Therapie der chronischen Hepatitis C 2015 –
Alle Probleme gelöst?
Michael Gschwantler, Wilhelminenspital, Wien
WHO. Wkly Epidemiol Rec. 2000;75:18-19.
HCV Infektion:
Weltweite Prävalenz
<1%
1%–2.4%
2.5%–4.9%
5%–10%
>10%
keine Daten
Hepatitis C - Epidemiologie
~ 200 Mio. Infizierte weltweit
~ 40.000 Infizierte in Österreich
Derzeit bereits häufigste Indikation für
LTX in Österreich
Hepatitis C Virus -
induzierte Lebererkrankungen
Infektion mit HCV
akute Hepatitis chronische Hepatitis
Ausheilung Zirrhose
Hepatom
Genotypen des Hepatitis C Virus
Ansprechtypen auf antivirale Therapie
Sustained
responder
(Heilung)
Nonresponder
Baseline Therapiephase
Zeit
Relapser
HCV RNA
nicht
nachweisbar
HC
V R
NA
Breakthrough
Nachweisgrenze
6 Monate
„Alte“ Standardtherapie der chron. Hepatitis C
Pegyliertes Interferon-α
Pegasys® (Peginterferon α-2a) 180µg 1 x wö. s.c.
PegIntron® (Peginterferon α-2b) 1,5µg/kg KG 1 x wö. s.c.
Plus
Ribavirin (Copegus®, Rebetol®)
1000-1200 mg tgl. (Genotyp 1 und 4)
800 mg tgl. (Genotyp 2 und 3)
Therapiedauer: 6-18 Monate bei Genotyp 1 und 4
3-12 Monate bei Genotyp 2 und 3
Therapie: Peginterferon + Ribavirin
Therapiedauer: abhängig von Genotyp und viralem Ansprechen
Erfolgsaussichten:
• Therapienaiv GT 1 und 4: 40-50%
• Therapienaiv GT 2 und 3: 80-90%
• Relapser: 30-40%
• Nonresponder: 6%
Weitere Probleme:
• Lange Therapiedauer, häufig Nebenwirkungen
• Viele Patienten haben Kontraindikationen: z.B. fortgeschrittene Leberzirrhose
„Alte“ Standardtherapie
Nebenwirkungen von Interferon α plus Ribavirin
Während der gesamten Therapiedauer:
• Müdigkeit, Schlafstörungen, Depressionen
• Gastrointestinale Unverträglichkeit, Übelkeit, Diarrhoe
• Appetitlosigkeit, Gewichtsverlust
• Anämie, Leukozytopenie, Thrombozytopenie
• Anstieg von Blutfetten und Harnsäure
• Juckreiz, Hautausschläge, Haarausfall
• Gelenks- und Muskelschmerzen
• Austrocknen von Schleimhäuten, chronischer Reizhusten
• Schilddrüsenfunktionsstörungen
• Induktion von Autoimmunerkrankungen
• Teratogenität
Kontraindikationen gegen Interferon
• Endogene Depressionen, Schizophrenie, Epilepsie
• Schwere Allgemeinerkrankung
• Autoimmunerkrankung
• Fortgeschrittene Leberzirrhose (Stadium CHILD-PUGH B
und C)
• Hepatische Enzephalopathie, Aszites,
Ösophagusvarizenblutung
• Schwangerschaft oder unzureichende Empfängnisverhütung
• Thrombozytopenie, Leukozytopenie
• Aktiver Drogen- oder Alkoholabusus
• Psoriasis und andere Hauterkrankungen
Genotyp 1:
Peginterferon + Ribavirin + Telaprevir oder Boceprevir
Genotyp 2/3:
Peginterferon + Ribavirin
„Neuere“ Therapieoptionen
Nebenwirkungen und Limitationen von Proteaseinhibitoren der 1. Generation
NW-Telaprevir:
• Anämie
• Hautausschläge
NW-Boceprevir:
• Anämie
• Dysgeusie
Hauptproblem von Telaprevir und Boceprevir:
• Interferon-basierte Therapie
Kontraindikationen gegen Interferon
• Endogene Depressionen, Schizophrenie, Epilepsie
• Schwere Allgemeinerkrankung
• Autoimmunerkrankung
• Fortgeschrittene Leberzirrhose (Stadium CHILD-PUGH B
und C)
• Hepatische Enzephalopathie, Aszites,
Ösophagusvarizenblutung
• Schwangerschaft oder unzureichende Empfängnisverhütung
• Thrombozytopenie, Leukozytopenie
• Aktiver Drogen- oder Alkoholabusus
• Psoriasis und andere Hauterkrankungen
Wünsche an eine „ideale“ Therapie
• Hohe Heilungsrate (am besten 100%)
• Keine Nebenwirkungen
• Keine Kontraindikationen
• Keine Wechselwirkungen
• Bei allen Patienten anwendbar
• Kurze Therapiedauer
• Einfacher Einnahmemodus
• Niedriger Preis
HCV Lebenszyklus und mögliche Angriffspunkte neuer Virostatika
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Rezeptorbindung und Endozytose
Fusion und Uncoating
Transport und Freisetzung
(+) RNA
Translation and Polyprotein-
Prozessierung RNA Replikation
Virion Assembly
ER Lumen
LD
LD ER Lumen
