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Review

Strategies to Eliminate HBV Infection

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Pages 565-585 | Published online: 25 Jul 2014

References

  • Ott JJ , StevensGA , GroegerJ , WiersmaST . Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity . Vaccine30 ( 12 ), 2212 – 2219 ( 2012 ).
  • Buster EH , FlinkHJ , CakalogluYet al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b . Gastroenterology135 ( 2 ), 459 – 467 ( 2008 ).
  • van Zonneveld M , HonkoopP , HansenBEet al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B . Hepatology39 ( 3 ), 804 – 810 ( 2004 ).
  • Wong VW , WongGL , YanKKet al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B . Hepatology51 ( 6 ), 1945 – 1953 ( 2010 ).
  • Buster EH , HansenBE , LauGKet al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa . Gastroenterology137 ( 6 ), 2002 – 2009 ( 2009 ).
  • Janssen HL , van ZonneveldM , SenturkHet al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial . Lancet365 ( 9454 ), 123 – 129 ( 2005 ).
  • Liaw YF , JiaJD , ChanHLet al. Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C . Hepatology54 ( 5 ), 1591 – 1599 ( 2011 ).
  • Chang TT , GishRG , de ManRet al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B . N. Engl. J. Med.354 ( 10 ), 1001 – 1010 ( 2006 ).
  • Chang TT , LiawYF , WuSSet al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B . Hepatology52 ( 3 ), 886 – 893 ( 2010 ).
  • Marcellin P , GaneE , ButiMet al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study . Lancet381 ( 9865 ), 468 – 475 ( 2013 ).
  • Heathcote EJ , MarcellinP , ButiMet al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B . Gastroenterology140 ( 1 ), 132 – 143 ( 2011 ).
  • Gish RG , ChangTT , LaiCLet al. Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B . J. Viral Hepat.17 ( 1 ), 16 – 22 ( 2010 ).
  • Iloeje UH , YangHI , SuJet al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load . Gastroenterology130 ( 3 ), 678 – 686 ( 2006 ).
  • Chen CJ , YangHI , SuJet al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level . JAMA295 ( 1 ), 65 – 73 ( 2006 ).
  • Lee MH , YangHI , LiuJet al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles . Hepatology58 ( 2 ), 546 – 554 ( 2013 ).
  • Clements CJ , CoghlanB , CreatiM , LocarniniS , TedderRS , TorresiJ . Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?   Bull. World Health Organ.88 ( 1 ), 66 – 73 ( 2010 ).
  • Devi U , LocarniniS . Hepatitis B antivirals and resistance . Curr. Opin. Virol.3 ( 5 ), 495 – 500 ( 2013 ).
  • Locarnini SA , YuenL . Molecular genesis of drug-resistant and vaccine-escape HBV mutants . Antiviral Ther.15 ( 3 Pt B ), 451 – 461 ( 2010 ).
  • European Association For The Study Of The L . EASL clinical practice guidelines: Management of chronic hepatitis B virus infection . J. Hepatol.57 ( 1 ), 167 – 185 ( 2012 ).
  • Fattovich G , OlivariN , PasinoM , D'OnofrioM , MartoneE , DonatoF . Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years . Gut57 ( 1 ), 84 – 90 ( 2008 ).
  • Moucari R , MarcellinP . [HBsAg seroclearance: prognostic value for the response to treatment and the long-term outcome] . Gastroenterol. Clin. Biol.34 ( Suppl. 2 ), S119 – S125 ( 2010 ).
  • Ruan P , XuSY , ZhouBP , HuangJ , GongZJ . Hepatitis B surface antigen seroclearance in patients with chronic hepatitis B infection: a clinical study . J. Int. Med. Res.41 ( 5 ), 1732 – 1739 ( 2013 ).
  • Chotiyaputta W , LokAS . Endpoints of hepatitis B treatment . J. Viral Hepat.17 ( 10 ), 675 – 684 ( 2010 ).
  • Chan HL , WongVW , TseAMet al. Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response . Clin. Gastroenterol. Hepatol.5 ( 12 ), 1462 – 1468 ( 2007 ).
  • Thompson AJ , NguyenT , IserDet al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers . Hepatology51 ( 6 ), 1933 – 1944 ( 2010 ).
  • Wieland SF , ChisariFV . Stealth and cunning: hepatitis B and hepatitis C viruses . J. Virol.79 ( 15 ), 9369 – 9380 ( 2005 ).
