
Sofosbuvir Simeprevir
Fibroscan values Baseline 34 kPa EOT 22 kPa Fu-24 19 kPa Fu-48 11 kPa
ALT 74 IU/L; AST 120 IU/L Bilirubin 1.1, albumin 35 Platelets 105.000 HCV RNA 900.000 IU/mL
-
H. Wedemeyer: 12-2015 HCV Treatment
FibroScan 25 kPa at baseline FibroScan > 25 kPa at baseline
Deterding et al., AP&T 2016 in press
Improvement of fibroscan values in patients with advanced cirrhosis: The Hannover Cohort
-
H. Wedemeyer: 12-2015 HCV Treatment
Improvement of liver function parameters after IFN-free cure of HCV infection
Wedemeyer et al., EASL 2015, P0808
- Analysis of the TURQUOISE-II trial data up to 48 wks after SVR12
Improvement of non-invasive fibrosis markers Improvement of liver function
-
H. Wedemeyer: 12-2015 HCV Treatment
Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort
Albumin Prothrombin time
Deterding et al., AP&T 2015
-
H. Wedemeyer: 12-2015 HCV Treatment
Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort
Bilirubin Cholinesterase
Deterding et al., AP&T 2015
-
H. Wedemeyer: 12-2015 HCV Treatment
Alexander (B)
52 years
Born in Siberia Cirrhosis Child B
HCV GT1b Ascites not controlled
ALT 74 IU/L; AST 120 IU/L Bilirubin 1.7, albumin 29 Platelets 83.000 HCV RNA 900.000 IU/mL MELD 18
August 2015
Sofosbuvir Ledipasvir
12 vs. 24 weeks? Ribavirin yes/no?
-
H. Wedemeyer: 12-2015 HCV Treatment
Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort
Deterding et al., AP&T 2015
Changes in MELD Scores baseline-FU-week 12
-
H. Wedemeyer: 12-2015 HCV Treatment
Horst
62 years Cirrhosis HCV GT3a
Treatment-nave 7.6 x106 IU/ml
ALT 114 IU/L; AST 104 IU/L Bilirubin, albumin, INR normal Platelets 175.000 Fibroscan: 17.1 kPa Refuses PEG-IFNa
Possible Treatments Options
12 weeks
12 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
Sofosbuvir Ribavirin 24 weeks
24 weeks
24 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
16 weeks Sofosbuvir Daclatasvir Ribavirin
-
H. Wedemeyer: 12-2015 HCV Treatment
24-week SOF + RBV: clinical trial and real-world data
THESE ARE NOT HEAD-TO-HEAD STUDIES AND NO DIRECT COMPARISONS CAN BE MADE
aAmong patients with available outcomes. 1. Zeuzem S et al. N Engl J Med 2014;370:19932001. 2. Foster G et al. EASL 2015, Abstract L05. 3. Alqahtani S et al. EASL 2015, Abstract P0840.
BOSON (Phase 3): N = 182 GT-3 patients2
65 72
18 22
44 54
26 34
VALENCE (Phase 3): N = 250 GT-3 patients1
SV
R12
, pat
ient
s
87 92
12 13
85 98
29 47
+ Cirr - Cirr
SOF + RBV 24 weeks
SV
R12
, pat
ient
s
+ Cirr - Cirr
SOF + RBV 24 weeks
HCV-TARGET (Real-world): N = 226 GT-3 patients
(interim data)3a
SV
R12
, (%
pat
ient
s)a
30 37
17 23
18 23
22 50
+ Cirr - Cirr
SOF + RBV 24 weeks
n = N
+ RBV + RBV + RBV 24 weeks
24 weeks
24 weeks
Treatment naive Treatment experienced
Diagramm1
90
82
82
77
Noncirrhotic
Sheet1
NoncirrhoticCirrhotic
TN Noncirrhotic9092
TE Noncirrhotic826286.397.63.77.6
TN Cirrhotic8278.492.73.610.7
TE Cirrhotic776499.81817.8
46.475.530.6-1.5
Diagramm1
952.68.7
875.78.6
927.828
6213.515.6
Noncirrhotic
Sheet1
NoncirrhoticCirrhotic
TN Noncirrhotic9592
TE Noncirrhotic876286.397.68.72.6
TN Cirrhotic9278.492.78.65.7
TE Cirrhotic626499.8287.8
46.475.515.613.5
Diagramm1
81
78
74
44
Noncirrhotic
Sheet1
NoncirrhoticCirrhotic
TN Noncirrhotic8192
TE Noncirrhotic786286.397.6-5.316.6
TN Cirrhotic7478.492.7-0.414.7
TE Cirrhotic446499.81025.8
46.475.5-2.431.5
-
H. Wedemeyer: 12-2015 HCV Treatment
DCV + SOF RBV, 12 or 24 weeks: clinical trial and real-world data in GT-3 patients
THESE ARE NOT HEAD-TO-HEAD STUDIES AND NO DIRECT COMPARISONS CAN BE MADE
73 75
11 19
32 34
9 13
ALLY-3 (Phase 3): N = 152 GT-3 patients1
DCV + SOF 12 weeks
SVR1
2 (%
pat
ient
s)
n = N
12 weeks
+ Cirra - Cirr
- RBV
Treatment naive
Treatment experienced
EU CUP (UK cohort) N = 189 GT-3
decompensated cirrhosis patients2
114 7
DCV + SOF 12 weeks
SVR1
2 (%
pat
ient
s)
aAmong n = 32 patients with cirrhosis, 11 (34%) had baseline platelet counts 100 109 cells/mL. bInterim data 1. Nelson DR et al. Hepatology 2015;61:11271135. 2. Foster G et al. EASL 2015, Abstract O002. 3. Welzel TM et al. EASL 2015, Abstract P0772.
