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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f cas
es
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
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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
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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
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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