  • Nowak MA , BonhoefferS , HillAM , BoehmeR , ThomasHC , McDadeH . Viral dynamics in hepatitis B virus infection . Proc. Natl Acad. Sci. USA93 ( 9 ), 4398 – 4402 ( 1996 ).
  • Hunt CM , McGillJM , AllenMI , CondreayLD . Clinical relevance of hepatitis B viral mutations . Hepatology31 ( 5 ), 1037 – 1044 ( 2000 ).
  • Sonneveld MJ , RijckborstV , ZeuzemSet al. Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B . Hepatology56 ( 1 ), 67 – 75 ( 2012 ).
  • Takahashi K , AoyamaK , OhnoNet al. The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection . J. Gen. Virol.76 ( Pt 12 ), 3159 – 3164 ( 1995 ).
  • Baumert TF , RogersSA , HasegawaK , LiangTJ . Two core promotor mutations identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication . J. Clin. Invest.98 ( 10 ), 2268 – 2276 ( 1996 ).
  • Fang ZL , YangJ , GeXet al. Core promoter mutations (A(1762)T and G(1764)A) and viral genotype in chronic hepatitis B and hepatocellular carcinoma in Guangxi, China . J. Med. Virol.68 ( 1 ), 33 – 40 ( 2002 ).
  • Kao JH , ChenPJ , LaiMY , ChenDS . Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers . Gastroenterology124 ( 2 ), 327 – 334 ( 2003 ).
  • Fung SK , LokAS . Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection?   Hepatology40 ( 4 ), 790 – 792 ( 2004 ).
  • Ito K , YotsuyanagiH , YatsuhashiHet al. Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults . Hepatology59 ( 1 ), 89 – 97 ( 2014 ).
  • Lin CL , KaoJH .  The clinical implications of hepatitis B virus genotype: recent advances .  J. Gastrenterol. Hepatol.26 ( Suppl. 1 ),  123 – 130  ( 2011 ).
  • Seeger C , MasonWS . Hepatitis B virus biology . Microbiol. Mol. Biol. Rev.64 ( 1 ), 51 – 68 ( 2000 ).
  • Sung JJ , WongML , BowdenSet al. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy . Gastroenterology128 ( 7 ), 1890 – 1897 ( 2005 ).
  • Werle-Lapostolle B , BowdenS , LocarniniSet al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy . Gastroenterology126 ( 7 ), 1750 – 1758 ( 2004 ).
  • Zoulim F . New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA . J. Hepatol.42 ( 3 ), 302 – 308 ( 2005 ).
  • Wu TT , CoatesL , AldrichCE , SummersJ , MasonWS . In hepatocytes infected with duck hepatitis B virus, the template for viral RNA synthesis is amplified by an intracellular pathway . Virology175 ( 1 ), 255 – 261 ( 1990 ).
  • Thursz MR , KwiatkowskiD , AllsoppCE , GreenwoodBM , ThomasHC , HillAV . Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia . N. Engl. J. Med.332 ( 16 ), 1065 – 1069 ( 1995 ).
  • An P , WinklerC , GuanL , O'BrienSJ , ZengZ , ConsortiumHBVS . A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese . J. Infect. Dis.203 ( 7 ), 943 – 947 ( 2011 ).
  • Hu L , ZhaiX , LiuJet al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development . Hepatology55 ( 5 ), 1426 – 1431 ( 2012 ).
  • Mbarek H , OchiH , UrabeYet al. A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population . Hum. Mol. Genet.20 ( 19 ), 3884 – 3892 ( 2011 ).
  • Nishida N , SawaiH , MatsuuraKet al. Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean . PLoS ONE7 ( 6 ), e39175 ( 2012 ).
  • Wang L , WuXP , ZhangWet al. Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case-control studies . PLoS ONE6 ( 3 ), e17608 ( 2011 ).
  • Kamatani Y , WattanapokayakitS , OchiHet al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians . Nat. Genet.41 ( 5 ), 591 – 595 ( 2009 ).
  • Almarri A , BatchelorJR . HLA and hepatitis B infection . Lancet344 ( 8931 ), 1194 – 1195 ( 1994 ).
  • Jiang YG , WangYM , LiuTH , LiuJ . Association between HLA class II gene and susceptibility or resistance to chronic hepatitis B . World J. Gastroenterol.9 ( 10 ), 2221 – 2225 ( 2003 ).
  • Milich DR , Leroux-RoelsGG . Immunogenetics of the response to HBsAg vaccination . Autoimmun. Rev.2 ( 5 ), 248 – 257 ( 2003 ).
