Approved regimens for cirrhotic patients

Amsterdam, 4-5 december 2015

5th Workshop on HCV THERAPY ADVANCES New antivirals in clinical practice

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Num

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Year

F0

F1

F2

F3

F4 ans its complications

Deuffic-Burban et al, Gastroenterology 2012

Peak cirrhosis and its complications

2030

In the next 10 yrs, the number of decompensated cirrhosis will increase by 4.

Disease burden in Spain

Case 1. Fibrosis 4

63 yrs old man. HCV genotype 1b. Naïve. Asymptomatic

Blood transfusion 35 yrs before Liver biopsy 20 yrs before: chronic active hepatitis

Fibroscan: 15 kpas Elevated transaminases (ALT 87 IU, AST 68 IU)

Upper endoscopy: normal Lack of comorbidities

3 cm HCC detected on screening US-------RF-----Complete RX response

Case 1. Fibrosis 4

63 yrs old man. HCV genotype 1b. Treatment experienced* Asymptomatic

Blood transfusion 35 yrs before Liver biopsy 20 yrs before: chronic active hepatitis

Fibroscan: 15 kpas Elevated transaminases (ALT 87 IU, AST 68 IU)

Upper endoscopy: normal Lack of comorbidities

*- 2005: pegIFN + RBV at optimal doses----Partial Response - 2012: Triple therapy with telaprevir, pegIFN, RBV---- Response with relapse

HCV genotype 1a

Case 2. Compensated cirrhosis with portal HPT

63 yrs old man. HCV genotype 1a. IL28B CT. Asymptomatic

Two prior failed therapies: - 2005: pegIFN + RBV at optimal doses----Partial Response - 2012: Triple therapy with telaprevir, pegIFN, RBV---- Response with relapse

Fibroscan: 19 kpas Upper endoscopy: small EV

Laboratory tests: ALT 87 IU, AST 68 IU, GGT 69 IU, Hgb 12.5 g/dl, platelet count 78,000/u Child A, MELD score 8

Comorbidities: IDDM, depression (citalopram)

Case 3. Decompensated cirrhosis

HCV genotype 1a. IL28B CT. Two prior failed therapies:

- 2007: pegIFN + RBV at optimal doses----Null Response - 2011: Triple therapy with telaprevir, pegIFN, RBV----premature D/C.

Relapse

Upper endoscopy: large EV (prophylaxis - B-blocker) Ascites (spironolactone 200 mg + furosemide 40 mg/day)

Laboratory tests: ALT 87 IU, AST 68 IU, GGT 69 IU, Hgb 11.5 g/dl, platelet count 30,000/u; Bilirubin 3.2 mg/dl, Albumin 2.7 mg/dl, INR

1.7, creatinine 1.5 mg/dl MELD score 20, Child C

Natural history of HCV cirrhosis

Modified from Friedman SL. Gastroenterology 2008;134:1655–69

HCS: hyperdynamic circulatory status; HE: hepatic encephalopathy; HRS: hepatorrenal syndrome; HVPG: hepatic venous gradient; RA: refractory ascites; SBP: spontaenous bacterial peritonitis;

Major Descompensation

Recurrent variceal bleeding, HRS, SBP

Insoluble scar

Clinical

Symptoms

Histology

F1–F3 F4 (Cirrosis)

HVPG

Biology

Hemodynamic

HCS

Functional

No cirrhosis

None

Compensated

None (no varices)

Scar & cross linking

Compensated

No (varices present)

Thick scars & nodules

Decompensated

Ascites, variceal bleeding, EH

Insoluble scar

Increasing fibrogenesis

≥10 ≥12 >20

Increasing vasodilatation

Worsening liver function

>6

Fibrogenesis and neovascularization

Agenda

Aims / Benefits of antiviral therapy in the cirrhotic population

Treatment of the cirrhotic patient with DAAs

Agenda

Aims / Benefits of antiviral therapy in the cirrhotic population

Treatment of the cirrhotic patient with DAAs

Goals of antiviral therapy in the cirrhotic population

Compensated cirrhosis: Reduce rates of decompensation Reduce rates of HCC development/HCC recurrence? Reversal of cirrhosis

Decompensated cirrhosis:

Improve survival while in the WL for LT Prevent HCV recurrence post-LT Improve clinical condition and reduce the need for LT

HCV & Therapy: effects on outcome

0 10 20 30 40 50 60 70 80 90

100

Pretreatment Postreatment

D’Ambrosio R, et al. Hepatology. 2012;56:532-543.

