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