Viral kinetics in patients with lamivudine-resistant hepatitis B during adefovir-lamivudine combination therapy.

BACKGROUND/AIMS Mathematical analysis of viral kinetics during lamivudine-adefovir combination therapy has not yet been performed in patients with lamivudine-resistant hepatitis B. METHODS In 8 patients with lamivudine-resistant hepatitis B, adefovir dipivoxil (10 mg/day) was added to ongoing lamivudine. Viral decay during the first 8 weeks of combination therapy was described by a biphasic model to determine the efficacy: epsilon, of blocking viral production, the clearance: c, of free virus, and the loss of infected cells: delta. RESULTS Median epsilon was 98%, median c was 0.7/day, and median delta was 0.07/day. No significant association was found between viral kinetic and baseline parameters and virologic and biochemical treatment response. When compared with viral kinetic constants reported for higher dose adefovir dipivoxil monotherapy, epsilon was lower (P=0.026) and delta was higher (P=0.008) in this study whereas c did not differ between both studies. CONCLUSIONS Although a recent study did not show any differences in the reduction of HBV DNA comparing monotherapy with adefovir dipivoxil to adefovir-lamivudine combination therapy in patients with lamivudine-resistant chronic hepatitis B, mathematical analysis of early viral kinetics suggests an additional effect of lamivudine on the infected cell loss during adefovir-lamivudine combination therapy.

[1]  E. Schiff,et al.  Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy , 1999, Hepatology.

[2]  N. Leung,et al.  Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: Results after 3 years of therapy , 2001, Hepatology.

[3]  M. Wulfsohn,et al.  Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B , 2003, Hepatology.

[4]  R. D. de Man,et al.  Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B. , 2002, Journal of hepatology.

[5]  N. Leung,et al.  A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. , 1998, The New England journal of medicine.

[6]  R. D. de Man,et al.  Viral dynamics in chronic hepatitis B patients treated with lamivudine, lamivudine–famciclovir or lamivudine–ganciclovir , 2002, European journal of gastroenterology & hepatology.

[7]  A. Bertoletti,et al.  Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. , 1998, The Journal of clinical investigation.

[8]  F. Chisari,et al.  Hepatitis B virus immunopathogenesis. , 1995, Annual review of immunology.

[9]  A. Perelson,et al.  Dynamics of alanine aminotransferase during hepatitis C virus treatment , 2003, Hepatology.

[10]  V. Calvez,et al.  Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study , 2001, The Lancet.

[11]  B. Moss,et al.  The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis , 1995, The Journal of experimental medicine.

[12]  C. Gibbs,et al.  Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy , 1999, Hepatology.

[13]  S. Hadziyannis,et al.  Efficacy of long‐term lamivudine monotherapy in patients with hepatitis B e antigen–negative chronic hepatitis B , 2000, Hepatology.

[14]  E. Schiff,et al.  Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B , 2002, Hepatology.

[15]  Antonio Bertoletti,et al.  The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. , 2000 .

[16]  Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. , 1999 .

[17]  G. Gerken,et al.  Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial , 2005, The Lancet.

[18]  H. Blum,et al.  Inhibitory effect of adefovir and lamivudine on the initiation of hepatitis B virus infection in primary tupaia hepatocytes , 2003, Hepatology.

[19]  F. Chisari,et al.  Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen , 1991, The Journal of experimental medicine.

[20]  E. Herrmann,et al.  Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon , 2003, Hepatology.

[21]  E. Schiff,et al.  Lamivudine as initial treatment for chronic hepatitis B in the United States. , 1999, The New England journal of medicine.

[22]  P. Marcellin,et al.  Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. , 2004, The New England journal of medicine.

[23]  U. Spengler,et al.  Hepatitis B virus antigen-specific T-cell activation in patients with acute and chronic hepatitis B. , 1991, Journal of hepatology.

[24]  William M. Lee,et al.  Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. , 2004, Gastroenterology.

[25]  Angeline Bartholomeusz,et al.  Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. , 2003, Gastroenterology.

[26]  G. Ogg,et al.  Lamivudine treatment can overcome cytotoxic T‐cell hyporesponsiveness in chronic hepatitis B: New perspectives for immune therapy , 2001, Hepatology.

[27]  C. Gibbs,et al.  Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil , 2003 .

[28]  Alan S. Perelson,et al.  Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-α Therapy , 1998 .

[29]  A. Neumann,et al.  The influence of baseline characteristics on viral dynamic parameters in chronic hepatitis B patients treated with lamivudine. , 2002, Journal of hepatology.

[30]  C. Gibbs,et al.  Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks , 2002, Hepatology.

[31]  J. Schmidt,et al.  Dynamics of hepatitis B virus infection in vivo. , 1997, Journal of hepatology.

[32]  Alan S. Perelson,et al.  Analysis of hepatitis B viral load decline under potent therapy: Complex decay profiles observed , 2001, Hepatology.

[33]  L. Corey,et al.  Kinetics of hepatitis B viral load during 48 weeks of treatment with 600 mg vs 100 mg of lamivudine daily * , 2004, Journal of viral hepatitis.

[34]  M. I. Barrasa,et al.  Apoptosis and Regeneration of Hepatocytes during Recovery from Transient Hepadnavirus Infections , 2000, Journal of Virology.

[35]  R. Rubin,et al.  Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. , 2004, Gastroenterology.

[36]  E. Schiff,et al.  Adefovir dipivoxil for the treatment of lamivudine‐resistant hepatitis B mutants , 2000, Hepatology.

[37]  Y. Liaw,et al.  Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. , 2000, Gastroenterology.

[38]  C. Gibbs,et al.  Combination therapy with lamivudine and famciclovir for chronic hepatitis B–infected Chinese patients: A viral dynamics study , 2000, Hepatology.

[39]  S. Zeuzem,et al.  Viral dynamics in chronic hepatitis B patients during lamivudine therapy. , 2002, Liver.

[40]  S. Locarnini,et al.  In Vitro Antihepadnaviral Activities of Combinations of Penciclovir, Lamivudine, and Adefovir , 2000, Antimicrobial Agents and Chemotherapy.

[41]  Anders Hedrum,et al.  Automated Quantitative Analysis of Hepatitis B Virus DNA by Using the Cobas Amplicor HBV Monitor Test , 1999, Journal of Clinical Microbiology.

[42]  E. De Clercq,et al.  Immunomodulatory activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent anti-HIV nucleotide analogue, on in vivo murine models. , 1991, Antiviral research.

[43]  C. Gibbs,et al.  Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. , 2003, Journal of hepatology.

[44]  Y. Liaw,et al.  Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B , 1999, Hepatology.

[45]  M. Wulfsohn,et al.  Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. , 2003, The New England journal of medicine.

[46]  M. Wulfsohn,et al.  Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. , 2003, The New England journal of medicine.

[47]  M. Wulfsohn,et al.  Adefovir dipivoxil therapy for lamivudine‐resistant hepatitis B in pre– and post–liver transplantation patients , 2003, Hepatology.

[48]  A. Bertoletti,et al.  Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. , 2003, Journal of hepatology.

[49]  M A Nowak,et al.  Viral dynamics in hepatitis B virus infection. , 1996, Proceedings of the National Academy of Sciences of the United States of America.