Transcript Asian-Pacific Consensus Statement on the Management of

STRATIFYING RISK OF
COMPLICATIONS IN
HCV CIRRHOSIS
Dr Ed Gane
NZ Liver Transplant Unit
Demand for Liver Transplantation is expected
to treble by 2025, because of aging population
60
Liver failure (NZLTU)
225
Liver cancer (NZLTU)
200
50
Numbers per annum
175
40
150
125
30
100
75
20
50
10
25
0
0
1992/3 1994/5 1996/7 1998/9 2000/1 2002/3 2004/5 2006/7 2008/9 2010/112012/13
1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2013
2
Hepatitis C has already become the most
common indication for Liver Transplantation
Liver transplant (ANZLTR)
225
200
# per annum
175
150
Other
ALD
NASH
HBV
HCV
HCV-related mortality will treble by 2030
125
100
75
50
25
0
1992
1994
ANZLTR DATA TO 31/12/2012
SECTION 2 : Primary Diagnosis
1996
1998
2000
2002
2004
2006
2008
2010
2012
3
24th ANZLT Registry
Report
What are predictors for decompensation?
 HALT-C: 1050 patients with advanced fibrosis followed 8 yrs
– 622 with F3 (bridging fibrosis); 428 with F4 (cirrhosis)
– After 5 years mortality twice as high in cirrhotics
Dienstag JL et al. Hepatology 2011; 54: 396-405
DiBisceglie A, et al. NEJM 2008; 359: 2429-55
Baseline Cirrhosis is associated with more liverrelated complications than Bridging Fibrosis
Liver-related death
Death
Death/Transplant
50
50
40
40
30
30
20
20
10
10
0
0
60
Cumulative incidence (%)
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
Years after randomisation
Years after randomisation
Years after randomisation
Cirrhosis
Bridging Fibrosis
Dienstag JL et al. Hepatology 2011; 54: 396-405
Low albumin and platelets are associated with high
rate of liver-related complications
Dienstag JL et al. Hepatology 2011; 54: 396-405
Liver stiffness is as good as biopsy for predicting
liver-related complications and reduced survival
 1457 untreated HCV+ patients followed for 5 years
Vergniol J, et al. Gastroenterology 2011; 141: 1970-9
Liver stiffness is associated with high rate of liverrelated complications and reduced survival
 1457 untreated HCV+ patients followed for 5 years
Vergniol J, et al. Gastroenterology 2011;140:1970–79
Presence of oesophaeal varices is associated with
high rate of liver-related complications
 352 patients with compensated HCV-cirrhosis
– 16% had oesophageal varices (Stage II)
– followed for 14.5 years
139 developed ascites or encephalopathy
109 developed HCC
158 died
9 transplanted
Bruno S, et al. Am J Gastro 2009; 104: 1147-58
Presence of oesophaeal varices is associated with
high rate of liver-related complications
Bruno S, et al. Am J Gastro 2009; 104: 1147-58
Presence of oesophaeal varices is associated
with high rate of liver-related complications
Bruno S, et al. Am J Gastro 2009; 104: 1147-58
Baseline MELD is associated with high rate of
liver-related complications and reduced survival
 MELD = 9.57 x Loge Creatinine (mg/dl) +3.78 x Loge Bilirubin (mg/dl)
+ 11.2 x Loge (INR) + 6.43 (bili, INR and creat <1.0 adjusted to 1.0)
Wiesner R, et al. Gastroenterol;2003:124:91-96.
Bruno S, et al. Am J Gastro 2009; 104: 1147-58
Predictors of liver-related complications
and mortality in patients with HCV cirrhosis
Viral Factors
Host Factors
 HCV genotype
genotype
 HIV co-infection
co-infection
 HBV co-infection
co-infection






Age
Immunosuppression
Alcohol abuse
Cannabis abuse
Metabolic syndrom
Coffee consumption
Treatment Response
 SVR
HCV Genotype 3 associated with
accelerated fibrosis progression
Progression to Fibrosis Stage 1-2
Bochud et al. J Hepatol 2009; 51: 655-666.
