HepatitesNon A-E

Virus G et TTV …et autres considérations métaboliques

Vlad Ratziu,

DU Hépatites Virales 2008

Hôpital Pitié Salpêtrière,

Paris, France

Evidencefor Additional HepatitisAgents

Prospective transfusion-associated hepatitisstudies : 12%

Acute cases of overt hepatitis : 20%

Fulminant hepatitis : 25%

Chronic liver disease : 20-30%

Hepatitis-associated aplastic anemia : most ofthem

VHG : GBV-C, 95 % homology

VHG : HCV, 29 % homology

HGV Epidemiologyand Diagnosis

� HGV transmission:parenteral +++; vertical� Risk groups:polytransfused, hemophiliacs,

hemodialysis, patients infected with HIV, HCV, HBV

� Diagnosis:� ongoing infection : HGVRNA without anti-E2� exposure with viral clearance : anti-E2 Ab

HGV Epidemiologyand Diagnosis

� HGV prevalence :� blood donors 1.5-2.5%

� chronic NA-NE hepatitis 10-13%

� cryptogenic cirrhosis 20%

� HCV infection 18-20%

� HBV infection 8-10%

Prevalence of Serum HGVRNA in Acute Hepatitis of Viral Origin

� non A-E 9

� HBV 32*

� HAV 25

� HCV 20

%

* : p<0.05 vs HAV and HCV

Alter M, NEJM 1997

HGV : is it an HepatotropicVirus ?

Pessoa, Hepatology 1998

HGV : is it an HepatotropicVirus ?

� low level of hepatic HGVRNA compared to HCVRNA

� no interaction of hepatic HCVRNA and HGVRNA levels when patients with monoinfection are compared with those infected with both viruses

Pessoa, Hepatology 1998

HGV has no Pathogenic Role on the Course of Acute Hepatitis

� No apparent effect on the clinical course of acute disease among the patients with hepatitis A, B or C

� No effect on the frequency or severity with which chronic hepatitis C develops

� Long-standing HGV viremia but no chronic hepatitis

HGV and Transfusion associatedHepatitis (TAH)

HGV can be transmitted by transfusion +++

Protracted viremia possible (years) but 90% are mild

Prevalence of HGV is not higher in non-A-C transfusion associated hepatitis than in HCV, minor ALT elevationor transfused patients with no hepatitis

HGV milder forms than HCV; HCV-HGV not more severe than HCV

A CAUSAL RELATION BETWEEN HGV AND TAH IS NOT ESTABLISHED

Alter H, NEJM 1997

HGV in End-StageLiver Disease and Liver Transplantation

HGV infection frequently present in end-stageliver disease (13% in HCV, 22-64% incryptogenic cirrhosis)

HGV frequently present and/or acquired afterliver transplantation

HGV does not influence the clinical outcomeafter liver transplantation.

Fried, Hepatology 1997Pessoa, Hepatology 1998

DoesHGV Impact on theCourse of other Viral Infections?

� HCV

� HIV

No Histopathologic Impact of HGV on Chronic Hepatitis C

� Patients: � Chronic HCV alone in 85 pts

� Chronic HCV-HGV in 17 pts

� No difference in the necroinflammatory grade, fibrosisstage, proportion of cirrhosis, steatosis or bile ductlesions

HGV INFECTION DOES NOT MODIFY THE COURSE OF CHRONIC HCV INFECTION

CONTRIBUTION TO LIVER DISEASE LESS THAN OTHER HEPATOTROPIC VIRUSES

Bralet, Gastroenterology 1997

Improved Survival in HGV -HIV Coinfection

Tillmann, NEJM 2001

Improved Survival in HGV -HIV Coinfection

Improved survival even after development of AIDS and introduction of HAART

Slower progression to AIDS

Beneficial effect independent of age, sex, CD4+, CD8+ cell counts

Inverse correlation HGV viral load- HIV viral load

Under HAART, increase in HGV viral load whiledecrease in HIV viral load

Tillmann, NEJM 2001

Multicenter AIDS Cohort StudyBaltimore, Chicago, Pittsburgh, LA

• Cohorte de patients homosexuels mâles infectés par le VIH et suivis avant 1996

• Recherche du VHG au moment de l’infection, 12 à 18 mois et 5 à 6 ans après la séroconversion VIH� RT-PCR : infection en cours