F4 F3

F2 F1 Changes in Fibrosis

N=530

van der Meer AJ, et al. JAMA. 2012; 308(24):2584-2593

HCC (n=307)

Liver-Related Complications* (n=307)

*Ascites, variceal bleeding. 307 HCV patients with bridging fibrosis (n=127) or cirrhosis (n=180) Non-SVR in 67% of patients treated with pegylated interferon plus ribavirin. Median follow-up: 3.5 years.

Cumulative Incidence (%

)

Follow-Up (years)

SVR

Cumulative Incidence (%

)

Follow-Up (years)

Non-SVR

P

Effect of SVR on the risk of LT, HCC, death Meta-analysis of 129 studies in 34.563 patients with HCV

(mean FU ≈5 yrs)

Hill et al, AASLD 2014 (abst 44)

LT

HCC

Death

SVR NR

Agenda

Aims / Benefits of antiviral therapy in the cirrhotic population

Treatment of the cirrhotic patient with DAAs

Treatment of the compensated cirrhotic patient with DAAs

Compensated cirrhosis

PK profile of treatment

HCV genotype

Prior treatment response

Patient comorbidities (i.e: renal

impairment,..)

Drug-Drug interactions

Severity of liver

impairment

Possible Mechanisms for Decreased Response in Cirrhosis

•Drug toxicity Increased adverse events with early discontinuation

•Drug delivery Intrahepatic shunting with decreased exposure in hepatocytes

•Drug uptake/metabolism Altered cytochrome p450 function

•Altered Immune function Reduced Kuppfer cell mass Altered cytokine milieu

493/513

SV

R12

(%)

305/322 188/191

Overall 12 Weeks 24 Weeks

21

• Of 513 patients, 20 failed to achieve SVR12 – 18 relapsed – 1 LTFU, 1 death (presumed infection)

SOF/LDV ± RBV 12-24 weeks

Bourliere M, AASLD 2014

Gráfico1

Overall1.62

12 Weeks1.93.3

24 Weeks1.72.5

SVR12 Gt 2

96

95

98

Sheet1

SVR12 Gt 2hilohilo

Overall961.6297.694

12 Weeks951.93.396.991.7

24 Weeks981.72.599.795.5

Total Treatment

Naïve Treatment

Experienced

Overall SVR12

Duration 12 wk

24 wk

Regimen LDV/SOF

LDV/SOF + RBV

Duration/ ± RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

SOF/LDV ± RBV 12-24 weeks

SVR12, %

96% 98% 95%

95% 97% 94%

98% 99% 98%

95% 96% 95%

97% 99% 96%

92% 96% 90%

96% 98% 96%

98% 97% 98%

100% 100% 100%

22

Gráfico1

97.51.83.7

96.72.65.9

98.61.46.4

96.32.96.9

98.81.25.5

95.73.810.2

97.82.19.6

972.912.8

10009.7

0��

9

8

7

6

5

4

3

2

1

Forest Plot

Treatment Naïve: SVR12CI lowerCI upperRateCI lowerCI upperlowerupper

Overall997.593.899.33.71.8

Duration 12896.790.899.35.92.6

Duration 24wk798.692.21006.41.4

Regimen LDV/SOF696.389.499.26.92.9

Regimen LDV/SOF + RBV598.893.31005.51.2

Duration 12wk495.785.599.510.23.8

w/ RBV 12wk397.888.299.99.62.1

24wk29784.299.912.82.9

w/ RBV 24wk110090.31009.70

0

Forest Plot

99.390.8

10092.2

99.289.4

10093.3

99.585.5

99.988.2

99.984.2

10090.3

��

Plan1

This work is licensed under a Creative Common license Attribution 3.0 Unported (CC BY 3.0).

More information at http://creativecommons.org/licenses/by/3.0/

Permission to use program if source is cited. Neyeloff J, Fuchs S, Moreira L. Meta-analyses and forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.

More information at http://creativecommons.org/licenses/by/3.0/

Gráfico1

96.11.52.1

94.72.23

98.41.32.9

95.22.33.4

96.91.82.8

92.44.16.4

96.12.23.7

97.71.84.2

10006.2

0��

9

8

7

6

5

4

3

2

1

Forest Plot

Total: SVR12CI lowerCI upperRateCI lowerCI upperlowerupper

Overall996.19497.62.11.5

Duration 12894.791.796.932.2

Duration 24wk798.495.599.72.91.3

Regimen LDV/SOF695.291.897.53.42.3

Regimen LDV/SOF + RBV596.994.198.72.81.8

Duration 12wk492.48696.56.44.1

w/ RBV 12wk396.192.498.33.72.2

24wk297.793.599.54.21.8

w/ RBV 24wk110093.81006.20

0

Forest Plot

96.991.7

99.795.5

97.591.8

98.794.1

96.586

98.392.4

99.593.5

10093.8

��

Plan1

This work is licensed under a Creative Common license Attribution 3.0 Unported (CC BY 3.0).

