HDV - ANRS

Hepatite Delta,
o desafio amazônico
Christian Trepo
Hepato-Gastro-Enterologia – Hospital de la CroixRousse, Lyon –– França
INSERM Unit Research U1052 – Lyon – França
HEPATITIS VIRUSES DISCOVERY
HBV
Blumberg et al
1963
Serology
HDV
HAV
Feinstone et al
Rizzetto et al
1973
1977
IEM
(stool)
Serology, IF
(liver)
HEV
Balayan et al
1983
Serology, IEM
(stool)
HCV
Houghton et al
1989
Cloning (liver)
Cirrhosis
Evolution of Hepatitis D
Compared to Hepatitis B and C
HDV
Fibrosis
HBV
HCV
0
Years
1980s: Global Anti-HDV Prevalence in
HBsAg Carriers (15,000,000 Positive)
Hepatitis B in Brazil
HBs Ag prevalence
GuyanaFrancaise
Roraima
high
Acre
HIGHEST
Amazonas
Hepatitis in Amazonia
Serra do Navio
Tocantins
Carajás
Pará
Moderate
Fortaleza
No data
Rondônia
Mato
D.
Moderate
Grosso
F.
Major cause of
Fulminant
Bahia
Bahia
Goiás
Pernambu
co
Aracaju
Moderate
Minas Low
Gerais
Espírito Santo
São
Paulo
do Sul
Rio de Janeiro
Paraná
Mato
Grosso
Fonseca, 1993
Arraes et al., 2001
Santa Catarina
(West)
R. G. Sul
Lowest
Endemicity
High - > 8%
Moderate - 1,0 -3,0%
Low - < 1,0%
HBV - Genotype distribution in Brazil and
South America
F > Native population / Amerindians
A> Non-Native populations/Caucasians and African decendents
D> Related to Italian immigration
B/C in a few areas of Asian immigration
F
C
A
B D/E
C
D B
D
AG D
B DC
B
G
A/F
Aa
A,B,CD
C
A
D
A,B,C,D,F
Norder et al. 1994; Arauz-Ruiz et al. 1997; Sitnik et al. 1999; Swenson PD. Et al. 2001;Moriya T. et al. 2002 Viana et al , 2003
Variabilité génétique du VHD
D'après Radjef et al 2004
8 génotypes
Distribution géographique
Prévalence des génotypes de VHB et
de VHD au Brésil
A1, D3
HDV-1
F>A
F>A
HDV-3
HDV-3
A1>F
D>A2
A1>D3>F2 au Brésil
F2>A1>D3 en Amazonie
A1, D
Adapté: Roncato, 2008; Souto, 2008
A1
ANRS-BRAZIL
HEPATITIS CLINICAL RESEARCH
1)
Repriorisation of hepatitis
-
2)
Brazil and France are pioneers : long standing fruitful
collaboration for 20 years :
-
3)
WHO resolution … and Road map
40 international publication and 15 Brazilian
HBV, HCV and HDV all culminate in Amazonia active programmes
are ongoing
- LIA/ANRS project
4)
Results of studies are most promising and breakthroughs are at
hand.
Objectives
1)
2)
Describe genomic variations of
HBV/HDV among hepatitis cases in
Salvador (BA), Cruzeiro do Sul (AC),
Rio Branco (AC) Porto Velho (RO)
Correlate it with disease severity
Population de l´étude

Zone géographique

Taille de l´échantillon estimée:
3320 patients
3000 patients VHB+
300 pacients VHD+
20 patients Fièvre Noire Labrea

Argentina et Foz do Iguaçu
• Fréquences génotypiques des VHB et VHD de 92 patients.
• VHD génotype 3 Mutant
 Hybridation des produits de PCR nichée du VHD avec la sonde de génotype 3
 Séquences du VHD génotype 3 sauvage et mutant
F193Y
• L'état clinique et sérologique associée à l'âge, le sexe et le VHB / VHD
génotypes des patients co-infectés.
17 patients HDV 3 mut/HBV non-F  75.5% (12/17) hépatite chronique
 23.5% (4/17) cirrhose
(2= 2.833; p=0.092)
CONCLUSION (2) :
PATHOGENIC CORRELATIONS
1) Most severe cases including fast progressive
and fulminant hepatitis associated with
coinfection HBV/F and HDV/3
2) Non F genotype in Amazonia are often
associated with mutant genotype 3
3) Strong correlation between mutant genotype
3 and less severe liver disease
HBV/HDV co-infection in the Western
Brazilian Amazonia: an intriguing mutation
among HDV Genotype 3 carriers
Alan Kay1, Edinete Melo da Silva1, Hermes Pedreira2, Suiane Negreiros3,
Cirley Lobato3, Wornei Braga4, Richard Muwonge6, Paul Dény1, Mitermayer
Reis2, Fabien Zoulim1,5, Christian Trepo1,5, Argemiro d´Oliveira Jr7, Juan
Miguel Salcedo7, Maria Isabel Schinoni7 and Raymundo Parana2,7
1INSERM,
U1052, Lyon, France; 2Laboratory of Pathology and Molecular Biology, CPqGM/FIOCRUZ, Salvador, Brazil; 3Acre State
Secretariat of Health, Rio Branco, Brazil; 4Institute of Tropical Medicine of Amazonas, Manaus, Brazil; 5Service d'HépatoGastroentérology, Hôpital de la Croix-Rousse, Lyon, France; 6International Agency for Research on Cancer (IARC) /World Health
Organization (WHO), Lyon, France; 7University Hospital, Federal University of Bahia, Amazon Hepatitis Group, Salvador, Brazil.
Journal of Viral Hepatitis,
Soumis le 25 octobre 2013
PERSPECTIVES (1) :
2 MERIEUX FOUNDATION PROJECTS
1) 2014 :
Establish Charles Mérieux Training Center in
Salvador to teach health professionals from Amazon
regions
2) 2014-15 :
Build Rodolphe Mérieux Laboratory
for molecular virology diagnostics in Rio Branco
University Hospital
In Salvador:
1.Creation of a well-designed laboratory for molecular diagnostics at
the university hospital (HUPES) of Salvador/Bahia
2.Development and standardizing of qualitative and quantitative
molecular diagnostics for HBV, HCV and HDV
3.Basic and advanced teaching of laboratory technicians of Salvador
and Acre
4.Monitoring and supervising of the activities of the local labs in the
North of Brazil
5.Coordination with Amazon Centers
In Acre:
1.Evaluation and analysis of the actual situation of molecular
diagnostics in the local laboratories
2.Reorganization of existing processes to fulfill the standards for
molecular diagnostics
3.Creation of a new Laboratory for molecular diagnostics of viral
Hepatitis in Rio Branco
4.Development and Installation of missing analyzes
5.Teaching of physicians and laboratory technicians locally and in
Salvador
PERSPECTIVES (2) :
• Relaunch new collaborative extended LIA project
• Fiocruz (Porto Velho)
with new partners
• Merieux Foundation
from Brazil/France
• Pasteur Institute
• Further elucidate role of small monkeys in HDV transmission
• Attempt to develop HBV and HBV/HDV co-infection small
primate models
Remerciements
Equipe
Alan Kay (INSERM- U1052)
Christian Trépo (INSERM-U1052)
Raymundo Paraná (HUPES/UFBA)
Patients
Nord
Nord-est
Financements
Rio Branco (AC)
Salvador (BA)
Porto Velho (RO)
Muito obrigado
por sua atenção!