LD
NS3/4 Protease- Inhibitoren
- Boceprevir - Telaprevir - Simeprevir - Paritaprevir
NS5B Polymerase-Inhibitoren Nukleosidische/nukleotidische
Nicht-Nukleosidische - Sofosbuvir - Dasabuvir
*Rolle im HCV Lebenszyklus noch ungeklärt
NS5A* Inhibitors
- Daclatasvir
- Ledipasvir
- Ombitasvir
Aktuelle Therapieoptionen bei Genotyp 1/4
Sofosbuvir + Simeprevir
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
Paritaprevir/Ritonavir + Ombitasvir + Dasabuvir
Sofosbuvir + Simeprevir
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
Paritaprevir/Ritonavir + Ombitasvir + Dasabuvir
Aktuelle Therapieoptionen bei Genotyp 1/4
2
(2/87)
COSMOS: naïve and prior null responder, F3–F4 – SVR12
Cohort 2; intent-to-treat population
Non-VF, Non-virologic failure, patients who did not achieve SVR12 for
reasons other than virologic failure Lawitz E et al. Lancet 2014
24 weeks
SMV + SOF + RBV SMV + SOF
100
SVR12
Pa
tie
nts
(%
)
12 weeks
Non-VF Relapse
80
60
40
20
0 SMV + SOF + RBV SMV + SOF
100
80
60
40
20
0
93
(28/30)
100
(16/16)
7
(2/30)
7
(2/27)
7
(1/14)
96
(26/27)
93
(13/14)
100
80
60
40
20
0
94
(82/87)
SMV + SOF ± RBV
Overall 3
(3/87)
19
SOF/P/R
N=384
SOF/RBV
N=667
SOF/SMV
N=784
SOF/SMV/RBV
N=228
Safety and Efficacy of SOF-Containing Regimens for HCV
HCV-TARGET
Jensen, AASLD, 2014, Oral #45
Genotype 3
SOF/PegIFN/RBV
8.5%
SOF/RBV
91.5%
SOF SMV
1.…
Genotype 2
SOF/PegIFN/RBV
0.9%
SOF/RBV
99.1%
Genotype 1
SOF/SMV/RBV
14.9%
SOF/PegIFN/RBV
23.1%
SOF/RBV
8.8%
SOF/SMV
53.1%
Real-world observational study of 2,063 patients treated with DAAs at academic (n=38) and community medical centers (n=15) in North America and Europe
Started Therapy HCV-TARGET 2.0
N=2063
20
Efficacy and Safety of SOF-Containing Regimens
HCV-TARGET
n (%)
SOF+PegIFN+
RBV
n=384
SOF+SMV
±RBV
n=228
SOF+SMV
n=784
SOF+RBV
n=667
Total
n=2063
Completed treatment 332 (86.5) 189 (82.9) 663 (84.6) 429 (64.3) 1613 (78.2)
Ongoing treatment 41 (10.7) 32 (14.0) 101 (12.9) 205 (30.7) 379 (18.4)
D/C Prematurely* 11 (2.9) 7 (3.1) 20 (2.6) 33 (4.9) 71 (3.4)
AE 6 (1.6) 5 (2.2) 16 (2.0) 17 (2.5) 44 (2.1)
Death 1 (0.3) 2 (0.9) 6 (0.8) 3 (0.4) 12 (0.6)
85 89 81
90
0
10
20
30
40
50
60
70
80
90
100
SV
R4, %
SOF+PegIFN +RBV
SOF+SMV ±RBV
SOF+SMV±RBV Prior PI Failures
SOF+RBV
140/164 269/303 44/54 168/187
GT 1 GT 2
12 Wk Regimens
SVR4/SVR12 Concordance: 94.4–98.2% PPV
Jensen, AASLD, 2014, Oral #45
*Not all premature D/C are summarized. Full list available in final slides.
Aktuelle Therapieoptionen bei Genotyp 1/4
Sofosbuvir + Simeprevir
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
ABT450/Ritonavir + Ombitasvir + Dasabuvir
DCV: a highly active replication complex inhibitor with pangenotypic coverage
• In vitro studies demonstrate EC50 values in the picomolar to low nanomolar range across all HCV genotypes1,2
• DCV displays a therapeutic index (CC50/EC50) of at least 100,000 in vitro1
• DCV exhibits additive to synergistic effects in combination studies with1:
– NS3 protease
– NS5B polymerase inhibitors
– Interferon 2 & ribavirin (RBV)
22 1. Gao M, et al. Nature 2010;465:96–100; 2. Gao et al. Curr Opin Virol. 2013;3:514;
Assay2 EC50
HCV replicon genotype 1a, WT 0.020 nM
HCV replicon genotype 1b, WT 0.004 nM
HCV replicon genotype 2a, JFH 0.071 nM
HCV replicon genotype 3a 0.15 nM
HCV replicon genotype 4a 0.012 nM
HCV replicon genotype 5a 0.033 nM
HCV replicon genotype 6a 0.054 nM
AI444-040 study: objective and design
• Objective: Phase 2 study to evaluate DCV + sofosbuvir (SOF), ± ribavirin (RBV), in treatment-naive, genotype (GT)-1-3 infected patients, and in GT1-infected patients who failed telaprevir (TVR) or boceprevir (BOC) treatment
• Primary endpoint: SVR12 following 12 or 24 weeks of treatment
RBV: 1000-1200 mg/day, weight-based (GT 1); 800 mg/day (GT 2/3).