More information at http://creativecommons.org/licenses/by/3.0/

Permission to use program if source is cited. Neyeloff J, Fuchs S, Moreira L. Meta-analyses and forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.

More information at http://creativecommons.org/licenses/by/3.0/

Gráfico1

95.51.92.8

93.92.73.9

98.41.44.2

94.72.94.5

96.12.33.9

90.15.89.4

95.62.64.5

981.85

100015.4

0��

9

8

7

6

5

4

3

2

1

Forest Plot

Treatment Experienced: SVR12CI lowerCI upperRateCI lowerCI upperlowerupper

Overall995.592.797.42.81.9

Duration 12893.99096.63.92.7

Duration 24wk798.494.299.84.21.4

Regimen LDV/SOF694.790.297.64.52.9

Regimen LDV/SOF + RBV596.192.298.43.92.3

Duration 12wk490.180.795.99.45.8

w/ RBV 12wk395.691.198.24.52.6

24wk2989399.851.8

w/ RBV 24wk110084.610015.40

0

Forest Plot

96.690

99.894.2

97.690.2

98.492.2

95.980.7

98.291.1

99.893

10084.6

��

Plan1

This work is licensed under a Creative Common license Attribution 3.0 Unported (CC BY 3.0).

More information at http://creativecommons.org/licenses/by/3.0/

Permission to use program if source is cited. Neyeloff J, Fuchs S, Moreira L. Meta-analyses and forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.

More information at http://creativecommons.org/licenses/by/3.0/

HCV Subtype 1a Poordad F, et al. N Engl J Med. 2014;370:1973-82

92.2

12-week arm

24-week arm

92.9

Naïve Prior Relapse Response

3D + RBV

SVR1

2, %

Pat

ient

s

59/64 14/15 52/56 13/13

93.3 100 100 100 80.0 92.9

11/11 40/50 10/10 39/42

Prior Partial Response

Prior Null Response

3D: ABT-450/ ritonavir/ombitasvir, 150 mg/100 mg/25 mg qd; dasabuvir, 250 mg bid RBV: 1000-1200 mg/d

SVR in HCV GT1 treatment-naive and experienced cirrhotic patients

Turquoise II

Zeuzem S et al. N Engl J Med 2014

Noncirrhotic

212/250 12/13

94

86/92 Naïve,

Noncirrhotic

87

87/100 Experienced, Noncirrhotic

92

Naïve, Cirrhotic

60

27/45 Experienced,

Cirrhotic

SVR12 (%

)

0

20

40

60

80

100 85

Overall

212/250

Overall

Cirrhotic

Sofosbuvir + RBV for G3 24 weeks therapy

Valence

ALLY-3: DCV+SOF 12 weeks SVR12

Nelson DR, et al. Hepatology. 2015. 2015;61:1127-1135.

96 97 94

63 58

69

0

20

40

60

80

100

Present Absent Present Absent Present Absent

b

SVR

12 (

%)a

Naïve Pretreated All Patients

105 109

20 32

73 75

11 19

32 34

9 13

Cirrhosisc

aHCV-RNA14.6 kPa), or FibroTest ≥0.75 & APRI >2 in 141 patients,; 11 patients had non conclusive results

(FibroTest between >0.48 & 1 - ≤2).

ALLY-3+: SOF+DCV+RBV 12 vs 16 wks SVR12: Patients with Cirrhosis

ALLY-3+

ITT ANALYSIS

VBTa 0 0 0 Relapseb 4 2 2 Deathc 1 1 0

VBT 0 0 0 Relapse 4 2 2

OBSERVED ANALYSIS

0102030405060708090

10089 88 89

16 18

Overall 12 Weeks 16 Weeks HC

V RN

A <

LLO

QTD

/TN

D (%

)

31 35

15 17

0102030405060708090

100

15 18

16 18

86 83 89

Overall 12 Weeks 16 Weeks

HCV

RNA

< LL

OQ

TD/T

ND

(%)

31 36

27

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; cirrhosis status diagnosed by liver biopsy (F4) n = 9; FibroScan ≥ 14.6, n = 27.