  • Ahn SH , HanKH , ParkJYet al. Association between hepatitis B virus infection and HLA-DR type in Korea . Hepatology31 ( 6 ), 1371 – 1373 ( 2000 ).
  • Meng XQ , ChenHG , MaYL , LiuKZ . Influence of HLA class II molecules on the outcome of hepatitis B virus infection in population of Zhejiang Province in China . Hepatobiliary Pancreat. Dis. Int.2 ( 2 ), 230 – 233 ( 2003 ).
  • Ramezani A , Hasanjani RoshanMR , KalantarEet al. Association of human leukocyte antigen polymorphism with outcomes of hepatitis B virus infection . J. Gastrenterol. Hepatol.23 ( 11 ), 1716 – 1721 ( 2008 ).
  • Thio CL , CarringtonM , MartiDet al. Class II HLA alleles and hepatitis B virus persistence in African Americans . J. Infect. Dis.179 ( 4 ), 1004 – 1006 ( 1999 ).
  • Zhang SY , GuHX , LiDet al. Association of human leukocyte antigen polymorphism with hepatitis B virus infection and genotypes . Jpn. J. Infect. Dis.59 ( 6 ), 353 – 357 ( 2006 ).
  • Thursz M , YeeL , KhakooS . Understanding the host genetics of chronic hepatitis B and C . Semin. Liver Dis.31 ( 2 ), 115 – 127 ( 2011 ).  
  • Frodsham AJ , ZhangL , DumpisUet al. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence . Proc. Natl Acad. Sci. USA103 ( 24 ), 9148 – 9153 ( 2006 ).
  • Bertoletti A , FerrariC . Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection . Postgrad. Med. J.89 ( 1051 ), 294 – 304 ( 2013 ).
  • Yan H , ZhongG , XuGet al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus . eLife1 , e00049 ( 2012 ).  
  • Gripon P , CannieI , UrbanS . Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein . J. Virol.79 ( 3 ), 1613 – 1622 ( 2005 ).
  • Schulze A , SchieckA , NiY , MierW , UrbanS . Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction . J. Virol.84 ( 4 ), 1989 – 2000 ( 2010 ).
  • Petersen J , DandriM , MierWet al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein . Nat. Biotechnol.26 ( 3 ), 335 – 341 ( 2008 ).
  • Volz T , AllweissL , BenMMet al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus . J. Hepatol.58 ( 5 ), 861 – 867 ( 2013 ).
  • Deres K , SchroderCH , PaessensAet al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids . Science299 ( 5608 ), 893 – 896 ( 2003 ).
  • Stray SJ , BourneCR , PunnaS , LewisWG , FinnMG , ZlotnickA . A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly . Proc. Natl Acad. Sci. USA102 ( 23 ), 8138 – 8143 ( 2005 ).
  • Stray SJ , ZlotnickA . BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly . J. Mol. Recognit.19 ( 6 ), 542 – 548 ( 2006 ).
  • Wu GY , ZhengXJ , YinCCet al. Inhibition of hepatitis B virus replication by Bay 41-4109 and its association with nucleocapsid disassembly . J. Chemother.20 ( 4 ), 458 – 467 ( 2008 ).
  • Zhu X , ZhaoG , ZhouXet al. 2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly . Bioorg. Med. Chem. Lett.20 ( 1 ), 299 – 301 ( 2010 ).
  • Billioud G , PichoudC , PuerstingerG , NeytsJ , ZoulimF . The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication . Antiviral Res.92 ( 2 ), 271 – 276 ( 2011 ).
  • Delaney WEt , EdwardsR , ColledgeDet al. Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro . Antimicrobial Agents Chemother.46 ( 9 ), 3057 – 3060 ( 2002 ).
  • Feld JJ , ColledgeD , SozziV , EdwardsR , LittlejohnM , LocarniniSA . The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging . Antiviral Res.76 ( 2 ), 168 – 177 ( 2007 ).
  • Katen SP , ChirapuSR , FinnMG , ZlotnickA . Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators . ACS Chem. Biol.5 ( 12 ), 1125 – 1136 ( 2010 ).
  • Katen SP , TanZ , ChirapuSR , FinnMG , ZlotnickA . Assembly-directed antivirals differentially bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure . Structure21 ( 8 ), 1406 – 1416 ( 2013 ).
  • Ganem D , PrinceAM . Hepatitis B virus infection – natural history and clinical consequences . N. Engl. J. Med.350 ( 11 ), 1118 – 1129 ( 2004 ).
