In chronic hepatitis B, both host and viral factors may predict the response to interferon (IFN) treatment. Whether IFN sensitivity-determining regions exist within the hepatitis B virus (HBV) genomic background remains largely unknown. We therefore performed full-length viral genomic comparison between HBVs obtained from IFN responders and non-responders.
Methods
We enrolled 18 HBV genotype Ba patients who had received 24-week IFN 5 MU three times weekly and were followed monthly for 12 months post-treatment. There were 10 responders and eight non-responders. Pretreatment full-length viral nucleotide consensus sequence was obtained. In six non-responders and four responders, post-treatment viral nucleotide sequence was further compared with their corresponding pre-treatment specimens. In addition, the average number of nucleotide substitutions of the HBV quasispecies was compared between three responders and three non-responders.
Results
HBV nucleotide consensus sequence was identical between responders and non-responders. We found 0–15 (mean 7.7) nucleotide substitutions in the post-treatment HBV genome in the six non-responders and 0–14 (mean 3.8) nucleotide substitutions in the four responders, respectively. Genetic complexity of HBV quasispecies was comparable between responders and non-responders.
Conclusions
Our results suggest that an IFN sensitivity-determining region might not exist within the genome of HBV genotype Ba. Host factors and virus–host interactions may be more important in determining the response to IFN treatment.
References
1.
ChenD.S.From hepatitis to hepatoma: lessons from type B viral hepatitis.Science1993; 262: 369–370.
2.
KaoJ.H., & ChenD.S.Global control of hepatitis B virus.Lancet Infectious Diseases2002; 2: 395–403.
3.
LokA.S., HeathcoteE.J., & HoofnagleJ.H.Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology2001; 120: 1828–1853.
MarcellinP., ChangT.T., LimS.G., TongM.J., SievertW., ShiffmanM.L., JeffersL., GoodmanZ., WulfsohnM.S., XiongS., FryJ., & BrosgartC.L.; Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.New England Journal of Medicine2003; 348: 808–816.
6.
HadziyannisS.J., TassopoulosN.C., HeathcoteE.J., ChangT.T., KitisG., RizzettoM., MarcellinP., LimS.G., GoodmanZ., WulfsohnM.S., XiongS., FryJ., & BrosgartC.L.; Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.New England Journal of Medicine2003; 348: 800–807.
7.
HadziyannisS.J., PapatheodoridisG.V., DimouE., LarasA., & PapaioannouC.Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B.Hepatology2000; 32: 847–851.
8.
LeeC.M., OngG.Y., LuS.N., WangJ.H., LiaoC.A., TungH.D., ChenT.M., & ChangchienC.S.Durability of lamivudine-induced HBeAg seroconversion for chronic hepatitis B patients with acute exacerbations.Journal of Hepatology2002; 37: 669–674.
9.
SongB.C., SuhD.J., LeeH.C., ChungY.H., & LeeY.S.Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.Hepatology2000; 32: 803–806.
10.
BrookM.G., KarayiannisP., & ThomasH.C.Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors.Hepatology1989; 10: 761–763.
11.
HuK.Q., VierlingJ.M., & RedekerA.G.Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection.Journal of Viral Hepatitis2001; 8: 1–18.
12.
YehS.H., ChenD.S., & ChenP.J.A prospect for pharmacogenomics in the interferon therapy of chronic viral hepatitis.Journal of Antimicrobial Chemotherapy2003; 52: 149–151.
13.
KingJ.K., YehS.H., LinM.W., LiuC.J., LaiM.Y., KaoJ.H., ChenD.S., & ChenP.J.Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: a pilot study.Hepatology2002; 36: 1416–1424.
14.
KaoJ.H., WuN.H., ChenP.J., LaiM.Y., & ChenD.S.Hepatitis B genotypes and the response to interferon therapy.Journal of Hepatology2000; 33: 998–1002.
15.
WaiC.T., ChuC.J., HussainM., & LokA.S.HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.Hepatology2002; 36: 1425–1430.
16.
EnomotoN., SakumaI., AsahinaY., KurosakiM., MurakamiT., YamamotoC., OguraY., IzumiN., MarumoF., & SatoC.Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infections.New England Journal of Medicine1996; 334: 77–81.
17.
EnomotoN., SakumaI., AsahinaY., KurosakiM., MurakamiT., YamamotoC., IzumiN., MarumoF., & SatoC.Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.Journal of Clinical Investigation1995; 96: 224–230.
