1. Hepatites Non A-E
Virus G et TTV …
et autres considérations métaboliques
Vlad Ratziu,
DU Hépatites Virales 2008
Hôpital Pitié Salpêtrière,
Paris, France

2. Evidence for Additional Hepatitis
Agents
Prospective transfusion-associated hepatitis
studies : 12%
Acute cases of overt hepatitis : 20%
Fulminant hepatitis : 25%
Chronic liver disease : 20-30%
Hepatitis-associated aplastic anemia : most of
them

3. VHG : GBV-C, 95 % homology
VHG : HCV, 29 % homology

4. HGV Epidemiology and 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

5. HGV Epidemiology and 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%

6. 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

7. HGV : is it an Hepatotropic Virus ?
Pessoa, Hepatology 1998

8. HGV : is it an Hepatotropic Virus ?
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

9. 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

10. HGV and Transfusion associated
Hepatitis (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 elevation
or 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

11. HGV in End-Stage Liver Disease
and Liver Transplantation
HGV infection frequently present in end-stage
liver disease (13% in HCV, 22-64% in
cryptogenic cirrhosis)
HGV frequently present and/or acquired after
liver transplantation
HGV does not influence the clinical outcome
after liver transplantation.
Pessoa, Hepatology 1998
Fried, Hepatology 1997

12. Does HGV Impact on the Course
of other Viral Infections?
HCV
HIV

13. 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, fibrosis
stage, proportion of cirrhosis, steatosis or bile duct
lesions
HGV INFECTION DOES NOT MODIFY THE COURSE
OF CHRONIC HCV INFECTION
CONTRIBUTION TO LIVER DISEASE LESS THAN
OTHER HEPATOTROPIC VIRUSES
Bralet, Gastroenterology 1997

14. Improved Survival in HGV-HIV
Coinfection
Tillmann, NEJM 2001

15. 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 while
decrease in HIV viral load
Tillmann, NEJM 2001

16. Multicenter AIDS Cohort Study
Baltimore, 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

17. L’infection par le GBV-C Améliore
la Survie des Patients VIH
SURVIE A 10 ANS CD4+
GBV-C pos 75% -26/mm3
GBV-C éliminé 39% -70/mm3
GBV-C neg 16% -107/mm3
Effet dépendant du taux de CD4 et virémie VIH
Effet significatif pls années après primoinfection VIH
Williams, NEJM 2004

19. Inhibition of HIV Replication by
HGV in PBMC
No effect on the entry
of HIV into the cells
No differences in
expression of CD4,
CXCR4 or CCR5
Xiang, NEJM 2001

20. Molecular Interactions Between GBV-C and HIV

21. TT Virus and Transfusion
Associated Hepatitis
Strong association with blood transfusion : risk
increases with number of units
Same prevalence in transfused patients regardless
of the occurrence of transfusion associated
hepatitis
Same ALT level in transfusion associated hepatitis
regardless of the presence of TTV
Does not alter the course of hepatitis C
Matsumoto, Hepatology 1999

22. TTV and Acute Viral Hepatitis
% with
Condition TTV No correlation
Controls (100) 37 between TTV
Acute hepatitis (125) 35 infection and clinical
features of acute
Acute HAV (28) 29
infection
Acute HBV (29) 24
No effect on the
Acute HCV (33) 42 clinical course of
Acute NA-E (35) 43 HAV, HBV, HCV
NO ETIOLOGIC ROLE !
Kanda, Hepatology 1999

23. Chronic TTV Carriage
Longitudinal study of 173 multiple transfused
patients
Prevalence of TTV : 28%
Chronic infection in 86% of TTV infected
patients
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

24. TTV and Chronic Liver Disease
No significant differences in prevalence
between chronic HCV, HBV or cryptogenic
liver disease
No difference in genotype distribution
according to the etiology of liver disease
No association with hepatocellular
carcinoma
Tagger, Hepatology 1999
Kato, J Hepatol 1999
Nakano, J Hepatol 1999

25. TTV, Chronic Hepatitis C and
Response to 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 FEATURES
OF CHRONIC HEPATITIS C OR RESPONSE TO IFN
Hagiwara, J Viral Hepat 1999