EU CUP (AI444-237) N = 24 GT-3 patients at high risk of hepatic
decompensation or death3b
Pool
ed
DCV + SOF 24 weeks
11 11
11 13
22 24
n = N
24 weeks
+
RB
V
- RB
V
12 weeks
+
RB
V
- RB
V
French CUP N = 106 GT-3 patients
+ cirrhosis4b
SV
R4
(%
patie
nts)
22 29
11 12
52 59
5 6
+ Ci
rr
- Cirr
12 weeks
24 weeks
DCV + SOF RBV
n = N
+ Ci
rr
- Cirr
24 weeks 12 weeks
n =
Diagramm1
97
94
58
69
Noncirrhotic
Sheet1
NoncirrhoticCirrhotic
ncTN9792
ncTE946286.397.610.70.6
cTN5878.492.715.6-1.3
cTE696499.8-641.8
46.475.522.66.5
Diagramm1
7071
DCV + SOF + RBV
DCV + SOF
43
Sheet1
LDV + SOF + RBVLDV + SOFDCV + SOF + RBVDCV + SOF
GT-186818260
GT-359487071
To resize chart data range, drag lower right corner of range.
Diagramm1
1008592
DCV + SOF
DCV + SOF + RBV
Overall
SVR12 (%patients)b,c
100
Sheet1
DCV + SOFDCV + SOF + RBVOverall
1a97.0100.098.0
1b100.095.098.0
20.0100.0100.0
3100.085.092.0
4100.0100.0100.0
NK0.0100.0100.0
Diagramm1
7692
8883
Cirrhotic
Noncirrhotic
Sheet1
CirrhoticNoncirrhoticSeries 3
DCV + SOF RBV 12 weeks7692
DCV + SOF RBV 24 weeks8883
To resize chart data range, drag lower right corner of range.
-
Ally 3+ Study: DAC+SOF+RBV 12 vs. 16 weeks
a VBT (virologic breakthrough}: confirmed HCV RNA 1 log10 IU/mL above nadir, or LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA LLOQ at any posttreatment visit following < LLOQTND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment.
VBTa 0 0 0
Relapseb 4 2 2
Deathc 1 1 0
ALLY-3+
VBTa 0 0 0
Relapseb 4 2 2
Overall 12 Weeks 16 Weeks
HCV
RNA
< LL
OQ
TD/T
ND
(%)
90 88 92
45 50
21 24
24 26
ITT ANALYSIS (Primary Endpoint)
92
Overall 12 Weeks 16 Weeks
91 92
45 49
24 26
21 23
HCV
RNA
< LL
OQ
TD/T
ND
(%)
OBSERVED ANALYSIS
26
Diagramm1
906.67249064110
87.59.84406850140
92.30769230776.74676859190
Data
ALLY-3+ AI444326
SVR4 = Proportion of subjects with HCV RNA < LLOQ TD or TND at Follow-up Week 4
alpha0.05
GroupsTotal12 weeksDCV+SOF+RBV16weeksDCV+SOF+RBV
x (Successes)452124Overall
n502426
SVR490.087.592.3
95% Conf Lower Limit0.00.00.0
95% Conf Upper Limit96.797.399.1
Lower Error0.00.00.0
Upper Error6.79.86.7
Advanced FibrosisCirrhosis
GroupsTotal12 weeksDCV+SOF+RBV16weeksDCV+SOF+RBVTotal12 weeksDCV+SOF+RBV16weeksDCV+SOF+RBV
x (Successes)1468311516
n1468361818
SVR4100.0100.0100.086.183.388.9Adv Fibrosis
95% Conf Lower Limit0.00.00.00.00.00.0
95% Conf Upper Limit100.0100.0100.095.396.498.6
Lower Error0.00.00.00.00.00.0
Upper Error0.00.00.09.213.19.7
Cirrhosis
Data
6.67249064110
9.84406850140
6.74676859190
Treatment Groups
906.67249064110
87.59.84406850140
92.30769230776.74676859190
0
0
0
0
0
0
9.2211228286
0
13.0881583545
0
9.7359895447
0
4650
2124
2526
HCV RNA < LLOQ, TD or TND (%)
Advanced Fibrosis_Cirrhosis
10000
10000
10000
86.11111111119.22112282860
83.333333333313.08815835450
88.88888888899.73598954470
1414
66
88
3236
1518
1718
ADVANCED FIBROSIS
CIRRHOSIS
HCV RNA < LLOQ, TD or TND (%)
Diagramm1
91.83673469395.89417724180
91.30434782617.62465557010
92.30769230776.74676859190
Data
ALLY-3+ AI444326
SVR4 = Proportion of subjects with HCV RNA < LLOQ TD or TND at Follow-up Week 4 (OBSERVED DATA EXCLUDING PATIENT WHO DIED ON TREATMENT)
alpha0.05
GroupsTotal12 weeksDCV+SOF+RBV16weeksDCV+SOF+RBV