Progression to Fibrosis Stage 3-4
HCV Genotype 3 associated with increased
risk for HCC
15 year study of 425 French patients with HCV-cirrhosis
HCV genotype was the strongest predictor for HCC
– After 5 years, HCC in 44% HCV GT-3 vs. 26% non-GT-3 (p<0.001)
Nkontchou G. J Viral Hep 2011; 18: e516-22;
HCV Genotype 3 may be associated with
accelerated disease progression
 Epidemiological studies in Pakistan, India and
France all reported higher HCC rates in GT-31,2,3
 Putative mechanisms include:
1.Accelerated progression to cirrhosis1
• Increased alcohol abuse (link with IDU)
• HCV GT-3 induced steatosis
2.Accelerated hepatocarcinogenesis
• Steatotic effect of HCV GT-3a leading to increased
oxidative stress from lipid peroxidation4
• Anti-apoptopic effect of HCV GT-3a core protein5,6
1Nkontchou
G. J Viral Hep 2011;18:e516-22; 2Khan J Med Virol 2009; 81: 1189-97; 3Larsen C. J Med Virol
2010; 82: 1647-54; 4Jahan S. Virology Jn 2011; 8: 522-33; 5Jahan S. Inf Agents and Cancer 2012;7:2-9
6 Moriya K. Nature Med 1998; 9: 1065-69
Predictors of liver-related complications
and mortality in patients with HCV cirrhosis
Viral Factors
Host Factors
 HCV genotype
 HIV co-infection
 HBV co-infection






Age
Immunosuppression
Alcohol abuse
Cannabis abuse
Metabolic syndrom
Coffee consumption
Treatment Response
 SVR
Alcohol Consumption is associated with doserelated increased risk of HCV progression
1. Epidemiological evidence in patients with HCV
Study
N
Outcome
Amount
OR
Thomas 2000, USA IDU
1667
Cirrhosis
>40 g/day
3.6
Bedogni 2008, Italy
139
Cirrhosis
>30 g/day
4.1
Hutchison 2005, USA
15,000
Cirrhosis
>40 g/day
2.3
Delarocque 2005, France
3404
Cirrhosis
>5 drinks/day 3.4
Kayali 2007, USA VA
854
Cirrhosis
>145 kg/life
10.6
Tagger 1999, Italy
221
HCC
40-80 g/day
>80 g/day
2.4
4.0
Hassan 2002, USA
245
HCC
>80 g/d
4.5
Said 2011, USA
1611
Liver Death
>30 g/day
2.8
Bedogni 2008, Italy
139
Liver Death
>30 g/day
8.5
Alcohol Consumption is associated with doserelated increased risk of disease progression
 Hepatotoxic effects explained by:
1. Increased HCV replication, quasispecies generation and
cellular protein expression (acute effect within 48 hrs)
2. Increased hepatocyte fat accumulation
3. Increased liver iron accumulation
4. Increased oxidative stress from depletion of free radicals
5. Increased apoptosis
6. Impaired cellular immune response to HCV infection due to




Block cytoplasmic transduction pathways
Decreasing T cell stimulation and interferon production
Altered dendritic cell function
Inhibition of antiviral actions of exogenous IFN
Alcohol Consumption is associated with doserelated increased risk of disease progression
 What level of alcohol intake is safe in HCV?
– 260 HCV+ patients who drank <50g/day
P<0.001
68
38
34
28
Hézode et al. Alimentary Pharmacology and Therapeutics 2003; 17:1031–1037
Cannabis Consumption is associated with doserelated increased risk of disease progression
 204 referrals with HCV underwent liver biopsy
– 59% used cannabis; 14% daily
– 18% had severe fibrosis/cirrhosis
 Multivariate analysis of risk factors for cirrhosis
Odds Ratio
P-value
Daily cannabis
6.78 (1.89–24.3)
use
4 drinks per day 1.72 (1.02–2.90)
(per 10 years)
0.003
Age
(per 10 years)
0.064
2.19 (0.95–5.05)
0.044
Ishida J, et al. Clin Gastro Hepatol 2008;6:69–75
Cannabis Consumption is associated with doserelated increased risk of disease progression
 270 referrals with HCV underwent liver biopsy
– Careful history of cannabis and alcohol use
% with cirrhosis
60%
<1 joint per day
At least 1 joint per day
45%
39%
40%
20%
60%
12%
 activation of CB1 receptors on hepatic
<3 drinks/day
at least 3 drinks/day
myofibroblasts
 stellate cell
Alcohol Consumption
proliferation and rapid fibrogenesis
 Effect synergistic with alcohol
0%
Hezode C, et al. Hepatology 2005;42:63-71.)
