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LiverCenter

Epidémiologie et histoire naturelle de l’hépatite virale C

DU 2009Thierry PoynardGroupe Hospitalier Pitié Salpêtrière

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Plan

• Natures

• Prévalence

• Facteurs de contamination

• Facteurs de gravité: vitesse de progression de la fibrose

2

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Différentes natures de l’ Hépatite C

• Historique

• Emotionnelle

• Rationnelle

• Economique

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Case 1: Mlle Koretz-Seef née Optimiste

• 85 ans

• Transfusée âge de 10 ans

• HIV négative

• Pas d’alcool

• Pas de diabète

• A0 F1

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Case 2: Mr Pitié-Salpêtrière né Pessimiste

• Mort à 40 ans

• Hémophile infecté à l’âge de 30 ans

• HIV positif

• Alcool 60g par jour

• Diabétique

• A3 F4, Carcinome Hépatocellulaire

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Cancer

F4

HCV InfectionA virologic and fibrotic disease

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Prevalence of extra-hepatic manifestations

0

15

30

45

60

HCV n=1614 Control n=412

FatigueArthralgiaParesthesiaMyalgiaPruritusSicca syndromHypertensionDiabetesRaynaudThyroiditisPsoriasis

Cacoub, et al Arthritis Rheum 1999 Poynard, et al J Viral Hepatitis 2001

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Plan

• Natures

• Prévalence: Monde, France

• Facteurs de contamination

• Facteurs de gravité: vitesse de progression de la fibrose

9

F4

F1

F0

Fibrotic Liver Disease

F2

F3

Hemorrhage Liver failure Cancer

Poynard Lancet 1997

16 janv. 2009

Insulin resistance

Alcool consumption

Hepatitis B

Hepatitis C

Hemochromatosis

0 150 300 450 600

No advanced fibrosis Advanced fibrosis

11

Population at risk of liver fibrosis, cirrhosis and hepatocellular carcinoma (Millions)

Chronic Hepatitis C:180 Millions Worldwide

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Genotype

1,2,3

4

5

6

3

2

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Mortality 2002Chronic liver disease (HBV, HCV)

• 1 death out 40 worldwide due fibrotic liver

• HBV 30% HCV 27% 929 000 / 1,6 millions

• Death: HCV 366 000 HBV 563 000

• Cancer HCV 155 000 HBV 328 000

• Cirrhosis HCV 211 000 HBV 235 000

Perz J Hepatol 2006

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Perz J Hepatol 2006

HCC were attributable to HBV and HCV. Regionalestimates of the alcohol-attributable fractions were alsoconsistent with our estimates. Reported alcohol-attrib-utable fractions were generally high where viral hepati-tis-attributable fractions are low, and vice versa. It haspreviously been noted that alcoholic cirrhosis may pre-dominate in areas with low prevalences of HBV andHCV infections and be associated with a high propor-tion of HCC cases [8]. However, co-morbidity fromalcohol abuse and HBV and/or HCV infection is sub-stantial in certain regions and future e!orts to character-ize the burden of end-stage liver disease should aim at amore integrated accounting of these and other riskfactors.

Additional limitations in our study stem from issuesrelated to sampling, classifying and testing liver diseasepatients. In general, we found that the quality and quan-tity of studies appropriate for our analysis was loweramong cirrhosis patients relative to HCC patients, whileresource poor regions tended to have fewer well-suitedstudies available for inclusion overall. Such regionsmight have less reliable diagnostic tools available to cli-nicians and researchers (for viral hepatitis testing andfor the diagnosis of cirrhosis and HCC). Another con-cern relates to the fact that we utilized serologic testresults exclusively to classify subjects as HBV or HCVinfected, rather than considering the results of nucleicacid testing when available. This might have resultedin a degree of under-ascertainment of HBV- or HCV-re-lated cases [103], but was necessary to assure a uniformapproach.

Our findings help illustrate the great need for pro-grams aimed at preventing HBV or HCV transmission.In 1992, WHO recommended that all countries includehepatitis B vaccine in their routine infant immunizationprograms. As of 2003, WHO/UNICEF estimated 42%hepatitis B vaccination coverage among the global birth

cohort [106]. Therefore, implementation of this strategy,which represents the most e!ective way of preventingchronic HBV infection and related end stage liver dis-ease, is far from complete [107,108]. Other key primaryprevention strategies include screening blood donorsand maintaining infection control practices to preventthe transmission of healthcare-related HBV and HCVinfections [105,109,110]. In countries where these activi-ties have not been fully implemented, they should be giv-en a high priority. In most developed countries, injectiondrug use and high-risk sexual behaviors represent themajor risk factors for HCV infection and HBV infec-tion, respectively, indicating the importance of relatedprevention e!orts (e.g., reducing the numbers of new ini-tiates to injection drug use).