  • Rehermann B , NascimbeniM . Immunology of hepatitis B virus and hepatitis C virus infection . Nat. Rev. Immunol.5 ( 3 ), 215 – 229 ( 2005 ).
  • Dunn C , PeppaD , KhannaPet al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection . Gastroenterology137 ( 4 ), 1289 – 1300 ( 2009 ).
  • Dougherty AM , GuoH , WestbyGet al. A substituted tetrahydro-tetrazolo-pyrimidine is a specific and novel inhibitor of hepatitis B virus surface antigen secretion . Antimicrobial Agents Chemother.51 ( 12 ), 4427 – 4437 ( 2007 ).
  • Heermann KH , GoldmannU , SchwartzW , SeyffarthT , BaumgartenH , GerlichWH . Large surface proteins of hepatitis B virus containing the pre-s sequence . J. Virol.52 ( 2 ), 396 – 402 ( 1984 ).
  • Yu W , GoddardC , ClearfieldEet al. Design, synthesis, and biological evaluation of triazolo-pyrimidine derivatives as novel inhibitors of hepatitis B virus surface antigen (HBsAg) secretion . J. Med. Chem.54 ( 16 ), 5660 – 5670 ( 2011 ).
  • Op den Brouw ML , BindaRS , GeijtenbeekTB , JanssenHL , WoltmanAM . The mannose receptor acts as hepatitis B virus surface antigen receptor mediating interaction with intrahepatic dendritic cells . Virology393 ( 1 ), 84 – 90 ( 2009 ).
  • Xu Y , HuY , ShiBet al. HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells . Mol. Immunol.46 ( 13 ), 2640 – 2646 ( 2009 ).
  • Korba BE , MonteroAB , FarrarKet al. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication . Antiviral Res.77 ( 1 ), 56 – 63 ( 2008 ).
  • Prange R . Host factors involved in hepatitis B virus maturation, assembly, and egress . Med. Microbiol. Immunol.201 ( 4 ), 449 – 461 ( 2012 ).
  • Durantel D , AlotteC , ZoulimF . Glucosidase inhibitors as antiviral agents for hepatitis B and C . Curr. Opin. Invest. Drugs8 ( 2 ), 125 – 129 ( 2007 ).
  • Lazar C , DurantelD , MacoveiAet al. Treatment of hepatitis B virus-infected cells with alpha-glucosidase inhibitors results in production of virions with altered molecular composition and infectivity . Antiviral Res.76 ( 1 ), 30 – 37 ( 2007 ).
  • Mehta A , CarroueeS , ConyersBet al. Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: therapeutic implications . Hepatology33 ( 6 ), 1488 – 1495 ( 2001 ).
  • Mehta A , ZitzmannN , RuddPM , BlockTM , DwekRA . Alpha-glucosidase inhibitors as potential broad based anti-viral agents . FEBS Lett.430 ( 1–2 ), 17 – 22 ( 1998 ).
  • Simsek E , LuX , OuzounovS , BlockTM , MehtaAS . alpha-Glucosidase inhibitors have a prolonged antiviral effect against hepatitis B virus through the sustained inhibition of the large and middle envelope glycoproteins . Antiviral Chem. Chemother.17 ( 5 ), 259 – 267 ( 2006 ).
  • Carroll D . Genome engineering with zinc-finger nucleases . Genetics188 ( 4 ), 773 – 782 ( 2011 ).
  • Zimmerman KA , FischerKP , JoyceMA , TyrrellDL . Zinc finger proteins designed to specifically target duck hepatitis B virus covalently closed circular DNA inhibit viral transcription in tissue culture . J. Virol.82 ( 16 ), 8013 – 8021 ( 2008 ).
  • Cradick TJ , KeckK , BradshawS , JamiesonAC , McCaffreyAP . Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs . Mol. Ther.18 ( 5 ), 947 – 954 ( 2010 ).
  • Handel EM , GellhausK , KhanKet al. Versatile and efficient genome editing in human cells by combining zinc-finger nucleases with adeno-associated viral vectors . Hum Gene Ther.23 ( 3 ), 321 – 329 ( 2012 ).
  • Cai D , MillsC , YuWet al. Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation . Antimicrobial Agents Chemother.56 ( 8 ), 4277 – 4288 ( 2012 ).
  • Lucifora J , XiaY , ReisingerFet al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA . Science343 ( 6176 ), 1221 – 1228 ( 2014 ).
  • Belloni L , AllweissL , GuerrieriFet al. IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome . J. Clin. Invest.122 ( 2 ), 529 – 537 ( 2012 ).