18.
KaoJ.H., ChenP.J., LaiM.Y., & ChenD.S.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology2000; 118: 554–559.
19.
KaoJ.H.Hepatitis B viral genotypes: clinical relevance and molecular characteristics.Journal of Gastroenterology & Hepatology2000; 17: 643–650.
20.
IshakK., BaptistaA., BianchiL., CalleaF., De GrooteJ., GudatF., DenkH., DesmetV., KorbG., & MacSweenR.N.Histological grading and staging of chronic hepatitis.Journal of Hepatology1995; 22: 696–699.
21.
LiuC.J., ChenP.J., LaiM.Y., KaoJ.H., ChangC.F., WuH.L., ShauW.Y., & ChenD.S.A prospective study characterizing full-length hepatitis B virus genomes during acute exacerbation.Gastroenterology2003; 124: 80–90.
22.
LiuC.J., ChenP.J., LaiM.Y., KaoJ.H., & ChenD.S.Hepatitis B virus variants in patients receiving lamivudine treatment with breakthrough hepatitis evaluated by serial viral loads and full-length viral sequences.Hepatology2001; 34: 583–589.
23.
LiuC.J., KaoJ.H., WangH.Y., LaiM.Y., ChenT.C., ChenP.J., & ChenD.S.Origin of serum hepatitis B virus in acute exacerbation: comparison with that in the liver and from other exacerbation.Hepatology2004; 40: 310–317.
24.
KaoJ.H., ChenP.J., LaiM.Y., & ChenD.S.Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection.Journal of Clinical Microbiology2002; 40: 1207–1209.
25.
KaoJ.H., & ChenD.S.Clinical relevance of hepatitis B virus genotypes Ba and Bj in Taiwan.Gastroenterology2003; 125: 1916–1917.
26.
GalibertF., MandartE., FitousiF., TiollaisP., & CharnayP.Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli.Nature1979; 281: 646–650.
27.
NorderH., CourouceA.M., & MagniusL.O.Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.Virology1994; 198: 489–503.
28.
GeissG.K., CarterV.S., HeY., KwieciszewskiB.K., HolzmanT., KorthM.J., LazaroC.A., FaustoN., BumgarnerR.E., & KatzeM.G.Gene expression profiling of the cellular transcriptional network regulated by alpha/beta interferon and its partial attenuation by the hepatitis C virus nonstructural 5A protein.Journal of Virology2003; 77: 6367–6375.
29.
GaleM.J.Jr., KorthM.J., TangN.M., TanS.L., HopkinsD.A., DeverT.E., PolyakS.J., GretchD.R., & KatzeM.G.Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein.Virology1997; 230: 217–227.
30.
PromratK., McDermottD.H., GonzalezC.M., KleinerD.E., KoziolD.E., LessieM., MerrellM., SozaA., HellerT., GhanyM., ParkY., AlterH.J., HoofnagleJ.H., MurphyP.M., & LiangT.J.Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.Gastroenterology2003; 124: 352–360.
31.
NakaoK., NakataK., YamashitaM., TamadaY., HamasakiK., IshikawaH., KatoY., EguchiK., & IshiiN.p48 (ISGF-3gamma) is involved in interferon-alpha-induced suppression of hepatitis B virus enhancer-1 activity.Journal of Biological Chemistry1999; 274: 28075–28078.
32.
RangA., HeiseT., & WillH.Lack of a role of the interferon-stimulated response element-like region in interferon alpha-induced suppression of hepatitis B virus in vitro.Journal of Biological Chemistry2001; 276: 3531–3535.
33.
GuanR.Interferon monotherapy in chronic hepatitis B.Journal of Gastroenterology & Hepatology2000; 15: E34–40.
34.
ChenR.Y., BowdenS., DesmondP.V., DeanJ., & LocarniniS.A.Effects of interferon alpha therapy on the catalytic domains of the polymerase gene and basal core promoter, precore and core regions of hepatitis B virus.Journal of Gastroenterology & Hepatology2003; 18: 630–637.
35.
HannounC., KrogsgaardK., HoralP., LindhM., & the INTERPRED Trial Group. Genotype mixtures of hepatitis B virus in patients treated with interferon.Journal of Infectious Diseases2002; 186: 752–759.
36.
ShindoM., & OkunoT.Genomic variations in precore and cytotoxic T lymphocyte regions in chronic hepatitis B in relationship to interferon responsiveness.Liver2000; 20: 136–142.