GT, genotype, DCV, daclatasvir, SOF, sofosbuvir (GS-7977), RBV, ribavirin, TVR, telaprevir, BOC, boceprevir, SVR, sustained virologic
response
Chronic HCV
GT1a/1b naive
(n = 126)
n=41
n=15
n=14 C: DCV+SOF
E: DCV+SOF+RBV Follow-up
n=41
n=15
A: 7 d Lead-in × SOF, then DCV+SOF Follow-up
Follow-up
Follow-up
Follow-up
G: DCV + SOF
H: DCV+SOF+RBV
Week 24 SVR12
Week 12 SVR12
Chronic HCV
GT2/3 naive
(n = 44)
n=16 Follow-up
D: DCV+SOF Follow-up
F: DCV+SOF+RBV Follow-up
n=14
B: 7 d Lead-in × SOF, then DCV+SOF
n=14
Follow-up
Week 24 SVR12
I: DCV+SOF Follow-up
J: DCV+SOF+RBV Follow-up
n=21
n=20
Chronic HCV
GT 1, TVR or
BOC failure
(n = 41)
7dLI
7dLI
Sulkowski et al. N Engl J Med 2014;370:211–21.
100% 100% 100% 100% 95%
0
20
40
60
80
100a
A
LIb SOF,
DCV
+ SOF
H
DCV
+ SOF
+ RBV
C
DCV
+ SOF
E
DCV
+ SOF
+ RBV
G
DCV
+ SOF
24 weeks
HC
V R
NA
<LL
OQ
Pa
tie
nts
, %
AI444-040 study: SVR12 primary endpoint (mITT) for
treatment-naive patients
• SVR12 rates were 98% in GT1a and 100% in GT1b
• SVR24 rates ranged from 93–100% in GT1, and 88–100% in GT2/3c
15
15
14
14 41
41
39
41
15
15
12 weeks
aOne patient had missing data at post treatment week 12 but achieved SVR24, and one who was lost to follow-up after achieving SVR4 bLI (lead in) with SOF was not included in subsequent trials c93% and 88% were the percentage for the lead in arm.
HC
V R
NA
<LL
OQ
Pa
tie
nts
, %
92% 89%
0
20
40
60
80
100
24
26
16
18
DCV + SOF
± RBV
24 weeks
DCV + SOF ±
RBV
a
LI, lead in; LLOQ = lower limit of quantitation (25 IU/mL), mITT, modified intent to treat
GT1 GT2 GT3
Sulkowski et al. N Engl J Med 2014;370:211–21.
Treatment duration…
Treatment-naive patients Prior TVR or BOC failures
24 weeks 12 weeks 24 weeks
Patients with event, n (%)
A and B
SOF 7-d lead-in
SOF +DCV
(n=31)
C and D
DCV+SOF
(n=28)
E and F
DCV+SOF
+RBV
(n=29)
G
DCV+SOF
(n=41)
H
DCV+SOF
+RBV
(n=41)
I
DCV+SOF
(n=21)
J
DCV+SOF
+RB (n=20)
Any AE 25 (81) 26 (93) 26 (90) 38 (93) 38 (93) 16 (76) 20 (100)
AE occurring in ≥25% in any groupa
Fatigue
Headache
Nausea
9 (29)
5 (16)
5 (16)
14 (50)
8 (29)
9 (32)
9 (31)
11 (38)
9 (31)
16 (39)
14 (34)
8 (20)
15 (37)
9 (22)
8 (20)
6 (29)
7 (33)
0
9 (45)
7 (35)
2 (10)
Grade 3 or 4 AE 0 2 (7)b 2 (7) 1 (2) 0 0 1 (5)
Discontinuation due to AEd 0 1 (4) 1 (3) 0 0 0 0
SAEc 2 (6) 4 (14) 2 (7) 1 (2) 0 0 1 (5)
Grade 3 or 4 laboratory abnormality occurring in ≥ 3 patients in any group
Phosphorous < 2.0 mg/dL
Glucose
Fasting value > 250 mg/dL
Non-fasting value > 250 mg/dL
0
0
0
1 (4)
1 (4)
0
1 (3)
1(3)
1 (3)
0
1 (2)
0
3 (7)
0
0
0
1 (5)
1 (5)
0
0
1 (5)
AI444-040 study: adverse events
aAll events listed were mild or moderate in intensity. b2 patients had a total of 4 events. C 5 events of overdose (extra study medication doses),
classified as SAEs, are not included in the table; no clinical significant effects were reported from any of the overdoses. d1 patient due to
fibromyalgia / 1 patient due to stroke
Sulkowski et al. N Engl J Med 2014;370:211–21.