  • zu Putlitz J , WielandS , BlumHE , WandsJR . Antisense RNA complementary to hepatitis B virus specifically inhibits viral replication . Gastroenterology115 ( 3 ), 702 – 713 ( 1998 ).
  • Welch PJ , TritzR , YeiS , BarberJ , YuM . Intracellular application of hairpin ribozyme genes against hepatitis B virus . Gene Ther.4 ( 7 ), 736 – 743 ( 1997 ).
  • Nash KL , AlexanderGJ , LeverAM . Inhibition of hepatitis B virus by lentiviral vector delivered antisense RNA and hammerhead ribozymes . J. Viral Hepat.12 ( 4 ), 346 – 356 ( 2005 ).
  • Hannon GJ . RNA interference . Nature418 ( 6894 ), 244 – 251 ( 2002 ).
  • Chen Y , ChengG , MahatoRI . RNAi for treating hepatitis B viral infection . Pharm. Res.25 ( 1 ), 72 – 86 ( 2008 ).
  • Klein C , BockCT , WedemeyerHet al. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA . Gastroenterology125 ( 1 ), 9 – 18 ( 2003 ).
  • McCaffrey AP , NakaiH , PandeyKet al. Inhibition of hepatitis B virus in mice by RNA interference . Nat. Biotechnol.21 ( 6 ), 639 – 644 ( 2003 ).
  • Morrissey DV , LockridgeJA , ShawLet al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs . Nat. Biotechnol.23 ( 8 ), 1002 – 1007 ( 2005 ).
  • Shlomai A , ShaulY . Inhibition of hepatitis B virus expression and replication by RNA interference . Hepatology37 ( 4 ), 764 – 770 ( 2003 ).
  • Akira S , UematsuS , TakeuchiO . Pathogen recognition and innate immunity . Cell124 ( 4 ), 783 – 801 ( 2006 ).
  • Woltman AM , Op den BrouwML , BiestaPJ , ShiCC , JanssenHL . Hepatitis B virus lacks immune activating capacity, but actively inhibits plasmacytoid dendritic cell function . PLoS ONE6 ( 1 ), e15324 ( 2011 ).
  • Wieland S , ThimmeR , PurcellRH , ChisariFV . Genomic analysis of the host response to hepatitis B virus infection . Proc. Natl Acad. Sci. USA101 ( 17 ), 6669 – 6674 ( 2004 ).
  • Colonna M , TrinchieriG , LiuYJ . Plasmacytoid dendritic cells in immunity . Nat. Immunol.5 ( 12 ), 1219 – 1226 ( 2004 ).
  • Gilliet M , CaoW , LiuYJ . Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases . Nat. Rev. Immunol.8 ( 8 ), 594 – 606 ( 2008 ).
  • An BY , XieQ , LinLYet al. [Expression of Toll-like receptor 3 on peripheral blood dendritic cells in HBeAg positive patients with chronic hepatitis B] . Zhonghua gan zang bing za zhi15 ( 10 ), 729 – 733 ( 2007 ).
  • Chen Z , ChengY , XuYet al. Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients . Clin. Immunol.128 ( 3 ), 400 – 408 ( 2008 ).
  • Hirsch I , CauxC , HasanU , Bendriss-VermareN , OliveD . Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer . Trends Immunol.31 ( 10 ), 391 – 397 ( 2010 ).
  • Momeni M , ZainodiniN , BidakiRet al. Decreased expression of toll like receptor signaling molecules in chronic HBV infected patients . Hum. Immunol.75 ( 1 ), 15 – 19 ( 2014 ).
  • Isogawa M , RobekMD , FuruichiY , ChisariFV . Toll-like receptor signaling inhibits hepatitis B virus replication in vivo . J. Virol.79 ( 11 ), 7269 – 7272 ( 2005 ).
  • Wieland SF , GuidottiLG , ChisariFV . Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice . J. Virol.74 ( 9 ), 4165 – 4173 ( 2000 ).
  • Zhang X , KraftA , BroeringR , SchlaakJF , DittmerU , LuM . Preclinical development of TLR ligands as drugs for the treatment of chronic viral infections . Expert. Opin. Drug Discov.7 ( 7 ), 597 – 611 ( 2012 ).
  • Schwabe RF , SekiE , BrennerDA . Toll-like receptor signaling in the liver . Gastroenterology130 ( 6 ), 1886 – 1900 ( 2006 ).
