Complex dynamics of hepatitis B virus resistance to adefovir

In patients with hepatitis B e antigen‐negative chronic hepatitis B, adefovir dipivoxil administration selects variants bearing reverse transcriptase rtN236T and/or rtA181V/T substitutions in 29% of cases after 5 years. The aim of this study was to characterize the dynamics of adefovir‐resistant variant populations during adefovir monotherapy in order to better understand the molecular mechanisms underlying hepatitis B virus resistance to this class of nucleotide analogues. Patients included in a 240‐week clinical trial of adefovir monotherapy who developed adefovir resistance‐associated substitutions were studied. The dynamics of hepatitis B virus populations were analyzed over time, after generating nearly 4,000 full‐length reverse transcriptase sequences, and compared with the replication kinetics of the virus during therapy. Whatever the viral kinetics pattern, adefovir resistance was characterized by exclusive detection of a dominant wild‐type, adefovir‐sensitive variant population at baseline and late and gradual selection by adefovir of several coexisting resistant viral populations, defined by the presence of amino acid substitutions at position rt236, position rt181, or both. The gain in fitness of one or the other of these resistant populations during adefovir administration was never associated with the selection of additional amino acid substitutions in the reverse transcriptase. Conclusion: Our results suggest that adefovir administration selects poorly fit preexisting or emerging viral populations with low‐level adefovir resistance, which subsequently compete to fill the replication space. Viral kinetics depends on the initial virological response to adefovir. Lamivudine add‐on restores some antiviral efficacy, but adefovir‐resistant variants remain predominant. Whether these adefovir resistance–associated substitutions may confer cross‐resistance to tenofovir in vivo will need to be determined. (HEPATOLOGY 2009;49:50‐59.)

[1]  F. Zoulim,et al.  Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. , 2008, Journal of hepatology.

[2]  P. Swaan,et al.  Multi-level Analysis of Organic Anion Transporters 1, 3, and 6 Reveals Major Differences in Structural Determinants of Antiviral Discrimination* , 2008, Journal of Biological Chemistry.

[3]  A. Lok,et al.  Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. , 2008, Journal of hepatology.

[4]  Jean-Michel Pawlotsky,et al.  Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach. , 2008, Gastroenterology.

[5]  P. Lampertico,et al.  Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. , 2007, Gastroenterology.

[6]  Michael D. Miller,et al.  In Vitro Drug Susceptibility Analysis of Hepatitis B Virus Clinical Quasispecies Populations , 2007, Journal of Clinical Microbiology.

[7]  Angeline Bartholomeusz,et al.  Antiviral drug‐resistant HBV: Standardization of nomenclature and assays and recommendations for management , 2007, Hepatology.

[8]  C. Yurdaydın,et al.  A Novel Mutation Pattern Emerging during Lamivudine Treatment Shows Cross-Resistance to Adefovir Dipivoxil Treatment , 2007, Antiviral therapy.

[9]  J. Pawlotsky,et al.  Efficacy and safety of adefovir dipivoxil 20 mg daily in HBeAg-positive patients with lamivudine-resistant hepatitis B virus and a suboptimal virological response to adefovir dipivoxil 10 mg daily. , 2007, Journal of hepatology.

[10]  A. Cross,et al.  [781] FOUR YEAR ASSESSMENT OF ETV RESISTANCE IN NUCLEOSIDE-NAIVE AND LAMIVUDINE REFRACTORY PATIENTS , 2007 .

[11]  J. Villeneuve,et al.  Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. , 2007, Journal of hepatology.

[12]  C. Mazzucco,et al.  Two-Year Assessment of Entecavir Resistance in Lamivudine-Refractory Hepatitis B Virus Patients Reveals Different Clinical Outcomes Depending on the Resistance Substitutions Present , 2006, Antimicrobial Agents and Chemotherapy.

[13]  C. Mazzucco,et al.  Entecavir resistance is rare in nucleoside naïve patients with hepatitis B , 2006, Hepatology.

[14]  George Kitis,et al.  Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. , 2006, Gastroenterology.

[15]  J. Villeneuve,et al.  Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient. , 2006, Gastroenterology.

[16]  T. Berg,et al.  Tenofovir for patients with lamivudine‐resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy , 2006, Hepatology.

[17]  Huiling Yang,et al.  In Vitro Susceptibility of Adefovir-Associated Hepatitis B Virus Polymerase Mutations to other Antiviral Agents , 2006, Antiviral therapy.

[18]  Angeline Bartholomeusz,et al.  HBV drug resistance: mechanisms, detection and interpretation. , 2006, Journal of hepatology.

[19]  J. Pawlotsky,et al.  Dynamics of Hepatitis B Virus Resistance to Lamivudine , 2006, Journal of Virology.

[20]  J. Pawlotsky.  The concept of hepatitis B virus mutant escape. , 2005, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[21]  P. Colson,et al.  Unusual Selection of Rta181V Hbv Mutants Cross-Resistant to Adefovir following Prolonged Lamivudine Monotherapy: Report of Two Cases , 2005, Antiviral therapy.

[22]  J. Villeneuve,et al.  Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir , 2005, Hepatology.

[23]  T. Berg,et al.  Comparison of adefovir and tenofovir in the treatment of lamivudine‐resistant hepatitis B virus infection , 2004, Hepatology.

[24]  P. Angus,et al.  Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine , 2004, Antimicrobial Agents and Chemotherapy.

[25]  E. Keeffe,et al.  Management of Antiviral Resistance in Patients with Chronic Hepatitis B , 2004, Antiviral therapy.

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

[27]  Michael D. Miller,et al.  The Hepatitis B Virus Polymerase Mutation rtV173L Is Selected during Lamivudine Therapy and Enhances Viral Replication In Vitro , 2003, Journal of Virology.

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

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

[30]  F. Zoulim,et al.  Inhibitory activity of dioxolane purine analogs on wild‐type and lamivudine‐resistant mutants of hepadnaviruses , 2002, Hepatology.

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

[32]  F. Zoulim,et al.  Transient selection of a hepatitis B virus polymerase gene mutant associated with a decreased replication capacity and famciclovir resistance , 1999, Hepatology.

[33]  K. Walters,et al.  Identification and characterization of mutations in hepatitis B virus resistant to lamivudine , 1998 .

[34]  Y. Cheng,et al.  Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance. , 1998, Biochemical pharmacology.