DCV+SOF±RBV in GT-3 SVR4 in advanced fibrosis/cirrhosis

(French ATU GT3) Hezode et al. Poster LP05. EASL 2015

76 88 92 83

0102030405060708090

100

DCV + SOF ± RBV 12 weeks

DCV + SOF ± RBV 24 weeks

Cirrhosis No cirrhosis

SVR-

4, %

22/29 11/12 52/59 5/6

(N=106)

Genotype 1 Treatment

Population LDV/SOF OMV/PTV/RTV + DSV SMV + SOF GT 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV GT 1a, cirrhosis 12 wks 24 wks + RBV 24 wks ± RBV GT 1b, no cirrhosis 12 wks 12 wks 12 wks GT 1b, cirrhosis 12 wks 12 wks + RBV 24 wks GT 1 P/R failure, no cirrhosis 12 wks

12 wks + RBV (1a) 12 wks (1b) 12 wks ± RBV

GT 1 P/R failure, cirrhosis 24 wks or 12 wks + RBV 24 wks + RBV (1a) 12 wks + RBV (1b) 24 wks ± RBV

GT 1 SOF failure, cirrhosis 24 wks ± RBV Not recommended Not recommended

GT 1 PI failure, no cirrhosis 12 wks Not recommended Not recommended

GT 1 PI failure, cirrhosis 24 wks or 12 wks + RBV Not recommended Not recommended

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C.

GT3 recommendations (EASL 2015)

24 sem GT-3

SOF + RBV

-

SOF + LDV

-

OBV/ PTV/r +

DSV

OBV/ PTV/r

-

SOF + SMV

DCV + SOF

- 12 weeks

Non-cirrhotic patients* (mono & coinfected)

Compensated cirrhosis* (mono & coinfected)

- GT-3

SOF + RBV

-

SOF + LDV

-

OBV/ PTV/r +

DSV

OBV/ PTV/r

-

SOF + SMV

DCV + SOF

- 24 weeks + RBV

EASL guidelines 2015, DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.025. Access: May 2015. *naïve & non-responders to PegIFN+RBV

12 + RBV?

Toxicity associated with RBV

Patients, n (%)

LDV/SOF 12 and 24 Wk

n=251

LDV/SOF + RBV 12 and 24 Wk

n=262 Total

N=513

AEs 190 (76) 225 (86) 415 (81)

Treatment-related AE 118 (47) 196 (75) 314 (61)

Grade ≥3 AE 19 (8) 20 (8) 39 (8)

Serious AE 15 (6) 9 (3) 24 (5)

Treatment-related serious AE 1 (

Natural history of HCV cirrhosis: SVR rates with IFN-free regimes

Modified from Friedman SL. Gastroenterology 2008;134:1655–69

HCS: hyperdynamic circulatory status; HE: hepatic encephalopathy; HRS: hepatorrenal syndrome; HVPG: hepatic venous gradient; RA: refractory ascites; SBP: spontaenous bacterial peritonitis;

Major Descompensation Recurrent variceal bleeding, HRS, SBP

Insoluble scar

Clinical

Symptoms

Histology

F1–F3 F4 (Cirrosis)

HVPG

Biology

Hemodynamic

HCS

Functional

No cirrhosis

None

Compensated

None (no varices)

Scar & cross linking

Compensated

No (varices present)

Thick scars & nodules

Decompensated

Ascites, variceal bleeding, EH

Insoluble scar

Increasing fibrogenesis

≥10 ≥12 >20

Increasing vasodilatation

Worsening liver function

>6

Fibrogenesis and neovascularization

100% 95% 90% 80-85%

Any antiviral combination (GT, local availability))

PK (renal &liver impairment), DDI

Approved regimens for cirrhotic patientsSlide Number 2Slide Number 3Slide Number 4Slide 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 17Slide Number 18Slide Number 19Slide Number 20SOF/LDV ± RBV 12-24 weeksSOF/LDV ± RBV 12-24 weeksSlide Number 23Slide Number 24Slide Number 25ALLY-3: DCV+SOF 12 weeks�SVR12ALLY-3+: SOF+DCV+RBV 12 vs 16 wks�SVR12: Patients with CirrhosisDCV+SOF±RBV in GT-3�SVR4 in advanced fibrosis/cirrhosisGenotype 1 TreatmentGT3 recommendations (EASL 2015)�Toxicity associated with RBVSlide Number 32Slide Number 33