The role of programs to identify, counsel, and pro-vide medical management for the many personsalready infected with HBV or HCV requires carefulconsideration [105,110]. Counseling that includesadvice regarding avoidance of alcohol and educationregarding modes of transmission can help reduce therisks for developing chronic disease or spreading infec-tion to susceptible persons. The widespread applicationof therapeutic interventions also has the potential toaccelerate the declines in end-stage liver disease thatwill eventually follow from hepatitis B vaccinationand other primary prevention e!orts [104,107]. Recentadvances have occurred in the therapeutic managementof chronic hepatitis B and chronic hepatitis C, buttreatments are long and involve substantial costs andside e!ects [111–113]. Countries will need to considerthe potential benefits of treatment while insuring thatscarce healthcare resources are allocated in a mannerthat does not undermine primary prevention e!orts[114].

The relative contributions of HBV and HCV to end-stage liver disease are subject to temporal trends and

CIRRHOSIS HEPATOCELLULAR CARCINOMA

0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100%

EMRO-D

WPRO-B

WPRO-A

EMRO-B

AFRO-D/E

EURO-B/C

SEARO-B

EURO-A

AMRO-A

SEARO-D

AMRO-B/D

HBV

HCV

WPRO-A

WPRO-B

SEARO-D

EMRO-D

EMRO-B

EURO-B/C

AFRO-D/E

AMRO-A

AMRO-B/D

SEARO-B

EURO-A

HBV

HCV

a b

Fig. 1. Estimates of the attributable fractions of cirrhosis and hepatocellular carcinoma due to infection with HBV or HCV, by region.

J.F. Perz et al. / Journal of Hepatology 45 (2006) 529–538 535

Chine

Europe

4682 patients

180 HIV-HCV701 Alcohol812 HBV

382 Hemochromatosis2313 HCV 93 Steatosis BMI>25200 PBC

Poynard et al J Hepatol 2003

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Prevalence Anti-VHC France

• 1994: 575.000 (500.000-650.000)

• 2004: 370.000 (270.000-470.000)

• 2014: 270.000 ?

INVS www.2007, Dubois Hepatology 1997

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Infection chronique: PCR+ / Anti-VHC+

• 1994: 81% 460.000

• 2004: 65% 240.000

• 2014: 50% 135.000 ?

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“Connaissance du statut sérologique”

• 1994: 24% 137.000

• 2004: 56% 207.000

• 2014 ? 75% 202.000

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Traitement: 2002-2005

• 54.200 Traités

• 33.600 Naif

• 20.600 Non naif

• 13.500 par an

Deuffic et al J Hepatol 2008

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Mortality in France: HCV and HBV

• Deaths associated HCV 3618

• Deaths attributed HCV 2646

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Marcellin et al Journal of Hepatology 2008

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S. Deuffic-Burban et al Journal of Hepatology 2008

HCV related mortality and treatment impact

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Mortality 2001 World vs France (1% of world)Chronic liver disease (20% HCV of liver)

0

0,375

0,750

1,125

1,500

All liver HCV

0,120

0,600

0,160

0,800

Cirrhosis Liver cancer

0

3 500

7 000

10 500

14 000

All liver HCV HCV Marcellin HCV Deuffic

1 200

6 000

3 3002 646

1 600

8 000

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S. Deuffic-Burban et al Journal of Hepatology 2004

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1994-2014

0

150 000

300 000

450 000

600 000

1994 2004 2014

HCV-Ab PCR+ Informed Treated Cured Dead

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1994-2014

0

37 500

75 000

112 500

150 000

1994 2004 2014

Treated Cured Dead

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Où sont passés les 200.000 entre 1994 et 2004 ?

• Variabilité échantillonage ?

• 1994: n=6.283 20-59 ans

• 2004: n=14.416 18-80 ans

• Morts ? 4.000/an= 40.000 OK pour PCR

• Traités (et Guéris) ?: 13.000/an (20à60%)

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Plan

• Natures

• Prévalence

• Facteurs de contamination

• Facteurs de gravité: vitesse de progression de la fibrose

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Dépistage: Discussion

• IVDU: 70%

• Non transfusés Non IVDU: 28%

• Elargir dépistage

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Risque élevé: Exposition au sang

• Transfusion avant 1991

• Hémophiles transplantés, hémodialysés, gammaglobulines, chimiotherapies

• Injection drogue intra-veineuse

• Personnel de santé avec accidents d’exposition au sang

• Enfants nés mère infectée HCV surtout si coinfection HIV

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Risque modéré: Exposition au sang

• Comportement sexuel à risque

• Infection herpes simplex 2

• Cocaine et paille

• Médical: chirurgie, endoscopie, dents ...

• Para-médical: acupuncture, sclérose...

• Autres: tatouage, piercing, bagarre...

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Risque nul ?

• Urines

• Selles

• Sécrétions vaginales

• Sperme ?

• Moustiques

• Tiques ??