Coffee Consumption is associated with doserelated reduced risk of disease progression
1. Epidemiological evidence
Study
N
Aetiology Outcome
Amount
Klatsky 1992, USA
128,934
ALD
Cirrhosis
>4 cups 0.2
Ruhi 2005, USA
9849
All
Cirrhosis
>2 cups 0.43
Modi 2010, USA
177
HCV
Cirrhosis
>2 cups 0.33
Malloy 2012, USA
306
NASH
Cirrhosis
>2 cups 0.5
Freedman 2009, USA
766
HCV
Liver failure
>2 cups 0.73
Leung 2011, HK
234
HBV
HCC
>2 cups 0.54
Johnson 2011, China
63,257
HBV
HCC
>2 cups 0.53
Bravi 2007, Italy
1551
All
HCC
>1 cup
Larsson 2007
241,405
All
HCC
>2 cups 0.57
NASH
Liver Death
>2 cups 0.34
Boon 2014, Singapore 63,275
OR
0.59
Coffee Consumption is associated with doserelated reduced risk of disease progression
1. Epidemiological evidence
Study
N
Aetiology Outcome
Amount
Klatsky 1992, USA
128,934
ALD
Cirrhosis
>4 cups 0.2
Ruhi 2005, USA
9849
All
Cirrhosis
>2 cups 0.43
Modi 2010, USA
177
HCV
Cirrhosis
>2 cups 0.33
Malloy 2012, USA
306
NASH
Cirrhosis
>2 cups 0.5
Freedman 2009, USA
766
HCV
Liver failure
>2 cups 0.73
Leung 2011, HK
234
HBV
HCC
>2 cups 0.54
Johnson 2011, China
63,257
HBV
HCC
>2 cups 0.53
Bravi 2007, Italy
1551
All
HCC
>1 cup
Larsson 2007
241,405
All
HCC
>2 cups 0.57
NASH
Liver Death
>2 cups 0.34
Boon 2014, Singapore 63,275
OR
0.59
Coffee Consumption is associated with doserelated reduced risk of disease progression
2. Prospective Study
 376 HCV+ Japanese patients followed for 12 months
 229 had normal ALT, 149 had elevated ALT at baseline
Normal ALT at baseline
25%
% with ALT> ULN
24%
23%
20%
Elevated ALT at baseline
18%
100%
P=0.01
P=0.03
90%
82%
14%
15%
12%
10%
10%
5%
60%
0%
50%
Baseline
78%
80%
Nil
1 cup
70%
2+ cups
6 months 12 months
71%
70%
71%
62%
Baseline
6 months 12 months
 Coffee had dose-related cumulative protective effect
 Decaf coffee, Black tea, Green Tea had no effect
Sasaki Y. PLOS ONE 2014; Volume 8 | Issue 12 | e83382
Coffee Consumption is associated with doserelated reduced risk of disease progression
 Hepatoprotective effects could be explained by:
1. Decreased TGF-b and connective tissue-GF expression
2. Increased adiponectin levels and decreased leptin levels
3. Increased detoxification through activation of UGP
4. Anti-oxidant effects of caffeine and CGA, a polyphenol
(found in high levels only in Columbian coffee)
5. Anti-tumour effect of kahweol, a diterpene with potent
anti-angiogenic and anti-inflammatory properties
Predictors of liver-related complications
and mortality in patients with HCV cirrhosis
Viral Factors
Host Factors
 HCV genotype
 HIV co-infection
 HBV co-infection






Age
Immunosuppression
Alcohol abuse
Cannabis abuse
Metabolic syndrom
Coffee consumption
Treatment Response
 SVR
Aims of therapy in cirrhosis
1. Improve quality of life
2. Reverse fibrosis
3. Prevent liver failure
4. Prevent hepatocellular carcinoma
5. Prevent death/transplant
IFN-based therapy is less effective in cirrhosis
 Chariot Study: 896 GT 1 pts (Australian/NZ)
– Peg-IFN(180mg or 360mg) plus RBV for 48wks
Peg-IFN 360mcg+RBV
71%
Rate of SVR (Cure)
80%
62%
60%
51%
40%
33%
20%