x (Successes)452124Overall
n492326
SVR491.891.392.3
95% Conf Lower Limit0.00.00.0
95% Conf Upper Limit97.798.999.1
Lower Error0.00.00.0
Upper Error5.97.66.7
Data
5.89417724180
7.62465557010
6.74676859190
Treatment Groups
91.83673469395.89417724180
91.30434782617.62465557010
92.30769230776.74676859190
4650
2124
2526
HCV RNA < LLOQ, TD or TND (%)
Advanced Fibrosis_Cirrhosis
000
1414
66
88
3236
1518
1718
ADVANCED FIBROSIS
CIRRHOSIS
HCV RNA < LLOQ, TD or TND (%)
-
H. Wedemeyer: 12-2015 HCV Treatment
Horst (b)
56 years Cirrhosis HCV GT3a
Treatment-nave 7.6 x106 IU/ml
ALT 104 IU/L; AST 119 IU/L Bilirubin, albumin, INR normal Platelets 135.000 Fibroscan: 22.1 kPa Strongly refuses PEG-IFNa
Possible Treatments Options
12 weeks
12 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
Sofosbuvir Ribavirin 24 weeks
24 weeks
24 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
16 weeks Sofosbuvir Daclatasvir Ribavirin
-
H. Wedemeyer: 12-2015 HCV Treatment
Horst (c)
56 years Cirrhosis HCV GT3a
Treatment-nave 7.6 x106 IU/ml
ALT 114 IU/L; AST 104 IU/L Bilirubin, albumin, INR normal Platelets 175.000 Fibroscan: 17.1 kPa Strongly refuses PEG-IFNa
Possible Treatments Options
12 weeks
12 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
Sofosbuvir Ribavirin 24 weeks
24 weeks
24 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
16 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir PEG-IFNa Ribavirin 12 weeks
-
H. Wedemeyer: 12-2015 HCV Treatment
BOSON: SOF + PEG-IFN/RBV vs SOF + RBV in GT-3 patients cirrhosis
Foster G et al. Gastroenterology Nov 2015.
N = 544 GT-3 patients n = 171 with cirrhosis n = 265 treatment experienced
SOF + RBV 16 weeks SOF + PEG/RBV 12 weeks SOF + RBV 24 weeks
SV
R12
(% p
atie
nts)
100
60
40
20
0
80
99 124
80
109 126
87
117 123
95
58 90
64
70 88
80
79 87
91
Treatment naive
70 91
77
83 94
88
89 94
95
Cirrhosis
29 57
51
44 56
79
51 58
88
Treatment experienced
+ Cirr - Cirr
n = N
Relapsesa: 5% 12% 27%
-
H. Wedemeyer: 12-2015 HCV Treatment
Horst (d)
56 years Cirrhosis HCV GT3a
Treatment-nave 7.6 x106 IU/ml
ALT 114 IU/L; AST 104 IU/L Bilirubin, albumin, INR normal Platelets 175.000 Fibroscan: 17.1 kPa NS5A RAV at position 93
Possible Treatments Options
12 weeks
12 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
Sofosbuvir Ribavirin 24 weeks
24 weeks
24 weeks Sofosbuvir Daclatasvir Ribavirin
Sofosbuvir Daclatasvir
16 weeks Sofosbuvir Daclatasvir Ribavirin
-
H. Wedemeyer: 12-2015 HCV Treatment
Was kann der Patient noch tun?
Kaffee ist gut fr die Leber
Slide Number 1Slide Number 2HCC, decompensated cirrhosis and transplant:Germany, England, France and SpainAge distribution, 2013 Germany, England, France and SpainSlide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Improvement of liver function parameters after IFN-free cure of HCV infectionSlide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 2324-week SOF + RBV: clinical trial and real-world data DCV + SOF RBV, 12 or 24 weeks: clinical trial and real-world data in GT-3 patientsAlly 3+ Study: DAC+SOF+RBV 12 vs. 16 weeksSlide Number 27Slide Number 28BOSON: SOF + PEG-IFN/RBV vs SOF + RBV in GT-3 patients cirrhosisSlide Number 30Slide Number 31