� antiE2 : infection passée, disparition du virus

Williams, NEJM 2004

L’infection par le GBV-C Améliore la Survie des Patients VIH

GBV-C pos

GBV-C éliminé

GBV-C neg

SURVIE A 10 ANS CD4+

75%

39%

16%

-26/mm3

-70/mm3

-107/mm3

Effet dépendant du taux de CD4 et virémie VIH

Effet significatif pls années après primoinfection VIH

Williams, NEJM 2004

Inhibition of HIV Replicationby HGV in PBMC

� No effect on the entryof HIV into the cells

� No differences in expression of CD4, CXCR4 or CCR5

Xiang, NEJM 2001

Molecular Interactions BetweenGBV-C and HIV

TT Virus and Transfusion AssociatedHepatitis

Strong association with blood transfusion :riskincreases with number of units

Same prevalencein transfused patients regardlessof the occurrence of transfusion associatedhepatitis

Same ALT levelin transfusion associated hepatitisregardless of the presence of TTV

Does not alter thecourse of hepatitis C

Matsumoto, Hepatology 1999

TTV and Acute Viral Hepatitis

Controls(100) 37

Acute hepatitis(125) 35

Acute HAV (28) 29

Acute HBV (29) 24

Acute HCV (33) 42

Acute NA-E (35) 43

� No correlationbetween TTV infection and clinicalfeatures of acute infection

� No effect on theclinical course ofHAV, HBV, HCV

% withTTVCondition

Kanda, Hepatology 1999

NO ETIOLOGIC ROLE !

ChronicTTV Carriage

� Longitudinal study of 173 multiple transfusedpatients

� Prevalence of TTV : 28%

� Chronic infection in 86% of TTV infectedpatients

� Persistence of TTV for a mean period of 3.1 years

� No biochemical evidence of liver disease for the majority of chronic TTV carriers

Lefrere JJ, Blood 1999

TTV and ChronicLiver Disease

� No significant differences in prevalencebetween chronic HCV, HBV or cryptogenicliver disease

� No difference in genotype distribution according to the etiology of liver disease

� No association with hepatocellularcarcinoma

Tagger, Hepatology 1999

Kato, J Hepatol 1999

Nakano, J Hepatol 1999

TTV, ChronicHepatitis C and Responseto IFN

� N=247 Japanese hepatitis C treated patients

� Prevalence of TTV : 46%

� Same sustained HCV clearance rate in TTV negative and positive patients

� TTV clearance after IFN therapy was common(52%)

TTV DOES NOT MODIFY CLINICAL FEATURESOF CHRONIC HEPATITIS C OR RESPONSE TO IFN

Hagiwara, J Viral Hepat 1999

PrognosticSignificanceof TTV in Patients withHIV Infection

High TTV viremia associated with :

� decreased survival

� lower CD4+ T cell counts

� higher HIV viral load

� proportion of patients with AIDS

Shibayama, AIDS 2001

Christensen, J Inf Dis, 2000

TTV - TheEssentials

� Transmission : parenteral route +++ ; fecal-oral route ?

� High prevalence in Japan

� Replicates in the liver

� Role in post transfusion hepatitisnotconfirmed

� Does not aggravatechronic HCV or HBV

� Negligible role in the etiology ofchronic liverdisease(the role of certain genotypes cannotbe excluded…)

EstablishingCausalityfor New Viruses

� Pathogen present in most cases of the disease

� Pathogen found preferentially in the target organ

� Should not be significantly detectable in subjects without the disease

� Copy number should decrease or becomeundetectable with resolution of the disease

� Copy number should correlate with diseaseseverity

Alter, Postgraduate Course, AASLD 2000

ChronicLiver Disease - BeyondtheViruses...