  • Visvanathan K , SkinnerNA , ThompsonAJet al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein . Hepatology45 ( 1 ), 102 – 110 ( 2007 ).
  • Lang T , LoC , SkinnerN , LocarniniS , VisvanathanK , MansellA . The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway . J. Hepatol.55 ( 4 ), 762 – 769 ( 2011 ).
  • Wang H , RyuWS . Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion . PLoS Pathog.6 ( 7 ), e1000986 ( 2010 ).
  • Yu S , ChenJ , WuM , ChenH , KatoN , YuanZ . Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3 . J. Gen. Virol.91 ( Pt 8 ), 2080 – 2090 ( 2010 ).
  • Wu J , MengZ , JiangMet al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells . Hepatology49 ( 4 ), 1132 – 1140 ( 2009 ).
  • Lanford RE , GuerraB , ChavezDet al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees . Gastroenterology144 ( 7 ), 1508 – 1517 , 1517 e1501–1510 ( 2013 ).
  • Lopatin U , WolfgangG , TumasDet al. Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist . Antiviral Ther.18 ( 3 ), 409 – 418 ( 2013 ).
  • A Study Evaluating GS-9620 in Virologically Suppressed Subjects With Chronic Hepatitis B Virus Infection . http://clinicaltrials.gov/show/NCT01590654  
  • A Study Evaluating GS-9620 in Treatment Naive Subjects With Chronic Hepatitis B . http://clinicaltrials.gov/show/NCT01590641  
  • Nanjappa SG , KimEH , SureshM . Immunotherapeutic effects of IL-7 during a chronic viral infection in mice . Blood117 ( 19 ), 5123 – 5132 ( 2011 ).
  • Pellegrini M , CalzasciaT , ToeJGet al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology . Cell144 ( 4 ), 601 – 613 ( 2011 ).
  • Toe JG , PellegriniM , MakTW . Promoting immunity during chronic infection--the therapeutic potential of common gamma-chain cytokines . Mol. Immunol.56 ( 1–2 ), 38 – 47 ( 2013 ).
  • Mackall CL , FryTJ , GressRE . Harnessing the biology of IL-7 for therapeutic application . Nat. Rev. Immunol.11 ( 5 ), 330 – 342 ( 2011 ).
  • Dose Escalation of Interleukin-1 (IL-7) Added on Antiviral Treatment and Vaccination in HBeAg-negative Chronic Hepatitis B Virus (HBV) Infected Patients (CONVERT) . https://clinicaltrials.gov/ct2/show/NCT01027065?term=NCT01027065&rank=1  
  • Dose Escalation of Interleukin-1 (IL-7) Added on Antiviral Treatment and Vaccination in HBeAg-negative Chronic Hepatitis B Virus (HBV) Infected Patients (CONVERT) . www.clinicaltrials.gov/ct2/show/NCT01027065  
  • Elsaesser H , SauerK , BrooksDG . IL-21 is required to control chronic viral infection . Science324 ( 5934 ), 1569 – 1572 ( 2009 ).
  • Frohlich A , KisielowJ , SchmitzIet al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection . Science324 ( 5934 ), 1576 – 1580 ( 2009 ).
  • Yi JS , DuM , ZajacAJ . A vital role for interleukin-21 in the control of a chronic viral infection . Science324 ( 5934 ), 1572 – 1576 ( 2009 ).
  • Publicover J , GoodsellA , NishimuraSet al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B . J. Clin. Invest.121 ( 3 ), 1154 – 1162 ( 2011 ).
  • Ma SW , HuangX , LiYYet al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B . J. Hepatol.56 ( 4 ), 775 – 781 ( 2012 ).
  • Hashmi MH , Van VeldhuizenPJ . Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma . Expert Opin. Biol. Ther.10 ( 5 ), 807 – 817 ( 2010 ).
  • Boni C , FisicaroP , ValdattaCet al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection . J. Virol.81 ( 8 ), 4215 – 4225 ( 2007 ).
  • Day CL , KaufmannDE , KiepielaPet al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression . Nature443 ( 7109 ), 350 – 354 ( 2006 ).
  • Latchman YE , LiangSC , WuYet al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells . Proc. Natl Acad. Sci. USA101 ( 29 ), 10691 – 10696 ( 2004 ).
  • Maier H , IsogawaM , FreemanGJ , ChisariFV . PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver . J. Immunol.178 ( 5 ), 2714 – 2720 ( 2007 ).
  • Okazaki T , HonjoT . The PD-1-PD-L pathway in immunological tolerance . Trends Immunol.27 ( 4 ), 195 – 201 ( 2006 ).