0%
14%
17/25
20/28
F0
60/104 66/107
57/113 62/121
F1
F2
15/51
15/46
F3
1/16
2/14
F4
Stage of Fibrosis (Metavir)
Cheng W, et al. J Hepatol 2010; 53: 616-23
SVR Rates in Patients With HCV GT 1 Cirrhosis
1986 1998
2013 - 14
2001 2004 2011
2015 - 16
100
SVR Rate (%)
80
60
40
20
0
IFN
24 wks
IFN
48 wks
IFN/RBV
48 wks
PEGIFN/RBV
48 wks
TVR/BOC
PEG/RBV
48 wks
SMV/PEG SOF/PEG
/RBV
/RBV
24 wks
12 wks
AbbVie
3D+RBV
12 wks
LDV/SOF
FDC
12 wks
Highly Effective DAA therapy may
paradoxically increase numbers of HCC
20-yr outcomes based on SVR rate
80
% HCC
% death ESLD
% death overall
60
40
20
0
0
10
20
30
40
50
60
SVR rate (%)
Kim WR, et al. J Hepatol 2013; A653
70
80
90
100
SVR reduces all-cause mortality
All-cause mortality (%)
230 HCV patients with advanced fibrosis/cirrhosis
treated with an IFN-based regimen from 1990–2003
P<0.001
Time (y)
Non-SVR
van der Meer AJ, et al. JAMA 2012;308:2584–93.
SVR
IFN: interferon
Liver-related mortality or
liver transplantation (%)
SVR is associated with a reduction in
liver-related mortality and HCC
Liver-related mortality or liver transplantation
P<0.001
n=530
Without SVR
With SVR
Hepatocellular carcinoma (%)
Time (y)
Hepatocellular carcinoma
P<0.001
n=530
van der Meer AJ, et al. JAMA 2012;308:2584–93.
Without SVR
With SVR
Time (y)
SVR is associated with a reduction in HCC
 1647 HCV pts in Vienna, followed for 10 yrs (2-27)
 99 cases of HCC (5.7%)
Impact of fibrosis stage
30
Impact of SVR
30
SVR
Non-SVR
20
HCC pts (%)
HCC pts (%)
F (0–2)
F3
F4
p<0.001
10
20
p<0.0001
10
0
0
0
5
10
15
Time (y)
Purevsambuu T, et al. EASL 2014, London, O125
20
25
0
5
10
15
Time (y)
20
25
SVR reduces but does not eliminate HCC
HCC Incidence in various groups
 Overall:
12.1% in non-SVR vs. 1.8% in SVR, (p<0.0001)
 Cirrhotics:
15.6% in non-SVR vs. 7.7% in SVR, (p=0.0009)
 Platelets<100: 24.7% in non-SVR vs. 16% in SVR, (p=0.0009)
MVA: Predictors of HCC following SVR
Parameter
Coefficient
Std. error
p-value
Age >50 y
–0.006
0.013
0.64
BMI ≥25 kg/m2
0.012
0.011
0.26
Cirrhosis
0.044
0.015
0.005
AFP >10
0.044
0.025
0.08
Platelet <100
0.173
0.027
<0.0001
RNA ≥800,000
0.017
0.018
0.35
Purevsambuu T, et al. EASL 2014, London, O125
Surveillance increases survival in cirrhotic
patients who develop HCC
100
79%
Cumulative Survival
80
Screened group
Median survival = 2054 days
n = 284
54%
60
40
Log-rank: P<0.0001
Non-screened group
Median survival = 99 days
n = 374
20
21%
3%
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Survival (Years)
Fung J, et al. Hepatology 2005; 42:258A
What is correct interval for surveillance?
 Retrospective Italian study of 370 HCCs
– 155 cases detected with 6mthly US; 215 with 12mthly
No difference in tumour stage, treatment options, or
overall survival
Trevisani F,et al. Am J Gastroenterol 2002;97:734-44
 Prospective Korean study of 10,327  400 HCC
– 219 cases detected with ≤ 6mthly US; 181 with 12mthly
US ≤6 monthly US >6 monthly P-Value
(n=219)
(n=181)
Size
5 yr Survival
3.0  1.7cm
4.0  2.6cm
<0.001
32%
23%
<0.001
Han J, et al. J Clin Gastroenterol. 2013 47:538-44.
