What happens to the liver after
cure?
Vincent Mallet
Université Paris Descartes, Institut Pasteur,
Assistance Publique—Hôpitaux de Paris, France
Disclosures
• Vincent Mallet has been a scientific advisor or
consultant for Gilead, Abbvie, MSD, Janssen-
Cilag and Bristol Myers Squibb and has
received payment for lectures through
speakers’ bureaus for Abbvie, Bristol Myers
Squibb, Gilead, JJ/Janssen-Cilag, Novartis and
Roche.
45 year-old woman
Past acute myeloid leukemia (age 6)
Bloodborne chronic hepatitis C
• Antiviral Rx 2006 (LSM 17 kPa): SVR
• March 2015; AFP 3000 UI; multilocular hepatocellular
carcinoma (HCC); Liver stiffness 4 kPa
• Transarterial chemoembolisation x 2
• Liver transplant October 2015
• Native liver: Cirrhosis, HCC x 4 (partial necrosis),
cholangiocarcinoma x 1
Will „SVR-for-all“ eventually
improve outcomes?
Date of download: 12/11/2015Copyright © 2015 American Medical
Association. All rights reserved.
From: Association Between Sustained Virological Response and All-Cause Mortality Among Patients With
Chronic Hepatitis C and Advanced Hepatic Fibrosis
JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878
Date of download: 12/11/2015Copyright © 2015 American Medical
Association. All rights reserved.
From: Life Expectancy in Patients With Chronic HCV Infection and Cirrhosis Compared With a General
Population
JAMA. 2014;312(18):1927-1928. doi:10.1001/jama.2014.12627
Overall Survival in Patients With Chronic Hepatitis C Virus Infection and Advanced Hepatic Fibrosis With
and Without Sustained Virological Response (SVR) Compared With an Age- and Sex-Matched General
PopulationTime zero is 24 weeks following cessation of antiviral therapy, at which time it was determined
whether patients attained SVR.
The Scottish experience
Hepatology 2011
Alcohol-Related
Hospital
Episodes
Non-Liver-
Related Hospital
Episodes
Liver-Related
Mortality
-5 0 5 10 15 20
Innes HA et al. 2011
1
Age, Sex, and Calendar Period Adjusted Standardized Morbidity
Ratios (95% CI) in Persons Known to Have Spontaneously
Resolved HCV Infection in Scotland
Hepatology 2015
Innes HA et al. 2015
Hazard reduction associated with SVR (vs.non-SVR), for each outcome
event, according to APRI. Estimates are adjusted for differences in basic
demographics; medical comorbidities; viral genotype; behavior factors and
liver function tests. (N=3385)
Universal access to treatment
is the objective
A real-life Hep C patient
We may shortly remember
Hep C: the underlying cause of
death (after liver transplant)
A real-life Hep C patient
We may shortly remember Lou Reed’s quote
Hep C: the underlying cause of
death (after liver transplant)Alcohol Use Disorders: a major
cause of liver transplant (and
death)
Date of download: 6/2/2015
From: The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002
Ann Intern Med. 2006;144(10):705-714. doi:10.7326/0003-4819-144-10-200605160-00004
Prevalence of antibodies to hepatitis C virus (HCV) by age group (A) and year of birth (B) in the Third National Health and Nutrition
Examination Survey (NHANES III, 1988–1994) and the current NHANES (1999–2002).The vertical bars represent 95% CIs.
Figure Legend:
Copyright © American College of Physicians. All rights reserved.