Aktuelle Therapieoptionen bei Genotyp 1/4
Sofosbuvir + Simeprevir
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
Paritaprevir/Ritonavir + Ombitasvir + Dasabuvir
27
Ledipasvir/Sofosbuvir: A Single Tablet Regimen (STR)
SOF nucleotide
polymerase
inhibitor
LDV NS5A
inhibitor
SOF nucleotide
polymerase
inhibitor
SOF nucleotide
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
NS5B
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
NS5B
polymerase
inhibitor
FDA Approval 10 Oct 2014
European Approval 18 Nov 2014
FDC, fixed-dose combination
Ledipasvir
– Once-daily, oral, 90-mg NS5A inhibitor
Sofosbuvir
– Once-daily, oral, 400-mg NS5B inhibitor
Ledipasvir/Sofosbuvir FDC
– Once-daily, oral, fixed-dose (90/400 mg) combination tablet
– Single-tablet regimen (STR) for hepatitis C
SOF/LDV ± RBV: ION-1 – baseline demographics and
disease characteristics
Treatment duration 12 Weeks 24 Weeks
SOF/LDV
N=214
SOF/LDV + RBV
N=217
SOF/LDV
N=217
SOF/LDV + RBV
N=217
Mean age, years (range) 52 (18–75) 52 (18–75) 53 (22–80) 53 (24–77)
Male, n (%) 127 (59) 128 (59) 139 (64) 119 (55)
Black, n (%) 24 (11) 26 (12) 32 (15) 26 (12)
Hispanic, n (%) 26 (12) 20 (9) 29 (13) 26 (12)
Region Europe, n (%) 89 (42) 99 (46) 85 (39) 80 (37)
Mean BMI, kg/m2 (range) 27 (18–41) 27 (18–42) 27 (18–48) 26 (18–48)
Cirrhosis, n (%) 34 (16) 33 (15) 33 (15) 36 (17)
Albumin <3.5 g/dL, n (%) 6 (3) 6 (3) 11 (5) 12 (6)
Platelet count <90,000/mm3, n (%) 5 (2) 6 (3) 8 (4) 4 (2)
IL28B CC, n (%) 55 (26) 76 (35) 52 (24) 73 (34)
IFN ineligible, n (%) 14 (7) 20 (9) 19 (9) 14 (7)
Genotype 1a, n (%) 144 (67) 148 (68) 146 (67) 143 (66)
Mean HCV RNA, log10 IU/mL (range) 6.4 (1.6–7.5) 6.4 (4.4–7.6) 6.3 (3.7–7.4) 6.3 (3.2–7.5)
HCV RNA ≥800,000 IU/mL 169 (79) 173 (80) 168 (77) 173 (80)
Afdhal N, et al. N Engl J Med. 2014 [epub ahead of print]
SOF/LDV ± RBV: ION-1 – SVR12 with and without cirrhosis
treatment naïve patients
Afdhal N, et al. N Engl J Med. 2014 [epub ahead of print]
99 97 98 99 94 100 94 100
0
20
40
60
80
100
SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV
12 weeks
179/180
24 weeks
SV
R1
2 (
%)
No cirrhosis Cirrhosis
32/34 178/184 33/33 181/184 31/33 179/181 36/36
Cirrhosis is defined as any one of :
1) Liver biopsy showing cirrhosis (e.g. Metavir = 4 or Ishak ≥5)
2) Fibroscan showing cirrhosis or results> 12.5 kPa
3) FibroTest® score of > 0.75 AND an APRI of > 2during Screening
SOF/LDV ± RBV: ION-2 – baseline demographics and
disease characteristics
Treatment duration 12 Weeks 24 Weeks
SOF/LDV
N=109
SOF/LDV + RBV
N=111
SOF/LDV
N=109
SOF/LDV + RBV
N=111
Mean age, years (range) 56 (24–67) 57 (27–75) 56 (25–68) 55 (28–70)
Male, n (%) 74 (68) 71 (64) 74 (68) 68 (61)
Black, n (%) 24 (22) 16 (14) 17 (16) 20 (18)
Hispanic, n (%) 7 (6) 12 (11) 11 (10) 11 (10)
Mean BMI, kg/m2 (range) 29 (19–47) 28 (19–45) 28 (19–41) 28 (19–50)
Cirrhosis, n (%) 22 (20) 22 (20) 22 (20) 22 (20)
IL28B CC, n (%) 10 (9) 11 (10) 16 (15) 18 (16)
Genotype 1a, n (%) 86 (79) 88 (79) 85 (78) 88 (79)
Mean HCV RNA, log10 IU/mL (range) 6.5 (5.0–7.5) 6.4 (4.6–7.3) 6.4 (4.7–7.4) 6.5 (3.1–7.4)
HCV RNA ≥800,000 IU/mL 103 (95) 98 (88) 93 (85) 96 (87)
Prior non-responders, n (%) 49 (45) 46 (41) 49 (45) 51 (46)
Prior PI failures, n (%) 66 (61) 64 (58) 50 (46) 51 (46)
Afdhal N, et al. N Engl J Med. 2014; 370:1483–1493
SOF/LDV ± RBV: ION-2 SVR12 rates
Afdhal N, et al. N Engl J Med. 2014; 370:1483–1493
Treatment experienced
94 96 99 99
0
20
40
60
80
100
SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV
12 weeks
102/109 107/111 108/109 110/111
24 weeks
SV
R1
2 (
%)
SOF/LDV ± RBV: ION-3 – baseline demographics and
disease characteristics
Treatment duration 8 Weeks 12 Weeks
SOF/LDV
N=215
SOF/LDV + RBV
N=216
SOF/LDV
N=216
Mean age, years (range) 53 (22–75) 51 (27–71) 53 (20–71)
Male, n (%) 130 (61) 117 (54) 128 (59)
Black, n (%) 45 (21) 36 (17) 42 (19)
Hispanic, n (%) 13 (6) 12 (6) 14 (7)
Mean BMI, kg/m2 (range) 28 (18–43) 28 (18–56) 28 (19–45)
IL28B CC, n (%) 56 (26) 60 (28) 56 (26)
Genotype 1a, n (%) 171 (80) 172 (80) 172 (80)
Mean HCV RNA, log10 IU/mL (range) 6.5 (1.4–7.8) 6.4 (3.9–7.7) 6.4 (2.3–7.8)
HCV RNA ≥800,000 IU/mL 181 (84) 171 (79) 172 (80)
Fibrosis score, n(%) 156 (73) 116 (63) 156 (72)
F0-F2 127 (59) 108 (50) 127 (59)
F3 28 (13) 28 (13) 29 (13)
Kowdley KV, et al. N Engl J Med. 2014 [epub ahead of print]
GT1 treatment-naïve patients without cirrhosis
SOF/LDV ± RBV: ION-3 SVR12 rates
treatment naïve non-cirrhotic patients
Cirrhosis defined as one of:
(1) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5)
(2) FibroTest® score of > 0.75 AND an APRI >2 during screening
In the absence of a definitive diagnosis by the above, a liver biopsy is required Kowdley KV, et al. N Engl J Med. 2014 [epub ahead of print]
12 weeks
94 93 95
0
20
40
60
80
100
SOF/LDV SOF/LDV + RBV SOF/LDV
SV
R1
2 r
ate
(%
)
8 weeks
201/216 206/216 202/215
Treatment naïve
34
LDV/SOF + RBV
Cohort A:
Advanced
Liver
Disease
n = 25
n = 25
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV Group 1
CTP B; 7-9
Group 2
CTP C; 10-12
Group 3
F0-F3, no
decomp.
