Therapie der chronischen Hepatitis C 2015 Alle Probleme ......Peginterferon + Ribavirin + Telaprevir...

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

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.





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




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


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


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

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

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


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


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


Sofosbuvir + Ribavirin



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 =

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


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


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.


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

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

http://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

Therapie der chronischen Hepatitis C 2015 Alle Probleme ......Peginterferon + Ribavirin + Telaprevir...

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