  • Petrovas C , CasazzaJP , BrenchleyJMet al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection . J. Exp. Med.203 ( 10 ), 2281 – 2292 ( 2006 ).
  • Barber DL , WherryEJ , MasopustDet al. Restoring function in exhausted CD8 T cells during chronic viral infection . Nature439 ( 7077 ), 682 – 687 ( 2006 ).
  • Cai G , KarniA , OliveiraEM , WeinerHL , HaflerDA , FreemanGJ . PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells . Cell. Immunol.230 ( 2 ), 89 – 98 ( 2004 ).
  • Finnefrock AC , TangA , LiFet al. PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination . J. Immunol.182 ( 2 ), 980 – 987 ( 2009 ).
  • Freeman GJ , WherryEJ , AhmedR , SharpeAH . Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade . J. Exp. Med.203 ( 10 ), 2223 – 2227 ( 2006 ).
  • Trautmann L , JanbazianL , ChomontNet al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction . Nat. Med.12 ( 10 ), 1198 – 1202 ( 2006 ).
  • Urbani S , AmadeiB , TolaDet al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion . J. Virol.80 ( 22 ), 11398 – 11403 ( 2006 ).
  • Velu V , TitanjiK , ZhuBet al. Enhancing SIV-specific immunity in vivo by PD-1 blockade . Nature458 ( 7235 ), 206 – 210 ( 2009 ).
  • Zhang E , ZhangX , LiuJet al. The expression of PD-1 ligands and their involvement in regulation of T cell functions in acute and chronic woodchuck hepatitis virus infection . PLoS ONE6 ( 10 ), e26196 ( 2011 ).
  • Liu J , ZhangE , MaZet al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and pd-l1 blockade in chronic hepadnaviral infection . PLoS Pathog.10 ( 1 ), e1003856 ( 2014 ).
  • Fisicaro P , ValdattaC , MassariMet al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B . Gastroenterology138 ( 2 ), 682 – 693 , 693 e681–e684 ( 2010 ).
  • Brahmer JR , TykodiSS , ChowLQet al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer . N. Engl. J. Med.366 ( 26 ), 2455 – 2465 ( 2012 ).
  • Topalian SL , HodiFS , BrahmerJRet al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer . N. Engl. J. Med.366 ( 26 ), 2443 – 2454 ( 2012 ).
  • Peng G , LiS , WuW , SunZ , ChenY , ChenZ . Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection . Immunology123 ( 1 ), 57 – 65 ( 2008 ).
  • Otano I , SuarezL , DotorJet al. Modulation of regulatory T-cell activity in combination with interleukin-12 increases hepatic tolerogenicity in woodchucks with chronic hepatitis B . Hepatology56 ( 2 ), 474 – 483 ( 2012 ).
  • Inchauspe G , MichelML . Vaccines and immunotherapies against hepatitis B and hepatitis C viruses . J. Viral Hepat.14 ( Suppl. 1 ), 97 – 103 ( 2007 ).
  • Kutscher S , BauerT , DembekC , SprinzlM , ProtzerU . Design of therapeutic vaccines: hepatitis B as an example . Microb. Biotechnol.5 ( 2 ), 270 – 282 ( 2012 ).
  • Michel ML , TiollaisP . Hepatitis B vaccines: protective efficacy and therapeutic potential . Pathol. Biol. (Paris)58 ( 4 ), 288 – 295 ( 2010 ).
  • Bertoletti A , GehringA . Therapeutic vaccination and novel strategies to treat chronic HBV infection . Expert Rev. Gastroenterol. Hepatol.3 ( 5 ), 561 – 569 ( 2009 ).
  • Xu DZ , ZhaoK , GuoLMet al. A randomized controlled Phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients . PLoS ONE3 ( 7 ), e2565 ( 2008 ).
  • Yao X , ZhengB , ZhouJet al. Therapeutic effect of hepatitis B surface antigen-antibody complex is associated with cytolytic and non-cytolytic immune responses in hepatitis B patients . Vaccine25 ( 10 ), 1771 – 1779 ( 2007 ).
  • Xu DZ , WangXY , ShenXLet al. Results of a Phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings . J. Hepatol.59 ( 3 ), 450 – 456 ( 2013 ).
  • Bocher WO , DekelB , SchwerinWet al. Induction of strong hepatitis B virus (HBV) specific T helper cell and cytotoxic T lymphocyte responses by therapeutic vaccination in the trimera mouse model of chronic HBV infection . Eur. J. Immunol.31 ( 7 ), 2071 – 2079 ( 2001 ).
