title: Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection.
abstract: We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (L-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.
authors.affiliation: Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Md., USA. korbabe@georgetown.edu
authors.forename: Brent E
authors.initials: BE
authors.lastname: Korba
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cote
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
authors.forename: Ilia
authors.initials: I
authors.lastname: Toshkov
authors.forename: Betty H
authors.initials: BH
authors.lastname: Baldwin
authors.forename: Frances V
authors.initials: FV
authors.lastname: Wells
authors.forename: Bud C
authors.initials: BC
authors.lastname: Tennant
authors.forename: John L
authors.initials: JL
authors.lastname: Gerin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D018450:Disease Progression; D005260:Female; D017325:Hepatitis B Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D017919:Hepatitis B Virus, Woodchuck / Q000276:immunology* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D008297:Male; D008392:Marmota; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D017325:Hepatitis B Vaccines; D001086:Arabinofuranosyluracil; C034935:clevudine