High Incidence Of A Hepatitis B Virus PRES2 Deletion In West Africa Among HBV Chronic Carriers : Association With Hepatocellularcarcinoma

Isabelle CHEMIN, CRCL, Inserm U1052, France
HALL J. 1 , NDOW G. 2 , NJIE R. 2 , SHIMAKAWA Y. 3 , LEMOINE M. 4 , ABEDI-ARDEKANI B. 5 , MENDY M. 5 , THURZ M. 4 , CHEMIN I. 1

1 Team "Hepatocarcinogenesis and viral infections", CRCL , InsermU1052, 151 Crs A Thomas 69003 Lyon, F
2 MRC Gambia, The Gambia
3 Pasteur Institute, rue du Dr Roux, Paris, F
4 Imperial college, London, United Kingdom
5 Head, Laboratory Services and Bio bank Group (LSB) Office of the Director (DIR) International Agency for Research on Cancer 150, Cours Albert Thomas, F-69372 Lyon Cedex 08

Hepatitis B virus (HBV) is endemic in Sub-Saharn Africa driving high rates of related cirrhosis and Hepatocellularcarcinoma (HCC). PROLIFICA (EU-FP7) aims to prevent HCC by treating HBV chronic carriers in West Africa. Demographic data project confirm early (30-40 yr ) development of cirrhosis and HCC in Gambia. We aimed to evaluate the contribution of HBV genetic variability for progression of liver diseases in West Africa.
Population based screenings of HBV were done on more than 6500 people. Quantification of HBV DNA, HBsAg and HBV genotyping were performed to know the genotypes and mutational profile. Further in-vitro characterization of mutant HBV strains were done in vitro.
We further tested 195 HBsAg positive cases in the community (HBV viral load > 150 IU/ml) and 121 HBsAg positive HCC cases. Finally we sequence 217 samples. 80% of them were genotype E and rest genotype A. 40% were carrying in frame deletion in PreS2 region, subsequently affecting overlapping polymerase gene. Deletion mutants proportion was significantly higher in cirrhosis (35%) and HCC (55%) as compared to chronic hepatitis (22%). Presence of 2-4 types of preS2 deletion mutant were observed along with the wild type (WT) in same samples. In-vitro study in Huh7 cells shows PreS2 mutant strains have significantly reduced release of HBsAg and retention within cells as compared to WT. Our data suggest that HBeAg (-) hepatitis with PreS2 deletion and a complex quasispecies formation among treatment naive individuals may have influence progression to cirrhosis and HCC. Our hypothesis is the retention of HBsAg within hepatocytes may exert ER stress. Immunohistochemistry for HBV antigens in liver biopsies are ongoing to explore further. Also pyrosequencing studies are ongoing to better understand the quasispecies complexity. This study highlighted the underestimated genetic complexity among the HBV genotype E strain and potential role of PreS2 deletion in HCC.