What is correct interval for surveillance?
 Prospective Taiwanese study of 744 HBV or HCV
cirrhotics randomised to 4-6 vs 12 monthly US
BCLA early stage considered for resection/RFA
39 HCCs detected
US 4-6 monthly
(n=24)
US 12 monthly
(n=15)
P-Value
0/24
5/15
0.05
Size
1.9  0.7cm
2.9  1.5cm
<0.001
<2cm
71%
20%
0.001
Single
75%
46%
0.01
BCLC Stage A
38%
6%
<0.001
Curative Rx
54%
20%
<0.001
Not screen-detected
Wang J-H at al. Am J Gastroenterol 2013; 108:416–424
What is correct interval for surveillance?
 Does NOT depend on degree of risk
 Depends on
– Tumour growth rate
– Prognosis of HCC at different sizes
 31 HBV or HCV Taiwanese with early HCC (<5cm)
– Followed by Ultrasound
– Median doubling time =117 days
• 13 cm=18.5 months (4.6-28)
• Most rapid growth 13 cm=4.6 mths
Sheu JC, et al. Cancer. 1985; 56:660-6.
 59 HCV or ALD Italians with small HCC (<5cm)
– Followed by Ultrasound
– Median doubling time 171 days
Barbara M, et al. Hepatology. 1992;16:132–137
Updated AASLD Management Guidelines
for Hepatocellular Carcinoma (2011)
Recommendations
 Surveillance should be performed with ultrasound
 Patients should be screened at 6month intervals
 The surveillance interval does not need to be
shortened for patients at higher risk of HCC
Bruix J, Sherman M. Hepatology 2011; 53: 1-34
Reducing the Risks of Liver-related complications
Conclusions
 Modify lifestyle to slow disease progression
– reduce alcohol and cannabis consumption and
drink more coffee!
 Eradicate HCV with antiviral therapy
– 2014: treat cirrhotics with triple therapy early
before albumin and platelet counts fall
– 2015: treat cirrhotics with IFN-free DAAs
– 2016+: treat F2/3 to prevent cirrhosis
– 2020?: treat ALL HCV+ to eliminate HCV
 Continue HCC surveillance with 6 monthly US in
cirrhotics after SVR
DAA Therapy in Decompensated HCV
Cirrhosis
Wk 0
Wk 24
Wk 48
HVPG at Day 0 and Week 48
Arm 1
n=25
SOF 400 mg + RBV 1000‒1200 mg
Wk 72
SVR12
HVPG at Day 0, and Weeks 24 and 72
Arm 2
n=25
Observation
Wk 96
SVR12
SOF 400 mg + RBV 1000‒1200 mg
 Inclusion Criteria
– SOF+RBV for 48 weeks
– All HCV genotypes
– Liver failure PLUS portal hypertension (HVPG >6mmHg)
 Endpoints
– SVR12
– Resolution of liver failure
– Reduction in portal hypertension
Afdhal et al. EASL 2014.
43
SOF/RBV in Decompensated HCV Cirrhosis
Efficacy: On-treatment Virologic Response
100
HCV RNA < LLOQ (%)
100
100
100
100
94
80
94
93
75
CPT A
60
56
CPT B
44
40
5/9
7/16
9/9
12/16
8/8
15/16
8/8
15/16
7/7
14/15
20
2
4
8
12
24
Week on treatment
Afdhal et al. EASL 2014.
44
SOF/RBV in Decompensated HCV Cirrhosis
Efficacy: On-treatment Clinical Response
(a) Ascites
(b) Encephalopathy
Baseline
40
24 weeks
20
20
36
16
% Patients
24
20
15
% Patients
28
30
10
8
5
10
0
0
0
0
SOF/RBV (n=25)
Afdhal et al. EASL 2014.
Observation
(n=25)
SOF/RBV
(n=25)
Observation
(n=25)
45
SOF/RBV in Decompensated HCV Cirrhosis
Efficacy: On-treatment Biochemical Response
SOF+RBV
Observation 24 weeks
Increase in Platelets*
17
D Albumin (g/L)
D Platelets 1000/m l
20
15
10
5
0
-5
-10
Increase in Albumin*
6
5
4
3
2
1
0
-1
-2
5
-1
-9
-15
*C-P A patients shown
Afdhal et al. EASL 2014.
46