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Plan

• Natures

• Prévalence

• Facteurs de contamination

• Facteurs de gravité: vitesse de progression de la fibrose

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HCV and Fibrosis: Stellate, Inflammatory and Apoptotic Cells

Feld Hepatology 2006

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HCV proteins and Fibrosis, Inflammation, Steatosis, Apoptosis

Shuppan Cell Death Differ 2003

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Survival of truth in HCV natural history

• 1980-1990: Necrosis biopsy, ALT

• Chronic persistent or active

• 1990-2000: Fibrosis biopsy

• Scheuer, Knodell-Ishak, METAVIR

• 2000-2010: Non invasive markers

• FibroTest, FibroScan…

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FibroTest

F4

F1

F0

Fibrotic Liver Disease

F2

F3

Hemorrhage Liver failure Cancer

No sexNo alcoholNo sugar

No fat No drug

HBV vaccination

ScreeningTreatment

Poynard Lancet 1997

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Fibrosis progression modeling

• Poynard Lancet 1997

• Kenny-Walsh NEJM 1999

• Poynard J Hepatol 2001

• Westin JVH 2002, Deuffic JVH 2002

• Ghany Gastroenterology 2003

• Wright Gut 2003, Poynard J Hepatol 2003

• Ryder Gut 2004, Yi JVH 2004

• Thein Hepatology 2008

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Fibrosis progression estimates : Methods

• Fibrosis estimate:

• « Observed »: 2 biopsies,

• « Estimated »: 1 biopsy,

• Time estimate:

• Between biopsies: short, bias, small sample

• Time of infection to biopsy: variability

• Age at biopsy = age at infection + infection duration

• Type of association between time and fibrosis:

• Linear, exponential…

• Markov transition

• Time dependent : hazard function

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0

1

2

3

4

0 10 20 30 40 50

Stage Fibrosis METAVIR

Duration in years

Rapid fibroser

Slow fibroser

Poynard et al Lancet 1997

Dynamic Concept: Fibrosis progression rate

Intermediate fibroser

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Poynard et al Lancet 1997

0

1

2

3

4

0 10 20 30 40 50

Duration in years

Male, > 40y, > 50 g alcohol

Female, < 40y, < 50 g

Stage Fibrosis METAVIR

2313 patients

>50 n=14941-50 n=211

31-40 n=348

21-30 n=851

<21 n=754

Poynard T et al. J Hepatol 2001

Large Scale Studies (AASLD 2004)FibroTest in 32,527 patients

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Factors associated with fibrosis progression in HCV

Sure

• Fibrosis stage

• Age (Duration)

• Alcohol >50g/d

• HIV

• CD4 <200/ml

• Male

• Necrosis

• BMI, Steatosis,Diabetes,

• Schistosomiasis

Not sure

• Inflammation

•Hemochromatosis hH

•Cigarette, Cannabis

•Alcohol <50g/d

•HBV

•Transplantation

•Genotype 3

Poynard et al Lancet 2003, EASL 2004

Not associated

•Last viral load

•Genotype non-3

•Mode of infection

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Expression of liver steatosis in HCV infection and pattern of response to interferonLiver steatosis in a patient genotype 3 with recurrent hepatitis C after transplantation

Rubbia-Brandt et al, J Hepatol 2001

Before therapy Response Relapse

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Effect of HCV Treatment on SteatosisGenotype Non-3

0

20

40

60

80

Sustained Responders n=461 Non Responders n=439

Before After

Poynard et al Hepatology, 2003

16 janv. 2009

0

25

50

75

100

Sustained Responders n=113 Non Responders n=21

Effect of HCV Treatment on Steatosis Genotype 3

Before After

Viral Steatosis

Poynard et al Hepatology, 2003

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Poynard circa 1990

Patients are seen 15 years after Infection

« Qui a fibrosé fibrosera »

« Who had fibrosed will fibrose »

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Risk of errors : Florilege (2)

• Good estimates with good quality biopsy

• ALT is very useful for clinician to predict fibrosis progression

Ghany Gastroenterology 2003

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Risk of errors : Florilege (1)

• Fibrosis progression is

• Linear

• Roughly linear

• Roughly linear by decades

• Roughly linear by decades with progressive acceleration after 40 years of age

• Roughly linear by decades with progressive acceleration after 40 years of age despite competitive risks (Gastroenterology 2005)

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Annual cost of Hepatitis C: US $

• No complications 110

• Ascites refractory 18 730

• Variceal bleeding 19 127

• Encephalopathy 12 278

• HCC 32 995

• Transplantation 108 650

Wong et al. Am J Public Health 2001

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FibroTest!First Line!

Reference Center FibroScan for!Confirmation !

Biopsy!If discordances!

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Résumé (1): Histoire naturelle de la fibrose

• Grossière linéarité par décades avec une accélération progressive après 40 ans

• Confirmation

• du rôle majeur de l ’âge

• de l’alcool > 50 g

• de l’insulino-résistance (diabète, surpoids, stéatose)

• HIV

• Absence d ’association

• Mode de contamination, génotype non-3, dernière charge virale

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Résumé (2): Mortalité

• Tueur lent et silencieux

• Deux sujets contaminés sur trois exposés à un risque majeur

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Résumé (3): Hépatite C en France

• 220.000 contaminés

• 4.000 morts / an (en augmentation)

• 50 % détectés

• 25 % traités

• Le traitement guérit plus de 50% des sujets et freine la progression de la maladie chez les autres

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Conclusion:

Dépister mieux et traiter plus