� Definition

� Etiologies

Etiologie de la Cirrhose (n=78) Etude Dionysos (Hepatology 1994)

HCV28 %

HBV 9 %

HBV+ALCOOL 3 %

HEMOCHROMATOSE

1 %

ALCOOL26 %

CBP1 %

HCV+ALCOOL 3%

CRYPTOGENIC24 %

Factors Associated with ALT Levels

� SEX

� BMI

� Cholesterol

� Triglycerides

� Glycemia

� Oral contraceptives

� Smoking

� Age

� Physical exercise

� Medications

Piton, Hepatology 1998Prati, Ann Intern Med 2002

What is a Normal ALT Value ?

“Normal” ALT ranges from� 26 UI/l (females, 95th percentile) to� 66 UI/l (males BMI > 26 kg/m²)

New definitions of normal ALT (no overweight, lipid, carbohydrate alterations) :

� 30 UI/l for men

� 19 UI/l for women Piton, Hepatology 1998Prati, Ann Intern Med 2002

Clinical Implications of the Different Thresholds for Normal ALT

Blood donors � male donors : 4 - 20%

� female donors : 1.5 - 16%

HCV infection � males : 13 - 22 %

� females : 20 - 45 %

Piton, Hepatology 1998

abnormal ALT

Chronic Liver Disease - BeyondtheViruses ...

� Etiologies :� Overweight, Diabetes +++

� Covert Alcohol

� Drugs

� Seronegative autoimmune liver diseases

� Vascular liver diseases

� Celiac disease

� Occult HBV

Impact of Overweight on ChronicLiver Disease

< 25 32 0.3 (0.32-0.33)

25-27 25 1.16 (1.15-1.17)

> 27 45 1.83 (1.81-1.85)

BMI (kg/m2) % Relative Risk (CI 95%)

Dionysos Study, n = 1211 (6917 total)

(Bellentani Hepatology 1994)

Proportion of Patients With Cryptogenic Cirrhosis according to BMI - UNOS Database

0

5

10

15

20

25

30

35

40

> 40 BMI35 - 4030 - 3525 - 30< 25

HCV Alcohol CryptogenicN =19271

%

(Nair, Hepatology 2002)

0

5

10

15

20

25

30

35

40

Obésité et Cirrhose Cryptogénétique

Cirrhose X NASH Cirrhose C CBP

N

Age

Obésité(%)

Femmes (%)

Diabète(%)

70 50 39 33

63(+/- 11) 49(+/-14) 60(+/-7) 54(+/-10)

70 56 36 100

47 64 3 15

53 42 25 15

Caldwell, Hepatology 1999

Normal : 10 %

Steatosis alone : 48 %

Steatohepatitis : 42 %

Liver Histology in OverweightPatients

n = 858 ; 9 studies, 1978 - 2002

Prevalence of NASH/NAFLD

First (or second) cause of chronic liver disease in Western Countries

Prevalence among patients with abnormal LFTsof undetermined etiology (n=673, 5 studies)

steatosis alone : 30%

steatohepatitis : 26%

Hepatic Fibrosis in NASH

None or mild 65Severe (cirrhosis excepted) 20Cirrhosis 15

%

n= 572, 9 studies 1980 - 2001

Risk Factors for Severe Fibrosis in NASH

Age > 45-50 yrs

Diabetes

ALT>2N

BMI > 27 kg/m²

HTA

HyperTG

AST/ALT > 1Ratziu, Ratziu, GastroenterologyGastroenterology 20002000

AnguloAngulo, , HepatologyHepatology 19991999

Dixon, Dixon, GastroenterologyGastroenterology 20012001

Abnormal Liver FunctionTests

A frequent problemin clinical hepatology

New viruses : less of a problem

NAFLD : more of a problem

Identifying patients at risk of liver disease -that is the problem!

Viral Etiologies of Acute Hepatitis in the US(1985-1986 and 1991-1995)

� HAV 48

� HBV 34

� HCV 15

� non A-E 3

%

Alter, NEJM 1997

N=10 533