Group 4
CTP A; 5-6
Group 6
CTP C; 10-12
Group 5
CTP B; 7-9
Cohort B:
Post-
Transplant
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
LDV/SOF + RBV
n = 50
n = 50
Group 7
FCH
SOLAR-1 (US) Status: Groups 1-5 enrolled, interim CSR Jul 2014
SOLAR-2 (ex-US) Status: FSFV Jan 2014, enrolling
Wk 0 Wk 12 Wk 24
n = 25
n = 25
n = 25
n = 25
n = 25
n = 25
n = 25
n = 25
n = 25
n = 25
Study Weeks
LDV/SOF + RBV for Treatment of HCV in Patients with Decompensated Cirrhosis or Post-Transplant Recurrence
SOLAR-1
Clinicaltrials.gov NCT01938430
All arms continue with 5 years of long-term follow-up for clinical outcomes
35
Demographics
SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis
CTP B CTP C
12 Weeks
n=30
24 Weeks
n=29
12 Weeks
n=23
24 Weeks
n=26
Median age, y (range) 60 (28-69) 58 (35-69) 58 (41-71) 59 (48-68)
Male, n (%) 22 (73) 18 (62) 14 (61) 18 (69)
White, n (%) 29 (97) 26 (90) 21 (91) 24 (92)
BMI ≥30 kg/m2, n (%) 10 (33) 10 (34) 13 (57) 9 (35)
Mean HCV RNA, log10 IU/mL (range) 5.9
(4.3-6.7)
5.8
(3.2-7.1)
5.6
(4.1-6.5)
5.8
(3.7-6.9)
GT 1a, n (%) 19 (63) 22 (76) 15 (65) 18 (69)
IL28B non-CC, n (%) 26 (87) 23/28 (82) 17 (74) 19 (73)
Prior HCV treatment, n (%) 22 (73) 19 (66) 11 (48) 18 (69)
MELD score, n (%)
<10 6 (20) 8 (28) 0 0
10‒15 21 (70) 16 (55) 16 (70) 13 (50)
16-20 3 (10) 5 (17) 7 (30) 12 (46)
21-25 0 0 0 1 (4)
Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96)
Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88)
Flamm, AASLD, 2014, Oral #239
36
Results: SVR12
SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis
87 86 89 90
0
20
40
60
80
100
CTP B CTP C
SV
R1
2 (
%)
26/30 19/22 18/20 24/27
Error bars represent 90% confidence intervals.
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV
Flamm, AASLD, 2014, Oral #239
37 37
-6
-4
-2
0
2
4
-6
-4
-2
0
2
4
n=5 n=5 n=2 n=3
(-8)
(+10)
CPT B CPT C
12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*
*Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk.
Change From Baseline to Follow-Up Week 4
Laboratory Results: MELD Score
Flamm, AASLD, 2014, Oral #239
1. Feld JJ, et al. N Engl J Med 2014 [epub ahead of print];
2. Zeuzem S, et al. N Engl J Med 2014 [epub ahead of print]; 3. Ferenci P, et al. EASL 2014. P1299 LB
4.Bernstein D, et al. DDW 2014. Chicago IL. Poster; 5. Poordad F, et al. N Engl J Med 2014 [Epub ahead of print]
Trial Population Treatment Regimen Treatment Duration
SAPPHIRE-I1 GT1 naïve without
cirrhosis
N=630
3D + RBV 12 weeks
Placebo 12 weeks, then 12 weeks
active treatment
SAPPHIRE-II2 GT1, experienced
without cirrhosis
N=400
3D + RBV 12 weeks
Placebo 12 weeks, then 12 weeks
active treatment
PEARL-III3 GT1b naïve without
cirrhosis
N=400
3D + RBV 12 weeks
3D 12 weeks
PEARL-IV4 GT1a naïve without
cirrhosis
N=300
3D + RBV 12 weeks
3D 12 weeks
TURQUOISE-
II5
GT1 naïve and exp
(with compensated
cirrhosis)
N=380
3D + RBV 12 weeks
3D + RBV 24 weeks
3D – Phase III studies in HCV mono-infection
3D + RBV in patients without cirrhosis:
SAPPHIRE-I and -II – study designs
Randomised, double-blind, placebo controlled Phase III studies to evaluate the efficacy and
safety of 3D + RBV (NCT01716585/NCT01715415)
Absence of cirrhosis
3D: co-formulated ABT-450/r/ombitasvir 150 mg/100 mg/25 mg QD
dasabuvir 250 mg BID; RBV: 1000–1200 mg/day
Feld JJ, et al. N Engl J Med 2014 [epub ahead of print]
2Zeuzem S, et al. N Engl J Med 2014 [epub ahead of print]
n=97
Week 0 24 12
SAPPHIRE-I
Treatment-naïve HCV
genotype 1 patients
Primary endpoint: SVR12
n=473 3D + RBV
n=158 Pbo
n=297
3D + RBV
3D + RBV
Pbo 3D + RBV
SAPPHIRE-II
Treatment-experienced
HCV genotype 1
patients
Double-blind treatment
period
Open-label treatment