  • Lobaina Y , GarciaD , AbreuN , MuzioV , AguilarJC . Mucosal immunogenicity of the hepatitis B core antigen . Biochem. Biophys. Res. Commun.300 ( 3 ), 745 – 750 ( 2003 ).
  • Betancourt AA , DelgadoCA , EstevezZCet al. Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens . Int. J. Infect. Dis.11 ( 5 ), 394 – 401 ( 2007 ).
  • Akbar SM , Al-MahtabM , UddinMH , KhanMS . HBsAg, HBcAg, and combined HBsAg/HBcAg-based therapeutic vaccines in treating chronic hepatitis B virus infection . Hepatobiliary Pancreat. Dis. Int.12 ( 4 ), 363 – 369 ( 2013 ).
  • Guo Z , KemmlerCB , MannDLet al. Recombinant yeast therapeutic vaccines expressing hepatitis B virus (HBV) X, S,and core antigens generate antigen specific T cell responses and tumorprotection in mice .  Hepatology56 ( 4 Suppl. ),  Abstract 375  ( 2012 ).
  • Kemmler CB , MannDL , KingTHet al. Recombinantyeast therapeutic vaccines expressing hepatitis B virus (HBV) X, S, andcore antigens generate antigen specific T cell responses in clinicalimmune cell samples from healthy volunteers .  Hepatology56 ( 4 Suppl. ),  Abstract 372  ( 2012 ).
  • Martin P , DuboisC , JacquierEet al. TG1050, a viral-vectorbased immunotherapeutic designed to treat chronic hepatitis B induces immuneresponses with properties similar to those displayed by HBV resolving patientsand has an early antiviral effect in a HBV tolerant model .  Hepatology224A , Abstract 33  ( 2013 ).
  • Liu MA , UlmerJB . Human clinical trials of plasmid DNA vaccines . Adv. Genet.55 , 25 – 40 ( 2005 ).
  • Scott-Algara D , Mancini-BourgineM , FontaineH , PolS , MichelML . Changes to the natural killer cell repertoire after therapeutic hepatitis B DNA vaccination . PLoS ONE5 ( 1 ), e8761 ( 2010 ).
  • Yang SH , LeeCG , ParkSHet al. Correlation of antiviral T-cell responses with suppression of viral rebound in chronic hepatitis B carriers: a proof-of-concept study . Gene Ther.13 ( 14 ), 1110 – 1117 ( 2006 ).
  • Depla E , Van der AaA , LivingstonBDet al. Rational design of a multiepitope vaccine encoding T-lymphocyte epitopes for treatment of chronic hepatitis B virus infections . J. Virol.82 ( 1 ), 435 – 450 ( 2008 ).
  • Pol S , MichelML . Therapeutic vaccination in chronic hepatitis B virus carriers . Expert Rev. Vaccine5 ( 5 ), 707 – 716 ( 2006 ).
  • Senturk H , TabakF , OzarasRet al. Efficacy of pre-S-containing HBV vaccine combined with lamivudine in the treatment of chronic HBV infection . Dig. Dis. Sci.54 ( 9 ), 2026 – 2030 ( 2009 ).
  • Boni C , PennaA , BertolettiAet al. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B . J. Hepatol.39 ( 4 ), 595 – 605 ( 2003 ).
  • Boni C , PennaA , OggGSet al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy . Hepatology33 ( 4 ), 963 – 971 ( 2001 ).
  • Al-Mahtab M , BazinetM , VaillantA , SheikhB . Rep 9AC is a potent HBSAG release inhibitor which clears serum HBSAG and elicits SVRS in patients with chronic hepatitis B . J. Hepatol.54 , S25 – S44 ( 2011 ).
  • Guo Z , CharlesB . KemmlerCB , MannDLet al. Recombinant yeast therapeutic vaccines expressinghep- atitis B virus (HBV) X, S, and core antigens generate antigen specific Tcell responses and tumor protection in mice .  Hepatology.56 ( 4 Suppl. ),  373A – 375A  ( 2012 ).
  • A Phase 1a Trial Assessing the Safety, Tolerability, and Immunogenicity of GS-4774 (GI-13020) at Various Dose Levels and Regimens in Healthy Adults . http://clinicaltrials.gov/show/NCT01779505  
  • Safety and Efficacy of GS-4774 for the Treatment of Chronic Hepatitis B . http://clinicaltrials.gov/show/NCT01943799  

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