Higher rates of severe comorbidities in real-life
Hep C patients in Western countries
• Injection Drug Use (reported by ≥ 50%)
⇒ Alcohol Use Disorders
⇒ Coinfection with HIV and/or Hepatitis B Virus
• Receipt of donated blood, blood products, and
organs (once a common means of transmission)
⇒ Liver and other solid organ transplant receipt
⇒ Severe comorbidities (e.g. hemodialysis)
15
Burden of chronic HCV infection
in France: 2008-2012 raw data
• End-stage liver disease, primary liver cancer, liver transplant
HCV+ HCV-
Patients 112,146 [0.39%] 28,841,609
Men 58.2% 42.4%
Mean (SD) age (2008) 53.0 (15.2) 49.7 (20.9)
Liver-related event* 21,144 [4.0%] 505,930
In-hospital mortality 15,104 [1.0%] 1,491,349
Schwarzinger et al. EASL 2015
Record of confounding factors
in hep C vs. other hospitalized patients
Confounding factors
on prognosisHCV+ HCV- aOR [95% CI]*
Alcohol Use Disorders 20.8% 2.4% 6.33 [6.23-6.43]
One or more
severe comorbidities56.2% 28.7% 2.43 [2.40-2.46]
* Adjusted Odds-Ratio (aOR) on gender, 5-year age category, 5 French regions, and teaching hospital care
Schwarzinger et al. EASL 2015
Burden of confounding factors
on prognosis in 112,146 hep C patients
Presence of
confounding factorsLiver-related event* In-hospital death
Patients 21,144 (18.9%) 15,104 (13.5%)
Alcohol Use Disorders 46.3% 33.7%
Severe comorbidity
without AUD39.9% 57.5%
None 13.8% 8.8%
• End-stage liver disease, primary liver cancer, liver transplant
Schwarzinger et al. EASL 2015
0%
10%
20%
30%
40%
50%
60%
70%
End-Stage Liver Disease
(N = 21,135)
Decompensated cirrhosis
(N= 17,601)
Primary liver cancer (N =
9,022)
Liver transplant in
patients less than 70
years (N = 1,326)
Any factor of liver fibrosis progression Alcohol use disorders
Diabetes mellitus Chronic hepatitis B virus infection
Liver transplant recipient before 2008 Other solid organ transplant recipient before 2008
Schwarzinger et al. EASL 2015
Population Attributable Risks of End-Stage Liver
Disease in French Patients with Chronic HCV Infection
(N = 112,146)
Benefits of alcohol withdrawal/abstinenceon the risk of liver-related event or death
in 112,146 hep C patients
* Stratified on gender, 5 French regions, and teaching hospital care
0
1
2
3
4
5
20 25 30 35 40 45 50 55 60 65 70 75 80 85
Ha
zard
Ra
tio
(9
5%
CI)
Age in 2008 (years)
AUD without abstinence: n=9,045 (33%)/27,058; HR= 3.88 [3.77-3.98]
Alcohol withdrawal/abstinence: n=1,636 (6%); HR= 0.71 [0.67-0.75]
What happens to the liver after
cure?
Outcome of 341 patients with HCV and
cirrhosis stratified on AUD
P. Sultanik et al. Submitted
W/o Alcohol use disorders With Alcohol use disorders
Conclusion
Poor prognosis of Hep C patients is largely explained
by the selection of a high-risk subpopulation
– Alcohol Use Disorders => liver (+++) and nonliver death
– Severe comorbidities => liver and nonliver (+++) death
– 88.3% of 27,058 liver-related event or death
⇒ Expected value of IFN-free treatments in cost-
effectiveness models is overestimated in real-life
patients without AUD or severe comorbidities
45 year-old woman
Past acute myeloid leukemia (age 6)
Bloodborne chronic hepatitis C
• Antiviral Rx 2006 (LSM 17 kPa): SVR
• March 2015; AFP 3000 UI; multilocular hepatocellular
carcinoma (HCC); Liver stiffness 4 kPa
• Transarterial chemoembolisation x 2
• Liver transplant October 2015
• Native liver: Cirrhosis, HCC x 4 (partial necrosis),
cholangiocarcinoma x 1
96 HCV patientsMETAVIR F3-F4
Median follow-up118 months; IQR=86-138 months
10-year incidence of HCC
among HCV Patients with F3-F4 disease
Mallet et al. Ann Intern Med 2008
LSM of 341 patients with HCV and
cirrhosis stratified on SVR
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
HCV RNA positive HCV RNA negative
< 0.0001L
ive
r sti
ffn
ess
, kP
a
Sultanik P et al. Submitted
LSM and outcome of 341 patients
with HCV and cirrhosis
Sultanik P et al. Submitted
Conclusions
• Some HepC patients will remain at risk of
disease progression after cure;
• There is no accurate method to assess
prognosis of HepC patients, especially
after cure;
• The benefits of healthcare-induced
lifestyle modifications should be
investigated.28