period
3D + RBV: SAPPHIRE-I and -II – SVR12
*Products are unlicensed in EU
1. Feld JJ, et al. N Eng J Med 2014 [epub ahead of print]
2. Zeuzem S, et al. N Eng J Med 2014 [epub ahead of print]
96 95 98
0
20
40
60
80
100
All patients Genotype 1a Genotype 1b
SV
R12 (
%)
455/473 307/322 148/151
96 95 95 100
0
20
40
60
80
100
All patients Nullresponders
Relapsers Partialresponders
SV
R12 (
%)
286/297 139/146 65/65
Treatment-naïve1 Treatment experienced2
82/86
3D + RBV: TURQUOISE-II – study design
Randomised, open-label study to evaluate the safety and efficacy of the 3D + RBV
(NCT01704755)
3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD
dasabuvir, 250 mg BID, RBV: 1000–1200 mg/day
Poordad F, et al. N Engl J Med 2014 [Epub ahead of print]
Week 0 24 12
TURQUOISE-II
Treatment-naïve and
experienced HCV
genotype 1 patients
with cirrhosis
Primary endpoint:
SVR12
n=208 3D + RBV
n=172 3D + RBV
3D + RBV: TURQUOISE-II – SVR12
*Products are unlicensed in EU Poordad F, et al. N Engl J Med 2014 [Epub ahead of print]
92 89
99 94
97 94
87
96 94 100
95 100 100
95
0
20
40
60
80
100
All patients Genotype 1a Genotype 1b Treatmentnaïve
Relapsers Partialresponders
Nullresponders
SV
R1
2 (
%)
191/
208
165/
172
124/
140
114/
121
67/
68
51/
51
81/
86
70/
74
28/
29
23/
23
17/
18
13/
13
65/
75
59/
62
12 weeks 24 weeks
99,5 99,0
0
20
40
60
80
100
3D + RBV 3D
SV
R12 (
%)
209/210 207/209
PEARL-III – effect of addition of RBV on SVR12
ITT population Ferenci P, et al. N Engl J Med 2014 [Epub ahead of print]
Treatment-naïve HCV genotype 1b patients (non-F4)
Superiority
threshold
(84%)
Non-
inferiority
threshold
(74%)
Fibrosis
stage
ABT-450/r/267 +
ABT-333 + RBV
(N=210)
ABT-450/r/267
+ ABT-333
(N=209)
F0-F1 150 (71.4) 141 (67.8)
F2 38 (18.1) 47 (22.6)
F3 22 (10.5) 20 (9.6)
ABT-450/r/267
+ ABT-333 +
RBV
SVR12 48 wk
follow-up
60 24 12 0
N=210
N=209 ABT-450/r/267
+ ABT-333
(+ RBV PBO)
ABT-450/r/267 +
ABT-333 + RBV
ABT-450/r/267 +
ABT-333
97.0
90,2
0
20
40
60
80
100
3D + RBV 3D
SV
R12 (
%)
PEARL-IV – effect of addition of RBV to 3D on SVR12
ITT population Ferenci P, et al. N Engl J Med 2014 [Epub ahead of print]
Superiority
threshold
(84%)
Non-
inferiority
threshold
(74%)
3D +
RBV
SVR12 48 wk
follow-up
60 24 12 0
N=100
N=205 3D
(+ RBV PBO)
3D + RBV 3D
Treatment-naïve HCV genotype 1a non-cirrhotic patients
97/100 185/205
Double-blind treatment period
Aktuelle Therapieoptionen bei Genotyp 2/3
Sofosbuvir + Ribavirin
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
Aktuelle Therapieoptionen bei Genotyp 2/3
Sofosbuvir + Ribavirin
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
VALENCE: SVR12 With 12 or 24 Wks of
SOF + RBV in GT2 and GT3 Pts
No increase in AEs seen with longer duration treatment
– AEs seen consistent with RBV
GT2 12-Wk Treatment (n = 73)
GT3 24-Wk Treatment (n = 250)
100
80
60
40
20
0
SV
R1
2 (
%)
Zeuzem S, et al. NEJM 2014
SV
R1
2 (
%)
100
80
60
40
20
0 Naive,
Noncirrhotic
Naive,
Cirrhotic
97 100
91 88
Exp’d
Noncirrhotic
Exp’d,
Cirrhotic
29/30 2/2 30/33 7/8
94 92 87
60
Naive,
Noncirrhotic
Naive,
Cirrhotic
Exp’d
Noncirrhotic
Exp’d,
Cirrhotic
86/92 12/13 87/100 27/45 n/N = n/N =
Aktuelle Therapieoptionen bei Genotyp 2/3
Sofosbuvir + Ribavirin
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
AI444-040 study: objective and design
• Objective: Phase 2 study to evaluate DCV + sofosbuvir (SOF), ± ribavirin (RBV), in treatment-naive, genotype (GT)-1-3 infected patients, and in GT1-infected patients who failed telaprevir (TVR) or boceprevir (BOC) treatment
• Primary endpoint: SVR12 following 12 or 24 weeks of treatment
RBV: 1000-1200 mg/day, weight-based (GT 1); 800 mg/day (GT 2/3).