26. Prognostic Significance of TTV
in Patients with HIV Infection
High TTV viremia associated with :
decreased survival
lower CD4+ T cell counts
higher HIV viral load
proportion of patients with AIDS
Christensen, J Inf Dis, 2000
Shibayama, AIDS 2001

27. TTV - The Essentials
Transmission : parenteral route +++ ; fecal-
oral route ?
High prevalence in Japan
Replicates in the liver
Role in post transfusion hepatitis not
confirmed
Does not aggravate chronic HCV or HBV
Negligible role in the etiology of chronic liver
disease (the role of certain genotypes cannot
be excluded…)

28. Establishing Causality for 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 become
undetectable with resolution of the disease
Copy number should correlate with disease
severity
Alter, Postgraduate Course, AASLD 2000

29. Chronic Liver Disease - Beyond
the Viruses ...
Definition
Etiologies

30. Etiologie de la Cirrhose (n=78)
Etude Dionysos (Hepatology 1994)
HCV
28 % HBV+
ALCOOL 3 %
HBV 9 %
HCV+
ALCOOL 3% HEMO
CHROMATOSE
1%
ALCOOL
26 % CRYPTOGENIC
CBP 24 %
1%

31. Factors Associated with ALT
Levels
SEX Cholesterol
BMI Triglycerides
Glycemia
Oral contraceptives
Smoking
Age
Physical exercise
Medications
Piton, Hepatology 1998
Prati, Ann Intern Med 2002

32. 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 1998
Prati, Ann Intern Med 2002

33. Clinical Implications of the Different
Thresholds for Normal ALT
abnormal ALT
Blood donors
male donors : 4 - 20%
female donors : 1.5 - 16%
HCV infection
males : 13 - 22 %
females : 20 - 45 %
Piton, Hepatology 1998

34. Chronic Liver Disease - Beyond the
Viruses ...
Etiologies :
Overweight, Diabetes +++
Covert Alcohol
Drugs
Seronegative autoimmune liver diseases
Vascular liver diseases
Celiac disease
Occult HBV

35. Impact of Overweight on Chronic
Liver Disease
Dionysos Study, n = 1211 (6917 total)
BMI (kg/m2) % Relative Risk (CI 95%)
< 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)
(Bellentani Hepatology 1994)

36. Proportion of Patients With Cryptogenic
Cirrhosis according to BMI - UNOS Database
N =19271 HCV Alcohol Cryptogenic
% 40
35
30
25
20
15
10
5
0
< 25 25 - 30 30 - 35 35 - 40 > 40 BMI
(Nair, Hepatology 2002)

37. Obésité et Cirrhose Cryptogénétique
Cirrhose X NASH Cirrhose C CBP
N 70 50 39 33
Age 63(+/- 11) 49(+/-14) 60(+/-7) 54(+/-10)
Femmes (%) 70 56 36 100
Obésité (%) 47 64 3 15
Diabète (%) 53 42 25 15
Caldwell, Hepatology 1999

38. Liver Histology in Overweight
Patients
n = 858 ; 9 studies, 1978 - 2002
Normal : 10 %
Steatosis alone : 48 %
Steatohepatitis : 42 %

39. Prevalence of NASH/NAFLD
First (or second) cause of chronic liver disease in
Western Countries
Prevalence among patients with abnormal LFTs
of undetermined etiology (n=673, 5 studies)
steatosis alone : 30%
steatohepatitis : 26%

40. Hepatic Fibrosis in NASH
n= 572, 9 studies 1980 - 2001
%
None or mild 65
Severe (cirrhosis excepted) 20
Cirrhosis 15

41. Risk Factors for Severe Fibrosis
in NASH
Age > 45-50 yrs
Diabetes
ALT>2N
BMI > 27 kg/m²
HTA
HyperTG
Angulo, Hepatology 1999
AST/ALT > 1
Ratziu, Gastroenterology 2000
Dixon, Gastroenterology 2001

42. Abnormal Liver Function Tests
A frequent problem in clinical hepatology
New viruses : less of a problem
NAFLD : more of a problem
Identifying patients at risk of liver disease -
that is the problem !

44. Viral Etiologies of Acute Hepatitis in the US
(1985-1986 and 1991-1995)
N=10 533
%
HAV 48
HBV 34
HCV 15
non A-E 3
Alter, NEJM 1997