Adefovir for chronic hepatitis B treatment: identification of virological markers linked to therapy response.
BACKGROUND
HBV variants rtA181V/T, rtN236T and rtl233V, which confer resistance to adefovir dipivoxil (ADV), are not detected in many non-responding patients. Virological characteristics useful for predicting response have not been clearly elucidated. We determined pretreatment virological markers to predict non-response and possible emergence of new variants during therapy.


METHODS
This longitudinal study included 41 patients with chronic hepatitis B virus (HBV) infection receiving ADV monotherapy or ADV plus lamivudine (3TC). A fragment of HBV polymerase including catalytic domains was analysed for ADV-resistant variants.


RESULTS
Complete virological response (CVR; HBV DNA < 2.5 log10 copies/ml) was observed in 15 (36.6%) patients and partial virological response (PVR; HBV DNA < 4 log, copies/ml) in 23 (56.1%) patients. On multivariate analyses, hepatitis B e antigen (HBeAg) status was independently associated with CVR (hazard ratio [HR] = 0.27, P = 0.002) and PVR (HR = 0.21, P < 0.001) and viral genotype with CVR (HR = 0.13, P = 0.01). Predictive values for HBeAg were 88% for PVR in HBeAg-negative and 79% for non-CVR in HBeAg-positive patients. Predictive values for viral genotype were 93% for non-CVR and 72% for non-PVR for genotype A. On sequencing, variant rt217R (associated with subgenotype A2) was predictive of non-CVR (100%) and non-PVR (72.7%); the rtS219A variant emerged during therapy in three non-PVR patients. Both positions are located in a region likely to be related to the substrate union site, as predicted by our structural model of the HBV polymerase.


CONCLUSIONS
Virological pretreatment characteristics (HBeAg, viral genotype and rtL217R polymorphism) are potentially associated with ADV response. HBV polymerase structural modelling has provided a hypothesis to explain the molecular mechanism for ADV resistance associated with rtR217.
Rodriguez-Frias
Francisco
F
Department of Biochemistry, Hospital Universitario Vall d'Hebron, Barcelona, Spain. frarodri@vhebron.net
Jardi
Rosendo
R
Schaper
Melanie
M
Buti
Maria
M
Ferrer-Costa
Carles
C
Tabernero
David
D
Homs
Maria
M
Esteban
Rafael
R
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers; D005838:Genotype; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use; D008958:Models, Molecular; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism; D012189:Retrospective Studies
D000998:Antiviral Agents; D015415:Biomarkers; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D012194:RNA-Directed DNA Polymerase; D000225:Adenine