GT, genotype, DCV, daclatasvir, SOF, sofosbuvir (GS-7977), RBV, ribavirin, TVR, telaprevir, BOC, boceprevir, SVR, sustained virologic
response
Chronic HCV
GT1a/1b naive
(n = 126)
n=41
n=15
n=14 C: DCV+SOF
E: DCV+SOF+RBV Follow-up
n=41
n=15
A: 7 d Lead-in × SOF, then DCV+SOF Follow-up
Follow-up
Follow-up
Follow-up
G: DCV + SOF
H: DCV+SOF+RBV
Week 24 SVR12
Week 12 SVR12
Chronic HCV
GT2/3 naive
(n = 44)
n=16 Follow-up
D: DCV+SOF Follow-up
F: DCV+SOF+RBV Follow-up
n=14
B: 7 d Lead-in × SOF, then DCV+SOF
n=14
Follow-up
Week 24 SVR12
I: DCV+SOF Follow-up
J: DCV+SOF+RBV Follow-up
n=21
n=20
Chronic HCV
GT 1, TVR or
BOC failure
(n = 41)
7dLI
7dLI
Sulkowski et al. N Engl J Med 2014;370:211–21.
100% 100% 100% 100% 95%
0
20
40
60
80
100a
A
LIb SOF,
DCV
+ SOF
H
DCV
+ SOF
+ RBV
C
DCV
+ SOF
E
DCV
+ SOF
+ RBV
G
DCV
+ SOF
24 weeks
HC
V R
NA
<LL
OQ
Pa
tie
nts
, %
AI444-040 study: SVR12 primary endpoint (mITT) for
treatment-naive patients
• SVR12 rates were 98% in GT1a and 100% in GT1b
• SVR24 rates ranged from 93–100% in GT1, and 88–100% in GT2/3c
15
15
14
14 41
41
39
41
15
15
12 weeks
aOne patient had missing data at post treatment week 12 but achieved SVR24, and one who was lost to follow-up after achieving SVR4 bLI (lead in) with SOF was not included in subsequent trials c93% and 88% were the percentage for the lead in arm.
HC
V R
NA
<LL
OQ
Pa
tie
nts
, %
92% 89%
0
20
40
60
80
100
24
26
16
18
DCV + SOF
± RBV
24 weeks
DCV + SOF ±
RBV
a
LI, lead in; LLOQ = lower limit of quantitation (25 IU/mL), mITT, modified intent to treat
GT1 GT2 GT3
Sulkowski et al. N Engl J Med 2014;370:211–21.
AI444-040 study: viral breakthrough and relapse
• Confirmed in 1 GT3-infected patient (LI SOF + DCV group B)
• Preexisting NS5A-A30K polymorphism at baseline and relapse No other resistance-associated changes were detected at relapse
Relapse
• GT3 patient (LI SOF + DCV group B) Detectable HCV RNA < 25 IU/ml at weeks 8 and 10
Undetectable HCV RNA at week 12
SVR was achieved following rescue therapy (peg-interferon alfa + RBV)
Viral
breakthrough
• GT1a patient (LI SOF + DCV group A) IV drug-use history
HCV RNA level 670,722 IU/ml at follow-up week 24
Different viral sequences found than at baseline, inconsistent with a viral
relapse
New HCV
infection
Viral breakthrough was defined as a confirmed increase from the nadir in the HCV RNA level of ≥ 1 log10 IU/mL or a confirmed HCV
RNA level of ≥ 25 IU/mL at or after week 8. Relapse was defined as a confirmed HCV RNA level of ≥ 25 IU/mL in patients with an
HCV RNA level that was < 25 IU/mL at the end of treatment.
Sulkowski et al. N Engl J Med 2014;370:211–21.
ALLY-3: Study Design
52
■ Primary endpoint: SVR12
– HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12a
■ Eligible patients
– Age ≥ 18 years with chronic GT 3 infection and HCV RNA ≥ 10,000 IU/mL
– Treatment-naive or -experienced (prior treatment failures), including patients with cirrhosis
– Those who received prior treatment with NS5A inhibitors were excluded
Follow-up DCV 60 mg + SOF 400 mg QD
Day 1 Week 24 Week 36
DCV 60 mg + SOF 400 mg QD
Week 12
Treatment-naive N = 101
Treatment-experienced N = 51
SVR12
GT 3
a Assessed using the Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL).
SVR12 in Patients With Cirrhosis
53
a Cirrhosis status determined in 141 patients by liver biopsy (METAVIR F4), FibroScan (> 14.6 kPa), or FibroTest score ≥ 0.75 and APRI (aspartate aminotransferase to platelet ratio index) > 2. b Cirrhosis status for 11 patients was inconclusive (FibroTest score > 0.48 to < 0.75 or APRI > 1 to ≤ 2).
