HCV Treatment around the world: Patients in Germanyregist2.virology-education.com/2015/5thHCVadv/13_Wedemeyer.pdf · 1 Heiner Wedemeyer Hannover Medical School Germany HCV Treatment

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


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


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


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


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?


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


ALT 84 IU/L; AST 50 IU/L Bilirubin, albumin, INR normal Platelets 205.000


Possible treatment options in Germany




Petra

42 years





Petra

42 years



Treatment for 8 weeks No ribavirin! SVR!

Jan 2015




Petra

42 years



Still 8 weeks?


Assay: Abbott ART



Petra

42 years




How long to treat?



Are 8 weeks possible? SOF/LDV label allows 8 weeks SIM-SOF 8 weeks? 3D 8 weeks in G1b?


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


Alexander

52 years


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


Possible treatment options in Germany





Alexander

52 years






Ombitasvir/Paritaprevir/r + Dasabuvir without ribavirin in patients with compensated cirrhosis

Turquoise III

Feld et al. J Hepatol 2015; epub


Alexander

52 years



Treatment for 12 weeks SVR

June 2014


Fibroscan values Baseline 34 kPa EOT 22 kPa Fu-24 19 kPa Fu-48 11 kPa



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


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


Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort

Albumin Prothrombin time

Deterding et al., AP&T 2015



Bilirubin Cholinesterase



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


12 vs. 24 weeks? Ribavirin yes/no?




Changes in MELD Scores baseline-FU-week 12


Horst



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 Ribavirin 24 weeks

24 weeks





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


TN Noncirrhotic9592

TE Noncirrhotic876286.397.68.72.6

TN Cirrhotic9278.492.78.65.7


46.475.515.613.5

Diagramm1

81

78

74

44

Noncirrhotic

Sheet1


TN Noncirrhotic8192

TE Noncirrhotic786286.397.6-5.316.6

TN Cirrhotic7478.492.7-0.414.7


46.475.5-2.431.5


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


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


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


Advanced Fibrosis_Cirrhosis

000

1414

66

88

3236

1518

1718

ADVANCED FIBROSIS

CIRRHOSIS



Horst (b)



ALT 104 IU/L; AST 119 IU/L Bilirubin, albumin, INR normal Platelets 135.000 Fibroscan: 22.1 kPa Strongly refuses PEG-IFNa


12 weeks




24 weeks





Horst (c)



ALT 114 IU/L; AST 104 IU/L Bilirubin, albumin, INR normal Platelets 175.000 Fibroscan: 17.1 kPa Strongly refuses PEG-IFNa


12 weeks




24 weeks




Sofosbuvir PEG-IFNa Ribavirin 12 weeks


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%


Horst (d)



ALT 114 IU/L; AST 104 IU/L Bilirubin, albumin, INR normal Platelets 175.000 Fibroscan: 17.1 kPa NS5A RAV at position 93


12 weeks




24 weeks





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

Documents

HCV Treatment around the world: Patients in Germanyregist2.virology-education.com/2015/5thHCVadv/13_Wedemeyer.pdf · 1 Heiner Wedemeyer Hannover Medical School Germany HCV Treatment