■ Among patients with cirrhosis, 34% (11/32) had baseline platelet counts < 100,000/mm3
96 97 94
63 58
69
0
20
40
60
80
100
SV
R1
2, %
𝟐𝟎
𝟑𝟐
𝟏𝟎𝟓
𝟏𝟎𝟗
𝟕𝟑
𝟕𝟓
Present Absent
𝟏𝟏
𝟏𝟗
Present Absent Present Absent
Treatment-naive Treatment-experienced Overall
𝟑𝟐
𝟑𝟒
𝟗
𝟏𝟑
Cirrhosisa,b
Aktuelle Therapieoptionen bei Genotyp 2/3
Sofosbuvir + Ribavirin
Sofosbuvir + Daclatasvir
Sofosbuvir + Ledipasvir
55
LDV/SOF + RBV for 12 Weeks for HCV GT 3 Treatment-Experienced
ELECTRON-2
Two-center, open label study in New Zealand Wk 0 Wk 12 Wk 24
LDV/SOF + RBV SVR12
Demographics
Mean age, y (range) 52 (28–66)
Male, n (%) 39 (78)
White, n (%) 40 (80)
Asian, n (%) 3 (6)
Mean BMI, kg/m2 (range) 26.0 (17.5–34.5)
IL28B non-CC, n (%) 32 (64)
Cirrhosis 22 (44)
Mean HCV RNA, log10 IU/mL (range) 6.3 (4.5–7.3)
HCV GT 3a, n (%) 49 (98)
n=50
Gane, AASLD, 2014, Poster #LB-11
56
LDV/SOF + RBV for 12 Weeks for HCV GT 3 Treatment-Experienced
ELECTRON-2: LDV/SOF+RBV in GT 3
LDV/SOF+RBV for 12 weeks resulted in high SVR rates in TE GT3
Overall No Cirrhosis
Cirrhosis
SV
R1
2, %
41/50 25/28 16/22
82 89
73
0
20
40
60
80
100
41/50 25/28 16/22
Gane, AASLD, 2014, Poster #LB-11
Die ideale Therapie der chronischen Hepatitis C
SVR-Raten von (fast) 100%
Auch für Patienten mit dekompensierter Leberzirrhose,
prä-LTX, post-LTX, Coinfizierte geeignet
Keine Nebenwirkungen
Kurze Therapiedauer
Einfacher Einnahmemodus
Haare in der Suppe
Abbau und Transport von Medikamenten (Typ 1)
Metabolisierende Enzyme CYP 3A4 CYP 2C8 UGT 1A1
Inhibitor
Substrate (Begleitmedikation)
Transporter P-gp BCRP
OATP1B1/B2
Viekirax Exviera
Substrate (Begleitmedikation)
Benzodiazepine
Calcium-Kanal-Blocker
DOSISREDUKTION DER BEGLEITMEDIKATION
Statine
Viekirax & Exviera EU SmPC Nach Leonie Meemken, Pharmakologin (SMZ Süd)
Carbamazepin Phenobarbital
Phenytoin Johanniskraut
Metabolisierende Enzyme CYP 3A4
Induktor
Transporter P-gp
ALLE DAAs
Carbamazepin Phenobarbital
Phenytoin Johanniskraut
ALTERNATIVE: GABAPENTIN, PREGABALIN
Abbau und Transport von Medikamenten (Typ 4)
Viekirax & Exviera EU SmPC Nach Leonie Meemken, Pharmakologin (SMZ Süd)
www.hep-druginteractions.org
Mögliche Interaktionen leicht herausfinden
Diese Medikamente sollten nicht verabreicht werden
Mögliche Interaktion– Monitoring oder Dosisanpassung ev. nötig
Keine Interaktion zu erwarten
Website: www.hep-druginteractions.org
38,7
86,7 80.0 94,7
0
20
40
60
80
100
4 wks 6 wks 6 wks 8 wks
SVR
4/8
(%
) D1
102 G1 ± cirrhosis treated with grazoprevir 100 mg/elbasvir 50 mg FDC QD + SOF 400 mg QD
G1a 76–87%
Viral load >6 million IU/mL in 17–19% non-cirrhotics and 0–5% in cirrhotics
Safety
HA, fatigue, nausea (3–10%)
No anemia, no bili >5x BL; no AST/ALT >5x ULN
C-SWIFT: MK-5172 (grazoprevir)+ MK-8742 (elbasvir) + SOF in treatment-naive G1 pts with/without cirrhosis, for 4, 6, or 8 weeks
Lawitz E, et al. AASLD 2014, Boston. #LB-33
TW4 TW8 TW12
n=31
n=30
n=20
n=21
n=20
n=15
n=10
No
n-
cirr
ho
tic
Cir
rho
tic
G3
G
1
Primary endpoint: SVR12
Cir
rho
tic
No
n-
cirr
ho
tic
Non-cirrhotic Cirrhotic
FU2
8 wks 6 wks 6 wks 4 wks
TW 1 2 4 FU2 1 2 4 6 FU2 1 2 4 6 FU2 1 2 4 8
16
68
81
100 100 100 100 100 100
20
83 97
25
45
85 90
10
32
0
25
50
75
100
HC
V R
NA
<1
5IU
/mL
5/ 31
21/ 31
60
25/ 31
31/ 31
6/ 30
18/ 30
25/ 30
29/ 30
30/ 30
5/ 20
9/ 20
17/ 20
20/ 20
20/ 20
2/ 19
6/ 19
17/ 19
19/ 19
19/ 19
12/31 26/30
Breakthrough 0 0 0 0
Relapse
All relapse 19 4 4 1
Relapse at FU4 10 4 2 1
Relapse at FU8 9 0 2 0
16/20 18/19
Ungelöste Probleme
Hohe Therapiekosten
Erfassung aller Infizierten
(Screeningprogramme)
Zusammenfassung
• Die Entwicklung der neuen Hepatitis C Therapien stellt wahrscheinlich die größte medizinische Sensation der letzten Jahre dar.
• Mit den neuen Patienten könnte (fast) jeder Patient ohne relevante Nebenwirkungen geheilt werden.
• Aus medizinischer Sicht sollte jeder Patient mit chronischer Hepatitis C behandelt werden.
• Die Hepatitis C wäre die erste virale Erkrankung, die durch eine Therapie ausgerottet werden könnte.
• Leider gibt es derzeit zwei limitierende Faktoren: - Hohe Therapiekosten - Fehlendes Screening